IN MEMORIAM

DR. M.H. SIKMOHS

PHYSIOLOGY AND BIOCHEMISTRY
IN MODERN MEDICINE

BY

J. J. E. MACLEOD, M.B.

PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF TORONTO, TORONTO, CANADA; FORMERLY

PROFESSOR OF PHYSIOLOGY IN THE WESTERN RESERVE UNIVERSITY,

CLEVELAND, OHIO

ASSISTED BY
ROY G. PEARCE, A. C. REDFIELD, AND N. B. TAYLOR

AND BY OTHERS

THIRD EDITION

WITH 243 ILLUSTRATIONS, INCLUDING
9 PLATES IN COLORS

ST. LOUIS

0. V. MOSBY COMPANY

1920

COPYRIGHT, 1918, 1919, 1920, BY C. V. MOSBY COMPANY

(All Rights Strictly Reserved)

Press of

C. V. Mosby Company
St. Louis, U.S.A.

TO
M. W. M.

•w,.J

PREFACE TO THIRD EDITION

Many changes have been made in the present (third) edition of the
book. The section on the nervous system has been entirely recast and re-
written by my colleague, A. C. Redfield, who, besides bringing this part
of the subject up to date, has incorporated with it an account of the funda-
mental principles of neuromuscular physiology. Although no applica-
tion of this subject may at present be apparent in the investigation of
disease it is certain that such exists; but it can be made only after the
clinical researcher has become familiar with the brilliant work which has
been done in the field in recent years by Keith Lucas, Adrian, and others.
It is the function of a volume of this nature to describe not merely what
already has been achieved in the clinical applications of physiology, but
also to anticipate where this application is likely soon to be made and to
prepare the way by describing the physiological principles that may be
involved.

Another section in which complete changes have been called for, is
that relating to the chemistry of respiration. This has been rewritten and
rearranged so as to incorporate the recent work on the effects of deficiency
of oxygen on the respiratory center, as well as the interesting and important
clinical applications of the subject. Several new chapters have been added
dealing with such practical problems as the measurement of the functional
capacity of the heart, the principles of ventilation and the therapeutic
value of oxygen, and the chapters on vitamines, on the capillary circula-
tion, on surgical shock, and on the interpretation of polysphygmograms
have been rewritten.

In practically every other section of the book many additions have
been made, particularly in that which deals with the endocrine organs,
and several new figures and tables have been added. To make room for
these changes some of the more technical details, appearing in the previous
editions, have been put in small print and some of the figures removed.
This has been done in order to keep the volume as near to its original
bulk as possible.

I wish to take this opportunity to thank my colleagues here and else-
where for many valuable suggestions and for their encouraging comments
on the book. I am also greatly indebted to Dr. N. B. Taylor for his as-
sistance in the preparation of this edition and for reading the proofs.

J. J. R. MACLEOD.

Toronto. Canada.
1920.

VI PREFACE

PREFACE TO SECOND EDITION

The opportunity has been taken in this second edition to eliminate
typographical errors and to alter the wording in certain chapters where
there was ambiguity of statement in the first edition. The most en-
couraging reception afforded the volume has fully confirmed the author's
conviction that acquaintance with modern physiology is fundamental to
sound medical and surgical practice.

J. J. R. MACLEOD.

Toronto, Canada.
1919.

PREFACE TO FIRST EDITION

The necessity of allotting the various subjects of the medical curric-
ulum to different periods, so that the more strictly scientific subjects
are completed in the earlier years, has the great disadvantage that the
student, being no longer in touch with laboratory work, fails to employ
the scientific knowledge with full advantage in the solution of his clin-
ical problems. He is apt to regard the first two or three years in the
laboratory departments as inconsequential in comparison with the sup-
posedly more practical instruction offered during the subsequent clinical
years. He is taught by his laboratory instructors to observe accurately,
and to correlate the observed facts, so that he may be enabled to draw
conclusions as to the manner of working of the various functions of the
animal body in health, and before proceeding to his clinical studies, he
is required to show a proficiency in scientific knowledge, because it is
recognized that this must serve as the basis upon which his knowledge
of disease is to be built. When the clinic is reached, however, the meth-
ods of the scientist are. not infrequently cast aside and an understanding
of disease is sought for largely by the empirical method; namely, by the
endeavor to see and examine innumerable patients, to diagnose the case
according to the grouping of the signs and symptoms, and to treat it by
the prescribed methods of experience. So much has to be learned and so
much has to be seen during the clinical years, that the student gives little
thought to the nature of the functional disturbance which' is responsible
for the symptoms; he fails to realize that after all, there is no essen-
tial difference between the condition brought about in his patient by
some pathological lesion, and that which may be produced in the labora-
tory by experimental procedures, by drugs or by toxins. It must of
course be recognized that just as the science of medicine originated by
the grouping of symptoms into more or less characteristic diseases for

PREFACE Vil

which the most favorable method of treatment had to be discovered by
experience, so must a certain part of the medical training be more or
less empirical but it should at the same time be realized that such a
method is only a means to an end, and that the real understanding of
disease can be acquired only when every abnormal condition is inter-
preted, as a primary or secondary consequence of some perverted bodily
function, and when the training in observation and the inductive method
is carried from the laboratory into the clinic.

It is a constant experience of clinical instructors who would employ
scientific methods of instruction, that they find the students not only
indifferent to an analysis of their cases from the functional standpoint,
but also that they are too inadequately prepared in fundamental phys-
iological knowledge, to make the analysis possible. The student may
have a superficial acquaintance with the main facts of physiological science
but have failed to acquire the enquiring habit of mind which will en-
able him, through reflection, comparison, and personal research, to ap-
ply the knowledge in practical medicine and surgery.

For this lack of correlation between the laboratory and clinical stud-
ies, the clinical instructors are not alone responsible. The laboratory
courses are frequently given without any attempt being made to show
the student the bearing of the subject in the interpretation of disease,
or to train him so that in his later years he may be able to adapt the
methods of investigation which he learned in the laboratory, to the study
of morbid conditions. It is self-evident that (without any knowledge
of disease) the extent to which the student in the earlier years of the
course could be expected to appreciate the clinical significance of what
he learns in the laboratory is limited, but this should not deter the in-
structor from indicating whenever he can, the general application of
scientific knowledge in the interpretation of diseased conditions. But
the chief remedy of the evil undoubtedly lies partly in the continuance
of certain of the laboratory courses into the clinical years, and partly
in the study of medical literature in which the application of physiology
and biochemistry in the practice of medicine is emphasized.

Notwithstanding the sufficient number of excellent textbooks in phys-
iology available to the medical student, there is none in which partic-
ular emphasis is laid upon the application of the subject in the routine
practice of medicine. In the present volume the attempt is made to
meet such a want, by reviewing those portions of physiology and bio-
chemistry which experience has shown to be of especial value to the
clinical investigator. The work is not intended to be a substitute,
either for the regular textbooks in physiology, or for those in functional

Vlll PREFACE

pathology. It is supplementary to such volumes. It does not start like
the modern test in functional pathology, with a consideration of the
diseased condition, and then proceed to analyze the possible causes and
consequences of the disturbances of function which this exhibits; but
it deals with the present-day knowledge of human physiology in so far
as this can be used in a general way to advance the understanding of
disease. In a sense it is therefore an advanced text in physiology for
those about to enter upon their clinical instruction, and at the same
time, a review for those of a maturer clinical experience who may desire
to seek the physiological interpretation of diseased conditions.

In attempting to fulfil these requirements, it has been deemed essen-
tial to go back to the fundamentals of the subject, and to explain as
simply as possible the physical and physicochemical principles upon
which so large a part of physiological knowledge depends. Physiology
may be considered as an application of the known laws and facts of
physics and chemistry to explain the functions of living matter, and it is
only after the extent to which this application can be made has been
appreciated, that the knowledge may be used to serve as the foundation
upon which a superstructure of clinical knowledge can be built.

In order that the volume might be maintained of reasonable size, it
has been necessary to select certain parts of the subject for particular
emphasis, the basis of selection being the degree to which our knowledge
clearly shows the value of the application of physiological methods both
of observation and of thought in the study of diseased conditions. This
has not been done to the extent of omitting the apparently less essential
parts, for these have been treated in sufficient detail to link the others
together so as to preserve a logical continuity, and show the bearing of
one field of knowledge on another. There are however certain parts
of the science, particularly the physiology of nerve and muscle, of the
special senses, and of reproduction, for which application in the general
fields of medicine and surgery is limited, and these parts have been
omitted entirely. It has been judged that this perhaps somewhat arbi-
trary selection is justified on the ground that the ordinary text in
physiology covers these subjects sufficiently, except for the specialist,
for whom on the other hand, no adequate review would have been pos-
sible within the limits of such a volume as this. With reference to bio-
chemistry, no attempt is made to review the properties or describe the
characteristic tests of the various chemical ingredients of the body tis-
sues and fluids. This is already sufficiently done in the textbooks on
biochemistry, and in the numerous manuals on clinical methods. Bio-
chemical knowledge is treated rather from the physiologist's stand-
point, as an integral part of his subject, particular attention, neverthe-

PREFACE IX

less, being paid to the far-reaching applications of this latest depart-
ment of medical science, in the elucidation of many obscure problems
of clinical medicine, such as those of diabetes, nephritis, acidosis, goiter
and myxedema. To make the volume of value to those who may not
have had time or opportunity to familiarize themselves with the techni-
cal methods of the physiologist and biochemist as used in the modern
clinic, a certain amount of space is devoted to a brief description of the
methods that appear at present to be receiving most attention, and to
be of greatest value.

Finally, it should be mentioned that the principles of serum diagnosis
and therapy are omitted, since these belong to a highly specialized science
requiring an intensive training of its own.

In the hope that the volume may be instrumental in arousing sufficient
interest to stimulate a more intensive study of the various subjects
which it introduces, a brief bibliography is given at the end of each
section. The references selected are to papers that are more partic-
ularly known to the author; they are not necessarily the most impor-
tant publications on the subject, but are often chosen because of the
useful reviews of previous work contained in them, rather than because
of their own originality. Some of the papers, however, are referred to
as authority for statements of fact which may arouse in the reader a
desire to ponder for himself the evidence upon which these are based.
The references are usually divided into two groups, "monographs" and
"original papers," and it is only occasionally that specific reference is
made to the former in the context. The original papers, on the other
hand, are referred to by numbers. With the general field of the subject
so well covered by such excellent textbooks as Bayliss' "Principles of
General Physiology," Stewart's, HowelPs, Starling's, and Halliburton's
"Human Physiologies," and Leonard Hill's "Recent and Further Ad-
vances in Physiology," the author has felt free to pick and choose from
the monographs and original papers, topics that are ordinarily passed
over cursorily in the textbook, and when this has been done, the refer-
ences are somewhat more extensive. Such is the case for example . in
the chapters relating to the chemistry of respiration, to the metabolism
of carbohydrates and fats, to the problems of dietetics and growth, to the
physicochemical basis of neutrality regulation in the animal body, and to
the action of enzymes.

Acknowledgment is gratefully made for the assistance and advice
in the preparation of the book, particularly to Doctor R. G. Pearce, for
the contribution of several chapters, to which his name is attached, and
for which he is entirely responsible; and to Doctor E. P. Carter, whose
criticisms, after patient perusal of the unfinished manuscript, were of

X PREFACE

inestimable value in its final revision. Acknowledgment is also made
to Doctor R. W. Scott and Professor F. E. Lloyd, for valuable criticism
and advice, and to the former for a chapter on the "Clinical Applica-
tion of Electrocardiographs. " To Miss Achsa Parker, M.A., the author
owes a great debt of gratitude for the thorough and painstaking way in
which she prepared the manuscript for the press, and for her never-
tiring endeavors to have the spelling and punctuation in conformity
with Webster's Dictionary. For assistance in the preparation of the
index thanks are due to Miss Marion Armour and Mrs. MacFarlane,
and for permission to use certain of the figures and illustrations, to the
various authors and publishers who granted it. For the excellent man-
agement and careful execution of the presswork, the author wishes to
thank the publishers, whose courteous and friendly dealings have always
made the work easier.

J. J. R. MACLEOD.

University of Toronto,
Toronto, Canada.

CONTENTS

PART I

THE PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL

PROCESSES

CHAPTER I PAGE

GENERAL CONSIDERATIONS 1

The Laws of Solution, 3; Gas Laws, 3; Osmotic Pressure, 4; Biological Meth-
ods for Measuring Osmotic Pressure, 6; Hemolysis, 7; Plasmolysis, 8.

CHAPTER II

OSMOTIC PRESSURE (CONT'D.) 10

Measurement by Depression of Freezing Point, 10; The Role of Osmosis, Dif-
fusion, and Allied Processes in Physiological Mechanisms, 11.

CHAPTER III

ELECTRICAL CONDUCTIVITY, DISSOCIATION, AND IONIZATION . . 10

Biological Applications, 19.

CHAPTER IV

THE PRINCIPLES INVOLVED IN THE DETERMINATION OF THE HYDROGEN-ION CONCEN-
TRATION 22

Titrable Acidity and Alkalinity, 22; Actual Degree of Acidity or Alkalinity,
23; Mass Action, 23; Application to the Measurement of H-ion Concentration,
26; Application in Determining the Real Strength of Acids or Alkalies, 28.

CHAPTER V

THE PRINCIPLES INVOLVED IN THE MEASUREMENT OF HYDROGEN-ION CONCENTRA-
TION (CONT'D) 29

The Electrical Method, 29; The Indicator Method, 32.

CHAPTER VI

REGULATION OF NEUTRALITY IN THE ANIMAL BODY AND ACIDOSIS 3G

Buffer Substances, 36 ; Theory of Acidosis, 38 ; Measurement of the Reserve
Alkalinity, 41; Tit-ration Methods, 41; CO,-Combining Power, 42; Indirect
Methods, 46.

CHAPTER VII .
COLLOIDS 51

Characteristic Properties, 51 ; Characteristics of True Colloidal Solutions, 5L> ;
Tyndall Phenomenon, 52; Relative Indiffusibility, 52; Electrical Properties,
56; Browuian Movement, 58; Osmotic Pressure, 58.

xi

Xll CONTENTS

CHAPTER VIII PAGE

COLLOIDS (CONT'D) Gl

Suspensoids and Emulsoids, 61; Gelatin ization, 62; Imbibition, 63; Action of
Electrolytes on Colloids, 63; Proteins as Colloids, 64; Surface Tension, 65;
Adsorption, 66; Reactions which Depend on Adsorption, 67; Conditions that
Influence or are Influenced by Adsorption, 68; Biological Processes Depend-
ing on Adsorption, 70.

CHAPTER IX

FERMENTS, OR ENZYMES 71

The Nature of Enzyme Action, 72 ; Properties of Enzymes, 73 ; Reversibility
of Enzyme Action, 77 ; Specificity of Enzyme Action, 79 ; Peculiarities of
Enzymes, 80 ; Types of Enzyme, 81 ; Enzyme Preparations, 82 ; Conditions for
Enzymic Activity, 82.

PART II
THE CIRCULATING FLUIDS

CHAPTER X

BLOOD: ITS GENERAL PROPERTIES (BY R. G. PEARCE) 85

Quantity of Blood in the Body, 85; Water Content, 87; Proteins,. 88; Fer-
ments and Antifcrments, 90.

CHAPTER XI

THE BLOOD CELLS (BY R. G. PEARCE) 92

Red Blood Corpuscles, or Erythrocytes, 92 ; Origin, 93 ; Rates of Regeneration,
94; Hemolysis, 96; Leucocytes, 97; Blood Platelets, 98.

CHAPTER XII

BLOOD CLOTTING '. 99

Visible Changes in the Blood During Clotting, 99; Methods of Retarding
Clotting of Drawn Blood, 100; Nature of the Clotting Process, 102; Influence
of Calcium Salts, 104; Influence of Tissues, 105.

CHAPTER XIII

BLOOD CLOTTING (€ONT'D) 107

Theories of Blood Clotting, 107; Intravascular Clotting, 108; Measurement of
the Clotting Time, 109; Blood Clotting in Various Physiological Conditions,
111; Blood Clotting in Disease, 111; Hemorrhagic Diseases, 113; Thrombus
Formation, 113.

CHAPTER XIV

LYMPH FORMATION AND CIRCULATION — CEREBROSPINAL FLUID 115

General Considerations, 115; Experimental Investigations, 118; Edema, 120;
Cerebrcspinal Fluid, 121.

CONTENTS Xlll

PART III
CIRCULATION OF THE BLOOD

CHAPTER XV PAGE

BLOOD PRESSURE 124

The Mean Arterial Blood Pressure, 125; Mercury Manometer Tracings, 125;
Spring Manometer Tracings, 128; Clinical Measurements, 129.

CHAPTEE XVI

THE FACTORS CONCERNED IN MAINTAINING THE BLOOD PRESSURE 135

Pumping Action of the Heart, 135 ; Peripheral Resistance, 135 ; Amount of
Blood in the Body, 138; Effects of Hemorrhage and Transfusion, 140; Vis-
cosity of the Blood, 141; Elasticity of Vessel Walls, 143.

CHAPTER XVII

THE ACTION OP THE HEART . . 145

The Pumping Action of the Heart, 145; Intracardiac Pressure Curves, 146;
Comparison of the Curves, 148.

CHAPTER XVIII

THE PUMPING ACTION OF THE HEART (CONT'D) '. 151

Contour of the Intracardiac Curves, 151; Ventricular Curve, 151; Auricular
Curve, 153; The Mechanism of Opening and Closing of the Valves, 154; The
Heart Sounds, 156; Causes of Sounds. 157; Record of Heart Sounds (Elec-
trophonograms), 158.

CHAPTER XIX

THE NUTRITION OF THE HEART 161

Blood Supply, 161; Ferfusion of the Heart Outside the. Body, 161; Heart-
Lung Preparation, 163; Resuscitation of the Heart in Situ, 165; Relationship
of the Chemical Composition of the perfusion Fluid in Cold-blooded and
Warm-blooded Hearts, 166.

CHAPTER XX

PHYSIOLOGY OF THE HEARTBEAT 170

Origin and Propagation of the Beat, 170; Physiological Characteristics of
Cardiac Muscle, 170; Myogenic Hypothesis, 171; Neurogenie Hypothesis,
172; The Pacemaker of the Heart and Heart-block, 174; Physiological Char-
acteristics of Cardiac Muscle, 176.

CHAPTER XXI

PHYSIOLOGY OF THE HEARTBEAT (CONT'D) 182

Origin and Propagation of the Beat in the Mammalian Heart, 182; Conduct-
ing Tissue in Mammalian Heart, 182; Site of Origin of Beat, 187. .

CHAPTER XXII

PHYSIOLOGY OF THE HEARTBEAT (CONT'D) 191

Mode of Propagation in the Auricles and from the Auricles to the Ventricles,
191 ; Spread of Beat in the Ventricle, 193 ; Fibrillation of the Ventricles and
Auricles, 195.

XIV CONTENTS

CHAPTER XXIII PAGE

THE BLOODFLOW IN THE ARTERIES IDS

The Pulses, 198; General Characteristics, 198; Eate of Transmission of Pulse
Waves, 198; Contour of the Pulse Curves, 200; Velocity Pulse, 200; Palpable
Pulse, 202; Analysis of the Curve, 202; The Dicrotic Wave, 203; Causes of
Disappearnce of the Pulse in the Veins, 205.

CHAPTER XXIV

RATE OF MOVEMENT OF THE B-LOOD IN THE BLOOD VESSELS 200

Velocity of Flow in a Vessel, 206; Mass Movement of the Blood in a Vas-
cular Area, 208; The Visceral Bloodflow in Man, 212; Circulation, 212; Work
of the Heart, 213; Circulation Time, 214; Movement of Blood in the Veins,
214.

CHAPTER XXV

THE OUTPUT OF THE HEART IN RELATION TO THE VENOUS INFLOW, CHANGE OF

RATE, ETC 21G

Output of the Heart per Beat, 216; Reserve Power, 218; Effect of Alteration
in Rate of Heart Beat on Output of Blood, 218 ; Tone pi the Heart, 220.

CHAPTER XXVI

THE CONTROL OF THE CIRCULATION , 221

Nerve Control, 222; Vagus Control in the Cold-blooded and the Mammalian
Heart, 217; Tonic Vagus Action, 226; Afferent Vagus Impluses, 227; Mech-
anism of Action of Vagus on the Heart, 229; Termination of the Vagus Fi-
bers in the Heart, 230 ; Sympathetic Control, 232.

CHAPTER XXVII

THE CONTROL OF THE CIRCULATION (CONT'D) 234

Nerve Control of the Peripheral Resistance, 234; Detection of Vasomotor Fi-
bers in Nerves, 236'; Origin of Vasomotor Nerve Fibers, 237; Vasomotor
Nerve Centers, 240; Independent Tonicity of B-lood Vessels, 241.

CHAPTER XXVIII

THE CONTROL OF THE CIRCULATION (CONT'D) 242

Control of the Vasomotor Center, 242 ; Hormone Control, 242 ; Nerve Control,
243; Pressor and Depressor Impulses, 243; Reciprocal Inncrvation of Vas-
cular Areas, 247; Influence of Gravity on the Circulation, 248; Capillary
Circulation, 251.

CHAPTER XXIX

PECULIARITIES OF BLOOD SUPPLY IN CERTAIN VISCERA 254

Circulation of the Brain, 254; Anatomical Peculiarities, 254; Physical Condi-
tions of the Intracranial Circulation, 256; Physiological Conditions of the In-
tracranial Circulation, 258; Vasomotcr Nerves, 262; Intracranial Pressure,
263; Circulation through the Lungs, 264; Circulation Through the Liver,
265; The Coronary Circulation, 267.

CHAPTER XXX

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL METHODS 270

Electrocardiograms, 270; The Ventricular Complex, 273; Interpretation of
Electrocardiograms by the Triangle Method, 276.

CONTENTS XV

CHAPTER XXXI PAGE

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL METHODS (CONT'D) . . . 278
Electrocardiograms of the More Usual Forms of Cardiac Irregularities, 278;
Sinus Arrhythmia, 278; Sinus Bratiycardia, 278; The Extrasystoles, 278;
Paroxysmal Tachycardia, 281 ; Auricular Fibrillation, 281 ; Auricular Flutter,
281; Heart-block, 282.

CHAPTER XXXII

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL METHODS (CONT'D) . . . 285
Polysphygmograms, 285; Venous Pulse Tracings, 285; Abnormal Pulses, 291.

CHAPTER XXXIII

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL METHODS (CONT'D) . . . 296
Measurement of the Mass Movement of the Blood, 296; The Normal Flow,
297; Clinical Conditions Which Affect the Bloodflow, 298.

CHAPTER XXXIV

SHOCK 301

Varieties of Shock, 301; Experimental Investigations of Shock, 304; Hista-
mine Shock, 307; Traumatic Toxemia Factor in Shock, 309; Cause of Second-
ary Symptoms, 310; Treatment and Prognosis, 311.

PART IV
RESPIRATION

CHAPTER XXXV

RESPIRATION 316

Mechanics of Respiration, 316; Pressure of the Air in the Lungs, 316; Respir-
atory Tracings, 320; The Intrapleural Pressure, 321; Influence on Blood
Pressure, 323.

CHAPTER XXXVI

THE MECHANICS OF RESPIRATION (CONT'D) (BY R. G. PEARCE) 327

Variations in Dead Space, Residual Air and Mid and Vital Capacities in
Various Physiological and Pathological Conditions, 327.

CHAPTER XXXVII

THE MECHANICS OF RESPIRATION (CONT'D) .< ' . . . . 332

Mechanism of the Changes in Capacity of the Thorax and Lungs, 332; The
Movements of the Ribs, 332; The Action of the Musculature of the Ribs, 336;
The Action of the Diaphragm, 337; The Effects of the Respiratory Movements
on the Lungs, 342.

CHAPTER XXXVIII

THE CONTROL OF THE RESPIRATION 344

The Respiratory Centers, 344; Reflex Control of the Respiratory Center, 348.

XVI CONTENTS

CHAPTER XXXIX PAGE

THE CONTROL OF RESPIRATION (CONT'D) 352

Hormone Control of the Respiratory Center, 352; Tension of CO2 .and O., in
Arterial Blood, 354; Tension of CO2 and O, in Alveolar Air, 356; Tension
of CO2 in Venous Blood, 359.

CHAPTER XL

THE CONTROL OF RESPIRATION (CONT'D) 301

Estimation of the Alveolar Gases, 361; Method of Normal Subjects, 362;
Clinical Method, 364.

CHAPTER XLI

THE CONTROL OF RESPIRATION (CONT'D) 366

The Nature of the Respiratory Hormone, 366 ; Relationship between CO, of
Inspired Air and Pulmonary Ventilation, 367; Possibility that CO, Specifically
Stimulates the Center, 368; Relationship between Alveolar CO, and Respira-
tory Activity, 371.

CHAPTER XLII

THE CONTROL OF RESPIRATION (CONT'D) 373

Alveolar CO, Tension in Conditions of Anoxemia, 373 ; Constancy of the Al-
veolar CO2 Tension under Normal Conditions, 373; The Nature of Changes
Produced in the Body in Anoxemia, 378.

CHAPTER XLIII

THE CONTROL OF RESPIRATION (CONT'D) 382

Apnea, 382; Periodic Breathing, 385; Types of Periodic Breathing-, 385;
Causes of Periodic Breathing, 386.

CHAPTER XLIV

INSPIRATION BEYOND THE LUNGS 391

Transportation of Gases by the Blood, 392; Transportation of Oxygen, 392;
Dissociation Curve of CO2, 396; Difference between Curves of Blood and
Hemoglobin Solutions, 396; Rate of Dissociation, 399; Dissociation Constant,
401.

CHAPTER XLV

RESPIRATION BEYOND THE LUNGS (CONT'D) 403

Means by Which the Blood Carries the Gases, 403 ; Oxygen Requirement of
the Tissues, 408; Mechanism by which the Demands of the Tissues for Oxy-
gen are met, 412.

CHAPTER XLVI

THE PHYSIOLOGY OF BREATHING IN RAREFIED AND COMPRESSED AIR 415

Mountain Sickness, 415; Compressed Air Sickness (Caisson Disease), 420;
Application of Foregoing Laws in Practice, 424.

CHAPTER XLVII
ADAPTATIONS OF THE CIRCULATORY AND RESPIRATORY SYSTEMS DURING MUSCULAR

EXERCISE 427

Circulatory Changes Accompanying Muscular Exercise, 427; .Mechanical Fac-
tors, 428: Nervous Factor, 430; Hormone Factor, 431.

CONTENTS XV11

. CHAPTER XLVIII PAGE

ADAPTATIONS OF THE CIRCULATORY AND RESPIRATORY MECHANISMS DURING MUS-
CULAR EXERCISE (CONT'D) 4-35

The Effect of Muscular Exercise on the Composition of the Alveolar Air, 435 ;
Second-Wind, 438; Influence of Oxygen, 439; After Effects, 440; Effort Syn-
drome, 441.

CHAPTER XLIX

OXYGEN UNSATURATION OF THE BLOOD CYANOSIS. THE THERAPEUTIC VALUE OF

OXYGEN 443

Oxygen ITnsaturation of the Blood, 443; Therapeutic Value of Oxygen, 445.

PART V
DIGESTION

CHAPTER L

GENERAL PHYSIOLOGY OF THE DIGESTIVE GLANDS 453

Microscopic Changes During Activity, 453 ; Mechanism of Secretion, 455 ;
Other Changes During Activity, 456 ; Control of Glandular Activity, 457 ;
Nervous Control, 458.

CHAPTER LI

PHYSIOLOGY OF THE DIGESTIVE GLANDS (CONT'D) 460

Hormone Control, 460; Nervous Control of Pancreas, 462.

CHAPTER LII

PHYSIOLOGY OF THE DIGESTIVE GLANDS (CONT'D) 465

Normal Conditions of Secretion, 465; Normal Secretion of Saliva, 466; Se-
cretion of Gastric Juice, 467; The Intestinal Secretions, 476.

CHAPTER LIII

THE MECHANISMS OF DIGESTION 478

Mastication, 478; Deglutition or Swallowing, 479; The Cardiac Sphincter,
482; Vomiting, 483.

CHAPTER LIV

THE MECHANISMS OF DIGESTION (CONT'D) 485

Movements of the Stomach, 485; Character of the Movements, 485; Effect of
the Stomach Movement on the Food, 488; Emptying of the Stomach, 490;
Control of the Pyloric Sphincter, 490; Rate of Emptying the Stomach, 492;
Influence of Pathological Conditions on the Emptying, 494; Gastroenteros-
tomy, 494.

CHAPTER LV

THE MECHANISMS OF DIGESTION (CONT'D) 497

Movements of the Intestines, 497; Movements of the Small Intestine, 497;
Movements of the Large Intestine, 503; Effect of Clinical Conditions on the
Movements, 504.

XV111 CONTENTS

CHAPTER LVI PAGE

HUNGER, APPETITE AND THIRST 506

Hunger, 506; Remote Effects of Hunger Contractions, 509; Hunger During
Starvation, 510; Control of Hunger Mechanism, 511; Thirst, 514; Sensation
of Thirst, 514.

CHAPTER LVII

BIOCHEMICAL PROCESSES OF DIGESTION 515

Digestion in the Stomach, 515; Functions of Hydrochloric Acid, 516; Amount
of Acid, 516; Source of Acid, 517; Action of Pepsin, 519; Clotting of Milk
in the Stomach, 521.

CHAPTER LVIII

BIOCHEMICAL PROCESSES OF DIGESTION (CONT'D) 52.°>

Digestion in the Intestines, 523; Pancreatic Digestion, 523; The Bile, 5-6;
Chemistry of Bile, 528.

CHAPTER LIX

BACTERIAL DIGESTION IN THE INTESTINE ., 533

Bacterial Digestion of Protein, 535; Botulism, 537.

PART VI
THE EXCRETION OF URINE

CHAPTER LX

THE EXCRETION OF URINE (BY R. G. PEARCE) 541

Structure of Kidney, 541; Mechanism of the Excretion of Urine, 544;
Theories of Renal Function, 545; Diuretics, 552; Albuminuria, 552; Influence
of the Nervous System on the Excretion of Urine, 553.

CHAPTER LXI

THE AMOUNT AND COMPOSITION OF THE, URINE TN HEALTH AND DISEASE (By R. G.

PEARCE) 555

Amount, 556; Specific Gravity, 556; Depression of Freezing Point, 557;
Reaction, 558 ; Solid Constituents, 560 ; Quantitative Changes in the Blood and
Urine in Disease, 567.

PART VII
METABOLISM

CHAPTER LXII
METABOLISM 570

Energy Balance, 571; Methods for Measuring Energy, 572; Normal Values,
573; Influence of Age and Sex, 577; Influence of Diseases, 578; Material
Balance of the Body, 579; Methods for Measuring Outputs, 579.

CONTENTS XIX

CHAPTER LXIII PAGE

THE CARBON BALANCE 582

Respiratory Quotient, 582; Influence of Diet, 582; Influence of Metabolism,
584; Magnitude of the Respiratory Exchange, 585; Influence of Body Tem-
perature, 586.

CHAPTER LXIV
A CLINICAL MKTHOD FOR DETERMINING THE RESPIRATORY EXCHANGE IN MAN

(BY R. G. PEARCE) 589

The Valves, 590; Tissot Spirometers, 591; Douglas Bag, 592; Haldane Gas
Apparatus, 593; Calculations, 596.

CHAPTER LXV

STARVATION 600

Excretion of Nitrogen, 600; Energy Output, 602; Nitrogenous Metabolites,
602; Excretion of Furines, 603; Excretion of Sulphur, 603; Normal Metab-
olism, 604; Nitrogenous Equilibrium, 605; Protein Sparers, 605.

CHAPTER LXVI

NUTRITION AND GROWTH * . . . . 608

The Food Factor of Growth, 608; Relationship of Proteins to Growth and
Maintenance of Life, 609.

CHAPTER LXVII

NUTRITION AND GROWTH (CONT'D) 617

Relationship of Carbohydrates and Fats to Growth, 617; Accessory Food Fac-
tors, or Vitamines, 618.

CHAPTER LXVIII

DIETETICS 625

Calorie Requirement, 625; The Protein Requirement, 627; Accessory Food
Factors, 630; Digestibility and Palatability, 630.

CHAPTER- LXIX
THE METABOLISM OF PROTEIN 632

Introductory, 632; Chemistry of Protein and of the Amino Acids, 633.

CHAPTER LXX

THE METABOLISM OF PROTEIN (CONT'D) 641

Amino Acids in the Blood and Tissues, 641; Fate of the Amino Acids, 645.

CHAPTER LXXI

THE METABOLISM OF PROTEIN (CONT'D) 647

End Products of Protein Metabolism, 647; Urea and Ammonia, 649; Urea
Ratio, 650; Influence of Liver on Ammonia-Urea Ratio, 651; Perf vision of Or-
gans, 652; Clinical Observations, 654.

CHAPTER LXXII

THE METABOLISM OF PROTEIN (CONT'D) 656

Creatine and Creatinine, 656; Essential Chemical Facts, 656; Metabolism,
657; Influence of Food, Age, and Sex, 657; Origin of Creatine and Creatinine,
659.

XX CONTENTS

CHAPTER LXXIII PAGE

THE METABOLISM OF PROTEIN (CONT'D) 662

Undetermined Nitrogen and Dctoxication Compounds, (562; Ethereal Sul-
phates and Glycuronates, 660.

CHAPTER LXXIV

URIC ACID AND THE PURINE BODIES 667

Chemical Nature of the P'urines, 667 ; Chemical Nature of the Substances Con-
taining Purine and Pyrimidine Bases, 669 ; History of Nucleic Acid in the
Animal Body, 671; Balance Between Intake and Output of Purine Substances
under Various Physiological and' Pathological Conditions, 674.

CHAPTER LXXV

URIC ACID AND THE PURINE BODIES (CONT'D) 676

Source of Endogenous Purines, 676; Influence of Various Physiological Con-
ditions, of Drugs, and of Disease on the Endogenous Uric-acid Excretion,
680; Uric Acid of Blood, 681.

CHAPTER LXXVI

THE METABOLISM OF THE CARBOHYDRATES 685

Capacity of the Body to Assimilate Carbohydrates, 685; Assimilation Limits,
685 ; Tolerance of the Body for Glucose, 688 ; Digestion and Absorption, 689 ;
Sugar Level in the Blood, 690; Value of Blood Examination in Diagnosis of
Diabetes, 691; Relationship Between Sugar Concentration of the Blood and
the Occurrence of Glycosuria, 692.

CHAPTER LXXVII

THE METABOLISM OF THE CARBOHYDRATES (CONT'D) 694

Fate of Absorbed Glucose. Glueoneogenesis, 694; Shortage of Sugar, 694;
Sources of Glycogen, 694; Glueoneogenesis in Normal Animals, 699.

CHAPTER LXXVIII

THE METABOLISM OF THE CARBOHYDRATES (CONT'D) 701

Fate 'of Glycogen, 701; Regulation of the Blood Sugar Level, 703; Nerve Con-
trol and Nervous Experimental Diabetes, 704; Nervous Diabetes in Man, 706;
Hormone Control and Permanent Diabetes, 707 ; Utilization of Glucose in Tis-
sues, 708; Diabetes and the Ductless Glands, 710; Relationship of Pancreas
to Sugar Metabolism, 710; Pathogenesis of Pancreatic Diabetes, 712; Dia-
betic Acidosis or Ketosis, 715; Starvation Treatment, 716.

CHAPTER LXXIX

FAT METABOLISM 718

Chemistry of Fatty Substances, 718; Digestion of Fats, 721; Absorption of
Fats, 722.

CHAPTER LXXX

FAT METABOLISM (CONT'D) . 726

Fat of Blood, 726; Methods of Determination, 726; Variations in Blood Fat,
727; Depot Fat, 730; Fat in the Liver, 731.

CONTENTS XXI

CHAPTER LXXXI PAGE

FAT METABOLISM (CONT'D) 736

Production of Fatty Acid out of Carbohydrate, 736; Method by which the
Fatty Acid is Broken Down, 737.

CHAPTEE LXXXII

CONTROL OF BODY TEMPERATURE AND FEVER 742

Variations in Body Temperature, 742 ; Factors in Maintaining the Body Tem-
perature, 743; Control of Temperature, 747; Fever, 748; Causes of Fever,
748; Changes in the Body During Fever, 750; Heat-regulating Center, 752;
Significance of Fever in the Organism, 753.

CHAPTER LXXXIII

THE PHYSIOLOGICAL PRINCIPLES OF VENTILATION 754

Relationship Between Chemical Composition of the Air and the Well-being
of the Body, 754; Relationship Between the Physical Conditions of the Air
and the Well-being of the Body, 757; Relationship between the Conditions of
Ventilation and Susceptibility to Infections, 759; Methods for Determining
the Healthfulness of Air, 763.

PART VIII
THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

CHAPTER LXXXIV

GENERAL CONSIDERATIONS, THE ADRENAL GLANDS 766

Methods of Investigation, 767; Adrenal Gland, 768; Cortex, 768; Medulla,
770 ; Adrenalectomy, 771 ; Adrenal Disease in Man, 772 ; Suprarenal Extracts,
773; Physiological Action, 774.

CHAPTER LXXXV

Tin-: ADRENAL GLANDS, (CONT'D) 779

Variations in Physiological Activity, 779; Assaying the Epmephriue Content
of the Gland, 779; Epinephrine Content of the Blood, 780; Autoinjection
Method, 784; Association of the Adrenal with Other Endocrine Organs, 788.

CHAPTER LXXXVI

THE THYROID AND PARATHYROID GLANDS 791

Structural Relationships, 791; Thyroid Gland, 792; Condition of Gland, 792;
Experimental Thyroidectomy, 794; Disease of the Thyroid, 795; Relationship
with Other Endocrine Organs, 800; Parathyroids, 800; Experimental Para-
thyroidectomy, 800; Injury or Disease of the Parathyroids in Man, 801.

CHAPTER LXXXVII
THE PITUITARY BODY . 806

Structural Relationships, 806; Functions, 807; Clinical Manifestations of
Deranged Pituitary Function, 816; Relationship with Other Endocrine Or-
gans, 818.

XX11 CONTENTS

CHAPTER LXXXVIII

PAGE

THE PINEAL GLAND, THE GONADS, AND THE THYMUS 820

Pineal Gland, 820; Goiiads or the Generative Organs, 821; Generative Glands
of the Male, 821 ; Generative Organs of the Female,. 822 ; Thymus, 824.

PART IX

THE CENTRAL NERVOUS SYSTEM AND THE CONTROL OF
MUSCULAR ACTIVITY

(Rewritten by A. C. Redfield)

CHAPTER LXXXIX

THE EVOLUTION OF THE NEUROMUSCULAR MECHANISM 827

Primitive Neuromuseular Mechanisms, 827 ; The Nerve Net, 830 ; The Cen-
tral Nervous System, 830.

CHAPTER XC

THE CONDITION OF THE NERVOUS IMPULSE 836

Conduction in the Nerve Fiber, 837; The All or None Law, 837; Refractory
Period, 839 ; Conduction between Neurons, 841 ; Resistance Due to Synapse,
842 ; Summation, 842 ; Inhibition, 843 ; Canalization, 844 ; Myoneurarl Junc-
tion, 845.

CHAPTER XCI

THE NUTRITION OF NERVOUS TISSUE 846

Function of the Nerve Cell Body, 846; Degeneration and Regeneration of
Nerve Fibers, 846; Metabolism of the Nerve Fiber, 850; Metabolism of the
Central Nervous System, 851.

CHAPTER XCII
THE RECEPTORS 854

The Evolution of Specialized Receptors, 854; Quality of Sensation and Its
Local Sign, 855; Referred Pain, 858; Cutaneous and Deep Sensibility, 859;
Touch, 860; Heat and Cold, 861; Pain, 862; Distribution of Sensitivity in
the Body, 863.

CHAPTER XCIII

THE AFFERENT PATHS OF SENSORY IMPULSES 866

Segmental Distribution of Afferent Nerves, 866 ; Ascending Pathways in the
Spinal Cord, 868; Afferent Paths in the Brain Stem, 871; Afferent Impulses
Which Fail to Produce Sensation, 872.

CHAPTER XCIV

THE SENSORY CENTERS OF THE BRAIN 876

The Sensory Center of the Optic Thalamus, 876; The Sensory Centers of the
Cerebral Cortex, 878; The Visual Areas, 880; Sensory Hallucinations, 883.

CONTENTS XX111

CHAPTEE XCV

PAGE

THE MOTOR AREAS OF THE CEREBRUM AND THE EFFERENT PATHWAY TO SKELETAL

MUSCLE 884

The Motor Area of the Cerebral Cortex, 885; The Visuo-Motor Areas, 886;
The Efferent Pathway in the Brain and Cord, 888; Distribution of Efferent
Nerves, 890; Spinal Ecflexes, 891.

CHAPTEE XCVI

THE AUTONOMIC NERVOUS SYSTEM, OR THE EFFERENT PATHWAY TO SMOOTH MUS-
CLES AND GLANDS 893

The Organization of Efferent Nerves to the Viscera, 893; The Double Inner-
vation of the Visceral Organs, 896; The Function of the Autonomic Nervous
System, 897; The Axon Eeflex, 898; Function of the Bulbo-sacral Divisions,
899 ; The Mechanism for Emptying the Bladder, 900 ; Function of the Thorac-
ico-Lumbar Division, 901 ; Effects of Impulses from the Viscera Upon Central
Nervous Activity, 902.

CHAPTEE XCVII

MUSCULAR CONTRACTION 904

The Tonic Contraction of Skeletal Muscle, 905; Tetanic Contraction of
Skeletal Muscle, 906; The All or None Law, 908; Chemistry of Tetanic Con-
traction, 910; Smooth Muscle, 912.

CHAPTEE XCV11I
POSTURAL COORDINATION 914

Eeflex Adjustment of Tone, 914; The Posture of the Body as a Whole, 917;
Compensatory Movements of the Eyes, 918; Clinical Tests of Labyrinthine
Mechanism, 920; The Tendon Jerks, 921.

CHAPTEE XCIX

THE CENTRAL CONTROL OF POSTURAL EEACTIONS; THE CEREBELLUM 921

The Influence of the Brain on the Local Tonic Eeflex, 924; Function of tl^
Cerebellum, 926; Localization of Function in the Cerebellum, 929; Compensa-
tion for Cerebellar Injuries, 931.

CHAPTEE 0

THE INTEGRATION OF ACTION WITHIN THE EEFLEX ARC t);;;;

The Eeceptors, 933; Summation, 934; Refractory Period, 934; Reciprocal
Inhibition, 937; Action of Strychnine and Tetanus Toxin on Beeiprocal In-
hibition, 941; The Eeflex Figure, 941; Eules for the Spread of Spinal Be-
flexes, 944.

CHAPTEB CI

THE INTEGRATION OF SIMULTANEOUS AND SUCCESSIVE BEFLEXES 945

Principle of the Final Common Path, 945; Integration of Allied Eeflexes,
946; Integration of Antagonistic Eeflexes, 947.

CHAPTEE CII

THE INTEGRATIVE ACTION OF THE CEREBRUM . . . 951

Eolation of the Cerebrum to the Distance Eeceptors, 952; Conditioned Be-
flexes, 954.

XXIV CONTENTS

CHAPTEE GUI

PAGE

THE HIGHER FUNCTIONS OF THE CEREBRUM IN MAN; APHASIA 958

Psychopathological Applications, 960.

CHAPTER CIV

SUMMARY OF THE ORGANIZATION OF THE MAMMALIAN NERVOUS SYSTEM; SPINAL

SHOCK 9G3

Spinal Shock and the Recovery of Reflexes in Animals, 965; Spinal Shock
and the Recovery of Reflexes in Man, 967; The Cause of Spinal Shock, 969.

ILLUSTRATIONS

FIG. PAGE

1. Diagram of osmometer 5

2. Hematocrite 7

3. Plasmolysis in cells from Tradeseantia discolor 9

4. Apparatus for measurement of the depression of freezing point of solution . 11

5. Diagram of conductivity cells 18

6. Wheatstone Bridge for the measurement of electric resistance 18

7. Diagram to show type of electrodes used in studying electromotive force . . 30

8. Diagram of apparatus for the measurement of the H-ion concentration . . 31

9. Chart of tints as used in colorimetric measurement of H-ion concentration

(Color Plate) 34

10. Diagram of apparatus for saturating blood and plasma with expired air . . 43

11. Van Slyke's apparatus for measuring the CO2-combining power of blood in

blood plasma 44

12. Ultramicroscope (slit type) for the examination of colloidal solutions ... 53

13. To show diffusion into gelatin of a crystalloid stain, and the nondiffusion of a

colloid stain 54

14. Diagram from W. Ostwald showing the relative size of various particles and

colloidal dispersoids compared with a red blood corpuscle and an anthrax

bacillus 55

15. Capillary analysis of colloids 57

16. Diagram to show structure of gels 62

17. Diagram to illustrate surface tension 65

18. Traube's stalagmometer 66

19. Diagram of the graphic coagulometer 110

20. Coagulometer 110

21. Mercury manometer and signal magnet, arranged for recording the mean ar-

terial blood pressure in a laboratory experiment 126

22. The arterial blood pressure recorded with a mercury manometer (lower trac-

ing) along with a tracing of the respiratory movement of the thorax . 127

23. Hiirthle's spring manometer 128

24. Normal curve of arterial blood pressure obtained with spring manometer . . 128

25. Diagram based on experiments on dogs to show the systolic, diastolic and

mean blood pressures at different parts of the circulatory system . . . 129

26. Apparatus for measuring the arterial blood pressure in man 131

27. Effect of cutting the vagus nerve on the arterial blood pressure 136

28. Effect of stimulating the peripheral end of the right vagus on the arterial

blood pressure 136

29. Effect of stimulation of the left splanchnic nerve on the arterial blood pressure 137

30. Composite curves to show effects of hemorrhage and transfusion of various

solutions on blood pressure 140

31. Diagram of experiment to show that the diastolic pressure depends on the

elasticity of the vessel wall 144

32. Diagram of Wiggers' optical manometer 147

XXVI ILLUSTRATIONS

TIG. PAGE

33. Optical records of intraventricular ^pressure 148

34. Superimposed pressure curves after being graduated 150

35. Von Frank's maximal and minimal valve, which is placed in the course of

the tube between heart and mercury manometer 152

36. Diagram to show the positions of the cardiac valves 156

37. Electrophonograms along with intraventricular pressure curves from three

different experiments 159

38. Arrangement of apparatus for heart-lung preparation . . . 164

39. Volume curve of ventricles of cat (lower curve) in a heart-lung perfusion

preparation 169

40. Heart and cardiac nerves of Limulus polyphemus . . . 173

41. Heart-block produced by applying clamp 175

42. Tracing of contraction of ventricle, showing the effect -of the local appli-

cation of heat to the auricle 175

43. Frog heart showing the position of the first and second ligatures of Stannius 176

44. Effects of stimuli of increasing strength on skeletal and cardiac muscle to

illustrate the "all or nothing" principle in the latter 177

45. The effects of successive stimuli on skeletal and cardiac muscle to show the

prominence of the staircase phenomenon, or treppe, in the latter . . . 178

46. The effects of successive stimuli and of tetanizing stimuli on skeletal muscle

and cardiac muscle 179

47. Myograms of frog's ventricle, showing effect of excitation by break induc-

tion shocks at various moments of the cardiac cycle 180

48. Heart of tortoise as suspended 183

49. Dissection of heart to show auriculoventricular bundle 184

50. Photograph of model of the auriculoventricular bundle and its ramifications,

constructed from dissections of the heart 184

51. Diagram of an auricle showing the arrangement of the muscle bands; the

concentration point; and the outline of the node 186

52. Diagram to show the general ramifications of the conducting tissue in the

heart of the mammal 186

53. Diagram to illustrate the development and spread of the wave of negativity

in a strip of muscle (curarized sartorius) when stimulated at the end . 188

54. Simultaneous electrocardiograms to show the cause for extrinsic deflections 190

55. Diagram of experiment by Lewis showing the times at which the excitation

wave appeared on the front of the heart 194

56. Diagram of Chauveau's dromograph 200

57. Diagram to show principle of Pitot's tubes for measuring velocity pulse . . 201

58. Cybulski's photohematotachometer 201

59. Dudgeon's sphygmograph 201

60. Pulse tracing (sphygmogram) taken by sphygmograph 202

61. Forms of apparatus for measurement of blood velocities 207

62. Plethysmograph for recording volume changes in the hand and forearm . . 210
03. Effect of venous supply on volume of heart . 217

64. Simultaneous tracings from auricle and ventricle of turtle's heart .... 223

65. Effect of vagus stimulation on heart of turtle 223

66. Tracing to show that vagus stimulation may diminish transmission from

auricles to ventricles . . 224

ILLUSTRATIONS XXV11

FIG. PAGE

67. Tracing to show that vagus stimulation may facilitate transmission from

auricles to ventricles 225

68. Diagram to show the innervation of the heart in the frog or turtle. (Color

Plate.) 228

69. Frog heart tracing showing the action of nicotine 231

70. Schematic representation of the innervation of the heart of the mammal.

(Color Plate.) .' 232

71. Tracings showing the effects on the heartbeat of the frog resulting from

stimulation of the sympathetic nerves prior to their union with the vagus

nerve 233

72. Boy's kidney oncometer 235

73. Pall of blood pressure from excitation of the depressor nerve 244

74. The effect of strong stimulation (heat) of the skin of the foot on the ar-

terial blood pressure and respiratory movements 245

75. Diagram showing the probable arrangements of the vasomotor reflexes . . 246

76. Aortic blood pressure, showing the effect of posture 249

77. Tracing to show the effect of gravity on the arterial blood pressure . . . 250

78. The effect of gravity on the aortic pressure after division of the spinal cord

in the upper dorsal region 250

79. Capillaries from abdominal wall of guinea pigs after injection of india ink . 252

80. Tracing showing simultaneous records of the arterial blood pressure, the

venous pressure, the intracranial pressure, the pressure in the venous

sinuses 260

81. Electrocardiographic apparatus as made by the Cambridge Scientific Ma-

terials Co. . 271

82. Normal electrocardiogram 272

83. Electrocardiogram (dog) taken simultaneously with curves from auricle and

ventricle 273

84. Records of electrocardiogram and movement of ventricle of frog showing that

when the apex is warmed a typical T-wave appears in place of a wave

in the opposite direction appearing when the apex is cooled ...... 275

85. Sinus bradycardia 279

86. Auricular extrasystole '. 279

87. Ventricular extra systoles arising in the right ventricle 279

88. Ventricular extrasystole arising in the left ventricle 279

89. Paroxysmal tachycardia 280

90. Auricular fibrillation . . 280

91. Auricular flutter 282

92. Delayed conduction 282

93. Partial dissociation 283

94. Complete dissociation 283

95. Tracings of the jugular pulse, apex beat, carotid and radial pulses .... 286

96. Polysphygmograph 288

97. Normal jugular tracing 288

97A. Superimposed pressure curves from aorta, ventricle and auricle, along Avith

electrocardiogram and phonocardiogram 289

98. Polysphygmograms including jugular, apex and radial tracings 290

99. Delayed conduction 291

100. Dropped beats . ,, . , 292

XXV111 ILLUSTRATIONS

FIG. PAGE

101. Premature beats (extrasy stoles) ventricular in origin 292

102. Paroxysmal tachycardia 293

103. Auricular flutter 294

104. Auricular flutter 294

105. Auricular fibrillation .295

106. Showing the appearance of the blood vessels in the ears of a rabbit in a

state of deep shock. (Color Plate.) . 304

107. Diagram showing amounts of air contained by the lungs in various phases

of ordinary and of forced respiration 318

108. Diagram of structure of air sacs, atria, alveolar ducts, etc 318

109* Pneumograph 321

110. Effect of abdominal and chest breathing on the pulse and blood pressure

of man 325

111. First dorsal vertebra, sixth dorsal vertebra and rib. Axis of rotation shown

in each case 333

112. Lower half of the thorax from the 6th dorsal to the 4th vertebra, seen from

the front ...... 335

113. Intercostal muscles of 5th and 6th spaces 336

114. Hamberger's schema to demonstrate the functional antagonism of internal

and external intercostals 336

115. Schema to demonstrate that the function of the internal intercartilaginous

intercostals is identical with that of the external interosseous intercostals 337

116. Diagram to show the effect of high and low positions of the diaphragm on

the costal angle 339

117. Diagram to show the effect of clinical displacements of the diaphragm on

the costal angle 340

118. Diagram to show cuts required for isolation of the phrenic center .... 345

119. Diagram to show certain positions in the medulla and upper cervical cord,

where sections may be made without seriously disturbing the respirations 346

120. Diagram to show where cuts are made to isolate the chief respiratory center

from afferent impulses 347

121. Diagram showing principle for measurement of the tension of CO2 in blood 355

122. The gas analysis pipette for the microtonometer shown in Fig. 123 . . . 356

123. Microtonometer, to be inserted into a blood vessel 356

124. Apparatus for collection of a sample of alveolar air by Haldane's method . 357

125. Fridericia's apparatus for measuring the CO2 in alveolar air 358

126. Curves to show the relationship between the O2 and CO2 tensions in alveolar

air and arterial blood 358

127. Same as Fig. 126, except that in this case the tension of CO, in the alveolar

air was experimentally altered 359

128. Arrangement of meters and connections of Pearce's method for measure-

ment of CO2 of alveolar air in normal subjects 363

129. Curve showing the respiratory response to CO2 in the decerebrate cat . . 368

130. The behavior of the respiratory volume, the blood pressure and the pulse

during progressive anoxemia 376

131. Curves showing variations in alveolar gas tensions after forced breathing for

two minutes 383

132. Various types of periodic breathing 385

ILLUSTRATIONS

FIG. PAGE

133. Quantitative record of breathing air through a tube 260 cm. long and 2 cm.

in diameter 388

134. Barcroft's tonometer for determining the curve of absorption of oxygen by

hemoglobin or blood 394

135. Barcroft's differential blood gas manometer 394

136. Barcroft blood gas manometer 395

137. Typical dissociation curve. (Color Plate.) 396

138. Average dissociation curves 397

139. Dissociation curves of hemoglobin 398

140. Dissociation curves of human blood 399

141. Curves showing relative rates of oxidation and reduction of blood as in-

fluenced by temperature and tension of CO2 400

142. Curve of CO2 tension in blood 405

142 A. CO2 tension at various altitudes 417

143. Cells of parotid gland showing zymogen granules 454

144. Parotid gland of rabbit in varying states of activity examined in fresh state 454

145. Diagrammatic representation of the innervation of the salivary glands in the

dog. (Color Plate.) 458

146. Pancreatic acini stained with hematoxylin 462

147. Three preparations of pancreatic acini stained by eosin orange toluidin blue 463

148. Diagram of stomach showing miniature stomach separated from the main

stomach by a double layer of mucous membrane 468

149. Typical curve of secretion of gastric juice collected in 5-minute intervals

on mastication of palatable food for 20 minutes 471

150. Cubic centimeters of gastric juice secreted after diets of meat, bread, and milk 475

151. Digestive power of the juice, as measured by the length of the protein column

digested in Mett's tubes, with diets of flesh, bread, and milk .... 475

152. Loop of intestine after tying off the portions, cutting the nerves running to

the middle portion and returning the loop to the abdomen for some time 477

153. The changes which take place in the position of the root of the tongue, the

soft palate, the epiglottis and the larynx during the second stage of swal-
lowing 480

154. Schematic outline of the stomach 486

155. Diagrams of outline and position of stomach as indicated by skiagrams taken

on man in the erect position at intervals after swallowing food impreg-
nated with subnitrate 4.86

156. Outlines of the shadows cast by the stomach at intervals of an hour each

after feeding a cat with food impregnated with bismuth subnitrate . . 487

157. Section of the frozen stomach (rat) some time after feeding with food given

in three differently colored portions 489

158. Outlines of shadows in abdomen obtained by exposure to x-rays 2 hours after

feeding with food containing bismuth subnitrate 492

159. Curves to show the average aggregate length of the food masses in the small

intestine at the designated intervals after feeding 493

160. Apparatus for recording contractions of the intestine 498

161. Diagrammatic representation of the process of segmentation in the intestine 499

162. Intestinal contractions after excision of the abdominal ganglia and section of

both vagi 500

XXX ILLUSTRATIONS

FIG. PAGE

163. The effect of excitation of both splanchnic nerves on the intestinal contrac-

tions . . 502

164. The effect of stimulation of light vagus nerve on the intestinal contractions 502

165. Diagram of time it takes for a capsule containing bismuth to reach the various

parts of the large intestine 504

166. Diagram of method for recording stomach movements 507

167. Tracing of the touus rhythm of the stomach three hours after a meal . . 508

168. Tracings from the stomach during the culmination of a period of vigorous

gastric hunger contractions 508

169. Showing augmentation of the knee-jerk during the marked hunger contrac-

tions 509

170. Diagram of the uriniferous tubules, the arteries, and the veins of the kidney 542

171. Cross section of convoluted tubules from kidney of rat 543

172. Diagram of blood supply of Malpighian corpuscle and of convoluted tubules

in amphibian kidney 549

173. Nerve supply of the kidney 553

174. Respiration calorimeter of the Russell Sage Institute of Pathology, Bellevue

Hospital, New York / 572

175. Chart of determining surface area of man in square meters from weight in

kilograms and height in centimeters according to formula 576

176. Diagram of Atwater-Benedict respiration calorimeter 580

177. Nose clip, face mask, and mouth piece 590

178. Diagram of respiratory valves 590

179. The Tissot spirometer 591

180. The Douglas bag method for determining the respiratory exchange . . . 592

181. Haldane gas apparatus and Pearce sampling tube 593

182. Curve constructed from data obtained from a man who fasted for- thirty-

one days 601

183. Curves of growth of rats on basal rations plus the various proteins indicated 610

184. Curves of growth of rats on basal rations plus the proteins indicated . . . 611

185. Photographs of rats of same brood on various diets 613

186. Curves of growth of rats as influenced by the accessory food factors . . . 620

187. Vividiffusion 'apparatus of J. J. Abel 642

188. Curves showing the amount of amino nitrogen taken up by different tissues

after the cutaneous injection of amino acids 643

189. Curves showing the concentrations of amino-acid nitrogen in the blood dur-

ing fasting and protein digestion 644

190. Curves showing the percentage of glucose in blood after a constant injection

of an 18 per cent solution into a mesenteric vein 691

191. Child aged 4^ years suffering from hypernephroma 769

192. Arrangement of apparatus for recording contractions of a uterine strip, intes-

tinal strip, or ring, etc 781

193. Tracing showing the effect of epinephrine on the intestinal contractions and

on the arterial blood pressure 782

194. Arrangement of apparatus for perfusion of the vessels of a brainless frog . 783

195. Microphotographs of thyroid gland of a dog 793

196. Cretin, nineteen years old 796

197. Case of myxedma before and after treatment : 797

19S. Drawing from a photograph of mesial sagittal section through the pituitary

gland of a human fetus 807

ILLUSTRATIONS XXXI

FIG. PAGE

199. Tracing showing the action of pituitrin on the uterine contractions and

blood pressure in a dog 812

200. Tracing showing the constructing action of pituitrin on the bronchioles and

its effect on blood pressure in a spinal dog 813

201. Showing the appearance before and after the onset of acromegalic symptoms 815

202. Hand of a person affected with acrornegaly 817

203. The evolution of the nervous system 829

204. Normal cell from the anterior horn, stained to show Nissl's granules . . . 831
20.1. Arborization of collaterals from the posterior root fibers around the cells of

the posterior horn 832

200. Part of an anterior cormial cell from the calf's spinal cord stained to show

neurofibrils 833

207. Schema of simple reflex arc 833

208. Diagram of nervous system of segmented invertebrate 834

209. Diagram illustrating the effect of areas of narcosis on the strength of the

nerve impulse 839

210. The recovery of excitability in the nerve fiber after the passage of a nerve

impulse 840

21.1. Degeneration and regeneration of a sectioned nerve fiber . , 847

212. Evolution of the sense organs 855

213. Cold spots and heat spots of an area of skin of the right hand 860

214. Diagram showing the segmented arrangement of the sensory nerves . . . 867

215. Diagram of the afferent paths followed by sensory impulses within the spinal

cord and brain 869

216. Afferent paths connecting the retina with the visual area of the cerebral

cortex 881

217. Outer aspect of the brain of the chimpanzee showing the position of the motor

centers 885

218. Diagram to illustrate the different arrangements of the internuncial neurons

of the voluntary and autonomic nervous systems 894

219. Diagram of the autonomic nervous system. (Color Plate.) 894

220. Diagram showing the main parts of the autonomic nervous system. (Color

Plate.) 896

221. Schematic representation of the autonomic nervous system. (Color Plate.) 898

222. Diagram of an axon reflex in a sensory nerve fiber of the skin 899

223. Electromyogram of the voluntary contraction of the flexor muscles . . . 907

224. The contraction of a single fiber of the sartorius muscle of the frog . . . 907

225. The all or none nature of the contraction of a single fiber of skeletal muscle 909

226. Eeciprocal inhibition 916

227. Kecords of the contraction of the isolated extensor muscle of the knee of

the cat 917

228. Compensatory movements of the eyes and fins of the dogfish 919

229. The semicircular canals of the ear 919

230. A tracing of the knee-jerks of a normal man and of a man with a cerebellar

injury 922

231. Schema of the parts of the mammalian cerebellum 929

232. Diagrams to represent a ventral view of the left half and a dorsal view of

the right half of the cerebellum 930

XXX11 ILLUSTRATIONS

FIG. . PAGE

233 and 234. The inferolateral and the posterior aspect of the human cerebellum

indicating certain cerebellar localizations according to Barany . . . 931

235. Footprints after destruction of the cerebellum in a dog 932

236. Tracing from the hind limb of a spinal dog during the scratching 'movements 935

237. Diagram showing the reflex arcs involved in the scratch reflex 936

238. The region of body of dog from which the scratch reflex can be elicited . . 936

239. Record from myograph connected with the extensor muscle of the knee . . 939

240. Sherrington's diagram illustrating the mechanism of reciprocal inhibition 940

241. Reflex figures 942

242. Successive induction illustrated by the crossed-extension reflex 949

243. Postures assumed by the robber fly when the eyes are unequally illuminated 953

PHYSIOLOGY AND BIOCHEMISTRY
IN MODERN MEDICINE

PART I

THE PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL

PROCESSES

CHAPTER I
GENERAL CONSIDERATIONS

The work of the physiologist consists, in large part, in ascertaining to
what extent the known laws of physics and chemistry find application
in explaining the phenomena of life. He gathers from the vast store-
house of physical and chemical knowledge whatever is of value in the
interpretation of the various mechanisms that work together to com-
pose the living machine, and having added to this knowledge he passes
it on for use by those who are concerned in the study and treatment of
disease.

Many of the most important steps in the advance of physiological
knowledge in recent years have depended upon the discovery of some
hitherto unknown physical or chemical law, or upon the elaboration of
some accurate method for the measurement of the phenomena upon
which these or previously known laws depend. The discoveries of
van't Hoff, Arrhenius, and OstwTald of the so-called laws of solution
were soon followed by important observations on their relationship to
the movement of fluids and dissolved substances through cell mem-
branes; the discoveries of Hardy, Willard Gibbs, etc., of the behavior of
colloids and of the phenomena of surface tension found application in
explaining many hitherto inexplicable, peculiarities in the activities of
ferments; the discovery by Nernst, etc., of methods for the measurement
of the electro-motive force of dissolved substances was applied to de-
termine the actual reaction or hydrogen-ion concentration of animal

2 PHYSICOCHKMICAL BASTS OP PHYSIOLOGICAL PROCESSES

fluids, and to explain the generation of the electric currents which ac-
company muscular, nervous, and glandular activity.

It would be out of place here to devote much space to a detailed ac-
count of such matters. They belong more properly in the domain of
general than in that of human physiology. General physiology is con-
cerned with the study of the essential nature of the vital processes;
whereas human physiology is merely a branch of the subject in which
special attention is devoted to the application of the truths of general
physiology to the working of the human machine. For the physician
and surgeon a knowledge of human physiology is as essential as is a
knowledge of the construction of a piece of machinery for the engineer
who attempts its repair, but obviously to acquire this knowledge the
fundamental principles of general physiology must first of all be under-
stood. For these reasons the introductory chapters are devoted to a
brief review of the most important of the physkochemical principles
upon which the working of the cell depends.

From the viewpoint of the physical chemist the cell consists of an
envelope of more or less permeable material inclosing a solution of
various crystalloids and colloids, in which these are in a state of
equilibrium with one another. This equilibrium is readily altered
by various influences that may act on the cell, and the resulting
changes manifest themselves outwardly -by alterations in the shape
and volume of the cell — growth and motion; by the extrusion of
some of its contents — secretion; or by the propagation to other parts of
the cell, or its processes, of the state of disturbed equilibrium — nervous
impulse. Besides the activities that are dependent upon physicochem-
ical changes, purely chemical processes go on in the cell. Many of
these consist in the breakdown and oxidation of complex unstable organic
molecules, a process identical with that occurring in combustion outside
the cell. Others involve the building up, stage by stage, of complex
substances out of the elements or out of simpler molecules. Chemical
transformations occur in the cell which, in the chemical laboratory, re-
quire the most powerful reagents and physicochemical forces, either the
strongest of acids, alkalies, oxidizing agents, etc., or extreme degrees
of heat, electrical energy, etc. But this is not all, for in the cell these
chemical transformations are capable of being guided to a very remark-
able degree of nicety so as to produce intermediate products that are
used for some special purpose either by the cell that produced them or,
after transportation by the blood, etc., by cells in other parts of the
organism.

It is customary to speak of the cell as a chemical laboratory, but it

LAWS OF SOLUTION 3

is more than this ; it is a laboratory furnished not only with the equip-
ment of the chemist but directed in the harmonious operation of its
many activities by a guiding hand which far surpasses anything else known
to man. Chemical transformations that require for their accomplishment
the greatest skill proceed without apparent difficulty in the cell. To
what are these changes due? What is the nature of the chemical rea-
gents and forces, and what is the directive influence that guides them
in their varied activities? To these, which are among the great ques-
tions of general physiology, the reply may be given that the reagents
are the ferments or enzymes, and that the directive influence operates
through the susceptibility of enzymic activities to changes in the envi-
ronment in which the enzymes are acting. In many cases these changes
can be explained on a physicochemical basis as dependent upon the
known laws of mass action or surface tension; in other cases they de-
pend on purely chemical changes in the cell contents, such as changes
in reaction or the accumulation of chemical substances that act like
poisons on the enzyme. But there are still others that appear to depend
on influences which as yet are quite unknown to the physical chemist,
such as the changes in cell activity that can be brought about by the
nerve impulse.

These preliminary remarks will serve to indicate the problems with
which we must first occupy our attention. They concern the physico-
chemical nature of saline solutions and of colloids, and the general na-
ture of enzyme action. The knowledge which we acquire will be found
to be of value, not only because it will help us to understand the nature
of the workings of the normal healthy cell, but because, here and there,
it will indicate possible causes for derangement in cellular function and
suggest rational means by which we may attempt to rectify the fault.

THE PHYSICOCHEMICAL LAWS OF SOLUTION

The Gas Laws

Three fundamental principles of general chemistry serve as the basis
for an understanding of the nature of solutions. The first is that if
we take a quantity of any gas equal to its molecular weight in grams
(called a gram-molecule or for sake of brevity a mol), it will occupy ex-
actly 22.4 liters at a temperature of 0° C. and a pressure of 760 mm. Hg. ;
the second is that, as we compress a gas, its pressure will increase in exactly
the same proportion as the volume diminishes (the volume of a gas is in-
versely proportional to its pressure) ; the third is that all gases expand by

4 PHYSICOCHTvMICAL BASTS OF PHYSIOLOGICAL PROCESSES

1/273 part of their volume at 0° C. for every degree C. that their tempera-
ture is raised.*

The pressure of a gas is measured by connecting a pressure gauge or
manometer with the vessel which contains the gas. Now, it is plain
that if the 22.4 liters, which is the volume occupied by a gram-molecular
quantity, were compressed so as to occupy a volume of 1 liter, its pressure
would be 22.4 times that of 1 atmosphere, or 22.4 x 760 mm. Hg — the
temperature remaining constant. Under these conditions we must im-
agine that the molecules of gas are crowded together by the compression,
and if we further conceive of these molecules as being in constant mo-
tion, then we can understand why the pressure should increase just in
proportion as we confine the space in which they can move.

One other property of gases must be borne in mind — namely, their
tendency to diffuse from places where the pressure is high to places
where it is low until the pressure is the same throughout.

OSMOTIC PRESSURE

These fundamental facts regarding the behavior of gases suggested
to van't Hoff the hypothesis that molecules of dissolved substances must
behave in a similar manner to those of gases. To put this hypothesis to
the test, it is necessary that we have some method for measuring the
pressure of dissolved molecules. We can not, as in the case of a gas,
use an ordinary manometer, for this would measure only the pressure
of the solvent on the walls of its container and would tell us nothing of
the pressure of the dissolved molecules. We must use some filter or
membrane that will allow the molecules of the solvent but not those of
the dissolved substance to pass through it. It is evident that if such a
filter is placed, for example, between a solution of sugar in water and
water alone, the molecules of the latter will diffuse into the solution
until this has become so diluted that the pressure of the dissolved mol-
ecules is equal on both sides of the membrane. Such a membrane is
called semipermeable; the diffusion of molecules through it is called
osmosis, and the pressure which is generated, the osmotic pressure. If
we prevent the water molecules from actually diffusing by opposing
a pressure which is equal to that with which they tend to diffuse through
the membrane, we can tell the magnitude of the osmotic pressure (Fig. 1).

In applying these facts to test the hypothesis that molecules in solution

*This implies that at -273° C. the gas would occupy no volume. Before this temperature is
reached, however, the liquefaction of the gas sets in. The temperature -273° C. is known as absolute
zero. An observed temperature plus 273° is called the absolute temperature. Another way of stat-
ing the above law is therefore that the volume is directly proportional to the absolute temperature.
At 273° C. the volume of a gas at 0° C. would be doubled, or if expansion were prevented the
pressure would be doubled.

LAWS OF SOLUTION

obey the same laws as .those in gaseous form, we must employ a semi-
permeable membrane which is rigid enough to withstand the pressure
and which forms part of the walls of a closed vessel connected with a
manometer. If we place in such an osmometer a solution containing the
molecular weight in grams of some substance dissolved in one liter of
solvent, a so-called gram-molecular solution, it is obvious that, if the
gas laws are to apply, the osmotic pressure should equal that of 22.4
liters of a gas compressed to the volume of one liter; in other words,
it should equal 22.4 x 760 = 17.024 mm. Hg. Although there are very
considerable technical difficulties in making a semipermeable membrane
that is strong enough to withstand such a pressure, yet this has been accom-

w

Fig. 1. — Diagram of osmometer. The cylindrical vessel (O), with a bottom of unglazed
clay, the pores of which are filled with a precipitate of copper ferrocyanide to form a semi-
permeable membrane, is suspended in an outer vessel, and is closed above by a tightly fitting
stopper pierced by a tube leading to a manometer (M). O contains a strong solution of cane
sugar, and W contains water. The water molecules tend to pass through the semipermeable
membrane into the cane sugar solution, and since the cane sugar molecules can not pass in
the opposite direction, the pressure in O rises and is recorded in M. This equals the osmotic
pressure.

plished, and the fundamental principle has therefore been firmly estab-
lished that substances in solution obey the same laws as gases.

Further proof that the gas laws apply to solutions has been secured by
showing that the osmotic pressure (of a dilute solution) is directly pro-
portional to the concentration of the dissolved substance (the solute)
and to the absolute temperature. It also obeys the law of partial pres-
sures, which states that the total pressure exerted by a mixture (of gases
or dissolved molecules) is the sum of the pressures which each constit-
uent of the mixture would exert were it alone present in the space
occupied by the mixture.

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

Since the osmotic pressure is analogous to the pressure of a gas and
is therefore proportional to the molecular concentration (i. e., number
of molecules in unit space), it follows that a semipermeable membrane
can be used to determine the relative concentration of two solutions of
the same substance. When a watery solution of some substance is
placed in an osmometer that is surrounded by a similar but more dilute
solution, water molecules will diffuse into the osmometer until the pres-
sure is equal on the two sides of the semipermeable membrane; that is,
the water will pass from the solution having a lower osmotic pressure
into the solution having the higher pressure. When two solutions have
the same osmotic pressure, they are said to be isotonic; when that of one
is greater than that of the other, it is hypertonic; and when less, hypotonic.

Biological Methods for Measuring Osmotic Pressure

A practical biological application of these principles can very readily
be made if, instead of a rigid semipermeable membrane such as that
figured in the diagram, we employ one that is extensible and takes the
form of a closed sac ; then as diffusion of water occurs the sac will either
distend when it contains a Stronger solution than that outside, or shrivel
or crenate when the reverse conditions obtain. Many animal and veg-
etable protoplasmic membranes are semipermeable, including the en-
velope of red blood corpuscles. Thus, if we examine blood corpuscles
under the microscope and add to them a saline solution of higher os-
motic pressure than blood serum, they will visibly diminish in size and
become irregular in shape; whereas if the solution is of lower osmotic
pressure, they will distend. If no change occurs, the osmotic pressure of
the cell contents must equal that of the saline solution in which the cells
are immersed, from which it is clear that we can readily determine the
magnitude of the osmotic pressure if we know the strength of the
saline solution.

Instead of measuring the individual cells under the microscope, we can
measure the space they occupy in the fluid in which they are suspended.
For this purpose a portion of the suspension is placed in a graduated
tube of narrow bore, which is rotated in a horizontal position by a cen-
trifuge after being closed at one end. The graduation at which the
upper edge of the column of cells stands after centrifuging is a measure
of the relative amounts of cells and of fluid in the suspension. Having
found this value for cells suspended in an isotonic solution, as for exam-
ple, blood corpuscles in blood serum, we may then proceed to ascertain it
for the same cells suspended in an unknown solution ; if we find that the
now occupy a greater volume, the saline solution must have an os-

LAWS OF SOLUTION 7

motic pressure that is lower than that of serum in approximate proportion
to the readings on the tube in the two cases, and vice versa.

The above apparatus, called a hematocrite (Fig. 2) has been very ex-
tensively used in the collection of data concerning the relative osmotic
pressures of different physiological fluids.

Hemolysis

Another way for determining the relative osmotic pressure of dif-
ferent solutions consists in placing equal amounts (a few drops) of
blood in a series of test tubes containing solutions of different strengths,
and after allowing the tubes to stand for some time, noting in which of
them laking of the blood corpuscles occurs. In solutions which are
isotonic or hypertonic with the contents of the corpuscles, the latter
will settle to the bottom of the tube and the supernatant fluid will be
untinted with hemoglobin, but in solutions which are distinctly hypotonic,
the sediment will be less distinct and the supernatant fluid red.

Fig. 2. — Hematocrite. The graduated glass tubes are filled with the two specimens of
blood, or corpuscular suspension, and then rotated rapidly by a centrifuge. The relative heights
at which the corpuscular sediment stands in the two tubes is proportional to the osmotic
pressures of the fluid in which the corpuscles are suspended.

By noting (1) the lowest concentration (percentage composition) of
the solutions in which the corpuscles sink to the bottom and leave the
supernatant fluid colorless, and (2) the highest concentration in which
the corpuscles when they settle leave the supernatant fluid tinted red, we
can determine the limiting concentrations for solutions of different sub-
stances. Thus, with bullock's blood the following results were obtained
(Hamburger) :

SUBSTANCE PERCENTAGE STRENGTH OF SOLUTION IN WHICH

I II

SUPERNATANT FLUID SUPERNATANT FLUID

WAS COLORLESS WAS RED

KN03

1.04

0.96

NaCl

0.60

0.56

K2S04

1.16

. 1.06

C^H^O,, (Cane sugar)

6.29

5.63

CH3C~OOH (Pot. acetate)

1.07

1.00

MgSO4.7H2O

3.52

3.26

CaCU

0.85

0.79

8 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

The mean of these limiting concentrations is the critical concentration
and indicates the strength of each solution that can be added to blood
without causing any damage to the corpuscles. This critical concen-
tration is not, as might at first sight be imagined, the same as that
which is isotonic with the contents of the corpuscles, but distinctly
below it. The reason for this becomes apparent if we observe the be-
havior of corpuscles suspended in an isotonic solution which is then
gradually diluted. As dilution proceeds, the corpuscles distend, until at
last their envelopes burst and the hemoglobin is discharged. The lim-
iting concentrations of a given salt vary for different corpuscles; thus,
the concentration of sodium chloride solution that just causes laking of
frog's blood corpuscles is 0.21 per cent, that of human blood 0.47 per cent,
and that of horse blood 0.68 per cent. It is the strength of the corpuscular
envelope rather than variations in the osmotic pressure of the contents
that is responsible for these differences.

The above described method of hemolysis, as it is called, can not be
used for comparisons of osmotic pressure in cases in which the solution
contains substances which alter the permeability of the corpuscular
envelop; for example, it can not be used when urea, or ammonium
salts, or certain toxic bodies are present. We may therefore ascertain
whether a given substance has a damaging influence on the corpuscular
envelope by finding whether hemolysis occurs when we suspend the cor-
puscles in a solution that is known by physical methods to be isotonic with
the corpuscular contents. We can further determine the approximate
degree of this toxic influence by estimating by color comparisons
(colorimetry) the amount of hemoglobin that has diffused out of the
corpuscles.

Plasmolysis

An analogous method for determining osmotic pressure is that of
plasmolysis, in which the behavior of certain plant cells is observed
microscopically while they are in contact with solutions of different
strengths. When the surrounding solution is isotonic with the cell
contents, the latter fill the cell and extend up to the more or less rigid
cell wall (A in Fig. 3) ; but when the solution is hypotonic, the cell
contents become detached from the cell wall at one or more places —
plasmolysis (B and C). The semipermeable membrane in this case is
therefore not the cell wall but the layer of protoplasm on the surface
of the cell contents. The method can be used only for detecting solu-
tions that are hypertonic, for wdth those that are hypotonic the cells
merely become turgid and exert more pressure on the more or less
rigid cell wall. Many of the conclusions that have been drawn from

LAWS OF SOLUTION

results obtained by the plasmolytic method have recently been called in
question, because no regard has been taken of the power of the colloids
of the cell to absorb (imbibe) water (see page 63).

The methods of hemolysis and plasmolysis have been used for the inves-
tigation of many problems in medicine besides those pertaining strictly to
osmotic pressure. In the case of certain toxic fluids, such as snake venom,
tetanus toxin, etc., determination of the hemolytic power has proved of
value in roughly assaying the damaging influence on other cells than
blood corpuscles. Studies in hemolysis have also been especially valuable
in working out the mechanism by which cellular toxins in general develop
their action, and the conditions under which this action may be counter-

Fig. 3. — To show plasmolysis in cells from Tradescantia discolor. A, normal cell; B,
plasmolysis in 0.22 M. cane sugar; C, pronounced plasmolysis in 1.0 M. KNO3; h, the cell
wall; p, the protoplasm. (After De Vries.)

acted, as by the development of antibodies. Furthermore, any solution
that is to be injected into the animal body, either intravenously or subcu-
taneously, should first of all be tested by the above methods in order to
find out whether it is isotonic with the body fluids. If a hypertonic so-
lution is injected, it will result in the abstraction of water from the tissue
cells, whereas a hypotonic solution will cause the water content of these to
increase. Advantage has recently been taken of this water-abstracting
effect of hypertonic solutions in the treatment of wounds. By constantly
bathing them with strong saline solutions, an outflow of water is set up
from the tissue cells that border on the wound, and this tends to bring to
the focus of infection the defensive substances that are present in animal
fluids.

CHAPTER II
OSMOTIC PRESSURE (Cont'd)

MEASUREMENT BY DEPRESSION OF FREEZING POINT

The limitations in the use of the plasmolytic and hemolytic methods
in the precise measurement of the osmotic pressure of the body fluids
have rendered it necessary to find some physical method that will be
generally applicable. Because of technical difficulties, it is impracticable
to measure the pressure directly by employing an osmometer, so that
some indirect method, depending on a readily measurable physical prop-
erty which varies in proportion to the osmotic pressure of the dissolved
substances, must be used. Fortunately, one such exists in the property
which dissolved substances have in lowering the temperature at which
the pure solvent solidifies; the freezing point of pure water, for example,
is lowered when substances are dissolved in it, and the extent of this
lowering, with certain reservations which will be explained later (page
16), is proportional to the molecular concentration of the solution and
independent of the chemical nature of the substance dissolved. This
lowering of temperature is designated by the Greek letter A, and to
measure it a thermometer is used which is not only extremely sensitive
but in which the level of the mercury column can be adjusted so that it
stands at a convenient level on the scale corresponding to the freezing
point of whatever solvent was used in making the solution under investi-
gation (Beckmairs thermometer) (Fig. 4). Having ascertained the exact
position on the scale of this thermometer at which the pure solvent freezes,
the observation is repeated with the solution, the osmotic pressure of which
is to be determined.

A gram-molecular solution in water (having therefore an osmotic pres-
sure of 17.024 mm. Hg) has a freezing point that is 1.86° C. lower than
that of pure water. This is known as the "freezing point constant,"
and it varies for different solvents, being 3.9 for acetic acid and 4.0
for benzene. If an unknown watery solution is found to have a freez-
ing point that is A° C. loAver than that of water, its osmotic pressure

, Ax 17.024

will equal — ^-^ mm. Hg.

l.ob

The depression of the freezing points produced by the various body

10

OSMOTIC PRESSURE

11

fluids has been compared, the objects in view being to see whether
osmotic pressure is a property which changes under different physiological
and pathological conditions, and to find out by comparison of the osmotic
pressures of the fluids in contact with a membrane, whether physical
forces alone can be held responsible for the transference of substances
through it from one fluid to the other.

THE ROLE OF OSMOSIS, DIFFUSION, AND ALLIED PROCESSES
IN PHYSIOLOGICAL MECHANISMS

The Transference of Substances Through Cell Membranes. — An ac-
count of some of the investigations in which the foregoing meth-

Fig. 4. — Apparatus for measurement of the depression of freezing point of solutions. The
solution is placed in the large test tube with the side arm, and in it is suspended the bulb
of a Beckmann thermometer with a platinum loop to serve for stirring. The upper end^of
the mercury column of the thermometer is shown magnified at the upper left corner. The
amount of mercury in the thermometer tube can be regulated by tapping the upper end with
the thermometer in various positions. The test tube is protected by an outer tube, which is
then placed in a vessel containing a freezing mixture.

ods have been used will illustrate their value in revealing the mech-
anism involved in the transference of water and dissolved substances
through cell membranes, as occurs in absorption of food in the
intestine, in the formation of lymph and urine, and so forth. In em-
ploying physical methods in the elucidation of such problems, it is
always most necessary to proceed with great care, since the physical

12 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

chemist works with pure solutions, while the physiologist has to use
fluids that are always complicated and frequently very variable in com-
position. We must simplify the problem as far as possible by having
clearly before us the' exact nature of the biological problem which a com-
parison of physicochemical values, such as osmotic pressure, may ena-
ble us to elucidate, and we must consider the other physical forces
which may assist or modify the particular one we are investigating.

In the physical experiments described above, the semipermeable mem-
brane may be conceived of as composed of pores of such a size that
they permit only the smallest of molecules — those of water — to pass
through them. Semipermeable membranes with larger pores may, how-
ever, exist — that is, membranes which permit water molecules and mole-
cules of simple chemical substances to pass, but hold back those com-
posed of large complex molecules. Such a semipermeable membrane
would allow the saline constituents but not the proteins of blood serum
to pass. It is, however, no longer semipermeable towards all of the dis-
solved substances, and the process of diffusion through it is more gener-
ally designated as one of dialysis than of osmosis.

Since the passage of dissolved molecules through membranes de-
pends upon the principle of diffusion, its rate will be proportional to
the osmotic pressures of the solutions on the two surfaces of the mem-
brane and to the size of the molecules, small molecules diffusing more
quickly than large ones. Suppose a membrane permeable to sodium
chloride and water is placed between two fluids containing sodium
chloride in solution, but in greater concentration in one of them than
in the other: although the sodium chloride will diffuse from the stronger
to the weaker solution, the water will tend to diffuse still more quickly (be-
cause its molecules are smaller) in the opposite direction, until the number
of sodium-chloride molecules in a given volume of solution is equal on
both sides of the membrane. For a time, therefore, the volume of the
stronger solution will increase. The differences which exist in the dif-
fusibility of dissolved molecules are analogous to those which have
long been known to exist in the diffusibility of gases, but the relation
between rate of diffusibility and molecular weight is not so simple as
the ratio between these tivo quantities in gases. These relationships,
however, indicate several further possibilities in the explanation of the
mechanism of exchange of substances through membranes, and must not
be overlooked, as they often are, in the interpretation of physiological
phenomena. An excellent review of the possible conditions is given
by Starling in his "Human Physiology."4 For example, let us suppose
the substances dissolved in the fluid on the two sides of a semipermeable
membrane, such as the peritoneum, to be different in diffusibility, as cane

OSMOTIC PRESSURE 13

sugar, which does not readily diffuse, and sodium chloride, which diffuses
quickly; the osmotic flow will take place from the sodium-chloride solu-
tion to that of cane sugar even though the sodium-chloride solution is
stronger than the sugar.

Furthermore, the simple laws of osmosis may be upset by an attrac-
tive influence of the membrane toward certain substances [due to their
becoming dissolved or adsorbed in it (see page 66)] but not toward
others. Many membranes of this nature are known to the chemist
(e. g., rubber membranes in contact with gases, pyridine solutions, etc.),
and it is probable that such a property of selective solubility may play
a not unimportant role in the transference of substances across animal
membranes (Kahlenberg5).

These few conditions which may modify the direction of the osmotic
flow, are indicated here to show how involved such problems are, and
how careful we must be not to assume that, because a substance is trans-
ferred through a living membrane contrary to the simpler laws of os-
mosia and diffusion, it must involve the expenditure of forces different
from those operating in dead membranes.

Another force comes into operation in causing transference of sub-
stances through membranes — namely, that of filtration. This is a purely
mechanical process, in which molecules are forced through the pores of a
filter (i. e., membrane) by differences in pressure on its two sides.

We are now in a position to consider in how far the above phj^sical
forces explain certain physiological problems.

The Physical Factors Involved in Absorption, Excretion and Lymph
Formation. — 1. 7s the absorption, into the blood and lymph circulating
in the intestinal walls, of substances in solution in the intestinal contents,
entirely dependent upon the processes of filtration, diffusion and osmosis?
The absorption of weak solutions of highly diffusible substances is probably
very largely a matter of osmosis and diffusion, and water passes quickly
into the blood because of osmotic attraction, but that other forces ordi-
narily come into play is very clearly established by the following ob-
servations. If a piece of intestine is isolated from the rest by placing
two ligatures on it, and the isolated loop filled either with a solution con-
taining the same saline constituents in similar proportions as in blood
serum, or better still, with some of the same animal's blood serum, it
will be found after some time that all of the solution becomes absorbed
into the blood; the contents of the loop are therefore absorbed into the
blood, even though the osmotic pressures of the dissolved substances are
the same on both sides of the membrane (Weymouth Eeid6).

The intestinal membrane seems to possess towards readily diffusible

14 PIIYSICOCHEMTCAL BASTS OF PHYSIOLOGICAL PROCESSES

substances a permeability which varies, not at all with the physical
diffusibility of the substance, but with its value from a physiological
standpoint. Thus, sodium sulphate and sodium chloride diffuse through
ordinary membranes with about equal facility, and yet if a solution con-
taining these two salts is placed in the intestine, the chloride will be
absorbed into the blood much more quickly than the sulphate. Sodium
sulphate in watery solution diffuses through a membrane fifteen times
more quickly than cane sugar, but from the intestinal lumen, cane
sugar is absorbed ten times more quickly than sodium sulphate. If.
however, the vitality of the epithelium is destroyed, as by first of all
bathing it with a solution of sodium fluoride, then the sulphate and
chloride will be absorbed at an equal rate.

Although diffusion and osmosis can not therefore play any significant
role in the normal process of absorption from the intestine, we must
not entirely discount them; under certain circumstances, these physical
forces may assert their influence as, for example, when concentrated
saline solutions are present. Such solutions will attract water from the
blood, and, other things being equal, more will be attracted the less
permeable the epithelium happens to be towards the saline employed.
Sulphates and phosphates will attract more water than chlorides or
acetates. This property of the saline solutions to attract water coun-
teracts the natural tendency for the water to be absorbed, and the
large volume of fluid stimulates peristalsis.

2. Do the physical processes of filtration, diffusion and osmosis suf-
fice to account for the production of urine by the kidney sf Under normal
conditions the molecular concentration of the urine, as determined by
the depression of freezing point, is considerably greater than that of
the blood. This indicates that excretion must have occurred contrary
to the laws of diffusion and osmosis ; in other words, that the renal cells
must have compelled dissolved molecules to be transferred from the
blood to the urine, although the difference in concentration would cause
them to pass in the opposite direction. This force, sometimes called for
want of a better name " vital activity," must depend on the operation of
processes that are quite distinct from those of diffusion, etc.; but that
they are necessarily of a nonphysical nature (e. g., vital) is less probable
than that they depend on some physical process the nature of which our
present knowledge does not permit us to understand.

By comparing the osmotic pressures of urine and blood, attempts
have been made to measure the work done by the kidney in the produc-
tion of urine. Thus, it has been found that A for normal urine (human)
is about 1.8, and for blood about 0.6, from which it may be calculated
that in the production of 1 kilogram of urine 150 kilogrammeters of

OSMOTIC PRESSURE 15

work are expended.* But that such comparisons of the osmotic pres-
sure of blood and urine are fallacious as an indication of the work of
the kidney is evidenced, not alone by the results of the above calcula-
tions, but also by the fact that under certain circumstances (as after
copious diuresis) the osmotic pressure of the urine may be considerably
loirrr than that of the blood.

For some time after the application of osmotic pressure measurements
to the study of biological problems, it was thought that determination
of A in urine might be of clinical value as a criterion of renal efficiency,
especially in one kidney as compared with the other. For this purpose
A was determined in samples of urine removed from each ureter by
catheterization. The tests of renal efficiency based on the rate of excre-
tion and on the specific gravity of the urine, following ingestion of a fixed
amount of water, have been found of much greater value.

3. Is the formation of lymph purely a physical process? The osmotic
pressure of normal lymph is nearly always somewhat below that of
blood serum, although occasionally it has been found to be a trifle
higher. Physical processes, such as filtration, might therefore suffice
to account for its formation under most conditions. But when we con-
sider the excessive production of lymph that occurs as a result of cel-
lular activity or following the injection of certain substances, called
"lymphagogues," it is not so easy to explain the production in such
terms, although some interesting attempts have been made to do so by
those that are wedded to the mechanistic view. For example, the very
marked increase in lymph flow which occurs as a result of muscular
exercise or glandular activity has been attributed to the fact that dur-
ing such processes large molecules become broken down into small ones
in the cell protoplasm, so that the osmotic pressure is raised and water
is attracted into the the cell until the latter becomes distended and a
process of filtration into the neighboring lymph spaces occurs (see
page 119).

There are several other physiological processes of secretion and excre-
tion which might be considered in the present relationship, but the above
instances will suffice to illustrate the general principle upon which all of
them have to be considered.

*Osmotic pressure corresponding to A = _0.6° C. enuals 5,662 mm. TTg (75 m. of TT..O), and
that corresponding to A = ~1.8° C. equals 16,986 mm. Kg (225 m. H2O). The difference "is there-
fore equal to a column of water 150 m. high. According to these calculations it would appear that
the kidney in producing the average daily output of 1500 c.c. urine performs 225 kilogrammeters of
work in comparison with the 14,000 kilogrammeters which the heart is computed to perform in the
same time (page 213).

CHAPTER III

ELECTRICAL CONDUCTIVITY, DISSOCIATION, AND
IONIZATION

The osmotic pressure is not infrequently found to be considerably
greater than that expected from the strength of the solution. Although
A of a gram-molecular watery solution of cane sugar (342 gm. to the liter)
is 1.86 (see page 10), that of sodium chloride (58.5 gm. to the liter) is
considerably greater. If the hypothesis regarding the relationship of
molecular concentration to osmotic pressure is to hold good, it becomes
necessary to explain this apparent inconsistency; xme must account for
a greater number of dissolved units than is represented by the actual
number of dissolved molecules (i.e., weight of dissolved substances).

It was observed that the power to conduct the electric current — electrical
conductivity — in the case of solutions (e. g., of sugar) which have an
osmotic pressure that corresponds to the weight of dissolved substances
is practically nil, whereas the conductivity of those solutions which give
higher osmotic pressure is quite pronounced. Arrhenius made the hy-
pothesis that the conductivity depends on the splitting of molecules into
two or more portions or ions, each of which carries either a positive or a
negative electric charge, and that it is only when such dissociation occurs
that the electric current can be conducted through the solution, the ions
serving as it were as floats carrying the electric current. When sodium
chloride is dissolved in water, it splits into Na carrying a positive charge
and Cl carrying a negative charge, or Na+Cl", as it is written; on the
other hand, when sugar is dissolved, the molecules remain unbroken and
no electric charges are set free.

Substances which thus dissociate are called electrolytes, and those which
do not, nonelectrolytes. When the electric current is passed through a
solution of electrolytes, the ions which carry a positive charge move to
the electrode or pole by which the current leaves the solution — that is, in
the same directions as the current; and since this electrode is called the
cathode, these are called cations. Hydrogen and the metals belong to
this group. The ions carrying a negative charge go in the opposite direc-
tion, against the current — that is, towards the electrode by which the cur-
rent enters, or the anode; they are therefore called anions. They include
oxygen, the halogens and the acid groups, such as S04, C03, etc.

It must be understood that this dissociation into ions is already present

16

ELECTRICAL CONDUCTIVITY, DISSOCIATION, IONIZATION 17

in the solution before any electric current passes through it, the ions
being however uniformly distributed throughout — that is, arranged so
that the negative charges of the anions precisely neutralize the positive
charges of the cations. The electric current causes the electrodes to be-
come charged, the one positively, the other negatively, so that an attrac-
tive force is exerted on the ions of opposite sign. This causes the nega-
tively charged ions to migrate towards the positive electrode, and the
positively charged, towards the negative electrode. It is this migration
of the ions that endows the solution with conducting qualities.

In water, or in a solution of a nonelectrolyte, molecules of H20 or non-
electrolyte exist thus:

H20 H20 H20

H20 H20 H20
H20 H20 H20

In a solution of an electrolyte, many of the molecules split into ions thus :

Na+ Cl- Na* Cl- Na+ Cl-

Na* Cl- Na+ Cl- Na+ Cl-
Na+ Cl- Na+ Cl- Na+ Cl-

When an electric current passes through a solution of an electrolyte,
the ions tend to arrange themselves thus:

• Cathode- Anode*

Na+ Na+ Na* Cl- Cl- Cl-

Na* Na+ Na+ Cl- Cl- Cl-

Na+ Na+ Na+ Cl- Cl- Cl~

It follows from the above considerations that the conductivity of a sub-
stance in solution will depend on the degree to which it undergoes dissocia-
tion. Furthermore, if we assume that in so far as osmotic pressure
phenomena are concerned, each ion behaves in the same way as a mole-
cule, then it follows th.at the electrical conductivity must be proportional
to the extent to which the osmotic pressure is greater than we should ex-
pect it to be from the amount of substance actually dissolved.

In the Determination of the Conductivity it is obviously necessary to
use standard conditions of depth and width of the fluid through which the
current is passed, and to have some standard of comparison. The value
is then known as the specific conductivity, the standard for comparison
being the conductivity of a hypothetical liquid which, if enclosed in a
centimeter cube, would offer a resistance of 1 ohm between two opposite
sides of the cube acting as electrodes. The actual determination is usu-

18

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

ally made in a cylindrical vessel of hard glass (from soft glass enough
alkali might be dissolved to affect the results), the electrodes being circu-
lar plates of platinum firmly cemented at a known distance from each
other (Fig. 5).* This conductivity cell, as it is called, is connected
with a suitable apparatus for measuring the resistance offered by the

Fig. 5. — Diagram of conductivity cells. The platinum discs are represented by the thick
black lines. They are held in position by thick-walled glass tubes, through which they are
connected with the terminals by platinum wires. (From Spencer.)

solution to the passage of an electric current (Wheatstone Bridge) (see
Fig. 6). The resistance is of course inversely proportional to the con-
ductivity.

As a saline solution is progressively diluted, its specific conductivity
naturally decreases (since there are now fewer molecules between the

Fig. 6. — Wheatstone Bridge for the measurement of electric resistance: a-b, bridge wire; c,

the movable contact.

two opposite faces of the centimeter cube, and the space between ions or
molecules is increased). This result will not, however, tell us whether
the salt itself is undergoing any alteration in conducting power as a con-
sequence, for example, of greater dissociation. To ascertain this we must

*This distance is determined not by direct measurement but by calculation from results obtained
by testing the actual resistance of a solution whose specific resistance is accurately known.

ELECTRICAL CONDUCTIVITY, DISSOCIATION, IONIZATION 19

obtain figures relating to the same quantity of salt at each dilution. If
we multiply the specific conductivity by the volume of solution in c.c.
which contains 1 gram-equivalent (see page 22), a value will be secured
which represents the conducting power of a gram-equivalent. This is
known as the equivalent or molecular conductivity * and is represented by
the sign A. When it is determined for progressively diluted solutions,
A gradually increases, indicating that the efficiency of the electrolyte itself
as a conductor increases with dilution, because it dissociates more. The
extent of this increase is found to become less and less as dilution
proceeds. By plotting the values of the molecular conductivity of suc-
cessive dilutions as a curve, the value at infinite dilution can be ascertained
by extrapolation. This value is represented by A °c .

Now, let us see how these facts bear out the theory of electrolytic dissocia-
tion. According to this hypothesis the conductivity depends on the num-
ber of ions (see page 17), and since it is at a maximum at infinite dilu-
tion, the value AOC must represent the total number of ions that can le pro-
duced "by the dissociation of 1 gram-equivalent, and A thai at some other
dilution. If, therefore, we divide A by AOC we obtain a value (called a)
which must represent the degree to which the electrolyte is ionized at the
various dilutions at which A is measured. From what has been said re-
garding the osmotic pressure of similar solutions, it is evident that the
value a could also be calculated by finding the extent to which the de-
pression of freezing point A is greater than would be expected from the
number of dissolved molecules. As a matter of fact, it has been found
that the two methods yield practically identical values for many substances,
thus furnishing almost incontrovertible proof in support of the dissociation
hypothesis. In the cases of weak acids and bases, it is possible to secure
a value, called the dissociation constant (K), which represents the rela-
tive values of a at all dilutions. Since the activity of acids and bases
is dependent upon the number of H- and OH-ions, respectively, set free
by dissociation, it follows that it must be proportional to K. It will be
necessary, however, to postpone a further consideration of the application
of this constant until we have studied mass action (page 23).

Biological Applications. — The practical value of a knowledge of the
laws of electrical conductivity rests, not so much on any direct application
that can be made of it in explaining physiological processes, as on the es-
sentially important bearing which it has in enabling us to understand the
nature and operation of other physicochemical laws. Without a clear com-
prehension of the elemental laws of dissociation, it is impossible to con-
sider such problems as those which concern the activities of enzymes (mass

*In other words, the molecular conductivity is the specific conductivity divided by the number of
gram-equivalents contained in 1 c.c.

20 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

action, etc.), the occurrence of electrical currents during the physiological
activity of muscles, glands, and nerves, and the all-important question of
the reaction or H-ion concentration of the body fluids.

There are, however, several instances in which measurements of electrical
conductivity and of dissociation have direct physiological value. The circu-
lation time of the bloodflow through an organ can be determined by first
finding the electrical resistance of a short piece of the vein of the organ,
and then observing the change in resistance which is produced when the
conductivity of the blood in the vein is altered by the arrival in it of
saline injected into the artery. The interval elapsing between the injec-
tion into the artery and the changes in resistance in the vein equals the
circulation time (G. N. Stewart).

The same investigator has used measurements by electrical conductiv-
ity to study the passage of electrolytes out of the red blood corpuscles into
the serum. Under normal conditions the blood serum has a certain elec-
trical conductivity equal to that of a 0.9 per cent sodium-chloride solution.
The conductivity of the defibrinated blood is only about one-half that of
serum, because it contains corpuscles which are nonconductors and there-
fore obstruct the free passage of the ions, just as a suspension of quartz
powder in a sodium-chloride solution lowers the conductivity of the lat-
ter. If anything occurs therefore to occasion a passage of the saline con-
tents of the corpuscles through their walls into the serum, an increase in
the electrical conductivity will be produced. The value of this method in
the investigation of changes in permeability of the red corpuscles is de-
pendent on the fact that such migration of electrolytes out of the cor-
puscles may occur before any of the less diffusible hemoglobin itself has
escaped. The rise in conductivity precedes the hemolysis (see page 7).

Although determinations of the specific conductivity of blood and urine
under various pathological conditions have also been made, the results
have not been found to possess any diagnostic value or clinical signifi-
cance. Measurements of the electrical conductivity of blood have, how-
ever, been used by Wilson7 and by Priestley and Haldane8 to detect the
degree of dilution when large quantities of water are ingested.

Another application of conductivity measurements in biochemistry has
been made in studying the digestive action of proteolytic enzymes (Bay-
liss). The general action of the enzymes is to break the large undisso-
ciated molecules of the higher proteins (albumin, casein, etc.), into
smaller molecules (ammo acids, etc.), which are partly ionized. As diges-
tion proceeds, therefore, the conductivity of the digestion mixture pro-
gressively increases, and is a measure of the rate of digestion.

Applications of the dissociation hypothesis in physiology concern the
explanation of such phenomena as the production of electric currents

ELECTRICAL CONDUCTIVITY, DISSOCIATION, IONIZATION 21

during muscular, glandular, and nervous activity. The exact details of
the application are not as yet sufficiently understood to warrant our at-
tempting to do more than indicate the general lines along which the
problems are being investigated. To do so we must delve a little further
into physicochemical research, when we shall find that there are two further
facts concerning ionized molecules that must be of importance in connec-
tion with our problem. The first is that the contribution which each ion
makes to the equivalent (or molecular) conductivity of a solution is inde-
pendent of the other ion with which it is associated; and the second, that
ions differ considerably in their conducting power. Since the univalent
ions, K., Na., CL', N03', carry charges of equal magnitude,* and yet all do
not conduct to the same degree, they must move at different velocities
through the solution. We are driven, therefore, to the conclusion that,
exposed to the same electrical force, different ions have different mobili-
ties ; that is to say, when an electric current passes through a solution of
an electrolyte, the positively charged ions move towards the cathode at a
different rate from that at which, the negatively charged ions move
towards the anode. Confirmation of this conclusion is obtained by exam-
ination of the concentration changes around the two electrodes of an
electrolytic cell. The actual velocity of each ion can be determined by
experimental means. The inequality in concentration of ions in different
regions of a tissue is no doubt the fundamental cause for the electrical
currents that are set up by injury and activity.

*Thus Faraday showed that the amounts of the various ions liberated by electrolysis are in the
same ratio as their chemical equivalents.

CHAPTER IV

THE PRINCIPLES INVOLVED IN THE DETERMINATION OF THE
HYDROGEN-ION CONCENTRATION

TITRABLE ACIDITY AND ALKALINITY

All acids have one property in common — namely, that they contain
hydrogen^and when the acid becomes neutralized, it is this element
which becomes replaced by some other cation. Evidently, then, the
strength of an acid is proportional to the number of displaceable hydro-
gen atoms which it contains. It may contain other hydrogen atoms
which are so bound up in the molecule that they do not become displaced
when an alkali is mixed with the acid. For example, in organic acids
like acetic, CH3COOH, it is only the H atom attached to the COOH
group, but not those attached to the CH3 group, that is replaceable. It
must therefore be possible to prepare for every acid a solution having
exactly the same neutralizing power as that of any other acid; that is,
the same volume of solution must be required in each case to neutralize
a given quantity of alkali, the point of neutralization being judged by
the change in color of indicators. As a standard a gram-molecular solu-
tion of an acid with one displaceable H ion, such as hydrochloric, is
chosen. This we call a "normal acid" (N). To prepare a normal solu-
tion of acids having two displaceable H atoms, such as H2S04, we can not
however use a gram-molecular quantity, but must take one-half of it;
and similarly in the case of those with three H atoms, such as H3PO4,
a one-third gram-molecular solution will be a normal acid solution. For
practical purposes, use is very generally made of solutions that are some
fraction of the normal, e. g., tenth or decinormal (written N/10), or hun-
dredth or centinormal (N/100).

In a similar way, alkaline solutions can be prepared, a normal alkali
being one which exactly corresponds in strength with a normal acid
(i.e., can exactly neutralize it). Now, the characteristic of alkalies is
that they produce in solution "OH" or hydroxyl ions; so that the process
of neutralization must consist in the union of the H ions of the acid with
the OH ions of the alkali to form water: KOH + HC1 = KC1 +H20. We
can, therefore, prepare normal solutions of alkalies by dissolving in 1
liter of water such quantities of alkali (in grams) as will yield the OH
required to react with the available hydrogen in normal acid solutions.

22

HYDROGEN-ION CONCENTRATION 23

Actual Degree of Acidity or Alkalinity. — According to the foregoing
method of titration a normal solution of a powerful mineral acid, such
as hydrochloric, is no stronger than a normal solution of a weak acid,
such as acetic or lactic. It requires no fewer c.c. of N alkali to neutralize
it. But the normal solution of the powerful acid is more acid to the taste,
is more toxic, dissolves metals more readily, and in all its other chemical
and physiological properties acts much more quickly than the weak acid,
so that the titrable acidity or alkalinity can not express the real strength
of the acid or alkali, or the actual degree of acidity or alkalinity. It is
in this connection that the dissociation hypothesis aids us, for it suggests
that the degree to which the acid becomes dissociated into H- and the
remainder of the molecule will determine its real strength (see page 16).
The question is, how are we to measure the latter ? One action of H ions
which we may measure is that known as catalytic — that is, the power to
accelerate reactions, such as the splitting of cane sugar (C^H^On) into
glucose and levulose, which otherwise would proceed very slowly (see
page 75). If then the real strength of an acid depends on the degree
of dissociation which it undergoes, figures representing the catalytic
power should correspond with those representing the relative conductivi-
ties of the acids in equivalent concentration (see page 19). That this is
actually the case is shown in the following table, in which the above values
of various acids are given compared with HC1, which is taken as 100.

ACID CATALYTIC POWER RELATIVE CONDUCTIVITY

HC1 100 100

Dichloracetic 27 25

Monochloracetic 4.8 4.9

Formic 1.5 1.7

Acetic 0.40 0.42

It will be evident that, if we could measure the concentration of free
H ions in a solution — that is, of H ions that are not matched by OH ions —
we should have a faithful index of its real acidity. This measurement
has been rendered possible by the application of two other physico-
chemical principles — namely, those of mass action and electromotive
force. Since the object of this volume is to present the scientific basis
for the various methods that are used in modern medicine, it will be nec-
essary for us to review the main principles of these two actions. We shall
see that they apply, not only in the measurement of H-ion concentration,
but in many other physiological processes.

Mass Action

When materials take part in a reaction, some molecules are decom-
posing while others are being formed. After some time, however, a

24 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

condition is reached in which the changes in one direction are exactly
offset by those in the other. An equilibrium is said to have become estab-
lished between the reacting substances. Bearing in mind that the ions
and molecules entering into these reactions are constantly moving about
and coming in contact with one another, it is easy to see that if we were
to add an additional quantity of one kind of molecule or ion, there would
be a change all along the line until a new equilibrium was established.
If, on the other hand, we were to remove one kind of molecule or ion
as fast as it is formed, the equilibrium could never be established, and
the reaction would proceed until all of this material had disappeared.
The natural rate at which any chemical reaction proceeds is dependent
upon a number of conditions, such as chemical affinity, temperature,
catalysis, and concentration. Of these conditions that of concentration
is most readily measured. If we maintain all of the conditions other
than that of concentration unchanged, and designate this combined in-
fluence as K (constant), we shall find that the speed of the reaction is
proportional to the molecular concentration of the reacting substances
(i. e., the number of gram-molecular weights per liter). In other words,
the speed with which two substances, a and b, unite to form other sub-
stances, c and d, will be expressed by the equation,

k (a)x(b) *± k' (c)x(d);*

which means that, when the reaction is complete, the composition of
the mixture will be dependent upon the ratio between k and k'. Since
however these are both constants, their quotient is also constant (K), and

we have the equation, -y-r — ~f = K, indicating that no matter how

\ / ^ \ ^*- /

the concentrations a, b, c, and d are varied, reaction will take place in
one direction or the other until the concentrations have become adjusted
so that K remains unchanged.

As an example of the application of these laws, let us take the reaction
which occurs between alcohols and organic acids to form the substances
called esters — a reaction which is analogous to that between mineral
alkalies and acids to form neutral salts, and which is of special interest
to us because it is the reaction involved in the splitting of animal fats.
The equation for the reaction is:

C2H5OH + CHSCOOII ?± C2HBOOCCH8 + H2O.
(ethyl (acetic (ethyl acetate,

alcohol) acid) an ester)

Or expressed according to the law of mass action:

[C2H5OH] x [CH3COOH]
[C2H6OOCCH3] x

*The brackets indicate that gram molecular quantities are used.

HYDROGEN-ION CONCENTRATION 25

Now it is clear that if we increase, say, H20 in the above equation, then
in order that K may remain unchanged C2H5OOCCH3 must diminish or
the substances which form the numerator of the equation must increase,
or both these changes must occur. As a matter of fact, in such a case as
the above, both of these adjustments take place, for, as the ester breaks
down, it must thereby increase the concentration of acid and alcohol.
Since in aqueous solutions the reaction occurs in the presence of an excess
of water, it is evident that the tendency for an ester is to break down into
alcohol and acid, and this must occur in all reactions in the body fluids in
which water enters into the equation.

Physiological Applications. — The application of the law of mass action
in the explanation of biochemical processes is very extensive. Most of
the reactions which enzymes or ferments are capable of influencing are
of the same general nature as that represented above, and the products
of their activities are usually the substances on the side of the equation
in which no water molecules appear — i. e., they are hydrolytic reactions.
Enzymes merely accelerate the reaction (page 72), so that if we start
with a mixture of the substances on either side of the equation, all they
do is to accelerate the production of a sufficient concentration of those
on the other side, until the equilibrium point is reached. For example,
an enzyme present in pancreatic juice, called lipase, accelerates the
breakdown of such esters as neutral fat, which consists of the triatomic
alcohol, glycerol, combined with the fatty acids palmitic (C15H31COOH),
stearic (C17H35COOH) and oleic (C7H33COOH):

C3H5 (O 00 C17H35)3 + 3H2O^3CnH35COOH + C3H5 (OH)8.

(the neutral fat, (the fatty acid, (glycerol)

tristearin) * stearic)

Under ordinary conditions the reaction proceeds until nearly all the
neutral fat has become decomposed because of the preponderance of
water, but if we start with a mixture of fatty acid and glycerol with
just enough water to permit the enzyme to act, the reaction will pro-
ceed in the opposite direction — i. e., so that some neutral fat will be
synthesized. This is called the reversible action of enzymes (page 77).

Because of the universal presence of water, it is plain that such re-
versible reactions could not alone be held responsible for the synthe-
sis of neutral fat or of similar substances in the animal body. The only
way by which synthesis could occur under these conditions would be
if the substance produced along with the water were removed from the
site of the reaction as soon as it was formed. This might occur by the
precipitation of the substance or by its becoming surrounded by an en-
velope of some inert material. In the synthesis of neutral fat which

26 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

occurs in the epithelium of the intestine out of the fatty acid and glycerol
absorbed from the intestinal contents, it is possible that the last men-
tioned process occurs. In other cases the substance may be carried
away by the blood or lymph or urine as fast as it is formed.

The Law of Mass Action as Applied to the Measurement of H-ion
Concentration. — Let us now return to the reaction or H-ion concentration
of substances in solution. As the standard of neutrality, pure water is
chosen. Let us consider, then, how the laws of mass action can be
applied in order to enable us to determine the H-ion concentration of
pure water. It has been stated above that chemically pure water is in-
capable of conducting the electric current. This however is not strictly
the case, for it conducts to a very slight degree. According to the dis-
sociation hypothesis, it must therefore be represented as containing
molecules of H20 and ions of H • and OH', and according to that of mass
action there must be a balanced reaction between the molecules and ions
represented thus:

=.

Since the concentration of H • and OH' is extremely small, there must
always be such an overwhelming preponderance of H20 molecules that
no changes in the concentration of H • and OH' will be capable of appre-
ciably affecting the concentration of H20 ; in other words, one may omit
the denominator of the equation and write it [H •] x [OH'] = K. If
then we know the value of K, it will only be necessary to measure the
concentration of either H • or OH' in order to express in numerical terms
the reaction of the solution. It has been found that the value of K is
about -1 x 10'14,* and since the concentrations of H • and OH' are nec-
essarily equal in pure wrater, it follows that [H] = [OH] = \flxlO~14,
i. e., each ion has a concentration of 1 x 10 7. This means that water con-
tains approximately 1 gram mol. each of H- and OH' ions, or 1 gram
H- and 17 grams OH' ions, in 10+7 or 10,000,000 liters. A consequence
of the above law is that no matter how much the concentration of one
ion is increased by adding another substance, the solution must still
contain some of the other ion. Thus, in acid solutions the concentration of
H • must increase and the concentration of OH' must decrease in such pro-
portion that the two multiplied together equals about 1 x 10~14. The H-ion
concentration can ~be used therefore to express the reaction of neutral, acid
and- alkaline solutions.

In place of water, let us substitute decinormal hydrochloric acid

*The sign 10-14 is simply a convenient way of expressing the degree of dilution. It gives the
number of times the value standing in front of it must be divided by 10 in order to find the
concentration.

HYDROGEN-ION CONCENTRATION 27

(0.1 N HC1) — that is, a hydrochloric acid solution containing one tenth
of the molecular weight of hydrochloric acid in grams dissolved in a
liter of water. At this dilution HC1 is 91 per cent dissociated; therefore
the H-ion concentration (or CH as it is written for short) is 0.091 Nt
or, in mathematical notation, 9.1 x 10 2.

Method of Expressing CH. — To avoid the necessity of having to use
several figures to express CH, as has been done above, Sorenson has intro-
duced a scheme by which only one figure is required. This figure, des-
ignated by PH, is found by subtracting from the power of ten (i. e.,
the figure standing behind 10) the common logarithm of the figure ex-
pressing the normality of the acid. In a decinormal HC1 solution,
therefore, we must subtract from the power 2, the common log. of 9.1,
which is .96 (ascertained from logarithm tables), leaving 1.04. . Take
another example: decinormal acetic acid is dissociated only to the ex-
tent of 1.3 per cent ; CH is therefore 0.0013 normal, or 1.3 x 10'3. Since
the logarithm of 1.3 is .11, PH equals 3-.11, or -2.89.*

The only objection to the use of the exponent PH as an expression of
the H-ion concentration is that it increases in magnitude as the acidity
becomes less; this is because the negative sign of the power is disre-
garded. As stated above, it is usual to express the strength of alkalies
as well as acids in terms of CH, or PH, because it is easier to measure the
concentration of H ions than of OH ions. A 0.1 NaOH solution is 84
per cent dissociated; therefore the "OH" ion is 0.084 N (i. e., 0.084 gram
equivalents OH per liter), and since the product of the II • and OH'
concentrations must always equal 10-14-14 (at 20° C.), it is clear that as
the H ion increases in concentration, the OH ion must reciprocally de-
crease. Expressed according to the above scheme, the 0.084 N NaOH
solution gives PH 13.06; thus, 0.084 = 8.4 x 10'2; the log. of 8.4 is .924,
and this subtracted from the power -2 = 1.08 as POH, or 14.14 - 1.08 =
13.06 as PH.**

Similarly, PH of 0.1 N NH4HO solution is 11.286. Its dissociation is
1.4 per cent; therefore the solution contains only 0.0014 gram equivalents
HO— i. e., 1.4 x 10-3 POH = 3 - 0.146 = 2.854 . • . PH 14.14 - 2.854 =
11.286.f

*If we wish to express the value of Pit in ordinary notation, we must find the antilogarithm
of the difference between the value of PH and the next higher whole numher; e. g., if PH = 7.45,
the antilogarithm of 0.55 being 3.55, the CH is 3.55 x 10'8, or 0.000,000,0355 N, or 3.55 gm. mol.
H ion in 100,000,000 liters.

**It must be remembered that the power of a number indicates the number of times by which
that number must be multiplied by ten; thus, Pn-6 does not mean that the H ion is six times less
than PH°, but 1 x 10 x 10 x 10 x 10 x 10 x 10, or 1,000,000 times less. Similarly, Pn'3 is 1000 times
as great as PH-«, not twice as great.

A solution containing almost exactly 1 gram molecule of dissociated hydrogen in 10,000,000 liters
constitutes a neutral solution (Pn — 7).

tThe expressions PH and CH may be used indiscriminately, but when the numerical value is
given, it is most convenient to use the former.

28 PHYSICOCH^MICAL BASIS OF PHYSIOLOGICAL PROCESSES

Application of the Law of Mass Action in Determining the Real
Strength of Acids or Alkalies. — We have seen that it is the degree of
dissociation upon which the real strength of an acid depends and that
this varies with dilution (page 19). The equilibrium between the un-
dissociated and dissociated molecules may therefore be shifted in either
direction by changing the concentration; in other words, the process of
dissociation is a reversible reaction, and may be represented as
AB ±5 A' + B •. The law of mass action must apply in such a case, and
as a matter of fact it has, been found that a constant can be calculated,
which is known as the dissociation constant.* It is an expression of the
inherent ability of the acid to dissociate into ions, and is therefore the
best measure of the strength of the acid. This is strictly the case for all
of the weaker acids, but strong mineral acids (and bases) do not give
a satisfactory constant, so that the comparison must not be made between
them and weaker ones. That the dissociation constant expresses the rela-
tive strength of organic acids can be shown by comparing its value with
that of the rate at which cane sugar is inverted (see page 23), this being
proportional to the concentration of the H ions present. K for some or-
ganic acids is: Acetic, 0.000018; Formic, 0.000214; Benzoic, 0.00006; Sal-
icylic, 0.00102.

a2
*The equation is -j- — r-rr- := K, where it is supposed that in volume V of the solution there is

1 gram-equivalent of electrolyte, and that the degree of dissociation is a; the quantity of undis-
sociated electrolyte stated in a fraction of a gram-equivalent will be 1-a, and the quantity of each
ion a. To illustrate, let us take acetic acid in various dilutions:

V a KxlO5

0.994 0.004 1.62

2.02 0.00614 1.88

15.9 0.0166 1.76

18.1 0.0178 1.78

CHAPTER V

THE PRINCIPLES INVOLVED IN THE MEASUREMENT OF THE
HYDROGEN-ION CONCENTRATION (Cont'd)

THE METHODS OF MEASUREMENT

The Electrical Method

In order to understand the principle of the standard method used for
measuring the H-ion concentration, it is necessary that a few words be
said concerning the factors governing the development of electric cur-
rents in chemical batteries. There may be a further application of this
knowledge in connection with the generation of the electric currents
which occurs during physiological activity, as in active glands and muscles.

When a metal is immersed in a solution of one of its salts, it has a
tendency to give off ions into the solution. Similar ions are, however,
already present in this solution, and these, by their osmotic pressure,
tend to oppose the passage of the ions coming from the metal. The
force with w^hich the metal sends out its ions into the solution is called
the electrolytic solution pressure. If this is equal to the osmotic pres-
sure of the metallic ions in the solution, there will be no electric current
generated, but if it is greater or less than the osmotic pressure of the
metallic ion, an electric current will be set up. "When the solution pres-
sure is the greater, the metal will become negatively charged, because its
ions carry positive charges into the solution (cations) ; on the contrary,
when the osmotic pressure is greater than the solution pressure, the metal
will have a positive charge, owing to the receipt of the positive cations
from the solution.

Because of a force called electrostatic attraction, the ions given off
from the metal can not travel any measurable distance from the oppositely
charged mass of metal, so that from one of the electrodes alone it is
impossible for us to lead off any electric current. For this purpose we
must form a circuit. This is done in the manner shown in Fig. 7 by
connecting side tubes coming from the electrode vessels with an inter-
mediate vessel containing a solution of high conductivity and by con-
necting the metals by wires. If the circuit is formed between the
same metals in solutions of the same concentration, no electric cur-
rent will be generated, because the two electrode potentials will be

29

30

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

equal and in opposite directions to each other. On the other hand, should
the concentration of the metallic ion in the solutions be unequal, the
electromotive force will flow from the one electrode to the other, and
the pressure with which it flows will be equal to the difference in con-
centration of the two solutions. This is the principle of a concentration
cell, and if we know the concentration of one of the solutions composing
it, and then proceed to measure the. electromotive force, we can obtain
the concentrations of the other solution by difference. To do this we
must employ a formula which takes into consideration the relation be-
tween the potential and the concentration of the solution.

The potential of an unknown electrode composed of a metal in con-
tact with a solution of one of its salts may also be determined by making
it one pole of a battery of which the other pole is composed of a stand-
ard electrode of unchanging known potential. An electrode of the latter

Fig. 7. — Diagram to show type of electrodes used in studying electromotive force. The
metal in each electrode is connected (through a glass tube) with a platinum wire, to which
the apparatus for measurement of the voltage is connected. The metal dips into a solution
contained in the electrode vessel and filling the side tube. The latter dips into an inter-
mediate vessel containing saturated KC1 solution. The currents flow through the circuit under
the following conditions: (1) dissimilar metals dipping into the same fluid; (2) similar metals
dipping into different fluids; (3) dissimilar metals dipping into different fluids.

type can most readily be made by bringing pure mercury in contact
with a -saturated solution of calomel (Hg2Cl2) in normal potassium chlo-
ride solution (Fig. 8). Under suitable conditions (i. e., when the circuit is
completed), a potential of .0560 v. is developed in this so-called calomel
electrode* — that is, positive ions of mercury are deposited on the mercury
from the calomel solution at this pressure. Suppose that we connect a
calomel electrode, through the intermediation of some solution which

*The calomel electrode consists of a suitably shaped glass vessel containing pure mercury, con-
nected by means of a platinum wire with a conductor, and filled with a saturated solution of pure
mercurous chloride in normal KC1 solution up to such a level that it also fills a side tube connected
with a vessel containing a saturated solution of potassium chloride. Into this vessel also runs a
similar side tube from the unknown electrode. By having an excess of midissolved calomel in the
solution in the calomel electrode its saturated condition is maintained during the chemical changes
which accompany the production of the electric current.

HYDROGEN-ION CONCENTRATION

31

will serve as a good conductor, with another electrode, the two elec-
trodes being also connected by wires with electrical apparatus for
measuring the total potential of the battery; then by adding +0.560 v.
to or subtracting this value from the total potential (depending on the
sign of the unknown electrode) we can tell the potential of the unknown
electrode.

We have discussed these principles of electrochemistry because they
form the basis upon which depends the standard method for the deter-
mination of the H-ion concentration of fluids. Suppose, for example,
that in place of using a metal in the construction of one electrode, we
use an electrode consisting of a layer of pure hydrogen gas in contact
with a solution in which are free H ions; then the rate at which H ions

CapVVf&vy .. „_.— I

5C«v3e - —

, --(-Jh)-- /

AMMwlqkpr

Fig. 8. — Diagram of apparatus for the measurement of the H-ion concentration. The cur-
rent generated in the battery (composed of calomel electrode, connecting vessel with KC1 solu-
tion, and the H electrode) or that from the normal element is transmitted through a reversing
key to the bridge wire, where the voltage is compared with a steady current flowing through the
bridge wire from an accumulator. The capillary electrometer is used to detect the flow of
current at various positions of the movable contact on the bridge wire. (Modified from
Sorensen.)

become added to the solution from the H layer, or taken from it, will de-
pend on the concentration of H ions in solution. In order to secure a
hydrogen electrode fulfilling the above requirements, it is necessary to
employ some means by which a layer of hydrogen may be furnished, and
fortunately this can be done by taking advantage of the property which
spongy platinum possesses of absorbing large quantities of this gas. It
is also necessary to keep an atmosphere of pure H in contact with the
fluid.

As is the case of the simpler cells described above, there are two
types which we might use for measuring the electromotive force gen-
erated in the unknown electrode: a concentration cell composed of two

32 PHYSICOCIIEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

hydrogen electrodes, of which, one contains a solution of "known H-ion
concentration, and the other the solution in which this is unknown;
and a cell of which one electrode is a standard calomel electrode and
the other, a hydrogen electrode containing the unknown solution.

The exact arrangement of the apparatus in which the calomel elec-
trode is used will be seen in the accompanying sketch. The hydrogen
electrode, it will be noticed, is a very small V-shaped tube, in which is
suspended a platinum wire coated with spongy platinum and dipping
into a solution which nearly fills the tube. The space above the solution
is filled with pure hydrogen. This and the calomel electrode are con-
nected with suitable electric measuring instruments, and the circuit is
completed by connecting the two electrodes by means of an intermediate
vessel containing a saturated solution of potassium chloride. This con-
necting solution is used because it has been found that the electric cur-
rents set up, at the contact between different solutions are so small that
they can be disregarded.*

As outlined above, the hydrogen electrode is that which is used to
determine the H-ion concentration of blood, the particular point about
it, in comparison with the apparatus used for simpler solutions, being
that the hydrogen is not changed in the course of the experiment. This
precaution is to prevent the carbon dioxide of the blood from being
"washed out" of it by a frequently changing atmosphere of hydrogen.
Many inaccuracies in the earlier results obtained by this method were
due to the removal of carbon dioxide, which, as we shall see later, is
one of the chief acids contributing to the H-ion concentration of blood.

The Indicator Method

As pointed out in a previous chapter (page 22), the method of titra-
tion for acidity or alkalinity in which a standard solution of alkali or
acid is added until a certain change in the color of a suitable indicator
is detected, does not afford any information regarding the H-ion con-
centration actually present in the solution. It tells us the total con-
centration of available acid or base, both dissociated and undissociated.
By modification of the method of procedure, however, we may also use
indicators for determining the H-ion concentration. The principle of
this method depends on the fact that there are certain dyes which
change quite distinctly in tint with very slight changes in the H-ion
concentration, so that if we use dyes which possess this property at a
point near that of neutrality (i. e., between PH6.5 and Pn8), we can es-

*A description of the technic for measuring the electric potential developed by the cell would
be out of place here. Suffice to say that the strength of the current is compared with that of a
current of known strength furnished by a normal cell, the comparison being made by a bridge wire
F, a capillary electrometer II being employed to detect the direction and degree of current.

HYDROGEN-ION CONCENTRATION

33

timate the H-ion concentration of the body fluids with very remarkable
accuracy, provided certain precautions are taken to circumvent the
disturbing influence which the protein and salts in these fluids may have
on the color change.

To understand this use of indicators, it is important to bear in mind
that one solution reacting neutral to one indicator may have a H-ion
concentration which differs very markedly from that of another solu-
tion reacting neutral to another indicator. This is because indicators
react to different H-ion concentrations. A solution that is neutral to
phenolphthalein has a PH of about 9, whereas one neutral to methyl or-
ange has a PH of about 4. This can be very clearly shown by titrating
a solution of phosphoric acid with decinormal alkali. After a certain
amount of alkali has been added it will be noticed that methyl orange
changes from red to yellow, but after it has changed and is therefore
alkaline as judged by this indicator, it still remains distinctly acid to-
wards phenolphthalein (shows no red tint) even though considerably
more alkali is added. The methyl orange is, therefore, itself unrespon-
sive to weak acids such as remain after the greater part of the phos-
phoric acid has been neutralized by the alkali.

The series of indicators which has been employed for this purpose is
given in the accompanying table, along with the PH limits through which
they change in color.

LIST OF INDICATORS

CHEMICAL NAME

COMMON

NAME

CONCEN-
TRATION

COLOR
CHANGE

RANGE
PH

Thymol sulfon phthalein

per cent

(acid range)

Thymol blue

0.04

Red-yellow

1.2-2.8

Tetra bromo phenol sul-

fon phthalein

Brom phenol

blue

0.04

Yellow-blue

3.0-4.6

Ortho carboxy benzene

azo di methyl

aniline

Methyl red

0.02

Red-yellow

4.4-6.0

Ortho carboxy benzene

azo di propyl

aniline

Propyl red

0.02

Red-yellow

4.8-6.4

Di bromo ortho cresol

sulfon phthalein

Brom cresol

purple

0.04

Yellow-

purple

5.2-6.8

Di bromo thymol sulfon

Brom thymol

phthalein

blue

0.04

Yellow-blue

6.0-7.6

Phenol sulfon phthalein

Phenol red

0.02

Yellow-red

6.8-8.4

Ortho cresol sulfon

phthalein

Cresol red

0.02

Yellow-red

7.2-8.8

Thymol sulfon phthalein

Thymol blue

0.04

Yellow-red

8.0-9.6

(see above)

Ortho cresol phthalein

Cresol

phthalein

0.02

Colorless-red

8.2-9.8

These dyes may now be obtained in this country.

(W. M. Clark and H. A. Lul»s.)»

34 PHYSICOOIIKMICAL BASIS OF PHYSIOLOGICAL PROCESSES

Briefly stated the method for measuring the H-ion concentration con-
sists in preparing a series of solutions containing known concentrations
of H-ion — that is to say, of known PH — and adding to each solution an
equal amount of an indicator which exhibits easily distinguishable
changes in tint at H-ion concentrations approximating those believed
to be present in the unknown solution. The same indicator is added to
the unknown solution, which is then placed side by side with the stand-
ards to find with which of them it most closely matches. The series
of solutions of known H-ion concentration is prepared by mixing fif-
teenth normal solutions of Na2IIP04 and KTT2P04 in varying propor-
tions as given in the following table:

PREPARATION of STANDARD SOLUTIONS
The solutions are mixed in the proportions indicated be-low to obtain the desired PH:*

PH 6.4 6.6 6.8 7.0 7.1 7.2 7.3 7.4 7.5 .7.6 7.7 7.8 8.0 8.2 8.4

I'rimary Potas. 73 63 51 37 32 27 23 19 15.8 13.2 11 8.8 5.6 3.2 2.0

Phos., c.c.
Secondary Sodium 27 37 49 63 68 73 77 81 84.2 86.8 89 91.2 94.4 96.8 98.0

Phos., c.c.

(From Levy, Rowntree and Marriott.)

*Standard phosphate mixtures are prepared according to Sorensen's directions as follows:
1/15 mol. acid or primary potassium phosphate. — 9.078 grams of the pure recrystallized salt
(KH2PO4) are dissolved in freshly distilled water and made up to 1 liter.

1/15 mol. alkaline or secondary sodium phosphate. — The pure recrystallized salt (NaslIPO,!. 12H2O)
is exposed to the air for from ten days to two weeks, protected from dust. Ten molecules of water
of crystallization are given off and a salt of the formulai Na2HPO4.2H2O is obtained; 11.876 grains
of this are dissolved in freshly distilled water and made up to 1 liter. The solution should give a
deep rose red color with phenolphthalein. If only a faint pink color is obtained, the salt is not
sufficiently pure.

The indicator method is extremely accurate when used with pure
solutions of acids, but, as mentioned above, it is apt to be inaccurate, at
least with most indicators, when protein or inorganic salts are pres-
ent in the solution, and of course it is quite unusable with colored
fluids such as blood. In order to overcome these difficulties, the
dialysis method has recently been evolved. It consists in placing the
fluid — blood, for example — in a dialyser sac composed of celloidin and
about as large as a small test tube. The sac is placed in a wider test
tube of hard glass containing an isotonic solution of sodium chloride
that has been carefully tested to ascertain that it is strictly neutral.
The amount of blood or serum required for this method is only 2 or
3 c.c., and the amount of salt solution placed outside the sac should be
about the same. It takes only from five to ten minutes for dialysis to
occur. The celloidin sac is then removed, a few drops of the indicator
are thoroughly mixed with the dialysate, and the tube compared with
the series of standards until the corresponding tint is matched. This
indicates the H-ion concentration in the dialysate. The tints produced
by using sulphonephenolphthalein are reproduced as nearly as possible

PH7-o PH7-/

10

PH7-5 PH7-6

PH6-o

Fig. 9. — Chart showing approximately the tints produced by adding sulphophenolphthalein to a series
of phosphate solutions of the H-ion concentrations indicated in each case by PH.

HYDROGEN-ION CONCENTRATION

35

in the accompanying chart. The H-ion concentration of the unknown
solution is that of the tint with which it matches in the series.

It might be thought that this method would be inaccurate because of
the loss of carbon dioxide from the blood. By actual experiment, how-
ever, it has been found that, if the blood is collected with certain pre-
cautions, the error is negligible. The method is, therefore, a most useful
one clinically.

The following table gives the hydrogen-ion concentration or true
reaction of the body fluids.

FLUID

PH

FLUID

PH

Blood 7.4

Urine (5.0

Saliva 6.9

Gastric juice (adult) 0.9-1.6

Gastric juice (infant) 5.0

Pancreatic juice (dog) 8.3

Small intestinal contents 8.3
Small intestinal contents (infant) 3.1

Bile from liver 7.8

Bile from gall bladder 5.3-7.4

Perspiration 7.1

Perspiration 4.5

Tears 7.2

Muscle juice (fresh) 6.8

Muscle juice (autolyzed) Variable

Pancreas extract 5.6

Peritoneal fluid 7.4

Pericardial fluid 7.4

Aqueous humor 7.1

Vitreous humor 7.0

Cerebrospinal fluid (fresh) 7.4
Cerebrospinal fluid (after standing) 8.3

Amniotic fluid 7.1

Amniotic fluid 8.1

Milk (human) 7*0-7.2

Milk (cow) 6.6-6.8

Milk (goat) 6.6

Milk (ass) 7.6

(W. M. Clark and H. A. Lubs.)

CHAPTER VI

THE REGULATION OF NEUTRALITY IN THE ANIMAL BODY

AND ACIDOSIS

Nothing is more constant in the animal economy than the H-ion con-
centration (CH) of the fluids which bathe the tissues. This regulation
is fundamentally of a physicochemical nature, depending on the inter-
action of alkalies with acids, of which carbonic and phosphoric acids
are the most important.* When different amounts of acids or al-
kalies are added to water, the range of variation in H ion is
very extensive, whereas in blood the range is very limited indeed, not
extending beyond PH7 and PH7.52 (i. e., CH never goes above that of a
0.000,000,1 N solution or below that of a 0.000,000,03 N solution). In
• other words blood can withstand considerable additions of acid or al-
kali without much change.

Buffer Substances. — The chemical reactions upon which this remark-
able constancy in reaction depends have been explained by Lawrence
J. Henderson.10 The fundamental equations are as follows:

M ,HPO4 + HA = MII2PO4 -f MA, and
MHCCX + HA z= H2C03 + MA,

when M — a basic radicle, and A, an acid radicle.

Now it has been discovered that weak acids, like carbonic and phos-
phoric, possess the remarkable property of maintaining the reaction
constant when they are present in a solution which also contains an
excess of their salts. Under these circumstances the concentration of
ionized hydrogen is almost exactly equal to the product of the dissocia-
tion constant! of the acid (see page 1.9) multiplied by the ratio be-
tween free acid and salt; in other words,

If carbonic acid is present in a solution of bicarbonates so that there

*Under certain circumstances, proteins may also act either as acids or as alkalies. They are
therefore called amphoteric. The neutralizing properties of proteins are, however, of little conse-
quence in the neutrality regulation in the animal body (Bayliss20).

tThe dissociation constant has already been referred to as a figure which expresses the tendency
of a weak acid or base to dissociate in an aqueous solution. "It expresses the proportion in which
the nondissociated part is capable of existing in the presence of its ions," and therefore is a gauge
of the strength. The dissociation constant amounts to about 0.000,000,5 for carbonic acid ; that is,
the dissociation of HoCOs into H' + ITCO?/ at room temperature will be such that the concentra-
tion of H-ion equals a 0.000,000,5 N solution.

36

ACIDOSIS 37

are equivalent quantities of free H2C03 and bicarbonate — i. e., : A1 =—

L-BAJ 1

—the H-ion concentration will be exactly the same as the dissociation
constant of carbonic acid; therefore 0.000,000,5 N (PH = 6.31), or about
five times the value of neutrality, 0.000,000,1 N (PH = 7.31). If ten
times as much free carbonic acid as bicarbonate is present, then the H-ion

concentration will be fifty times that of neutrality, i. e., rp . • =^r-

L-bAj . i

x 0.000,000,5 = 0.000,005 (PH = 5.31) ; if there is ten times less carbonic
acid than bicarbonate, the H-ion concentration will be one-half that of

neutrality, i. e., -lT"- TX 0.000,000,5 = 0.000,000,05) (PH = 7.31) • or

if twenty times less, one fourth (PH = 7.6). Since a large amount of
bicarbonate is actually present in blood (enough to yield from 50 to 65 c.c.
C02 per 100 c.c. of blood), and the free carbonic acid undergoes fluctua-
tions which are only trivial when compared with those which have been
chosen in the above examples, it is clear that there must be very little
change in the H-ion concentration of the blood in comparison with the
variations which would occur were no bicarbonate present.

Another weak acid which acts like carbonic in maintaining neutral-
ity is acid phosphate (MH2P04), and for the same reason — namely, that
its dissociation constant is of similar magnitude to the H-ion concen-
tration. Although the blood plasma itself contains much less phosphate
than bicarbonate, the tissues contain a considerable amount, which en-
ables them to maintain their neutrality. This action of bicarbonates and *
phosphates is styled the buffer action, meaning that it serves to damp \
down the effect on the H-ion concentration which additions of acids or
alkalies would otherwise have. As pointed out by Bayliss, however, a
better word to use would be "tampon action," since the substances
actually soak up much of the added H- or OH' ions. It is not confined
to the fluids of the higher animals, but is very widely distributed
throughout nature ; for example, in the ocean and in the fluids of marine
organisms and animalcules (see L. J. Henderson).11

Although the actual reaction by which neutrality is maintained is
purely of a physicochemical nature, some provision must obviously be
made so that the acid and basic substances that take part in it may be
supplied and those produced by the reactions removed as occasion re-
quires. The source of supply is partly exogenous and partly endogenous.
The exogenous source is the basic and acid substances present in the
food; and although we do not ordinarily attempt to control the amounts
of these substances ingested, we may do so, as, for example, by the
persistent administration of soda in cases of pathological acidosis. The
endogenous source depends on the constant production in metabolism

38 PHYSICOCHEMICAL BASIS OP PHYSIOLOGICAL PROCESSES

of acids such as carbonic, phosphoric, lactic, and sulphuric, and of
alkalies such as ammonia and fixed alkali, a considerable reserve of which
is undoubtedly available in the animal organism.

The removal is affected by three pathways: (1) through the lungs
gaseous carbonic acid is eliminated; (2) through the kidneys, the fixed
acids; and (3) through the intestines, some of the phosphoric acid.

Carbonic acid is produced in large amounts in the normal process of
metabolism, and is excreted in a gaseous condition by the lungs. Varia-
tion in its excretion is the most important mechanism for controlling
temporary changes in CH. In order to make this clear, it may be well to
revert for a moment to the physicochemical equation by which carbonic
acid is enabled to maintain neutrality. This may be written: CH =

TT QQ

molecular ratio - * T^e rat*° may ^e "lcrease(^ either by adding

free carbonic acid to the blood (as by causing an animal to respire some
of the gas), or by the addition of some other acid (e. g., oxybutyric, as in
diabetes) which will decompose some of the NaHC03 and produce
H2C03. The increase which these changes would cause in CH of the
blood is prevented by the remarkable sensitivity of the respiratory cen-
ter to changes in CH. An increase which is much less than can be
measured by physicochemical means stimulates the center, causing in-
creased pulmonary ventilation, so that the carbonic acid is immediately
eliminated through the lungs. This elimination does not stop when the

old level of carbonic-acid concentration is reached, but proceeds until
TT c*r\

the original ratio TjptA is again attained in the blood, and CH is
JNaJtluUo

restored exactly to its original value. If it stopped at the old C02 con-
centration, the ratio would be too high because there is less NaHC03.

THE THEORY OF ACIDOSIS

Although these considerations indicate that variations may occur in
the bicarbonate content of the blood without any significant change in
CH, they also show that the bicarbonate content must be a criterion of
the acid-base balance of the blood, and probably of the body fluids in
general. As pointed out by Van Slyke,12 bicarbonate represents the ex-
cess of base which is left over after all the fixed acids have been neu-
tralized. It represents the base that is available for the neutralization of
any excess of such acids that may appear — a measure of the reserve of
<( buffer substance" or, more specifically, the alkaline reserve of the body.
Under normal conditions the amount of NaHCO3 in blood plasma is very
constant (amounting to 50-65 vols. per cent C02), and when it is reduced,
it indicates that an excess of fixed acid must be present? This is taken

ACIDOSIS 39

by Van Slyke and others to constitute the real definition of acidosis —
namely, "a condition in which the concentration of bicarbonate in the
blood is reduced below the normal level." If the respiratory center
for any reason should not respond promptly enough to an increase in

TT p/~)

the molecular ratio—,. Vrnrr > an(^ ^H consequently become greater, the
condition is called uncompensated acidosis, but if the center does respond
so that CH is held constant (although NaHC03 is decreased), the condition
is one of compensated acidosis.

For practical reasons, therefore, the study of pathological acidosis de-
pends on an estimation of the bicarbonate content of the blood or, since
it is simpler to carry out and is of equal value, of the plasma. When
plasma is obtained by removing blood from a vein of the arm and cen-
trifuged immediately out of contact with air (so that C02 may not be
lost from it) it contains approximately 60 vols. per cent of C02. Since
we know that the partial pressure of C02 in blood is equal to 42 mm. Hg
(ascertained from determinations of the alveolar C02) (see page 361),
we can calculate how much of the 60 vols. per cent must be in simple
solution by application of the law of solution of gas in a liquid (page
353'). One cubic centimeter of plasma at body temperature and at
760 mm. Hg (atmospheric pressure) dissolves 0.54 c.c. C02, so that at

42

42 mm. it will dissolve T^TTX 100 x 0.54 = 3 vols. per cent. Transcribing

[H2C03] 3 1

the figures to our equation we get -- = — , or — .*

[NaHC03] 60 20
This definition of acidosis leaves out of regard all conditions that may

TT r^ri
raise the ratio -A- V tne addition of H2C03 without decomposing

any of the NaHC03, such, for example, as occurs when an excess of free
carbonic acid is present in the blood plasma. Since increases in free
C02 are not infrequent in both health and disease — e. g., asphyxial con-
ditions — the above definition is not sufficiently comprehensive. When
we come to study the control of the respiratory center, we shall see that

FT C*O

an increase in the ratio -A- °^ sufficient magnitude to cause an

actual increase in CH can be brought about by causing an animal to respire
air containing an excess of CO2 — a true acidosis, but one for which no
place is found in the above definition.

*This agrees sufficiently with the result as calculated from the known values of the equation

'XT 2u/~A~ = — ^~- • Thus, if we take CH as 0.35 x 10-7, \ as 0.605 for blood conditions, and
NaHCUj K

r- 1n 7 ,,,. , .. HoCO3 0.605 x 0.35 x 10-7 1

K as 4.4 xlO-7 (Michaehs and Rona), we get = 4.4 x IQ-T -- = JT

40 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

Nevertheless, Van Slyke's definition has a real value, because it em-
phasizes the importance of a determination of the bicarbonate as a cri-
terion of the degree of the forms of acidosis usually met with in disease.
The bicarbonate under such conditions may become reduced either be-
cause of the appearance of improperly oxidized fatty acids, like /?-oxy-
butyric and acetoacetic, when carbohydrate metabolism is upset as in
diabetes or starvation, or because the acids produced by a normal
metabolism are inadequately eliminated by the kidneys, as in nephritis.

Accordingly, if the respiratory mechanism and increased mass move-
ment of the blood (for an increase in CH accelerates this also) should

TT f^Ci

fail to eliminate C02 quickly enough so as to keep the -n-pr? ratio at
one twentieth, then CH will rise. This is not likely to happen until a
large part of the NaHC03 has been used up, so that an estimation of that
actually present must be a reliable index of the proximity to this
condition.

A sustained increase in CH is incompatible with life. The NaHC03 is
the buffer, the factor of safety which prevents its occurrence. Although
it is only in arterial blood (i. e., after elimination of excess of C02 by

TT r^r\
the lungs has been accomplished) that constancy in the ratio 2 *

.vv'o

can be expected, it is fortunate, for practical reasons, that venous blood

collected during muscular rest and without stasis should be only slightly
different.

When acids are added to the blood, they will first of all be neutralized
by the "buffers" of the plasma — namely, NaHC03 (and protein), as we
have seen. But this is only the first line of defense against acidosis, for
buffer substances present in the corpuscles may also be used. This intra-
corpuscular reserve of base is supplied partly by transference of K
and Na from corpuscle to plasma, but mainly by that of HC1 from the
plasma into the corpuscle, so releasing base in the former to combine
with the added acid (e. g., H2C03), according to the equation:
H2C03 + NaCl *± NaHC03 i- HC1. The HC1 on entering the corpuscle
reacts with phosphates according to the equation: HCl + Na2HP04^
NaH2P04 + NaCl. This is a particularly important, detail of the buffer
action of the blood, not only because it shows us how the phosphates of
the corpuscles (of the blood of species in which much phosphoric acid is
present) are rendered available for neutralizing acids added to the plasma,
where there are practically no phosphates, but also because the transference
of acid must go on with the other cells of the body, so that the plasma,
itself rather poor in buffer substances, has all those of the body at its
disposal.

ACIDOSIS 41

THE MEASUREMENT OF THE RESERVE ALKALINITY OF THE

BODY FLUIDS

Titration Methods

There are several methods by which the reserve alkalinity of the blood
may be measured. The simplest in theory consists in seeing how much
standard acid must be added to a measured quantity of blood plasma in
order to reach the neutral point as judged by change in tint of some
indicator. The indicators employed (e. g., methyl orange) are such as
change their tints at H-ion concentrations that are well to the acid side
of neutrality (i. e., at a high CH or low PH). To bring the plasma to this
point of neutrality the added acid will need to neutralize, not only the
bicarbonate of the plasma, but other acid-binding substances as well.
This will give us a false impression of the acid-binding powers Of the
plasma, since, at the normal CH of the blood, proteins do not absorb acids
to anything like the extent they do at higher degrees of CH. Another
objection to the method is that the proteins interfere with the sensitive-
ness of the indicators.

The objections can be removed by determining the end point electro-
metrically or by indicators that change tint at about PH7. The most
practical way is to determine the change in CH produced by adding a
known volume of standard acid to blood plasma. The resulting change
in CH will then be greater the less the alkaline reserve. In the electro-
metric method irregularities that might be caused by variable amounts
of carbonic acid in the blood to start with are best controlled by removing
the C02 from the plasma after adding the standard acid. The procedure
therefore consists in mixing 1 c.c. plasma with 2 c.c. N/50 HC1 in a small
separating funnel, wrhich is then evacuated so as to remove the C02,
after which the fluid is transferred to a hydrogen electrode and CH
measured (see page 29). In normal blood this should be 10 5-6 (PH5.6).
In acidosis, where there is a depleted alkaline reserve, the 2 c.c. of acid
will cause a much greater change in CH — in diabetic blood to below 5
or lower.

The technic involved in the above method is, however, too exacting for
routine clinical work. For such purposes the colorimetric method of Levy
and Kowntree may be employed.

The Method of Levy and Rowntree.is — A test tube made of hard ("nonsoT') glass
of about 20 c.c. capacity, containing about a gram of powdered neutral potassium oxa-
late, is filled with newly drawn blood, immediately stoppered and placed on ice. Quan-
tities of 2 c.c. each of the blood are then placed in a series of seven small (nonsol) test
tubes and allowed to stand for five to six minutes in order to permit a narrow layer
of plasma to separate on the surface (this prevents laking of the blood during the sub-

42 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

sequent addition of acid or alkali). The blood in the first tube is used for the de-
termination of the normal H-ion. In each of the next three tubes are added respec-
tively 0.1, 0.2 and 0.3 c.c. N/50 HC1, and to the last three, similar quantities of N/50
NaOH. After inverting the tubes so as to mix the contents, the blood in each is trans-
ferred to celloidin sacs and the CH determined according to the method described else-
where (page 32).

The tubes are noted in which a change in tint from that of the normal blood is
evident, and the results are expressed as the c.c. of N/50 HC1 or NaOH which must
be added to blood to change its OH. Thus, the alkali buffer is the c.c, of N/50 NaOH
which can be added to 2 c.c. of blood without change of CR of the dialysate, and
the acid buffer the c.c. of N/50 HC1.

The method suffers from the following drawbacks:

1. Very small quantities of acid and alkali are employed.

2. It is often difficult to tell just exactly when a slight difference in tint has been
produced.

3. Even with the precautions described above, it is impossible to be sure that the
amount of OX) in the different samples of blood is the same, which means, of course,
that some bloods will, on this account alone, be able to bind more alkali than others.

The Method of Van Slyke. — A method based on somewhat the same principle, but
which is more accurate because it meets the above objections, is that suggested by Van
Slyke, Stillman and Cullen.14 Plasma is freed of CO2 by placing it in a vacuum,
and is then mixed with an equal volume of N/50 HC1 (or NaOH) and the CH deter-
mined by the electric method (see page 29). In the case of normal blood, after such
an addition of acid, a practically normal CH will be found, whereas in the blood of
cases of acidosis it will be very distinctly increased (i.e., PH lower).

C02-combining Power

The above objections to the titration of blood plasma or dialysate
with standard solutions of acids are removed if we measure the com-
bining power of the blood alkali towards carbonic acid itself at normal
blood reaction. This may be done either in blood immediately after its
removal from the animal or in blood that has been first of all saturated
outside the body with- carbonic acid at a partial pressure equal to that
existing in the body. Since for practical reasons venous blood must be
used — in the clinic at least — the former of these methods suffers from
the fault that varying amounts of carbonic acid^will be added to the
blood during its passage through the tissues, and the error thereby
incurred will become greatly aggravated if venous stasis has been pro-
duced in drawing the specimen for analysis. But the chief reason why
this method has not been extensively employed, as pointed out by Van
Slyke, is the technical difficulty of making the necessary analysis.

It is most satisfactory to collect venous blood after a period (one hour at least)
of muscular rest (so that there is no excess of CO ) and without venous stasis, and
to centrifuge without permitting any considerable loss of carbonic acid. The latter
precaution is necessary because there is a migration of acid radicles, e. g., HC1, from
plasma into corpuscles when the CO,, of the former is increased, and in the reverse

ACIDOSIS

43

direction when the CO is decreased. If the COo in the blood were not the same dur-
ing centrifuging as it is in the body, the separate plasma would not contain the same
amount of alkali — i. e., its reserve alkalinity would be altered. Although theoretically,
therefore, centrifuging should be performed in an atmosphere containing the same
partial pressure of COs as exists in the body (i. e., the alveolar air) (see page 361),
this has been found impracticable for general use, and is unnecessary if loss of CO,
from the specimen of blood is prevented by allowing it to flow into the syringe very
slowly (without any suction). It is mixed in the syringe with powdered (neutral)
potassium oxalate (enough to make a 1 per cent solution with the blood), and imme-
diately delivered into a centrifuge tube under paraffin oil, which by floating on its
surface serves. to diminish free diffusion of CO2 to> the 'outside air (even though such
oils dissolve more CO than water). To mix the blood with the oxalate, the syringe
should be moved backward and forward several times, but it must not be shaken.

After centrifuging, ab'out 3 c.c. of plasma are removed and saturated with CO at
the same tension as in alveolar air (i. e., 5.5 per cent). This is done by placing the
plasma in a separating funnel of 300 c.c. capacity, laying the funnel on its side and
displacing the air in it by alveolar air secured by quickly making as deep an inspira-

Fig. 10. — Diagram of apparatus for saturating blood or plasma with expired air. The glass
beads in the bottle condense excess of moisture. The separating funnel, as soon as it has been
filled with expired air, should be closed by a stopper and the stopcock turned off. It is then
rotated so that the blood forms a film on its walls.

tion as possible through the tube and bottle containing glass beads (Big. 10). The
glass beads remove excess of water vapor from the air. The funnel must be restop-
percd before the end of the expiration, so that no outside air enters. It is then ro-
tated, for about two minutes, in such a way that the plasma forms a film on its walls.
If it is necessary to postpone the saturating of the plasma, this should me pipetted off
from the corpuscles and preserved in hard glass test tubes coated with paraffin. From
ordinary glass enough alkali is soon dissolved out to vitiate the results. After satura-
tion of the plasma with C02, the funnel is placed in the upright position and the
plasma allowed to collect in the narrow portion, after which 1 c.c. is removed with
an accurate pipette and analyzed for CO,.

The analysis may be done by using either the Van Slyke or the ITaldanc-Barcroft
apparatus. The Van Slylcc method is as follows:

The apparatus is filled to the top of the graduated tube with mercury (Fig. 11)
by raising the mercury reservoir F, care being taken that D and E are also filled.
One c.c. of the CO -saturated plasma is then delivered into A (which has been rinsed
out with CO -free ammonia water), and the stopcock I turned so that by cautiously
lowering the level of the reservoir F, the plasma runs into E (but no trace of air).

44

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

The same procedure is repeated with 1 c.c. water, so as to wash in all of the plasma,
and finally 0.5 c.c. of 5 per cent H SO is sucked in, after which stopcock I is turned
off. The reservoir F is then lowered sufficiently to allow all of the mercury, but none
of the blood, to run out of B and C. A vacuum is thus produced in B and C.

As the level of the mercury falls in B and C, the plasma effervesces violently,* be-
cause it is exposed to a vacuum. To be certain that all traces of CO have been
dislodged from the solution, the apparatus is inverted several times. To ascertain how
much CO has been liberated, stopcock II is now turned so as to bring C and E into
communication, and by cautiously lowering the reservoir the fluid in C is allowed to
rim into the bulb E. Stopcock II is thereafter turned so as to connect C and D, and
the reservoir raised so that the mercury runs into C as far as the CO2 that has col-

Fig. 11. — Van Slyke's apparatus for measuring the CO2-combining power of blood in blood plasma.
For description, see context.

lected in the burette will permit it to go. After bringing the level of the mercury
in F to correspond to that in the burette, the graduation at which this stands is read.
It gives the c.c. of CO liberated from the plasma. Under the above conditions normal
plasma binds about 75 per cent of its volume of COo; therefore, since the total capacity
of the pipette is 50 c.c., the mercury should stand at 0.375 e.c. on the burette. For
accurate measurement it is necessary to allow for the CO9 that remains dissolved in
the water, etc., as well as for barometric pressure and temperature. This is best done
by the use of a table based on the known solubility of CO2 under the various condi-
tions obtaining, which is given in Van Slyke 's paper.12

The Haldane-Barcroft apparatus that is most suitable for the above analysis is

'This may be prevented by adding a small drop of caprylic alcohol.

ACIDOSIS 45

shown in Fig. 136, page 395." One c.c. of CCX-free ammonia water is placed in the
bottle and the 1 c.c. of plasma delivered beneath it. The bottle is then connected
with the manometer with the precautions described elsewhere in this volume. When
temperature conditions have been allowed for, saturated tartaric acid is mixed with
the plasma solution and the gas evolved measured by the displacement of the fluid
in the manometer. The apparatus may also be used with blood in place of plasma.
In this case, however, it is necessary that the oxygen be removed before adding the
tartaric acid. This precaution is necessary, since acid can dislodge some of the H, from
hemoglobin. The blood is therefore first of all laked with ammonia containing some
saponin, then shaken with 0.25 c.c. saturated potassium ferricyanide solution, and
finally with the saturated acid solution. If blood is used, the estimations must be
made on strictly fresh blood, since on standing the CO2 combining power greatly de-
teriorates.

From what has been said in the introductory part of this chapter it is
clear that the plasma furnishes only the first line of defense of the body
against excess of acid; the corpuscles form the second line of defense, so
that a truer estimate of the * ' reserve alkalinity ' ' is afforded when the C02-
combining power of whole blood rather than that of plasma is used. The
reason why Van Slyke recommends the latter is because the estimations
are much easier, there being no hemoglobin to complicate the process, and
there can be no doubt that his method has been of immense value in the
elucidation of the acidosis problem, and that for the majority of diagnos-
tic purposes it is perfectly satisfactory. For further advancement of
knowledge it is advisable, however, to use the whole blood as has been
done by Christiansen, Haldane and Douglas,22 and by Morawitz and
Walker,23 and more recently by Haggard and Henderson21.

Another question remains to be considered, namely, whether arterial or
venous blood should l>e employed. For various reasons arterial blood is
preferable. In the first place the percentage of C02 actually present in it
is proportionate to the alkaline reserve, because the respiratory center is
so sensitive to the slightest excess of this acid (see page 353) that it stimu-
lates respiration so as to remove the excess and thus maintain the C02 of
the arterial blood at exactly the point which corresponds to its alkaline
reserve. It is, therefore, unnecessary to expose the blood to an atmosphere

*This form of Haldane-Barcroft apparatus is not quite the same as the differential manometer
that is used for measurement of the Oa-combining power of hemoglobin (page 395). In the form
used for the present purpose, a side tube at the bend of the U-tube is connected with a small rub-
ber bag, which can be compressed by a screw. When the gas is evolved in the bottle, it presses
down the fluid in the proximal limb of the manometer correspondingly and raises that in the distal
limb. Since the calculation of the amount of gas evolved depends on finding the pressure produced
without any change in volume, it is necessary after the gas has been evolved to compress the rubber
bag until the meniscus of fluid in the proximal limb of the manometer is brought back to its original
level. The height at which the fluid stands in the distal limb then obviously corresponds to the
pressure created by the evolved gas.

The equation for determining the amount of gas evolved depends on the gas law, which states
that the pressure of a gas is inversely proportional to its volume (page 353). Suppose that the
volume of gas evolved was equal to the volume of the bottle, then, since the volume has been
kept constant, the pressure would be doubled — that is, the fluid in the distal limb would equal that
of 1 atmosphere, or 10,400 mm. of water or 10,000 of clove oil, which is the fluid actually used to
fill the manometer. Any other observed pressure would therefore correspond to the volume of
evolved gas according to the equation,

... vol. of bottle (and tubing to meniscus)

V = nnn :- — ^ — X mm. Pressure m Manometer.

10,000 (when clove oil is used)

In using the apparatus in the above manner, only one of the bottles is employed, and the tartaric
acid is added from a pocket in the stopper by a simple manipulation.

46 PHYSICOCHIvMICAL BASTS OF PHYSIOLOGICAL PROCESSES

containing C02 before measuring the C02 content. In the second place,
the arterial blood represents the mixed blood of the body, and not that of
one locality only, as is the case with blood removed from a peripheral vein.
If venous blood is collected with the precaution that the muscles in the
corresponding area have been at rest for some time it appears that there is
practically no difference between the alkaline reserve of arterial and ve-
nous blood; but if there has been any muscular contraction, the venous
blood will have a lower reserve than the arterial, because of the lactic acid
thrown into it by the active muscles. But even when we take the precau-
tion of avoiding muscular action it is probable that there is not a strict
parallelism between the buffer action of arterial and venous blood, as in
cases in which the demands on the alkaline reserves are such that those of
the tissues are being called on as well as those of the blood itself.

Even when the whole Wood is used, however, we do not necessarily
measure the total reserve of the body, a final reserve being afforded by the
alkalies and possibly .certain of the proteins of the tissue cells. Now it is
clear that there can be no test tube method by which measurement of the
magnitude of all of these defensive agencies is possible ; and we are there-
fore compelled to supplement them by certain indirect methods.

Indirect Methods

The chief criticism against the use of the C02 carrying power of blood
or blood plasma, is therefore, that it tells little if anything concerning the
acid-absorbing powers of the tissues. Is there not, therefore, some test of
the acid buffer which can be applied to the intact animal 1 One such is the
percentage of C02 in alveolar air (see page 361).

1. Determination of the Tension of C02 in Alveolar Air. — Since this
method is employed more particularly in investigating the hormone con-
trol of the respiratory center, we shall defer a description of it until later
(page 361). For the present, however, it should be remarked that the alve-
olar C02 can be a precise gauge of the acid-base equilibrium only provided
that the respiratory center is perfectly normal, and that there is no in-
terference with the diffusion of C02 from the blood into the alveolar air.
In order to place an estimate on the "relative value of this method com-
parisons have been made between the C02 tension of the alveolar air and
the C02 absorbing power of the blood. This has been done both in nor-
mal and pathological subjects. In normal subjects the comparisons have
been made under conditions, such as the taking of food and during mus-
cular exercise, in which slight alterations in the acid-base equilibrium are
known to occur. Van Slyke, Stillman and Cullen9b found that the ratio

— plasma C°2 varies from 1.27 to 1.80 in different resting individu-

mm. alveolar C02

als, there being apparently a characteristic ratio for each individual, and

ACIDOSIS 47

that the taking of food invariably raises the alveolar C02-combining power.
This would seem to indicate that it must be the excitability of the respi-
ratory center rather than the acid-base equilibrium that becomes altered
so as to cause variations in alveolar C02.

Technical difficulties have also to be overcome in the collecting of the
alveolar air, for it is now well established that the original method of Hal-
dane and Priestley is approximately accurate only when it is carried out
under strictly controlled conditions — so strict that they can not be prac-
tised in the clinic — and even then, as R. G. Pearce, Carter, Krogh, Sie-
beck and others have shown, we can not be certain of the results. At best,
therefore, the alveolar C02 can serve as an accurate index of the acid-base
equilibrium of the blood only under strictly controlled conditions.

2. The Measurement of the Acid Excretion by the Kidney. — As might
be expected, the acid-base equilibrium of the body may also be gauged by
measurement of the acid excretion of the urine, in which the acids are
contained partly in combination with ammonia or a fixed base, and partly
in a free state. We shall first of all consider the methods of acid
excretion and then examine the evidence showing that the total acid
excretion is proportional to the alkaline reserve as measured by the
above described methods.

EXCRETION OF ACID IN COMBINATION WITH AMMONIA. — The production
of ammonia is essentially an endogenous process, and when excessive
quantities of acid make their appearance in the organism, the fixed alkali
may not be sufficient to neutralize it all, so that ammonia, derived from
the breakdown of amino acids (page 650), instead of being converted
into urea is employed to neutralize the excess of acid. Most workers
have in this way explained the very large ammonia excretion that has
long been known to occur in such conditions as diabetic acidosis. Some
recent workers are, however, inclined to question the significance of
ammonia in this connection, believing that the increased ammonia ex-
cretion is, like the acetone bodies themselves, a product of perverted
metabolism. Be this as it may, it is no doubt true that ammonia is used
for neutralizing acid in disease, although it may not be an important
factor in the maintenance of neutrality under normal conditions. It is
a factor of safety, in that it helps to care for an increase in acid when
the normal mechanism of the body is overtaxed.

EXCRETION OF PHOSPHATES. — The more permanent control of neutrality
depends on the excretion of phosphates by the kidney. The principle
governing this process is exactly the same as that already discussed in
connection with carbonic acid. In the one case it is the volatile acid
C02, and in the other, the fixed phosphoric acid that is concerned in the
reaction. The ratio between the acid salts of phosphoric acid, MH2P04,

48 PHYSICOCHIvMICAL BASIS OF PHYSIOLOGICAL PROCESSES

and the alkaline salts, M2HP04, in blood is approximately 1 to 5, but in
the urine this ratio varies according to the amount of H ion that must
be eliminated from the blood. In other words, a definite amount of phos-
phoric acid is enabled to carry variable amounts of H ion out of the body
by causing the amount of alkali excreted in combination with it to be-
come altered. For example, in the form of MH2P04 a given amount of
P04 obviously carries out more H ion than wrhen it is excreted as
M2HP04. The adjustment between these two salts is a function of the
kidney. We may accordingly measure the amount of alkali retained by
the organism by finding how much standardized alkali must be added
to a given quantity of urine until the reaction of the blood is obtained.
Since the latter value is constant, the titration can be done simply by
titrating the urine with an indicator such as sulphonephenolphthalein,
which changes tint at about PH of blood.

A more serviceable indicator to use, however, is phenolphtkalein, be-
cause its end point is such that when human urine just reacts neutral
to it — that is, when the titrable acid approaches zero — the C02-absorb-
ing power of the plasma is at its maximum of 80 vols. per cent and the
ammonia excretion by the urine is zero (Van Slyke). It is advantageous,
therefore, to use this indicator, because it happens to have its turning
point situated for a reaction which is well to the alkaline side of neu-
trality, and which is reached in urine when the blood is at its maximal
acid-combining power and no ammonia is being used for neutralization
purposes. As the C02-combining power of the blood decreases, there
should, therefore, be a proportionate increase in ammonia and in the
titrable acidity of the urine.

3. Determination of Alkali Retention. — Another valuable criterion of
the alkaline reserve is the amount of alkali required to change the re-
action of the urine. In health the CH of the urine varies from
0.000,016 N (PH = 4.8) to about 0.000,000,035 N (PH = 7.46) with a mean
of about 0.000,001 N (PH = 6). These extremes are rarely overstepped
in disease, but frequently the average is considerably different. In car-
dio-renal disease, for example, the mean acidity may be approximately
0.000,005 N (PH = 5.3), or five times the normal value. A certain de-
gree of acidosis is therefore common enough in this condition — a fact
which has indicated the advisability of administering sodium bicarbon-
ate. It has been found that 5 grams or less of soda, given by mouth to
a normal person, causes a distinct diminution in the CH of the urine,
whereas in pathologic cases it may be necessary to give more than 100
grams before a similar effect is observed (L. J. Henderson and Palmer15
and Sellards16).

This test has been found of particular value in the diagnosis of acidosis

ACIDOSIS 49

accompanying certain forms of renal disease (chronic interstitial nephri-
tis), which raises the question as to whether the retention may not be
due to faulty elimination of the bicarbonate rather than to its retention in
order that a deficient alkaline reserve may be corrected. It has not been a
very simple matter to entirely disprove this possible explanation, and ex-
periments of a variety of types have had to be devised in connection with
the problem. One of them consists in determining the effect of a second
dose of bicarbonate administered to an acidosis patient to whom a suffi-
cient amount had previously been given to render the urine just alkaline.
It has been found that a few grams now suffice, indicating, apparently,
that the alkaline reserve must have been restored to its normal level.
Even to this experiment the objection can be raised, however, that the
large doses 'were retained because the threshold of the kidney for the ex-
cretion of bicarbonate was a very high one, and that the second, smaller
administration just sufficed to overstep this threshold.

Sellards' careful work with this method seems quite clearly to establish
its value, however, and for practical purposes it is probably the most prac-
ticable test of acidosis at present available in routine clinical work. It
has the important advantage, furthermore, of being simple and of requir-
ing no elaborate apparatus.

It may be advantageous in this place to classify the possible causes
which might lead to a want of stability in the CH of the blood; that is,
to threatened acidosis or alkalosis, not of acidosis in the narrow sense im-
plied in Van Slyke's definition, but in the broader sense of any disturb-
ance in the acid-base equilibrium.

In general, a tendency to acidosis might be due to an increase in the
numerator or decrease in the denominator of the molecular equation
TT .r<(\ -i

= — , or to a proportionate decrease in both. In the latter

XT T-T

J\aH(JO3 20

case, there would be no actual change in CH, but the alkaline buffer would
be depleted so that the change would very readily set in when foreign
acids were added. Furthermore, it should be understood that NaHC03
only stands as a symbol for all substances that might serve as alkaline re-
serves, for although this salt is no doubt the most important of these, the
alkaline phosphates, of the corpuscles, and the protein of the blood and
tissues must also be considered. A tendency to alkalosis — which is no
doubt extremely rare as a pathologic condition — would be due to changes
of a reverse character. A theoretic classification of the conditions which
might cause these changes is given:

50

PHYSICOCHEMTCAL BASIS OP PHYSIOLOGICAL PROCESSES

Addition or accumula-
tion of acid

Decrease of base

Addition or accumula-
tion of base

Removal of acids

Increase of CH.

Accumulation of COo (asphyxial conditions).

Incomplete oxidation of carbohydrate (lactic and in mus-
cular exercise).

Defective oxidation of fat (ketosis).

Eenal insufficiency (nephritis).

Decomposition of protein (as in acidosis of fever).

Intestinal fermentation.

Administration of acid (experimental).

Diarrhea and hemorrhage, respectively (may explain acido-
sis in cholera and in certain forms of shock).

Decrease in €„.

xi

Ammonia (faulty metabolism of urea).

Intestinal putrefaction (infantile conditions).

Administration of alkalies (experimental).

Excretion of CO (excessive pulmonary ventilation, as in

faulty ether administration).
Excretion of acid urine. '

CHAPTER VII

COLLOIDS

Substances which can be obtained in the crystalline state and which,
when in solution, are capable of readily diffusing through membranes,
are designated as crystalloids, and are to be distinguished from another,
larger group of substances not having these characteristics or having
them only in very minor degree — the colloids. In every field of chem-
istry the properties of colloids have been studied extensively during
recent years, but in no field more than in that which covers the chem-
istry of biological fluids and tissues, into whose composition colloids
enter much more extensively than crystalloids. The subject of colloidal
chemistry has indeed become so extensive that an attempt to do more
than indicate some of the most important characteristics of colloids
would take us far beyond the limitations of this book. The far-reaching
applications of the subject in physiology and medicine are only begin-
ning to be realized.

The term "colloid," or "colloidal," does not refer to a class of chemical
substances, but rather to a state of matter which is quite independent
of the chemical composition of the substance. We are familiar with
more colloids in the organic than in the inorganic world, yet they are
plentiful in both, and the same substance may at one time be colloidal
and at another noncolloidal. Indeed, under appropriate conditions prob-
ably all substances may assume the colloidal state — not solids and liq-
uids alone, but gases as well. It is mainly with liquids, however, that
we are concerned in biochemistry.

CHARACTERISTIC PROPERTIES

The distinction between molecular* and colloidal solutions is a rela-
tive one. Suppose, for example, that we take a piece of gold in water
and divide it up into smaller and smaller parts. At a certain stage, the
particles will be so fine that they will remain in suspension and be in-
visible by ordinary means. They are then said to be in the colloidal
state. If we divide them further until they become molecules of gold,
a molecular solution will be obtained. In the colloidal state, there are

*Molecular solutions include those of nonelectrolytes, such as sugar, and electrolytes, such as
inorganic salts.

51

52 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

two distinct phases in the solution, one solid and the other liquid, and
between the two, because of the great subdivision of the original par-
ticle, is an enormous surface of contact. The solution is heterogeneous,
and at the interface between the two " phases" the physical forces which
depend on surface — e. g., surface tension (see page 65) — are enormously
developed, and are responsible for the peculiar properties of colloidal
solutions as compared with those of molecular solutions, which may,
therefore, be styled homogeneous. The solutions of crystalline substances
which we have hitherto been concerned with, are homogeneous.

Between these two groups of solutions is an intermediate one — namely,
suspensions (as suspensions of quartz or carbon, or oil emulsions). Be-
sides being turbid in transmitted light, the solutions may be seen by
means of the ultramicroscope to contain particles. These can be sepa-
rated by filtration from the fluid they are suspended in, except in the
case of many emulsions in which the particles can squeeze their way
through the filter pores by changing their shape.' On standing or being
centrifuged suspensions may also separate into their constituents, al-
though this can be greatly hindered by the addition of a suspending'
substance such as gelatin or certain bodies having a so-called protec-
tive action (as peptone, proteose, etc.).

True Colloidal Solutions

1. The Solution Is More or Less Turbid. — Frequently this can be recog-
nized by holding the solution in a thin-walled glass vessel against a
dark background, but the turbidity may be so slight that it requires
for its detection the use of the Tyndall phenomenon. This is familiar
to all in the effect of a beam of sunlight let in through a small aperture
into an otherwise darkened room. In the course of the beam suspended
dust particles, which are invisible in an equally illuminated room, be-
come visible, and thus render very 'distinct the pathway of the beam.
If a colloidal solution contained in a glass vessel, preferably with paral-
lel sides, is held in the course of such a beam, the Tyndall phenomenon
will be seen in the liquid, which is not the case with molecular solutions.
Focused artificial light may be employed for intensifying the effect.
The light that is sent out at right angles to the beam is plane-polarized,
which means that the particles reflecting the light must be smaller than
the mean wave length of the light forming the beam. It should be under-
stood that the individual particles themselves may not be rendered
visible to the naked eye by the beam, although in such cases they can
often be seen by using intense illumination and a dark-field (ultramicro-
scope) combined with suitable magnification (Fig. 12).

2. Colloids Do Not Readily Diffuse. — To demonstrate this, test tubes

COLLOIDS 53

are half filled with a 5 per cent solution of pure gelatin or a 1 per cent
solution of pure agar, and, after the jelly is set, the solution under
examination is poured on the surface; or, when it is of high spe-
cific gravity, the tube of gelatin, etc., is placed mouth downwards in
the solution. In the case of colloidal solutions very little if any diffu-
sion into the gelatin or agar will occur, even after several days; whereas
true molecular solutions will diffuse for a considerable distance. "When
colored solutions are used, the diffusion can readily be recognized by
inspection (see Pig. 13), but when they are colorless, the presence or
absence of diffusion must be determined by removing the column of
gelatin or agar and dividing it into slices of equal size, which are
then examined chemically for the substance in question.

A further test is afforded by the failure of colloids to diffuse through
membranes (dialysis). This was the method originally used by Thomas
Graham to distinguish between molecular and colloidal solutions. The
solution under examination is placed in a dialyzer, which is then im-
mersed in a wide vessel containing the pure solvent. The older forms

Fig. 12. — Ultramicroscope (slit type) for the examination of colloidal solutions. The arrange-
ment of diaphragms, etc., in this form removes the absorptive effects of the surfaces of the glass
vessel or slide used to contain the colloidal solutions.

of dialyzer consisted in general of a bell-shaped glass vessel closed be-
low with parchment paper, but more recently so-called diffusion sacs
have been adopted. These consist of pig or fish bladders or of col-
lodion sacs. The latter are made by placing some collodion dissolved
in ether in a test tube, which is then tilted so that the collodion runs
out except for a thin layer which remains adherent to the walls. When
the collodion has set, the sac can be removed after loosening it by allow-
ing a little water to flow between the sac and the walls of the test tube.
The sac containing the colloidal solution is then suspended in water
or some of the solvent used in preparing the colloidal solution, care
being taken that the menisci of the fluids inside and outside of the sac
stand at the same level. Sometimes, especially when collodion sacs are
used, some colloid may at first diffuse through, but if the outer fluid
(the dialysate) is renewed and the dialysis allowed to proceed, this
ceases.

54

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

When a fluid solution exhibits both of the above properties (i. e., the
Tyndall phenomenon and indiffusibility), there can be no doubt as to its
being in a true colloidal state, but there are substances, such as congo
red, or protein solutions of certain strengths, which may exhibit a very
slight divisibility in a dialyzer but not show the Tyndall phenomenon.
Substances of this group constitute transitional types between molecular
and colloidal solutions, and to determine their true nature it is neces-

Fig. 13. — To show diffusion into gelatin of a crystalloid stain in b and the nondiffusion of a
colloid stain in o. (From W. Ostwald.)

sary to employ refined methods sucht as those of ultramicroscopy, ultra-
filtration, etc., which can not be described here.

3. The Size of Colloidal Particles. — It will be apparent that the essential
property upon which the above-mentioned phenomena depend is the size
of the particle. Particles which can still be seen under the microscope
are called microns. They have been computed to have a dimension of
0.1 p (0.001 mm.) or more, and they form suspensions. Particles which
are invisible microscopically under the ordinary conditions of illumina-

COLLOIDS

55

tion, but are still visible when the ultramicroscopic illumination is
used, are called submicrons. They have a dimension between 0.1 /A and
1 w (0.000,001 mm.),* and they constitute the colloids. Particles smaller
than 1 fj.fji are called amicrons, this term being used to include the mol-
ecules and ions present in molecular solutions. (The amicron of hydro-
gen is, for example, computed to be 0.067 to 0.159 /X/A, and that of water
vapor, 0.113 /*/*.) This classification of dissolved substances according
to the size of the particles and molecules shows the relationship of one

Fig. 14. — Diagram from W. Ostwald showing the relative size of various particles and colloidal
dispersoids compared with a red blood corpuscle and an anthrax bacillus.

class of substances to others. An idea of the relative sizes of colloidal
particles and molecules in comparison with such familiar objects as a
blood corpuscle and an anthrax bacillus is given in Fig. 14. The fluid
in which the "particle" is suspended is called the dispersion medium, or
external phase, and the particle itself the dispersoid, or internal phase.
It is the enormous development of surface which determines the dif-

*/t rz 0.001 mm., and fifi = 0.000,001 mm.

56 PHYSICOCHEMICAL .BASIS OF PHYSIOLOGICAL PROCESSES

ference in the properties of a colloidal solution from those of a suspen-
sion of the same substance. Thus, the difference between a colloidal
solution of platinum (prepared by allowing an electric arc to form be-
tween platinum electrodes in water) and pieces of platinum in water
depends on the fact that the surface of the platinum in the former case
has been increased many million times. When the subdivision becomes
still greater and the particles gain the size of molecules, the phenomena
due to surface development become suppressed and those due to con-
centration in unit volume become accentuated. The properties depend-
ent on osmotic pressure, diffusibility, etc., are exhibited by all dispersoids,
whether ions, molecules or particles, but some of these properties are
much more pronounced when the dispersoids are of large dimensions,
and others when they are small. In other words, the phenomena due to
surface, such as those of surface tension (see page 65), become apparent
only when the dispersoids have the properties of matter in mass; when
the dispersoids become molecular in size, they manifest the properties
characteristic of true solutions.

4. Electrical Properties of Colloids. — Most colloids carry a charge, which
may be either positive or negative tOAvard the dispersion medium. Both
crystalloids and colloids therefore carry electric charges; in the former
case, however, the charge does not reveal itself until the molecules in
solution have become dissociated, when each ion carries a charge of
opposite sign (see page 16), whereas in the case of colloids, each col-
loid particle usually carries a charge which is always of one sign, either
positive or negative. Colloids may therefore be grouped into positive
and negative, according to the charges which they carry, and there is
a third group in which the charge may be either positive or negative ac-
cording to the nature of the dispersion medium.

A colloid not carrying a charge to begin with can be caused to assume
one by the action of electrolytes, for the electrical properties of colloids,
as well as those of inert powders suspended in water, are readily in-
fluenced by the charges present in the ions of the dispersion medium.
The H- and OH' ions are especially liable to exert this influence. The
particles of inert powders in suspensions (kaolin, sulphur, etc.) carry
a positive charge when the water in which they are suspended is acidi-
fied, and a negative charge when it is made alkaline. In general, it may
be said that suspensions of most powders and of insoluble organic acids
in water (e. g., charcoal, cellulose, kaolin, caseinogen, mastic, free acid
of congo red, etc.) are electro-negative. Of true colloids ferric hydrox-
ide (ferrum dialysatum) and serum globulin are positive in acid solu-
tions; arsenious sulphide and serum globulin are negative in alkaline
solution, and serum globulin in neutral solutions has no charge.

COLLOIDS

57

To ascertain the nature of the charge various methods may be em-
ployed, of which the following are important:

1. The method of electrophoresis. The colloid solution is placed in a
U-tube, each side of which carries a platinum electrode dipping into the
solution. After a strong continuous electric current has been allowed
to pass for some time through the solution, it will be found that the
colloid collects at the anode (where the current enters) when it is a
negative colloid (since unlike electric charges attract each other), and
at the cathode when it is positive. In the case of colored solutions, the
migration can be readily seen, but otherwise it may be necessary to ana-
lyze the solution at the two poles.

Fig. 15. — Capillary analysis of colloids. Strips of filter paper, after being suspended with
the lower ends dipping into colloidal solutions. Those on the right hand were positive colloids,
which did not rise in the strips, but formed a sharp line of demarcation at the lower end on
account of precipitation. Those on the left hand were negative colloids. (From W. Ostwald.)

2. The method of capillary analysis. For this purpose a long strip of
filter paper is arranged vertically over the solution, with its lower end
dipping into it. In the case of negative colloids the colloid, as well as
the dispersion medium, rises uniformly on the strip of paper (it may be
to a height of 20 cm.) ; whereas with positive colloids the dispersion
medium alone rises, the colloid itself doing so only to a very slight ex-
tent, but becoming so highly concentrated at the interface between the
solution and the paper that it coagulates on the end of the strip of paper,
where it forms a sharp line of demarcation (Fig. 15).

3. The method of mutual precipitation of colloids. When a positive

58 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

and a negative colloid are mixed in such proportions that the electric
charges are neutralized, precipitation usually occurs. When it does so,
we can tell the nature of the electric charge of an unknown colloid by
its behavior when a colloid of known electric sign is added to it. For
example, if ferric hydroxide (positive) causes a precipitate to form
when it is added to an unknown colloidal solution, the electric charge
of the latter must be negative; if it does not precipitate with ferric
hydroxide, but does so with arsenious sulphide (negative), it must be
positive.

5. Brownian Movement, — Like the particles in fine mechanical suspen-
sions, those of colloidal solutions, especially when examined ultra-
microscopically, exhibit the so-called Brownian movements, which have
been described as "dancing, hopping and skipping." These movements
occur in straight lines, which are suddenly changed in direction and
are quite independent of external sources of energy, such as change in
temperature (although they become quicker as the temperature of the
solution is raised), earth vibrations, chemical changes, or the electric
charge of the colloid. The movements become more rapid the smaller the
particles, and they become sluggish as the viscosity of the solution in-
creases. Addition of electrolytes decreases the movement by causing the
particles to clump together. The density and viscosity of the disper-
sion medium, the electric charge of the dispersoid and the presence of
Brownian movements, are the forces which operate together to prevent
sedimentation of the particles in a colloidal solution.

6. Osmotic Pressure. — As one of the distinguishing properties of col-
loids we have seen that their diffusibility, as into gelatin or agar jel-
lies, is extremely slow when compared with that of a molecular solution.
This does not mean, however, that colloids are possessed of no power of
diffusibility if left long enough. Indeed the existence of the Brownian
movement indicates that such diffusion must occur, and therefore it
should be possible, by the application of the same principles as those
which govern molecular solutions (e. g., by using a semipermeable mem-
brane), to measure the osmotic pressure.

Many studies of the osmotic properties of colloidal solutions have been
undertaken, especially by those who are interested in the possibility
that the colloids of blood serum (serum albumin and globulin) may cre-
ate an osmotic pressure. If this should prove to be the case, it would
be necessary for the osmotic pressure to be overcome by mechanical
pressure such as that supplied by the heart (i. e., the blood pressure) in
the various physiological processes of filtration and diffusion taking place
through cell membranes (as in the formation of urine in the kidney).

For measuring the osmotic pressure of colloids, osmometers similar

COLLOIDS 59

to those already described (page 4) can be employed. Most of the
recent work has been done either with collodion sacs, or with unglazed
clay cups impregnated with some gel, such as silica or gelatin. When
such an osmometer, filled with some colloidal solution (like a solution of
pure albumin) and provided with a vertical glass tube, is placed in an
outer vessel containing water, the fluid will be seen to rise in the ver-
tical tube, the height to which it rises being proportional to the osmotic
pressure.

But the observed pressure does not necessarily give us the osmotic pressure of
the pure colloid, for to this, even when highly purified, there is almost certain to
be attached a considerable amount of inorganic salt, which may be responsible for
the osmosis. It has indeed been maintained by some observers that electrolytes form
an integral part of certain colloids, being bound to them perhaps by adsorption (sec
page 66), and that they are essential to the maintenance of the colloidal state. In
any case, since electrolytes are always present, the osmotic pressure of the pure
colloid can be measured only when means are taken to discount their influence. Sev-
eral devices have been used, of which the following may be mentioned:

1. Addition to the fluid outside the osmometer of a percentage of salt equal to that
found by chemical analysis to be present in the colloid. (This method is untrust-
worthy.)

2. The use of a limited quantity of fluid on the outside of the osmometer so that
equality of saline content soon becomes established, by diffusion, in the fluids on the
two sides of the membrane.

3. The use of a membrane which is permeable to electrolytes but not to colloids.
Even when the greatest care is taken in its measurement, the osmotic pressure of

a given colloid has been found to vary considerably not only according to the method
used in its preparation, but also according to the amount of mechanical agitation
(shaking, stirring, etc.) to which the colloid solution has been subjected. Regarding
the influence of the method of preparation, it was found in one series of experiments
that albumin that had been repeatedly washed (but still contained considerable ash)
gave no osmotic pressure, whereas another preparation that had been purified by crystal-
lization twice (and contained much less ash) had a pressure of 3.38 mm. Hg. Ac-
cording to these results the ash content of the colloid is not fundamentally responsible
for its osmotic pressure. As to the influence of mechanical agitation, the osmotic pres-
sure of a gelatin solution is increased by shaking, while that of a solution of egg albu-
min is decreased.

The property upon which the osmotic pressure depends is undoubtedly the state of
dispersion of the colloid particles, and until we know all of the factors which may in-
fluence this, measurements of osmotic pressures of colloids can scarcely be of very
much value. Nevertheless, that this property has some physiologic bearing is clear
from the effect which colloids have in restoring the blood pressure after hemorrhage
(page 141).

Further evidence that the osmotic pressure of colloids has not the significance that
it has in the case of molecular solutions is furnished by the fact that the osmotic pres-
sure is only approximately proportional to the concentration of the solution ; it may
either increase or decrease relatively to the strength of the solution. Temperature also
has quite a different influence on the osmotic pressure of colloids from that which it
has on the osmotic pressure of molecular solutions, and it frequently has an influence
which persists after the solution is brought back to its original level.

60 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

The influence of added substances on the osmotic pressure of colloidal solutions
is of considerable interest to the biologist, for, whereas in the case of molecular solu-
tions this is purely additive, in the case of colloids the added substance may at one
time cause the osmotic pressure to increase, at another, to decrease. It has been found
that the osmotic pressure of gelatin solutions at first decreases, then rapidly increases
as the H-ion concentration is raised. The addition of alkali increases the osmotic
pressure until a maximum is reached, beyond which it begins to fall. Both acids and
alkalies lessen the osmotic pressure of egg albumin. Electrolytes always decrease the
osmotic pressure of gelatin and albumin solutions, and the degree to which they exert
this influence depends on the nature of the cation and anion composing the electrolyte.
In the order of their depressing influence the cations arrange themselves:

Heavy metals > alkaline earths > alkalies;
and the anions:

S04 > 01 > NOo > Br > I > CNS.

The influence of a given electrolyte varies extraordinarily with the reaction of the
colloid, a fact which must be carefully regarded in all work in this field.

CHAPTER VIII
COLLOIDS (Cont'd)

SUSPENSOIDS AND EMULSOIDS

According to whether colloids form solutions that are more or less
viscid than the suspension medium, they are divided into emulsoids and
suspensoids. Examples of the former class are silicates and gelatin, and
of the latter, dialyzed iron and arsenious sulphide. The following char-
acteristics are used to distinguish between suspensoids and emulsoids:

1. Measurement of the time it takes, at a standard temperature, for a
given volume of the fluid to flow out of a standard pipette (10 c.c.) shows
the viscosity to be, roughly, inversely proportional to the time of outflow.
In the case of suspensoids the viscosity is no different from that of the
dispersion medium alone, and does not vary much when the solution is
cooled. The viscosity of emulsoids even in very dilute solutions is, on
the other hand, considerably greater than that of the dispersion medium
itself, and it becomes greatly increased by cooling.

2. Suspensoids are much more readily coagulated by the addition of
electrolytes than emulsoids. This is particularly true when water is
the dispersion medium (so-called hydrosols), and when electrolytes hav-
ing a polyvalent ion (such as Al or Mg.) are employed. Thus, practically
all suspensoids are coagulated in the presence of 1 per cent of alum,
which has no influence on emulsoids. We shall return to this phase of
our subject later on.

The division of colloids into emulsoids and suspensoids is more or less
arbitrary, since one class may be changed into the other, the determining
factor being the water content of the dispersoid. The water content of
suspensoids is low (lyophobe), while that of emulsoids is high. By
changing the relative amounts of water and solid of which a colloidal
solution is composed, the nature of the dispersoid may be changed. If
the water is diminished, the dispersoid behaves as a suspensoid and be-
comes readily precipitated. The practical importance of this fact is
that it explains the salting out of proteins — a process extensively used
in their separation. Ordinarily these behave as emulsoids, but the addi-
tion of salt raises the osmotic pressure of the dispersion medium, and
thus attracts water from the dispersoids, with the result that they come

61

62

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

to behave as suspensoids, and are accordingly precipitated by the elec-
trolytes.

Another property of emulsoids of biological importance is the pro-
tection which they can afford against the precipitating influence of
electrolytes on suspensoids. If a colloidal solution of gold is mixed with
a trace of gelatin, the subsequent addition of salts will be found to
produce no precipitation. The explanation of this is that the emulsoid
becomes distributed as a film on the suspensoid particles, thus practically
converting them into emulsoids.

Gelatinization

One of the best known properties of emulsoids is that of gelatiniza-
tion, which has an interesting bearing on many problems of biology.
After the gel has set, an enormous pressure is required to squeeze out

any water from it, indicating that the water no longer forms the con-
tinuous phase but must be enclosed in vesicles formed of more solid
material.

By observing solutions of pure soaps under the ultramicroscope it has
been noted that as the solution cools, the gel at first forms a polarized cone
of light, but the very fine particles which are responsible for this effect
soon increase in number and size so that they obstruct one another in
their Brownian movements and adhere, giving an appearance of fine
felt-like threads throughout the solution.25 A sort of impervious sponge
work of the more solid phase is therefore formed, the more fluid phase
being inclosed in the meshes.

If, as in the accompanying diagram, the dispersion medium is repre-
sented by white and the dispersoid in black, the relationship between
the two in a suspensoid is as in B, and that in a gel as in A. To express

COLLOIDS 63

any of the dispersion medium in A, it will require a pressure sufficient to
cause the more fluid phase to penetrate the more solid. If the gel is
treated with reagents like formaldehyde, the liquid can bet readily pressed
out. This occurs during fixation for histological purposes.

Imbibition

Closely related to gel formation is the process of imbibition — the
power of taking up large quantities of water without actually forming
liquid solutions. Besides gelatin the dried tissues of plants and animals
exhibit the phenomenon, and it is undoubtedly of importance in many
physiological processes such as growth and the passage of water into
cells, etc. The materials present as vacuoles in plant cells attract water
from the environment of the cell by imbibition, and thus exert on the
cell wall a pressure which, acting along with the osmotic pressure,
maintains the turgor of the cell. The initial growth of pollen is also
dependent upon imbibition, and important observations on this process,
under varying conditions, are likely to furnish us with useful informa-
tion concerning the significance of imbibition in connection with growth
of cells in general.

By measuring the rate of increase in length of long, narrow strips of gelatin placed
in Petri dishes containing solutions of varying composition, the factors that influence
the imbibition process can be quantitatively investigated. Working in this way, F. H.
Lloyd1'? has found that for all acids there is a certain concentration (about N/320
H2SO4) which induces a maximum rate of swelling, and another, much weaker (N/2800
H2SO4), in which the rate of swelling is even less than in pure water. In higher con-
centrations of acid than N/320, the gelatin at first swells very quickly, but the rate
slows off so that it soon comes to be less than that with intermediate concentrations.
Regarding alkalies, at high concentrations the effect is similar to that of acids. Salts
alone seem to repress the swelling below that of water. It should be pointed out
that the concentrations of acid and alkali in the above observations are much greater
than those that could occur in the animal body. The experiments recall the attempts
made some years ago by Martin Fischer to explain edema as due to excessive imbibition
of water by the proteins of the tissues because of increased acidity of the blood and
tissue fluids. That imbibition might possibly play some role in such processes is not
denied, but Fischer disregards entirely the now well-established facts that hydrogen-
ion concentration is one of the most constant properties of the blood, that very low
concentrations of acid may diminish rather than increase imbibition, and that it is
manifested only in the absence of inorganic salts.* Moreover, the fluid in edema can
often be drained off by hollow needles, and it passes by gravity from one part of
the body to another, neither of which processes would be possible if imbibition were
the essential factor concerned. If further evidence against this hypothesis should be
demanded, it might be found in the utter failure of the therapeutic measures — alkali
administration — that are recommended to combat the edema.

Action of Electrolytes on Colloids (apart from their effect on osmotic
pressure). — It has been stated above that the charge which a colloidal

*Determinations of the hydrogen-ion concentration of the blood recently published from Fischer's
laboratory do not inspire confidence.

64 PHYSICOCHEMICAL BASIS OP PHYSIOLOGICAL PROCESSES

particle assumes may be neutralized by a charge of opposite sign car-
ried by an ion present in the dispersion medium. The neutralization
of the electric charge causes coagulation of the suspensoids but not of
the emulsoids. Of the positive and negative ions into which the elec-
trolytes dissociate, the one producing the coagulation is that which is
opposite in sign to the electric charge of the colloidal particle.-

A quantity of electrolyte which is capable of producing complete pre-
cipitation when added all at once to suspensoids will be ineffective when
added in small quantities at a time. This phenomenon, which is also
known to be exhibited when toxins and antitoxins are mixed together, is
probably owing to the fact that precipitation depends on inequality and
irregular distribution of electric charges, a condition which becomes
established when the electrolyte is suddenly added, -but not so when it
is gradually added. The particles in the latter case become, as it were,
acclimated to the electric charges introduced by the addition of the
electrolyte.

Proteins as Colloids. — The most prominent colloids in the field of bio-
chemistry are the proteins. On account of complexity of structure,
however, certain factors intervene which render the investigation of
their behavior very difficult. As we shall see later, proteins are made
up of combinations of amino acids, each of which contains basic (NH2)
and acid groups (COOH). The various amino acids are linked together
in protein by the COOH of one uniting with the NH2 of another, with
the elimination of water — thus, CO ! OH + H ! HN — but some NH2 and
COOH groups are left uncombined. According to the relative number
of these uncombined radicles, the protein (or polypeptid, see page 636)
will exhibit faintly acid or basic or neutral properties. With acids, for
example, a salt will be formed by union with the NH2 groups, which will
dissociate into the anion of the acid and a large organic cation; whereas
with alkalies union will occur with the COOH group, and the salt on
dissociating will form a small cation of the metal of the salt and a large
complex anion. We may therefore obtain the protein with either a
positive or a negative electric charge by altering the chemical nature of
the fluid in which it is dissolved, so that the reaction towards other
colloids and towards electrolytes will vary.

One feature of proteins of importance in this connection is that known
as the isoelectric point, at which the protein exists with a maximum of
electrically neutral molecules. This point is reached by adding acid to
a protein solution. The acid represses the dissociation of the protein
acting as an acid, and therefore diminishes the number of free hydrogen
ions; and at the same time it combines with the NH2 groups and neutral-

COLLOIDS 65

izes the basic characteristics. The alteration in electric charge thus in-
duced alters the water-absorbing powers of the protein and therefore
all of the properties which we have seen to be associated therewith
(page 64).

SURFACE TENSION

Before we consider a very important property of colloids known as
adsorption, by means of which they are able to perform many reactions
that do not conform with the laws of mass action, it will be well to
say a few words concerning the physical phenomenon upon which this
depends — namely, surface tension. The creation of this force is due
to the fact that, whereas the molecules within a liquid are subjected to
equal forces of attraction on all sides, at the surface these forces act on
one side of the molecules only, and therefore tend to pull them inwards.
This causes the surface to pull itself together so as to occupy the least
possible area, and it is this force which constitutes surface tension.
The surface behaves as if stretched. There are various simple experi-

B.

Fig. 17. — Diagram to illustrate surface tension. The rings A and B inclose soap films in
which a very fine loop of silk is suspended. In A it is loose but in B, where the film inclosed
in the loop has been broken, it is drawn into a circle by the tension of the soap film. (From
Bayliss.)

ments that reveal the presence of surface tension. If a film is made on
a loop of wire by dipping it in soap solution, a fine silk thread can be
floated in the film, so that it forms a loop that is quite loose. If the
portion of the film inside the loop is destroyed by touching it with filter
paper, the film will break in the loop, which will now be pulled into a
circular shape by the tension of the film around it (Fig. 17).

For the measurement of surface tension, various methods are used.
The size of drops of liquid falling from an orifice is dependent on sur-
face tension; the larger the drops, the greater the surface tension. If
the number of drops obtained by allowing a liquid to drop from a stand-
ard orifice in a given time is counted, we have a measure of the surface
tension. Account must of course also be taken of the specific gravity
of the liquid. The instrument used for this purpose is called a
stalagmometer (Fig. 18). Another method depends on the fact that
the height to which a fluid rises in a capillary tube is dependent on

66 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

surface tension (and inversely on the diameter of the capillary). The
difference in the heights to which two liquids rise in capillary tubes of
known bore permits us to compare their surface tensions, and if this
is known for one of the solutions, it can be determine4 for the other.
Besides existing between liquid and air, surface tension also exists at

Fib. 18. — Traube's stalagmometer. The surface tension is proportional to the number of
drops formed in a given time. The right-angled tubes are for thin liquids, and the straight
one for blood and other viscous fluids.

the interface between two immiscible liquids, and at that between sus-
pended solid particles and liquid, as in colloidal solutions. Since, as
we have seen, the surface area (interface) is enormously increased in
these solutions, a very great surface energy is present, for this is equal
to the surface tension multiplied by the surface area.

ADSORPTION

The surface tension between liquid and air is lowered when organic
substances are dissolved in the liquid, but is slightly raised when inor-
ganic salts are dissolved. The degree of lowering varies markedly ac-
cording to the organic substance dissolved, being very pronounced with
bile salts, upon which fact the well-known (Hay) test for the presence
of bile in urine is based. Between liquid and liquid, as well as between
solid and liquid, the surface tension is always lowered T)y dissolving sub-
stances in the liquid. Now, at the interfaces between solid particles and
liquid there must be a local accumulation of free surface energy, which
will be equal to the surface tension multiplied by the surface (inter-
face) area. A constant tendency exists for such free energy to be de-
creased and, since dissolved substances have this effect, they will become
concentrated at the interface. This is known as the principle of Willard
Gibls, and it is of fundamental importance to the biochemist, because

COLLOIDS 67

on it depends the phenomenon known as adsorption, which in the case
of colloidal solutions may therefore be defined as the local concentra-
tion or condensation of dissolved substances at the interface between
the two phases. The amount of substance concentrated at the interface
can be calculated by a formula which takes into account the concentra-
tion of the dissolved substance, the temperature, and the surface tension
at the interface (the Gibbs formula). After adsorption has occurred, vari-
ous reactions of a chemical, electrical or purely physical nature (e. g., dif-
fusion) may follow at a rate which depends on the amount of the
condensation.

Reactions Which Depend on Adsorption

1. Decolorization of liquids by charcoal. That no chemical reaction occurs in such
a case is readily shown by the ease with which the pigment can be extracted from
the charcoal.

2. Adsorption of gases by such solids as charcoal and spongy platinum. In these
cases there must be great condensation, even a liquefaction of the gas, during which
heat must be evolved. By adsorbing oxygen and hydrogen, spongy platinum causes
these gases to combine and form water. The hemoglobin of blood may take up
oxygen by a similar process.

3. Formation of solid surface films on solutions of protein, saponin, etc. The con-
densation may lead to coagulation, which explains why, if the froth produced by beat-
ing the white of an egg is allowed to stand, it can not be again beaten into a froth,
the albumin having gone out of solution by surface coagulation.

An interesting phenomenon depending on the surface tension occurs
when the protoplasmic contents of a ciliated infusorian is pressed out in
water. A new membrane forms on the protoplasm because of surface con-
centration of all constituents which lower surface energy. By application
of the principle of Willard Gibbs, A. B. Macallum18 concludes that not only
adsorption, as exhibited in a colloidal solution, but also the local accumula-
tions of material often seen in cells, are associated with changes in sur-
face energy. His conclusions are based largely on microscopic studies
of various forms of cell exhibiting different degrees and types of activity,
and ingeniously stained for potassium by cobalt hexanitrite. By such
a means the potassium stains intense black. In vegetable cells, local
accumulations of potassium occur either near the interface between the
clear and the chlorophyl-containing parts of the cell (spirogyra) or
under a portion of the cell wall from which later a protrusion grows out
to form the first stage in conjugation. The outgrowth from the cell,
as well as the accumulation of potassium, may be the result of a low
surface tension. In unicellular animal organisms, such as Vorticella,
much less potassium is present, being confined to the base of the cilia,
which Macallum believes indicates that the structures are produced as
an outcome of low surface tension.

68 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

In the cells of higher animals, deposits of potassium are also localized ;
in striated muscle, for example, they occur in a zone at each end of the
doubly refractive band and immediately adjacent to the singly refrac-
tive band. Changes in surface tension, associated with changes in the
distribution of potassium, are believed by many to be responsible for
muscular contraction. In nerves and nerve cells, potassium is concen-
trated at the axon and at the surfaces of the cells. Interesting sugges-
tions are offered to explain the relationship among changes in surface
tension at the terminations of axons (synapses, terminations in gland and
muscle cells) brought about by the nerve impulse acting as a change in
electric potential. Surface condensation of potassium has also been
observed at the lumen border of gland cells (pancreas), and on the lu-
men surface of the cells of the renal tubules. Such observations indicate
in what way surface tension may be called into play to control. cellular
activities. The field is new and almost unexplored, but there is already
much to indicate that surface energy plays a most important role in the
performance of many cellular activities.

Conditions That Influence or Are Influenced by Adsorption

Electrical Changes. — Besides mere concentration, other forces come into play to assist
or retard adsorption. One of the most important of these is electrical. Most solids
Vvhen present as particles in a fluid carry a negative charge of electricity, some a posi-
tive one. In conformity with the Willard Gibbs law, a constant tendency will exist
for this free energy to be diminished by the neutralization of the electric charge.
This can occur by deposition on the interface of other particles carrying an electric
charge of opposite sign or by the action of that present on ions. Charcoal in suspen-
sion in water, for instance, has a negative charge. If colloidal iron, which has a pos-
itive charge, is added to the solution, it will become deposited on the charcoal, as will
also the cations of an inorganic salt. On account of electric adsorption, dyestuffs and
bile salts are adsorbed much more freely than they would be if the process depended
solely on surface condensation; that is, if the Gibbs formula is used to calculate the
adsorption, it will give values that are much below those actually found.

If the dissolved substance and the particles both have the same electric sign, ad-
sorption will not occur. Filter paper, for example, has a negative charge and can not
therefore adsorb a negative dye such as congo red (as shown by the depth to which
it becomes stained) ; whereas it readily adsorbs night blue, which is positively charged.
If the negative charge of the paper is lowered, it becomes capable of adsorbing some
of the negative congo red. This can be effected either by placing the paper in al-
cohol or by adding inorganic salts (NaCl) to the water with which it is in contact.
The positive-charged ions of Na, produced by dissociation, neutralize some of the nega-
tive charge on the paper, and allow a certain amount of adsorption of the negative-
charged congo red to occur. As would be expected, acids and alkalies are capable of
greatly altering the electric charges by the II and OH ions which they contribute.

Chemical Forces. — If the nature of the phase at the surface of which adsorption
occurs is such that it can enter into chemical combination with the substance ad-
sorbed, reactions will occur that do not obey the laws of mass action. By adsorption,

COLLOIDS 69

reactions of a certain type may be encouraged over other reactions, even although the
necessary reacting substances may be present in the solution (specific adsorption). The
adsorbing substance itself is not, however, usually susceptible of chemical change
even when it exists as very minute particles, as in the case of colloidal solutions.
Nevertheless, adsorption may accelerate chemical reactions by bringing together in
concentrated form substances of high chemical reactivity. In such cases the adsorbing
substance itself does not enter into the chemical reaction, and can be recovered at the
end in an unchanged condition. It acts as a catalyst (page 72). As we shall see
later, enzymes act in this way — i. e., their rate of reaction is controlled by adsorp-
tion.*

The distinguishing feature of such adsorption phenomena is that a curve of the
reaction (drawn by plotting amount of chemical change against concentration of react-
ing substances) is a parabola, indicating that the laws of mass action (page 23) are
no longer followed. In order to be able to determine whether some particular process
— as, for example, a fermentation process, or the absorption of oxygen by blood — is
caused by adsorption, we must compare its curves, constructed according to the same
principles, with the typical adsorption curve. A formula may be used in constructing
the curves. In arriving at this formula, two facts have to be remembered: (1) As ad-
sorption proceeds and less and less of the free energy on the adsorbing surface re-
mains to be neutralized, the reaction slows off, until equilibrium is reached. The more
dilute the solution, the greater is the proportion of its contents to be adsorbed, which
means that if a is the amount of substance adsorbed from a certain solution, then,
from a solution of twice that strength, somewhat less than 2 a will be adsorbed — i. e.,
a multiplied by some root of 2. Although the formula is one belonging to the class
known as parabolic, it must not be assumed that every reaction which happens to give
such a parabolic curve (such as the combination of O^ with hemoglobin under certain
conditions) (see page 396) must be one dependent on adsorption.

It must be understood that although the substance that is removed from a solution
by adsorption is no longer capable of contributing to the conductivity or the osmotic
pressure of the solution, it is nevertheless not so firmly fixed that it can not be set
free again by purely mechanical means, as by constant dilution of the fluid. If char-
coal which has adsorbed sugar is placed in a dialyzer made of membrane, the pores of
which allow sugar but not charcoal to pass through, the sugar will gradually be re-
moved if the dialyzer is immersed in running water. A certain equilibrium exists be-
tween the substance adsorbed and the same substance still remaining in solution. If
the latter is constantly diminishing by dialysis, the adsorption compound must break
down to maintain the equilibrium. It is clear, however, that the process of removal
will be extremely slow. The ability of adsorbed substances to withstand removal by
washing is taken advantage of by nature in holding back foodstuffs in the soil.

*Another instance of the influence of surface energy on the course of chemical reactions is seen
in the accelerative influence of charcoal on such reactions as the oxidation of formic acid, glycerol,
etc. Surface tension may also cause retardation of chemical reactions, as is seen in the turbidity

(due to the separation of chloroform) which gradually develops when a ---].-— Na2COg solution is
mixed with a L chloral hydrate solution. The surface remains clear, because surface energy has

prevented the reaction.

An important effect of surface tension on chemical reactions is also seen in the relationship
between it and the absorption coefficient of gases (volume of gas dissolved by unit volume of
liquid). The lower the surface tension, the greater the solubility of the gas. Oxygen and nitrogen
are, for example, much more soluble in alcohol, hydrocarbons or oil than in water. This shows
the futility of attempting to prevent the loss of gases from fluids such as blood by covering them
with oils or hydrocarbons.

70 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

Biological Processes Depending on Adsorption

Instances in which, adsorption undoubtedly plays a most important
part in physiological processes are as follows :

1. The action of enzymes (see page 71).

2. The combination of toxin with antitoxin occurs according to the laws
of adsorption rather than those of mass action. In this case it is im-
portant to note that when the toxin of diphtheria is added in small suc-
cessive quantities to diphtheria antitoxin, more toxin is neutralized than
when the toxin is all added at once. A similar phenomenon can also be
observed by adding filter paper to congo red, more of the pigment being
adsorbed when the paper is added in small quantities than when added
all at once. The explanation is that relatively more adsorption of a
given substance occurs from a dilute than from a strong solution (cf.
page 69).

3. The sensitizing of leucocytes by opsonins, as well as the subsequent
ingestion of bacilli by the sensitized leucocytes, both of which follow the
course of an adsorption reaction.

4. The formation of adsorption compounds, such as the inorganic salts
and proteins and the complex lecithin compounds that can be extracted
from egg yolk or brain tissue. In such compounds the lawrs of chemical
proportion no longer hold, and properties may be exhibited that are quite
different from those of either one of its components. When yolk of egg
is extracted with ether, for example, a compound of lecithin with vitellin
goes into solution, although vitellin itself is quite insoluble in ether.*
There can be no doubt that adsorption compounds of this character are
very abundant in living cells, and that they are constantly being formed
and broken down.

"By mixing solutions of egg albumin, congo red and a dye called fustic in the presence of
alum, the colloidal particles of which each is composed run together to form larger colloidal ag-
gregates, which by ultramicroscopic examination can be seen to be composed of a red, a yellow
and a green colloidal particle. The attractive force holding the particles together is electric in
this case.

CHAPTER IX

FERMENTS, OR ENZYMES

One of the most striking developments of modern research in biochem-
istry concerns the nature of enzyme action. So remarkable are many of
the facts that have been brought to light that it can not fail to interest
every one engaged in the study of life phenomena — whatever the nature
of that study may be — to know something of the main questions at
present occupying the attention of investigators in this field. In this
chapter a brief survey will be given of some of these questions; no at-
tempt will be made at completeness, and only where necessary for the
sake of example will reference be made to individual types of enzyme
action.

The discovery by Buchner that an enzyme can be expressed from yeast
cells which is capable of instantly bringing about the alcoholic fermen-
tation of dextrose solutions has been responsible for a great deal of the
modern advance. Formerly, yeast cells were believed to bring about
alcoholic fermentation as a result of their growth: it was believed to be
a life phenomenon, or " vital process." Now we know that yeast cells
produce an intracellular ferment or endo-enzyme* to which its sucroclastic
properties are due and which can act apart from the cells that produce it.
It is no great stretch of imagination to think of all chemical reactions
mediated by cellular activity as due to a similar mechanism, and this thought
has led to the hypothesis that all processes of intermediary metabolism in
the animal and plant are caused by enzyme action. Before Buchner 's
day we knew only of the extracellular enzymes (such, for example, as
the digestive ferments), that is to say, of enzymes, produced indeed by
cells, but secreted from them and acting outside their protoplasm; now
we must recognize intracellular enzymes acting where they are produced,
in the protoplasm of the cell. But we must not permit this conception to
carry us too far. Without further investigation we must not imagine
that the riddle of life is thus solved.

As an example of the role which extra- and intracellular enzymes are
supposed to play in the animal economy may be cited the metabolism of
protein. Proteolytic enzymes are very widely distributed in the active
tissues of the animal and plant. By their agency in animal life, the com-

*The terms "ferment" and "enzyme" arc synonymous, but the latter is preferable as the noun,
leaving the former to be used as the verb.

71

72 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

plex protein molecule is split up to render it absorbable from the intes-
tine, and the tissues appropriate from the blood those of the degradation
products that they require for the construction of protoplasm, which,
later, they decompose so as to utilize the energy which the organism
demands. All these processes are believed to be the work of enzymes.

The Nature of Enzyme Action

The changes brought about by enzymes can also be accomplished by
ordinary chemical means, but these have often to be of a very energetic
nature to accomplish what the enzyme can so quickly and quietly
perform.

It is the custom to regard enzymes as catalysts. A catalyst is a sub-
stance which accelerates (or retards) a chemical reaction which in its
absence could proceed at a different (usually slower) pace. The action
of catalysts has been aptly likened to that of a lubricant. A weight
placed at the top of an inclined plane, so held that' the weight only slowly
slips down, has its velocity greatly increased if its under surface be
oiled. The oil accelerates the action but does not affect the ultimate
result. Catalysts do not combine with the final products of the reaction,
these being, as a rule, the same as they would have been had no catalyst
been added. Another characteristic is the tremendous amount of chem-
ical change which even a trace of catalyst can induce. There are many
examples of catalysts in the inorganic world, among which may be cited
the action, of spongy platinum on hydrogen peroxide. This substance
normally tends to decompose into water and oxygen, but if a small
amount of spongy platinum is added to it, the decomposition is greatly
accelerated: H,02 = H20 + 0.

A very good example of the action of an inorganic catalyst is that of
the hydrogen ion on cane sugar, or other disaccharides, in the presence
of water. It accelerates the hydrolysis. Cane sugar solution at room
temperature does not indeed, in sterile solution, undergo any appreciable
hydrolysis, but at 100° C. it does, which leads us to believe that, though
inappreciable, the action also occurs at room temperature. By adding
a little hydrochloric acid, or other acid not having an oxidizing effect
on sugar, we greatly accelerate the hydrolysis because of the hydrogen
ions present in the acid solution. Within certain limits the rate of hy-
drolysis is proportional to the amount of catalyst present.

Enzymes, like other catalysts, produce their action when present in
very small amounts (e. g., sucrase can hydrolyze 200,000 times its weight
of cane sugar; diastase can convert starch to sugar in a dilution of
1-1,000,000) and there is a distinct relationship between the amount of
enzyme present and the rate of the reaction. The final product of the

FERMENTS, OR ENZYMES 73

reaction is, however, the same at whatever rate it proceeds, and the
enzyme does not appear in the final products. Many enzymes such as
diastase can be found unaltered in amount after they have completed
their action. This is determined by adding a fresh supply of substrate
(that is, of material to be acted on), when the enzymic action proceeds
again in the usual way. The same is no doubt true for all enzymes,
though as yet it can actually be proved for only a few of them. Enzymes,
therefore, may be defined as catalysts produced by living organisms.

The Properties of Enzymes

Although enzymes are examples of catalysts, they exhibit many proper-
ties that appear to differ from those of inorganic catalysts. It will,
therefore, be advisable in considering each quality to compare it in
catalysts and enzymes, for by this method a much clearer conception of
the nature of enzyme action can be gained (Bayliss19). Those properties
that are strictly peculiar to enzymes we shall consider later.

1. Most enzymes are remarkably specific in their action, whereas inor-
ganic catalysts are very much less so. Thus, in the case of the enzymes
which bring about inversion of disaccharides, this specificity is clearly
shown. There is a special enzyme for each of the three disaccharides —
maltose, lactose and cane sugar — and one of these can not replace
another.

Still more strikingly is this specificity of enzyme action demonstrated
in the fact that certain enzymes, such as zymase (expressed from yeast),
will act only on bodies having a certain configuration, that is, having
their side chains arranged in a certain way. Thus, there are two varie-
ties of dextrose (a and /?), which differ from each other solely in the
fact that the side chains are arranged in different positions with rela-
tion to the central chain of carbon atoms. This form of isomerism is
called stereoisomerism because the two bodies rotate the plane of polar-
ized light to an equal degree in opposite directions. Zymase acts on one
of these but not on the other, and there are innumerable examples of the
same kind. Indeed, of all bodies that exist in two stereoisomers only
one is found in living cells and it is on this variety alone that the enzymes
in animals can act. A similar specificity exists between certain drugs and
their pharmacological action.

Specificity of action is explained by supposing that a union occurs
between the substrate and the enzyme, and for this union to take
place the enzyme must possess a configuration which corresponds accu-
rately with that of the substrate. The process has been compared to a
lock and key; the key must be shaped to fit the lock, or it can not
operate. The specificity does not, however, in itself disprove the close

74 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

relationship between enzymes and inorganic catalysts, for on the one
hand there are several enzymes which do not exhibit this property, and
on the other, there are inorganic catalysts which do. For example,
lipase, the fat-splitting enzyme of pancreatic juice, decomposes not only
fats but to a greater or less degree a number of bodies of the same gen-
eral build (esters), and tyrosinase can decompose, not tyrosin alone,
but all phenol compounds. Conversely, the hydrogen ion — to the pres-
ence of which acids owe their catalytic powers — can decompose the ordi-
nary esters (that is, of acids containing the carboxyl or COOH group)
but it has no action on the sulphonic esters. However, enzymes are cer-
tainly much more specific in their action than inorganic catalysts.

2. Temperature does not influence catalysis and enzyme action in the
same way. As the temperature is raised in the case of inorganic catalysts,
the reaction becomes about doubled in rapidity for each rise of 10° C.,
whereas in the case of enzymes it becomes increased up to a certain opti-
mum temperature, beyond which, as the temperatiire rises, the reaction is
first slowed and then disappears altogether.

This peculiarity of enzymes as compared with inorganic catalysts need
not in itself disprove the analogy between the twro, because enzymes do
not form true, but colloidal solutions. Colloidal solutions, as we have
seen, are really fine suspensions of ultramicroscopic particles ; there is no
splitting into ions of the dissolved substance, as is the case with true
(molecular) solutions, but the colloid is suspended in the water or other
solvent to form a heterogeneous system (page 52), on which account
the surface area of the menstruum is enormously increased. Eise in
temperature alters the extent of the surface area, and thereby intro-
duces an influence which progressively opposes catalysis.

Although inorganic catalysts in molecular solution show no optimum
temperature but increase in activity in proportion as the temperature is
raised, inorganic colloidal catalysts may show an optimum temperature.
Thus, spongy platinum shows an optimum temperature in its action on a
mixture of hydrogen and oxygen. It has therefore been suggested that
it is because they are colloids that enzymes exhibit this property.

3. Inorganic catalysts frequently carry the reaction to a further stage
than that attained by the action of enzymes. For example, acid breaks
down the protein molecule much more completely than do the proteolytic
enzymes. This difference is perhaps explained by the fact that enzymes
are retarded in their activities when there comes to be a certain accumu-
lation of the products of the reaction present. The final stages in the
reaction may become so slow as to be almost inappreciable. This de-
crease in activity is partly due to a union between the enzyme and the
products of its activity.

FERMENTS, OR ENZYMES 75

4. The velocity constant in the case of inorganic catalysts remains un-
changed throughout the reaction, whereas in the case of enzymes it 'be-
comes either less or greater as the process proceeds. When a substance is
changed by catalytic action, it is, of course, constantly being diminished
in concentration so that less and less of it remains to be acted on. This
implies that there are fewer molecules present for the same amount of
catalyst to act on and consequently that the amount changed in a unit
of time is progressively less. At any moment, therefore, the rate of
catalysis will be proportional to the amount of substance (substrate)
left. To understand this we must refer back to what we have learned about
mass action. If we suppose that two substances A and B react to form
two other substances C and D, then, by the law of mass action, the reac-
tion will not go on to completion but will stop when a certain equilibrium
is reached. The reaction can be represented by the equation
A + B +± C + D, which means that it proceeds at a rate proportional to
the reacting molecules. In some cases this reaction goes on until either
A or B has practically disappeared (that is, the equilibrium point is very
near the right of the equation), as is the case in the inversion of cane
sugar:

C12 H22 01X + H20 = C6 H12 06 + C6 H12 06

Taking place as it does in an excess of water, and there being very
little tendency for the reaction to go in the opposite direction (cf. re-
versible action page 25), the only thing which will influence its velocity
is the concentration of cane sugar; in other words, the velocity of the
reaction at any moment will depend on the concentration of the cane
sugar still left undecomposed. This can be determined by means of
an equation.*

The value of such an equation is that it gives us a figure K, represent-
ing the amount of inversion that would occur in each unit of time if the
cane sugar were kept in constant concentration. When, for example,
it is stated that K for a particular strength of acid acting on cane sugar

*If x be the amount of sugar inverted in time t, C, the concentration of the sugar not yet in-
verted, and if we use a figure called a constant (K) to express the fundamental rate of the reaction

(which will therefore be different for different reactions), then — = KC. But C can not be the same
at any two consecutive periods of time, because the reaction is going on continuously. This renders

it necessary to use the notation of the differential calculus, and we have ~ = KC. The sign 5

ot

indicates that the reaction is a constantly changing one so that 5x and 8t represent such infinitely
small amounts that they can not be measured. By methods of integration, however, it can be shown
that the above equation may be written:

K= „ * log. nat. -£i-,

I 2 i v-2

thus permitting us to find the value of K (d C2 being the concentrations of cane sugar at the

Any two determinations during the course of the reaction can be used for calculating K. These
equations apply only to cases in which but one substance is changing (monomolecular reaction).
When two substances are involved, the equation is more complicated.

76 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

solution is 0.002, this means that when volume, concentration of acid and
temperature are constant in a gram-molecular solution of sugar, 0.002
gram-molecule of sugar would be inverted the first minute and 0.002
gram each succeeding minute, provided we could keep the solution con-
stantly a gram-molecular one, that is, provided we could add sugar just
as quickly as it becomes inverted.

At first sight it may appear of little practical importance to determine
K. In our present discussion concerning the nature of enzyme action,
it is however of great value for, whereas with inorganic catalysis K is
really of constant value, with enzyme action it is not so. Thus, when
cane sugar is inverted by sucrase — an enzyme present in the intestine
and in yeast — the constant gradually rises; for most other unimolecular
reactions mediated by enzymes it gradually falls ; for example, the action
of trypsin on proteins.

Where there is a great excess of substance to be acted on, in compari-
son with the amount of enzyme present, it will be found that a more
constant value than K is obtained when we compute the absolute amount
of substance decomposed in a given time. In such a case, too, the
amount of change in a given time will be proportional to the amount of
enzyme present, indicating that some sort of combination between en-
zyme and substrate must be the first step in the fermentative process.
This fact has been noticed by us in connection with the hydrolysis of
glycogen in the liver. When there is an excess of glycogen present, the
amounts which disappear in equal intervals of time after death are the
same; when, on the contrary, there is not much glycogen, the amount
which disappears gradually declines, but, if K be computed by the above
equation, it is constant.

To make these facts clear it may be well to pause for a moment to
consider an illustration. The conditions obtaining when there is a large
excess of substrate over enzyme may be compared to those governing
the removal of a pile of bricks from one place to another by a number of
men. The pile of bricks represents the substrate ; the men, the enzyme.
If each man works up to his capacity, it is plain that the number of
bricks transferred in a given time will 'not depend at all on the size of
the pile to be transferred. When, however, the pile of bricks gets small,
though the same number of men continue to Avork the number of bricks
transferred in a given time falls off, because the men interfere with one
another's activities in securing their loads from the pile. When a similar
stage is arrived at in enzyme processes, we have to use the velocity con-
stant to show how much work could be clone by the enzyme if the amount
of substrate were maintained of constant amount.

In the large volume of recent work which has been done with the

FERMENTS, OR ENZYMES 77

object of discovering the cause of these variations in the velocity con-
stant in the case of enzymes, four important conditions have been recog-
nized: (1) reversibility; (2) gradual destruction of the enzyme; (3) com-
bination of the enzyme with products of the reaction; (4) autocatalysis.

Of these four influences the only one which could be held accountable
for an increase in the activity of the enzyme is autocatalysis; in this
process the enzyme by its action produces substances which intensify
its own activity. In some cases at least — for example, the action of
invertase on cane sugar — these are acid bodies, a moderate increase in
acidity favoring the action of this enzyme.

The other influences all tend to retard the reaction and progressively
lower the value of K. Negative autocatalysis occurs when the enzyme
produces products which interfere with its activity. Gradual destruc-
tion of the enzyme and its union with the products of its activity -will
manifestly also decrease its power. There is plenty of evidence that
both of these processes may occur.

Reversibility of Enzyme Action

But the most important of all the causes of retardation of enzyme
activity is undoubtedly reversibility of action, which is an application of
the law of mass action (page 25). If we take the saponification of an
ester, the equation is:

CH3CH,CH,COOC2H:; + H2O ±5 CH3CH2CH2COOH + C2H3OH.
(ethyl buty rate) (butyric acid) (ethyl alcohol)

The equilibrium point is not so near the position of complete hydrol-
ysis as in the case of the inversion of cane sugar; in other words, the
tendency for the bodies produced by the hydrolysis to reunite and form
the original substances is quite marked, so that the reaction comes to an
end before all the ethyl butyrate has been decomposed. For some time
before the equilibrium point is reached, there will have existed a progres-
sively increasing opposition to the breakdown of the ester, as a conse-
quence of which, when enzymes are used to accelerate the reaction, the
velocity constant, as determined by the above equation, will gradually
fall as the reaction proceeds. Conversely, in a mixture of ethyl alcohol
and butyric acid there is very slow synthesis to ethyl butyrate, and here
again lipase accelerates the process; it induces a recognizable synthesis
within a short time. Ethyl butyrate is usually employed for these ex-
periments because, on account of its odor, the ester is readily recognized.
Thus, if the alcohol and acid be mixed alone, no ester will be detectable,
but if some lipase be added, it will soon become so. Similar synthetic
action of lipase has also been demonstrated for mono- and tri-olein.

78 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

It should be clearly understood that pure catalysts, such as the hydro-
gen ion, in accelerating a reaction like the above, do so equally in both
directions, so that the position of equilibrium remains unchanged. En-
zymes may, however, cause this position to change because of their form-
ing intermediate combinations.

The reverse phase of certain reactions is probably the cause of at least
some of the synthetic processes which occur in the animal body. A great
difficulty in accepting such a view, however, is the fact that the equilib-
rium point of all hydrolytic reactions, in the presence -of an excess of
water, is so near complete hydrolysis that very little synthesis can be
possible. That is true so long as the substance synthesized is soluble,
but if it is nearly insoluble in water, or if it is immediately removed
from the site of the reaction by diffusion, or in any other way, then it is
obvious that it will go on being synthesized by the reaction. Thus, in the
intestine neutral fat is hydrolyzed by pancreatic, lipase into fatty acid
and glycerol, which are absorbed into the epithelium, where they again
come under the influence of intracellular lipase. This latter will tend to
accelerate the synthesis of neutral fat from the fatty acid and glycerol
until the equilibrium point of the system (fat acid + glycerol *± neutral
fat + H20) is again reached; but this point, although it is near the right
hand of the equation, will really never be reached for the reason that the
neutral fat, as quickly as it is formed, will become deposited in insoluble
globules in the protoplasm and thus be removed from the equation. In
support of this view it has been found that lipase is present in intestinal
mucosa after all traces of adherent pancreatic juice have been washed
away. By similar reactions the fat of the tissues becomes decomposed to
fatty acid and glycerol and passes out of the blood when the concentra-
tion of fat in this fluid falls below a certain level. Provided one of the
substances synthesized is insoluble or can in some other way be removed
from the reaction, it is plain that, even though the equilibrium point is
very near to that of complete hydrolysis, yet the reversion will be suf-
ficient to do all that is required of it.

Results such as the above have prompted many to conclude that it is
by such reversible action that all synthetic processes occur in the living
organism. But the demonstrable synthesis of an ester must not be taken
as evidence that all other syntheses are explainable on the same basis.
For example, we have seen above that in the case of cane sugar the equi-
librium point in the equation is so near that of complete hydrolysis, that no
measurable amount of cane sugar is formed when dextrose and levulose are
allowed to act on each other, and that cane sugar does not appear
when sucrase is added to the mixture. If instead of sucrase we take
another of the sugar enzymes — namely, maltase, which accelerates the

FERMENTS, OR ENZYMES * 79

decomposition of maltose into two molecules of glucose — there is, how-
ever, evidence of synthesis as a result of the acceleration of a reversible
reaction. To understand these results we must remember that ordinary
dextrose is a mixture of tAVO stereoisomers designated a and (3. When
- two molecules of a dextrose condense (that is, fuse togther with the
loss of a molecule of water) maltose is formed, but when two molecules
of (3 dextrose condense isomaltose results. There is some controversy
as to whether maltase is really responsible for the synthesis of a dextrose
molecules to maltose, it being claimed by some that this is accomplished
by another enzyme, emulsine. If this were true it would materially
minimize the importance of reversible action as a factor in cellular syn-
thesis. The latest evidence goes to show, however, that it is maltase
and not emulsine that is responsible in the above case (cf. Bayliss).

Evidence, both direct and indirect, is also steadily accumulating to
show that enzymes may accelerate the synthesis of proteins. As pieces
of indirect evidence we have: (1) the retardation of the digestive action
of trypsin, etc., which sets in after the process has gone on for a time,
and (2) the recommencement of a digestive process apparently at an
end, if the products of the digestion are removed by dialysis or other
means. As direct evidence may be cited the formation of synthetic
products when pepsin is added to concentrated solutions of peptone,
and the diminution in the number of small molecules, as judged by meas-
urements of electrical conductivity, when trypsin is added to the prod-
ucts of tryptic digestion of caseinogen. Protamine — a simple form of pro-
tein— has also been found to be produced when trypsin — obtained from
a mollusc — was added to a tryptic digest of the same protamine. The
significance of these facts in connection with the metabolism of the
ammo acids will be evident when we come to study this subject (page
634).*

Specificity of Enzyme Action

Although in all of the above features of enzyme action there is nothing
to contradict the view that they are catalytic agents, there remains one
peculiarity which at first sight seems uninterpretable on such a basis.
This is with regard to their often remarkable specificity of action. Thus,
as we have seen, maltase can hydrolyze maltose alone (which is com-
posed of two a-dextrose molecules), but not isomaltose (composed of
/^-dextrose). This means that mere difference in the configuration of
molecules is sufficient to alter the influence of enzymes on them. Since
such differences could not influence that of inorganic catalysts we must

*We have been unable in this laboratory to demonstrate any synthesis of glycogen when gly-
cogenase is added to a hydrolysis mixture of dextrine, maltose and glucose produced by the prolonged
action of glycogenase on pure glycogen.

80 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

explain the cause of the difference. This has been done on the basis
either that enzymes are colloids or that the active (catalytic) group of
the enzyme is attached to a colloid molecule. Before a substance can
be acted on, it must combine with the colloid, which it does by the proc-
ess of adsorption (see page 66). This can occur, however, only when
there is a harmony between the adsorbing substance and the substance
adsorbed. Instances of the specificity of adsorption have already been
given.

In support of this view it has been found that of the two proteases,
a and /?, in the spleen, one is adsorbed but not the other when a solu-
tion containing them is shaken with Kieselguhr. Furthermore, when
solutions of invertase are shaken with certain inert powders, the in-
vertase is adsorbed by some of them but not by others. In strong sup-
port of the adsorption hypothesis is also the fact that the same mathe-
matical laws as apply in the process of adsorption are obeyed in the
ratio which exists between the activity of an enzyme and its concen-
tration in the solution.

To sum up, then, catalysis as exhibited by enzymes involves three
processes: (1) contact between the enzyme and the substrate, which will be
dependent on their rates of diffusion; (2) adsorption between them, which
will depend on their configurations (cf. the lock and key simile) ; and
(3) the chemical change which itself probably takes place in two stages.
In connection with the third process, it is probable that an initial com-
pound of a definite chemical nature is first formed, followed by the
hydrolytic or other chemical change, after which the enzyme group
becomes free.

It is very significant in this connection to note that in their solubil-
ities there exists a distinct relationship between the ferments and the
substrates on which they react. Thus, trypsin is very soluble in water
and acts on water-soluble proteins; lipase is soluble in fat solvents.

Certain Peculiarities of Enzymes

Notwithstanding the very strong case that is made out for the cata-
lytic hypothesis, there are certain facts which many find it difficult to
make conform with such a view. One of these is that dextrose can
undergo three distinct and separate types of decomposition according
to the enzyme allowed to act on it. These are alcoholic fermentation,
butyric acid fermentation and lactic acid fermentation. It is difficult
to see how simple catalytic action can be responsible for all three results.
The enzyme must not only initiate the changes but also direct their
course.

Another peculiarity is that when certain enzymes — e. g., rennin, pep-

FERMENTS, OR ENZYMES 81

sin, etc. — are inoculated in animals, they cause specific antienzymes to
appear in the blood of the inoculated animal. Thus, when antirennin
serum is added to milk it greatly hinders clotting on the subsequent
addition of rennin. It is probable that powerful antienzymes are pro-
duced in the animal body for the purpose of protecting the tissues from
attack by enzymes. It is on account of the presence of antienzymes
that intestinal parasites can exist in the intestine, and the immunity
from digestion which the mucosa of the gastrointestinal tract enjoys,
is believed to be due to the same cause. But there is considerable doubt
regarding this claim. Fresh pancreatic juice when injected into the
empty intestine digests its walls. When food is present in the intes-
tine it evidently prevents digestion of the walls by diverting the enzyme
to itself.

Types of Enzymes

Having learned something about the general nature of enzyme action,
we may now turn our attention to certain details that have a practical
importance. In the first place, with regard to nomenclature, in the
earlier work each newly discovered enzyme received a name which was
often quite inappropriate. Many of these names are retained, such as
pepsin, trypsin, ptyalin, etc., but it is now customary to name the
enzyme according to the substance on which it acts. This is done either
by replacing the last part of the name of the substance acted on by the
termination -ase (for example, the enzyme which inverts maltose is called
maltase), or by merely adding -ase to the name of the substance acted
upon (thus, the enzyme which hydrolyzes glycogen is called glycogenase).

Most of the enzymes in the animal body accelerate hydrolytic proc-
esses and are classified according to the chemical nature of the sub-
strate on which they work. Thus, we have:

1. The amylases — accelerating the hydrolysis of polysaccharides, e.g.,
ptyalin (in saliva), amylopsin (in pancreatic juice), glycogenase (in
liver), diastase (in malt).

2. The invertases — accelerating hydrolysis of disaccharides, e. g., malt-
ase, lactase and sucrase (in succus entericus).

3. The proteinases — accelerating hydrolysis of proteins, e. g., pepsin
(in gastric juice), trypsin (in pancreatic juice), erepsin, intracellular
proteinases.

4. The Upases — accelerating disruption of neutral fats, e. g., steapsin
(in pancreatic juice), intracellular lipases.

5. Arginase — accelerating hydrolysis of arginin into urea and or-
nithin, (intracellular).

82 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

6. Urease — accelerating hydrolysis of urea to ammonium carbonate
(in many microorganisms and in the soy bean).

7. Glyoxylase — converting glyoxals into lactic acid (page 698).
Other enzymes accelerate oxidative processes and are called oxidases

and peroxidases. Others bring about the displacement of an amino
group by hydroxyl (desamidases) . Others cause coagulation (coagula-
tive ferments] , e. g., thrombin, rennin. One of the enzymes present in
succus entericus acts by converting the zymogen (trypsinogen) into the
enzyme (trypsin).

Enzyme Preparations

So far it has been impossible to prepare enzymes in a pure state al-
though, being colloidal in nature, they are readily precipitated or ad-
sorbed along with other colloids.

Since most enzymes exist in cells, it is necessary to break up the cells
in order to isolate the enzyme. This is done in various ways. By one
method the cells are ground in a mortar with fine sand, then made into
a paste with infusorial earth (Kieselguhr), the paste enclosed in stout
canvas and placed under an hydraulic press at about 300 atmospheres
pressure; a clear fluid separates and this contains the enzymes. An-
other way is to freeze the tissue with liquid air and grind it in a steel
mortar by means of a machine. Still another and less expensive method,
and one which we have found most useful for organs and tissues, con-
sists in reducing the tissue to a pulp and, after sieving it to get rid of
connective tissue, etc., spreading the pulp on glass plates and drying
in a slightly warmed, dry air current. The scales of dried material are
then ground in a paint mill with toluene, and the resulting suspension
filtered ; the powder which remains on the filter, after thorough washing
with toluene, is dried and kept for future use. The toluene removes all
the fatty substances, so that when shaken with water, etc., the enzymes
dissolve.

Conditions for Enzymic Activity

Reactions brought about by intracellular enzymes are very readily
inhibited when there comes to be a certain accumulation of their prod-
ucts of action. Thus, yeast ceases to ferment sugar when the alcohol
has accumulated to a certain percentage. This action is partially due
to a toxic action of the alcohol on the cell, which paralyzes its power of
absorbing the substance to be acted on by the intracellular enzyme. If
these products be not in some way removed, they will ultimately kill
the cell and stop the fermentation. We have seen above how the ac-
cumulation of products may interfere with the activities of enzymes in

FERMENTS, OR ENZYMES 83

other ways in which the enzyme does not suffer .destruction, as is shown
by the fact that it resumes its original activities on removal of the
products.

Enzymes, both intracellular and extracellular, are very sensitive to-
wards the inorganic composition of the medium in which they are act-
ing. For the intracellular enzymes this is what \ve should expect when
we bear in mind the profound influence of inorganic salts on the heart
beat and on cell growth and division. This influence of salts and of
reaction (acidity, etc.) on the life of the cell is so pronounced as to lead
some observers to believe that abnormal cell multiplication in the body,
as in the case of tumor formation, is due to changes in the inorganic
composition of the tissue fluids. Extracellular enzymes are also very
susceptible to the influence of inorganic salts but more especially so
towards the reaction of the solution. In terms of modern chemistry
we may say that the concentration of H- and OH' ions has a profound
influence on the activities of enzymes. Most of the enzymes of the an-
imal body perform their action normally in the presence of a slight ex-
cess of OH' ions, that is, in faintly alkaline reaction. Indeed the only
exception of importance to this is the pepsin of gastric juice, which nor-
mally acts in an acid medium. An excess of either OH' or H- ions
inhibits the activity of the enzyme and usually destroys it permanently.
The activities of enzymes are also influenced by light, many of them
being destroyed by sunlight; cells such as microorganisms are similarly
affected.

Before being secreted the digestive enzymes exist in the cells which
produce them as inactive precursors called zymogens. The granules seen
in resting gland cells are of this nature. The activation of the zymogen,
or its conversion into the enzyme, occurs after it has left the cell, and
this has been considered as another safeguard to digestion of the cell.
Sometimes the activation does not occur until the zymogen has travelled
some distance along the gland duct, as in the case of the proteolytic
enzyme of pancreatic juice. Till it reaches the intestine, this exists as
trypsinogen (the zymogen), but it is here acted on by another enzyme-
like body produced by the intestinal epithelium and called enterokinase

PHYSICOCHEMICAL REFERENCES

(Monographs and Original Papers)

]Bayliss, W. M.: Principles of General Physiology, Longmans, Green & Co., 1915.
2Philip, J. C.: Physical Chemistry, Its Bearing on Biology and Medicine, Arnold,

ed. 2, 1914.
3McClendon, J. S.: Physical Chemistry of Vital Phenomena, Princeton University

Press, 1917.
*Starling, E. H.: Principles of Human Physiology, ed. 2, 1915, Lea and Febiger.

84 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

^Kahlenberg, L.: Jour. Physical Chem., 1006, x, 141.

eKeid, E., Weymouth: Jour! Physiol., 1898, xxii, Ivi.

T Wilson, T. M.: Am. Jour. Physiol , 1905, xiii, 150.

sllaldane, J. S., and Priestley, J. G.: Jour. Physiol., 1910, 1, 296; Priestley, J. G.:

Ibid., p. 304.

aClark, W. M., and Lubs, H. A.: Jour. Bacteriology, 1917, ii, 1 and 109.
loHenderson, L. J.: The Excretion of Acid in Health and Disease, Harvey Lectures,

J. B. Lippiricott Co., 1915, x, 132.

nHenderson, L. J.: The Fitness of the Environment, Macmillan, N. Y., 1913.
i^Van Slyke, D. D. : Jour. Biol. Chem., 1917, xxx, 289, 347, 363.
isLevy, E. L., and Eowntree, L. G.: Arch. Int. Med., 1916, xvii, 525.
"Cullen, G. E.: Jour. Biol. Chem., 1917, xxx, 369.
ispalmer, W.- W., and Henderson, L. J. : Arch. Int. Med., 1913, xii, 153; and Jour.

Biol. Chem., 1912, xiii, 393 ; xix, 81 ; xvii, 305 ; xxi, 37.
"Bollards, A. W.: The Principles of Acidosis and Clinical Methods for Its Study,

Harvard University Press, Cambridge, 1917.
i?Lloyd, F. H.: Private communication.
isMacallum, A. B, : Surface Tension and Vital Phenomena. University of Toronto

Studies, No. 8, 1912; also Ergebnisse der Physiologic, 1911, ii, 598.
19Bayliss, W. M.: Enzymic Action, ed. 2. Monographs in Biochemistry, Longmans,

Green & Co.

2°Bayliss, W. M. : Neutralisation, etc.
siHaggard, and Henderson, Y. : Jour. Biol. Chem., 1919.
22Christiansen, Douglas, and Haldane, J. : Jour. Physiol., 1914, xlviii, 246.
23Morawitz, P., and Walker, J. C.: Biochem. Ztschr., 1914, Ix, 395.
2'*Macleod, J. J. K. : Jour. Lab. and Clin. Med., 1919, iv, 1.
25Bradford, S. C. : Biochem. Jour., 1918, xii, 351.

PART II
THE BLOOD AND THE LYMPH

CHAPTER X

BLOOD: ITS GENERAL PROPERTIES
(Partly Contributed by R. G. PEARCE)

The blood, being the carrier of the nutritive and waste substances of
the body's metabolism, must at one time or another contain all the ma-
terials which compose the tissues in addition to those which are peculiar
to the blood itself. It is a very complex fluid, and all of its constituents
are not fully known. Structurally it is composed of water in which are
dissolved various gases and organic and inorganic bodies, the corpuscles
and platelets.

THE QUANTITY OF BLOOD IN THE BODY

The volume of blood in the body may be measured by bleeding and
subsequently washing out the blood from the vessels and then estimating
the amount of hemoglobin in the total fluid (Welcher's method). This
method employed in the case of two criminals who had been decapitated
gave the weight of the blood as 7.7 and 7.2 per cent of the body weight.
Bloodless methods for determining the total volume of blood are based
upon the principle of adding a definite quantity of a known substance to
the circulation and then estimating its concentration in a sample of blood
withdrawn from the body shortly afterward. If the substance can not
leave the blood vessels and does not cause fluid to be withdrawn from the
tissues, the total quantity of blood in the body can be calculated from the
concentration of the injected substance in the blood. The most accurate
methods based on this principle are Haldane and Smith's, in which car-
bon monoxide gas is inhaled in a given amount and the carbon monoxide
hemoglobin subsequently determined colorimetrically ; and Keith,18 Rowii-
tree and Geraghty's,20 which employs vital red, a dye of low diffusibility.
The dye remains long enough in the body to be thoroughly mixed with the
blood, and its concentration in the plasma is determined colorimetrically
by comparing with a suitable standard mixture of dye and serum. These

85

86 THE BLOOD AND THE LYMPH

methods give the total amount of blood in the body as from 5 to 8.8 per
cent of its weight. Meek has recently developed a method in which gum
acacia is used. After mixing with the blood, the concentration of this
substance is determined from the calcium content. Being colloid, none
of the gum leaves the blood vessels.

The vital red method is employed as follows: A 1.5 per cent solution of vital red is
preserved in sterile condition in 15-20 c.c. quantities. A needle is inserted in the
basilic vein and 6-8 c.c. of blood withdrawn into a dry syringe containing finely pow-
dered pot. oxalate. The syringe is removed from the needle, and another syringe con-
taining an amount of the vital red solution corresponding to 3 mg. vital red per kilo body
weight, is connected with the needle and the dye slowly injected. The blood removed
in the first syringe is now transferred to a paraffined centrifuge tube, and in about
10 minutes a third syringe is connected with the needle and 8-10 c.c. of blood removed
and transferred to two paraffined tubes. From one of these a specimen is taken for
the hematocrit. The tubes are then centrifuged rapidly for some time. The dilution
of dye in the plasma is now determined colorimetrically, using1 as a stanclard the fol-
lowing: 1 c.c. diluted dye (0.5 e.c. of the original dye solution to 100 c.c. 0.8 per cent
NaCl sol.)

1 c. c. plasma before injection

2 c. c. 0.8 per cent NaCl.
and using as test .solution

1 c. c. plasma after dye injection

3 c. c. 0.8 per cent NaCl.
The formula for calculation is

200

- X c- c- dye injected X 10° = c- c- plasma
E
Where R — per cent reading of test solution.

By use of the above method Keith, Rowiitree and Geraghty found that
in man the plasma normally constitutes 5 per cent or %0 the body weight,
i.e., 50 c.c. plasma per kg.

To determine total blood volume the hematocrit must also be used, and
it was found that the total volume = 8.8 per cent or l/11.4th of body
weight. Normal individuals therefore have 85 c.c. blood per kg.

In pregnancy, before term the blood and plasma volumes are increased,
but within a week or so of delivery the volumes return to normal. In
obesity the plasma and blood volumes are relatively small. Many cases
of anemia exhibit a relatively larger plasma volume. Hypertension may
be accompanied by a small blood volume, therefore this condition is not
due to large blood volume.

The newer methods have shown that the volume of the circulating
fluid is maintained fairly constant in spite of influences tending to alter
it. The body accomplishes this by drawing upon the reserve fluid in
the tissues and by varying the rate of water excretion, particularly
through the kidneys. Years ago the doctrine of an increased amount of

BLOOD: ITS GENERAL PROPERTIES 87

blood in the body (plethora) gave rise to the therapeutic use of bleeding.
Especially was this thought to be useful in conditions which wre now
recognize as chronic hypertension, and which show no increase in blood
volume. Indeed variation in blood volume is not common, although
plethora may occur in polycythemia, chlorosis, and anemias, and there
may be a temporary reduction in the amount of blood in diseases in
which there is a great depletion of water, as in Asiatic cholera, and fol-
lowing very severe hemorrhage.

While the total quantity of the blood in the body does not vary greatly,
the concentration of its various constituents is subject to distinct change.
The volume percentages of the corpuscles and the plasma can be approx-
imately determined by allowing oxalated blood to sediment or by cen-
trifuging in a graduated cylinder by the use of the hematocrit. Such
methods are not very reliable, but may yield some important information.
Normally 45 to 50 per cent of the volume of blood is composed of cor-
puscles. It varies more or less directly with the number of red blood
cells.

THE WATER CONTENT OF THE BLOOD

Since the blood plasma is essentially a watery solution, some idea of
its water content can be obtained by a determination of the specific
gravity. The most accurate method for accomplishing this is to deter-
mine directly the weight of a given volume of blood and compare it
with the weight of the same volume of water. Since this method re-
quires a rather large amount of blood, indirect methods using smaller
amounts have been devised. One of these (Hammerschlag's) uses a
solution of chloroform and benzol of a specific gravity of about- 1.050,
in which a drop of blood is suspended by delivering it cautiously from
a pipette bent at right angles near its tip. If the drop sinks, chloroform
is added; if it rises, benzol is added until the drop remains suspended.
The specific gravity of the benzol-chloroform mixture is then determined,
and this value is supposed to give the specific gravity of the blood.

The specific gravity of the blood determined in this way varies be-
tween 1.040 and 1.065. It is somewhat less after eating and increases
after exercise; it is slightly lower during the day than at night, and
the variation in individuals is considerable. The changes which occur
in the specific gravity of the blood in disease are chiefly due to variation
in the percentage of protein, since the salt content of the blood is rela-
tively fixed. It is only when great changes occur in the concentration
of the noncolloidal salts that they markedly affect the specific gravity.

From 90 to 92 per cent of the plasma and from 59.2 to 68.7 per cent of
the corpuscles consist of water. Of the whole blood, from 60 to 70 per cent

88 THE BLOOD AND THE LYMPH

by volume or about 55 per cent by weight consists of plasma; and from
40 to 30 per cent by volume or 45 per cent by weight consists of cor-
puscles.

THE PROTEINS OF THE BLOOD

The plasma obtained by centrifuging the blood rendered noncoagula-
ble by oxalates, hirudin or other means (see page 100), contains 5 to 8
per cent of c.oagulable proteins. These proteins are serum albumin,
serum globulin, and fibrinogen. They can be separated from each other
by the use of acids and neutral salts. Their proportion varies under dif-
ferent conditions, but is approximately as follows:

Fibrinogen 0.15-0.6%

Serum globulin 3.8%

Serum albumin 2.5%

The amount of fibrinogen is subject to the greatest variation (Mathews).

Fibrinogen

The least soluble of the blood proteins is fibrinogen. The plasma is
almost freed of it by half-saturation with sodium chloride, or with a
small amount of acetic acid. It is precipitated as fibrin in the process
of blood coagulation (see page 102), and is estimated by weighing the
amount of fibrin which it produces.

Serum Globulin and Serum Albumin

Globulins are ordinarily defined as being insoluble in distilled water,
and albumins as being soluble. It is, however, impossible to separate
serum globulin and albumin satisfactorily in this manner. The globu-
lin obtained by dialysis can be returned to solution by the addition of
a suitable amount of water, which makes the salt adherent to the pre-
cipitate a weak saline solution. In neutral or acid solutions it is coag-
ulated by heat at about 75° C. But it does not act as an individual pro-
tein, since a portion of it is precipitated by dialysis or by carbon diox-
ide. Probably serum globulin really consists of two or more proteins.

The serum albumin remaining in solution after saturation with am-
monium sulphate likewise does not represent a chemical entity. It is
possible by carefully heating the solution of serum albumin to distin-
guish three separate coagulation temperatures. This fact has been in-
terpreted as meaning that the serum albumin consists of at least three
closely related proteins.

Since the refractive index of the blood depends primarily upon the

BLOOD: ITS GENERAL PROPERTIES 89

amount of protein present, this has been taken as a means of determining
variations in the concentration of the proteins. It has been found that
the concentration of the blood proteins varies somewhat; during ex-
ercise it is increased probably because of the taking up of water by
the tissues, and during profuse bleeding it is diminished because
large amounts of fluid are being added to the blood from the lymph,
which is relatively poor in proteins. The ingestion of considerable
amounts of salts has been found to reduce the concentration of the blood
proteins for a short time. In pathological conditions, as in diabetes, when
rapid changes in the body weight due to alterations in the diet are oc-
curring, changes in the fluid content of the blood are often observed.
Likewise in edema caused by faulty renal function, there may be a re-
tention of fluid in the blood before there is any indication of edema. The
hydremic condition of the blood can therefore be considered as a useful
diagnostic aid in determining the water metabolism.

The relative concentration of the proteins of the blood is also of some
interest, especially since in certain diseases a considerable amount of
blood protein is lost. By refractrometric methods it is possible to sep-
arate the globulin and albumin fractions. Normally the total proteins
range between 6.7 and 8.7 per cent, of which the albumins lie between
4.95 and 7.7 per cent, and the globulins between 1 and 2.54 per cent. In
some diseases, as in chronic nephritis, pneumonia, and syphilis, the
total proteins of the blood are decreased and the relative amount of
serum globulin is increased On the other hand, in many mild infections
and chronic septic conditions the globulin fraction may be increased
with no change occurring in the total protein content.3

Our knowledge of the origin and the function of the blood proteins is
quite unsatisfactory. Previous to the discovery of amino acids, the
building stones of the proteins, in the blood it was thought that the
nitrogenous nutrients were converted somehow into blood proteins dur-
ing or immediately following their absorption from the alimentary
canal, and that the tissue cells were nourished from this common pro-
tein. It is now known that the amino acids are not immediately syn-
thetized into blood proteins after their absorption from the digestive
system. The blood proteins are radically different from the tissue pro-
teins. Substances which retard or accelerate nitrogen metabolism do
not alter the relationship existing between the protein bodies of the
blood. This fact indicates that the serum proteins have a function quite
independent of the nitrogenous metabolism of the body. They un-
doubtedly maintain the viscosity of the blood and assist in preserving
its neutrality. Attempts to localize the site of formation of the blood
proteins have not been successful. There is some evidence that fibrin-

90 THE BLOOD AND THE LYMPH

ogen is formed for the most part in the tissues of the splanchnic area
(liver). It is quite possible that the blood forms its own proteins, just
as do other tissues, from the amino acids it contains.

THE FERMENTS AND ANTIFERMENTS OF THE BLOOD

The blood plasma contains many of the ferments present in the tissues.
The nature of these ferments has been the subject of many investiga-
tions in recent years, primarily because it has been found that they are
intimately connected with the problems of immunity.

Among the ferments the following have been demonstrated in the
blood:

Proteases are probably present normally in the human blood serum
in small amounts, but they are found in large amounts in the white
blood corpuscles. A protein foreign to the body if injected into the
blood ordinarily produces no untoward symptoms, but a second injec-
tion following the first by some days will produce symptoms of poison-
ing known as anaphylaxis. This fact has led to the assumption that
the injection of any foreign protein into the blood promptly leads to
the appearance therein of specific proteolytic enzymes which will digest
the strange protein into its derivatives, which are poisonous. This
power of the body to produce specific proteases has been the subject
of much research and debate, and Aberhalden proposed a test for preg-
nancy, for cancer, and for other conditions in which he made use of this
phenomenon. He believes that the presence of placenta or tumor tissue
causes proteins to be formed which bring about the production of specific
ferments whose duty it is to rid the system of these substances. Other
investigators fail to find the specificity in proteolytic action claimed by
Abderhalden, and believe that proteolytic ferments which are capable
of digesting foreign proteins are absorbed from the alimentary canal
from the digestive juices (Boldyreff). Some investigators fail to confirm
the claim that the proteolytic activity of the blood serum is increased under
the above conditions.

Blood contains an antiferment known as antitrypsin. This can be
removed from the blood serum by several substances, among which are
kaolin, colloidal iron and starch. Serum thus treated shows strong pro-
teolytic activity and autodigestion will occur. In this case there can be
no question of the specific origin of proteases. Abderhalden believes
that the ferments of the blood of the pregnant woman are able to digest
the placenta! tissue. Human placental tissue has the ability of absorb-
ing antitrypsin and it is very questionable as to whether the test pro-
posed by Abderhalden is due to the new formation of ferments or to

BLOOD: ITS GENERAL PROPERTIES 91

the removal of the antitrypsin and the action of the protease normally
present in the blood.

Nucleln ferments are capable of decomposing nucleic acid and purins
into the simpler bodies.
- Lipases have been demonstrated in the blood.

Amylase. — The presence of starch-splitting ferments in the blood was
first shown by Magendie in 1841, and later Bernard showed that gly-
cogen or starch injected into a vein produced glycosuria. Since then
it has been proved conclusively that diastatic enzymes are normally
present in the blood and lymph. The source of these enzymes has given
rise to much speculation. Some observers believe that they are derived
from the amylopsin of the pancreatic secretion, while others believe that
they are manufactured by the liver. Ligature of the pancreatic ducts
is said to increase the amount of amylase, while removal of the pan-
creas may (Carlson and Luckhart) or may not (Schlesinger) increase
the amylase of the blood. In some forms of experimental diabetes the
amylase of the blood has been found increased, and this is the case in
human diabetes (Myers and Killian). If this is true, a cause for the
inability of the diabetic to store up glycogen is found. In impairment
of renal function, there is usually an increase in the blood amylase and
a decrease in the urine amylase. This has been suggested as being of
diagnostic value.

The blood contains a feeble glycolytic enzyme capable of destroying
glucose. It is claimed that this power is reduced in diabetics (Lepine).

Catalase is found in the blood and tissues generally. It has the power
of liberating oxygen from hydrogen peroxide without any accompany-
ing oxidation process. Its physiological significance is not known. It
is said that the amount of catalase is increased during excitement and
exercise, and is decreased in conditions where the body's activity is
lowered. Its determination is clinically unimportant at present.

CHAPTER XI

BLOOD: THE BLOOD CELL

(Contributed by R. G. PEARCE)

THE RED BLOOD CORPUSCLES, OR ERYTHROCYTES

The most prominent function of the blood is to carry oxygen to the
tissues. It owes this property chiefly to the red blood cells which are
present in large numbers (5,000,000 per c.mm. of blood). These cells
are biconcave discs, having a diameter of about 7.7 ju. They are con-
structed out of a framework composed largely of lipoid material, in
the meshes of which is deposited a substance called hemoglobin, to
which the remarkable oxygen-carrying power of the blood is due. Nei-
ther the manner by which the red cell carries its hemoglobin nor the
intimate structure of the cell itself is accurately known. It is com-
monly believed that the hemoglobin is held enmeshed in a framework
or stroma, or encased in the cell membrane. One thing is certain, how-
ever, that the union of hemoglobin with the stroma of the red cell is
a fairly strong one, since mere fragmentation of the corpuscle fails to
liberate the hemoglobin. The fact that the framework contains a large
amount of lipoid substances enables the corpuscles to maintain their shape
and is responsible for their characteristic permeability.

Hemoglobin is a very complex substance belonging to the group of
conjugated proteins. By chemical means it can be broken up into a
simple globulin and a pigment hematin, containing iron. When com-
pletely saturated, oxygen is present in hemoglobin in the proportion
of two atoms of oxygen to one atom of iron (Peters); or 401 c.c. of
oxygen can 'be carried by hemoglobin containing one gram of iron, the
molecular weight of the molecule being about 16.669, or some multiple
thereof (Barcroft and Peters) (see also page 392). At this figure the
iron in the molecule would represent 0.34 per cent of the total weight
of the molecule. The corpuscular surface area has been estimated to
be 3200 square meters. There is therefore a very large surface avail-
able for the absorption of oxygen from the alveolar air, as the blood
corpuscles pass in single file through the capillaries of the lungs.

Since the amount of oxygen which the blood can carry depends upon
its hemoglobin content, it is of some importance clinically to have

92

THE BLOOD CELL 93

methods of determining the approximate amount present. The amount
of hemoglobin present in a quantity of blood is usually determined
colorimetrically by comparing the color of the blood with standard col-
ors which correspond to known strengths of hemoglobin. In normal
persons the amount of hemoglobin varies greatly at different ages, and
in order to determine whether or not a given blood contains more or
less hemoglobin than normal, it is imperative to consider the age. The
greatest variations occur between birth and the sixteenth year. After
the sixteenth year the blood in males usually contains a larger amount
than that in females (Williamson4). Instruments used in determining
the amount of hemoglobin should be standardized to give the value in
grams hemoglobin per 100 c.c. of fluid.

The amount of hemoglobin which is present in each corpuscle in
terms of normal is therefore of some clinical interest. This relation of
the number of red cells to the amount of hemoglobin is known as the
color index and is computed as follows: The average red count in man
is 5,000,000 to the c.mm., and the average minimal amount of hemo-
globin is taken as 13.88 grams in 100 c.c. of blood (=80, Sahli; =90,
Miescher; =86, Plesch; and 110, Tallquist methods). These relative
values give a color index of one. The percentage of normal red cells
divided by the percentage of normal hemoglobin present gives the
color index.

The Origin of the Red Blood Cells

In fetal life the spleen and the liver are generally believed to be re-
sponsible for the formation of the red blood cells. In extrauterine life
this function is taken over by the red bone marrow. In the primitive
condition all red blood cells are supposed to be nucleated. In extra-
uterine life the nuclei of the red cells are lost, and nonnucleated forms
are alone present in the blood stream. In fetal life and in certain path-
ologic conditions, the rate of blood formation is so rapid that some
nucleated cells appear in the blood. The normal response of the body
to a loss of red blood corpuscles consists in an increased activity of the
blood-forming cells of the red bone marrow. It is not easy to follow
the course of the regeneration of the red corpuscles or to discover the
mechanism of their formation in the bone marrow, since this tissue pre-
sents a mixture of cells which are precursors of the varied corpuscles
found in the blood and the identity of which can not be determined.

Recently new methods of staining blood for microscopic examina-
tion have allowed more detailed study to be made on the site and
method of blood cell formation. When fresh unfixed blood is treated
with solutions of various dyes, such as brilliant cresyl blue, polychrome

94 THE BLOOD AND THE LYMPH

methylene blue or neutral red, an otherwise invisible structure appears
in some cells in the form of coarse granular particles or threads, which
give a reticulated appearance to the corpuscles. These reticulated cells
are more abundant in infants' blood and in patients suffering with se-
vere anemia or hemolytic jaundice than in normal blood, and may be
taken as evidence of the youth of the red cell and not as a degenera-
tive process. Since the number of the reticulated cells that are present
in the blood is more or less directly proportional to the hemopoietic
activities of the bone marrow, enumeration of the reticulated cells is
of clinical importance in anemias. In conditions in which animals have
been made plethoric by the transfusion of blood, it has been found that
the number of reticulated cells is decreased; the bone marrow of these
animals also shows a marked reduction in reticulated erythroblasts.
The diminished rate of blood cell formation sometimes noted after blood
transfusions may be explained by assuming that the stimulus which
awakens the formation of red cells in the bone marrow is absent or
made subnormal on the injection of red cells into the blood, and thus
the formation of red cells is depressed. Small transfusions are there-
fore preferable to large ones in cases in which the rate of blood forma-
tion is greatly impaired. By means of living cultures of red bone mar-
row the different stages of the development of the normoblasts into
true red corpuscles may be studied (Tower and Herm5). Some evidence
has been gathered from such studies which points to the conclusion that
in place of the red cells being cells which have lost their nucleus, as is
the current teaching, they are rather cells which develop as a nuclear
bud and escape into the circulation as true red cells. The nucleated
red cell and the red nucleated corpuscle of the bird are the product of
intranuclear activity and are morphologically identical.

Rates of Regeneration of Erythrocytes

Microscopic examination of the blood during rapid regeneration of
red cells shows the presence of nucleated forms. Nucleated red cells
in the blood have therefore been taken as an inevitable feature of rapid
blood regeneration. The evidence upon which this belief depends,
however, is hardly complete, since changes in the manner of red blood
cell formation may be responsible for the nucleated forms. Th'e red
bone marrow is considered the seat of red cell formation, and it is true
that an abnormal increase in the red bone marrow usually accompanies
increased red cell formation. The nature of the stimulus which brings
about the new formation of red cells is not understood. Oxygen want
may be an important factor, since we find the presence of an abnormally
large number of red cells in conditions where there is a scarcity of

THE BLOOD CELL 95

oxygen in the inspired air, as in life at high altitudes, or a difficulty in
its absorption through the lungs, as in congenital heart disease.

The red cells produced following hemorrhage and in simple anemia
contain less than the normal amount of hemoglobin, but their shape and
size are approximately normal, and few nucleated cells are present. In
the regeneration of red cells which is found in pernicious anemia, we
find the cells containing an unusually large amount of hemoglobin.
The red cells in this disease have abnormal forms, many being large,
with or without a nucleus, and containing basic staining granules.
This type of blood cell formation is due to degenerative changes.

The Fate of the Erythrocytes

The length of life of the red blood cell is unknown. Estimates based
upon the daily excretion of bile pigments are not reliable, since Hooper
and Whipple have shown that the pigments, in part at least, arise from
pigments which the liver has made in excess of its needs for the manu-
facture of hemoglobin, and which, not being needed, are excreted.15
There is no question however that every erythrocyte sooner or later
undergoes disintegration, a process formerly thought to be ushered in
by the ingestion of the red blood cell by a phagocyte in the spleen or
in a hemolymph gland, the hemoglobin of the disintegrated cell being set
free and carried to the liver, where it is broken up into hematin, which
the body stores for future use, and into bile pigments, which are ex-
creted. Rous and Robertson6 fail to find evidence that this process
occurs in man to an extent sufficient to account for the normal destruc-
tion of the blood cells. However they have recently found another and
unsuspected method for blood destruction in all animals thus far
studied — namely, the disintegration of the blood cells by fragmentation
while they are circulating, without loss of their hemoglobin. These
fragmented cells are found most frequently in the spleen. They believe
that the small ill-formed cells, known as microcytes and poikilocytes,
observed in severe experimental anemias, are due not to the fact that
they are produced by the bone marrow, but rather to the fact that the
marrow in its anemic condition is not able to produce a resistant ery-
throcyte, and fragmentation therefore takes place too readily. A sim-
ilar condition may exist in the severe anemias of man and account for
the general high resistance of the red cells found in the blood of these
patients, inasmuch as the weak cells are generally fragmented very soon
after they are formed. Long ago Ehrlich stated that the microcytes
and poikilocytes of anemia are the result of fragmentation of the cells
in the circulating blood, but he believed that this fragmentation was a

96 THE BLOOD AND THE LYMPH

purposeful division in order to increase the total surface of the red
cells. The ultimate fate of the red cell fragments is not known. It is
reasonable to suppose that the fragmented bits containing hemoglobin
are carried to the liver, where the hemoglobin is transformed into
hematin and bile pigments.

Hemolysis

Another method of red blood cell destruction, which, however, does
not take place normally, is by hemolysis. The nature of the combina-
tion of the hemoglobin with the stroma of the red cell, as already re-
marked, is not definitely known. That it is not merely contained in a
sac is shown by the fact that the cell may be cut into bits without the
hemoglobin being set free. In some manner the hemoglobin is chem-
ically bound with the stroma of the red cell, from which it can be
freed by a number of physicochemical and chemical agents. This proc-
ess is known as hemolysis, and the substances which bring it about are
known as hemolytic agents. The manner in which these agents effect
the release of hemoglobin from the blood is quite varied.

If the osmotic pressure of the plasma is lowered by dilution, the pres-
sure within the corpuscle remains high, and water is absorbed by the
cell. If this absorption is sufficient, the cell ruptures and the hemoglobin
is discharged. For this reason it is necessary in diluting the blood to
use solutions of salt having an osmotic pressure equal to that of the
blood to protect the red cell from hemolysis. This is obtained by using
a 0.9 per cent solution of sodium chloride. Better results are had,
however, by using either Ringer's solution (0.9 per cent NaCl, 0.026
per cent CaCl2, and 0.03 per cent KC1) or Locke's solution (0.9 per cent
NaCl, 0.024 per cent CaCl2, 0.042 per cent KC1, 0.01-0.03 per cent
NaHC02 and 0.1 per cent, glucose).

In normal corpuscles hemolysis occurs to a small extent in solu-
tions containing about 0.42 per cent of sodium chloride. In certain
diseases the fragility of the corpuscles may be increased (Butler7).

The membrane and stroma of the erythrocyte contain lipoidal ma-
terial which is soluble in alcohol, ether, fatty acids, and bile salts.
Addition of these agents to the blood brings about hemolysis, presum-
ably by dissolving the lipoidal material present. The hemolysis which
occurs with saponin is similar in type, since saponins combine with
lipoids, the compound being soluble in water.

The hemolytic properties of serum, whether they are found to be
normally present when the bloods of certain animals are mixed or to
be produced artificially by the injection of foreign red cells, furnish a
subject of great interest from the standpoint both of immunology and

THE BLOOD CELL 97

of clinical medicine. The hemolytic serum produced by the injection
of foreign corpuscles owes its activity to two substances. The one
called the amboceptor, or immune body, is specific against the type
of cell injected and is increased during immunization. The second
body is the complement; it is nonspecific, and is not increased dur-
ing immunization. Complement is destroyed by heating the serum for
one hour at 55° C., leaving the amboceptor alone present. Corpuscles
placed in such serum are not hemolyzed until complement either from
fresh immune or from nonimmune serum is added.

The serum of animals possessing natural hemolytic properties towards
the corpuscles of other animals likewise owes its effect to the joint action
of amboceptors and complement.

Ordinarily the serum from animals of one species does not exhibit
hemolytic properties to blood from another animal of the same species.
In unusual cases, however, the serum of an animal will produce hemol-
ysis of the corpuscles of an animal of the same species. Such sera are
said to possess isohemolysins. The fact is of great importance in the
transfusion of blood from one individual to another.

The cause of the acute hemolysis which occurs in the disease parox-
ysmal hemoglobinuria is not known. It is probably due to the presence
of a hemolytic substance which unites with the blood corpuscles at
temperatures below the normal body temperature, since the attack fol-
lows exposure to cold, and blood from patients subject to the condition
may be hemolyzed in vitro by cooling and subsequently heating it.

LEUCOCYTES

There are a number of varieties of white cells in the blood. These are
differentiated from one another by their shape, staining properties, and
the granules in their protoplasm. We may divide them into two main
groups — nongranular mononuclear cells and granular polynuclear cells.

The nongranular mononuclear cells are termed lymphocytes. Two va-
rieties are differentiated, the small and the large.

The small mononuclear leucocyte makes up from 23 to 28 per cent
of the total leucocytes and the large mononuclear, from 2 to 4 per cent.

The polynuclear leucocytes are divided into three groups according
to whether their granules stain with basic, neutral or acid stains. The
leucocytes that stain with basic dyes, or the basophile cells, are very
few, making up less than one per cent of the total count. Likewise the
acid-staining granular cells, acidophile, are few, comprising from 2 to
4 per cent of the total count. The most numerous are the neutrophiles,

98 TTIK KLOOD AND THE LYMPH

or the polynuclear leucocytes, with neutral-staining granules. These
comprise from 65 to 75 per cent of the total count.

Another type of white cell is known as the transitional cell, because
it was supposed to represent an intermediate form between the mono-
and polynuclear cells. Probably such transitions do not occur, and the
transitional leucocyte is related to the mononuclear cells.

The polynuclear cells originate in the bone marrow, and for this
reason have been termed myeloid cells. They develop from cells in
the bone marrow termed myeloblasts, which are nongranular and con-
tain a large nucleus. In the course of development the characteristic
granules appear, and the nucleus remains round and later becomes
lobulated. These intermediate forms are called myelocytes. The mono-
nuclear cells originate in the lymphatic tissues of the body.

The leucocytes possess the ability to make ameboid movement and
to ingest foreign particles which may be presented to them. On ac-
count of this latter ability they are commonly called phagocytes. In
the process of inflammation the leucocytes assemble at the spot which
is the seat of the injury or infection, and remove the foreign organism
or necrotic tissue by ingesting and digesting it.

It is not definitely known whether or not the lymphocytes func-
tion as phagocytes. Other functions besides those as phagocytes have
been ascribed to the white cells, but they are not universally ac-
cepted. The number of leucocytes in the blood is subject to con-
siderable variation. They normally number between 6,000 and 8,000
per c.mm. At the height of digestion and after strenuous exercise
there is usually a small increase, and under pathological conditions,
especially in infectious diseases, this becomes quite marked. Some
infections increase the polymorphonuclear cells, while others add to
the lymphocytes. The factors governing the type of increase are not
fully known, nor are the functions of the various forms differentiated.

The Blood Platelets

These are small oval particles about 3 //, in diameter, which are found
in large numbers (250,000 to the c.mm.) in the blood. They are sup-
posed to be formed from particles of protoplasm which are pinched
off from the large blood cells in the bone marrow. Their biological
and chemical properties are not understood. They probably play a
very important role in the coagulation of the blood (see page 104).

CHAPTER XII
BLOOD: BLOOD CLOTTING

On leaving the blood vessels, the blood clots so as to form a plug,
which assists in preventing further hemorrhage. The clotting must
therefore be considered as a protective mechanism against excessive
draining of blood out of the organism. When the wounded vessels
are small, the clotting, along with constriction of the damaged vessels
and the formation in them of thrombi containing large numbers of
platelets, serves to effect complete stoppage of the hemorrhage even
though the blood pressure may not have become materially reduced.
The greater loss of blood from larger vessels causes the arterial pressure
to fall, and this enables the clot to stiffen and seal the wound before
the pressure again rises. When the clotting power of the blood is
subnormal, life is endangered by even trivial wounds; under these
conditions the smallest surface scratch may continue to bleed exces-
sively in spite of whatever local treatment is applied. The most ex-
treme degree of this condition occurs in hemophilia, a disease which
is characterized by a most interesting family history — namely, that
although it affects only certain of the male members of a family,
yet it is transmitted from generation to generation by the female side
alone. The disease has existed in certain of the royal families of
Europe for many generations, which has made it possible by con-
sulting: the genealogical trees to demonstrate the infallibility of this
law of inheritance.

The clotting of the blood is also either depressed or increased in a
variety of physiological and pathological conditions. We shall, however,
defer further consideration of these until we have learned something
of the nature of the factors which are responsible for the process itself.

The Visible Changes in the Blood During Clotting

In a few minutes after it leaves the blood vessels, the blood forms a
jelly-like clot, which adheres to the walls of the container in which the
blood is collected and soon becomes so solid that the vessel may be
inverted without spilling any of the blood. Clotting is now said to be
complete. The clot soon begins to contract, and as it does so, drops of
clear fluid or serum become expressed and float on the surface of the

99

100 THE BLOOD AND THE LYMPH

clot or collect between it and the walls of the container, so that after
some time the clot breaks away from the container and comes to float
in the serum. The latter may be perfectly clear, but usually is more or
less opalescent, partly because of the presence of fat, and partly be-
cause of leucocytes which have migrated out of the clot on account of
their power of diapedesis.

If a drop of freshly shed blood is examined under the microscope, it
will be observed that the first step in clotting consists in the formation
of fine threads radiating from foci, which are undoubtedly the blood
platelets. The fine threads are called fibrin. They multiply rapidly,
so as to form an interlacing meshwork which entangles the red blood
corpuscles and leucocytes. By the use of the' ultramicros,cope (page 52),
Howell1 and others have observed that the fibrin (produced by adding
thrombin to oxalated plasma) is really deposited in the form of fine
crystalline needles — " fibrin needles" — which become packed together
as they increase rapidly in numbers. Although the process of clotting
consists therefore in the conversion of a hydrosol into a hydrogel (see
page 61), it is a unique process; a solution of the blood protein which
is responsible for the formation of the fibrin (fibrinogen) may, like other
colloidal solutions, be precipitated in a variety of ways, but it is only
when the conditions are favorable for blood clotting that fibrin needles,
and therefore fibrin threads, are formed. The blood of invertebrates
forms a structureless gel when it clots (Howell).-

Methods of Retarding Clotting of Drawn Blood

To understand the nature of the clotting process and the factors that
are responsible for its occurrence, it is advantageous to simplify the
conditions somewhat by getting rid of the red corpuscles and most of
the other formed elements of the blood and then using the fluid in
which these are suspended in living blood — namely, the plasma. This
separation of blood into corpuscles and" plasma is readily effected either
by sedimentation or by centrifuging after measures have been taken to
inhibit or greatly delay the clotting process. The methods used for this
purpose are numerous. A few of the most important are as follows:
(1) Keeping the blood at a temperature very slightly above freezing
point. This method is, however, not very effective unless the blood is
immediately received into narrow vessels placed in ice and the tempera-
ture kept most strictly at the low level. In the case of horses' blood and
other slowly clotting bloods, the method succeeds without these precau-
tions. (2) Eeceiving the blood through a strictly clean and smooth can-
nula, coated with a layer of paraffin or vaseline, into a vessel similarly
coated. This method is of practical importance when it is necessary to

BLOOD CLOTTING 101

transfuse blood without making a vessel-to-vessel anastomosis. (3) Mix-
ing the blood with chemicals that are capable of removing the calcium
from solution. Such reagents are potassium or sodium oxalate (in a con-
centration of 0.1 per cent after mixing), and sodium fluoride and sodium
citrate (2 per cent solution, with one part of the solution to four parts
of blood). (4) Mixing the blood with certain neutral salts, particularly
the sulphates of sodium and magnesium (one part of 27 per cent solution
of magnesium sulphate mixed with four parts of blood). Blood thus
treated is known as " salted blood," and the plasma separated by centri-
fuging, as "salted plasma." Clotting is readily induced by adding water
to the salted blood or plasma, and in this way diminishing the concen-
tration of the salts. (5) The addition to blood of one of a class of sub-
stances known as antithrombins. Leech extract or the purified substance
separated from it, known- under the trade name of "hirudin," and sub-
stances present in blood removed from animals after they have been
injected with peptone solutions, are examples.

The methods which have just been described are those applied to blood
after it has left the blood vessels. Another interesting group of anti-
coagulants prevent clotting only when injected into the blood vessels of
the living animal. The most powerful example of this group is snake
venom, certain varieties of which can prevent clotting in the dosage of
%oo of a milligram for each kilogram of body weight. Similar but much
less potent effects are produced by the injection of several proteolytie
enzymes, but most attention has been paid to the effect of commercial
peptone injected in solution intravenously in the proportion of 0.3 gram
to each kilogram of body weight. Blood subsequently removed up to about
half an hour or more does not clot, and as we have already seen, if added
to blood from another animal, materially retards clotting. This group of
intra vitam anticoagulants is particularly interesting, since none of the
substances belonging to it is capable of preventing clotting of blood
when mixed with this after it has been shed. Their action therefore
obviously depends on the production of some substance in the body,
probably, as we shall see later, in the liver, since they fail to act after
the" removal of this organ from the circulation (see page 111).

The time of clotting varies greatly according to the conditions under
which the blood is collected and the animal from which it is derived.
Human blood, for example, received into a test tube ff6m a puncture
through the skin may clot at any time within three or ten minutes, five
minutes being taken as ah average time for blood kept at a temperature
of about 20° C. This time may be considerably shortened by increasing1
the extent of foreign material with which the blood comes into Contact,
and more particularly by whipping the blood with a bunch of twigs or

102 THE BLOOD AND THE LYMPH

wires. In this latter case, however, the clot does not form in the usual
manner, but the fine threads of fibrin collect on the twigs or wires, leav-
ing behind the blood serum with the corpuscles still suspended in it.
The fibrin removed in this way may then be washed free of adherent
serum. The serum and corpuscles now form defibrinated blood, which
is used for many physiological purposes. Clotting is also greatly acceler-
ated by allowing the blood to flow over exposed tissues. Something is
evidently added to it from the tissues which accelerates the clotting
process, this influence being particularly marked in the case of blood
of the lower vertebrates. When the blood of the bird, for example, is
received through a cannula inserted directly into a vessel with as little
injury to the walls as possible, it very slowly clots if at all, but soon
does so if the blood is allowed to come into contact with excoriated
tissues, or if it is mixed with tissue extract, such as that of muscle.
Clotting is considerably accelerated by warming the blood. The ap-
plication of a cloth or tampon well wrung out with hot physiological
saline to a wounded surface is a most efficient means of allaying hem-
orrhage from vessels too small to ligate.

The Nature of the Clotting Process

Plasma obtained by centrifuging blood that has been prevented from
clotting by one of the foregoing methods can be made to clot by removing
the inhibiting influence; for example, in cooled plasma by warming the
blood to room temperature, in salted plasma by diluting it with at least
an equal volume of water, and in decalcified plasma by adding a suffi-
cient amount of soluble calcium salts to combine with all the added
oxalate and leave a small trace of calcium salts in excess.

The first question concerns the source of the fibrin, and the answer to
it is furnished by comparing the composition of bood plasma with that
of serum. Though both of these fluids contain the proteins, albumin
and globulin, in approximately the same concentrations, the plasma also
contains another protein not unlike globulin in most of its reactions,
but distinguished from typical globulin in that it is precipitated by
half-saturation with sodium chloride, in which typical globulin is solu-
ble, and is more readily coagulated by heat. To produce half-saturation
of the plasma with sodium chloride, equal volumes of plasma and satu-
rated sodium-chloride solution are mixed together. The precipitate of
fibrinogen, as the substance is called, is then collected at the bottom of
the tube by centrifuging and is washed several times by decantation with
half-saturated sodium-chloride solution. The washed precipitate, dis-
solved in weak saline solution (preferably containing a trace of bicar-
bonate), will then be found to clot under certain conditions.

BLOOD CLOTTING 103

The next question concerns the nature of the conditions that cause the
fibrinogen to clot. When a fibrinogen solution is mixed with a few drops
of blood serum, a clot usually forms, which however is not the case when
plasma is added or when the serum is heated before adding it. Because
a small quantity of serum is capable of causing the clotting of a large
quantity of fibrinogen solution or plasma, it is supposed that the active
substance present in it is of the nature of a ferment — fibrin ferment or
tkrombin. It must be pointed out, however, that there is considerable
doubt whether this active body is really of the nature of a ferment or
enzyme. For example, although heated serum does not cause clotting,
thrombin, prepared from serum by the method about to be described, in
the absence of inorganic salts can withstand even a boiling temperature.
Moreover, true enzymes are characterized by the fact that, like other
catalytic agents, a very minute quantity can effect a change in an indef-
inite amount of substance without the enzyme becoming used up in the
process (page 72). When thrombin is allowed to act upon a fibrinogen
solution, on the other hand, it is said that only a fixed amount of fibrin
can be formed when a small amount of thrombin is added. Neither does
this amount increase when the time of reaction is prolonged.

Whatever may be the significance of the foregoing facts, it is impor
tant to know that the clotting substance, thrombin, can be isolated from
blood serum in a tolerably pure condition. For this purpose blood
serum is allowed to stand under a large volume of alcohol for a week or
two; the precipitate is then collected and rubbed up with water, which
extracts the thrombin from it, leaving the serum protein in a coagulated
state. The resulting watery solution of thrombin may be further pre-
cipitated by alcohol, the precipitate washed in alcohol and redissolved
in water, yielding ultimately a solution which exhibits very marked co-
agulating powers when added to plasma or fibrinogen solution. Throm-
bin shows most of the protein reactions but it is not coagulated by heat.,
As would be expected, a considerable quantity of thrombin remains
adherent to the fibrin formed in the process of clotting, and Howell8
describes a very useful method by which it can be separated from fibrin
and preserved in a dry condition. Briefly stated, this method consists
in allowing washed fibrin to stand overnight under eight per cent
sodium-chloride solution, which dissolves the thrombin. The resulting
extract is then mixed with an equal volume of acetone, which throws
down a precipitate containing the thrombin. To preserve it, the precip-
itate is collected on a number of small filter papers, which are subse-
quently opened out and dried by exposure to a current of cold air before
an electric fan. When the thrombin solutions are desired, the dried pre-
cipitates are extracted with a little water.

104 THE BLOOD AND THE LYMPH

Thrombin does not exist in blood plasma, for if a clean and paraffined
glass tube is inserted into an artery and the blood collected under al-
cohol, the precipitate after standing a few weeks will yield no thrombin
when triturated with water. Quite clearly, therefore, the thrombin is
produced at the time the blood clots, and the question arises, What is
it produced from? It will be remembered that, when the blood is ex-
amined under the microscope during the clotting process, the fibrin
threads are seen to start from foci which correspond to the blood plate-
lets. It would appear therefore that the thrombin must be derived from
some substance that is shed forth from the platelets during the disin-
tegration which they undergo shortly after the blood is shed. The sub-
stance is called prothrombin. The platelets or their precursors, the
megacaryocytes of red bone marrow, are probably not its only source,
for clotting may occur in the complete absence of platelets, when it
appears to come from the leucocytes. Prothrombin appears plentifully
in the fluid used to perfuse red bone marrow outside the body (Drinker
and Drinker9).

To sum up what we have so far learned, it may be stated that the
process of clotting starts with the disintegration of blood platelets and
probably of leucocytes, as a result of which there is shed forth into the
plasma a substance called prothrombin, which immediately afterward
becomes activated or converted into thrombin. The thrombin then at-
tacks a protein present in plasma called fibrinogen, producing from it in
thread-like form the insoluble protein, fibrin. But this does not com-
plete the history, for at least two other important factors come into
play ; the one is the presence of soluble calcium salts, and the other that
of peculiar substances derived from the tissues outside the blood vessels
and called thromboplastic substances or thromboplastin (Howell). We
must now consider the action of these two factors.

The Influence of Calcium Salts. — As already explained, the proof that
soluble calcium salts are necessary for clotting is furnished by the ob-
servation that the process is entirely prevented when the freshly drawn
blood is mixed with soluble oxalate. To this proof, however, objection
might be made on the score that the oxalate per se inhibited the clotting.
That such is not the case is indicated by the fact that, if the oxalated
blood or plasma is dialyzed against physiological saline solution till all
the soluble oxalate has been removed from it, clotting is still absent but
immediately supervenes if some soluble calcium salts are added. The
question arises as to how the calcium ion acts. Two possibilities exist:

(1) that it is concerned in the conversion of fibrinogen to fibrin, and

(2) that it is necessary for converting prothrombin into thrombin. It
can quite readily be shown that it is by the second of these processes

BLOOD CLOTTING 105

that the calcium acts; for example, clotting occurs when purified throm-
bin is added to dialyzed oxalate blood or plasma or to a pure solution of
fibrinogen. Citrates prevent clotting by forming calcium citrate, which
although soluble does not ionize in solution. It is the free calcium ions
that are important. The action of the fluoride is somewhat mysterious,
for it has been found that to produce clotting in fluoride plasma the sim-
ple addition of calcium chloride will not suffice; thrombin itself must be
added as well. Some authors assert, however, that if the calcium chlo-
ride is added cautiously to "fluoride" blood, it will induce clotting
(Eettger). In any case it appears that the fluoride does something more
than precipitate the calcium; possibly it prevents the breaking up of
platelets and leucocytes.

The Influence of the Tissues. — As already stated, when slowly clotting
blood, like that of a bird, is collected through a sterile glass tube into a
thoroughly clean vessel and immediately centrifuged, the plasma will
often remain indefinitely unclotted. If an extract of some tissue, such
as muscle, is added, however, the plasma immediately clots. To a much
less degree, the same phenomenon is exhibited by mammalian plasma
when it is collected in a similar manner. From these observations the
conclusions may be drawn that the tissues furnish some substance as-
sisting in the clotting process, and that this substance is also formed
from certain elements present in mammalian but not present in avian
blood. The absence of platelets from the latter blood suggests that
these must be the source of the activating substance in mammalian blood.
It is plain that this tissue factor in clotting is of importance in hasten-
ing the process when an animal is wounded.

Before attempting to formulate an hypothesis that will explain the
process of clotting, it is necessary to call attention to one other impor-
tant fact. This refers to the presence in blood of a substance that pre-
vents clotting and is hence called antithrombin. Antithrombin is pres-
ent in normal blood, for a given specimen of pure fibrinogen will clot
less rapidly when mixed with serum to which some oxalated plasma has
been added than with an equal amount of the same serum correspond-
ingly diluted with a solution of soluble oxalate. A striking increase
in the concentration of antithrombin in blood can be brought about by
rapidly injecting a solution of commercial peptone into the blood ves-
sels fifteen to thirty minutes before bleeding. The peptonized blood or
plasma will remain fluid for many hours, if not indefinitely. That the
failure of this blood to clot depends on the presence of some anticlotting
substance, and not upon the absence of one of the necessary clotting sub-
stances (fibrinogen, thrombin, etc.), is evidenced by the fact that the
addition of some of it to a mixture of thrombin and fibrinogen inhibits

106 THE BLOOD AND THE LYMPH

the coagulation, which it does not do, however, if it is first of all heated
to 80° C. and filtered free of the coagulated protein. Moreover, the
antagonistic action is quantitative in the sense that a fixed amount of
the peptone-plasma inhibits the action of a fixed amount of thrombin.
The source of antithrombin in the body appears to be mainly at least
the liver, for it has been found: (1) that peptone injection into an animal
from which the liver has been removed does not cause antithrombin to
be formed (Denney and Minot) ;10 (2) that peptone injections into the
portal vein cause antithrombin to appear in the blood much more rap-
idly than when the injection is made into a systemic vessel; and (3) that,
when the liver is perfused outside the body with a perfusion fluid con-
taining peptone, antithrombin accumulates in the perfusion fluid.

A fluid containing a high concentration of antithrombin is secreted
by the so-called salivary gland at the head end of the leech. The func-
tion of the fluid is to prevent clotting of the blood, so that the animal
may continue to suck it without interference by clotting. After apply-
ing leeches for medicinal purposes it is therefore necessary to wash the
wround thoroughly with water so that all traces of the antithrombin may
be removed ; otherwise the bleeding may continue for a considerable time.
Practical use is made of this effect of the leech to prevent clotting of blood
outside the body, or it may be used to inhibit coagulation intra vitam in
experiments where clotting would otherwise interfere with their prog-
ress; for example, in crossed circulation experiments (page 384) and in
experiments in vivid diffusion (page 641). For such purposes the leech
head is cut off and extracted either with saline or by treatment with
chloroform, which removes other proteins from the saline solution leav-
ing a strong antithrombin, known under the trade name of "hirudin."
At temperatures about that of the body the action of antithrombin is
greatly augmented. In animals like the mammals in which the content
of antithrombin is small, this may be important in maintaining the flu-
idity of the blood (Howell). Blood containing antithrombin can be
made to clot by the addition of thrombin, and therefore of blood serum.

CHAPTER XIII
BLOOD: BLOOD CLOTTING (Cont'd)

THEORIES OF BLOOD CLOTTING

Attempts to link all the foregoing facts together in the form of a
simple theory have not so far been entirely successful. All agree that
the fibrin is derived from fibrinogen by the action of thrombin, the points
in dispute being those which concern the origin of the thrombin and
the mode of action of the calcium and thromboplastic substances. The
theory most widely accepted in Europe is that of Morawitz, according
to which the thrombin exists in living blood in an inactive state called
thrombogen (prothrombin), which becomes converted into thrombin by
the simultaneous action on it of soluble calcium salts and of thrombo-
plastic substances furnished by the tissue cells in general and by the
cellular elements of the blood platelets and leucocytes. According to
this view the thromboplastic substance, aided by the presence of calcium
ions, converts thrombogen (prothrombin) to thrombin. It acts there-
fore as a kinase and is called thrombokinase. The fundamental fact of
this theory, then, is that kinase is necessary for the union of the cal-
cium with prothrombin — a fact, however, which is challenged by Howell,
who states that prothrombin may be converted to thrombin by the action
of calcium ions alone. This investigator believes that the thrombo-
plastic substance acts not as a kinase but because it neutralizes anti-
thrombin, which is constantly present in the blood, and the function of
which is to prevent the calcium from uniting with the prothrombin to
form thrombin. HowelPs theory in his own words is as follows: "In
the circulating blood we find as constant constituents fibrinogen, pro-
thrombin, calcium salts and antithrombin. The last named substance
holds the prothrombin in combination and thus prevents its conversion
or activation to thrombin. When the blood is shed, the disintegration
of the corpuscles (platelets) furnishes material (thromboplastin) which
combines with the antithrombin and" at the same time liberates more
^prothrombin; the latter is then activated by the calcium and acts on
the fibrinogen." Antithrombin can also prevent the action of thrombin
on fibrinogen. As already pointed out, the thromboplastin can be de-
rived from the blood itself in the mammals, but only from the tissues
in the lower vertebrates. It is interesting to note that the thromboplastin

107

108 THE BLOOD AND THE LYMPH

can be extracted from the tissues by fat-solvents, and that it appears to
belong to the class of phosphatids, being indeed closely related to, if
not identical with, kephalin (Howell).

Intravascular Clotting

The practical application of the theory of blood clotting concerns the
manner in which the blood is maintained in a fluid condition in the blood
vessels, and the disturbance of this function causing intravascular clot-
ting. According to the one theory, the blood is maintained fluid by the
absence from it of any considerable quantity of kinase, and according
to the other, by the presence in it of an amount of antithrombin suffi-
cient to prevent the union of calcium with prothrombin. The fluidity
is maintained even when large amounts of thrombin or of blood serum,
which contains this substance, are injected into the living animal. We
can best explain the immunity of the blood to the action of thrombin un-
der these circumstances as being due to the instantaneous appearance in it
of antithrombin in amounts sufficient to prevent the action of thrombin
on fibrinogen, for, as stated above, it is claimed by Howell that anti-
thrombin has this influence as well as that of preventing the conversion
of prothrombin into thrombin. »

Intravascular clotting may be brought about by a variety of means:
(1) Mechanical damage to the lining of the blood vessels; after the ap-
plication of a ligature, for example, the damaged endothelium is soon
covered by a clot, which gradually becomes firmer and firmer, and may
spread up the vessel to the next branch. (2) The presence of foreign
substances in the bloQd. Emboli, for example, are apt to cause clots
to form at the places where they stick, namely, in the smaller vessels.
Clotting is also a frequent occurrence when there are local dilatations of
the cardiovascular tube, and it may occur under imperfectly understood
conditions causing the condition known as thrombosis. (3) An inter-
esting variety of intravascular clotting is that caused by the intrave-
nous injection of saline extracts of cell-rich tissues, such as the thymus,
lymph glands or testes (Wooldridge). By precipitation with acetic
acid and digestion with peptone, a residue can be obtained from these
extracts which, when dissolved in alkali, has a very pronounced intra-
vascular clotting effect. Since these precipitates are very rich in phos-
phorus, it is probable that they are of the nature of phosphoprotein
(nucleoalbumin). Their action must depend on neutralization of anti-
thrombin, according to HowelPs theory, or because they serve as throm-
bokinases (according to Morawitz' theory).

As a matter of fact, however, the foregoing observation is not com-
pletely explained by either theory. If in place of making one injection

BLOOD CLOTTING 109

frequent injections of small amounts of the above material are made,
instead of intravascular clotting, a delay in the coagulation time is
likely to occur. Indeed, repeated injections of small amounts may en-
tirely remove the clotting power of the blood. The readiness with which
this so-called /'negative phase" appears, seems to depend on the nutri-
tive condition of the animal at the time of injection. If a large dose is
injected into a fasting dog, for example, thrombosis is confined to the
portal area, whereas if it is injected into a recently fed animal, the
thrombosis is universal throughout the vascular system. The develop-
ment of the negative phase is undoubtedly dependent upon some reac-
tion on the part of the living cells of the organism, since it does not occur
on the addition of similar substances to blood outside the body. The
reaction is, indeed, akin to that by which immune bodies in general are
produced. For example, a toxin injected in large amount has a cer-
tain toxic effect, but in repeated small doses with intervening intervals
it leads to the production of an antitoxin. So with the substance in
question; a large dose injected at one time causes a positive effect — clot-
ting— but smaller doses frequently injected, the opposite effect — want of
clotting. It is probable, as suggested by Starling, that more intensive
study of the conditions causing intravascular clotting will throw con-
siderable light on the general question of the production of immunity.

Measurement of the Clotting Time

To measure the clotting time of drawn samples of blood, several conditions must
be observed. These have been tabulated by Addis1* as follows:

1. The specimens of blood must always be obtained by exactly the same technic. It
would introduce serious errors to compare the clotting time of one specimen of blood
received from an incision of the skin (ear lobe) with that of another collected in a
syringe by venipuncture.

2. The temperature conditions must always be the same. Probably 25 °C. is the best
temperature to use. Higher temperatures are unsuitable for two reasons: first, be-
cause during its collection the blood will have become cooled to about or below this
point, and time would be consumed in raising it higher; and second, because the time
of coagulation is more and more shortened for each degree that the temperature is
raised, this acceleration becoming especially pronounced for temperatures above 25 °C.
Quite apart from the liability to incur errors incident to measurement of shorter
periods of time, observations at higher temperatures necessitate most rigorous adher-
ence to a fixed temperature of the water-bath. Temperatures much below 25 °C. are
unsuitable, because the clotting sets in gradually and it is difficult to tell precisely
when it occurs.

3. The blood must always be collected in the same sort of vessel and come in con-
tact with the same kind and amount of foreign material. To this it may be added
that the receiving vessel must be scrupulously clean; any trace of old blood clot or of
serum is especially to be guarded against.

4. The end 'point must be sharp. It is here that the greatest technical difficulties
are met with in making precise measurements, and it is greatly to be desired that

110

THE BLOOD AND THE LYMPH

different investigators should adopt some uniform method. For experimental pur-
poses the method of Cannon and Mendenhall1'- is no doubt the best, and it lias the
added advantage of giving a graphic record of the observations. The accompanying
figure (Fig. 19) shows the principle of the method. The blood is received through a
standard cannula (C) into a tube (T) 5 cm. long and of 5 mm. internal diameter;
and a loop (of 2 mm. diameter) at the end of a copper wire (Z>), which is 8 cm. long
and 0.6 mm. in diameter, is allowed to fall gently into the blood at regular intervals.
The upper end of the wire is articulated with the short arm of a light lever so counter-
poised that when the stop (-R), which ordinarily holds it in a horizontal position, is
released, the wire, now having a net weight of 30 mg., falls on the blood in the tube.

Fig. 19. — Diagram of the graphic coagulometer. The cannula at the right rested in a water
bath not shown in this diagram. For further description see text. (From Cannon and Men-
denhall.)*

The long arm of the lever is provided with a writing point, which is made to inscribe
its movements on a drum. So long as the blood is unclotted the loop sinks into it when
the lever is released and a vertical line is traced, but whenever clotting occurs the
loop sticks on the blood and the writing point does not rise.

For clinical purposes where blood collected in a syringe by venipuncture is used, the
method of Howell13 is most accurate. It consists in placing 2 or 4 c.c. of the blood in
a wide tube (of 21 mm. diameter), that has been cleaned by a bichromate-acid mixture.
The period that elapses between the moment of the entry of fluid into the syringe and

Fig. 20. — Coagulometer. The drop of blood is placed on the upper end of the glass cone and
the air stream is directed against it from the side tube shown by the black dot. The apparatus
is placed on the stage of the microscope and the drop observed by the low power.

that at which the clot has become firm enough so that the tube can be inverted without
spilling any blood, is taken as the clotting time. Since the blood does not come in
contact with exposed tissues, it takes from 20 to 60 minutes to clot by this method.

For routine clinical examination of blood taken from a skin wound Brodie and
Bussel's method14 is most satisfactory. This consists, in principle, in observing a drop
of blood, under the low power of the microscope, while a fine current of air is gently
blown against it at regular intervals in a tangential direction. Until clotting sets in,

*Am. Jour. Physiol., May

1914, xxxiv, No. 2.

BLOOD CLOTTING 111

the individual corpuscles move freely in a circular direction, but as soon as clotting
begins they move in masses which soon tend to become fixed so that, although they
move somewhat when the air impinges on them, they immediately return to their
original position when the current is discontinued. When clotting is complete, the air
current merely presses on the corpuscles at one point. By this method the clotting
time averages five minutes. A convenient apparatus for this method is that of Boggs,
which is shown in Fig. 20. It consists of a truncated cone of glass, projecting into a
moist chamber provided with a tube 011 the side so arranged that when air is blown into
the chamber, it strikes the drop of blood placed on the end of the cone tangentially.

Blood Clotting in Certain Physiological Conditions

Besides the experimental conditions already enumerated as changing
the clotting time in the blood of laboratory animals, special mention
must be made of the influence of epinephrine injections, of conditions
supposed to cause a hypersecretion of this hormone, of the emotions,
and of hemorrhage.

Epinephrine added to drawn blood does not affect the clotting time,
but if small amounts are injected intravenously or even subcutaneously,
a marked decrease occurs (Cannon and Gray; cf. Cannon, loc. cit.).
Larger injections may have the opposite effect, and intermediate amounts
may cause at first a prolongation and later a shortening of the time.
These results with larger doses are related to Howell's observation that
repeated doses of relatively large amounts of epinephrine in dogs may
so greatly retard coagulation as to make the animals practically hemo-
philic. It was further found by Cannon and his co-workers that epineph-
rine does not influence the clotting time when injected into animals
from which the abdominal viscera have been removed from the circulation
by ligation of the inferior vena cava and the abdominal aorta. In the light
of the influence which destruction of liver cells (by phosphorus, chloro-
form, etc.) is known to have in lengthening clotting time, it would seem
reasonable to conclude that it must be through this organ that epineph-
rine develops its clotting effects.

Stimulation of the splanchnic nerves also shortens the clotting time,
and it would appear that this action depends on the resulting hyperse-
cretion of epinephrine (page 787), for it is not observed following stimula-
tion of the nerves in animals from which the adrenal glands have been
excised (Cannon and Mendenhall). The interesting suggestion is made
by Cannon that the shorter clotting time observed in animals showing
strong emotions of frisrht or fear may also be due to the hypersecretion
of epinephrine which this worker believes accompanies such states.

Blood Clotting in Disease

With the factors concerned in the process so wrapped in mystery, it is
not surprising that the underlying causes responsible for delayed or de-

1-12 THE BLOOD AND THE LYMPH

ficient clotting of blood in diseased conditions or for the formation of
intravaseular clots (thrombi) are little understood. According to How-
ell's theory of the nature of the process, which is the most satisfactory at
the present time, abnormal clotting might be due to the following
causes: (1) A diminished amount of fibrinogen. This occurs when the
hepatic cells are greatly damaged, as in poisoning by chloroform or
phosphorus and in such diseases as acute yellow atrophy and yellow
fever. In many cases of chronic cirrhosis of the liver, as "Whipple, etc.,15
have shown, the blood also clots feebly because of deficient fibrinogen.
It should be pointed out that it is not so much the clotting time that is
increased in such cases, as the firmness or consistency of the clot that
is affected.

2. A deficiency in prothrombin. In the condition known as "melena
neonatorum," undoubted benefit is derived from intravenous injections
of blood serum or by direct blood transfusions, probably because throm-
bin or prothrombin is thus furnished.

3. A deficiency of thromboplastin. Since this substance is derived from
both blood cells and tissue cells, it does not seem likely that a deficiency
could ever occur. Certain observers, however — Morawitz, for example —
lay great stress on this as an important factor in hemorrhagic Diseases.

4. An excess of antithrombin. The undoubted increase in this substance
that can be brought about experimentally by injecting hirudin or pep-
tone into animals, has stimulated careful search for a similar increase in
the blood in clinical conditions in which abnormal blood clotting is one
of the symptoms (Whipple16). Antithrombin is said to be increased in
septicemia, pneumonia, miliary tuberculosis, etc.

5. A deficiency of calcium ions. Although at one-time it was supposed
that this might be responsible for the feeble clotting in hemophilia, it
has not been found, after very extensive trials, that ,the exhibition* of
Ca salts in any way relieves the condition. It is said, however, that the
slow coagulation seen in obstructive jaundice is decidedly shortened by
treatment with calcium salts.

One thing stands out prominently in connection with the whole problem;
arid 'that is the close relationship of the blood platelets to the .clotting
process. From these cells are derived, according to Howell, rnot toi*ly ithe
prothrombin but also, as from other cells, thrombbplastin. It is not sur-
prising therefore to find that decided alterations in the^ platelet r Count
occur in cases of faultyrblood .clotting,, and :that -local accumulations of
these elements within the ^ blood vessels, produced by their clumping to-
gether or agglutinating, is followed" by a formation of local clbisj '
thrombosi^.

fcLOOD CLOTTING 113

Hemorrhagic Diseases

In many of the so-called hemorrhagic diseases (acute leuceinia and
aplastic anemia) and in the hemorrhagic varieties of diphtheria and
smallpox, the platelet count drops from its normal of between 200,000
and 800,000 per cubic millimeter to well below 100,000, and indeed in
these conditions it is frequently difficult to find any platelets. Samples of
blood clot outside the body within the normal time, but the clot is soft
and usually fails to retract in the normal manner. It is on account of
this, rather than slow clotting that the hemorrhage continues, so that in
appraising the gravity of the symptom it is best to measure not the clot-
ting time but the time that it takes for bleeding to cease from a small
skin wound, as in the lobe of the ear. This can be very accurately done
by applying blotting paper at regular intervals to the puncture (Duke17).

The most interesting and at the same time the most mysterious of all
conditions in which blood clotting is interfered with is hemophilia. The
clotting time is longer than normal, but even after the clot forms, bleed-
ing is likely to continue because the clots are very readily displaced. Both
clotting time and bleeding time are increased. So far no change in the
clotting factors of the blood has been demonstrated in this disease; the
corpuscles and the platelets are normal in numbers, fibrinogen and cal-
cium salts are normal, and, as Howell has shown, there is no excess of
antithrombin. One significant fact, however, is that the addition of
thromboplastin or of its active ingredient, kephalin, greatly shortens the
clotting time of the blood when it is removed by venipuncture. In agree-
ment with this observation it has been found that hemophilic blood clots
much more rapidly, indeed sometimes in the usual time, if it is allowed to
flow over cut or damaged tissue and so become mixed with thromboplas-
tin. These facts taken together would seem to indicate that the fault
must lie in a deficiency in prothrombin, and since this is derived mainly
from the platelets, which however are not decreased in number, we must
further assume that these elements have undergone some qualitative
change preventing their disintegration. An accompanying defect in
their agglutinating properties would at the same time explain their fail-
ure in hemophilia to clump together at the site of the hemorrhage so as
to block the smaller vessels with thrombi; hence the prolonged bleeding
time even after clotting has occurred.

Thrombus Formation

The first formed portion of a thrombus is paler than those formed later,
because it contains excessive numbers of platelets; and it seems clear
that it is by agglutination of these into masses, which then stick in the

114 THE BLOOD AND THE LYMPH

blood vessels and by disintegrating shed forth prothrombin and thrombo-
plastin, that the clotting starts. This platelet agglutination may result
from stagnation in the bloodflow, or from roughening and damage to the
vessel walls. Stagnation may be due either to failure of the circulation
as a whole as in heart disease, or to local physical alterations in the vas-
cular tube, setting up conditions in which eddy currents with stagnant
pools of blood are formed, such as will occur at places where the vessels
suddenly become wider, as in varicose veins, in aneurisms and at the
sudden bend of large veins. The first formed (platelet) thrombus is fol-
lowed by one of a darker color, which fills the vessel up to the next
anastomotic branch. Similar stagnation may also follow the obstruc-
tion caused by lodgment of emboli in the smaller vessels (air, foreign
bodies in fine suspension, bacteria, etc.). The thrombi in such cases are
very small and occur particularly in the capillaries of the liver, spleen,
and lungs. The small thrombi often serve as foci from which clotting
spreads into the larger vessels, this being often encouraged by an increase
in the coagulability of the blood. When the intima is inflamed, it is pos-
sible that excessive amounts of thromboplastin are produced and that
this neutralizes the antithrombin in blood moving so slowly that it is not
replaced by fresh blood before clotting ensues, or it may be that sub-
stances derived from the inflamed tissue cause the platelets to aggluti-
nate. The increased clotting often observed after the injection of hemo-
lytic agencies (foreign sera, snake venom, etc.) may also be due to
platelet agglutination. Like the thrombosis following embolism, the
clotting occurs at first in the capillaries, the initial thrombi containing
masses of platelets along with skeletons of blood corpuscles and cells
from the blood-forming organs.

CHAPTER XIV

LYMPH FORMATION AND CIRCULATION— CEREBROSPINAL

FLUID

GENERAL CONSIDERATIONS

Lymphatics are modified veins. They grow from the veins in embry-
onic life as bnds of endothelium, which are first visible in the human
embryo in the sixth week of development. The earliest outgrowth oc-
curs from the internal jugular vein, and the endothelial buds soon be-
come hollow and join together, forming first a plexus and subsequently
a sac, from which again lymphatic vessels made of endothelium grow
out to invade the skin of the head, neck, thorax and arm, and partly
the deep structures of the head. The sac is ultimately transformed into
groups of lymph glands. At a later stage similar nodes develop from
certain of the abdominal veins, forming a retroperitoneal sac, from which
grow out the lymphatics of the abdominal and, to a certain extent, of
the thoracic viscera. A similar pair of sacs also develops from the iliac
veins supplying the lymphatics for the skin of the legs and abdominal
walls. The retroperitoneal and iliac sacs then become connected with
the jugular sac by means of the thoracic duct. In the embryo there are
no valves in the lymphatic vessels, so that the whole system can be in-
jected either from the thoracic duct or from the skin, showing clearly
that the superficial and deep lymphatics are parts of one closed system
of vessels.

Anatomists have succeeded in tracing the course of the lymphatics in
many parts of the body. This knowledge is of great importance in
connection with the spread of infections, etc. Lymphatics are abun-
dant in the skin, the intestine, and connective tissues, but are absent
from the muscle bundles, from the hepatic lobules (though present in
the connective tissue between them), from the substance of the spleen,
and from the central nervous system.

The lymphatics have the same functions as blood capillaries, namely,
to absorb substances from the tissue spaces. There is some evidence to
show that this absorption may be selective. When injections are made
into the peritoneal cavity, the pathway of absorption may be either the
blood vessels or the lymphatics, according to the nature of the sub-

115

116 THE BLOOD AND THE LYMPH

stance injected. True solutions are absorbed by the blood, but granules
are taken up by special large cells showing phagocytic powers, and trans-
ferred to the lymphatics — for example, those of the diaphragm. A sim-
ilar selective absorption is well known in the case of the villi of the in-
testine, where fat passes into the lacteals and carbohydrates into the
blood. It appears as if lymphatic adsorption, both of solid materials
and of solutions, requires the cooperation of phagocytic cells.

The newer conception of the lymphatics as a closed system is at vari-
ance with the older one, in which they were supposed to get smaller and
smaller, and their walls less and less complete until ultimately they
faded off into the tissue spaces. These, however, bear no closer relation-
ship to lymphatics than they, do to blood capillaries. The tissue spaces
include all the minute spaces between the fibers and cells of the con-
nective tissues and between the parenchyma of the organs and the great
serous cavities of the body (pleural, peritoneal), as well as specially
developed tissue spaces, forming the subarachnoid spaces of the brain,
the scala vestibuli and tympani of the cochlea and the anterior chamber
of the eye. The fluids in these spaces — the tissue fluids — are quite dif-
ferent from the lymph in the lymphatics both in composition and in
function. Indeed, the tissue fluids are among the most varied of all
the fluids of the body. The spaces may themselves become linked to-
gether so as to form a circulatory system, which is quite independent of
the lymphatics. This is particularly the case in the brain, where the tis-
sue spaces surrounding every individual nerve cell extend into the sub-
arachnoid area, where they drain into the cerebral sinuses through the
arachnoidal villi, which exist as lace-like projections of the arachnoid
into the dural sinuses, being covered by a layer of mesothelial cells spe-
cially abundant at the tips of the villi, where they form cell nests. Ob-
servations of the passage of substances in solution by these pathways
have been made by injecting potassium ferrocyanide and citrate of iron
into the subarachnoid and subdural spaces and afterwards detecting
the presence of the salts by mounting sections in acid media, so as to
permit prussian blue to develop. Ordinarily the precipitate is found in
or near the villi, but after cerebral anemia it forms in the tissue spaces
that surround the nerve cells.

There are therefore three fluids concerned in the transference of food
materials and gases betVeen the gastrointestinal apparatus and lungs
and the tissue cells — namely, the blood plasma, the tissue fluids, and the
lymph. The tissue fluid, being in contact with the tissue elements, serves
as their immediate nutritive fluid, and it is the function of the blood and
lymph to maintain it of proper composition. Everything must be trans-
ferred to and from the tissue cells through the tissue fluid, making it

LYMPH FORMATION AND CIRCULATION 117

therefore in many ways the most important of the fluids of the body.
In the tissue cells themselves there is also the fluid in which the various
colloids and crystalloids that enter into the composition of protoplasm
are dissolved. This can be removed from cells only by mechanical means,
such as grinding with fine sand in a mortar and subjecting the mass
to a pressure of several thousand atmospheres in a hydraulic (Buchner)
press. This is known as the tissue juice. The ultimate exchange of
foodstuffs occurs between the tissue fluids and the tissue juices across
the cell membrane. The extent and character of this exchange depend
on many circumstances, some affecting the cell wall, others, the osmotic
and other properties of the two fluids. Obviously, the function of the
circulation is to maintain the tissue fluids of correct composition, the
blood plasma serving to carry food materials and dissolved oxygen to
them (see page 393), but being assisted in the opposite function of re-
moval of effete products by the lymph. The lymph is purely a scavenger ;
the blood is both purveyor and scavenger.

The above description of the lymphatics is not universally accepted
by anatomists, certain of whom believe that the lymphatics are developed
from tissue spaces and are consequently much more extensive than they
appear to be from injected specimens. The above conclusions are based on
reconstruction models, made from serial sections of- embryonic tissues,
in which the lymphatics frequently appear as isolated vesicles without
visible connections. The failure of injections to penetrate into the re-
moter parts of such a lymphatic system in the embryo is attributed to
the discontinuity of spaces, which is, however, removed at later stages
of development.

The manner of absorption of injected fluids does not, however, sup-
port the view that the lymphatics are directly connected with the tis-
sue spaces. When all the structures of a part are ligated except the
main artery or vein, injected poisons which affect central structures,
such as the nerve centers, develop their action as quickly as in the in-
tact animal (e.g., strychnine). Similarly, when pigments such as meth-
ylene blue are injected into the pleural cavity or subcutaneously, they
appear in the urine long before the lymph of the thoracic duct. Such
results indicate the pathway of absorption to be the blood rather than
the lymph vessels. Through this latter channel absorption proceeds
more slowly, but can be greatly assisted by massaging the site of injec-
tion. When colored solutions, such as India ink or carmine, are injected
subcutaneously, however, a very perfect injection of the neighboring
lymphatics may ultimately occur, and through the same pathways mi-
croorganisms spread from an infected area.

118 THE BLOOD AND THE LYMPH

EXPERIMENTAL INVESTIGATIONS

It has proved a most difficult problem to gain any exact knowledge
of the production of lymph by experimental means. Starling, some years
ago, in repeating many of the experiments of older physiologists in the
light of the newer facts of physical chemistry, added much, that is of
interest, and it is chiefly with his work that we will concern ourselves
here.

The unequal lymph supply of different regions of the body is strik-
ingly demonstrated by comparing the lymph flow from the lymphatics
of the leg with that from the thoracic duct. No lymph flows from the
former unless the muscles are throwTn into activity or the blood is pre-
vented from leaving the limb by ligaturing all the veins. Changes in the
arterial blood pressure do not affect the flow. On the other hand, a great
increase in the flow from the thoracic duct can readily be induced by
disturbances in the blood supply. Obstruction of the portal vein, for
example, immediately increases the lymph flow four or five times because of
venous congestion in the intestinal capillaries, whilst a still greater
increase — perhaps tenfold— is induced by obstruction to the inferior vena
cava, which raises the capillary pressure in both the liver and the intes-
tines. After ligation of the hepatic lymphatics (at the hepatic pedicle),
obstruction of the vena cava no longer causes the outflow of lymph to
increase, indicating that the lymph in the last mentioned experiment
must have come from the hepatic lymphatics.

These results, so far as they go, could be satisfactorily explained on
the basis that lymph, formation is a filtration process, that is, a process
dependent upon difference in mechanical pressure between the blood
capillaries and the tissue spaces. The lymphatics would then serve as
channels to return this fluid to the blood vessels through the thoracic
duct. The difference in the magnitude of the increased lymph flow from
increase in capillary pressure in different regions would be dependent
on the permeability of the filter, the capillaries of the limbs being much
less permeable than those of the intestine, and particularly of the liver.
Another fact in conformity with this view concerns the composition of
the lymph from the two regions, that from the limb lymphatics being
poor in protein, whereas that from the thoracic duct does not fall far
behind the blood plasma in this regard.

Although filtration may explain the considerable increase in lymph
flow produced by extreme changes in capillary pressure, it by no means
suffices to explain lymph formation under less abnormal conditions.
When a muscle or a gland is at rest, it produces practically no lymph,

LYMPH FORMATION AND CIRCULATION 119

but during activity the flow becomes marked. This can not be explained
by filtration, but may be accounted for by a physico-chemical process —
namely, osmosis. The energy required for the activity of the tissue
cell is produced by chemical changes, whereby large molecules become
broken down into numerous smaller ones. These smaller molecules are
then discharged into the surrounding tissue fluids, the osmotic pressure
of which they increase, with the consequence that water is attracted
by osmosis from the plasma in the blood capillaries (see page 4). This
increases the volume of tissue fluid, which is then drained away by the
lymphatics. The increase in molar concentration will also affect the
tissue juices, tending to make the cell swell up by absorbing water.
In gland cells this extra water is immediately extruded to form the
water of the secretion (see page 455).

An analogous method of lymph formation is not confined to situations
where the capillaries are relatively impermeable, for it also occurs in
the liver, the lymph flow from which is greatly increased by the injec-
tion of bile salts. A similar process no doubt results from muscular
activity, although in this case the tissue spaces must form a continuous
system of their own, there being, according to most authorities, no
lymphatics.

Considerable interest has been taken in the stimulating effect which
certain chemical substances have on the secretion of lymph from the
thoracic duct. These so-called lymphagogues belong to two classes —
crystalline and colloidal. Of the former, glucose, urea, and sodium
chloride in hypertonic solution, are the best known. Starling explains
their action as dependent upon an increase in the osmotic pressure of
the blood. This attracts water into the blood from the tissue juices,
and leads to an hydremic plethora, with a consequent increase in capil-
lary pressure. If the blood pressure is lowered by hemorrhage before
the hypertonic solution is injected, very little stimulation of lymph flow
occurs, because there is no available fluid in the tissue to produce the
plethora. This observation does not, however, very strongly support
the explanation, because so many other disturbances may result from
hemorrhage.

The colloidal lymphagogues include watery extracts of the dried tis-
sues of leeches, crayfish, and mussels, as well as commercial peptone.
They probably act by damaging the endothelium of the capillaries, so
that filtration occurs more readily. Although their action is displayed
more particularly on the lymphatics of the liver and intestines, it is also
apparent on the skin capillaries, producing cutaneous edema and the
formation of blisters (nettle rash).

120 THE BLOOD AND THE LYMPH

EDEMA

With such an imperfect knowledge concerning the physiology of
lymph formation, it is not surprising that the causes of excessive accu-
mulation of fluid in and between the tissue elements should be little un-
derstood. All of the conditions which have been mentioned as capable
of causing an increased secretion of lymph — such as increase in capillary
pressure, hydremic plethora, action of poisons on the endothelium — are
likely to cause edema if the lymphatics of the part are simultaneously
obstructed. To produce in animals edema of the subcutaneous tissues
like that observed clinically, it is, however, necessary that the vascular
disturbance be accompanied either by local damage to the capillary
endothelium, such as is produced by arsenic or uranium; or by a gen-
eral toxemic condition, such as is set up by nephritis. When large
amounts of saline solution are injected intravenously, extensive ex-
travasation of fluid may occur into the liver, peritoneum and intestinal
lumen, without any subcutaneous edema.

Clinical edemas are of at least three types:

1. The inflammatory edemas, in which the fluid permeates the cells of
the inflamed area and does not shift to other parts of the body under
the influence of gravity.

2. The nephritic edemas, in which the fluid is more or less loose in the
subcutaneous tissues and readily changes its position, and which is
accompanied by excess of water in the blood with a corresponding in-
crease of sodium chloride ; the percentage concentration of sodium chlo-
ride in the blood remains unchanged, but that the other constituents
diminished.

3. Cardiac edemas, which are also hypostatic, but are unaccompanied
by changes in the relative amount of water and sodium chloride in the
blood.

The second and third varieties of edema may of course be more or
less present together, for the kidneys are likely to become secondarily
affected during venous stasis.

The salt retention in nephritic edema is very significant. As ex-
plained elsewhere, it is revealed by comparing the daily output of so-
dium chloride by the urine with the concentration of this salt in the
blood. Less salt is eliminated than would be the case in a normal in-
dividual with the same percentage of salt in the blood. In many cases
also edema can be diminished by withholding salt from the food. Widal
and Javal have conclusively shown the relationship of retention of water
in the body, as judged by variations in body weight, to the hydremic
condition, as judged by the refractive index of the blood serum, and

LYMPH FORMATION AND CIRCULATION 121

to the amount of salt in the diet. A very considerable retention of
water usually occurs before there is any evidence of edema; indeed, as
a result of giving salt, the body weight may increase from five to seven
kilograms (10 to 15 pounds) within a day or two without the appear-
ance of puffiness.

The cause of the edema during salt retention is no doubt closely re-
lated to the action of lymphagogues. In a normal person excessive in-
gestion of salt is immediately followed by excretion of the excess through
the kidney. Where the kidneys are diseased, this excess of salt is re-
tained in the blood, raising its osmotic pressure and attracting water
from the tissue fluids. This leads to excessive thirst, the imbibed water
being used to replace that lost from the tissues. But all the crystalline
lymphagogues do not, when present in excess in the blood of nephritic
patients, necessarily cause edema; urea, for example, may accumulate
considerably without any such effect. The different action is usually
attributed to inequality in the diffusibility of the two crystalloids through
animal membranes, sodium chloride diffusing much less readily than
urea.

It is most important to note that the fluid in edema is loose in the
tissues and can be drained away by the insertion of tubes. There is
absolutely no evidence in support of the claim of Martin Fischer that
edema is due to imbibition of water by the colloids of the tissues. This
question has been fully discussed elsewhere (page 63).

THE CEREBROSPINAL FLUID

Considerable attention is now paid to the cerebrospinal fluid which is
present in the subarachnoid spaces of the spinal cord and brain. This is
because the fluid is readily collected by the method of lumbar puncture,
which is performed for the purpose either of relieving increased inter-
cranial pressure as in hydrocephalus, delirium tremens, eclampsia, enceph-
alitis, etc., or of collecting some of the fluid for diagnostic purposes.
The rationale of the removal for the relief of pressure in the brain case
is somewhat difficult to understand, as will be evident from a perusal of
the chapter on the circulation of blood in the brain (page 254). There is no
doubt, however, that the procedure gives relief. It is more particularly
with the biochemical characteristics of the fluid that we are concerned here
(of Levinson19). The normal fluid (i.e., obtained from patients not suf-
fering from inflammatory processes of the cerebrospinal membranes) is
colorless, it contains only from 4-6 cells per cubic mm., its specific gravity
varies between 1,000 and 1,008 and it does not clot. The H-ion concentra-
tion of perfectly fresh fluid, removed during life, can be accurately meas-
ured by the colorimetric method without dialysis (page 32) and has been

122 THE BLOOD AND THE LYMPH

found by Levinson to vary between PH 7.4 and 7.6, being therefore practi-
cally that of blood. On standing in unstoppered vessels the alkalinity
gradually increases so that PH of 8 may be reached in two hours. If the
vessel be tightly stoppered, however, PH may remain almost stationary.
The reason for this change is that there is as large a percentage of bicar-
bonate in the cerebrospinal fluid as in the blood plasma. The so-called
alkaline reserve, as determined by the Van Slyke method is therefore the
same as in blood plasma (viz., about 60). With regard to organic constit-
uents, there is only a trace of protein (0.02-0.04 total N.) but the urea
and sugar are present in about the same percentage amounts as in the
blood plasma. There is no certain evidence that any enzymes are con-
tained in the fluid.

The pathological changes observed in the fluid are of two types, systemic
and meningitic. In connection with the former, it may be mentioned that
in uremia the amount of fluid is usually increased and there is a high per-
centage of urea; in diabetes, the sugar is increased; in the various psy-
choses, in epilepsy and chorea there may or may not be changes. In
hydrocephalus the amount of fluid is increased, but it is normal in its
properties. It is also, although less markedly the case, in encephalitis and
cerebral tumor. Regarding conditions in which the meninges are in-
flamed (tubercular, meningococcic, pneumococcic) the changes in the fluid
are very marked and of decided diagnostic value ; it is somewhat increased
in amount, turbid, forms a sediment, shows many cells, contains excess of
protein (globulin) and gives a typical culture of the infecting organism
when examined by bacteriological methods. Levinson has found that
there are significant changes in PH in various diseases and he considers
that several tests that have been devised for diagnostic purposes are in-
timately associated with the changes in PH. These tests are known as the
cataphoresis test, the colloidal gold reaction of Lange and the mastic reac-
tion, and they all depend on the manner in which the protein colloidal
particles aggregate or become precipitated.

BLOOD AND LYMPH REFERENCES
(Monographs)

iHowell, W. H.: The Harvey Lectures, J. B. Lippincott Co., xii, 272.
2Starling, E. H.: Human Physiology, Lea & Febiger, 1915.
sKowe, A. H.: Arch. Int. Med., 1917, xix, 354,
^Williamson, C. S.: Arch. Int. Med., 1916, xviii, 505.
sTower and Herm: Proe. Soc. Biol. and Med., 1916, xviii, 505.
eTCous and Kobertson: Jour. Exp. Mod.. 1916, xxiii, 219, 239, 549.
TButler, G. G.: Quart. Jour. Med., 1912, vi, 145.

SHowell, W. H.: cf. Harvey Lecture; also Am. Jour. Physiol., 1913, xxxii, 264.
»Drinker, C. K., and K. K.: Am. Jour. Physiol., 1916, xli, 5.

loDenny and Minot: Arch. Int. Med., 1916, xvii, 101; Am. Jour. Physiol., 1915,
xxxviii, 233.

LYMPH FORMATION AND CIRCULATION 123

nAddis, T.: Quart. Jour. Med., 1910, iv, 14.

i2Cannon and Mendenhall: Am. Jour. Physiol., 1914, xxxiv, 225.
isHowell, W. H.: Arch Int. Med., 1914, xiii, 80.
i<Brodie, T. G.: Jour. Physiol., 1897, xxi, 403.

isWhipple, G. H.: Arch. Int. Med, 1912, ix, 365; Jour. Exp. Med., 1911, xiii, 136.
i6Whipple, G. H.: Arch. Int. Med., 1913, xii, 637.
iTDuke, W. W : Arch. Int. Med., 1912, ix, 258.

isKeith, 1ST. M. : Report 27 Medical Research Committee, London, 1919.
i<>Levinson, A. : Cerebrospinal Fluid in Health and in Disease, C. V. Mosby Co., 1919.
, N. M., Rowntree, L. G., and Geraghty, J. T. : Arch. Int. Med., 1915, xvi, 547.

PART III
THE CIRCULATION OF THE BLOOD

CHAPTER XV

BLOOD PRESSURE

The object of the circulation is to maintain through the tissues a sup-
ply of blood that is adequate to meet their demands for nutriment and
oxygen and to remove the effete products of their metabolism. The de-
mands vary according to the activities of the tissue, being particularly
variable in the case of such tissues as the muscular and the glandular.
In studying the physiology of the circulation we have therefore to bear
in mind two aspects of the problem: (1) the cause for the continuous
bloodflow, and (2) the mechanism by which alterations in this bloodflow
are brought about.

If we open an artery we shall find that the blood escapes from it
under such a pressure that it is thrown to a height of about six feet,
that its outflow is proportional to the size of the artery, and that it pul-
sates. If, on the other hand, we open a vein, we shall find that the
blood wells out without any very evident pressure, and that it flows
in a continuous stream, its outflow being the same in a unit of time as
that of the artery, provided the two vessels are the only ones supplying
the particular area. The general conditions governing the bloodflow
are the same as those governing the flow of fluid through any system of
tubes. For example, in the city water mains it is known to every one
that the rate of outflow from any part of the system depends finally on
two factors: (1) the difference in pressure at the beginning and end of
the system, and (2) the caliber of the tube at the outlet. We may in-
crease the outflow either by raising the pressure at the beginning of the sys-
tem, the caliber of the outlet meanwhile remaining constant, or by main-
taining the pressure constant but .increasing the caliber of the outlet.

In the circulation of the blood, the difference in pressure at the be-
ginning and end of the circulation is furnished by the pumping action
of the heart, and the alteration of the caliber of the outlet is provided
for by the constriction or dilatation of the blood vessels. These simple
physical principles indicate the direction which a stud}' of the circulation

124

BLOOD PRESSURE 125

should take. They indicate that our first consideration should be of the
mean blood pressure, how it is maintained, and how it can be made to
vary. After we have learned this, we may then proceed to a more
particular examination of the mechanism of the pump — that is, of the
heartbeat; then finally we may proceed to examine the nature of the
processes by which the caliber of the arteries is controlled.

THE MEAN ARTERIAL BLOOD PRESSURE

The first prerequisite to the investigation of the blood pressure, as of
any other physical problem, is that we should possess some means by
which it can be quantitatively measured. The earliest attempt to accom-
plish this was made by the English scientist, the Rev. Stephen Hales, a
little over a century after Harvey published his account of the circula-
tion of the blood. Hales connected a glass tube nine feet in length with
a severed artery of a horse, the connection between the two being made
by means of a piece of brass pipe joined to the windpipe of a goose as a
substitute for rubber tubing. He found on untying the ligature on the
artery that the blood rose in the tube to a height of eight feet and three
inches above the level of the left ventricle of the heart, and that when
at full height it rose and fell with each pulse through a distance of two,
three or four inches.

Mercury Manometer Tracings

The somewhat crude but very significant experiment of Hales clearly
established the existence of the enormous pressure at which the blood is
made to circulate through the arteries. To render possible a further
investigation of the factors on which this pressure depends, it became
necessary to invent some more convenient means for its measurement,
but this was not accomplished until a century later, when Poiseuille ap-
plied the mercury manometer, which Ludwig subsequently adapted so
that tracings might be taken (Fig. 21).

Having before us such a tracing as shown in Fig. 22, let us consider
how it may be used in the study of blood pressure. The first thing we
must do is to measure the average height of the tracing above the line of
zero pressure; the mean arterial blood pressure is then equal -to this
distance multiplied by two, because the distance through which the mer-
cury has moved up in the limb of the manometer carrying the writ-
ing point is only one-half of its total displacement. Since mercury
is about 13.5 times heavier than an equal volume of blood, the above
measurement must be multiplied by this figure if we desire to express

126 THE CIRCULATION OF THE BLOOD

our result in terms of the height to which the blood pressure could raise
a column of blood.

In arteries of approximately the same size, the mean arterial blood
pressure does not markedly vary in different mammals. Thus, in the
carotid artery of the dog it averages about 110 to 120 mm. Pig, in that
of the cat about 105 to 115 mm., in the rabbit from 90 to 105 mm., in
the sheep about 150 mm., in the horse about 200 mm., and in man some-

Fig; 21. — Mercury manometer and signal magnet, arranged for recording the mean arterial
blood pressure in a laboratory experiment. The pressure bottle (R) is filled with anticoagulating
fluid and is connected by tubing with the manometer (M), the cannula for the artery (U) being
connected with the T-piece (J). By this arrangement it is possible to flush out the tubing
when clotting interferes with the experiment. (From Jackson — Experimental Pharmacology.)

where between 120 and 140 mm. The pressure varies in different parts
of the vascular system, being greatest in the aorta and least in the small-
est arterioles but the fall in pressure — the pressure gradient — does not
become very pronounced until the arterioles have become so small that
it is no longer possible to insert a cannula into them; thus, the mean

BLOOD PRESSURE

127

blood pressure in the renal or femoral artery is very little less than that
in the aorta.

If we examine the contour of the tracing whic'h the pressure draws, we
shall find that it exhibits two types of wave, small and large ; and if we
observe the animal while the tracing is being taken, we shall find that

Fig. 22. — The arterial blood pressure recorded with a mercury manometer (lower tracing),
along with a tracing of the respiratory movements of the thorax. Note that the beginning of
respiration occurs distinctly before the rise in blood pressure.

the former are caused by the heartbeats and the latter by the respir,a-
tions — an observation which immediately raises the question as to the
trustworthiness of the method, for it will be asked, How can it be that
the heartbeat produces an effect an blood pressure which is less than
that of the respirations? Obviously the tracing must be faulty in re-
gard to the relative significance of the waves.

128

THE CIRCULATION OF THE BLOOD

Spring- Manometer Tracings

The cause of this inaccuracy depends on the inertia of the mercury,
an inertia which is so great that the sudden changes of pressure produced
by each heartbeat are not able to overcome it, whereas the much. less
significant but more prolonged pressure changes produced by each respi-
ration develop their full effect on the mercury. These facts led investi-
gators to seek for instruments in which the inertia error is eliminated,
with the result that they invented what are known as spring manometers.

Fig. 23. — Hiirthle's spring manometer.

Many forms of this instrument have been devised, but for our pur-
pose it is necessary to describe the principle of only the simplest and
most efficient — the Hiirthle manometer. As shown in Fig. 23, it consists
of a variety of tambour, which differs from the ordinary tambour in two
important particulars : (1) the chamber is made as small as possible, and
(2) it is covered not with an elastic membrane but with one of leather or of
thin fluted metal. These two precautions are taken in order to avoid spuri-
ous waves set up on account of elastic recoil. Such errors are further
reduced by filling the tubing and chamber of the tambour with a fluid
so as to eliminate the elastic recoil of air.

Fig. 24. — Normal curve of arterial blood pressure obtained with spring manometer.

( Burdon- Sanderson. )

Before the tracing taken with the spring manometer can be em-
ployed for quantitative measurements, it must obviously be graduated
according to some scale. This is accomplished immediately before or
after the experiment by connecting the manometer through a T-piece
with a pressure bottle, which can be raised or lowered to a specified
height, and with a mercury manometer. The displacement of the writing
point of the spring manometer corresponding to each 10 mm. Hg of
pressure is then written on the tracing.

The tracings taken with such a manometer, as shown in Fig. 24, are
quite different from those with the mercury manometer. It will be seen

Rt.OOD PfcESSUfcE

129

that now the cardiac waves are decidedly the more pronounced, the respira-
tory, being comparatively inconspicuous. The pressure in %the arteries,
instead of being fairly steady, undergoes very considerable alteration
tion during each heartbeat.

Examination of this tracing gives us accurate information regarding
the blood pressure both between the heartbeats — diastolic, as it is called —
and during them — systolic. It gives us a means of measuring the
dead load of the circulation — that is, the pressure that is constantly
present — as well as the live load that is superadded to this by each heart-
beat. This difference is often called the pressure pulse, and in man it
amounts to somewhere about 35 mm. Hg. If we take tracings with a
spring manometer from different parts of the arterial tree, we shall find

120

L /ne of
SYSTOLIC PRESSURE

L/ne of
M£ A A/ PRESSURE

Line of

D/ASTOLtC

Pressure

D/ASTOL/C PRESSURE

between

Fig. 25. — Diagram based on experiments on dogs to show the magnitude of the systolic,
diastolic and mean blood pressures at different parts of the circulatory system. O is the line
of zero pressure, and the letters below it indicate the parts of the system to which the curves
refer. (From Brubaker.)

that, as we travel towards the periphery, the pressure pulse becomes less
and less marked, until finally by the time the capillaries are reached it
has almost entirely disappeared. This decline in the pressure pulse can
moreover be seen to be dependent more largely on a fall in systolic than
in diastolic pressure. In other words, the dead load of the circulation —
the diastolic pressure — remains practically constant all along the arte-
rial tree, whereas the systolic pressure falls relatively quickly (Fig. 25).

Clinical Measurements

The methods of blood-pressure measurement in man have recently
become so perfected that the results are almost as accurate as those eb-

130

THE CIRCULATION OF THE BLOOD

tained in laboratory animals by direct measurement through the use of
cannulae inserted into the vessels. Both the systolic and the diastolic
pressure can be measured with equal facility and accuracy. Since the
technic for making the systolic measurements was described at a much
earlier date than that for the diastolic, it has until recently been the
habit with a great part of the medical profession to be satisfied with
systolic readings alone. This is most unfortunate, because the knowledge
wrhich such information gives us is incomparably inferior to that which
can be obtained by gauging the diastolic pressure. Until we have learned
more about the dynamics of circulation, it would be profitless to go
into any details as to the reasons for this statement, but it will soon
become self-evident. Suffice it for the present to state that the diastolic
pressure is the more important because it gives us the load which the ves-
sels and aortic valves must constantly ~bear, and the resistance which must
be overcome prior to the opening of these valves at the beginning of
systole. Moreover, it helps us to gauge the peripheral resistance.

The first step in the technique of blood-pressure measurements in man
is the placing of an armlet or cuff around the arm or leg. This armlet
consists of a rubber bag at least 12 cm. broad and covered on its outer
surface by cloth or leather. The bag is connected by tubing with a pres-
sure gauge and a pump. The pressure gauge may be either an ordinary
mercury manometer (Fig. 26) or one of the numerous gauges built on
the aneroid principle that are now on the market. For measuring the
blood pressure in the vessels of the upper extremities, the armlet should
be applied around the fleshy part of the upper arm and for the lower limbs
around the thigh. For accurate reading of both pressures in the arm the
following procedure should be followed. Having applied the armlet, the
pulse is palpated at the radial artery, and the pressure in the arm-
let then raised until the pulse can no longer be felt, at which moment
the pressure in the manometer is noted. The cuff is then slowly
decompressed and the pressure noted at which the pulse reappears.
These two readings of systolic pressure should be close together, but
they will not usually agree exactly for reasons which will be explained
immediately. They give us the palpatory systolic index, as it is called.
The pressure is now lowered about 15 mm. Hg, and a stethoscope is
placed in front of the bend of the elbow over the artery and as close up
to the cuff as possible. With each heartbeat a distinct sound like a pistol
shot will be heard. The decompression is now continued slowly, and as
the pressure falls the sounds will be heard to become louder and prob-
ably somewhat murmurish in quality. At a certain pressure this loud
character of the sound will suddenly become much less marked, and the
murmurish quality if present will disappear. This point corresponds to
the diastolic pressure, which is now read off from the manometer.

BLOOD PRESSURE

131

It must be remembered that below this point, as the pressure in the
cuff is further lowered, a sound is still heard in the artery; indeed it
does not entirely disappear until the pressure has become quite low. This
point of final disappearance is, however, of no significance. The cuff is
now entirely decompressed, and should be left so for a moment or more,
so that the circulation in the part of the arm below it may return to the
normal.

The above readings should then be controlled by a second observa-

Fig. 26. — Apparatus for measuring the arterial blood pressure in man. The pressure in the
cuff is raised by means of the syringe until the pulse can no longer be felt at the wrist. This
pressure is read off on the mercury manometer (systolic pressure).

tion, in which the procedure is slightly modified. With the stetho-
scope at the bend of the elbow the pressure in the cuff is run up to
a little above the previously determined diastolic pressure, so that the
sound is clearly heard. The pressure is then further raised till the
sound disappears. This point indicates the systolic pressure; it is called
the auditory systolic index. It will be found to give a systolic pressure
a little higher than that obtained by palpation of the artery at the wrist.
The sound being now absent, the pressure in the cuff is lowered until
the sound reappears, and the point at which this occurs should almost

132 THE CIRCULATION OP THE BLOOD

exactly correspond to that at which the sound was found to disappear.
If the palpatory systolic index is not below the auditory, it indicates
that some error has been made in the application of the apparatus, and
that the reading of the diastolic pressure will be unreliable. The usual
source of error is in the position of the stethoscope. If readjustment of
this does not bring the two indices into proper relationship, the auscul-
tatory method can not be relied upon for either systolic or diastolic
readings.

In case of failure of the auscultatory method, we have to fall back upon
the palpatory method for measurement of the systolic pressure; and for
measurement of diastolic, we must use the method known as the oscillatory,
which until recent years was the only one known for gauging the dias-
tolic pressure. This consists in observing the oscillation of the indicator
of the pressure gauge; as the pressure in the cuff falls gradually from
below the systolic pressure, these oscillations will be observed to increase
in amplitude, until they reach a maximum beyond which with lower
pressure they rapidly decline. The pressure in the cuff at the moment
when the oscillations are at the maximum represents the diastolic pres-
sure. With a mercury instrument it is obviously difficult to employ this
method, but with a modern spring instrument it can with a little practice
be used with great accuracy and will serve as a valuable check on the
diastolic reading as taken by the auscultatory method.

The procedure may be altered in various ways, there being only one pre-
caution to bear in mind ; namely, that the pressure in the cuff should not be
applied continuously for more than a few moments of time, for if this
is done for long periods, not only will it interfere with the accuracy
of the reading, but it may cause considerable discomfort to the patient.

There are several conditions affecting the accuracy of the readings by each method
which it is well to bear in mind. These have been investigated by MacWilliam,i Leon-
ard Hill, 2 and Erlanger.3 The most important conditions affecting the systolic pressure
are as follows: (1) The compression cuff should be a wide one (12 cm.), and it
should never be applied so that there is any chance of its compressing the artery
against a bony surface. This precaution is necessary, since it has been found that
much less pressure is required to obliterate any perceptible pulse below, the armlet
when the artery is flattened against some hard structure than when it is uniformly
compressed in the tissues in which it lies. (2) Discrepancies are often noted between
the systolic readings on compression and decompression of the artery; that is, the
pulse may reappear on decompression at a lower pressure than that at which it dis-
appeared on compression, the difference being most marked when the decompression
is done quickly. This difference is owing to the fact that the full force of the pulse
does not reach the forearm until all the vessels have become distended with blood.
(3) There are often discrepancies in the systolic readings taken from different limbs;
thus, it is not uncommon to find that the systolic pressure in the leg is higher than
that in the arm even when the observed person is in the horizontal position. These
differences are most commonly observed in patients suffering from aortic regurgita-

BLOOD PRESSURE 133

tion or thickened arteries. In aortic regurgitation the pulse is of the water-hammer
variety, and the greater systolic pressure observed in the leg vessels in such cases
seems to depend on differences in the physical conditions concerned in the transmission
of this exaggerated pulse wave to the vessels of the two extremities.

The reason for the discrepancies in cases of hardened arteries is no doubt that the
hardening is likely to be more pronounced in the vessels of the thigh than in those of the
arms. When a hardened vessel is compressed it does not collapse uniformly— rthat is,
it does not become completely closed — but its walls come together at the middle part
while chinks still remain at the sides. The blood continues to pass through these chinks,
and a very considerably higher pressure in the cuff is required to obliterate them.
That this is probably the correct explanation is supported by the observation that, al-
though in such patients the pulse does not disappear in the vessels of the foot at the
same pressure as it does at the wrist, a distinct change is nevertheless perceptible in
the pulse of the foot at a cuff pressure equal to that producing obliteration in that of
the wrist. In a patient showing a systolic pressure of 1.15 mm. for the upper arm and
198 mm. for the leg, at 116 mm. the pulse in the leg, although not obliterated, became
notably cut down in volume. Thereafter it persisted at a small volume with little
alteration until the pressure became sufficient to obliterate it. It is said that re-
peated compression and decompression of the hardened arteries greatly reduces the dis-
crepancy in the systolic readings. Differences in systolic readings are also sometimes
observed in normal individuals, particularly after muscular exercise, but for these no
satisfactory explanation can be given.

While palpating the radial artery, it will often be noticed, as the pressure in the
cuff is gradually raised from zero, that the force of the pulse increases perceptibly
until a pressure of about 50 mm. is reached. This paradoxical behavior of the pulse
can also be demonstrated by the sphygmograph (see page 202). Its cause is not un-
derstood, but it is of significance that the greatest augmentations occur at the same
cuff pressure as that at which a sound first comes to be heard by listening over the
artery at the elbow.

With regard to the diastolic pressure, there has been some controversy as to whether
it is more accurately gauged by the oscillatory or the auscultatory method. If both
methods are employed it will usually be found that the oscillatory gives a higher read-
ing than the auscultatory. The consensus of opinion seems to be that the latter
method is the more accurate, and certainly it is the easier to apply, for with the
oscillatory there is often great difficulty in deciding just exactly when the maximum
oscillation occurs.

The strongest evidence supporting the conclusion that the auscultatory readings are
more reliable than the oscillatory has been gained by experiments with an artificial
schema, consisting of a wide glass tube representing the armlet, filled with Ringer 's
solution and closed by rubber stoppers pierced by tubes, which are connected with a
fresh artery, which therefore runs from end to end inside the tube. Through tubing
connected with the artery a pulsatile flow of oxygenated Ringer's solution is made
to flow at varying pressures, which are indicated by valved manometers (see page 152)
connected with the artery tubing just beyond the compression tube. The pressure in
the latter is also measured by a manometer, and it is caused to vary by a suitable
compressor. By comparing the- behavior of the artery with the pulsating movement of
a spring manometer connected with the compression chamber, under different degrees
of pressure inside and outside the artery, it has been observed that the maximal oscilla-
tion occurs when the artery is actually somewhat flattened between the pulse beats; that
is, it occurs at an outside pressure above the diastolic pressure, at which of course the
vessel should retain its circular shape. When a stethoscope is applied to the tube

134 THE CIRCULATION OF THE BLOOD

leading from the artery just beyond the compression chamber, in the above described
model, sounds similar to those in the arm are heard with each pulsation. While the
pressure is being gradually lowered from above the obliteration point, these sounds
will be found to become first audible as soon as a certain amount of fluid is forced
through the compressed area at each pulse (the systolic index), and to become louder
and often murmurish in quality as the decompression is proceeded with, until a pres-
sure is reached at which they suddenly become less intense and change in character. At
this moment it will be observed by watching the artery that the external pressure is
no longer capable of producing any flattening of the vessel between pulses. Evidently,
therefore, the change of sound corresponds exactly to the diastolic pressure.

With regard to the cause, it should be clearly understood that it is the
systolic wave that produces it, although its occurrence and character are
dependent upon the intra-arterial pressure existing during the diastolic
phase. The cause of the sound has been shown to depend on the pro-
duction of a water-hammer in the blood vessels below the compres-
sion cuff (Erlanger3). By a water-hammer is meant the pressure changes
which are caused by suddenly stopping the flow of water in a tube. These
changes in pressure cause the walls to be thrown into vibration and so
produce a sound. In the taking of blood-pressure measurements,
as above described, when the pressure in the cuff is between the
systolic and diastolic, the volume of the compressed artery will in-
crease abruptly with each heartbeat and thus permit a considerable
volume of swift-flowing blood to enter the rest of the artery underneath
the cuff. When this quickly moving column of blood comes into con-
tact with the stationary blood filling the uncompressed artery below the
cuff, it will become immediately checked, and thus distend the arterial
wall with unusual violence and set it into vibration.

CHAPTER XVI

THE FACTORS CONCERNED IN MAINTAINING THE
BLOOD PRESSURE

Having become familiar with the principles of the methods by which
blood-pressure measurements are made, the next problem is to examine
into the causes which operate to maintain the pressure. Two of these
causes may be considered as fundamental, since without them no such
pressure could exist. These are: (1) the pumping action of the heart,
and (2) the peripheral resistance — that is, the resistance to -outflow of
blood from the ends of the arterial system. Less essential though im-
portant factors are: (3) the volume of blood in the blood vessels, (4)
the viscidity or viscosity of the blood, and (5) the elasticity of the
walls of the vessels. We shall now proceed to examine the experimental
evidence which indicates the relative importance of each of these factors.

1. The Pumping Action of the Heart

Changes produced in the mean arterial blood pressure by alteration
in the pumping action of the heart are most strikingly demonstrated by
observing this pressure after cutting or during stimulation of the vagus
nerves. As will be explained later (page 222), impulses conveyed
through these nerves to the heart make the beats slower and weaker.
These impulses are constantly acting in the heart, so that when both
vagus nerves are cut, the beats become more frequent and stronger,
with the result that the mean arterial pressure rises considerably. A
lesser degree of this effect can usually be obtained by cutting the vagus
nerve on one side (Fig. 27). If now the peripheral end of a cut vagus
nerve is stimulated, as by applying an electric current to it, the heart will
either stop beating altogether or become very much slowed, with the result
that the mean arterial blood pressure will fall, in the former case almost to
zero and in the latter, to a level corresponding to the degree of slowing
of the heart (Fig. 28).

2. The Peripheral Resistance

To demonstrate the influence of peripheral resistance on mean arte-
rial blood pressure, the most striking experiment is performed by cutting
or stimulating the great splanchnic nerve. Through this nerve, impulses,

135

136

THE CIRCULATION OF THE BLOOD

Fig. 27. — Effect of cutting the vagus nerve on the arterial blood pressure.

Fig. 28. — Effect of stimulating the peripheral end *of the right vagus on the arterial blood

pressure.

BLOOD PRESSURE

137

which arc called vasoconstrictor because they constrict the lumen of the
blood vessels, are transmitted to the blood vessels in the abdomen.
The vessels are under the constant influence of these impulses so that,
when the nerves that transmit them are severed, the vessels dilate and
thus offer less resistance to the movement of blood. The result
produced on the mean arterial blood pressure by cutting the two
splanchnic nerves is therefore a marked and sudden fall, which is im-

Fig. 29. — l^ffect of stimulation of the left splanchnic nerve on the arterial blood pressure.
.Note the primary and secondary rises.

mediately recovered from if the peripheral end of one of the cut nerves is
stimulated artificially (Fig. 29). In choosing this experiment to prove the
relationship between peripheral resistance and the mean arterial blood
pressure, it must be remembered that it is not entirely conclusive, since
the results observed on the mean arterial blood pressure from cutting
or stimulating the nerve may be in part explained as due to variation
in the total capacity of the circulation ; more room is created by cutting
the nerves, less room by stimulating them.

138 THE CIRCULATION OF 1HE BLOOD

3. The Amount of Blood in the Body

This can be altered by hemorrhage or transfusion, and the results
of such procedures are of interest not only on account of their physi-
ological bearing, but also because of their great practical importance.

To appreciate the significance of the results, it is important to bear in
mind that the total volume of the Hood constitutes from 5 to 7 per cent
of the weight of the animal (see page 85).

The immediate effect of hemorrhage on the blood pressure depends on
the rate of bleeding. If a large artery, such as the femoral, is cut across,
the pressure will show an immediate but moderate fall, due largely to the
fact that we have suddenly decreased the peripheral resistance. If on
the other hand only a small artery or a vein is opened, the bleeding will
at first produce no effect on the blood pressure, and it is only after some
considerable amount of blood has been removed that it begins to fall.
To be more exact, we may state that the removal of 5 c.c. of blood per
kilogram of body weight does not influence the blood pressure. The re-
moval of a second portion of 5 c.c. per kilogram causes the blood pres-
sure to begin to fall, the fall of pressure for each subsequent 5 c.c. of
blood per kilogram removed averaging about 6 mm. Hg, until after 20
to 25 c.c. of blood per kilogram have been removed, when a more rapid
fall in pressure sets in (Downs'*). When the pressure reaches the level
of from 20 to 30 mm. Hg, the danger limit is reached, for there now
supervenes a train of symptoms known as ' ' shock, ' ' and the chances for the
animal's recovery become uncertain. That the removal of the first por-
tion of blood, if this removal is slow enough, does not influence the blood
pressure, indicates that some adjustment has occurred in the vascular
system to hold up the pressure in spite of the loss of blood. This adjust-
ment is believed to consist in vasoconstriction.

Recovery from hemorrhage is remarkably rapid, the original volume of
blood being restored within a few hours. The chances of recovery de-
pend upon the amount of blood lost. A loss equal to 2 or 3 per cent of
the body \veight can almost always be recovered from in laboratory ani-
mals, and in the case of man there is reason to believe that recovery
may occur after as much as 3 per cent of the body weight has been lost.
The recovery of blood pressure is brought about partly by a transfer
of fluid from the tissues to the blood. This abstraction causes a drying
out of the tissues, which soon excites an extreme degree of thirst. The
dilution of blood by fluid derived from the tissues occurs very rapidly,
as can be shown by comparison of the hemoglobin content, or the number
of blood corpuscles, in samples of blood removed immediately before

BLOOD PRESSURE 139

and immediately after a hemorrhage. The specific gravity of the post-
hemorrhagic blood is also decidedly below normal, indicating that the,
diluting fluid contains a lower concentration of dissolved substances than
the blood plasma. The dilution of the blood is indeed often so great that
hemolysis occurs, the plasma being distinctly tinted red.

Hemorrhage also slightly raises the hydrogen-ion concentration of the
blood plasma, and diminishes the store of reserve alkali, so that the ad-
dition of a certain amount of acid to the blood (e.g., carbon dioxide)
causes a greater rise in the hydrogen-ion concentration.

The deficiency in the blood elements produced by the dilution is recti-
fied by the manufacture of new corpuscles in the bone marrow, etc., but
this process in a liberally fed animal takes several days for accomplish-
ment, and while it is going on microscopic examination of the blood will
reveal the presence of immature corpuscles.

Careful studies of blood regeneration following the removal on two
successive days, of 25 per cent of the blood, have shown that even in
starving animals the total amount of hemoglobin (percentage of hemo-
globin multiplied by the volume of blood) slowly recovers (Whipple
and Hooper). Recovery is greatly hastened by feeding with flesh or
even with gelatin. Removal of the spleen or the establishment of a bili-
ary fistula does not interfere with the recovery.

Incidentally it will be advantageous to consider here the effects of
transfusion. These are very different according to the nature of the fluid
used for transfusion. Three transfusion fluids have been investigated:
(1) blood itself, (2) physiological saline solution (see page 96), and (3)
physiological saline solution containing viscid substances such as gum or
gelatin. The effects are also very different according to whether the solu-
tions are injected into animals with normal blood pressure or into those
whose blood pressure has been lowered by preceding hemorrhage. The
general effects are shown in the curves of Fig. 30.

When blood is injected into animals with normal blood pressure, it
will very soon cause the pressure to rise, and as the injection is main-
tained the rise may continue until the pressure is perhaps 50 per cent
or more above its normal level. If the injection is long continued, how-
ever, a sudden fall of pressure occurs, on account of engorgement of the
right side of the heart. If the injection is not pushed so far, the increased
blood pressure after being maintained for a short time returns to its old
level.

Injection of saline into a normal animal, if made slowly, has no effect
at all on the blood pressure; if more rapidly injected, the pressure will
rise slightly, but to a much less extent than that observed when blood
itself is injected. Much larger quantities of the saline than of the blood

140

THE CIRCULATION OF THE BLOOD

can be tolerated before cardiac embarrassment ensues. After the dis-
•continuance of the > saline injection, the blood pressure returns very
rapidly to its old level. The most striking result of such experiments is
the enormous volume of saline solution which can be slowly injected
without perceptibly affecting the pressure. The question is, Where does
the fluid go ? If the urinary outflow is examined, a certain increase will

Fig. 30. — Composite curves to show effects on blood pressure of hemorrhage, and transfusion
with various solutions (N. M. Keith, from P.ayliss). The average pressure in the various experi-
ments before and after hemorrhage is given on the left in a continuous line. The behavior of the
pressure after transfusion varied according to the solution used.

ftLOOD PfcESSUfcE 141

usually be observed, but never by any means sufficient to account for
the disappearance of the injected saline. If we open the abdominal cav-
ity, we shall find that a considerable transudation of the saline into the
peritoneal cavity has occurred, and that the liver is conspicuously edem-
atous. A certain degree of edema is also usually evident in the tissues
of the extremities.

Still more interesting and important, from a practical standpoint, are
the results obtained by injecting the above solutions into animals
whose blood pressure has been lowered by a previous hemorrhage. If
the blood removed during the hemorrhage is defibrinated (see page 102),
and then reinjected into the animal, it will bring the blood pressure al-
most but not quite back to its original level, which will then be fairly
well maintained. If, on the other hand, saline solution instead of blood
is injected, the restoration of blood pressure (with an amount of saline
equal to that of the removed blood) will amount only to about three-
quarters of the extent to wrhich it had fallen. This partial recovery is,
moreover, maintained for a short time only, after which the pressure
approaches the level to which it was reduced by the hemorrhage.

These observations raise two important practical questions: (1) Why
is saline relatively ineffective in the restoration of pressure? and (2)
Why is the restored pressure not maintained?

The answers to these questions brings us to a consideration of the next
of the factors concerned in the maintenance of the blood pressure,
namely, the viscosity of the blood.

4. The Viscosity of the Blood

The importance of this factor arises from the fact that facility of flow
in a tube is inversely proportional to the viscosity of the fluid and
directly proportional to the driving pressure to which it is subjected —
that is, to the difference in pressure between two points in the tube.
If therefore the output of the heart remain constant, but the viscos-
ity of the blood be decreased by a saline injection, the facility of flow
will be increased and the pressure decreased. This fact can easily
be shown experimentally in a model by causing gum solutions of various
concentrations to be driven through a glass tube by means of a small
piston pump delivering a constant amount of fluid into the tube with
each movement. Although the outflow from the narrow end of the tube
must remain constant, the pressure in the tubing will vary in proportion
to the viscosity of the gum solution (Bayliss5.)

Transferring these results to an animal whose blood pressure has been
lowered by hemorrhage, it has been found that if saline solutions con-

142 THE CIRCULATION OP THE BLOOD

taining a sufficient amount of gum acacia or gelatin to make the viscos-
ity about equal to that of blood, are injected, the original level of blood
pressure is recovered as well as it would have been had blood itself been in-
jected. A 7 per cent solution of gum acacia almost fulfills these require-
ments, but unfortunately this solution contains a slightly greater amount
of calcium than it is safe to inject into an animal. The excess of calcium
may, however, be removed by exactly neutralizing the gum solution with
sodium hydroxide, neutral red being used as an indicator. Most of the
calcium becomes precipitated as phosphate. The mucilage of the British
Pharmacopeia, diluted five times with water, makes a 7 per cent solu-
tion of gum acacia. A 6 per cent solution of gelatin, after being heated
to 100° C., gives a viscosity similaT to that of blood, but on account of
the possible presence of tetanus spores such solutions must be very care-
fully sterilized before injection, and the process of sterilization causes
a decrease in viscosity. The injection of a quantity of one of the above
solutions equal to that of blood lost by a hemorrhage will usually bring
the blood pressure back to its original height and hold it there for an
hour or so.

Viscosity is, however, not the only property of such solutions upon
which their desirable effect depends. The osmotic pressure of the colloids
also comes into play. By injecting saline solution containing a sufficient
amount of a colloid such as soluble starch, which gives it the correct
viscosity but has no osmotic pressure, the blood pressure, although it
temporarily recovers after transfusion, does not maintain its recovery in
the same way as with solutions containing gum or gelatin. The difference
between a starch solution and one of gum or gelatin is that the former
has no osmotic pressure, the effect of which is developed mainly on the
excretion of urine, as can be shown by observing the outflow from the
ureters during the injection into animals of equal quantities of saline
alone or of saline containing starch or gelatin (Knowlton6.) With the
first two fluids diuresis is produced, but not with the gelatinous solutions.
The reason that the osmotic pressure of certain colloids prevents passage
of water from the blood into the uriniferous tubules is that the develop-
ment of this pressure 011 the blood side of the renal epithelium tends to
counteract the filtration pressure by which the urine is formed (see
page 547).

Although the urinary factor will not in itself explain the efficiency of
the colloids in recovering the blood pressure, the conditions controlling
it reveal the mechanism by which the passage of fluid from the blood
vessels into the tissues is prevented when solutions of correct composi-
tion are injected. Normally the protein content of the blood plasma is
higher than that of the tissue lymph, so that there is a continual attrac-

BLOOD PRESSURE 143

tion of water from the tissues to the blood — an attraction which is nor-
mally balanced by nitration going in the opposite direction. When the
filtration pressure in the blood vessels exceeds the difference existing
between the osmotic pressure of their contents and that of the tissue
fluids, water will pass into the tissue spaces. When the blood is diluted,
as by the injection of saline solution, the osmotic pressure of the colloids
in a given volume becomes lowered and, the filtration pressure remaining
constant, fluid passes into the tissue spaces. Of course these explanations
rest on the assumption that the walls of the blood vessels consist of a
membrane which is permeable to crystalloids but impermeable or nearly
so to colloids. A further account of the use of the solutions for transfu-
sion in cases of surgical shock will be found on page 311.

Another important property of the transfused saline solution to con-
sider is its hydrogen-ion concentration. This value increases in the blood
left in the body after hemorrhage, and injection of sodium chloride solu-
tion aggravates the acidosis; addition of NaHC03 so as to make a 0.2
M solution restores the correct PH, and at the same time restores the
lost buffer influence (Milroy7.) These observations are of interest in the
light of the recent discovery of Cannon that a condition of acidosis, as
judged by the C02-combining power of the blood, is present in shock,
and that the development of this condition can often be guarded against
by bicarbonate injections.

5. Elasticity of Vessel Walls

The elasticity of the vessel walls is essential to the maintenance of the
diastolic pressure. If the walls presented no elasticity but were rigid,
blood pressure would fall to zero between the heartbeats. This fact can
very readily be shown by a simple physical model consisting of a pump
to represent the heart, connected through a T-piece with two tubes, one
of which is elastic, the other rigid. The free end of each tube is con-
tracted to a narrow aperture representing the peripheral resistance, and
either tube may be shut off from the pump by means of a stopcock (see
Fig. 31). Each tube should also be connected with a mercury manom-
eter. If now the stopcocks are arranged so that the fluid passes into
the rigid tube while the pump is in action, it will be found that with
each stroke of the pump the pressure in the tube rises considerably, but
that it falls to zero between the strokes. If now the stopcocks are turned
so that the flow is through the elastic tube, the action of the pump being
meanwhile kept up, it will be found that the pressure between the strokes
is maintained at a height which is dependent on: (1) the rate at which
the pump is operating, and (2) the resistance to outflow from the tube.

144

Till'] ClUri'LATION OF TIIK I5UHH)

The quicker the action of the pump and the higher the resistance, the
lower the fall of pressure between the beats.

The physical explanation of this result is clearly that the fluid within
the elastic tube when the wave of pressure travels into it from the pump
distends the walls of the tube, so that when the pressure from the pump
ceases to act, the stretched elastic walls recoil on the column of fluid
and maintain the pressure. We may say that the elastic fibers in the
vessel walls store up some of the systolic pressure and then transmit it to
the blood during diastole.

Fig. 31. — Diagram of experiment to show that the diastolic pressure depends on the elasticity
of the vessel wall. The pulse (produced by compressing the bulb J5) disappears when fluid
flows through an elastic tube (F) when there is resistance (<?) to the outflow. A, basin of
water; B, bulb -syringe; C and E, stopcocks; D, rigid tube; F, elastic tube; C, bulb filled with
sponge.

These considerations would lead us to expect that patients with hard-
ened arteries should exhibit a lower diastolic pressure than normal per-
sons, which, however, is not usually the case, since such patients also
suffer from an increase in the resistance to the flow of blood in the periph-
ery. The pressure pulse in these patients is, however, very marked.
On the other hand, when the vessel walls become more extensible and
elastic, as in certain cases of aneurism, the pressure pulse in the vessels
below the aneurism is distinctly less than that observed in normal ves-
sels of the same patient.

CHAPTER XVII
THE ACTION OF THE HEART

Having studied the methods for measurement and the main factors con-
cerned in the maintenance of the arterial blood pressure, we may now pro-
ceed to study in greater detail the two most important of these ; namely, the
action of the heart, and the peripheral resistance.

The heart action has to be studied from two viewpoints, the physical
and the physiological. From the physical viewpoint we have to study
the heart as the pump of the circulation. We must see how it acts so as
to raise the pressure of the blood within it, and how the valves operate
so as to direct the bloodflow always in one direction. We must also ex-
plain the causes of certain secondary physical phenomena, such as the
heart sounds which accompany the heart action, and of certain secondary
changes in pressure produced in the other thoracic viscera by each heart-
beat. From the physiological viewpoint we must investigate the conditions
responsible for the constant rhythmic activity of the heart and the con-
trol to which this is subjected through the nervous system.

THE PUMPING ACTION OF THE HEART

When the heart is viewed in the opened thorax of an animal kept alive
by artificial respiration and lying in the prone position, it can be noted
that with each contraction the ventricles become smaller and harder, that
the apex tends to rise up a little, so that if the thorax were intact it
would press more firmly against the walls, and that it rotates slightly
from left to right, but does not move nearer the base of the heart. If
the auriculoventricular groove is carefully observed, it will often be
noted that it moves slightly toward the apex with each systole, whereas
the base of the heart itself, where it is attached to the large vessels, re-
mains fixed. The auricles can often be seen to contract and relax before
the ventricles.

The most noteworthy results of this inspection are that during sys-
tole the apex of the heart does not move toward the base, but that
the auriculoventricular groove moves slightly toward the apex. That
these same movements occur in the intact animal can be shown by the
very simple experiment of pushing two long steel knitting needles

145

146 THE CIRCULATION OF THE BLOOD

through the thoracic walls into the heart walls, one of them so placed
that it pierces the apex of the ventricle, the other so that it pierces the
base. The needles then act as levers with their fulcra at the chest wall,
and if the movements of their outer free ends, produced by the movements
of the heart, are observed, they will be found to confirm the observations
made on the exposed heart.

More particular investigations of the changes occurring in the shape of the heart
cavity during systole and diastole have been undertaken by making measurements of sec-
tions across the heart in one or other of these conditions. For such purposes the heart in
diastole is easily obtained, but for the heart in systole it is necessary to use the some-
what artificial means of injecting the heart with hot chromic acid solution just be-
fore the death of the animal. The chromic acid causes the cardiac muscle to contract
and maintains it in this condition. The outcome of these investigations is, however,
not of much practical importance.

Although it is now common knowledge that the direction of the flow of the blood
is from the veins to the arteries, yet it may be of interest to consider for a moment
the general principle of the methods by which William Harvey succeeded in making
this discovery. . His evidence was partly anatomic, partly experimental. He pointed
out that the walls of the veins, and of the auricles to which they lead, are very thin,
whereas those of the arteries and ventricles are very thick, and he concluded that
la the veins the blood must flow gently from the tissues toward the heart, to which the
valves in the veins direct it, and that in the arteries it must be propelled by pulses
with each systole through the arteries towards the tissues by the contraction of the
walls of the ventricles. The experimental support for this hypothesis he furnished
partly by clamping the large vessels, veins and arteries leading to or from the heart,
and observing the resulting distention or collapse of the vessel; and partly by cal-
culation of the amount of blood Avhich must be expelled from the ventricles in a given
period of time.

Harvey's discoveries concerning the events of the cardiac cycle were
not much added to until experimental methods were "devised by which
the pressure changes occurring in the various cavities could be measured
and compared. Until such measurements were elaborated, it was impos-
sible to investigate the mechanism by which the various valves between
the heart cavities and the vessels connected with them perform their
function, or to describe with any degree of accuracy the events occurring
in the heart chambers during the various phases of the cardiac cycle.
It is for the purpose of ascertaining the exact time relationship of these
changes that intracardiac pressure curves are studied.

Intracardiac Pressure Curves

The earliest method for taking such curves consisted in introducing
into the cardiac chambers and the blood vessels of the horse, so-called
cardiac sounds. These consisted of a more or less rigid tube furnished at
one end with a little elastic bag or ampulla and connected at the other
with a tambour, by means of rubber tubing. One of these little bags

THE ACTION OF THE HEART

147

was placed in one of the ventricles, another in the auricle or aorta, the
tube being inserted in the former case through one of the large veins at
the root of the neck; in the latter case through the carotid artery. The
intracardiac pressure curves obtained in this way marked a great ad-
vance over the methods that had previously been used to study the events
of the cardiac cycle, but they were so faulty in comparison with tracings
taken by more modern methods that it is not worth while considering
them any further here.

The physical errors involved in the use of the older instruments were due mainly to
the elastic recoil of the membranes, etc., used in their construction. A great improve-
ment in technique was afforded by the use of the spring manometer of Hiirthle (see page
128), which was connected with one of the heart cavities by a cannula filled before

Fig. 32. — Diagram of Wiggers' optical manometer. The wide glass tube (A) (connected
with the ventricle, etc.) is connected with a brass cylinder (B) provided with a stopcock (C),
the lumen of which comes in apposition with a plate (a) having a small opening in it. The
freedom of communication between B and a is regulated by the position of the tap. Above a is
a segment capsule (£>) 3 mm. in diameter and covered by rubber dam. This carries a small
mirror (C) fastened so that it pivots on the chord side of the capsule. Above the capsule is
arranged an inclined mirror, from which a strong beam of light is reflected on to the mirror
(c) on the capsule. This beam then travels back and the mirror (£) is adjusted so that it
impinges on a moving photographic plate. The slightest movements of the small mirror (C)
are thus greatly magnified.

insertion with some anticoagulant fluid. The cavity of the tambour was made as
small as possible, and either left empty or filled with the anticoagulating fluid.

A searching investigation into the physical principles involved in taking records of
sudden changes in pressure by such instruments has, however, shown that considerable
errors are incurred, the inertia of the moving mass of fluid in the tubing and the
necessity of using levers in order to secure records being responsible for most of them
(cf. Wiggers). Their elimination has recently been achieved by using a so-called
optical manometer, one of which (Wiggers') is shown in the accompanying figure. It
consists of a wide glass tube A, connected above with a hollow brass cylinder B, pro-
vided with a stopcock C, the lumen of which tapers from below upward till it assumes
the same diameter as an aperture in the segment capsule b, above it — that is, a capsule

148 THE CIRCULATION OP THE BLOOD

cut away at one end — Avhich is 3 ram. in diameter and covered with rubber dam. By
adjustment of this stopcock the pulsations of the fluid in A and B can be damped to
a greater or less extent before they are transmitted into the segment capsule. A small
piece of celluloid carrying a tiny mirror rests on the rubber dam, being pivoted on the
chord side of the capsule. A mirror is attached to the capsule with its plane so ad-
justed that the image of a strong light placed at some distance from it is focused on the
little mirror carried by the celluloid. The ray reflected from the little mirror and
again reflected from the larger mirror is adjusted so as to impinge upon a moving
photographic plate travelling at a uniform rate in a suitably constructed photographic
apparatus. By the use of such an apparatus the chief errors encountered by the use
of the older instruments are eliminated, because there is no moving mass of fluid and
there are no levers to set up spurious vibrations. Curves secured by the use of this
instrument are shown in Fig. 33.

Fig. 33. — Optical records of intraventricular pressure; a-b, auricular systole; b-d, presphygmic
period; d-f, sphygmic period; after /, diastole. Instruments of varying degrees of sensitiveness
were employed in taking the curves. ('From Wiggers.)

Two objects must be kept in view in analyzing the curves: (1) Curves
obtained from the different cavities may be compared in order to de-
termine the exact moment during the cardiac cycle at which such pres-
sure changes occur as must serve to produce opening or closing of the
various valves; and (2) the contour of the curves obtained from each
cavity may be examined in order to find out exactly how the pressure
in that particular cavity is behaving.

Comparison of the Curves

Before using the curves for ascertaining the relative pressure in the
different cavities, they must be graduated according to some scale, for
it is clear that by the use of instruments like those we have been describ-
ing, the absolute pressure value of each curve will vary according to the
construction of the instrument (thickness of membrane, etc.), and in-
deed instruments of varying degrees of resistance must be employed in
taking curves from places having such different pressures as exist in
the auricles and ventricles. The graduation is, however, a very easy
matter, and consists, as already explained (page 128), in connecting the

THE ACTION OF THE HEART 149

instrument by means of a T-piece with a mercury manometer and a pres-
sure bottle and then marking on the tracing, the points corresponding to
each 10, 20 or 50 millimeters of increase of pressure, as the case may be.

To ascertain the time relationship between the opening and the closing
of the auriculoventricular valve, the tracings should be taken from the
right auricle and the right ventricle, and to ascertain the same with re-
gard to the semilunar valve, from the left ventricle and the aorta.*

By comparing the curves it is now an easy matter to ascertain the
exact moment at which the pressure in the one cavity comes to equal
that in the other. This moment, read on the accompanying time tracing,
will obviously indicate that at which the particular valve is just about to
open or close. From the results of such experiments, the curves may be
superimposed as in Fig. 34.

In the first place let us compare the curves from the right auricle and
ventricle. The curves begin at the very end of diastole, and they show
that a distinct increase in pressure is occurring in both auricle and ven-
tricle and lasting about 0.2 second. This is of course caused by auric-
ular systole, and since it occurs in both cavities, it indicates that the
passage between them, the auriculoventricular orifice, must be open.
The ventricular curve then suddenly shoots away beyond the auricular
because of the onset of systole in the ventricle, and the point at which
the two curves begin to separate indicates the moment at which the
auriculoventricular valves close. From this time on until ventricular
systole has given place to diastole, (about 0.4 second), the auricle is
therefore shut off from the ventricle. The exact moment in diastole at
which the two cavities are again brought into communication — i.e., the
auriculoventricular valves open — is indicated by the curves coming to-
gether.

Having thus determined the exact moments of opening and closing
of the auriculoventricular valve, we may now proceed to compare the
intraventricular pressure curve with that taken from the aorta. After the
necessary calibration corrections, this curve has been placed in Fig. 34
in its true relationship to the ventricular curve. Beginning again at the
end of diastole, we find that the aortic pressure is very considerably
above that of the ventricles, indicating that the semilunar valves must
be closed; and it will be observed that the intraventricular pressure at
the beginning of systole does not rise sufficiently to open them until an
appreciable interval (0.02 to 0.04 second) after the closure of the auric-
uloventricular valves; that is to say, there is a period at the beginning
of ventricular systole during which the ventricle is a closed cavity. It

*The connections with the heart may be made by pushing long cannul.-e down the large veins or
arteries, or in the case of the ventricles by inserting a cannula with a sharp point directly through
the wall of the ventricle.

150

THE CIRCULATION OF THE BLOOD

is a period during which, the ventricle by its contraction is getting up a
sufficient amount of pressure in the fluid contained in it to force open
the semilunar valves against the resistance of the pressure in the aorta,
and it has been popularly called "the period of getting up steam," or,
in physiological language, the isometric, or the presphygmic, period. We
shall use the last-mentioned term in our further discussion here.

After the aortic valves have been opened, it will be observed that the
pressure in the ventricles is just a little above that in the aorta, and that

Fig. 34. — Superimposed pressure curves from aorta, ventricle and auricle, along with electrocar-
diogram and phonocardiogram. A, aorta. V, ventricle. Aur, auricle. E, electrocardiogram. P,
phonocardiogram.

it continues so during the whole of ventricular systole. When diastole
sets in, the pressure in the ventricles quickly falls, and a point is soon
reached at which equality of pressure in ventricle and aorta is again
attained. This corresponds to the moment of the closure of the semi-
lunar valves. The pressure in the ventricle, although now rapidly fall-
ing, takes a little time before it has fallen low enough to permit the
auricular valves to open. Here again, then, the ventricle is a closed cavity,
and we have what is known as the postsphygmic period.

CHAPTER XVIII

THE PUMPING ACTION OF THE HEART (Cont'd)
THE CONTOUR OF THE INTRACARDIAC CURVES

The Ventricular Curve

From an analysis of the contour of each curve, further interesting
points are brought to light. The intraventricular pressure curve recorded
by older methods was shown as having a flat top or plateau. By the use
of the more modern, optically recording, instruments it has been shown
that this plateau becomes displaced by a peak if every precaution is
taken to prevent dulling down of the pressure changes in the instrument,
as by opening wide the stopcock in the instrument (Fig. 33). The peak
is, however, by no means a sharp one (Fig. 34), so that we may fitly de-
scribe the contour of the ventricular curve during the sphygmic period as
consisting of a rising portion, almost continuous with the curve during the
presphygmic period, a summit and then a declining portion, which is usu-
ally slower than the ascending. The practical value arising from a study
of the curves lies in the insight which they give us into the nature of the
stroke of the cardiac pump. They show us that the impulse which the
ventricle gives to the moving mass of blood in the aorta rises quickly,
attains a peak, and then more gradually falls until the aortic valves close,
when the fall becomes much more sudden.

Wiggers has shown that the exact contour of the curve during the
sphygmic period depends partly on the degree of sensitiveness of the op-
tical manometer used and partly on the tension existing in the ventricle
just before contraction. In the case of the right ventricle the contour of
the curve also depends on the degree of resistance to the bloodflow through
the pulmonary circuit. The top of the curve becomes broader when the
initial tension is high, and more rounded when there is a high pulmonary
resistance.

The interest of studying the contour of the curve lies in the fact that
it indicates the nature of the stroke of the cardiac pump. It shows that
this is maintained so that time may be afforded to overcome the inertia of
the heavy load of blood in the large arteries.

Another point of interest in connection with the ventricular curve is
that early in diastole it descends below the line of zero pressure, indicating

151

152

THE CIRCULATION OF THE BLOOD

that a negative or suction pressure must exist in the ventricle at this
time. It will be further observed, however, that this subatmospheric
pressure exists for only a very short time. The auriculoventricular
valves being opened, a similar negative pressure is also present in the
auricular tracing. Were wre to depend on such records alone for evidence
of the actual existence of this negative pressure in the heart, objection
might be taken to the conclusion on the ground that it was due to the
sudden recoil to which the instrument is subjected at the beginning of
diastole. It is necessary therefore to control these observations by the
use of an entirely different method. This consists in connecting the
heart with a valved mercury manometer (see Fig. 35). This instru-
ment does not of course record any sudden changes of pressure in the
cardiac cavity, but in obedience to changes in pressure the mercury slowly
moves in the direction in which the valve permits it to move. Such an
instrument, with the valve opening towards the heart, is called a minimal

to manometer

max valve

mm valve

to heart

Fig. 35. — Von Frank's maximal and minimal valve, which is placed in the course of the
tube between heart .and mercury manometer. By turning the stopcocks, it may be used as a
maximum, minimum, or ordinary manometer (central tubes open). (From Starling.)

manometer, and after it has been connected with the ventricle, it will be
found that a negative pressure of perhaps 40 or 60 mm. Hg is recorded.
Evidently, then, the negative pressure does actually exist in the ventricle
during some phase of the cycle, and the question arises as to whether it
is of importance in connection with the pumping action of the heart. At
first sight, considering the heart as an elastic structure, we might con-
ceive that the negative pressure would serve to suck blood into the heart,
just as it sucks water in an ordinary ball syringe. Closer consideration
will, however, show that this conclusion is untenable, partly because the
negative pressure exists in the ventricle for so short a period of time, and
partly because it would have to operate on the slowly moving column of
blood in the thin-walled veins, with the result that it would cause the walls

THE PUMPING ACTION OF. THE HEART 153

of these vessels to come together rather than produce a movement of the
blood contained in them. The negative pressure of the heart can not
therefore be of much consequence in attracting the venous blood into the
ventricle.

Several factors may cooperate to produce this negative pressure,
among which may be mentioned the sudden opening out of the base of
the ventricles at the beginning of diastole, the recoil of the elastic tissue
which becomes compressed in the heart walls during systole and the
turgescence of the walls of the ventricles produced by the sudden inrush
of blood into the coronary vessels at the beginning of diastole. These
processes tend to cause an opening out of the Avails of the ventricles with
a consequent increase in the capacity of their cavities.

The Auricular Curve

Examination of the intraauricular pressure curve is of particular in-
terest because of the relationship which it has to a tracing taken of the
movements in the jugular vein at the root of the neck (see page 285).
This jugular pulse curve, as it is called, is produced mainly by the
changes of pressure occurring in the auricle, from which it differs only in
the relative height of the various waves. By graduating the intra-
auricular pressure curve by the method described above, we can tell
exactly the magnitude in the changes of pressure occurring during each
cardiac cycle. This obviously can not be done with a tracing taken from
the jugular vein, although qualitatively the tracings reflect exactly the
changes that are occurring in the auricle.

On examining the auricular pressure curve (consult Fig. 34), we
find that after the wave of presystole, which of course corresponds exactly
with that on the intraventricular curve, a second wave occurs culminating
in a peak almost exactly at the beginning of the sphygmic period. The
curve then rapidly descends, usually indeed below the line of zero pres-
sure, and slowly rises throughout the rest of ventricular systole, until
the moment of opening of the auriculoventricular valve, when it descends
again and thereafter runs parallel with the ventricular curve. The let-
ters used to designate the waves are the same as those employed for
similar wraves shown on the jugular pulse tracing, and although the
lettering is more or less arbitrary, we must accept it because of its gen-
eral usage in all work of this kind.

As to the causes of the waves, A, is of course caused by auricular systole
or presystole; C, occurring as it does at the beginning of the period of
ventricular systole, is caused by the bulging into the auricle of the closed
auriculoventricular valve. The floor of the auricle, in other words, at

154 THE CIRCULATION OF THE BLOOD

this moment becomes somewhat elevated and imparts to the blood which
is resting upon it a slight wave of pressure, which is transmitted along
the veins for a considerable distance. The succeeding depression is
marked x, and the negative pressure which it indicates is probably due
to the co-operation of three forces, all tending to i-ncrease the auricular
capacity: (1) the diastole of the walls of the auricle; (2) the descent
of the auriculoventricular groove, thus tending to open out somewhat
the folds in the walls of the auricle ; and (3), no doubt most important of
all, the tendency of the thin-walled auricles to become dilated as a result
of the sudden diminution in intrathoracic pressure produced at each heart-
beat by the discharge of blood from the heart and intrathoracic blood
vessels into those of the rest of the body. All thin-walled structures
in the thoracic cavity, the auricles included, will expand to take up the
extra room created in the thoracic cavity. Similar negative heart pulses,
as they are called, can be observed with each systole in the lungs and
in the esophagus.

THE MECHANISM OF OPENING AND CLOSING OF THE VALVES

When physical valves open and close as a result of the changes in pres-
sure on their two surfaces, a certain amount of fluid must succeed in
passing the valve flaps before these become perfectly closed. But there
is every reason to believe that such is not the case in the heart, the flaps
of both the auriculoventricular and the semilunar valves being already
completely closed before pressure conditions entailing a possible regur-
gitation of blood through them become established.

Auriculoventricular Valves

During diastole the flaps of the auriculoventricular valves are hanging
down into the ventricle and floating in a half-open position in the blood,
which is meanwhile accumulating in the chamber. This position is de-
pendent upon the operation of two opposing forces on the valve flaps:
the pressure of the blood flowing from the auricle on their upper aspects,
and reflected waves of pressure from the walls of the ventricle on their
under aspects (centripetal reflux). When presy stole occurs, the pres-
sure of the auricular stream momentarily increases, thus slightly dis-
tending the wall of the meanwhile relaxed ventricle and after a moment's
delay causing the reflected wave to become more pronounced. At the
same time the muscular fibers in the valve flaps (Kiirschner's fibers)
contract and make the flaps shorter, the total effect of the two factors
being that the valve takes up a position nearer that of closure. When
presystole suddenly stops, the reflected waves will persist for an instant

THE PUMPING ACTION OF THE HEART 155

of time longer than the auricular wave which causes them, because of
the elastic nature of the ventricular wall, so that the valve flaps close
with perfect apposition not merely at their edges but also for a con-
siderable distance along their upper surfaces.

When ventricular systole starts, the only effect of the high pressure
which is brought suddenly to bear on the under surfaces of the already
closed valves is to cause them to vibrate and to bulge into the auricles,
being meanwhile anchored down and prevented from flapping into the
auricle by the chordae tendineae. There is reason to believe that the
musculi papillares to which these are attached begin to contract at the
very outset of ventricular systole — indeed slightly to precede it (see
page 274), and thus keep the chordae taut. As systole continues the
contraction of these muscles becomes more and more pronounced, and the
resulting tightening of the chordae serves to draw down the valve flaps,
so that progressively larger proportions of their upper aspects tend to
become opposed. Meanwhile the auriculoventricular orifice is also be-
coming narrowed down on account of the contraction of the musculature
of the auriculoventricular groove.

Semilunar Valves

The mechanism involved in the operation of the semilunar valves is
somewhat different. It has been shown that, when fluid is flowing in a
tube, the pressure and velocity are not equal in the axial and peripheral
parts of the stream. In the axis the velocity is greater than in the layers
of fluid next to the walls, but the pressure is less. This can be seen by
observing through a wide glass tube the flow of water in which are sus-
pended lycopodium spores. By placing within the wide tube small bent
tubes so arranged that one open end lies near the periphery and the other
near the axis, the differences in pressure between the axial and peripheral
streams can be seen to cause the fluid to flow in the narrow tubes from pe-
riphery to axis (centripetal eddies).

If the tube should suddenly expand the eddy currents become still
more pronounced just where the wider portion starts. In the conditions
obtaining at the beginning of the large arteries of the heart, the orifice into
the ventricles being constricted, a centripetal vortex must be set up, tend-
ing to throw the valve flaps into a closed position, which, however, is pre-
vented by the blood rushing between them from the ventricles. They thus
take up a mid-position and vibrate in the stream. When the efflux from
the ventricle stops at the end of systole, the reflux, lasting for a moment
longer and being now unopposed, immediately closes the valves, in which
position they are then maintained by the greater pressure on their aortic
surfaces.

156

THE CIRCULATION OF THE BLOOD

The position of the valves relative to the events of the cardiac cycle is
shown in Fig. 36.

The Venous Reservoir of the Mammalian Heart

In birds and mammals there are no valves between the venae cavaa and
the auricles such as there are in lower animals at the sino-auricular junc-
tion. Coincident with the appearance of the diaphragm, the sinus is
merged with the auricles which are left open to a large venous cistern
consisting of the venae cavae, the innominate, iliac, hepatic and renal veins.
This cistern is shut off from the remainder of the venous system by six
pairs of valves at the femoral, the subclavian and the jugular veins. Not
only is it capacious, being capable of holding at least 400 c.c. of blood in
man, but it is subject to considerable alteration in capacity because of the
collapsible nature of its walls. This cistern is moreover in free communi-
cation with another large cistern, capable of holding when full about 1000

Fig. 36. — Diagram to show the positions of the cardiac valves: 1, during diastole; 2, during
the presphygmic period; 3, during the sphygmic period.

c.c. of blood, represented by the liver and portal system. Alterations in
thoracic and abdominal pressures will greatly affect the emptying of this
cistern into the auricles which explains the marked influence of the tho-
racic movements and of abdominal compression on the filling of the heart.
A most important function of this cistern is to furnish an immediate re-
serve of blood to fill the heart during the performance of a great muscular
effort.

THE HEART SOUNDS

During certain phases of the cycle distinct sounds, the heart sounds,
can be heard by applying a stethoscope to the thoracic wall. The first
occurs at the beginning of ventricular systole and is best heard over the
apex beat; the second occurs at the beginning of diastole and is heard
best at the second right costal cartilage or in the second left intercostal

THE PUMPING ACTION OF THE HEART 157

space. A third sound, much less distinct, is sometimes heard in diastole
a short time after the second. To study the exact time relationship of
the sounds the vibrations which they set up can be recorded graphically
alongside cardiac tracings by means of a microphone attachment to the
electrocardiograph (see page 270).

Causes of Sounds

It has been found that the first sound consists of two distinct elements,
one high pitched and the other of a dull character. The former element
is believed to be the result of vibrations set up in the flaps of the auric-
uloventricular valves, and therefore in the blood in the heart, by the
sudden rise in systolic pressure. The dull element on the other hand
is undoubtedly of muscular origin. The evidence for these conclusions is
as follows: (1) When the auriculoventricular valves are prevented from
closing properly either by disease or by pushing a loop of wire down the
large veins, the high pitched quality disappears, and nothing but a rush-
ing sound accompanies the dull bruit produced by the contracting muscle.
(2) In a heart that -has been rendered bloodless by an incision near the
apex, or even in an excised but still beating heart, the dull element of
the first sound still continues to be heard for a short time. That con-
tracting muscle produces a sound is a well-established fact.

There are, however, many obscure phenomena connected with the
causation of the first sound, but we can not go into such controversial
matters here. A close inspection of the electrophonographic tracing
shows that the sound starts at the beginning of the presphygmic period,
and that it lasts with gradually declining but variable intensity until
well into the sphygmic period (Fig. 37).

The second sound occurs accurately at the beginning of diastole and
can readily be shown to be caused by the sudden shutting and stretching
of the semilunar valves, which throws them, the blood in contact with
them, and the neighboring walls of the aorta into vibration. Proof of
this conclusion is furnished by the following facts: The second sound
immediately disappears if the blood is let out of the heart by opening
the apex, and it is replaced by a rushing "bruit" if the flaps are pre-
vented from closing as a result of disease or of hooking them back by
passing a wire down the carotid artery. The third sound, although audi-
ble only in some individuals, can nevertheless be shown to exist by the
electrophonograph, and since it occurs at the time when the auriculo-
ventricular valves open, it is believed to depend upon the sudden inrush
of blood from auricles to ventricles.

The greatest importance of the sounds is in the clinical diagnosis of val-
vular and other lesions of the heart. When a valve leaks, for example,

158 THE CIRCULATION OF THE BLOOD

the blood escapes past it under great pressure, and is ejected into a mass
of blood at low pressure, these being conditions which are well known
to create sounds or bruits. By examining the exact relationship of such
bruits to the normal heart sounds, deductions can be drawn concerning
the condition of the .various valves.

Record of Heart Sounds

The heart sounds have been graphically recorded by transmitting them
through a stethoscope to a microphone placed in circuit with a string
galvanometer (electrophonograms,). Through this circuit passes a cur-
rent the strength of which depends on the resistance offered by the
microphone, and consequently to the number and amplitude of the
vibrations of the sounds transmitted to it through the stethoscope.
There are several objections to this method. One of these is depend-
ent on the varying distance of the' heart from the chest wall, which
causes many of the sound vibrations to be lost before they reach the
stethoscope; another, on adventitious sounds arising from contracting
muscles, the impact of the heart against the chest wall, etc., and still
another on unequal resonation by the air in the neighboring portions of
lungs. To investigate the problem more thoroughly, Wiggers,37 using
anesthetized animals, has recorded the sounds by carefully stitching to
the heart (exposed through a small opening in the pericardium) a lever,
the end of which was attached to a "transmitter" consisting of a
small capsule covered with rubber dam. The transmitter was connected
by rubber tubing to a ' ( recorder ' ' consisting of another small capsule carry-
ing on its membrane (made of rubber cement) an eccentrically placed small
mirror, on to which a beam of light was thrown. The movements of the
beam of light reflected from the mirror, and caused by the sound vibra-
tions, were photographed. Mechanical vibrations set up in the apparatus
itself were largely eliminated by a side opening on the recorder, and the
effect of outside sounds minimized by surrounding the recorder by a
ventilated glass housing.

Although this apparatus is not free from faults due to inherent vibra-
tion frequency and resonance, the records secured by it are valuable in
showing the exact relationship of the sounds to the events of the cardiac
cycle. The vibrations from the two ventricles are alike, but differ from
those taken from the aorta. The first ventricular sound consists of from
five to thirteen irregular vibrations, usually in three groups, the first
composed of two small vibrations, the middle one of several large vibra-
tions, and the third of a varying number of small vibrations. The
duration of the sound is from 0.05 to 0.152 seconds, and the periodicity
from 0.004 to 0.054 per second. When compared with an intraventricu-

THE PUMPING ACTION OP THE HEART

159

lar pressure curve, the initial vibrations occur 0.01 second prior to the rise
in pressure, the main vibrations reaching their greatest amplitude before
the sphygmic period begins, and the final vibrations occurring during
the early part of the sphygmic period and therefore just 'before the aortic

i 'V'A* ****** ' V >v*» -**M ' M -^ «-*

11 it

.-I.

s.

B.

C.

Fig. 37.— Electrophonograms along with intraventricular pressure curves from three dif-
ferent experiments. In A the uppermost curve shows the pressure, the middle one the sounds
of the right ventricle, and the lowermost one those of the aorta. P indicates the relative posi-
tion of the curves. M is due to mechanical oscillations. $2 indicates the second sound, and
/, 2, 3, and 4 the corrected time relations of the first sounds. In B, the pressure and sound
curves are both from the left ventricle (letters same as in A). In C, the aortic and pulmonary
arterial sounds are shown (letters same as in A). (From Wiggers and Dean.)

pressure has reached its height. The main vibrations therefore occur
during the descending limb of the R wave of the electrocardiogram (be-
ginning 0.01 second before its completion), the small preliminary vibra-

160 THE CIRCULATION OF THE BLOOD

tions occurring during the ascending limb. "When taken from the aorta,
the record of the first sound is somewhat different, there being no initial
vibrations and the main ones being of greater frequency and reaching
their maximum earlier than those taken from the ventricle. The sub-
sequent vibrations are also larger, especially when the aortic pressure
is high (Fig. 37).

The record of the second sound at the ventricle is much simpler and
usually of less amplitude than the first, consisting of two to six vibrations
lasting 0.015 to 0.056 second. They begin a short time after the ventricu-
lar pressure begins to fall, approximately at the dicrotic notch of the aortic
curve, being completed in from 0.015 to 0.025 second after the bottom
of the notch. Their relationship to the T wave is variable. Taken from
the aorta, the record of the second sound shows vibrations of greater
amplitude and of a greater frequency than that from the ventricle.

The absolute and the relative intensity of the heart sounds is of clin-
ical value in forming a judgment of the dynamic state of the heart muscle
and of the tension or pressure in the aorta and pulmonary artery. Ac-
centuation of the second sound, for example, is considered to indicate a
high pressure in the aorta. Wjggers46 has recently confirmed this by ex-
perimental methods. He recorded the sounds graphically by attaching
receivers to the shaved skin of the thorax over the apex and pulmonary
artery in anesthetized dogs, the receivers being connected with sound-
recording capsules. After taking normal tracings, various alterations were
brought about in the pumping action of the heart or in the blood pressure,
and the effect was noted on the amplitude and number of vibrations en-
tering into the sound tracings. It was found that the intensity of the
first sound varied with the tension which was developed within the ventri-
cles during systole, particularly during the presphygmic period. When
the vagus was stimulated for example, the first sound diminished because
of the 4ower diastolic pressure to be overcome during the presphygmic
period. Increase in the diastolic pressure without change in heart rate
(by reflex vasoconstriction, compression of aorta, etc.) caused the second
sound to become accentuated, and decrease of pressure (by nitrites)
caused it to become less. Of course in both these experiments the first
sound was also affected. It was possible to show, further, that when the
pressure changes were more marked in one circuit of the circulation than
the other, the sounds were more decidedly altered in the circuit in which
the changes predominated (see also Lewis47).

CHAPTER XIX
THE NUTRITION OF THE HEART

THE BLOOD SUPPLY

In cold-blooded animals, such as the frog, the heart muscle is nourished
by blood soaking into it from the heart chambers, which indeed do not
form definite cavities as in the mammalian heart, but exist as an inter-
lacement of muscular tissue. In the hearts of higher animals, the muscu-
lature is supplied by special arteries (the coronary), although a certain
amount of blood may still pass directly from the cardiac cavities into
the musculature through the veins of Thebesius.

The relative importance of the various branches of the coronary artery
in maintaining an adequate nutrition of the heart has been studied by
observing the effect of occlusion of one or more of them (W. T. Porter9.)
Occlusion of the circumflex branch of the left coronary artery caused
arrest of the heartbeat in about 80 per cent of cases, the arrest being
usually accompanied by fibrillary contraction. Occlusion of the right
coronary arrested the ventricular contraction in about 20 per cent of
the cases. Smaller branches may be occluded without any evident
change in the heartbeat.

These results indicate that the capillary areas supplied by the branches
of the coronary artery do not freely anastomose with one another. They
are more or less terminal arteries ; that is, each branch supplies a distinct
region of the cardiac muscle. If one of the smaller branches of the coro-
nary is occluded, although there is no immediate stoppage of the heart-
beat, yet after some time the area supplied by that branch usually under-
goes necrosis, again indicating that collateral circulation can not have
become established. It is interesting, however, to note in this connection
that anatomic studies have shown that a certain amount of anastomosis
does occur between capillaries of different branches, although it is evi-
dent, from the above observations, that no adequate collateral circulation
becomes established through this anastomosis.

PERFUSION OF HEART OUTSIDE THE BODY

In order that the blood supply through the coronary arteries may
adequately maintain the normal nutrition of the cardiac muscle, certain

161

162 THE CIRCULATION OF THE BLOOD

conditions must be fulfilled. The recognition of .these conditions has
been accomplished by observations on the excised heart, for it has been
found that if they are fulfilled the mammalian heart can be made to beat
in perfectly normal fashion for several hours after its removal from
the animal's body. Indeed certain mammalian hearts, such as that of the
rabbit, may be made to beat for several days outside the body. We may
consider the essential conditions of the blood supply under four headings:
(1) the temperature; (2) the oxygen supply; (3) the pressure; and (4)
the chemical composition. Successful perfusion may be performed with
artificial saline solutions (e. g., Locke's), but it is simplest in investigating
the relative importance of the above conditions to start the heart per-
fusion with defibrinated blood.

After bleeding an anesthetized animal, such as a dog or a cat, until
no more blood can be removed, the blood is defibrinated and filtered
through gauze to remove the fibrin. The thorax of the dead animal is
then quickly opened, ligatures placed around the main arteries springing
from the arch of the aorta, a cannula with its end pointing toward the
heart inserted into the descending thoracic aorta, and the latter cut
across below the point of insertion of the cannula. The heart is then
quickly removed from the thorax and an artificial saline solution
(Locke's) allowed to run into the aortic cannula through a side tube,
until all the blood has been washed out from the coronary vessels. Dur-
ing this operation the heart may develop a few beats even though the
solution is quite cool. The aortic cannula is now connected with a bottle
containing the defibrinated blood diluted with Locke's solution and
brought to body temperature by immersion in a water-bath. By means
of a suitably regulated air pressure exerted on the surface of the diluted
blood in the bottle, this is forced through an outlet at the foot of the
bottle into tubing which runs to the aortic cannula. The fluid thus finds
its way into the coronary vessels; for in passing toward the heart in the
aorta it will close the semilunar valves and force its way under pressure
into the coronary vessels, subsequently escaping by the coronary sinus into
the right auricle. Very soon after the perfusion is started the heart
begins to beat vigorously and regularly, thus offering a suitable prepara-
tion upon which to test the first three mentioned conditions necessary
for the nutrition of the cardiac musculature.

If the temperature of the solution is allowed to fall considerably, the
beat becomes much slower, and if the cooling is proceeded with, the heart
will after a while cease beating altogether. If the pressure is lowered,
the beat will not necessarily become slower but very much feebler, and
will soon cease. In general it may be said that the temperature of the

THE NUTRITION OF THE HEART 163

solution affects the rate of the beat, and the pressure affects its strength.
It is, however, obvious that in perfused preparations changes in pres-
sure are likely to cause alterations in rate as well as in force, unless
great care is taken to keep the heart itself as warm as the perfusion
fluid.

The importance of an adequate pressure in the coronary vessels has
been clearly brought out in certain experiments in which the beat has
been maintained for a short time by establishing a pressure in the cor-
onary vessels by means of indifferent fluids or gases. Thus, if oxygen
gas is allowed to pass through the vessels under pressure, the heart will
beat for a short time, and the same result has been observed even when
mineral oil or mercury has been perfused under pressure (Sollmann).

The necessity for an adequate oxygen supply is very readily demon-
strated. If the darker blood ejected from the right auricle with each
heartbeat is transferred immediately to the perfusion bottle, the heart-
beat will soon become feeble and irregular, to be readily restored to
normal when this dark blood is shaken up with air or oxygen.

By artificial perfusion in the manner above described, the automatism
of the heart may be restored many hours after death. Partial restora-
tion, confined to the auricles or to that part of the ventricles lying im-
mediately adjacent to the large blood vessels, can also be accomplished
in the heart of man several days after death, provided death has not
been caused by some acute toxic infection such as diphtheria or septice-
mia. The Russian physiologist Kuliabko, has succeeded in restoring for
over an hour the normal beat of the heart of a three-months-old boy
twenty hours after death from double pneumonia, but here again the
pulsation returns only in certain parts of the heart. As will be pointed
out, the remarkable resistance of the heart muscle displayed in these
experiments has been taken as an argument in favor of the myogenic
hypothesis for automatic rhythmic power of cardiac muscle, the argu-
ment being that nervous structures could not live so long a time after
death. The fallacies in this argument are discussed elsewhere.

Heart-Lung Preparation. — Although the isolated heart is most useful
for the investigation of many of the functions of this organ, particularly
for the study of the effect of alterations in the chemical composition of the
perfusion fluid and the action of drugs, it is not so suitable when blood
instead of artificial plasma is to be perfused or when the effects of altera-
tions in the physical conditions of the inflowing or outflowing blood are
under investigation. In such places it is better to use the heart-lung prepa-
ration, which moreover has the added advantages that it requires less
blood, and it ensures proper aeration of this through the lungs (,cf,48).

164

THE CIRCULATION OF THE BLOOD

The arrangement for perfusion of the heart and lungs is shown in Fig. 38. The
blood prevented from clotting by the addition of hirudin (page 101) is discharged
from the left ventricle into a cannula connected with the innominate artery, all other
branches of the aorta being tied off. A side tube, v, connects with an air cushion,
afforded by an inverted test tube to take the place of the resilient arterial walls, and the
tube then connects with a resistance E, which is furnished by a thin-walled rubber tube
(rubber finger stall) enclosed in a glass cylinder into which air is pumped so as to

Fig. 38. — Arrangement of apparatus for heart-lung preparation of mammalian heart.
(Knowlton and Starling.)

compress the tube. Beyond this resistance the blood flows into a wide test tube con-
nected with a siphon tube which discharges whenever the blood has reached a certain
level in the test tube. The blood discharges into a reservoir, from which it flows
through a spiral immersed in a water bottle, and thence to a cannula tied into the
superior vena cava. A tambour is connected with a lateral tube coming off the tube
of the siphon, and it records a movement every time the discharge occurs. The blood
is pumped by the right ventricle through the lungs, where it is oxygenated, artificial

THE NUTRITION OF THE HEART 165

respiration being maintained throughout the experiment. The chief source of difficulty
with the preparation is edema of the lungs. This occurs much more readily with the
lung of the cat than that of the clog. Analysis of the alveolar air in the preparation
gives information of great value regarding the nature of the gaseous metabolism of the
heart (consumption of oxygen and respiratory quotient), and by altering the CO^ con-
tent of the inspired air, the influence of changes in CH of the perfusion fluid can be ob-
served (Evans1*9).

RESUSCITATION OF THE HEART IN SITU

A suitable intracoronary pressure is a sine qua non for the mainte-
nance of the heartbeat, and this is a fact of great clinical significance,
for it indicates that any attempts to resuscitate a dead animal are cer-
tain of failure unless the method is such as will bring a nutrient fluid
under a certain pressura to bear on the coronary arteries. Injection of
fluid, even of defibrinated blood, into a vein will obviously fail to ful-
fill this condition, for the perfusion must be made into an artery so that
the fluid is carried down the aorta and thence into the coronary arteries.

The practical question, in so far as resuscitation of the heartbeat is
concerned, is therefore, How can we get the necessary fluid under pres-
sure into the beginning of the aorta? Even if we were to transfuse fluid
under considerable pressure into the aorta through the carotid artery,
it would mainly follow the large vessels leading away from the heart,
only a fraction of it reaching the beginning of the aorta. To compel the
fluid to pass towards the heart we must introduce some obstruction to
its passage peripherally. This can be done by the injection of a consid-
erable dose of epinephrine (adrenaline) in normal saline solution through
the needle of a hypodermic syringe inserted into the tubing leading
from the burette or pressure bottle to the cannula in the carotid artery.
As the perfusion fluid is running in, the epinephrine injection is quickly
made, artificial respiration and cardiac massage being meanwhile prac-
ticed. In the majority of animals it will be found that complete res-
toration of the normal blood pressure can be effected by this method.
Indeed by performing the resuscitation under aseptic conditions, some
animals may be permanently resuscitated so far as the circulation is
concerned, although the nervous structures, even after a few minutes
of " death, " never reacquire their normal condition.

The epinephrine acts mainly by constricting the small arterioles and
thus directing the bloodflow towards the heart, but partly also by a direct
stimulating action on the cardiac muscle. It does not, however, con-
tract the coronary vessels; on the contrary, it is said to cause these
slightly to dilate.

166 THE CIRCULATION OP THE BLOOD

THE RELATIVE IMPORTANCE OF THE VARIOUS CONSTITUENTS
OF THE PERFUSION FLUID

We can study the chemical conditions necessary for resuscitation
of the heartbeat by observing the beat of an artificially perfused heart
while solutions of different chemical composition are being perfused
through the coronary vessels. At the outset we are impressed with the
fact that for successful resuscitation the organic constituents of the
nutrient fluid are of trivial importance compared with the inorganic
constituents. With a solution containing the proper proportion of in-
organic salts, and of course an adequate supply of oxygen, the heart
of a rabbit, for example, may be made to continue beating for several
days. It is true that it will beat longer if some of the organic con-
stituents of the blood plasma, particularly carbohydrate, are present,
but on the inorganic constituents alone its ability to beat is truly
remarkable.

Observations on C old-Blooded Heart

The earlier experiments for the investigation of the chemical condi-
tions necessary for the maintenance of the heartbeat were performed
on the heart of the frog or turtle. By perfusing either of these hearts
with physiological sodium-chloride solution, it was observed that though
the beat might continue for some time, yet it gradually grew feebler
and feebler, until at last it ceased altogether with the heart muscle
in a condition of extreme relaxation or diastole. If small proportions
of potassium and calcium salts (as chloride) were added to the sodium-
chloride solution, the beat was much better maintained. Sidney
Ringer proved that the optimum concentration to produce efficient and
prolonged contraction for the heart of the frog or terrapin is as folloAVS:
potassium chloride, 0.03 per cent; calcium chloride, 0.025 per cent.
The effectiveness of the solution was also found to be increased by the
addition of 0.003 per cent of sodium bicarbonate. This acts as a buf-
fer substance (page 36), holding the hydrogen-ion concentration at a
constant level. More recent work has shown that the hydrogen-ion con-
centration of the perfusion solutions is of considerable importance in
determining the efficiency of the beat, but the optimum is not the same
for the hearts of different kinds of animal, and indeed it may differ
for different parts of the same heart.

The question naturally arises as to the relative importance of each
of the above salts; or rather, we should say, cations, since the anion,
chlorine, is the same for all of them. The function of the sodium chlo-
ride in the solutions is twofold: (1) to endow the solution with the

THE NUTRITION OP THE HEART 167

proper osmotic pressure (see page 4) ; and (2) to perform the special
role of the sodium ion in the origination and maintenance of the auto-
matic beat. The latter function of Na can be shown by observing the behav-
ior of strips cut out from the ventricle of the turtle heart and placed
in solutions of correct osmotic pressure but containing no sodium chlo-
ride— isotonic solutions of cane sugar, for example. They soon cease
to beat, but if a small amount of sodium chloride is added to the cane
sugar solution, rhythmic contractions return. The role of the calcium
ions is almost entirely a pharmacological one. If a strip of turtle ven-
tricle which has been made to cease beating by immersion in isotonic
sugar solution is placed in a weak solution of calcium chloride before
it is transferred to sodium chloride solution, the spontaneous contrac-
tions will return earlier and continue for a longer time. On the other
hand, if more than the correct amount of calcium salt is present in the
solution, the beats will soon be found to become smaller and smaller
in amplitude, because relaxation does not properly occur between them,
and ultimately they will cease altogether with the ventricle in a condition
of extreme contraction, called calcium rigor. The importance of calcium
may also be shown by attempting to perfuse a turtle heart with blood
serum from which the calcium has been removed by the addition of
sodium oxalate (which precipitates it as insoluble calcium oxalate). The
heart soon ceases to beat, but can readily be made to do so again by
adding a slight excess of calcium chloride.

The potassium ions do not appear, like those of calcium and sodium, to
be absolutely essential for the maintenance of the heartbeat; at least the
heart of the turtle will beat for a long time when perfused with a solu-
tion containing only sodium and calcium salts. The e'xplanation of this
result need not, however, necessarily be that potassium is an unessential
constituent of the perfusion fluid, for it may well depend on the fact that
there is a sufficient store of potassium locked away in the muscle fiber
to supply the requirements of the heart muscle for this ion for at least
as long as the beat would continue under any circumstances. In any
case, we know that potassium has a profound influence on the heart-
beat, for when the proportion of it in the perfusion fluid is increased, the
beat becomes very slow and the tone of the heart is greatly diminished —
that is, it becomes extremely relaxed between the beats; and if the
amount is further increased, will very soon come to a standstill in a
greatly dilated or diastolic position.

The striking antagonism displayed by these inorganic cations upon
the heartbeat has led some investigators to suggest that the stimulus re-
sponsible for the rhythmic activity of the heart depends on some sort
of chemical union occurring between the inorganic cations and the con-
tractile substance of the heart. Union of calcium with the contractile

168 THE CIRCULATION OF THE BLOOD

substance will lead to systole or contraction, whereas union of sodium
or potassium will lead to relaxation or diastole.

Observations on Mammalian Heart

Investigation of the efficiency of various saline solutions on the iso-
lated mammalian heart has shown that the proportion of the above salts
must be somewhat different from that used for the cold-blooded heart.
As might be expected, the most efficient proportions are those present
in the blood serum of the particular animal whose heart is being per-
fused. Basing his proportions upon the results of analyses of the inor-
ganic constituents of mammalian blood serum, Locke found that ai\
inorganic solution of the following composition is most efficient: so-
dium chloride, 0.9 per cent; calcium chloride, 0.024 per cent; potassium
chloride, 0.042 per cent; and sodium bicarbonate, 0.01 to 0.03 per cent.
When "Locke's solution,'' as it is called, is perfused, with oxygen in it,
under pressure through the isolated mammalian heart at body tempera-
ture, efficient beating can be maintained for many hours. More recently
a solution known as Tyrode 's is commonly used. It contains a small amount
of magnesium and of phosphates. Although undoubtedly superior for
some perfused preparations, such as the intestine, it does not seem to be
in any way superior to Locke's for the perfusion of the heart. The bicar-
bonates and phosphates in these solutions endow them with a hydrogen-ion
concentration near that of the blood (slightly on the alkaline side of
neutrality), and at the same time they act as buffer substances.

As already pointed out, the organic constituents of such perfusion
fluids do not appear to be relatively of nearly so much importance as
the inorganic. Nevertheless it appears that a small percentage (0.01
per cent) of glucose does materially improve the nutritive qualities of
the solution, and it has moreover been shown that after a while the con-
centration of glucose in the perfusion fluid distinctly decreases. This
does not of itself necessarily mean that the glucose is actually utilized
by the heart muscle: it might be stored away in it as glycogen. That
some consumption of carbohydrate does however occur in the heart has
been demonstrated by measuring the intake of oxygen and the output
of carbon dioxide through the lungs of an isolated heart-lung prepara-
tion perfused outside the body with defibrinated blood. By experiments of
this type the attempt has been made to show that the heart of diabetic
animals loses the power of burning glucose as compared with the hearts
of normal animals. While the experiments are very suggestive, the
results do not as yet justify us in claiming that in the latter disease the
power of burning glucose in the tissues has been material^ depressed.

The concentration of hydrogen ions in the perfusion fluid has an im-
portant influence on cardiac efficiency. We also know that the most

THE NUTRITION OF THE HEART

169

convenient method for changing the hydrogen-ion concentration of such
fluids is by altering their tension of carbon dioxide (see page 371). In
a heart-lung preparation (page 163), such alteration in carbon-dioxide
tension can very readily be brought about by altering the percentage of
this gas in the air with which the lungs are ventilated. To measure the
efficiency of the heartbeat in such an experiment, it is convenient to enclose
the organ in a cardioplethysmograph, the tracing of which will tell us the
degree to which the heart is contracted or relaxed, as well as the output
of blood per minute. By increasing the tension of carbon dioxide, it
has been found in such experiments that the dilatation of the ventricle
is encouraged, so that the heart with each beat discharges a larger quan-
tity of blood (Fig. 39). When defibrinated blood is used the optimum
pressure or tension of carbon dioxide has been found to lie between 5
and 10 per cent of an atmosphere.

Fig. 39. — Volume curve of ventricles of cat (lower curve) in a heart-lung perfusion prepara-
tion. The air used to ventilate the lungs was replaced between the arrows by a mixture con-
taining 20% CO2 and 25% O2. This caused dilatation of the ventricles along with feebler beats
and a tendency for the arterial pressure to fall (upper curve). The after effect was an im-
provement of the beat. (From Starling.)

That the effect of carbon dioxide in encouraging the relaxation of the
heart between beats is dependent upon the change in hydrogen-ion con-
centration of the perfusion fluid has been shown by securing the same
results in experiments with perfusion fluids to which different quanti-
tities of weak nonvolatile acids have been added. These observations are
of practical importance because of the light which they throw on the
cause of cardiac failure following upon conditions in which there has
been excessive removal of carbon dioxide from the blood, as in forced
ventilation of the lungs. Yandell Henderson has suggested that sur-
gical shock may be, partly at least, due to cardiac failure following the
"washing out" of carbon dioxide from the blood by the dyspnea so
often incident to the administration of anesthetics in surgical operations.

CHAPTER XX
THE PHYSIOLOGY OF THE HEARTBEAT

THE ORIGIN AND PROPAGATION OF THE BEAT— THE PHYSIO-
LOGICAL CHARACTERISTICS OF CARDIAC MUSCLE

The origin and propagation of the heartbeat are studied on the excised
heart of a frog or turtle, or on the mammalian heart by perfusing it
under suitable conditions, which have already been described. The results
obtained on the cold-blooded heart apply more or less directly to the
warm-blftoded. In the first place it is clear that the rhythmic contrac-
tility of the heart is not at all dependent upon the central nervous sys-
tem, for if it were so, .the excised heart could not continue beating. This
fact does not, however, necessarily imply that the beating power is In-
dependent of nervous structures, for in the heart itself an extended net-
work of nerve cells and connecting nerve fibers can readily be demon-
strated. It might quite well be the case that the rhythmic beat is de-
pendent upon the transmission to the muscle fibers of the heart of
impulses generated in the nerve cells and transmitted along the nerve
fibers of this local nervous system. Such is the neuroyenic hypothesis of
the heartbeat.

On the other hand, it may be that these nervous structures are not at
all responsible for the origination of the beat, but serve merely as sta-
tions on the pathway of the nerve impulses, transmitted to the heart
from the central nervous system along the vagus and sympathetic nerves,
for the purpose of altering the rate of the heartbeat so as to adjust it
to the requirements of blood supply in the various parts of the body. In
such a case the rhythmic power would reside in the muscular tissues of
the heart — that is, each cardiac muscular cell would have the power,
not merely like skeletal muscle of contracting in response to a stimulus
transmitted to it, but also of originating that stimulus within itself.
This is the myoyenic hypothesis. Much controversy has raged around
these two hypotheses and although space will not permit a detailed study
of the question, it will be necessary, on account of the great importance of
the subject from the physiological standpoint, briefly to review the main
arguments of each school of thought.

There is no piece of evidence offered by the advocates of either the
neurogenic or the myogenic hypothesis that can, taken singly, be con-

170

THE PHYSIOLOGY OF THE HEARTBEAT 171

sidered as absolutely conclusive. Although some of "the proofs" may
at first sight appear to be conclusive, yet each of them breaks down when
subjected to a closer scrutiny. It is only after we have collected all the
evidence for and against each view that we shall be in a position to come
to any conclusion, and even then it will be plain that our conclusion can
be only tentative.

Myogenic Hypothesis

Taking first of all the evidence in support of the myogenic hypothesis,
the following stands out most prominently:

1. The heart beats in the embryo chick before any nerve cells have
grown into it, and not only this, but if portions of heart muscle are re-
moved from the embryo and placed in blood plasma, they will continue
beating for many days It has also been observed that cells may wander
off from this mass of cardiac muscle and undergo multiplication and
differentiation, so as to produce isolated muscle cells which exhibit
rhythmic contractility. The rebuttal on the part of the neurogenists of
this apparently unassailable evidence is to the effect that, although em-
bryonic muscle cells may exhibit the power of rhythmic contraction, this
does not mean that the fully developed muscle cells will necessarily have
such power. In the eary stages of embryonic development, it is of course
evident that the functions which in the fully developed animal are del-
egated to various special organs and tissues should be performed by cells
having several such functions in common. The muscle cells of the heart,
for example, may to start with be possessed of a power not only of con-
tracting but also of initiating the contraction. It may be that they are
partly nervous in character and that only later, when the differentiation
is consummated, does the power of rhythmic contraction become dele-
gated to the nervous element and that of contraction retained by the
muscle itself.

2. The nervous structure in the heart may be damaged either by me-
chanical means or by drugs without apparently interfering with the
power of rhythmic contraction; for example, in the heart of large tur-
tles it is possible to dissect out a considerable amount of nervous tissue
Avithout any disturbance of the beat, and in all animals the administration
of atropine, which paralyzes the postganglionic fibers of the autonomic
nervous system" (see pa<re 231) found in the heart, does not affect it.

3. The apex of the ventricle in such hearts as that of the turtle can
be shown, by careful histologic examination, to contain no nerve cells,
and although a few nerve fibers may be found, these are functionless
without nerve cells. This virtually nerveless piece of heart muscle can
be made to contract rhythmically by perfusing it with suitable saline

172 THE CIRCULATION OF THE BLOOD

solution under pressure and starting the beating by application of elec-
trical stimuli. Isolated strips of ventricular muscle, in which, also no
nervous element can be demonstrated, may under favorable conditions
be caused to beat quite regularly if supplied with proper nutrient fluid.
The rebuttal of this evidence is twofold: In the first place, skeletal mus-
cle itself under certain conditions, such as exposure to solutions con-
taining an excess of phosphate (Biedermann's), may exhibit rhythmic
contractility, especially on cooling, which indicates that exhibition of rhyth-
mic power in isolated portions of cardiac muscle need not mean that under
ordinary conditions such power is responsible for the normal heartbeat.
In the second place, it is pointed out that although we can not reveal
their presence by present-day histologic methods, this is not conclusive
evidence that the heart-muscle fiber may not possess some nervous struc-
tures capable of functioning as nerve cells.

The heart even of mammals can be made to continue beating for sev-
eral days after excision from the body. The nerve cells, as we know them
in the central nervous system at least, can not, on the other hand, be
made to functionate for more than a few hours after death. Therefore,
it is argued, the heartbeat in surviving mammalian hearts can not de-
pend on the nervous structures. The argument is however easily refuted:
on the one hand, we do not know that the nerve structures situated
peripherally in the heart muscles are of the same viable nature as those
composing the central nervous system; and, on the other, the survival
of the heart may in itself be sufficient to maintain around the nerve cells
embedded in it a nutrient environment which is much more physiological
than that which we can supply in artificial perfusions of surviving
nervous tissues.

4. Circumstantial but nevertheless strong evidence is furnished by
the fact that many other varieties of involuntary muscle are endowed
with rhythmic contractility; thus, the muscle of the intestines, of the
ureters, of the bladder, of the uterus, of the blood vessels of certain
animals, and of the lymph vessels in the so-called lymph hearts, main-
tain rhythmic contractility after isolation from the animal body. The
rhythmic power seems in certain of these cases to be independent of
nervous control.

Neurogenic Hypothesis

In favor of this hypothesis the following evidence is offered:
1. The heart of certain animals — of Limulus, the king-crab, for exam-
ple, is definitely dependent for its rhythmic contractility upon neigh-
boring nervous structures. The heart of this animal is a tubular sac-
culated organ, and along its dorsal surface there runs longitudinally a

THE PHYSIOLOGY OF THE HEARTBEAT 173

nerve cord containing ganglion cells and giving off fibers which proceed
in part directly to the heart and in part to lateral cords (Fig. 40). Re-
moval of this median nerve cord is followed by total abolition of the
heartbeat; the heart becomes perfectly quiescent like an unstimulated
skeletal muscle. In appraising the evidence at its true value, it must be
noted that although by stimulation of the nerve fibers contraction of the
heart can be produced, the contraction is like that of a skeletal mus-
cle— it is not rhythmic; and moreover — and this is most important — if
the various physiological properties of muscle as described below be stud-
ied (page 176), it will be found that in all of them the quiescent heart
muscle behaves, not like the heart muscle of other animals, but like that
of skeletal muscle. This evidence, therefore, while indisputably showing
that the heart of Limulus depends for its rhythmic power upon neigh-
boring nerve structures, does not justify the assumption that this will be
the case in the heart of animals having different physiological properties.
2. The disposition of the nervous structures in the heart, especially of
the frog and turtle, exactly corresponds to the degree of development of

19'

Fig. 40. — Heart and cardiac nerves of Limnlus polyphemiis. (Carlson.) aa, anterior ar-
teries; la, lateral arteries; In, lateral nerves, nine, median ganglionic chain; os, ostii or afferent
stomata, each pair of which corresponds to one of the segments into which the Limnlus heart
is divided.

the rhythmic power of the different parts of the heart ; thus, the greatest
rhythmic power is manifested by the sinus and the least by the tip of the
ventricle at the bulbus arteriosus. In the former position the nerve
structures are very prominent; in the latter, no nerve cells and but few
nerve fibers can be detected. This proof is, however, easily assailed.
In the first place, it may merely be a coincidence that the disposition of
the nerve structures and the development of rhythmic power correspond.
The unequal rhythmic powers may depend primarily on a difference
in structure of the muscle fibers themselves, such differences having
been shown to exist between the muscle cells of the sinus and those
of, say, the ventricle. The former cells, for example, have much less
developed crossed striation and their protoplasm is much more gran-
ular ; in short, they are much more embryonic in type than the cells from
the tip of the ventricle.

If a jury had to return a verdict from evidence of so conflicting a char-
acter, it would no doubt be equivalent to that of the Scottish court — "not

174 THE CIRCULATION OF THE BLOOD

proven." But it is likely that the majority of the jury would vote
in favor of the myogenic hypothesis. Probably the safest viewpoint to
take at the present time is that the power of rhythmic contraction is
inherent in the cardiac muscle fibers, being most highly developed' in
those of the venous end of the heart, and least developed in those of
the arterial end. Such a conclusion does not deny to the nervous struc-
tures of the heart the power under certain conditions of also assuming
rhythmic activity. In one case at least — namely, the heart of Limulus —
we know that this is so. For some reason in this animal the cardiac
muscle fiber has lost its inherent rhythmic power, and is now dependent
for its activities upon rhythmic nervous discharges transmitted to it
from the neighboring nerve cords, a condition which is paralleled in
the higher animals in the innervation of the respiratory muscles. The
respiratory center rhythmically discharges impulses to the muscles, which
are quiescent in the absence of these impulses.

The Pacemaker of the Heart and Heart-block

In a volume of this nature, devoted primarily to the practical appli-
cation of physiology, the discussion of these problems may seem a little
out of place, but that this is not the case is seen when we consider that
the experiments upon which the various points of evidence depend
bring to light facts of the very greatest importance in the study of the
physiology of the heartbeat. One fact which stands out prominently
is that the greatest rhythmic power resides in the basal portion of the
heart — that is, in what corresponds, in the more primitive hearts, to the
sinus venosus.

Although the muscle of the entire heart possesses rhythmic power, it
does not do so to an equal degree; in the sinus the rhythmic power is
extraordinarily developed, while in the bulbus arteriosus it is scarcely
recognizable. This observation suggests the possibility that the sinus
may dominate the heartbeat — that it may be the "pacemaker" for the
heart as a whole. The most natural method for demonstrating such a
possibility would be to observe the effect on the heartbeat of some block
between the sinus and the rest of the heart. Such a block can be intro-
duced in the heart of cold-blooded animals by local compression around
the various junctions. If a thread is tied around the sinoauricular
junction, the sinus will go on beating uninterruptedly, but the auricles
and ventricles — that is, the greater part of the heart below the ligatures
— will cease beating, sometimes entirely (Stannius' ligature). After a
while, however, the heart below the ligature will usually begin to beat,
but at a rhythm which is slower than, and independent of, that of the
sinus.

THE PHYSIOLOGY OF THE HEARTBEAT 175

The experiment can be still better performed by using a wedge-
shaped clamp. (GaskelPs clamp.) If this is applied so that the heart
can be pinched either at the sinoauricular junction or at the auriculo-
ventricular, it will be found that, as the cardiac tissue is gradually

Fig. 41. — Heart-block produced by applying clamp at a-v junction. The clamp was tightened

at a. (From Brubaker.)

pinched, the portion of the heart below fails to beat as quickly as that
above the clamp (Fig. 41). This is known as partial heart-block, and
the degree of the block is indicated by the numerical expression 2 to 1,
3 to 1, 4 to 1, etc., meaning that the sinus is beating either twice as
quickly as the ventricle, or three times, or four times as the case may

Fig. 42. — Tracing of contraction of ventricle, showing the effect of the local application
• of heat to the auricle at /, and to the apex of the ventricle at 2. Note that the rate in-
creased in the former case.

be. Similar conditions of heart-block may also be produced by cutting
the cardiac tissue partly across at various places in the heart.

Further evidence that the sinus dominates the beat in the heart of

176 THE CIRCULATION OF THE BLOOD

cold-blooded animals is furnished by observing the effects of local heat-
ing or cooling of the various parts of the heart. In all rhythmically
acting structures it is well-known that heat increases the rate of the
rhythm and cold depresses it. If we locally warm the region of the
sinus, as by holding a heated wire near it the whole heart will immedi-
ately beat quicker; but if we locally heat the tip of the ventricle, no
alteration of rhythm will be observed to occur (Fig. 42).

The establishment of the fact that the sinus dominates the heartbeat
—that it is the pacemaker of the beat — raises the question as to how the
impulse originated at this place is transmitted over the rest of the
heart, and here again a neurogenic and a myogenic hypothesis have to
be considered. Before going into this question, however, it will be well
for us to consider briefly the manner of response of cardiac muscle
fiber to a stimulus, because the behavior of cardiac muscle under such
conditions is considerably different in many regards from that of skel-
etal muscle, and it is to these differences that many of the peculiar
alterations in the beat observed after interfering with the conducting
structures between the sinus and the rest of the heart, are to be ex-
plained.

The Physiological Characteristics of Cardiac Muscle

It is necessary to bring the heart into a quiescent state in order to
investigate the properties of its musculature. This is accomplished by

Fig. 43. — Frog heart showing the position of the first and second ligatures of Stannius
(Hedon): /, auricles; 2, sinus; j. ventricle. It is the first ligature which brings the heart
to a standstill.

the application of the Stannius ligature between the sinus and the auri-
cles (Fig. 43). After tightening the ligature the auricles and ventricles
become quiescent, and by observing the effects following by the appli-
cation of electric or other stimuli we can compare the behavior of the
cardiac muscle with that of skeletal muscle similarly stimulated. This
comparison is made because of the assistance which it offers in compre-
hending the properties of cardiac muscle. As a matter of fact, recent
investigations have shown that the differences between the two types of
muscle are not fundamental, since under certain conditions the one may

THE PHYSIOLOGY OF THE HEARTBEAT

177

be made to behave like the other. They are dependent upon the pres-
ence or absence of anastomosis between the muscle fibers.

1. When electric stimuli of varying strengths are applied to skeletal
muscle, the contraction produced by each stimulus is proportional to
the strength of the latter until this has become of such a strength that
the maximal response is elicited. In cardiac muscle, on the other hand,
an entirely different result is obtained, for the weakest stimulus, if it
produces any response at all, produces one that is maximal; that is, the
height of contraction is the same as it would have been had a much
stronger stimulus been applied. Expressing this result in general terms,
we may say that in cardiac muscle a minimal stimulus produces a maxi-

A.— Skeletal Muscle

B. — Cardiac Muscle

Fig. 44. — Effects of stimuli of increasing strength on skeletal and cardiac muscle to illustrate
the "all or nothing" principle in the latter. (From Practical Physiology.)

mal effect, whereas in skeletal, the effect, as measured by the height of
contraction, is proportional to the intensity of stimulation. This is some-
times known as the "all or nothing phenomenon" (Fig. 44).

2. If maximal stimuli are applied successively and at short intervals
of time to skeletal muscle, a slightly higher response results from each
succeeding stimulus, until about ten stimuli have been applied, after
which for some considerable time the same height of contraction follows
each stimulus. If each contraction is recorded, it will be seen that the
first few contractions give a staircase effect ; that is, if a horizontal line is
drawn from the top of each contraction to the next one, the effect of an

178 THE CIRCULATION OF THE BLOOD

ascending staircase with gradually diminishing steps will be produced. If
we repeat this observation with cardiac muscle, we shall find that the stair-
case phenomenon or treppe, as it is called, is very pronounced ; and more-
over, in obedience to the all or nothing principle, the treppe is obtained in
cardiac muscle whatever may be the relative strengths of the stimuli
applied to the heart, provided always that all of them are effective;
whereas in the case of skeletal muscle it can be demonstrated only pro-
vided the stimuli are of equal strength (Fig. 45).

3. If an effective stimulus is applied to a skeletal muscle while in process
of contraction, as in response to a preceding stimulus, the second stimulus
prolongs the contraction produced by the first one. If, however, the second

Skeletal muscle

Cardiac muscle

Fig 45. — The effects of successive stimuli on skeletal and cardiac muscle to show the prominence
of the staircase phenomenon, or treppe, in the latter. (From T. G. Brodie.)

stimulus is applied during the latent period* of the first one, it will have no
effect — that is, the muscle during this period is refractory.! From these
results it follows that stimuli succeeding each other during the contraction
period will, in the case of skeletal muscle, cause a continuous contraction, or
tetanus, as it is called, because the contraction produced by each stimu-
lus will add itself to that of its predecessor before any trace of relax-
ation has set in. If, however, the second stimulus is applied so late in
the contraction period of the first that time is not available for the latent

*By "latent period" is meant the period after the moment of application of a stimulus during
which no effect of that stimulus is observed.

fBy "refractory period" is meant the time following the application of a stimulus during which a
second stimulus develops less than its full effect or no effect at all.

THE PHYSIOLOGY OF THE HEARTBEAT 179

period of the former to be expended, then obviously a slight relaxation will
.have occurred before the effect of the second stimulus develops itself, and
tetanus will be incomplete. These facts will be evident from the accom-
panying tracings (Fig. 46).

Skeletal muscle Stannius' heart

Fig. 46. — The effects of successive stimuli and of tetanizing stimuli on skeletal muscle and
cardiac muscle. The small vertical marks show when the stimuli were introduced. (Compiled
from tracings published by T. G. Brodie and Leonard Hill.)

In the case of cardiac muscle the above described properties are quite
different, for the refractory phase extends throughout the whole period of
contraction; that is, a second stimulus applied during the contraction
produced by a previous stimulus has no effect whatsoever; it does not

180 THE CIRCULATION OF THE BLOOD

have one until the muscle has reached the full extent of its contraction
and is about to relax. Since a latent period must supervene upon the
application of this second stimulus, it follows that no complete fusion of
the contractions is possible. Complete tetanus therefore, does not occur
in cardiac muscle, however frequently the stimuli may be applied (Fig.
46).

The refractory phase is a property of extreme importance in under-
standing many of the peculiar irregularities observed in cardiac action.
If we observe the effect of stimuli applied at varying periods after the

Fig. 47. — Myograms of frog's ventricle, showing effect of excitation by break induction
shocks at various moments of the cardiac cycle. The line O indicates the commencement of
all the beats during which the shock is sent in. It will be noted that in /, 2 and 3, the heart
is refractory to the stimulus. The signals indicate the moments at which the stimuli were ap-
plied. From 4 to 8 the heart reacts by an extrasystole, after a delay, which is progressively less
the later in diastole the stimulus enters, as shown by the sections shaded obliquely to make them
more conspicuous. The extrasystoles increase in height from 4 to 8, each being followed by
a compensatory pause. (From I_uciani's Human Physiology.')

termination of the refractory phase of a previous stimulus, we shall find
that the height of the extra contraction is directly proportional to the
time after the end of the refractory period at which it is applied. If a
stimulus is applied at the very beginning of diastole, the extra contrac-
tion will be small, whereas if it is applied at the end of diastole, the
extra contraction will be at least as high as that of the preceding. It
may be higher because of the treppe.

THE PHYSIOLOGY OF THE HEARTBEAT 181

These observations enable us to interpret the results obtained by ap-
plying electric shocks (extra stimuli) to the beating heart during different
phases of systole and diastole. During systole, the muscle being refrac-
tory, no effect is produced by the extra stimulus, but during diastole
extra systoles which are progressively more pronounced the later in
diastole they occur, follow the application of each stimulus. These re-
sults are so far exactly like those obtained with a quiescent heart. But
another phenomenon now becomes evident; namely, that following each
extra systole there is a compensatory pause in the action of the heart,
of such duration that, when the next natural beat occurs, it does so
practically at the same time as it would have occurred had no artificial
stimulus been applied. This will be apparent from the accompanying
diagram (Fig. 47).

It should be noted that the refractory period is greatly diminished by
raising the temperature of the heart. Indeed, under these conditions
and with strong stimulation it may be possible to produce an almost
complete tetanus.

The importance of knowing the above facts is that we are thereby
enabled to explain the peculiar manner in which the ventricle responds
to stimuli transmitted to it from the sinus and the auricle. The muscu-
lature of the auricle and ventricle of the mammalian heart is not one
continuous sheet, but is separated by a space at the auriculoventricular
junction, across which, in specially organized structures, the beat of the
auricle is transmitted to the ventricle. Sometimes the stimuli are so
frequent that the ventricular muscle is unable to respond to each stimu-
lus transmitted to it, with the result that marked irregularities in con-
traction occur (see page 293). In this way certain of the cardiac irregu-
larities observed in man can be explained. Thus, the so-called pulsus
Ugeminus is due to every second beat being an extra systole. This second
beat is therefore generally weaker than the preceding and succeeding nor-
mal beats, and it is almost always followed by a compensatory pause. When
the intervals separating the beats are of uniform length, although every
second beat is diminished in size, the pulse is termed pulsus alternans.

CHAPTER XXI
THE PHYSIOLOGY OF THE HEARTBEAT (Cont'd)

THE ORIGIN AND PROPAGATION OF THE BEAT IN THE
MAMMALIAN HEART

As has been shown in the preceding chapter, there is no doubt that
in the cold-blooded heart the beat originates at the sinus venosus, whence
it spreads to the rest of the heart. Very strong evidence has also been
presented to indicate that the beating power is inherent in the muscle
fiber itself and independent of nervous structure. This would suggest the
further possibility that the structures through which the beat is propa-
gated are the muscle fibers and not the nerve fibers— in other words,
that the propagation of the heartbeat, like its origination, is myogenic
rather than neurogenic. Direct proof of this hypothesis is readily fur-
nished by numerous experiments, among which may be mentioned mak-
ing interdigitating cuts across the heart, or excising a ribbon of ven-
tricular muscle by an incision simulating the walls of Troy. In both
these cases the beat will be found to travel from one end of the muscular
band to the other, although it is evident that all the nerves proceeding
from base to apex of the heart must have been severed. Of course this
evidence is not irrefutable, for it might be argued that there are nerv-
ous structures disposed in the form of a plexus continuously all over the
heart, and that some branches of the plexus remain uncut in the above
experiments. It is only in the heart of Limulus that undoubted evidence
exists that the beat is transmitted by nerves, but as we have seen, this
heart in all its properties is probably the proverbial exception which
proves the rule. The balance of evidence stands in favor of the view
that the propagation of the beat over the cold-blooded heart is myogenic
and not neurogenic.

CONDUCTING TISSUE IN MAMMALIAN HEART

When we attempt to investigate the problems of the origin and propa-
gation of the beat in the warm-flooded heart, many experimental diffi-
culties of course face us. In overcoming these, the first thing we must
do is to establish the structural relationship between cold-blooded and
warm-blooded hearts. In the embryo of both classes of animals the

182

THE PHYSIOLOGY OF THE HEARTBEAT

183

heart arises as the so-called cardiac tube. As development proceeds,
diverticula grow out from the walls of this tube to form the auricles and
ventricles. In the comparatively simple heart of the turtle these dispo-
sitions of the auricles and ventricles in relationship to the cardiac tube
are more or less evident even in the fully developed heart, particularly
in the case of the auricles (Fig. 48) ; but in the heart of the higher
mammalia it is impossible by superficial examination alone to show any
remains of the primitive cardiac tube. More careful anatomic investiga-
tions during recent years have, however, shown that it exists in the form
of certain definite structures composed of tissue histologically quite dif-
ferent from, that of the rest of the heart, and disposed in such a manner

TH

Fig. 48.- — Heart of tortoise as suspended. B, body of tortoise; 'TH. threads to levers; CL, clamp
holding aorta; A, auricle; C, coronary nerve; S, sinus; V, ventricle. (From Gaskell.)

as would indicate not only that it is derived from the primitive cardiac
tube, but also that it is the main pathway along which the beat is
transmitted.

This primitive cardiac tissue is much better developed in certain re-
gions than in others, the first portion of it to be discovered being that
known as the auriculoventricular node, or the node of Stanley Kent* (Figs.
49 and 50). This structure is found at the base of the interauricular sep-
tum on the right side and near its posterior margin. It exists as a collection
of peculiar small primitive cells and fibers, and is continued downward as
a bundle of the same peculiar tissue to the interventricular septum,
where, near the union of the posterior and median flaps of the aortic

*The discovery of this node is often erroneously attributed to His, and called after his name.

184 THE CIRCULATION OF THE BLOOD

valve, it bifurcates so as to send a branch down each side of the septum
immediately below the endocardium. Each main branch, as it proceeds
downward on the septum, divides up into an intricate system of smaller
branches, which become reflected over the inner surface of the ventricles,
where their existence has been known for some time as the so-called

Fig. 49. — Dissection of heart to show auriculoventricular bundle (Keith); 3, the beginning of
the bundle, known as the A-V node; 2, the bundle dividing into two branches; 4, the branch run-
ning on the right side of the interventricular septum. (From Ho well's Physiology.)

Fig. 50. — Photograph of model of the auriculoventricular bundle and its ramifications, con-
structed from dissections of the heart (Miss De Witt). All of the branches in the left ventricle
are not included. (From Howell.)

Purkinje filters. The fibers ultimately end in close association with the
papillary muscles. The node and main bundle and the two branches
before they have begun to divide are surrounded by fibrous tissue, and
they seem to have a liberal blood supply. It is of interest that they con-
tain a high percentage of glycogen. In the human heart the auriculo-

THE PHYSIOLOGY OF THE HEARTBEAT 185

ventricular node and bundle measure about 15 mm. in length, and about
2 mm. in width.

The rest of the tissue between the auricles and ventricles is fibrous
in nature, although other connections like those of the auriculoventricular
bundle have been described by Kent. One of these, called the right lat-
eral connection, runs between the right auricle and the external wall of
the right ventricle.

Another, but much smaller, mass of similar embryonic cardiac tissue
has more recently been discovered by Keith and Flack in the parts of
the auricle which correspond anatomically to the sinus venosus of the
heart of cold-blooded animals — that is, in the area lying between the
openings of the vena cavae and around the coronary sinus. To be more
explicit, this tissue lies "in the sulcus terminalis just below the fork
formed by the junction of the upper surface of the auricular appendix
with, the superior vena cava." This sinoauricular node, as it is called,
is more or less club-shaped, the blunt end of the club being above, as
shown in the accompanying figure (Figs. 51 and 52). It is important to
note that there is no direct connection visible between the sinoauricular
and auriculoventricular nodes (Fig. 52).

Another anatomic fact seen also in the accompanying figure, concerns
the disposition of the muscular fibers of the auricle. These radiate in
bundles in a peculiar fan-shaped manner from a point which lies im-
mediately below the sinoauricular node to all parts of the superficies of
the right auricle. This point has been called the concentration point*
At the termination of the venae cavae, the muscle fibers are arranged more
or less circularly.

Having become familiar with the disposition in the mammalian heart
of the primitive cardiac tissue, along which in the heart of the lower
animals we know that the heartbeat spreads, we may now proceed to
examine the evidence showing that this tissue is also responsible for the
origination and propagation of the beat in the heart of mammals. With
regard to the origin of the beat in a normally beating mammalian heart,
it is of course impossible to tell where this takes place. If the heart is
excised, however, it will continue to beat for a few moments, and as it
dies it will be observed that the power of contraction remains in the au-
ricular region, and particularly at the bases of the venae cavae, for a con-
siderable time after the ventricles have ceased to beat. This part — the
ultimum moriens — is situated in most hearts somewhat lowrer than the
sinoauricular node. That it is the last part of the heart to cease con-
tracting does not necessarily mean that it is the part of the heart in
which the beat ordinarily originates ; it means simply that this is the
part of the auricle in which the power of contraction remains for the

186

THE CIRCULATION OF THE BLOOD

longest time after death. Although, the observation does not enable us
to determine exactly where the heartbeat originates, yet it makes it
very probable that this is somewhere in the auricles ; a conclusion which
is borne out by many other pieces of evidence, such as those obtained by

Fig. 51. — Diagram of an auricle showing the arrangement of the muscle bands; the concen-
tration point (C.P.); and the outline of the S.A, node (S.A.N.). The diagram is to scale, and
illustrates by the circles and connecting dotted lines the method of leading off by paired contacts
and the subsequent orientation/ (From Thomas Lewis.)

i Auricular appendage
,,-5/noaurfcuJar node

M.R-

.Auriculoventriculer node
-Aurlculoventricular bundle

•Right & left ventricular
bundles

-Musculi papillares

Fig. 52. — Diagram to sliow the general ramifications of the conducting tissue in the heart of
the mammal. Jt will be observed that there is none of this tissue between the sinoauriculo- and
auriculoventricular nodes.

the study of polysphygmograms (page 285), of electrocardiograms and
of observations on the heart during heart-block (page 270). Our problem
therefore narrows itself down to determining the exact point of the right
auricle at which the beat originates. .

THE PHYSIOLOGY OF THE HEARTBEAT 187

SITE OF ORIGIN OF THE BEAT

The working hypothesis from which we may proceed to attack this
problem is that the beat originates in the sinoauricular node, and to
put this to the test, various methods have been employed: (1) Warming
or cooling or injuring the node and noting the effect on the heartbeat.
Such procedures greatly affect the rate of the heartbeat, whereas they
produce no change when applied to. other parts of the heart. (2) De-
termination of the comparative rhythmic power of strips cut out from
different regions of the auricular walls. It is greatest in those taken
from the region of the node. (3) Determination by the use of galvan-
ometric curves of the relation of the node to the seat of origin of cardiac
impulse. By all these methods the results indicate clearly that the beat
originates in the sinoauricular node, but on account of the great im-
portance in connection with the interpretation of electrocardiograms in
man, it is particularly with the result of the third group of experiments
that we will concern ourselves here.

Evidence Furnished by Studying the Current of Action Which
Accompanies the Heartbeat

To start with, it is essential that we make ourselves familiar with
the principles of the methods employed. These principles are briefly as
follows: When a wave of contraction passes along a muscle, it is im-
mediately preceded by a change in electrical potential, which can be
detected by means of a galvanometer connected with the muscle through
so-called nonpolarizable electrodes. The galvanometer employed must
be extremely sensitive, and must not vibrate after the current has ceased
to pass. The form generally in use today is known as the string galva-
nometer of Einthoven. It differs from the galvanometer ordinarily em-
ployed in physical laboratories in that the current instead of passing
through a coil of wire surrounding a magnetic needle, passes through a
silverized quartz thread suspended in the strong magnetic field which
exists between the two opposing poles of a horseshoe electromagnet.
The string is thus surrounded on all sides by innumerable lines of force
extending between the two poles of the magnet. When a current; how-
ever small, passes along the string, it will generate lines of force of its
own, and these by reacting wTith the stationary lines of force of the field
will cause the string to move. The string is placed in the pathway of a
strong beam of light, and its shadow, after being magnified by lenses,
is projected on a moving photographic plate or paper arranged in a
suitable holder. The nonpolarizable electrodes referred to are employed
in place of ordinary electrodes in order to obviate the generation, of elec-

188 THE CIRCULATION OF THE BLOOD

trie currents set up by the contact of metal with the saline constituents
of the muscle juices.

If we connect a galvanometer by means of nonpolarizable electrodes
with two parts of a denervated muscle (the curarized sartorius of the
frog), it will be found that a current is set up whenever a wave of con-
traction passes over the muscle from one end to the other. The part
which first contracts becomes electrically negative to the rest of the muscle,
but as the wave of contraction passes along it, the "negativity" de-
creases at the end at which the wave started until, when the wave has
reached the middle of tho strip, neither end of the muscle shows any
difference in potential, so that the string comes back to a position of
rest. However, as the contraction wave reaches the farther end of the
muscle, this lead in turn becomes negative, and the string swings in the

_ Fig. 53. — Diagram to illustrate the development and spread of the wave of negativity in a
strip of muscle (curarized sartorius) when stimulated at the end (F). The shaded portions show
the position of the negativity. The portion of the curve drawn by the deflections of the galvanom-
eter at each stage are shown at the right (a, b, c, and d). (After Lewis.)

opposite direction (Fig. 53). From this comparatively simple experiment
it can be seen that a muscular contraction wave arises at the electrode which
is negative first, and that the movement of the string of the galvanometer is
most marked — that is, the deflection is greatest — when the two electrodes
are applied at the extreme ends of the muscle. When they are brought
closer together, the initial deflection becomes much less marked ; in other
words, the amplitude of the negative wave is greatest when the time
interval between the receipt of the excitation at the two contacts is
greatest.

The application of these facts to the study of the initiation of the beat
in the auricle requires that we should consider another proposition:
namely, if a pair of contacts are arranged in the center of a circular
sheet of muscle and the edge of this sheet is stimulated at different

THE PHYSIOLOGY OF THE HEARTBEAT 189

points, the amplitude of deflection of a galvanometer connected with the
pair of contacts will be most pronounced when these are radial to the
points of stimulation, for under these conditions it is evident that the
greatest possible difference will exist between the intervals required for
the w^ave to reach each contact.

Bearing these principles in mind, we may now proceed to examine the
evidence pointing to the origin of the heartbeat at the sinoauricular node:
(1) When two electrodes are applied at different points of the au-
ricle, the amplitude of movement of the string of the galvanometer
produced by each heartbeat is greatest when the line joining the elec-
trodes converges on the sinoauricular node. To make this clear the
movement of the string must be photographed in the manner above
described, the resulting tracing being called an electrocardiogram. From
the experiments with the circular sheet of muscle alluded to it is evident
that the stimulus to produce this result must have arisen in the neigh-
borhood of the node. (2) If one electrode is placed on the sinoauricular
node and the other electrode is moved about from place to place on the
auricle, the deflection being noted at each new position, the electrode
on the node will always be found to be negative to the other electrode.*
No such consistency will be manifest if both electrodes are moved about
on other parts of the auricle.

(3) As we shall see immediately, the current of action of the beating
heart may be recorded by connecting a galvanometer with various parts
of the body; for example with the right fore limb and the left hind
limb. On the electrocardiogram thus obtained are several waves, one
of which, called the P-wave, can easily be shown to correspond to the
contraction of the auricle (see Fig. 272). If now we compare such electro-
cardiograms with those obtained during contractions of the auricle
caused by applying electrical stimulation to various parts of it, it will be
found that the electrocardiogram of the artificial beat simulates the
normal curve only when the stimulated part is in the neighborhood of
the sinoauricular node. In other words, it is only when the stimulus is
applied to the sinoauricular node that a characteristic P-wave is obtained.
"When the appendix or the superior vena cava is stimulated, the P-wave is
distorted although the other waves of the electrocardiogram may be normal.

(4) By taking electrocardiograms from various direct leads placed
on the auricle and comparing the records with that of a standard
limb lead taken simultaneously, we shall find by exact measurement that
the time of onset of the excitation wave of the auricle, as measured in
relationship to the P-wave on the standard electrocardiogram, is shortest

*The connections between the electrodes and galvanometer are always arranged so that any
upward movement of the shadow of the string above the line of equal potential at the two electrodes
indicates electric negativity.

190

THE CIRCULATION OF THE BLOOD

when one electrode is over the upper end of the sinoauricular node, and
that in other regions of the auricle it always appears at a later interval.
Further details on this subject will be found in the papers by Eyster and
Meek8 and in Lewis monographs.

Frequently, in taking electrocardiograms from different parts of the auricle, it is
found that certain of the curves show small waves of positivity below the line of equal
potential preceding the main wave of negativity. These initial deflections are most
marked when both the electrodes are far removed from the sinoauricular node— for ex-
ample, when they are placed on the auricular appendix ; but they are never present when

Fig. 54. — Simultaneous electrocardiograms to show the cause for extrinsic deflections. The
upper curves are from the appendix and the lower ones from lead II. The chief or intrinsic
deflection (Tn) is seen to disappear in the right-hand appendix electrocardiogram, because the
base of the appendix has been crushed. The extrinsic deflection (£.r) remains, as do the ven-
tricular deflections (J71 V-). (From Lewis.)

one of the electrodes is placed on the sinoauricular node itself. In other words, curves
taken from leads at a distance from the sinoauricular node are more or less composite
in form, being made up partly of the main deflection due to the arrival of the excitation
and partly of the secondary deflections dependent upon extrinsic influences acting on
the electrodes; that is, the electrode picks up electric discharges from distant areas of
muscle while these are in a condition of contraction (Fig. 54). From these considera-
tions it follows that the intervals between the intrinsic and extrinsic deflections
should be longest in leads that are farthest from the node, and gradually become
less as one of the contacts approaches the node, until over this structure the ex-
trinsic deflection is no longer recorded. Such has been found to be the case. (Lewis.)

CHAPTER XXII
THE PHYSIOLOGY OF THE HEARTBEAT (Cont'd)

THE ORIGIN AND PROPAGATION OF THE BEAT (Cont'd)—

FIBRILLATION

Mode of Propagation in the Auricles

From the mass of evidence we have little doubt that the heartbeat
originates in the sinoauricular node, and the question now presents itself
as to how the beat is propagated over the remainder of the auricles and
into the ventricles. Regarding the propagation of the beat over the
auricles, two possibilities exist: (1) it may spread uniformly over the
muscular tissue of the auricular wall until it reaches the auriculoventric-
ular node, or (2) there may be laid down between the sinoauricular and
the auriculoventricular node a special strand of highly conducting tissue.
It is no argument against this second possibility that we should so far
have been unable by histological methods to differentiate any such struc-
tures.

There is considerable practical importance attached to the solution of
these questions, particularly with regard to the cause of certain types
of cardiac arrhythmia, such, for example, as that known as nodal rhythm.
Thus, it is evident that if the beat is transmitted uniformly over the
muscular tissue of the auricle, then the whole auricle will have con-
tracted before the beat has reached the auriculoventricular bundle, by
which it is then transmitted to the ventricles. On the other hand, if the
beat should travel between the two nodes by special conducting tissue,
then the impulse will have arrived at the auriculoventricular node be-
fore the auricle has contracted. As a matter of fact, it is not quite settled
yet as to which of these two views is the correct one, although the balance
of evidence seems to favor the former — that is, that the wave is transmitted
uniformly over the muscular tissue of the auricle. (Lewis.)

The methods employed in attacking the problem have been essentially
the same as those described above. One of them may be called the direct,
the other the indirect. In the former, a series of pairs of contacts is
placed on the auricle, each pair being in a radial direction to the sino-
auricular node. The time at which the excitatory process arrives at that
contact of each pair which is proximal to the sinoauricular node is accu-

191

192 THE CIRCULATION OF THE BLOOD

rately determined from the galvanometric record. The exact distance be-
tween the contact and the sinoauricular node is then measured and from
the data the average transmission time is estimated. From his results
Lewis concludes that the transmission rates are uniform from the node
to all parts of the auricle, with the exception of the superior vena cava,
in which the rate is considerably lower. One thousand millimeters per
second represents very fairly the average rate at which the excitation
wave travels. On the other hand, Eyster and Meek8 state that the wave
is propagated throughout the sinus node, and that it spreads to the
contiguous venffi cavse and to the auriculoventricular node with con-
siderable rapidity, reaching the mouth of the superior vena cava in 0.01
second, whereas its passage to the auricle itself takes 0.02 second. There is
therefore a delay in the passage of the wave to the auricle, which indi-
cates that the excitation must spread to the auriculoventricular node be-
fore involving the right atrium. These authors conclude that ' ' this leads
to the inevitable conclusion that the cardiac impulse spreads to the ven-
tricle and to the right auricle by different paths, and does not pass to
the ventricle through the auricle, as ordinarily stated."

In the second, or indirect, method, the onset of the negative wave from
different leads in the auricle is compared against a standard. For the
standard Eyster and Meek have used the record of the mechanical sys-
tole of the auricle, but the interpretation of the result is extremely dif-
ficult on account of the rate at which the changes are occurring. Lewis,
on the other hand, has used the standard electrocardiogram for purposes
of comparison.

Mode of Propagation of the Beat to the Ventricles

After reaching the auriculoventricular node, the beat is transmitted to
the ventricles along the auriculoventricular bundle — a fact which has been
most clearly demonstrated by the experiments on heart-block. We have al-
ready seen (page 174) that although each chamber of the heart of a
turtle or frog has a rhythm of its own, this is much more pronounced at
the venous end of the heart, and when the transmission of the beat to the
ventricles from the auricles is obstructed or blocked, as by compression
or partial cutting at the auriculoventricular junction, the ventricles,
after coming to a standstill for a time, subsequently contract with a
rhythm which is entirely independent of that of the auricles.

In the mammalian heart the same results may be obtained by arrang-
ing a clamp so that it compresses practically nothing but the auriculo-
ventricular bundle (Erlanger.) If the compression is extreme, the
rhythm of the ventricles is quite independent of that of the auricles, but
if it is only partial, the ventricular systoles follow regularly every sec-

THE PHYSIOLOGY OF THE HEARTBEAT 193

ond, third, or fourth auricular contraction. If after such a complete or
partial heart-block has been instituted, the clamp is removed, it will
usually be found that the heart-block disappears and the auricular and
ventricular contractions fall back into their usual sequence. The im-
portance of this discovery, apart from its physiological interest, rests in
the fact that it is exactly duplicated in clinical experience. If the pulse
tracing of the radial artery is compared with that of the jugular vein
in certain types of heart disease, it will be found that the auricle is beat-
ing two or three times more quickly than the ventricles. In many of
these cases it has been found on autopsy that definite lesions often syphi-
litic in nature involve the auriculoventricular bundle. In other cases,
however, such lesions, have not been discovered. Sometimes the bundle
is so severely diseased that the block is complete, the ventricles con-
tracting quite independently of the auricle. In such cases it is assumed
that the beat originates in the uninjured part of the bundle below the
seat of the block. It should be pointed out here, however, that all cases of
slow pulse in the arteries are not necessarily dependent upon heart-block,
but may depend upon a slow beat of the auricle itself. This is called
bradycardia.

Sometimes after complete destruction of the auriculoventricular bun-
dle the beat continues to be transmitted to the ventricle, and conversely
this transmission has sometimes been observed to be upset by lesions not
affecting the bundle. The explanation of both of these exceptional re-
sults almost certainly is that the right lateral connection described above
(page 184) is serving as the main pathway of transmission for the beat.

The facility of conduction through the auriculoventricular bundle is
subject to alteration by the impulses passing to it along the vagus nerve,
particularly the left vagus. It can also be altered by certain drugs,
especially digitalis and strophanthin. The clear demonstration that it is
along this bundle that the beat is transmitted is strong evidence in favor
of the myogenic hypothesis (page 171) concerning the transmission of
the heartbeat, but it does not necessarily disprove the neurogenic hypoth-
esis, for histological investigation has shown that the bundle is closely
surrounded by an intimate plexus of nerve fibers.

Spread of the Beat in the Ventricle

After the impulse has been transmitted by the bundle into the ven-
tricles, it spreads along the many branches into which, as we have seen,
the two main divisions of this bundle separate. The first part of the
ventricular musculature to contract is therefore located near the ter-
mination of these branches, at the papillary muscles. That these should
contract before the rest of the muscle of the ventricles, has an obvious

194

THE CIRCULATION OP THE BLOOD

significance in connection with their function of tightening the chordae
tendineae so as to prevent any bulging of the flaps of the auriculoven-
tricular valve into the auricles when, at the beginning of the presphygmic
period, the high intraventricular pressure is brought to bear on their
under surfaces. After starting at this point in the ventricle, the con-
traction wave seems to spread farther through the ventricular muscle at
a fairly uniform rate.

Investigation of this problem by means of the galvanometer has been
technically a very difficult matter, and the details of the researches by
Lewis and his pupils have not as yet been published in full. According
to the preliminary communications at hand, however, it appears that,

Fig. 55. — Diagram of experiment by Lewis showing the times at which the excitation wave
appeared on the front of the heart relative to the upstroke of R in lead II. R.A., right appen-
dix; D.B.L., descending branch of left coronary artery. (From Thomas Lewis.)

when nonpolarizable electrodes are placed at various parts of the outer
aspect of the ventricle, and comparison made of the moments at which
the cardiac impulse arrives, as judged by the appearance of the excita-
tion wave relative to R in a standard electrocardiogram, it has been
found that the time of arrival bears no relationship to the anatomical ar-
rangement of the muscle bundles of the ventricle. It arrives early and
simultaneously over an area of the surface near the anterior attachment
of the wall of the right ventricle. It arrives late at the base of the right
ventricle and in the part near the posterior intraventricular groove.
Histological examination has shown that the branches of the right division
of the auriculoventricular bundle are most closely connected with the

THE PHYSIOLOGY OF THE HEARTBEAT 195

place where the wave arrives earliest. Somewhat different results are
obtained from the left ventricle, but again they are dependent upon the
relationship of the part to the Purkinje fibers (Fig. 55). A further dis-
cussion of the manner of spread of the impulse in the ventricles will be
found in the chapter devoted to interpretation of the electrocardiogram
(page 270).

FIBRILLATION OF THE HEART

Ventricles

The even spread of the wave of contraction over the heart depends on
the uniform excitability of the muscular fibers. If certain of the muscu-
lar fibers, or bundles of fibers, have a greater or less excitability than
others, then, when the stimulus to contract arrives, it will not produce
a uniform contraction of neighboring bundles, and coordinated action of
the cardiac musculature will give place to a confused movement in which
each part of the heart is contracting independently of the rest. This
fibrillation, or delirium cordis, as it is called, can be produced by a large
variety of experimental methods, such, for example, as by stimulating
the ventricles with induced electric shocks, or by ligation of a large
branch of the coronary artery, or by the injection of lycopodium spores
into the coronary circulation, *or by mechanical stimulation of the heart
in the region of the auriculoventricular bundle.

Fibrillation of the ventricles is undoubtedly a common cause of death
in man, for of course the confused movements make the ventricles in-
capable of contracting on the contents of the heart. It is a condition
which can probably never be recovered from in the higher animals, but
it is of interest that the ease with which it is set up as the result of the
application of an electric stimulus varies to a marked degree in differ-
ent animals, and that in those hearts in which fibrillation can be elic-
ited only with difficulty, recovery can usually be effected either by stop-
ping the heart by means of cold and then allowing it to beat again, or
by the administration of epinephrine. Of the hearts investigated in
this way, that of the rat has been found to be most resistant to stimula-
tion; then in order come those of the rabbit, the cat, the dog, and the
horse. There is good reason to believe that the heart of man is readily
affected. Fibrillation of the ventricle is undoubtedly the main cause of
death in most cases of electrocution. Curiously enough, however, it has
been stated that, whereas, a current of ordinary intensity (2300 volts
alternating current) produces ventricular fibrillation in the heart of cer-
tain of the lower animals, at least in that of the horse, a very much
stronger current does not do so, and may indeed cause ventricular fibril-

196 THK CIRCULATION OF THE BLOOD

lation produced by a more moderate voltage to disappear. Unfortu-
nately, however, these stronger currents produce irreparable damage in
the central nervous system, so that the method of applying stronger cur-
rents, even were it' feasible to do so quickly enough, would be of no
therapeutic value in removing fibrillation.

The disappointing results that have followed the repeated attempts
to resuscitate persons killed accidentally by electric shocks is undoubt-
edly dependent upon the fact that in the heart of man it is impossible
to bring back the normal beat after the ventricles have been thrown into
fibrillation. Fibrillation of the ventricle is also the cause of the sudden
cardiac failure occurring when blood clots or emboli cause a blockage
of the coronary circulation (it is sometimes the cause of angina pec-
toris, for example). It must also be remembered in clinical practice
that mechanical stimulation of the ventricles may produce fibrillation, so
that in attempted resuscitation by cardiac massage care should be taken
not to apply this too vigorously.

Auricles

Although ventricular fibrillation is seldom recovered from, it has been
clearly shown in recent years that fibrillation of the auricles is relatively
common and that it is by no means immediately fatal. Indeed it is one
of the most common of the chronic cardiac disorders in man. Auricular
fibrillation can be produced experimentally by the application of a
strong electric stimulus to the auricles. If, however, a weaker stimulus
is applied, the auricles do not go into typical fibrillation, but come to
beat at a very rapid and regular rate, perhaps three or four hundred a
minute. This condition is called "auricular flutter," and is quite fre-
quently observed in the clinic.

The influence of auricular fibrillation and flutter on the beat of the ven-
tricle is an extremely important one in connection with the irregular-
ities of the heart observed in man, and this influence in most cases is
explained by considering (1) the narrowness of the path (in the auric-
uloventricular bundle) along which the impulses have to travel, and (2)
the varying conditions of excitability of the ventricular muscle, depend-
ing upon the existence of the refractory phase (page 178).

In auricular flutter, when three or four hundred impulses per minute
are passing along the bundle to the ventricle, the contraction produced
by the first one will scarcely have started before the second and imme-
diately succeeding ones arrive, so that the ventricle will beat at a rate
that is much less than that of the auricle, and a condition simulating
heart-block will become established. The characteristic feature which
distinguishes this from true heart-block, however, is the fact that the

THE PHYSIOLOGY OF THE HEARTBEAT 197

ventricular rate is above normal, whereas in true heart-block the rate
is much below normal. By means of the electrocardiogram or by
polysphygmographic tracings, it can also be shown that the auricle is
beating with perfect regularity although very rapidly.

In auricular fibrillation the ventricles obviously will respond at a very
irregular rate to the impulses transmitted to them, and the auricular
contractions, if examined by the methods above described, will show no
regular sequence. Further details of the method of eliciting these signs
will be described later (page 285).

CHAPTER XXIII
THE BLOODFLOW IN THE ARTERIES

THE PULSES

Returning to the physical laws that govern the circulation of the blood,
we may now consider the temporary changes produced in the bloodflow
in the arteries by each systolic discharge. These changes go under the
general term of the pulses, of which three may be distinguished: (1)
the pressure pulse, or the pulsatile increase of pressure produced by
each heartbeat (see page 129) ; (2) the velocity pulse, or pulsatile accel-
eration of velocity; and (3) the palpable pulse, or the pulsatile expansion
of the walls of the blood vessels produced by the sudden change of blood
pressure in their interior. The general characteristics of the three
pulses are the same, certain features being however more pronounced
in one than in another.

General Characteristics

Rate of Transmission of Pulse Wave. — The rate of transmission of
the pulse wave can be determined by taking simultaneous tracings of
the pulses from two far distant parts of the arterial system along with
accurate time-tracings. From records (cf. Fig. 95) taken from the apex or
the carotid and radial arteries we can determine how long it takes for
the beginning of the pulse wave to travel to the radial artery from the
point in the aorta from which the carotid artery springs. We shall find
that it takes about one-tenth of a second, which, considering the length
of the artery involved, would work out as a transmission velocity of
about seven meters per second or about seventeen miles an hour. The
pulse therefore travels along the blood vessels at a much greater speed
than the blood itself is moving, this being, as we shall see immediately,
about 0.5 meters per second in the larger blood vessels.

The pulse is a wave of sudden increase in pressure and velocity pass-
ing along a stream which is flowing in the same direction with a cer-
tain more permanent pressure and velocity. A simple physical experi-
ment may serve to make this clear: If the first of a row of billiard balls
be tapped with the cue, the end balls will fly off while the others are
moving slowly along in the direction of the stroke. Each ball becomes
accelerated by the ball behind it, and imparts its influence to the ball

198

THE BLOODFLOW IN THE ARTERIES 199

in front. In other words, a pulsatile acceleration of velocity is produced
by a pulsatile change in pressure between each two balls. The existence
of a pulse wave going in the same direction but quicker than a moving
column of fluid can also be illustrated by observing the waves traveling
down a stream when a stone is thrown into it.

The length of the pulse wave is such that the beginning of it has ar-
rived at the periphery of the arterial system before the end has disap-
peared from the beginning of the aorta. This is important to remem-
ber, for it is a common mistake to think of the wave as being a local
one. The determination of the length of the pulse wave depends upon
the following equation: L = VT, where L equals the length of the pulse
wave, V its velocity of transmission, and T its duration at a given point
in the artery. Under ordinary circumstances L would usually work out
from 3.25 to 4.5 meters.

The rate of transmission of the pulse wave varies according to the
rigidity of the walls of the arteries. To understand why this should be
so, it will be well for a moment to consider the physical conditions
upon which the pulse wave depends. If we connect a piece of rigid
tube with the nozzle of a large syringe, with each movement of the pis-
ton a wave of pressure will be transmitted to the fluid in the tube, along
which it will travel at such a high velocity that it will arrive at the
free end of the tube almost instantaneously, and incidentally the out-
flow of fluid from the end of the tube with each compression of the
pump will be exactly equal to that represented by the movement of the
piston. If, on the other hand, an elastic tube is employed, it will be
found that the sudden increase of pressure produced by each stroke of
the pump causes a distention of the walls, which travels along the tube
as a wave at a readily measurable velocity, which is slower the more
extensible the tube. Moreover, the outflow of fluid from the free end
of the tube will continue for some time after the cessation of the move-
ment of the pump. What happens in the tube with each discharge of
the fluid is that the portion which is immediately adjacent to the pump
undergoes distention and, being elastic, tends immediately afterward to
recoil and thus exert a recoil pressure- on the fluid contained in the tube.
As a result, pressure waves are set up in the fluid in all directions. Those
that travel back come to a stop because of the piston, while those that
travel distally act on the fluid in front of them so as to accelerate it
and by temporarily raising its pressure distend the next segment of the
vessel wall, until the end of the tube is reached. From this considera-
tion it is clear that the more extensible and elastic the wall of the tube
is, the longer will it take for the wave of pressure to travel from one
end to the other.

200

THE CIRCULATION OF THE BLOOD

Alteration in the rate of transmission of the pulse wave in the arter-
ies of man depends entirely upon an application of these principles.
When the arteries become hardened in old age, the rate of transmission
of the pulse wave is markedly increased. The pulse is also transmitted
more rapidly in the vessels of the lower extremities than in those of the
upper, since in the former the blood vessels are somewhat more rigid.
Delay in the transmission of the pulse wave is further observed as one
of the signs of aneurism in a vessel; as is well known, aneurism of the
subclavian artery on one side causes a delay of the pulse on that side
that is perceptible to the fingers.

The Contour of the Pulse Curves

For more particular study of the exact contour of the pulse wave, and
especially for determining the time relationships of the secondary waves,

Fig. 56. — Diagram of Chauveau's dromograph. a, tube for introduction into the lumen of the
artery, and containing a needle or vane, which passes through the elastic membrane in its side
and moves by the impulse of the blood current; c, graduated scale for measuring the extent of
the oscillations of the needle.

a large variety of methods of varying degrees of accuracy have been
elaborated for each kind of pulse.

Those devised for measuring the pressure pulse have already been de-
scribed (see page 128), and for the other pulses they are as follows:

Velocity Pulse. — Much ingenuity has been displayed in the elabora-
tion of methods for recording the velocity pulse. In one of these the
artery is cut across and the ends attached to a tube, into the lumen
of which projects a paddle or vane articulated with a light lever, which
passes through its wall (see Fig. 56). The vane floats in the blood
stream, and the outer end of the lever to which it is attached is con-
nected with some device to record its movements, which vary with the
velocity of bloodflow (hemodromograph). Another method depends on
the application of the instrument known as Pitot's tube used by phys-
icists. This consists of a horizontal tube having two side tubes, each of

THE BLOODFLOW IN THE ARTERIES

201

which is connected at its outer end with a manometer and prolonged
inside the horizontal tube, where they are bent at opposite right angles,
so that the inner end of one of them — the proximal tube — points up

(T

D

Fig. 57.

Fig. 58.

Fig. 57.- — Diagram to show principle of Pilot's tubes for measuring velocity pulse. In both
tubes the fluid will rise because of lateral pressure, but in the proximal (left-hand) tube it will
rise higher than in the distal, because it will also be affected by the velocity of flow.

Fig. 58. — Diagram to illustrate the principle of Cybulski's Phpto-hematotachometer. The fluid
in C stands higher than that in D in proportion to the velocity of flow of the blood along
AD.

Fig. 59. — Dudgeon's sphygmograph. (From Jackson.)

stream, and records not only the lateral pressure but also the pressure
produced by the sudden increase in velocity of the flow, wrhile the

202 THE CIRCULATION OF THE BLOOD

other — the distal tube — being bent down stream, records merely lateral
pressure. A photographic record of the movement of the fluid in the
two tubes gives the velocity pulse (see Fig. 57). For physiological pur-
poses the form of apparatus used is constructed as shown in Fig. 58.

Palpable Pulse. — To secure a record of the palpable pulse, the so-
called sphygmograph is employed, although a tambour having a button
in the center which is made to press on the artery may also be em-
ployed. The commonest form of sphygmograph is that known as
Dudgeon's (Fig. 59). It consists of a small button 'connected with a
spring, the movements of which are transmitted and magnified by means
of a system of levers connected with a writing point arranged so as
to inscribe its movements on a moving surface.

The Analysis of the Curve

The general contour of the pulse waves taken by any of the above
methods are in general very much the same. The pressure and velocity

Fig. 60. — Pulse tracing (sphygmogram) taken by sphygmograph. a d, the period of the pulse
curve; b, the primary; c, the dicrotic wave. Time marked in fifths of a second. (From Prac-
tical Physiology.)

pulse curves are, however, not usually taken for the purpose of observ-
ing the contour of the wave but rather for measuring the difference in
pressure or velocity actually produced during each pulse. It is a record
of the palpable pulse that is usually employed for studying the contour
of the wave and the presence of secondary waves. A record of the pal-
pable pulse wave (Fig. 60) shows two separate waves on the descending
limb of the main wrave. If a large number of similar pulse curves are
taken from different individuals or from the same individual under
different conditions, it will be found that of these two waves the second
one is by far the more constant ; and if the waves are timed in relation-
ship to the heart sounds, this second wave always occurs immediately
after the second sound, allowance, of course, being made for the time
required for the pulse to be transmitted from the heart to the artery
from which the pulse tracing is being taken. If the observation is
made very carefully, it can indeed be shown that the second sound cor-
responds exactly to the notch which precedes this wave. The waves that

THE BLOODFLOW IN THE ARTERIES 203

precede this notch can not be related to definite changes occurring in
the heart. Evidently, then, the secondary pulse waves are not all of
equal significance, by far the most important being that which occurs
immediately after the second sound, called the dicrotic wave (c), the
notch in front of it being called the dicrotic notch. Any secondary
waves occurring before the dicrotic are called predicrotic, or if they
occur on the ascending limb of the main pulse wave, as they sometimes
do, they are called anacrotic. Waves occurring after the dicrotic are
called postdicrotic.

The relative importance of the dicrotic, in comparison with the pre-
dicrotic and postdicrotic waves, is further, evidenced by the fact that
it alone is seen on a so-called hemataugram, which is the tracing ob-
tained by allowing a fine stream of blood, escaping from a pinhole made
in the wall of an artery, to impinge upon a moving sheet of white blot-
ting paper. That such a tracing shows a dicrotic but no secondary wave,
indicates that only the former is present in the blood stream itself, and
that the other secondary waves must be produced by some condition
arising either in the elastic tissue of the walls of the blood vessels, or
in the elastic properties of the instruments used for taking the pulse
tracing.

The Dicrotic Wave. — Because of its obviously greater significance, we
shall first of all consider the exact cause of the dicrotic wave and of the
notch preceding it. Theoretically, two possible causes might explain
the wave: either it is due to some secondary wave set up at the heart,
or it is dependent upon waves reflected from the periphery of the cir-
culation back along the blood stream, just as secondary waves are re-
flected from the walls of a tub of water when a stone is thrown in the
center. In considering this second possibility, we are of course making
the assumption that at the ends of the arterial system there is a sudden
resistance to the onward movement of blood. The frequent branching
which occurs when the arterioles open into the capillaries no doubt of-
fers many opportunities for the reflection of pulse waves back to the
heart, but these waves must be reflected at such varying distances along
the arterial system that there can be little opportunity for them to be-
come added together so as to form a wave of sufficient magnitude to
make itself perceptible in the blood flowing in the larger arteries. These
waves are relatively so small and they occur at such different times that
the net result of their addition, so far as the production of a larger
wave is concerned, must be practically nil. Notwithstanding these con-
siderations, it is possible that under some conditions, such as in cases
of high arterial tension, certain of the predicrotic or postdicrotic waves
may be due to the above causes.

204 THE CIRCULATION OF THE BLOOD

That the dicrotic is not a reflected ivave is clearly established by the
fact that if the distance between the dicrotic wave and the main pulse
wave is measured at different points of the arterial stream, it will al-
ways be found to be the same, which obviously would not be the case
were the dicrotic wave reflected. If, for example, we were to examine
the contour of the wave produced by throwing a stone into a tub of
water, we should find that near the edge the secondary wave was very
close to the main wave, whereas near the center the secondary wave
would occur much later.

Our problem therefore narrows itself down to an investigation of
the cause for the dicrotic wave at the central end of the circulation. It
occurs, as we have seen, immediately after the beginning of diastole.
That it can not be due to anything taking place in the ventricle itself is
evidenced by the fact that such a wave is absent from an intracardiac
pressure curve (see page 151), although it is present in the very begin-
ning of the aorta. Now, the only structures existing between those two
points which could be held responsible for this wave are the semilunar
valves — a conclusion which is sustained by the fact that, if the aortic
valves are rendered incompetent by hooking them back, or if the pulse
beat is examined in patients suffering from an aortic insufficiency, it
will be found that the dicrotic wave is not nearly so evident as usual.

To understand liow the valves are responsible for the production of the
wave, the mechanical changes occurring at the root of the aorta must
be clearly understood (see page 155). The stretching of the elastic walls
of the aorta which occurs with each systolic outrush of blood is fol-
lowed by a powerful and sudden contraction of the stretched walls,
and the pressure thus brought to bear on the column of blood in the aorta
tends to impel it both forward and backward. The forward movement
adds itself to the wave of increased pressure already produced by the
ventricular contraction. The backward component travels as far as the
semilunar valve, from which it is reflected, and now proceeds peripher-
ally along the blood stream during the time at which the original pres-
sure pulse is declining. It therefore imprints itself on the pulse trac-
ing as a separate wave, and does so all the more markedly when the
decline in the main pulse wave is rapid, as in cases in which the periph-
eral resistance is low, but fails to be prominent when, on account of
a high peripheral resistance, the decline in the main pulse wave is tardy.
This explanation coincides exactly with the well-known clinical fact
that the dicrotic wave is conspicuous in pulses of low tension, but ill
marked or absent in pulses of high tension.

One point remains to be considered, and that is the cause for the
sudden decline in the main wave at the cessation of the ventricular out-

THE BLOODFLOW IN THE ARTERIES 205

put, for, it might be said, why should there be such a sudden fall in
pressure near the heart, whereas toward the periphery, as we have seen,
the pressure between the heartbeats tends to be maintained on account
of the elastic recoil of the stretche.d arterial walls. The explanation
usually given is that the sudden cessation of outflow of blood from the
ventricle at the end of the sphygmic period causes a negative pressure
to be produced in the blood at the beginning of the aorta, thus tending
to cause a reflux of blood towards the heart, the effect of which is (1) to
bulge the closed valves, and (2) to produce the reflected dicrotic wave.
If, while fluid is flowing under pressure along a tube, the flow is sud-
denly arrested by turning a stopcock, it is possible by the use of manom-
eters to show that a negative wave is set up immediately beyond the
stopcock, and that this negative wave travels along the tube at a rate
depending on the elasticity of its walls.

Causes for Disappearance of the Pulse in the Veins

The disappearance of the pulse in the capillaries and its consequent
absence in the veins we have already seen to be owing to the combined
influence of the elasticity of the vessel Avails and the peripheral resist-
ance. On account of these two factors the pressure conveyed to the
blood during systole is stored up to be released during diastole by the
recoil of the stretched vessels. Sometimes, however, the pulse gets
through to the veins, either because the elasticity of the vessels is not so
marked, or because the peripheral resistance has been lowered (vaso-
dilatation). In patients with hardened arteries, or in normal individu-
als after taking nitrite, which dilates the peripheral arterioles, a pulse
may come through at the periphery and appear in' the veins. This may
be called the peripheral venous pulse, and it is to be carefully distin-
guished from the central venous pulse observed in the large veins, as
at the root of the neck, before any valves have intervened to block the
transmission of the auricular pressure wave back into the column of
blood in the veins. If a pulse is seen in a large vein and there is
doubt as to whether it is peripheral or central in origin, this doubt can
be immediately removed by locally constricting the vein; if the pulse
is peripheral, it Avill disappear on the heart side of the constriction; if
it is central, on the side away from the heart.

CHAPTER XXIV

THE RATE OF MOVEMENT OF THE BLOOD IN THE
BLOOD VESSELS

Since the object of the circulation is to maintain an adequate move-
ment of blood in the tissues and capillaries, it is evident that besides
measuring the pressure of bloodflow, we should also measure the rate
of its movement, or, as it is often called, the mean velocity. This measure-
ment may be undertaken either for a given vessel or for a complete
vascular area, such, for example, as that of one of the viscera or one
of the extremities — the mass movement of the blood. Or instead of
measuring the mean velocity we may desire to know how long it takes
for a particle of blood to traverse a given vascular area. Such a meas-
urement is called the circulation time; it does not at all tell us how long
it takes for all the blood to pass through the given area, but only, as
stated, the time required for the circulation of a fraction of the blood
through a particular field.

VELOCITY OF FLOW IN A VESSEL

Special methods have been devised for the measurement of each of
these three velocities. For the measurement of the velocity of flow
through a main artery or vein, methods similar to those employed by
hydraulic engineers are employed; that is to say, the volume of blood,
in cubic centimeters, which passes a given point is measured for r
given time, and the result divided by the cross section of the vessel at
the point of observation. The result gives us the mean lineal velocity.
To measure the outflow of blood in a given time, the simplest method
would be to cut across the vessel and collect the blood in a graduate,
but obviously in this method an error would be introduced, because
cutting the vessel would lower the peripheral resistance and remove the
natural obstruction to the flow present in the intact animal. Moreover,
the hemorrhage would in itself introduce a disturbing factor on account
of the loss of circulating fluid.

To make such measurements of any value, it is obviously necessary to
retain the peripheral resistance. For smaller vessels this can be done
by introducing in the course of the artery a long glass tube bent in the

206 *

RATE OF MOVEMENT OP THE BLOOD

207

shape of the letter U (Fig. 61 — No. 1), or by merely allowing the vessel to
bleed into a graduated tube and seeing how long the blood column takes
to travel from one end to the other. This method is of considerable
value in measuring the velocity of floAV from small vessels such as the
veins coming from glands and muscles. For larger vessels a so-called
stromuhr is employed. There are numerous forms of stromuhr; that
shown in the diagram (Ludwig's) (Fig. 61 — No. 2) consists of two glass
bulbs united above, and connected below with tubes that open flush with
the surface of a circular platform of brass. This is pivoted at its center
with another similar platform also having flush with the surface the open-
ings of two tubes which are connected below with the cut ends of the
artery or vein. In a certain position of the upper platform, the tubes
from the artery or vein are exactly opposite those of the bulbs, so that the

Fig. 61. — Forms of apparatus for measurement of blood velocities.

/. Volkmann's hemodromometer. The blood vessel is attached to the two short side tubes,
and according to the position of the stopcock, the blood flows either directly between them or
through the U-shaped glass tube.

2. Ludwig's stromuhr. The tubes on the lower end of each of the two glass bulbs pierce
a circular brass platform and end flush with its surface. This platform pivots at its center on
a similar lower platform with two openings connected with the tubes that lead to the blood
vessel.

blood can flow through the bulbs from the one end of the blood vessel to
the other. To use the instrument the proximal bulb is filled with oil and
the peripheral one with physiological saline. The clip is then removed
from the artery or vein and the blood flows in and displaces the oil, which
in turn displaces the saline into the peripheral end of the blood vessel.
When the blood has risen to a mark on the tube joining the two bulbs, the
instrument is rapidly rotated so that the oil is brought back again into the
proximal position, the rotation being effected so quickly that there is no
distinct interruption in bloodflow. The operation is repeated in this way
for a given period of time. Counting accurately the number of revolu-
tions, then multiplying the number of revolutions by the capacity of the

208 THE CIRCULATION OF THE BLOOD

bulbs, we get in cubic centimeters the amount of blood that has flowed
through the instrument in a definite unit of time. This gives us the vol-
ume flow and, if the result is divided by the cross section of the vessel in
square centimeters, we obtain what is known as the mean lineal velocity.
Many modifications have been made of this instrument, but it is unneces-
sary to go into them here.

The general result of such measurements has been to show that the
lineal velocity is inversely proportional to the cross section of the ves'sel
at the point of observation. It is obvious that the volume of blood
flowing out of the heart to the aorta in a given time is exactly equal
to that flowing into it by the vena cava, and likewise that the volume
flowing into an organ is exactly equal to that which flows out. Conse-
quently the lineal velocity will be inversely proportional to the sec-
tional area of the vessel. The principle is the same as that which gov-
erns the velocity of flow of a stream: when the bed is narrow, the cur-
rent is swift, but it becomes sluggish when the bed is wide. If the
arteries were of the same caliber as the veins, the mean velocity of the
bloodflow through the two would be the same, but actually it is much
greater in the arteries because the lumen of these at a given point in the
circulation is only from one-third to one-half that of the corresponding
vein.

It must be understood that we are dealing above with the mean
velocity in a unit of time, and that there must be considerable alteration
with each systole and diastole, constituting the velocity pulse (page 200).
The degree of this alteration with each velocity pulse is much less at
the periphery of the circulation than near the heart. As the periphery
is reached, the flow becomes more uniform. It must further be .re-
membered that, although the mean velocity depends essentially upon
the area of the vascular bed, yet it is subject to considerable variations
as a result of changes either in the force or rate of the heartbeat or
in the facility of outflow from the ends of the arterial system — that is,
changes in peripheral resistance.

It is usually stated that the mean lineal velocity in the carotid artery
is about 300 millimeters per second; and in the jugular vein, about 150
millimeters; whereas in the capillaries, where the total area of the
vascular bed has become enormously increased, being perhaps some 800
times that of the aorta, the velocity of flow is only about half a milli-
meter per second.

MASS MOVEMENT OF THE BLOOD IN A VASCULAR AREA

Methods. — In considering the bloodfloiv or mass movement of the l)lood
in the different regions of the body, it is usually more practical to

RATE OF MOVEMENT OP THE BLOOD 209

measure, not the mean lineal velocity of the inflowing and outflowing
blood, but rather how many cubic centimeters of blood are traversing
the part per 100 grams of organ or tissue per unit of time. Such meas-
urements may be made in a variety of ways. If there are but one artery
and one vein to the part, the stromuhr may of course be employed, and
it may be inserted in either .the arterial or the venous circuit. For
measuring the mass movement of blood through such large viscera as
the liver, this is indeed the only method that can be employed. The
stromuhr is inserted either in the course of the portal vein and he-
patic arteries, or, better still, in the vena cava just below the openings
of the hepatic vein, the vena cava being shut off for a moment between
the liver and the heart, and the blood, as it flows from the hepatic vein,
allowed to collect in the stromuhr. For other organs and tissues, how-
ever, methods which do not involve any interference with the blood
vessels may be employed. One of these is the so-called plethysmographic
method of Brodie. An organ, such as the kidney, is enclosed in a plethys-
mograph (see page 235), and while a record of its volume is being
inscribed on a quickly revolving drum, the vein is suddenly clamped,
with the result that the kidney volume expands in proportion to the
mass of blood flowing into it. When the expansion has reached a cer-
tain degree, the clamp is removed and the bloodflow allowed to pur-
sue its course. It is then an easy matter, by graduating the plethys-
mograph, to determine how many cubic centimeters of blood must have
flowed into the organ in a given time. To avoid serious local asphyxia
in the tissue, the clamp must be applied to the vein for only the briefest
period of time. This method may also be employed for measuring the
bloodflow through the extremities. Thus, if the arm is enclosed in the
plethysmograph (Fig. 62) and a band encircling the arm above the
plethysmograph is tightened so as to constrict the veins but not the ar-
teries, the rate at which the volume of the arm within the plethysmograph
expands will correspond to the rate at which blood is flowing into it
(Hewlett).

For the purpose of measuring blood flow through the upper or lower
extremities, a much more serviceable clinical method is that of G-. N.
Stewart. This depends on the principle that, provided the blood passing
from the thorax to the hands or feet is of constant temperature, the
rate at which heat is dissipated from the hands or feet will be directly
proportional to the rate of movement of the blood through these parts.
Fortunately for the method, the hands particularly, but also the feet,
are more or less perfect radiators — at least they are to this extent, that
if the temperature in their environment is not much lower than the
temperature of the blood, then while this is traversing the part, it will

210

THE CIRCULATION OF THE BLOOD

lose heat to the environment until the outflowing, or venous blood, is at
exactly the same temperature as the environment; for example, if the
hand is placed in water that is a little cooler than that of the blood,
and the temperature of the blood in one of the large veins of the hand
is measured, it will be found to be the same as that of the water in the
water-bath.

To measure the rate of flow, therefore, we must ascertain: (1) how
much heat has been given out by the part to the water surrounding it
in a given time, and (2) the difference in temperature of the inflowing
(arterial) and outflowing (venous) blood. We measure the amount of

Fig. 62. — Plethysmograph for recording volume changes in the hand and forearm. By observ-
ing the rate with which the volume increases when the arm is compressed, the mass movement of
the blood can be determined. (From Jackson.)

heat given out to the water in calories, a calorie being the amount of
heat required to raise the temperature of 1 c.c. of water from 0° C.
to 1° C. Suppose, for example, a hand were placed in 3,000 c.c. of
water at 33° C., and that after ten minutes the temperature had risen
to 33.5° C., then the amount of calories given out would be 3,000 x 0.5=
1500. Since calories equal cubic centimeters multiplied by change in
temperature, it follows that if we divide the figure representing them by
the actually observed difference in temperature between inflowing and
outflowing blood, the result must equal the number of cubic centimeters
of blood that has flowed through the part. The temperature of the in-
flowing blood has been found to be practically identical with that of the

RATE OF MOVEMENT OP THE BLOOD 211

mouth under the tongue; whereas of course the temperature of the venous
blood, as already explained, is equal to the mean temperature of the
water during the time that the hand was immersed in it. Further de-
tails of the technique of this method will be found elsewhere, but it may be
said here that it is extremely simple and accurate, and that it requires
nothing more than (1) an accurate thermometer ranging between about
25° C. and 50° C., with a scale so drawn out that readings can be made
to M.OO of a degree, and (2) a well-constructed vessel of about 3,000
c.c. capacity, with double walls, the space between them being packed
with some heat-insulating material such as ground cork.

Results. — Regarding the results obtained with these methods, it has been
found that the blood supply for each 100 grams of tissue per minute in the
viscera, as measured by the stromuhr method, is about as follows: stomach,
21 c.c. ; intestine, 71 c.c.; spleen, 58 c.c.; liver, arterial, 25 c.c.; liver,
venous, 59 c.c.; liver, total, 84 c.c.; brain, 136 c.c.; kidney, 150 c.c.; thy-
roid gland, 560 c.c. The large blood supplies of the thyroid gland and
of the kidney are the most striking results of these observations.

By the use of the calorimeter method the bloodflow through the hands
and feet of a healthy young man has been found to be about 13 grams
per 100 c.c. of hand per minute for the right hand, and about half a
gram less for the left. The footflow is only about one-third to one-half
that of the hand per 100 c.c. of tissue — a difference which is largely
owing to the greater proportion of skin and the smaller proportion of
bone in the hand. The average footflow or handflow for a given indi-
vidual under ordinary conditions is remarkably constant from time to time,
but it is extraordinarily sensitive to changes in the temperature of the
environment in which the subject has been living for some time previous
to the measurement. In one individual, when the room temperature was
20° C., the flow in the right hand, expressed in grams of blood per 100
c.c. of hand or foot, was 10.1; when it was 22.8° C., the flow was 12.8;
when it was 25° C., 12.1; when it was 30° C., 18.5. On account of the
influence of temperature on the flow, it is extremely important that the
measurements should be made in a small room the temperature of which
is kept constant, or if it must be made in the wards, the bed should be sur-
rounded by curtains. The measurements made on the hands of dispensary
patients shortly after coming in from outside air are very likely to be
fallacious. The importance of making such bloodflow measurements in
the clinic will be alluded to later.

Of course the measurements made by the above method in man tell us
only the rate of flow in the periphery of the body, and furnish us with no in-
formation regarding the flow of blood through the viscera. It is, how-

212 THE CIRCULATION OF THE BLOOD

ever, a well-established fact that the bloodflow in the central part of the
circulation is more or less reciprocal with that at the periphery, an
increase in the one place being accompanied by a corresponding de-
crease in the other.

The Visceral Bloodflow in Man

The visceral bloodflow in man can be measured indirectly in the case
of the lungs, either, (1) by finding the quantity of oxygen absorbed by the
blood during an interval of time that is less than that required for the
blood to travel once round the circulation (60 seconds) and comparing
this with the oxygen content of samples of arterial and venous blood, or (2)
by causing a person to breathe a known quantity of nitrous-oxide gas and
then finding how. much is taken up by the blood in the lungs. In the for-
mer method the difference in oxygen percentage between arterial and
venous blood will be less for a given absorption of oxygen from the alveoli
the more rapid the circulation of blood through the lungs; in the latter
method, the absorption of a given amount of nitrous oxide will be pro-
portional to the rapidity of the bloodflow. Obviously these estimations
must be made only over periods of time, less thai; that taken for any of
the blood to complete one circuit of the circulation.

Since it is likely that such measurements will find some application in the study
of cardiovascular disease, it may be well to indicate briefly how they are carried out.
In the oxygen absorption method, the amount of this gas that is absorbed from the
lungs in one minute is determined by analysis of inspired and expired air. The ar-
terial blood is considered as saturated with oxygen, and the percentage of this gas in
the venous blood (entering the lungs) is computed by using the dissociation curve.
Suppose 1,000 c.c. of t>2 was absorbed in one minute* and that the arterial blood con-
tained 10 per cent more O2 than the venous, then, since each 100 c.c. of blood carried
away 10 c.c. of gas it would take 10,000 c.c. to carry away the 1,000 c.c. of O actually
absorbed; and suppose the pulse to be 80 per minute then, with each heart beat

10,000

= 125 c.c. of blood must have flowed through the lungs. In the nitrous oxide

80

method1** the' person inspires a deep breath of a mixture of this gas and oxygen from a
meter, and after holding the breath for a few seconds (to allow the gas to mix uni-
formly with the alveolar air) he expires sufficiently to bring the lungs to their mid
position and again holds the breath for about 30 seconds, after which he finally expires
forcibly. Samples of the expired air are taken from the last portions of the two expira-
tions, and the percentage of nitrous oxide in them determined. From the percentages
of nitrous oxide found in the two samples, the amount of the gas in the air of the lungs
at the beginning and at the end of the period can be estimated. Suppose that 55 c.c.
N O was found to be absorbed in 0.327 minutes, that the percentage of N O is 11.08
then, since the absorption coefficient of N^O in blood at 37 °C is 0.405 (i. e., 1 c.c. of
blood dissolves 0.405 c.c. NoO at 37°C., Krogh and Lindhurd the amount of blood re-

*The average consumption of an adult at rest is only about 230-250 c.c. of Oo, the above value
of 1,000 c.c. being however observed during muscular exercise.

fcATE OF MOVEMENT OF THE BLOOD 213

55

quired to absorb 55 c.c. is --— — -— -———1.230 c.c. (1.23L.) or in one minute

U.4UO X 11, Uo X 1UU

1.230

= 3.75 liters.

0.327

The methods are admittedly only approximate, but the results are of
much interest, mainly because' of the indication they give us as to the
amount of blood pumped out by the ventricle with each heartbeat, or
during a given period of time. The results have been found to vary
considerably ; thus, Krogh and Lindhard45 give the output of blood per
minute as between 2.3 and 8.7 liters, which would correspond, at a
pulse rate of 70, to an output per heartbreat of from 40 to 120 c.c. An
immediate and very marked increase has been found to occur during
muscular work. By comparing the bloodflow through the hand with
that through the lungs, an estimate can be formed in a given individual
as to the relative magnitude of the peripheral and visceral moieties of
blood. Interesting results, which will be referred to later, have been
obtained from such measurements.

The Work of the Heart

Meanwhile it is of interest to note that we may calculate from the
ventricular output of the blood the amount of work that the heart is doing
in maintaining the circulation. Of course the calculation is again only
approximate, since we have to assume certain figures. If we assume that
in a 70-kilogram man the quantity of blood is 4,200 c.c. (see page 85),
and that it takes about one minute for all the blood to complete a cir-
culation, then the work performed by the left ventricle in one minute
will be equal to that done in raising the above quantity of blood to a
height corresponding to the mean pressure in the aorta. If we take this
pressure as 130 millimeters of mercury, which would correspond to a
column of blood 1,755 meters high (13.5x130=1755 mm. blood, or 1.755
meter), the work done by the left ventricle would be 1.755x4.2=7.37
kilogram-meters in one minute, or in twenty-four hours roughly about
10600 kilogram-meters. The work done by the right ventricle is probably
about one-third that of the left, this being about the ratio of the pres-
sures in the two chambers. The total work of the two ventricles is there-
fore about 14000 kilogram-meters. This represents an enormous amount
of work; indeed it has been computed that it is sufficient to raise a man
of 70 kilograms to about twice the height of the highest skyscraper in
New York. The work thus expended in forcing the blood through the
capillaries becomes converted by friction in the small blood vessels into
heat, the heat equivalent of the above amount of work being roughly
about 350 calories (see page 571).

214 THE CIRCULATION OF THE BLOOD

THE CIRCULATION TIME

The circulation time, or the time taken by a drop of blood to travel
between two points in the circulation, can be determined in laboratory
animals by a variety of methods, all depending on the principle of seeing
how long it takes for a drop of some substance injected into an artery to
appear in the corresponding vein. For example, to determine the time
taken for a drop of blood to pass from the jugular vein into the carotid
artery in a rabbit, a solution of methylene blue in isotohic saline is in-
jected into the former vessel and the moment of its appearance through
the walls of the artery determined by a stop-watch. If the walls are too
thick to a'dmit of the employment of this method, a strong solution of
sodium chloride may be substituted for the methylene blue, and the mo-
ment of its appearance at another point of the circulation determined by
observing the electrical conductivity of the vessel. Since the con-
ductivity of a blood vessel depends partly on the concentration of elec-
trolytes in the blood flowing through it, the moment at which the salt
solution appears will be indicated by a change in electrical resistance
(G. N. Stewart).

By such methods, it has been found that the time for the pulmonary
circulation is very short compared with that of the systemic circulation.
In a rabbit it is usually a little less than four seconds; in an average-
sized dog of about 12 kilograms, it is about eight seconds; and in man
it is computed to be about fifteen seconds. On the other hand, the cir-
culation time in such viscera as the spleen and kidney is relatively long,
and more susceptible than that of the lungs to different conditions of
temperature. In a dog in which the pulmonary circulation time was
about 8.5 seconds, that of the spleen was about 11 seconds, and of the
kidney about 17.5 seconds. The shortest circulation time of all is of
course that in the coronary artery, but that through the retina can not fall
far behind it.

To determine the total circulation time, we must know: (1) the average
amount of blood passing by each part in -a given time, and (2) the average
circulation time of each part. From such computations, which however
are obviously subject to considerable error, it has been reckoned that the
total circulation time in man must lie somewhere between 1 and 1.25
minutes.

MOVEMENT OF BLOOD IN VEINS

Before leaving this part of our subject, a few words may be said con-
cerning the forces concerned in the movement of blood in the veins from

RATE OF MOVEMENT OF THE BLOOD 215

the capillaries to the heart. By the time that the venules are reached,
owing to friction in the capillaries the blood will have lost most of the
force imparted to it by the heart action. Nevertheless, this remaining
vis a tergo must be considered as the basic cause for the movement of
the venous blood near the periphery. As the venules get larger, two
other factors come into play: the massaging influence of the muscles,
and the valves of the veins. By the movements of the muscles the veins
which lie between will be rhythmically compressed, and this will tend to
cause the blood to be moved forward and backward in them, the back-
ward movement being however prevented by the operation of the valves.
When the tonicity of the muscles is subnormal, as in conditions of ill
health, the absence of this massaging action permits the blood to stag-
nate in the veins> especially in those of the lower extremities in upright
animals, with the consequence that the veins become dilated, particularly
just above the valves, thus causing the condition known as varicose veins.

As the thorax is approached, two other factors become operative: the
aspirating influence of the thorax during inspiration, and the negative
intraventricular pressure (see page 152). There is no doubt that the
former of these is of considerable importance in maintaining the venous
return near the heart, for although the change of pressure induced by in-
spiration amounts to only 5 millimeters of mercury, yet it acts so
slowly that it produces a considerable influence. The aspirating effect
of the ventricle at the beginning of diastole is, however, of no sig-
nificance in attracting blood to the heart, for although, as we have seen,
it may be considerable, yet it lasts for so short a time that it could not
overcome the inertia of the column of blood in the vena cava. Even if
the negative pressure did last for a longer period, it could not attract
more than a small amount of blood, because it would cause the thin
collapsible walls of the veins to come together and thus block the pas-
sage towards the heart.

CHAPTER XXV

THE OUTPUT OF THE HEART IN RELATION TO THE VENOUS
INFLOW, CHANGE OF RATE, ETC.

The Output of the Heart per Beat

In the heart-lung preparation described on page 163 it is possible to
make accurate comparison between the output of the heart and such con-
ditions as its rate of filling during diastole, the frequency of its beat and
the nutritional condition of its musculature. Starling and his pupils have
in this way thrown much light on the methods by which the cardiac out-
put is adjusted so as to meet the ever-varying demands of the body for
blood. The fundamental principle which determines cardiac output may
be stated thus: the force with which the heart contracts during systole
varies directly with its volume at the end of diastole. Now, since the
heart does not exhibit any tone in diastole (see page 220), it is plain that
the rate of venous inflow must be the main factor determining the diastolic
volume, a secondary one being the arterial pressure. When the venous
inflow is rapid, the heart becomes dilated as far as the pericardium will
permit, and it contracts to its full force ; when the inflow is slow, it is im-
perfectly dilated when contraction supervenes, and the beat is feeble.
This is tlie law of the ~keart, and it is rigidly obeyed in the case of the
cold-blooded heart, which is demonstrated by the fact that when the per-
fusion fluid flowing into the venous end is suddenly increased by a cer-
tain amount, the ventricular output with the next beat is proportionately
augmented. If a record be taken of the volume of the heart, this will be
found to be unchanged at the end of systole, though it has of course
become greater during diastole because of the increased filling.

In the warm-blooded heart, at least under the conditions of experimen-
tation (heart-lung preparation) there is some lag in the adaptation of the
strength of systole to diastolic filling; the law however, is ultimately
obeyed. This is well shown in the tracings in Fig. 63, in which C is a
tracing of the volume of the isolated heart (obtained by using a cardiac
plethysmograph), B.P. the arterial blood pressure, and V.P., the venous
blood pressure.50

It will be observed that when V.P. is suddenly increased the cardiac
volume immediately becomes greater (indicated by a general fall in the
level of C), and that, although the contractions of the ventricle also bc-

216

OUTPUT OF HEART AND VENOUS INFLOW

217

come more vigorous, they do not do so with sufficient promptitude to main-
tain the systolic volume constant. In other words the output. of the heart
does not at first keep pace with the inflow, so that the mean volume of
the heart becomes progressively greater, and it is only ofter some mo-
ments that the contractile power increases sufficiently so that the output
equals the inflow and the mean volume recovers somewhat and then be-
comes steady. It is evident that precisely the same adjustments will oc-
cur when the arterial pressure is suddenly raised; the first beat following
the rise in pressure will be insufficient to lift all the extra load of blood

VP

Fig. 63. — Kffcct of alteration in venous supply on volume of heart. Read from left to right.
(Patterson, Piper and Starling.)

opposed to it in the aorta, so that some will remain in the ventricle when
diastole sets in; this will entail greater diastolic filling, the ventricle will
become dilated and iir obedience to the law of the heart the systolic dis-
charge will be increased. Dilation of the heart is therefore the first step
in the adjustment which it undergoes in response to an increase in venous
inflow or to higher arterial pressure, and the extent to which it may oc-
cur is considerable, being limited only by the pericardium. Indeed the
heart may entirely fill the pericardium, without there being any decided
increase in the output of blood with each beat, namely in cases where the

218 THE CIRCULATION OF THE BLOOD

venous or arterial pressure is high, and the cardiac musculature is not
sufficiently powerful to empty the ventricle completely; a similar state
of affairs will also exist when the aortic valves are incompetent.

The last statement in the preceding paragraph implies that the state
of the ventricular musculature must be an important factor in connection
with the law of the heart. Its degree of development, its nutritional con-
dition, and the presence or absence of fatigue, must greatly influence the
extent to which the ventricle is capable of obeying the law. When the
musculature is less powerful than normal, then, in order to increase the
output in proportion to a larger venous inflow, the heart must dilate more
during diastole, so as to bring about a sufficiently increased contraction;
when it is more powerful, as in hypertrophy, a small increase in the length
of the muscle fibers (i. e., a slight diastolic dilatation) will call forth a
sufficient contraction because of the cumulative effect on the larger number
of fibers.

The Reserve Power of the Heart. — These are the principles determining
the reserve power of the heart, and the practical question arises as to how
we are to know in man when this reserve has become used up. The most
useful method is by counting the pulse before and after exercise. When
the heart is well developed, as in a trained athlete, it is clear that the
increase in venous inflow which occurs during exercise (see page 219) will
stimulate the ventricle so that the output per beat exactly corresponds to
the inflow, and no increase in the frequency of the beats is required. But
when the musculature is feeble, as in a sedentary person, the dilatation
must become considerably greater in order to call out sufficient contractile
power, the output per beat only moderately increases and quickening be-
comes necessary if the minute volume is to be adequate to meet the in-
creased demands of the muscles for blood. When the reserve power of the
heart is very low, even extreme dilatation during diastole may be insuffi-
cient to stimulate contractions that are powerful enough to empty the
heart, blood is therefore left over in it at the end of systole, and when the
venous blood becomes superadded during diastole, extreme dilatation oc-
curs, and the beat becomes very rapid in the attempt to maintain an
adequate output.

The Effect of Alteration in Rate of Heart Beat on Output of Blood

At this stage it is important to analyze the effect on the output of the
heart per minute (the minute-volume) brought about by increase in the
rate of beat. When the venous inflow is slow, the ventricle does not dilate
to its full capacity in diastole, and acceleration of the beat does not im-
prove the output in a unit of time ; when the inflow is more rapid it dilates

OUTPUT OF HEART AND VENOUS INFLOW 219

to the maximal extent just before systole supervenes, so that more blood is
discharged than in the first case ; but, as in the first case, acceleration does
not improve the output ; when, 'on the other hand, the inflow is still more
rapid, the ventricle is practically filled to its limit some time before di-
astole ends and the output is also increased by acceleration. In other
words, when there is no so-called period of diastasis following active di-
astole acceleration of the beat will not increase the output in a unit of
time.

The condition in which increased heart rate occurs with greatest cer-
tainty is muscular exercise. The initial quickening is due to impulses
traveling to the cardiac centers in the medulla from centers in the cere-
brum (see page 229), and it is clear that should no change occur in the
rate of venous filling of the heart, the acceleration would be of no value in
increasing the cardiac output. But the venous inflow increases because
of the muscular activity, the diastolic filling is more complete, and the
systolic discharge greater. As the muscular activity continues, the heart
rate continues to accelerate, and although increase in the temperature and
in the CH of the blood (see pages 162 and 168) may be partly responsible
for the change, another, if not more probable, cause is increase in venous
pressure (Hooker56 and Bainbridge). This increased pressure, probably
by creating a slight tension on the walls of the ventricle (right) during
diastole, sets up afferent impulses which act on the vagus and sympathetic
cardiac centers.

These most important principles governing the cardiac output have been
admirably summed up by Bainbridge as follows : ' ' The minute volume of
the heart is the product of its output per beat and of the pulse rate; its
output per beat is the resultant of the rate of venous inflow, of the con-
tractile power of the heart and of the duration of diastole. It is clear that
an intimate relationship must exist between the pulse rate, the venous
inflow and the contractile power of the heart, if the optimal efficiency of
the heart as regards its minute volume is to be maintained."

Finally it should be pointed out that the maximal pulse rate that can
ultimately be attained by muscular exercise is very much the same in dif-
ferent individuals; it rarely exceeds 160 beats per minute. The maximal
minute volume, on the other hand, varies considerably for different indi-
viduals, because of variability in the capacity of the heart to increase its
output per beat. This adaptation depends, of course, on the nutritional
condition and the degree of development of the cardiac musculature. In
a trained athlete, for example, the heart does not become accelerated nearly
so rapidly as in an untrained person, because a slight increase in the
venous pressure calls forth a systolic discharge which is adequate to empty
the ventricle completely.

220 THE CIRCULATION OF THE BLOOD

The Tone of the Heart

Since the diastolic volume of the heart has been found to become altered
under certain conditions, such as a change in CH of the blood, it has been
common to assume it possesses tone like that exhibited by skeletal muscle.
This however is not the case, for there is but one thing which determines
the distensibility of the heart during diastole, namely the pressure under
which the blood is flowing into it from the great veins. When this is con-
stant, the ventricle always dilates to the same degree. Changes in CH act
solely by altering the duration of systole and diastole, an increase pro-
longing the latter and a decrease, the former.

CHAPTER XXVI
THE CONTROL OF THE CIRCULATION

The available blood in the body is parceled out to the various organs
and tissues according to their relative activities, and, since these vary
from time to time, the question arises as to the nature of the mechanism
or mechanisms involved in bringing about this adjustment. Two possible
methods of increasing the supply are: an increase in the mass movement
of all the blood in circulation, and a reciprocal adjustment of the resistance
to the flow in different vascular areas brought about by vasodilatation
in one and vasoconstriction in others. Both of these methods might
operate together.

Two agencies can be thought of as responsible for bringing about
the above changes: (1) chemical substances or hormones, present in
the blood, and (2) the nervous system.

The influence of chemical substances, or hormones (page 766), in the
control of the circulation is undoubtedly an important one, and of those
known at the present time two groups may be mentioned: (1) sub-
stances which alter the hydrogen-ion concentration of the blood, and
(2) so-called pressor and depressor substances, produced either by duct-
less glands, such as the adrenal, or by the activity of tissues. An in-
crease in hydrogen-ion concentration of the blood not only affects the
heartbeat (see page 168), but causes a marked dilatation of the blood
vessels, so that both the central and the peripheral changes will be such
as to encourage an increased flow of blood through the active organs
or viscus. Thus, during muscular activity of the leg muscles there will
be a tendency to an increase in the hydrogen-ion concentration of the
blood as a whole, resulting in a greater cardiac activity and a greater
outrush of blood through the aorta, and at the same time the vessels of
the acting muscle will have become especially dilated because of the
production by the active muscles either of lactic acid or of carbonic acid.
The active muscle also produces such substances as imidazole, which
have a powerful vasodilating action. Such substances are sometimes
called depressor.

Though the hormone control of the circulation is undoubtedly of great
importance, it is probably much less so than that exercised through the
nervous system, and here again the control is centered partly in the

221

THE CIRCULATION OP THE BLOOD

heart and partly in the peripheral resistance. The nerve control of the
heart is effected through the vagus and sympathetic nerves, and that
exercised on the blood vessels, through the so-called vasoconstrictor and
vasodilator nerves.

The activity of the nerve centers from which the cardiac and vaso-
motor impulses are discharged is controlled by afferent impulses com-
ing from the various regions of the body. When a gland becomes more
active, we must suppose that stimulation of the sensory fibers has caused
afferent impulses to be transmitted to the cardiac and vasomotor centers,
upon which they act in such a way as to produce increased heart ac-
tion and a local dilatation of the blood vessels of the active gland, with
perhaps a constriction of the blood vessels of the rest of the body.

THE NERVE CONTROL OF THE HEARTBEAT

The Vagus Control

With regard to the control exercised through the vagus nerve, we have
already seen that the cutting of the two nerves in the neck causes the
heart to quicken and the arterial blood pressure to rise, whereas a
stimulation of the peripheral end of the nerve causes the heart to be-
come slowed, if not stopped altogether, and the blood pressure to fall.

For the more detailed investigation of the nature of the vagus control
of the heart, it is necessary to observe the exposed heart itself — an ex-
periment which, for obvious reasons, can be most simply performed in
a cold-blooded animal, such as the frog or turtle, but which can also
be performed in mammals provided artificial respiration is maintained.
The general effect of the vagus in both groups of animals is the same,
although apparent differences may exist on account of the relative im-
portance of the different parts of the heart in the origination and propa-
gation of the heartbeat.

The Cold-Blooded Heart. — If the vagus nerve on the right side in the
turtle (the left nerve is usually more or less inactive in this animal) is
stimulated with a very feeble electric current, while simultaneous records
are being taken of the contractions of the auricles and ventricles in the
manner shown in the accompanying tracing (Fig. 64), it will often be
found that there is a weakening of the auricular beats without any change
in those of the ventricle. If the strength of stimulus is somewhat in-
creased, the auricular beat, besides becoming weaker, will also become
slower, but meanwhile the ventricular, although also slower, may become
distinctly stronger. At first sight this result may be a little confusing,
because it would seem to indicate that the vagus nerve weakens the auricu-

THE CONTROL OF THE CIRCULATION 223

lar, but strengthens the ventricular beat. It is clear, however, that the
strengthening of the ventricular* beat is merely due to the fact that the
cavity has become better filled with blood during diastole as a result of
the slowing of the auricle. These results indicate, then, that with weak
stimulation the vagus exerts its direct influence only on the auricle. If

Fig. 64. — Simultaneous tracings from auricle and ventricle of turtle's heart. Between the crosses
the vagus was stimulated, with the effect that the auricular beat diminished in force but not in
frequency, while the ventricular beats were practically unaffected. (From Howell's Physiology.)

the stimulation is strong enough both auricles and ventricles cease to
beat altogether, and if the stimulus is maintained, the inhibition may go
on for a very long time (Fig. 65).
Usually, even though the stimulus is maintained the heart begins to

Fig. 65. — Effect of vagus stimulation on heart of turtle. Note the after effect of augmentation.

beat again after a time, at first only occasionally but gradually more
rapidly. This is known as escapement, and it indicates that the energy
pent up in the heart during the vagus inhibition has at last overcome
the inhibiting influence of the nerve, which is meanwhile becoming
fatigued. All of these results could be quite satisfactorily explained on
the assumption that the action of the vagus is confined to the sinus,

224

THE CIRCULATION OF THE BLOOD

which, it will be remembered, dominates the beat in the rest of the
heart. There is evidence, however, that the vagus also directly affects
the rhythm of the ventricle. It may be stated as a general conclusion
from these results that the influence of the vagus upon the heartbeat is
chiefly centered upon those parts of the organ in ivhich the rhythmic power
is most highly developed.

Besides affecting the rate and strength of the heartbeat, the vagus also
exercises a control on the conductivity of the cardiac muscle. Thus, if
a partial block is instituted in the turtle heart by applying a clamp be-
tween the auricles and ventricles, stimulation of the vagus enfeebles the
auricular beat and may also cause a complete heart-block as shown in
the tracing reproduced in Fig. 66. It is important to point out here,
however, that under certain conditions the vagus may appear to increase
rather than decrease the conductivity of the tissue in the auriculoven-

Fig. 66. — Tracing to show that vagus stimulation may diminish transmission from auricles to
ventricles. It shows the effect of stimulating the left vagus on partial (2/1) block produced on
heart of turtle by application of clamp at auriculoventricular junction. Stimulation at ^ depressed
the conductivity and weakened the auricular contractions (lower tracing) without slowing their
rate. The result was an increase in the degree of block with cessation of ventricular contractions
(upper tracing). Initial auricular rate = 35 per minute. (From Carrey.)

tricular junction; for example, it has been observed in the turtle heart
that when a clamp is so tight as to produce complete block — that is to
say, to render the ventricle inactive while the auricle is still beating at
the usual rate — stimulation of the vagus, besides causing the auricles to
become distinctly slowed, may at the same time cause the ventricles to
respond to the auricular beats. This result is probably due to the better
chances of slow beats getting through the junction than those which are so
frequent as to crowd one another on the narrow bridge which the con-
stricted tissue offers to their passage (Fig. 67).

Very important work was contributed in this field by G. R. Mines13
shortly before his lamentable death. He found that the local applica-
tion of atropine to the sinus eliminates the effect of stimulation of the
(intracranial) vagus on the rate of the heartbeat, while the effect on the

THE CONTROL OF THE CIRCULATION

225

auriculoventricular junction and on the ventricle remains. After the
atropinization, vagus stimulation* delays the transmission of beat from
auricle to ventricle and shortens the time of each beat in the ventricle.
It was further found that by the local application of atropine various
parts of the ventricle can be rendered irresponsive to the influence of
the vagus and the effects of this nerve on the form of the cardiogram
modified at will. These results have an important bearing in the in-
terpretation of the cause of the T-wave of the electro-cardiogram
which will be referred to later. Mines' results show that the proba-
ble explanation is that the T-wave is due to the greater duration of the
excitatory state at the base than at the apex, for by altering the relative
duration of this state at base and apex by the above methods, he could
cause the T-wave to appear or disappear.

The direct excitability of the heart muscle to external stimuli is also
depressed during vagus stimulation. This effect is, however, not evi-

Fig. 67. — Tracing to show that vagus stimulation may facilitate transmission from auricles to
ventricles. It shows the effect of right vagus stimulation on heart-block produced in the turtle by
a clamp. Upper tracing records ventricle; lower tracing, auricles. Weak faradization of the right
vagus nerve beginning at A affected the degree of block only at T , when a lengthened period
between auricular contractions caused a single ventricular contraction. At B stronger faradiza-
tion of the same nerve produced marked slowing of the auricles, in consequence of which the block
disappeared and the ventricles contracted after each auricular contraction. Block reappeared when
the rate again became rapid. Initial auricular rate = 36 per minute. (From Garrey.)

dent in the case of all hearts, but is seen in those of certain fishes (e. g.,
the eel).

The Mammalian Heart. — The action of the vagus on the mammalian
heart may be investigated either by exposing the heart and connecting
the auricles and ventricles with specially designed recording levers
(myocardiograph), or if we desire to study the influence on the heart as
a whole, by taking a blood-pressure tracing from one of the large arteries
by means of a spring manometer. The results are in general similar to
those observed on the frog or turtle heart, the main effects being de-
veloped on the auricle. Considerable differences are found in the effect
on the heart as a whole in different animals, particularly with regard to
the facility with which escapement occurs. In the dog when the vagus

226 THE CIRCULATION OF THE BLOOD

is continuously stimulated, the heart is likely to remain inhibited for a
long time, whereas in the cat the inhibition is very quickly broken into
by escapement. If the tracing is taken directly from the heart, it will
frequently be observed in the dog that, when the escapement occurs dur-
ing vagus stimulation it is only the ventricle that is beating, the auricles
still remaining inhibited.

If the stimulation of the vagus is discontinued after some time in an
animal whose blood pressure is being recorded, the pressure will not
only quickly recover, but will usually overshoot the normal level, mainly
because of the asphyxia which has been produced during the period of
inhibition. The asphyxia raises the hydrogen-ion concentration of the
blood and this stimulates both the vasoconstrictor center and the heart
action (page 168). The increased heart action is, also partly owing to the
fact that during vagus inhibition the beating power of the heart becomes
improved (page 230).

As an outcome of recent work,14 it has been shown that the right vagus
nerve acts mainly on the sinoauricular node, and the left vagus on the
auriculo ventricular bundle. This is in agreement with the observations
described above on the cold-blooded heart (page 222). Stimulation of the
right vagus always causes slowing and weakening of both the auricular
and the ventricular beats, but stimulation of the left vagus is sometimes
observed to have but little influence on the auricular beat, although it
may produce a condition of partial heart-block; or, if a clamp is ap-
plied to the auriculoventricular bundle so as to produce a partial heart-
block, then during stimulation of the left vagus, the block may become
complete. There is, however, a considerable overlapping of these in-
fluences, at least in the case of the left vagus, for this nerve also acts
considerably on the ventricle, influencing perhaps not so much the rate
as the force of the contraction. It has been found experimentally that,
in order to demonstrate the specific action of the left vagus on the bun-
dle, it is most suitable to study the relationship between auricular and
ventricular beats when the auricle is beating rapidly as during the
application of artificial (electrical) stimuli to it. Ordinarily the con-
traction produced by each stimulus passes into the ventricle, but during
stimulation of the left vagus it is found that every contraction does not
pass. These experiments raise the question as to what the influence of
either nerve may be in blocking impulses from the auricles to the ven-
tricles when auricular fibrillation is present. It might be expected that
the left vagus would prove more effectual in this regard, but actually it
has been found that both vagi have the same effect.

Tonic Vagus Action. — Impulses are constantly passing along the vagi
to the heart. On account of this so-called tonic action, the heart rate

THE CONTROL OF THE CIRCULATION 227

increases when the continuity of ,the vagus nerve is broken either by
cutting or by freezing a portion of nerve (Fig. 27). The effect is usually
inconspicuous when one nerve only is cut, but in most mammals it 'be-
comes quite marked when both are cut. Change in the heart rate pro-
duced by muscular effort is much more gradual in animals with marked
vagus tone, such as hunting dogs, than in those with little vagus tone, as in
domestic rabbits. The degree of vagus tone therefore bears a relation-
ship to the staying power of the animal for prolonged muscular effort.
It is usually ill developed in cold-blooded animals. It is quite marked
in the case of man, as is evident on observing the heartbeat before and
after giving a sufficient dose of atropine to paralyze the termination of
the vagus in the heart.

The exact location of the nerve cells that form the center of discharg-
ing impulses along the vagus fibers to the heart can not be made out
with certainty, but they are no doubt part of the great motor nucleus
(ambiguus), from which arise the fibers not only of the vagus but of
the glossopharyngeal nerve. The tone of this vagus center is almost
without doubt dependent upon the constant transmission to it along the
sensory or afferent fibers of impulses coming from various portions of
the body. According to the strength or number of these impulses, the
tone may be increased or diminished, thus altering the rate of the heart.
It is possible of course that the tone can be maintained, independently
of the afferent impulses, by the action on the center of chemical meta-
bolic products or hormones produced in the cells or carried to them in
the blood. We know at least that, like the respiratory center, that of
the vagus is excitable by such hormones as the hydrogen-ion concen-
tration of the blood. The tonicity of the vagus center is, however, mainly
dependent upon the passage to it of afferent impulses, and as evidence
for this conclusion may be cited the observation that, after section of
most of the afferent nerves to the medulla (as by cutting the spinal cord
high up in the cervical region), subsequent section of the two vagi does
not produce anything like the usual degree of change in the heart rate.

The Afferent Vagus Impulses. — The afferent vagus impulses may come
from practically any part of the body, having been first discovered by
the simple experiment of tapping the abdomen of the frog with the han-
dle of a scalpel, when slowing of the heart rate is observed. Cutting the
vagi abolishes the reflex. Similar cardiac inhibition is produced by me-
chanical stimulation of the tail or gills of an eel. In mammals stimula-
tion of the central end of any sensory nerve usually slows the heart,
though sometimes the opposite effect occurs. The pulmonary branches
of the vagus are particularly sensitive in producing reflex inhibition,
and distinct results are usually obtained: by stimulation of the termina-

228 THE CIRCULATION OF THE BLOOD

tions of the fifth nerve in the mucosa of the upper respiratory passages,
as by inhaling ammonia vapor; by stimulation of the sensory nerve end-
ings in the pharynx, as by swallowing; and of the mucosa of the larynx,
as when a substance is "swallowed the wrong way." The sensory
nerves of the abdominal viscera seem to be particularly active on the
vagus center, as is seen in irritation of the sensory nerves of the stom-
ach such as occurs in gastritis. Profound inhibition may also be caused
by violent stimulation of the mesentery, as from a blow on the abdo-
men, or by irritation of the sensory nerves of the intestine, either me-
chanical or because of disease. Another interesting illustration of affer-
ent vagus stimulation is obtained by pressure on the outer canthus of
the eye. This oculomotor vagus reflex, as it is called, is very marked
in some individuals.

Through which of these afferent paths It may be that the constant
stimuli are transmitted to the vagus center to enable it to maintain its
tone, can not be said, although it is very likely to be through the vis-
ceral nerves.

In considering the cause for an observed change in heart rate, we
must of course bear in mind the possibility that the action may have
occurred, not through the vagus center, but through the sympathetic
center. Thus, when the heart becomes quicker, it may be owing either
to diminution in the vagus tone or to an increase in the discharges
along the sympathetic nerve from the augmentor center. That such
reflex action through the augmentor center does occur under experi-
mental conditions has been clearly shown; for example, if both vagus
nerves are cut and the peripheral end of one of them stimulated mod-
erately, so as to hold the heart at about its normal rate, the stimulation
of certain sensory nerves may cause increase in the heart rate. Eeflex
sympathetic control of the heartbeat is however no doubt much less
important than control through the vagus center. When it does exist
it means that the actual rate of the heartbeat at any given -moment
must represent the algebraic sum of two opposing influences, with that
of the vagus preponderating. The advantage of such a double inner-
vation is that it insures prompter adjustment of the beat. If, for ex-
ample, for any reason quickening of the heart rate is necessary, it is
brought about most promptly if the vagus tone is diminished at the same
moment that the sympathetic tone is increased. Such reciprocal action
of antagonistic influences is the usual rule in the animal economy. Thus,
when the knee joint flexes, it does so not merely because stimulating
impulses are transmitted to the hamstring muscles, but also because at
the same moment inhibiting impulses are transmitted to the extensor
muscles (see page 915).

Left Ant. Caval vein .Right Ant Caval vein

Remnkfr //7J7JZ+- Preqanqlionic rreurtin
Ganglion in///////// ' /Postonnnlinmr

Postganglionic neuron

^Auricular sfeptum

^^$£^^yvpe™ngfrom /)

:^^^^^^/W5^a^/c/eyy/-^-5^ of

*^^> f^v**

Ventr/de

Ho oh from

Inf. Vena cava-

vonBezotd's Ga

in Auricular septum

'Bidder's

laaers udngnon

in auricula-ventricular junction

- ^Stimulating electrodes
0 ,„ in sino-auricular junction [Crescent]

Sympathetic fibres- (Jotted lines

Fig. 68. — Diagram to show the innervation of the heart in the frog or turtle. The electrodes
are represented as applied to the white crescentic line where they will stimulate some postganglionic
fibers. (From Jackson.)

THE CONTROL OF THE CIRCULATION 229

Several possibilities have to be kept in mind when we attempt to
determine the exciting cause for an observed change in the heart rate in
man. Thus, a slowing of the rate may be due to mechanical stimulation
of the vagus trunk, as in pressure on the nerves by a tumor or aneurism
in the neck. That such mechanical irritation may stimulate the vagus
is easily demonstrated in many individuals by applying pressure to the
vagus where it lies in the neck in front of the sixth cervical vertebra.
Such pressure sometimes produces so profound an inhibition of the heart
that temporary loss of consciousness occurs. It is often an unsafe ex-
periment to perform.

Change in the heart rate in man may be caused by direct stimulation
of the vagus center, as by the presence of a tumor or a blood clot in the
medulla, or by the action on the center of some unusual hormone in the
blood. A general increase in intracranial pressure also stimulates the
vagus center. The slowing of the heart which occurs in asphyxia might
be due either to the action of hormones (hydrogen-ion concentration)
in the blood as the result of the asphyxia, or to the increased intra-
cranial pressure. That the latter is the more important cause is shown
by the fact that, if the rise in blood pressure is prevented by connecting
an artery with a mercury valve, — that is, with a tube dipping into a
cylinder of mercury to a depth corresponding to the normal blood
pressure, so that when the pressure tends to rise the blood escapes, —
the slowing of the heart is not observed. The excitability of the afferent
vagus fibers in the lungs is greatly increased during the earlier stage
of chloroform administration.

Finally it should be pointed out that, although wre have no voluntary
control of the activity of the vagus center, its activities are subject
to great variation as a result of impulses transmitted from centers higher
up in the cerebrpspmal axis. It is by the operation on the vagus center of
such impulses that changes in heart rate occur during emotional ex-
citement, fright, etc. The increased heart rate in muscular exercise is
probably dependent upon a number of causes, such as the irradiation of
the motor impulses on to the cardiac centers (see page 430), the rise in
temperature and changes in the hydrogen-ion concentration of the blood,
etc.

Mechanism of Action of Vagus on the Heart. — Physiologists have nat-
urally been curious as to the exact manner in which the vagus nerve
brings about inhibition of heart action. Similar inhibition as a result
of stimulation of efferent nerves exists in the case of the dilator fibers
to the blood vessels (page 239) and the sympathetic nerve to the intes-
tine (page 501). Inhibition of voluntary muscles can be produced only
through the central nervous system by stimulation of afferent nerves

230 THE CIRCULATION OF THE BLOOD

(page 915). It is not the nerve fibers themselves that are responsible
for the inhibitory effect, for it has been found that if the peripheral
end of a cut vagus nerve is connected with the central end of one of
the anterior roots of the cervical portion of the spinal cord, the axons
of the latter when they grow down into the vagus trunk during the
regeneration which follows, stimulation of the regenerated fibers will
still produce inhibition of the heart. The nature of the fibers can not
therefore be the factor upon which the inhibiting influence of the vagus
is dependent. This leaves the terminal apparatus of the vagus fibers in
the heart as the structures in which the stimulus conveyed to them is
rendered inhibitory in nature.

There has been considerable speculation as to what kind of change
must be occurring in the heart in order to cause the inhibition, but
practically nothing that is definite is known. One significant fact, how-
ever, is that the electrical current led off through nonpolarizable elec-
trodes from two portions of the auricle one of which is injured, does not
take the same direction when the vagus nerve is stimulated as that which
it takes when the motor nerve of a similarly observed muscle is stimu-
lated. A positive, instead of a negative variation is observed. Now,
since a negative variation is always accompanied by active chemical
breakdown changes occurring in the muscle to supply its energy of
contraction, it is assumed that the positive variation accompanying stim-
ulation of the vagus must indicate that, instead of a katabolic process,
a building up, or anabolic process, is being excited. This conclusion
would fit in perfectly with the well-known fact that, after the heart has
been held in standstill for some time by vagus stimulation, the beats are
stronger after the inhibition has passed off than they were before. The
vagus seems to have a conserving influence on the heart. During the
inhibition produced by it energy material is apparently stored up in the
heart, so that when the beat is reestablished it is stronger than before.

The Manner of Termination of the Vagus Fibers in the Heart. — This
subject is of considerable pharmacological and therefore therapeutic in-
terest. In approaching the problem it must be remembered that the
vagus fibers belong to the so-called bulbar autonomic system of nerves
(see page 894). They are therefore fibers which have cell stations situ-
ated near their peripheral termination — cell stations, that is to say, in
which ganglionic medullated fibers, by forming synapses around nerve
cells, become connected with postganglionic nonmedullated fibers. The
existence of ganglia in the heart, particularly of the frog, has been
known for a long time. These ganglia are located at the sinoauricular
junction, at the interauricular septum, and in the ventricle near the

THE CONTROL OF THE CIRCULATION

231

auriculoventricular junction. Th'e function of the ganglia is to serve as
cell stations on the course of the vagus nerves. (Fig. 68.)*

Nicotine is a drug which in certain concentrations, if applied locally
to sympathetic ganglia, specifically paralyzes the synapses between the
ends of the preganglionic fibers and the cells from which the post-
ganglionic fibers arise. If this drug is applied in a 1 per cent solution
to the heart, stimulation of the vagus trunk no longer produces inhibi-

mmmrnT

fl/VAMJ

•A a i\ l\ A

Fig. 69. — Frog heart tracing showing the action of nicotine. The vagus trunk was stimulated
as indicated. In the normal (lower) tracing inhibition occurs hut after nicotine (second tracing)
no inhibition follows. Stimulation of the crescent in the next two lines still is followed by inhibi-
tion. The final effects of the drug are shown in the last two (upper) tracings. (From Jackson.)

tion, but if the stimulus is applied to a portion of the heart known as
the white crescentic line, inhibition still occurs, because at this point the
postganglionic nerve fibers come near to the surface and therefore are
stimulated (Fig. 69). On the other hand, atropine is a drug which
paralyzes the postganglionic fibers, so that after its application to the
heart inhibition can not be produced by stimulating either the vagus

*The reader is referred to the chapter dealing1 with the autonomic nervous system for a de-
scription of the relationships of the fibers and ganglia.

232 THE CIRCULATION OF THE BLOOD

trunk or the white crescentic line. Pilocarpine and muscarine are drugs
which have an action exactly opposite or antagonistic to that of atro-
pine; that is, they stimulate the postganglionic fibers and produce a
slowing and possibly an enfeebling of the beat.

In the mammalian heart a large number of the fibers in the right
vagus nerve proceed directly to the sinoauricular node, where it can
be shown histologically that considerable masses of nervous tissue exist.
On the other hand, the great majority of the fibers in the left vagus
proceed to the auriculoventricular bundle, in which also nervous struc-
tures are abundant (page 183). As already indicated, the experimental
results which follow stimulation of either nerve can be explained by the
influence which the nerve exerts on the particular structure to which
the majority of its fibers proceed. In brief, stimulation of the right
vagus is likely to produce slowing and weakening of the beat, whereas
stimulation of the left vagus is more likely to institute a condition of
partial heart-block.

On account of the different results which may be obtained by stimu-
lating the vagus, some authorities have assumed that the heart must
contain four kinds of fiber, more strictly, of vagus nerve endings, one for
each kind of influence which the vagus can develop. These four influ-
ences are, it will be remembered, on the strength, the rate and the
propagation of the heartbeat, and the excitability of the cardiac muscle.
It is, however, almost certainly unnecessary to make such an assump-
tion, for the results can be explained as merely dependent upon dif-
ferent degrees of stimulation of the same kind of fiber and upon the
exact part of the heart to which the fiber runs. Sometimes, for ex-
ample, when the right vagus nerve is stimulated very feebly, there may
be only a diminution in the force of the beats without any change in
their rate, indicating that the effect has been upon the musculature of
the auricular walls and not on the sinoauricular node. If the stimulus
is increased a little, then both an enfeebling and a slowing of beat occur,
indicating that the stimulus has now passed both to the auricular mus-
culature directly and to the sinoauricular node.

The Sympathetic Control

The effect of the sympathetic nerve on the heart may be described as
being exactly opposite to that of the vagus. The pathway along which
the fibers of this nerve travel to the heart is more or less a devious one.
They arise in the mammal from nerve cells in the gray matter in the
upper thoracic portion of the spinal cord. The fibers leave by the cor-
responding spinal roots and pass by the white rami communicantes into
the sympathetic chain, up which they travel to the stellate and inferior

N.I

Postganglionic fibers

are dotted thus

Spinal
medulla
(cord)

Ram!

communican-
tes going to
symp. gang,
(preganglionic)
Ansa ' \
subclavia-
(Annulus of r

Thoracic -3
nerves

Jugular ganglion (Gang, of the root)
Depressor (Fall in pressure or slowing of heart.)
(Sensory) separate nerve in rabbit and opossum.

Nodosum ganglion (Gang, of the trunk) ( Hunf *
Inhibitory cranial autonomic fibers

Superior cervical ganglion

Descending sympathetic fibers in cord
^Cervical vago- sympathetic trunk

Harrington)

^Electrodes (slowing or stoppage of
Subclavian heart Augmentation in some
art ^ ^<-— E\ animals.)

First thoracic ganglion
(Stellate)

Electro des «y»

(Acceleration, or

augmentation of heart.)

Fig. 70. — Schematic representation of the innervation of the heart of the mammal. The red
continuous lines represent the sympathetic (accelerator) preganglionic fibers, and the broken red
lines, their postganglionic fibers. The cell stations are in the inferior cervical and stellate ganglia,
some extending up to the superior cervical ganglion. The green continuous lines represent the
vagus preganglionic fibers, and the broken green lines, their postganglionic fibers. The cell stations
in this case are located in the heart itself. It will be observed that electrodes applied to the so-
called vagus low down in the neck may stimulate some sympathetic fibers. (From Jackson.)

THE CONTROL OF THE CIRCULATION

233

cervical ganglia. Around the nerve cells of the stellate ganglion the
fibers end by synapsis, and the axons of the cells are then continued on
as postganglionic fibers, proceeding to the heart through branches com-
ing off from the stellate ganglion itself, or from the ansa subclavii or
inferior cervical ganglion. (Fig. 70.) In cold-blooded animals, such as
the frog, the sympathetic fibers run up to the upper end of the cervical
sympathetic and join the vagus immediately after it leaves the cranial
cavity. They then proceed along with this nerve — forming the vago-
sympathetic — to the heart. The effect of stimulation is shown in Fig. 71.
The sympathetic nerve differs from the vagus in that a much longer la-
tent period elapses before its influence becomes effective, and this persists
for a much longer period after tfye stimulus is withdrawn. If the vagus

B.

Fig. 71. — Tracings showing the effects on the heartbeat of the frog resulting from stimulation of
the sympathetic nerves prior to their union with the vagus nerve. (From Brodie.)

and sympathetic are stimulated at the same time, as by exciting the vago-
sympathetic in the frog, the first effect observed is that of the vagus
usually followed, after removal of the stimulus, by the sympathetic ef-
fect. If the stimulus is maintained for a long time, so that the vagus
becomes fatigued, escapement will occur earlier than with pure vagus
stimulation, and augmentation may become apparent. The sympathetic
influence is, however, never so strong as that of the vagus. The two
nerves are therefore not antagonistic in the sense that the one neutralizes
the effect of the other; but when both are stimulated, the heart responds
first to the vagus and later to the sympathetic.

CHAPTER XXVII
THE CONTROL OF THE CIRCULATION (Cont'd)

THE NERVE CONTROL OF THE PERIPHERAL RESISTANCE

As already explained, the nerve control of the peripheral resistance
takes place through the action of vasoconstrictor and vasodilator nerve
fibers on the musculature of the arte"riole walls. The vasoconstrictor
impulses like those in the vagus of the heart are tonic, so that when a
nerve containing such fibers is cut, the corresponding blood vessels un-
dergo dilatation (see page 135), and when their peripheral ends are s.tim-
ulated artificially, constriction occurs. On the other hand, the vasodi-
lator impulses do not appear, at least under ordinary circumstances, to
be tonic, so that the cutting of such fibers does not cause vasoconstriction ;
their stimulation, however, causes marked dilatation. Vasomotor fibers
are contained in most of the efferent (motor) nerve trunks, and to
detect their presence the nerve must be either cut or stimulated and the
condition of the blood vessels of the innervated area observed.

Methods for the Detection of Constriction or Dilatation

Several methods, varying with the exact area under observation, can
be used for the detection of vasoconstriction or dilatation. In many cases
visual inspection is sufficient, as in the well-known experiment of Claude
Bernard on the blood vessels in the ear of the rabbit (see Fig. 106) . When
this is held with a light behind it, arid the cervical sympathetic of the
corresponding side is cut, marked dilatation will become evident and
vessels will spring into view where previously there were none visible.
Visual inspection is usually also a satisfactory method of demonstrat-
ing vasodilatation or constriction in exposed glands, in mucous pas-
sages and in the vessels of the skin.

Another comparatively simple method is the observation of the tem-
perature of the part, this being particularly useful when the vascular
area is one situated in the peripheral part of the body, such as the hand
or foot (see page 209). When dilatation occurs the temperature of the
part rises, because the warmer blood from the viscera flows with greater
freedom through the peripheral regions, where it is cooled off by radia-
tion. When a thermometer is placed between the toes of a dog or cat, a

234

THE CONTROL OF THE CIRCULATION 235

•t

distinct rise in temperature will be observed when the sciatic nerve of the
corresponding limb is cut. The application of this principle in deter-
mining the mass movement of blood by the amount of heat given off from
the hands or feet has already been explained.

Other methods depend upon observation of the outflow of ~blood from
the veins of the part. A simple application of this method can be used in
the case of the ear of the rabbit. If the tip of the ear is cut off, bleeding
under ordinary circumstances is only very slight, but if the cervical
sympathetic is cut, it becomes quite marked, slowing down again or
even stopping entirely when the peripheral end of the nerve is stimu-
lated. By making measurements of the volume of the outflow of blood
from a vein by Jthis method, the extent of constriction or dilatation can

tube to recorder

oil enclosed
by membrane

Fig. 72. — Roy's kidney oncometer. (From Jackson.)

be followed quantitatively. Vasodilatation also causes changes in the
character of the venous flow, the usually continuous flow becoming pul-
satile and the color of the blood brightening. Comparison of the pressures
in the arteries and the veins of a part is also often of value in the detec-
tion of changes in the caliber of the blood vessels, for, of course, the
greater the difference in pressure between the two manometers, the
greater must be the resistance offered to the flow.

For experimental purposes, however, the standard method is that
known as the plethysmo graphic. For this purpose the organ or tissue is
enclosed in a so-called plethysmo graph or volume recorder, the prin-
ciple of which will be clearly seen by consultation of the accompanying
diagram of one adapted for the kidney (Fig. 72). Any increase de-
tected by this means in the volume of the part must be due either to

236 THE CIRCULATION OF THE BLOOD

an increase in blood flowing into the vessels because of increased heart
action or to a local vasodilatation; and vice versa, when shrinkage oc-
curs. We can not tell from the volume tracing itself which of these
changes is really responsible for the observed alteration, but we can do
so by simultaneously observing the mean arterial blood pressure. If this
falls when the volume decreases, it means that the volume of blood flow-
ing to the part must have become diminished. If, on the other hand, the
blood pressure remains constant or rises while the volume decreases, it
means that the blood vessels have locally constricted.

Methods for the Detection of Vasomotor Fibers in Nerve Trunks

If we wish to find out through which nerve trunks a given vascular
area is supplied with vasoconstrictor or vasodilator impulses, we should
proceed by the use of one of the above described methods to observe the
effect produced on the vessels by cutting the nerve and then by stimu-
lating the peripheral end of the cut nerve. As a result of such observa-
tions it has been found that the vasomotor fibers are frequently dis-
tributed so that those having a vasoconstricting action are collected
mainly in one nerve trunk' and those having a dilating action in another;
in some nerve trunks, however, the relative numbers of the opposing
fibers are about equal. Nerves containing a great preponderance of vaso-
constrictor fibers are the great splanchnic and the cervical sympathetic;
and those containing a great preponderance of vasodilator are the chorda
tympani nerve to the submaxillary gland and the nervi erigentes to the
external genitalia.

It must be clearly understood that, although one kind of vasomotor
fiber may preponderate in one of these nerves, yet the opposite kind is
also present. In the cervical sympathetic, for example, some vasodila-
tor fibers extending to the blood vessels of the mucous membrane of the
nose and cheeks can readily be demonstrated, as shown by the flushing
of these parts when the peripheral end of the nerve is stimulated; and
similarly, even in the great splanchnic nerve itself, vasodilator fibers
supplying the suprarenal capsule can quite readily be made out. When
the vasoconstrictor fibers greatly preponderate over the vasodilator, the
effect of the latter may be demonstrated by taking advantage of the fact
that ergotoxine paralyzes the vasoconstrictor but not the vasodilator
fibers, so that after its administration stimulation of the great splanch-
nic nerve gives rise to a vasodilatation instead of a vasoconstriction.
The presence of vasoconstrictor fibers in the so-called vasodilator nerves
(chorda tympani and nervi erigentes) has not however, been demon-
strated.

A good example of a nerve trunk containing about an equal admix-

THE CONTROL OP THE CIRCULATION 237

V

ture of both kinds of vasomotor fibers is the sciatic. ' If the hind limb of
a dog is placed in a plethysmo graph and simultaneously a record of the
mean arterial blood pressure taken, it will be found on cutting the sciatic
nerve that the volume of the limb increases, whereas the blood pressure
remains practically constant. Before placing the limb in the plethysmo-
graph, the muscles must of course be paralyzed by means of curare;
otherwise muscular contractions would confuse the result. If the
peripheral end of the cut nerve is now stimulated, vasoconstriction will
readily be observed. So far, then, the results demonstrate the presence
of vasoconstrictor nerve fibers alone.

To demonstrate the presence of vasodilators a different procedure is
necessary. This is based on the following facts: (1) The vasodilator
nerve fibers degenerate more slowly than the vasoconstrictor; (2) they
are less depressed in their excitability by cooling the nerve; and (3) they
are more sensitive to weak slow faradic stimulation than the vasocon-
strictor fibers. Accordingly, if we cut the sciatic nerve two or three
days before the actual experiment, and then, while observing the volume
of the limb, proceed to stimulate the half-degenerated nerve with feeble
electric stimuli of slow frequency we shall usually observe a dilatation
of the limb instead of constriction; and even if we cool a stretch of a
freshly cut nerve before applying the stimulus, the same result will
often be obtained.

The Origin of Vasomotor Nerve Fibers

Having seen how the presence of vasomotor fibers may be detected in
peripheral nerves, we must now proceed to trace them back to their
origin from the central nervous system. The method for doing this con-
sists, in general, in observing the effect on the blood vessels produced by
cutting or stimulating the various nerve roots through which the fibers
might pass on their way to the nerve trunks. As a result of such obser-
vations it has been found that all of the vasoconstrictor fibers emanate
from the spinal cord in the region between the level of the second thoracic
and that of the second or third lumbar spinal roots, but from nowhere
else in the cerebrospinal axis. Section of the spinal cord below the level
of the second lumbar spinal roots produces no change in the volume of
the hind limb, provided the muscles be thoroughly curarized, nor does
stimulation of the lower end of the cut spinal cord have any effect. If
the last two thoracic or the first two lumbar spinal roots are stimulated,
however, evidence of vasoconstriction will be obtained.

The restriction of the origin of vasoconstrictor fibers to the above-
mentioned regions of the spinal cord indicates that in proceeding to
the mixed nerve trunks they must travel along special nerve paths.

238 THE CIRCULATION OF THE BLOOD

These are provided by the sympathetic chain and its branches (Fig. 218).
The vasoconstrictor fibers in the anterior spinal roots leave the latter
by way of the corresponding white rami communicantes, and pass into
the neighboring sympathetic chain, along which they either ascend or
descend, according to their ultimate destination. In their course they
come into contact with the sympathetic ganglia, through one or two of
which they may pass without any change, but ultimately each fiber ar-
rives at some ganglion, in which it terminates by forming a synapsis
around one of the ganglionic nerve cells. The axon of this nerve cell
then continues the course by the nearest gray ramus commuhicans back
to the spinal nerve beyond the union of its anterior and posterior roots.
Up to the point where the fiber forms a synapsis with a ganglionic nerve
cell, it is medullated and is known as the preganglionic fiber. Beyond
the nerve cell, it is nonmedullated and is known as postganglionic
(page 894).

The exact ganglion in which a given vasoconstrictor fiber becomes connected with a
nerve cell can be determined by the nicotine method of Langley. Local application to
the ganglion of a weak solution of this drug (1 per cent) paralyzes the synaptic con-
nection, so that a stimulus applied to the preganglionic fiber no longer produces its
effect. Suppose, for example, that a vasoconstrictor fiber has been found by the stimula-
tion method to travel through several ganglia, and we wish to determine in which of
these the synapsis occurs : we can do so by applying the stimulus at a point central to
the ganglia after painting each of them in turn with the nicotine solution. If the
application of the drug to a given ganglion is found to cause no alteration in the
effect produced by stimulation, then we know that there can not be any synaptic
connection in that ganglion, and we proceed in the same way till we have located
the ganglion in which synapsis occurs. It is important to remember that the post-
ganglionic vasoconstrictor fibers in a gray ramus communicans do not coine from the
preganglionic fibers of the corresponding spinal root, but from fibers coming through
white rami at a higher or a lower level.

The above description applies to the vasoconstrictor fibers proceeding to the vessels of
the anterior and posterior extremities, those for the former arising (in the dog) from
about the fourth thoracic to the tenth; and those for the latter, from the lowest thoracic
and the first three lumbar nerve roots. The cell station for the fibers to the fore limbs
is in the stellate ganglion, and for the hind limbs in the last two lumbar and first two
sacral ganglia of the 'abdominal sympathetic chain.

The vasoconstrictor fibers to the vessels of the head and neck run a somewhat dif-
ferent course, there being no convenient cerebrospinal nerve along which the post-
ganglionic fibers may run. The fibers to the blood vessels of the head leave the cord
by the second to the fourth or fifth thoracic roots and pass by the corresponding white
rami communicantes into the sympathetic chain, up which they run, passing through the
stellate ganglion, the ansa subclavii, and the inferior cervical ganglion, then ascending
in the cervical sympathetic to the superior cervical ganglion, where their cell station
exists. The postganglionic fibers on leaving this ganglion travel to their destination
mainly along the outer walls of the blood vessels.

The vasoconstrictors to the abdominal viscera are carried by the splanchnic nervea,
the fibers of which come off from the lower seven thoracic and the uppermost lumbar

THE CONTROL OP THE CIRCULATION 239

v

roots. The thoracic libers pass down the sympathetic chain, which they leave by the
great splanchnic nerves. The lumbar fibers form the lesser or abdominal splanchnic
nerves. As preganglionic fibers, therefore, these fibers are carried by the greater and
lesser splanchnic nerves into the abdomen, where the former comes into close relation-
ship writh the suprarenal glands, giving off a branch to the suprarenal ganglion. The
main course of the nerve is continued on to the solar plexus, in the various ganglia of
which most of the preganglionic fibers end by syuapsis, the postganglionic fibers then
proceeding along the blood vessels to the vessels of the abdominal viscera. (See also
page 894).

Vasodilator fibers have a more varied origin than vasoconstrictor, and
they run an entirely different course. Vasodilator impulses may be
transmitted by fibers arising from practically any level of the cerebro-
spinal axis, not only by the motor roots, but by the sensory as well.
Thus, they pass out of the spinal cord in the posterior sacral roots to
enter the nerves of the hind limbs, as has been demonstrated by observ-
ing an increase in the volume of the curarized limb during electrical
stimulation of the exposed rootlets. The apparent inconsistency of these
observations with the well-known law concerning the direction of the
impulses contained in the posterior spinal roots is explained by assum-
ing that the dilator impulses are transmitted along the ordinary sensory
fibers, since there are no efferent fibers in these roots. They are impul-
ses which go against the ordinary stream (antidromic). In support of
this explanation it is of importance to note that at their termination
near the skin many sensory fibers split into several branches, some of
which run to blood vessels, and others to receptor organs (page 854).
Stimulation of the latter branches may cause dilatation of the local blood
vessels nearby, indicating that impulses must be transmitted up to the
point at which the branching occurs and then down the vascular branch,
this result being obtained even after the main trunk of the nerve has
been cut above the division.

For the blood vessels of the anterior extremity, the vasodilator impulses are similarly
transmitted through the posterior spinal roots of the lower cervical region of the spinal
cord. The vasodilator fibers to the abdominal viscera are transmitted with the splanchnic
nerves, but they may also be derived from the posterior spinal roots, for it has been
found that stimulation of posterior roots in the splanchnic area causes dilatation in the
intestine (Bayliss). Vasodilator fibers are also contained in the cranial nerves, par-
ticularly the seventh and the ninth, being distributed in the former nerve to the an-
terior portion of the tongue and the salivary glands, and in the latter to the posterior
portion of the tongue and the mucous membrane of the floor of the mouth. The vaso-
dilator fibers for the mucous membrane of the inside of the cheeks and nares have their
course in the cervical sympathetic, being distributed to the buccofacial region in the
branches of the fifth cranial nerve.

There is evidence to show that the vasodilator fibers, like the vasoconstrictor, become
connected by synapsis with nerve cells somewhere in their course. In the case of the
vasodilator fibers in the chorda tympani and nervi erigentes, such cell stations have
been clearly demonstrated in the hilus of the submaxillary gland in the former nerve

240 THE CIRCULATION OF THE BLOOD

and in the hypogastric plexus situated on the neck of the bladder in the latter.
It is therefore commonly assumed that, although not recognizable by histological methods,
such terminal cell stations must also exist in close association with all blood vessels
to which the vasodilator fibers run. Whether or not such peripheral cell stations exist,
there is a marked difference between the course of vasodilator and of vasoconstrictor
fibers.

The Vasomotor Nerve Centers

Our next problem is to trace these fibers farther into the central
nervous system, and find the location and study the characteristics of
the nerve centers from Avhich they are derived. We must postulate the
existence of both vasoconstrictor and vasodilator centers, but since there
is no adequate evidence at the present time which enables us to locate
the latter, we must confine our attention to the vasoconstrictor centers.
These exist at two levels in the cerebrospinal axis: (1) in the gray mat-
ter of the spinal cord, and (2) in the gray matter of the medulla
oblongata.

The spinal, or as they are often called, the subsidiary vasoconstrictor
centers, are represented by certain cells of the lateral horn of gray mat-
ter in the thoracic portion of the spinal cord, from which the pregan-
glionic vasoconstrictor fibers above described are derived. The exact
location of the nerve cells composing the chief centers in the medulla has
not as yet been definitely made out; they undoubtedly lie near those of
the vagus center (see Ranson). The axons of the medullary cells de-
scend in the lateral columns of the spinal cord to end by synapses
around the cells of the subsidiary vasoconstrictor center in the lateral
horns.

The experimental evidence which indicates the existence of chief and
subsidiary centers is quite definite. Thus, if the spinal cord is cut at the
lower cervical region (below the phrenic nuclei, so as not to interfere
with the movements of the diaphragm), the arterial blood pressure falls
profoundly, because the pathway connecting the two centers is broken.
After several days, however, the blood pressure will gradually rise again.
If after this has occurred, the spinal cord is destroyed by pushing a wire
down the vertebral canal, the arterial blood pressure will again fall,
indicating that the vascular tone which had been reacquired after sec-
tion of the pathway between the main and the subsidiary centers must
have been brought about by the development in the subsidiary centers
of an independent power of reflex tonic action. This experiment there-
fore demonstrates that in the intact animal the subsidiary centers do not
by themselves discharge tonic impulses. In other words, the subsidiary
centers ordinarily serve merely as transfer stations for the tonic im-
pulses coming from the chief center, but when these impulses no longer

THE CONTROL OF, THE CIRCULATION 241

arrive, then a hitherto dormant power of tonic activity becomes devel-
oped in the subsidiary centers.

Independent Tonicity of Blood Vessels

Even after complete disconnection of the spinal cord from the blood
vessels, as by cutting of the splanchnic nerve to the abdomen or abla-
tion of that portion of the lower spinal cord from which the fibers to
the hind limb arise, the disconnected blood vessels, although at first
completely dilated, may later acquire an independent tone of their
own, indicating therefore, that they must possess some neuromuscular
mechanism which can act independently of the nerve centers, and which
may be stimulated to activity by the presence of hormones in the blood.
The hormone was at one time thought to be epinephrine (see page 774).

Epinephrine control is indicated in the effect produced upon arterial
blood pressure by stimulation of the great splanchnic nerve. Careful
analysis of the curve, shown in Fig. 29, shows that the rise is both im-
mediate and delayed; that is, the curve mounts immediately, then flat-
tens out a little, and then assumes a further rise. This delayed response
seems to depend upon the secretion of epinephrine into the blood, for it
does not occur when the suprarenal veins are occluded, and is much de-
layed by temporarily clamping the suprarenal veins on the same side
as that on which the splanchnic nerve is stimulated. It has been stated
by certain observers that, after occlusion of the adrenal veins, there is
a downward tendency of the blood pressure, which however develops
with extreme slowness; and that a distinct elevation of blood pressure
follows the removal of a clamp temporarily placed on the adrenal veins.
This rise is pronounced if the splanchnic nerve is stimulated during the
occlusion of the veins. It must of course be understood that the imme-
diate rise in blood pressure following splanchnic stimulation is caused by
vasoconstriction in the splanchnic area itself, as is evidenced by the
fact that it does not occur, or is only very faint, when the abdominal
blood vessels are ligated prior to the stimulation of the splanchnic nerve.
Even after ligation of the adrenal veins and of the blood vessels of the
splanchnic area, stimulation of the splanchnic nerve may still cause a
slight rise in arterial blood pressure, possibly because some fibers may
run from the splanchnic to vascular areas not situated within the realm
of the splanchnic nerve — for example, the blood vessels of the lumbar
muscles.

CHAPTER XXVIII

THE CONTROL OF THE CIRCULATION (Cont'd)
CONTROL OF THE VASOMOTOR CENTER

The activities of the vasoxnotor center are controlled partly by hor-
mones and partly by afferent impulses.

The Hormone Control

As with the respiratory center, the chief hormone is the hydrogen-ion
concentration of the blood. When this is increased, as in asphyxia, the
vasoconstrictor part of the vasomotor center becomes stimulated, so
that the blood vessels are constricted and the blood pressure rises. Tak-
ing, as our criterion of hydrogen-ion concentration, the tension of the
carbon dioxide in the blood (see page 371), we may proceed to investi-
gate the relationship by observing the blood pressure during changes
in the carbon-dioxide tension brought about by causing the animal to
breathe atmospheres containing known percentages of the gas (Mathi-
son15). Thus, if a decerebrate cat is made to respire an atmosphere
containing 5 per cent or more of carbon dioxide, an immediate rise
occurs in the arterial blood pressure. That the inhaled carbon dioxide
acts by raising the hydrogen-ion concentration of the blood is indicated
by the fact that a similar rise in blood pressure can be obtained by intra-
venous injection of a weak solution of lactic acid (2 c.c. N/15) in a de-
cerebrate cat.

Oxygen deprivation also causes excitation of the vasoconstrictor center
as can be demonstrated either by causing a decerebrate cat to breathe in
an atmosphere of nearly pure nitrogen or by clamping the vertebral ar-
teries as they lie just below the centers. The rise in blood pressure is then
very prompt and is accompanied by hyperpnea.

The sensitivity of the medullary center towards the hydrogen ion is many times
greater than that of the subsidiary centers in the spinal cord. If an animal is kept
alive by artificial respiration for some time after cutting the cervical spinal cord,
the subsidiary vasomotor centers will, as we have seen, gradually acquire a tonic
action, and the lowered blood pressure will gradually rise again. If, wrhen this has
been attained, the animal is made to breathe an atmosphere rich in carbon dioxide,
a sudden rise in. blood pressure will occur, but to produce it a very much greater per-
centage of this gas must be inspired than when the pathway between the chief and

242

THE CONTROL OF THE CIRCULATION 243

v

subsidiary centers is intact. Whereas 5 per cent carbon dioxide is sufficient to cause
a rise of pressure in an animal having its chief vasomotor center, it takes 25 per
cent and upward to produce a like effect on a spinal animal; and similarly, although
2 c.c. of N/15 lactic acid will stimulate the chief vasomotor center, it takes 5 c.c. of
N/2 to excite the spinal-cord centers.

The Nerve Control

However important hormones may be in maintaining a tonic stimula-
tion of the center, the more sudden changes in activity are mainly
brought about by afferent nerve impulses. The afferent impulses are
of two classes: (1) those causing a rise in blood pressure, called
pressor, and (2) those causing a fall in blood pressure, called depressor.
The effect produced on the arterial blood pressure by stimulation of
either pressor or depressor fibers is usually more or less evanescent,
especially in the case of the depressor fibers ; and when the change fol-
lowing stimulation of the nerve passes off, the blood pressure always
returns to its former level. This indicates that the afferent impulses do
not affect the tonic control which the vasomotor center exercises on the
blood vessels. It has, therefore, been assumed by Porter16 that there are
really two kinds of vasomotor centers: one concerned merely in the
bringing about of temporary reflex changes, the other concerned in the
maintenance of the vascular tone. It may be that the activities of the
former are primarily dependent upon afferent impulses, and the latter,
upon hormones. Justification for this view has been found in observa-
tions made on the effects of stimulation of pressor and depressor fibers
in animals under the influence of curare or alcohol. With the former
drug, stimulation of a nerve containing a preponderance of pressor or
depressor fibers produces double its usual effect, but the mean level of
the blood pressure apart from this effect remains unchanged. With the
latter drug (alcohol), on the other hand, the reflex response entirely
disappears, although it immediately reappears when the alcohol effect
has passed off, and there is no evidence of a change in tone. The tonic
and the reflex mechanisms of the vasomotor center can not therefore be
identical.

At the present stage of our knowledge, it is only possible for us to
study the effect of stimulation of pressor and depressor fibers on the
vasoreflex center. Such fibers are contained in practically every sen-
sory nerve of the body, and it would appear that a fairly equal mixture
of both kinds of fiber exists in most of these nerves.

Pressor and Depressor Impulses. — Depressor impulses alone are present
in the cardiac depressor nerve. Sometimes as in the rabbit, this exists
as an independent nerve trunk, originating by two branches, one from
the superior laryngeal, the other from the vagus, and descending close to

244 THE CIRCULATION OF THE BLOOD

the vagus trunk, to end around the arch of the aorta. In other animals
the depressor is bound up with the vagus trunk from which it can some-
times be separated by careful dissection. The first prerequisite in inves-
tigating the cause of the changes produced by stimulation of these nerves
is the elimination of any chance of an alteration in heartbeat as a result
of simultaneous stimulation of afferent vagus fibers. This may be done
either by cutting both vagi or by administering atropine.

Stimulation of the central end of the cardiac depressor nerve in such
an animal causes an immediate fall in blood pressure, accompanied by an
increase in volume which can be demonstrated either in the hind limb or in
one of the abdominal viscera — evidence of general vasodilatation (Fig 73).

When the central end of a sensory nerve, such as the sciatic, is acted
on by a stimulus of moderate strength, it will usually be found that the
arterial blood pressure rises and that the volume of the limb or of some

Fig. 73. — Fall of blood pressure from excitation of the depressor nerve. The drum was
stopped in the middle of the curve and the excitation maintained for seventeen minutes. The line
of zero pressure should be 30 mm. lower than here shown. (From Bayliss.)

abdominal viscus becomes diminished — evidence of general vasoconstric-
tion. But when the sensory nerve is stimulated with extremely weak
faradic shocks, an entirely different result is likely to be obtained;
namely, a fall of blood pressure and an increase in volume of the limb
or viscus, indicating that in this manner we have stimulated depressor
fibers. By careful experimentation with quantitatively graduated elec-
trical stimuli, it has been found by Martin and others17 that on stimu-
lating an afferent nerve with weak shocks., a fall in blood pressure is
the first effect to be observed, and that this becomes more and more
marked as the strength of the stimuli is increased, until a certain opti-
mum is reached, after which the fall in blood pressure becomes less evi-
dent. When a certain strength of stimulation is exceeded, a rise instead
of a fall occurs. After this point additional increase in stimulation causes

THE CONTROL OF THE CIRCULATION

245

more and more marked elevation of blood pressure through a very long
range of stimuli.

Stimulation of two afferent nerves at the same time usually produces
a greater reflex vasomotor change than the stimulation with an equiva-
lent strength of current of either nerve alone. That is to say, the effect
produced by stimulating the central end of both sciatics simultaneously

Fig. 74. — The effect of strong stimulation (heat) of the skin of the foot on the arterial blood
pressure and respiratory movements. Upper tracing, thoracic movement; lower tracing, arterial
blood pressure.

will be greater than that produced by stimulating either alone with double
the strength of stimulus.

As has been stated above, the reflex change in blood pressure is often
quite transitory in nature, although the stimulation of the pressor nerve is
maintained. When this decline has occurred, the pressor reaction can

246

THE CIRCULATION OF THE BLOOD

often be renewed by shifting the stimulation to a second nerve. These
facts concerning the greater efficacy of combined stimulation of several
nerves are of considerable importance in connection with the general
question of reflex changes in blood pressure. For instance, many of the
pressor fibers found in the sciatic nerve are connected with the receptors
that mediate the sensations of the skin. When these receptors are
stimulated, as by heat or cold, reflex changes in blood pressure occur
(pressor reaction), (Fig. 74), and it is important to remember that

Fig. 75. — Diagram showing the probable arrangements of the vasomotor reflexes.

A. Muscle of arteriole.

D. Vasodilator nerve fiber terminating on A and inhibiting its natural tonus, as indicated by -
sign.

C. Vasoconstrictor fiber also ending in A, but exciting it ( + ). These two kinds of fiber arise
from the dilator center (DC) and the constrictor center (CC) respectively.

F. Afferent depressor fiber, dividing into two branches, one of which (-) inhibits the con-
strictor center, while the other (+) excites the dilator center causing dilatation of the arteriole and
fall of blood pressure.

R. Pressor fiber exciting CC and inhibiting DC, and therefore causing vasoconstriction and rise
of blood pressure.

a, b, c, and d represent the synapses of the pressor and depressor branches with the efferent
neurons. (From Bayliss.)

localized stimulation of the skin is less efficient in bringing about such
vascular changes than stimulation applied over large areas, even when
the local stimulus is intense and the general stimulus mild in character.
Jumping into a moderately cold bath will cause a much greater rise in
arterial blood pressure than plunging the hand into ice cold water.

THE CONTROL OF THE CIRCULATION 247

Mechanism of Action of Pressor and Depressor Impulses, — When we
consider the exact mechanism by which these afferent impulses operate,
we have to bear in mind four possibilities: the reflex fall produced by
stimulation of a depressor afferent fiber may be due either to a stimula-
tion of the vasodilator part of the center or to an inhibition of the tone
of the vasoconstrictor part; and, conversely, a rise in arterial pressure
caused by vasoconstriction may be dependent either on a stimulation of
the vasoconstrictor part of the center or on an inhibition of the tone of
the vasodilator part. All of these changes have, as a matter of fact, been
shown to occur, at least under certain conditions, although the evidence
for the inhibition of dilator tone is as yet a little uncertain (see Fig. 75).

Without going into the subject in detail, we may nevertheless take
as an example of the methods by which the information has been ob-
tained, the experiment performed by Bayliss,18 showing that the vasodi-
lation which results from stimulation of the depressor nerve is owing
partly to removal of vasoconstrictor tone and partly to vasodilator
stimulation. The volume of the hind limb of a curarized and vagotomized
rabbit increases when the central end of the cardiac depressor nerve is
stimulated. In order to determine whether this dilatation is due solely
to the removal of vasoconstrictor tone, the above experiment was repeated
on a rabbit in which the sympathetic chain had been cut below the level
of the second lumbar spinal roots. By such an operation all the vaso-
constrictor fibers to the vessels of the hind limb are severed, but the
vasodilator fibers, since they emanate through the sacral sensory roots,
are left intact. It was nevertheless found on stimulating the depressor
nerve that dilatation of the hind limb still occurred, thus* indicating
that stimulation through vasodilator fibers must have taken place. Con-
versely, in another experiment, instead of the sympathetic chain, the
spinal cord was cut below the level of the second lumbar segment, thus
severing the dilator but not the constrictor path, and again depressor
stimulation caused the volume of the limb to increase, indicating that
an inhibition of constrictor tone must have occurred.

Reciprocal Innervation of Vascular Areas

It must not be imagined that changes in the caliber of the blood ves-
sels occurring in one vascular area are necessarily occurring all over
the body. On the contrary, a most important reciprocal relationship
exists in the blood supply to different parts. After food is taken, for
example, more blood is required by the digestive organs than when they
are at rest, and this is insured by dilatation of their own vessels along
with reciprocal constriction of those of other parts of the body. On

248 THE CIRCULATION OF THE BLOOD

account of the relatively great capacity of the abdominal vessels, their
dilatation during digestive activity is usually greater than the reciprocal
constriction of the other vessels, so that the diastolic blood pressure falls,
necessitating a more powerful cardiac discharge in order to maintain
the mean pressure. After taking food, the systolic pressure does not
as a rule fall so much as the diastolic, if it falls at all; and the pres-
sure pulse therefore becomes greater and causes a greater live load to
be applied to the vessels with each heartbeat. During the sudden strain
that is thrown on them, weakened arteries may give way, especially in
the brain.

Another example of reciprocal action of the vascular system is seen
in muscular exercise. The vessels of the active muscles dilate, while
those elsewhere constrict. The local dilatation in this case is, however,
not entirely at least a nervous phenomenon, being caused in fact, as we
shall see, by hormone action 011 account of the local increase in hydro-
gen-ion concentration (see page 431). There can be little doubt that
local irritants to the surface of the body, such as hot applications, lini-
ments, etc., act in the same way; they cause local dilatation of the super-
ficial and perhaps of the immediately underlying vessels and constric-
tion of those elsewhere in the body. Application of cold to local areas
of skin similarly causes local constriction accompanied by reciprocal
dilatation elsewhere. This action of cold is very marked in some parts of
the body, such as the hands, where by Stewart's method (page 296) it
can be shown, not only that the bloodflow of the hand to which the cold
is applied is greatly curtailed, but also that of the opposite side.

Experimental demonstration of reciprocal vascular innervation is fur-
nished by numerous experiments. If the central end of the great auric-
ular nerve of the ear is stimulated in a rabbit, dilatation of the ves-
sels of the ear occurs at the same time as a rise in arterial blood pres-
sure (Loven reflex). Similarly when the central end of one of the sen-
sory roots of the leg of a dog is stimulated, there is a rise in arterial
blood pressure and an increase in the volume of the limb.

THE INFLUENCE OF GRAVITY ON THE CIRCULATION

If the arterial blood pressure is measured in the arm and leg in a man
standing erect, a difference corresponding to the hydrostatic effect of
gravity will be found between the two readings. In comparison with
the high pressure normally existing in the arteries, this difference is,
however, of little significance. On the other hand, in the veins, where
the average pressure is low, gravity would cause serious embarrassment

THE CONTROL OF THE CIRCULATION 249

•t

to the circulation of blood were it not for the valves and the forces
which move the blood beyond them (page 214).

In erect animals the part of the circulation in which blood might stag-
nate as a result of gravity is the splanchnic area. Were such stagna-
tion to occur, the blood would not be returned to the right heart, so
that the arteries would not receive sufficient blood to maintain an ade-
quate circulation, particularly in the vessels of the brain.

Simple experiments devised by Leonard Hill19' 2S illustrate these prin-
ciples. When a snake, for example, is pinned out on a long piece of
wood and an opening made opposite the heart, this organ can be seen
to fill adequately with blood as long as the animal is maintained in the
horizontal position. When placed vertically, however, the heart be-
comes bloodless. If now the tail end of the animal is placed in a cylinder
of water so as to overcome the effect of gravity, the heart will be seen

Fig. 76. — Aortic blood pressure showing the effect of posture: A, vertical, head-up; B, hori-
zontal; C, vertical, head-down; D, horizontal. (L.H.)

to fill again with blood. Evidently in such an animal there is no mechan-
ism to compensate for gravity.

If a domestic rabbit with a large pendulous abdomen is held in the
vertical tail-down position, stagnation of blood in the splanchnic ves-
sels occurs to such an extent that in from fifteen to twenty minutes the
animal dies from cerebral anemia. If an abdominal binder is first of all
applied, the vertical position will not have the same consequences. This
experiment illustrates clearly the possible evil effects that gravity may
produce in animals in which no mechanism exists to compensate for it.

Placing an animal such as a dog under light ether anesthesia in the
vertical tail-down position produces an immediate fall in arterial blood

250

THE CIRCULATION OF THE BLOOD

pressure, as shown in the tracing (Fig. 76), followed by a certain de-
gree of compensation even while the animal is still in the erect position.
The extent to which this compensation occurs varies with the depth of
the anesthesia. If the experiment is repeated after administering a large
dose of chloroform, not only will the initial fall be much greater, but
subsequent compensation will be practically absent. The application of
these facts in the operating room will be self-evident.

Leonard Hill has shown that three factors are involved in the com-
pensating mechanism: (1) the tonicity of the abdominal musculature;

Fig. 77. — Tracing to show the effect of gravity on the arterial blood pressure. At A, the
animal was placed in the vertical position; at B, the abdomen was compressed; at C, a crucial
incision was made in the abdomen; at D, the pleural cavity was opened; at F, the animal was
returned to the horizontal position. (From Leonard Hill.)

Fig. 78. — The effect of gravity on the aortic pressure after division of the spinal cord in the
upper dorsal region. By placing the animal in the vertical feet-down posture, the pressure fell
almost to zero, but on returning it to the horizontal posture, the circulation was restored. (From
Leonard Hill.)

(2) the tone of the splanchnic blood vessels; (3) the pumping action of
the respiratory movements. The importance of the first-mentioned fac-
tor can be readily shown by making a crucial incision of the abdom-
inal walls in an animal in the erect position (Fig. 77), and that of
the second factor by cutting the great splanchnic nerves, or the spinal
cord. After such an operation, even while in the horizontal position,- as
we have seen, the blood pressure falls to a considerable extent. If the

THE CONTROL OF THE CIRCULATION 251

v

animal is now placed in the vertical tail-down position, however, it falls
to the zero line and the animal soon dies (Fig. 78). The influence of the
third factor is not so great as of the other two, but can be shown by the
increased respiratory activity which is likely to develop in the vertical
tail-down position, the anemic condition of the respiratory center being
no doubt the cause of the increased respiration.

THE CAPILLARY CIRCULATION

It has been the custom to assume that the walls of the capillaries are
incapable of constricting or dilating independently of changes of pressure
in the blood circulating in them. According to this view the magnitude
of the capillary circulation, the pumping action of the heart being constant,
depends primarily on the state of contraction or dilatation of the arterioles
from which they spring and secondarily, on the venous pressure; when
the arterioles are dilated, the pressure will rise in the capillaries, causing
them to become passively dilated, and when the arterioles are constricted,
the capillaries in virtue of their elasticity will contract again.

Krogh57 has recently brought forward unassailable evidence to show that
this conception is wrong. He has shown not only that the capillaries
possess powers of constricting and dilating quite independently of the
arterioles, but also that their caliber when the tissue they supply is at
rest is very much less than when the tissue is active, indicating therefore
that they exist in a condition of constrictor tone. These discoveries were
made by examining, chiefly by reflected light, with the binocular
microscope thin muscles in living frogs and guinea pigs (under methane),
or by injecting intravenously a solution of india ink, then killing the
animals, and examining either fresh or fixed tissues by the microscope to
determine into. which capillaries the black particles of the ink had pene-
trated. In resting muscles it was found that relatively few capillaries are
visible, these being however evenly distributed, and .forming an elongated
mesh-work along the fibers. When the muscles contract (either spontane-
ously, or as a result of artificial stimulation) many more capillaries spring
into view, and when the contraction is over they disappear again. This
microscopic evidence of extreme variability in open capillaries was con-
firmed by noting the color of the muscles after injections of india ink;
those that had been resting before the animal was killed being stained only
a faint grey, whereas those that had been active were almost black.

Another fact of very great importance, which was revealed by these in-
vestigations, was that the blood corpuscles often crowd themselves through
capillaries having diameters that are much less than those of the corpus-
cles. The average diameter of the capillaries in the resting muscles of
frogs is 4.5 /*, whereas that of the corpuscles is 22 /* (long) and 15 fi

252

THE CIRCULATION OF THE BLOOD

(broad) ; in the muscles of guinea pigs the diameter of the capillaries is
3.5 ^ that of the corpuscles being 7.2 p. In order that they may pass, the
corpuscles become folded, and the capillaries become deformed in shape,
as is shown in Fig. 79, which depicts several capillaries from the abdom-
inal wall of the guinea pig, after injecting india ink. The black particles
between the corpuscles indicate that these have been moving along during
the life of the animal. It will be observed that the corpuscles, in order to
force their way through the capillaries, become sausage-shaped as well as
being rolled in. It could be observed in living preparations in the frog
that the bloodflow is retarded when the deformation of the corpuscles is
great. These facts have naturally many most important applications.

The great variability in the number of patulous capillaries according to
the activity of the tissues (muscles) shows that the oxygen supply must be-

n

Fig. 79. — Capillaries from abdominal wall of guinea pigs after injection of india ink. The
black particles are absent from the corpuscles which will be seen to be distorted in shape. Note
that in a transverse section of a capillary the corpuscles may become folded. (Krogh.)

come altered to meet the varying demands. Indeed Krogh has shown by
mathematical calculations based on: (1) the depth of actual muscle tissue
which each capillary supplies, (2) the rate of oxygen consumption and
(3) the diffusion rate of oxygen through tissues that the oxygen pressure
necessary to supply the muscle fibers is remarkably small, even during
the heaviest muscular work. This means that the oxygen pressure in the
muscular tissue must at all times be practically the same as that of the
venous blood, and that the call for oxygen by the tissues is readily met by
diffusion from the capillary blood. That a measurable pressure of oxygen
in the tissues is difficult to demonstrate does not contradict this conclusion

THE CONTROL OF THE CIRCULATION 253

because the oxygen is so rapidly used up. In urine, where this is not the
case, the pressure of 02 is about the same as in the venous blood, and when
a neutral gas is placed in the plcural or peritoneal cavities, it ultimately
becomes mixed with oxygen up to 3-4 per cent. (Tobiesen cf. Krogh.)

The independent state of contractility of the capillaries suggests that
their behavior towards the actions of drugs and other agencies and to
nervous impulses may be opposite to that of the arterioles. This is actu-
ally the case, at least when adrenin and histamine (page 307) are present
in the blood — the arterioles constrict and the capillaries dilate — and there
is convincing evidence that the same changes occur during surgical shock
(page 306). Capillary dilatation also occurs when mustard, chloroform,
etc., are applied locally to tissue, and when the salts of certain heavy metals
e.g., AuCl4Na) are injected intravenously. In these cases the capillary
dilatation is not to be explained by dilatation of the arterioles. The action
of lymphagogues and of substances causing urticaria is to be thought of
in this connection. The independent dilatation of capillaries also explains
the association of local hyperemia with cyanosis. In such cases the blood
is flowing so slowly in the dilated capillaries that its oxygen all becomes
used up. It is as yet unknown whether the capillaries are supplied with
vasomotor nerves.

CHAPTER XXIX

PECULIARITIES OF BLOOD SUPPLY IN CERTAIN VISCERA

Up to the present we have been considering the circulation of the blood
from a general point of view. There are certain organs and tissues, how-
ever, in which the general mechanism is altered in order to meet pecu-
liar requirements of blood supply. Thus, it is evident that the brain,
incased as it is in the rigid cranium, will be unable to contract and
expand as a result of vasoconstriction or vasodilation. On the other
hand, we know that the blood supply to this organ does vary con-
siderably from time to time. What is the nature of the mechanism by
which such changes are brought about? In the case of the liver the cir-
culation is peculiar on account of the fact that blood is carried to the
organ by two vessels, in one of which it is supplied under high pressure
and in the other, under low pressure. We must investigate the rela-
tionship of these two sources of blood supply. The circulation through
the coronary and pulmonary vessels must likewise receive special atten-
tion on account of the highly specialized functions of these organs.

THE CIRCULATION IN THE BRAIN

Anatomical Peculiarities

Serious curtailment of the blood supply to the brain is guarded against
by the existence of the circle of Willis. Besides the four main arteries —
the vertebrals and the two carotids — the spinal arteries contribute to
the blood supply of the circle, and consequently in certain animals, such
as the dog, the four main arteries may be ligated without causing death.
In man, however, ligation of both carotids is usually fatal. The free
anastomosis displayed in the circle of Willis is not maintained in the
case of the arteries which run from it to supply the brain structure. On
the contrary, these vessels are more or less terminal in character; that
is to say, the capillary systems of the different vessels do not freely anasto-
mose, so that obstruction of one vessel, or an important branch, is followed
by death of the supplied area. The vessels which go to the pia mater, how-
ever, break up into numerous smaller branches, which freely anastomose
before entering the brain tissue.

254

PECULIARITIES OF BLOOD SUPPLY IN CERTAIN VISCERA 255

The venous blood is collected by the small, very thin-walled and valve-
less cerebral veins. These run together to form larger veins dis-
charging into the sinuses, the openings into which are kept patent by
the arrangement of dura mater around the orifices. The sinuses exist
between the dura and skull and are so constructed that they can not
be compressed, particularly those at the base of the brain. From them
the blood is conveyed mainly to the internal jugular vein, some of it
however escaping by the anastomoses existing between the cavernous
sinus and the opththalmic veins, and by the venous plexus of the spinal
cord. The most striking peculiarities of the veins are their patulous con-
dition and the absence of valves, so that any change in the blood pres-
sure in the internal jugular vein must.be immediately reflected in that of
the venous sinuses. This explains why compression of the abdomen
causes venous blood' to flow from an opening made in the longitudinal
sinus.

In considering the cerebral circulation, another factor that must be
borne in mind is the presence of cerebrospinal fluid. This is contained
in the subarachnoid spaces of the brain and spinal cord, these spaces, in
the case of the brain, being often considerably enlarged to form the
cisternae. The cerebrospinal fluid is also present in the ventricles of the
brain, which it will be remembered communicate with the subarachnoid
spaces through the foramen of Magendie, etc. There is free communication
between the cerebral and spinal portions of the fluid, as is evidenced by
the fact that blood clots appear in the spinal fluid (collected by spinal
puncture) when there is hemorrhage into the ventricles of the brain. It is
unlikely that the cerebrospinal fluid is of much importance in connection
with the control of the blood supply to the brain tissue. It may be merely
a lubricating fluid; at least it is so small in amount (60 to 80 c.c. in man)
as to be apparently of little value in bringing about an alteration in brain
volume. Although normally so scanty, its secretion can become re-
markably stimulated under certain conditions as in fractures of the base
of the skull. Under these conditions in man, it may drain away at
the rate of about 200 c.c. a day or more. In cerebrospinal rhinorrhea as
much as 700 c.c. of cerebrospinal fluid may run away in a day.

The fluid is apparently secreted from the choroid plexus, for when the
pathways by which the ventricles communicate with the subarachnoid
space are obstructed it collects in the ventricles, producing internal hy-
drocephalus. Under certain conditions absorption is also very rapid, as
shown experimentally by the rate with which physiological saline is
absorbed when it is injected into the subarachnoid space. This absorp-
tion is believed to occur through various pathways, the most important
of which is, directly into the blood stream, through the capillaries lining

256 THE CIRCULATION OF THE BLOOD

the subaraclmoid spaces of the brain and cord. There is no evidence to
support the view that absorption occurs through the Pacchionian bodies.
A smaller degree of absorption occurs by way of the lymphatics which
run between the interior of the cranial cavity and the deep cervical
glands, some also occurs into the lymphatics of the upper nasal passages
and the perineural sheaths.

The cerebrospinal fluid1 is believed to undergo a slow circulation from
the ventricles through the foramen of Magendie into the subarachnoid
spaces of the spinal cord down which it travels on the posterior aspect,
and then ascends on the anterior aspect where the greater part of its ab-
sorption occurs. The biochemical properties of this important fluid will
be found elsewhere (page 121).

Physical Conditions of the Intracranial Circulation

Considered from a physical standpoint the circulation through the
brain has been recognized for long to be unique in comparison with that
of any other organ or tissue in the body with the exception of the bone
marrow. Encased in the rigid cranium, the volume of the brain can not,
like that of other vascular areas, expand and contract in proportion to
changes in the blood supply ; neither can the caliber of its blood vessels
become altered, unless some special mechanism may exist whereby a part
of the cranial contents are quickly expelled from and aspirated into the
rigid case. In a general way, the physical conditions of the intracra-
nial circulation are similar to those existing in a flask full of water and
having a thin-walled rubber tube suspended in the water with its free
ends connected with glass tubes passing through the stopper of the flask.
If fluid be made to circulate through the tubing, no change in the caliber
can be produced by altering the pressure of inflow; but the rate of dis-
charge from the other end of the tube will be proportionate to the pres-
sure. Although the tubing itself is readily distensible and elastic, these
properties are entirely annulled by the incompressible fluid in which
the tube is suspended.

If any expansion or contraction of the tubing as a whole is to occur,
provision must be made for changes in the volume of fluid in the flask
by inserting in the stopper a third tube connected with an overflow
flask, and in applying this second model to represent the circulatory
conditions as they exist in the brain, the question arises as to whether
the cerebrospinal fluid which lies in the large subarachnoid spaces at
the base of the brain and in the ventricles, by communicating through
the foramen of Magendie with the spaces surrounding the spinal cord,
may not be capable of functioning as the overflow fluid. This is at
least conceivable, especially when one bears in mind that some outflow

PECULIARITIES OF BLOOD SUPPLY IN CERTAIN VISCERA 257

is also possible along the sheaths of certain of the cranial nerves. Re-
cent investigation has, however, clearly demonstrated that under nor-
mal conditions the amount of cerebrospinal fluid is too limited to make
it of any significance in this connection. As explained on page 255 the
main function of the fluid is to equalize the pressure between the brain
and the cord.

Although it is therefore improbable that the vessels as a whole could
expand or contract, it is still possible that some provision might exist
by which extra room could be made to allow of localized dilatation of
certain parts of the vessels. The veins, for example, might contract
in proportion as the arteries dilated and the possibility becomes all the
more likely when we consider that because of the great capacity of the
cerebral veins, their lumina might be considerably constricted without
any serious obstruction being offered to the bloodflow through them.
Such a reciprocal dilatation and constriction of the proximal and dis-
tal halves of a thin-walled rubber tube suspended in water in a closed
flask can be demonstrated provided some resistance be inserted between
the two halves. This resistance would be represented in the intracra-
nial vessels by the capillary area. It is impossible to say to what extent
this reciprocal mechanism between arteries and veins may prevail, but
in any case it can not well extend beyond the cerebral veins to the
sinuses, since these are partly embedded in the cranium itself and are
protected by relatively thick membranes on their free sides. The mech-
anism may be employed for permitting the arteries of a local area to
expand, but it can not obtain over any large area, since otherwise the
total outflow of blood from the sinuses through the jugular foramen
would be curtailed, which we know to be contrary to what actually oc-
curs when the arterial pressure is raised, and which moreover would be
highly detrimental, since it would cause self-strangulation of the intra-
cranial bloodflow.

These physical considerations lead us to expect that there can not be
any dilatation or constriction in the intracranial vessels which is com-
parable with that which occurs in other vascular areas, although it may
take place to a degree which is limited by the extent to which the cere-
bral veins can be passively contracted or expanded without curtailment
of the bloodflow. Acting to this extent, the dilatation produced in the
arteries by each cardiac systole accounts for the rise in pressure which
occurs simultaneously in the venous sinuses (as measured in the torcu-
lar Herophili), but it is unlikely that the amount of blood supplying the
brain will be determined by local dilatation or constriction of the blood
vessels, as is the case, for example, in a gland or muscle. Of this we
are certain, that the total volume of blood within the brain case at any

258 THE CIRCULATION OF THE BLOOD

given moment can undergo no considerable change. Provision for more
or less blood must therefore be afforded by changes in the velocity of
flow.

Physiological Conditions of the Intracranial Circulation

We must now proceed to test these hypotheses by physiological ex-
periment, for, if they are found to apply to the intracranial circulation,
the conclusion becomes inevitable that changes in the total blood supply
to this, the most important organ in the body, are dependent not on any
local adjusting mechanism in that organ itself, but upon conditions pre-
vailing in other parts of the body, with the possibility that a local vaso-
dilatation may be provided for by a secondary compression of neigh-
boring venules, or perhaps even by an active constriction of the arteri-
oles of neighboring inactive centers.

The questions of greatest practical importance are, therefore, as fol-
lows : (1) What determines the intracranial pressure, and how does this
vary during each heart beat! (2) If there can be no change in the actual
volume of blood in the vessels as a whole, what provision is made to
cause changes in blood supply with varying degrees of activity of the
brain, and how are these changes brought about? (3) Is it possible with-
out change in the total volume of blood in the brain for certain vascular
areas to expand at the expense of others that correspondingly constrict?

The Pulsations of the Brain and the Cause of Intracranial Pressure.—
Examination either of the fontanelles in an infant or of the surface of
the brain exposed by trephining shows distinct pulsations, but this does
not prove that similar pulsations occur in the intact brain, for the ab-
sence of a part of the cranial wall might be responsible for the pulsa-
tion. The presence or absence of pulsation must be sought for in the
still rigid brain case. This has been done by closing a trephine hole by
a glass window through which the cranial contents can be seen when
strong illumination is used: pulsations of the vessels are clearly visible.
To determine the exact relationships of the pulsations, the trephine hole
is connected with a delicate recording tambour by screwing into it a
brass tube closed at its inner end by a thin rubber membrane. It has
been found that the arteries expand somewhat with each cardiac sys-
tole, and that there are further expansions with each expiration, but not
with inspiration, as is the case in other vascular areas. The room for
the expansions is no doubt provided mainly by compression of the
cerebral veins, thus causing the blood within them to exhibit corres-
ponding waves of pressure. The reason why expiration and not in-
spiration causes the increase in volume is that there are no efficient valves
between the right side of the heart and the cerebral veins. This allows

PECULIARITIES OF BLOOD SUPPLY IN CERTAIN VISCERA 259

the expiratory rise in venous pressure which is well known to occur in
the former to be directly transmitted to the brain.

This brings us to the second part of our first question : What determines
the intracranial pressure ? To answer it we must know something of the
method by which the pressure is measured. This has been most successfully
done by Leonard Hill,19 who devised an instrument called the cerebral
pressure gauge, consisting of a brass tube closed at one end by rubber
membrane and screwed into a trephine hole. The outer end of the tube
is joined to a narrow glass tube connected with a pressure bottle. The
whole system is filled with fluid except for a minute bubble of air in the
narrow glass tube. Any changes in pressure in the brain cause correspond-
ing movements of the bubble, and the magnitude of the change is meas-
ured by readjusting the pressure bottle so as to bring the bubble back to
its original level. It has been found that the pressure may vary from
zero to 50 mm. Hg. (as in strychnine convulsions), and that these variations
depend entirely on circulatory conditions, there being no compensatory
mechanism by which the pressure is kept constant. The average pressure
under physiological conditions is 100-130 mm. H20.

The intracranial pressure varies directly with the venous pressure within
the skull, and. it passively follows changes in the pressures in the arteries
and veins of the systemic circulation. This implies that the efficiency of
the cerebral circulation will be dependent very largely upon alterations
in the capacity of the splanchnic area, the greatest reservoir of blood in
the body. By actual measurement it has also been found that:

1. The pressure within the lateral sinuses of the brain (measured by
connecting a tube and manometer with the torcular Herophili) varies
absolutely with the intracranial pressure. It therefore exhibits pulsa-
tions which mirror precisely those observed in the cerebral pressure
gauge.

2. Both these pressures passively follow changes in the pressure in
the right auricle. They also run more or less parallel with changes in
arterial pressure, and there is never any change in either of them which
can not be traced to some general circulatory condition.

A few of the many experiments performed by Leonard Hill and others will serve
to prove these far-reaching conclusions:

1. In asphyxia caused by cessation of the respiratory movements in a curarized
animal, the cerebral venous pressure at first falls with the fall in systemic pressure
and then rises as the arterial hypertension sets in. In the last stage, however, al-
though the arterial pressure is quickly falling, the venous pressure rises and with
it the cerebral venous pressure. During vagus inhibition the fall in arterial pressure is
so marked that the intracranial pressures fall at first and only rise later, correspond-
ing to the rise in venous pressure (Fig 80).

2. During administration of ether, alterations in cerebral pressure become marked
only when there is extensive muscular movement or hyperpnea. Chloroform, on the

2GO

THE CIRCULATION OP THE BLOOD

other hand, by acting more directly on the heart so as to produce a fall in arterial and
9, rise in venous pressure, causes at first a decided rise in cerebral pressure and later
a fall following the development of decided arterial hypotension.

3. Amyl nitrite, injected into the jugular vein, causes at first a rise in venous
pressure and therefore in cerebral pressure. Later, however, marked arterial hypo-
tension develops, and the intracranial pressure declines.

Fig. 80. — To show simultaneous records of the arterial blood pressure (A), the venous pres-
sure (B), the intracranial pressure (C), the pressure in the venous sinuses (£>). The fall in ar-
terial pressure produced by stimulation of the peripheral end of the vagus will be found to cause
a fall of intracranial and cerebral venous pressure, accompanying that in the arteries, but a rise
in that of the venous system. (From Leonard Hill.)

4. During epileptic fits induced experimentally by excitation of the cortex, there
is a rise in venous pressure and correspondingly in intracranial pressure. In the more
violent convulsions produced by absinthe, there is very little change in systemic venous
pressure while the arterial pressure shows extreme variations, with which the intra-
cranial pressure runs parallel. With adrenalin, where both arterial and venous sys-
temic pressures rise enormously, there is of course a great rise in intracranial pressure

PECULIARITIES OF BLOOD SUPPLY IN CERTAIN VISCERA 261

and there is never any local change in the latter which would indicate that this potent
drug had locally caused these vessels to constrict.

5. The alterations in systemic pressure induced by the operation of the force of
gravity and coming into play when the position of the body is changed, if not per-
fectly compensated for by constriction of the splanchnic area, will cause correspond^
ing changes in the intracranial tensions. Under the influence of gravity, for example,
the intracranial and the intracranial-venous pressures may fall below zero.

The comparatively slight amount of extra room which can be provided in the
-cranial cavity by compression of the venules and capillaries has suggested to some
writers that a self -strangulation of bloodflow might occur when the pressure suddenly
rises in the basal and cerebral arteries. The increased pressure would be transmitted
un diminished through the incompressible brain substance to the thin-walled vessels and
compress them because of the lower pressure within. This is, however, impossible for
any curtailment in the bloodflow through the venules and capillaries could only be
transitory, since the compression will be overcome by the arrival of the pressure wave
through the blood stream itself. For it is obvious that the arterial pressure trans-
mitted directly must be greater than that pressure after it has overcome the tension
of the arterial wall and is transmitted to the venules through the brain substance.
Whenever this readjustment has occurred, the cerebral vessels become expanded to
the greatest extent possible and they become virtually rigid tubes comparable with
the rubber tube suspended in water in a closed flask, as in the schema referred to
above.

The only variation in intracranial blood supply which can occur is
one affecting the velocity of flow or if you prefer the term — the mass
movement of the blood; the volume can not change. After all, however,
that is what is necessary to meet the demands for more blood, and the
conceptions which have been formed by studies on expansible vascular
areas, such as the kidney and spleen, that increased blood supply runs
parallel with increased volume, do not apply.

That the mass movement of the blood in the cranium increases when
the arterial pressure rises has been shown by direct experiment. Hill
and Nabarro found it increased from two to six times during the con-
vulsions produced by absinthe.

Local Readjustments of Blood Supply in Different Parts of the Brain.—
Limited though any change in caliber of the cerebral arteries can be, it
is nevertheless sufficient to make it possible that local variations in blood
supply might occur as a result of active constriction or dilatation of the
vessels. Just as the blood supply of a muscle or gland may be varied
independently of any change in general blood pressure, by local changes
in the caliber of its blood vessels, so might that of the brain be varied,
and this might occur to a limited extent for the supply as a whole, as
by constriction of the circle of Willis, or to a greater extent in one or
other of the arteries which spring from the circle. By the latter adjust-
ment a greater blood supply might be directed into an area which had
become especially active, the flow to other relatively quiescent areas
being meanwhile somewhat curtailed.

262 THE CIRCULATION OF THE BLOOD

Vasomotor Nerves. — These possibilities raise the question as to whether
there are functionally active vasomotor nerves to the cerebral vessels.
Histologists have definitely demonstrated nerve fibers running on to the
cerebral vessels, especially by the use of the intra vitam methylene blue
method of staining (Huber, Hunter, etc.), but this does not of course
necessarily indicate that the fibers normally cause the arterial walls to
expand and contract. The only basis upon which such a claim could be
put forth is an actual demonstration of changes in intracranial blood-
flow occurring independently of changes in systemic arterial or venous
pressures.

Leonard Hill and Bayliss, and later Leonard Hill and Macleod,20 have
most diligently sought for such evidence, but with entirely negative
results. Kecords were taken of the intracranial pressure, the cerebral
venous pressure and the pressure in the circle of Willis (by a cannula
inserted in the peripheral end of the internal carotid artery), as well
as the arterial and venous pressures in the systemic vessels carotid and
jugular). Since any vasomotor fibers must presumably be derived from
the vasomotor centers, and since these fibers must gain the cerebral
vessels through the stellate ganglion and ultimately travel into the
cranial cavity along the outer coats of the arteries, the above pressures
were simultaneously observed before and during electrical stimulation
at these places. It was found that any change that did occur could in-
variably be attributed to changes in the circulation as a whole ; there
was never any alteration in pressure locally in the brain for which the
occurrence of local constriction or dilatation of the vessels had to be
assumed.

Other observers have attempted to investigate the problem by meas-
urement of the volume of blood leaving the brain, but with similarly
negative results.

But an objection can be raised to these experiments on the ground that there
might be feebly acting vasomotor influences, the effect of which would become entirely
masked by the much more potent influence exerted on the bloodflow by changes in the
circulation as a whole. As pointed out by Wiggers, the only way by which local
changes in the bloodflow through the intracranial vessels can be expected to reveal
themselves is by measuring the entire outfloAV, a measurement which, however, it is im-
possible to make in an intact animal on account of the many patlnvays through which
the venous blood can leave the skull. Measurement of the outflow by one of them
does not by any means indicate the magnitude of total outflow. To overcome these
difficulties, Wiggers proceeded to measure the outflow from all the cranial vessels of
oxygenated Locke's solution perfused into the cerebral artries under constant pressure.
It was found that the otherwise constant rate of outflow became decidedly curtailed
when adrenalin was added to the Locke 's solution. If we assume that this drug acts
only on arterial. muscle having functionally active vasoconstrictor nerves, then the result
would prove the presence of such fibers to the cerebral vessels, but even granted this,

PECULIARITIES OF BLOOD SUPPLY IN CERTAIN VISCERA 263

the result does not warrant the conclusion that, under normal conditions in the intact
enimal, such fibers display any activity. Wiggers. does not claim that his results
prove that a local vasomotor mechanism is important, but thinks that "they are favor-
able to the view that cerebral vasoconstrictor nerves are present. ' '

Intracranial Pressure

One word more with regard to what is known as intracranial pressure,
that is, the pressure in. the space between the skull and the brain.
Under ordinary conditions it must be equal to that in the cerebral capil-
laries, and may be measured by connecting a sensitive manometer with
a tube screwed into the cranium as described above. It has been found
to vary from 0 mm. Hg in a man standing erect to 50-60 mm. Hg in a
dog poisoned by strychnine. It becomes increased, not only by com-
pression of the veins of the neck and by an increase in general arterial
pressure, but also in pathological conditions, such as hydrocephalus. A
new growth in the brain, if it occupies more space than the tissue which
is destroyed, exerts pressure on all parts of that region of the cranial
cavity, but this pressure may not be transmitted equally throughout
the cranial contents, for the falciform ligaments and the tentorium sup-
port a part of it, thus directing the spread of pressure along certain
pathways. The structures at the base of the brain, the optic nerves,
the veins of Galen and the Sylvian aqueduct are most affected in this
way. If the pressure is rapidly applied, however, it may rise through-
out the cranial contents. In such cases the pressure is, of course, cir-
culatory in origin, since immediately after death from cerebral tumor
the intracranial pressure is not found to be raised.

The major symptoms of cerebral compression are no doubt due to
anemia of the medulla oblongata, which may be the result either of
pressure applied locally in the bulbar region, where the presence of a
very small foreign body or only trivial tumor formation is sufficient to
destroy life, or of pressure transmitted from the cerebral cavity, in
which case, on account of the support offered by the tentorium, a much
larger growth is required to affect the medulla. Internal hydrocephalus
produced by blocking of the aqueduct of Sylvius and the veins of Galen
causes the greatest rise in intracranial tension, and may affect the me-
dulla, because the brain is driven downwards so as to pinch the bulb
against the occipital bone. It must be emphasized that it is not the
pressure per se that causes the symptoms, but the attendant anemia,
the symptoms of acute cerebral anemia and of compression being iden-
tical (Leonard Hill19). To relieve the compression, trephining is the
common practice. The trephine hole should be as large and as near
to the source of compression (tumor, etc.) as possible.

264 THE CIRCULATION OF THE BLOOD

CIRCULATION THROUGH THE LUNGS

The pulmonary or lesser circulation, as it is called, is quite different
from the systemic circulation. In the first place, because the pressure
in the pulmonary arteries does not amount to more than about 20 mm.
Hg, or about one-sixth of that of the systemic arteries, the peripheral
resistance in the blood vessels of the lungs is much less than that of
the body in general. This lower resistance is owing partly to the large
diameter of the arterioles and the small amount of muscular fibers in
their walls, and partly to the fact that the capillaries are held con-
stantly in a somewhat dilated condition on account of the subatmos-
pheric pressure in the thorax (see page 323).

Another peculiarity of the pulmonary circulation is that the caliber
of the vessels is to a very large extent dependent upon the changes
that occur in the intrathoracic pressure with each inspiration and ex-
piration. They become dilated on inspiration and contracted on ex-
piration. The extent to which these respiratory changes affect the
amount of blood contained in the lungs, is very considerable. At the
height of inspiration it is computed that a little more than eight per
cent of the whole blood in the body is contained in the lungs, whereas
on expiration it diminishes to between five and seven per cent.

A third peculiarity is that the pulmonic blood vessels are not sup-
plied with vasomotor nerve fibers — at least with such as can readily be
demonstrated. It is said that, when the pulmonary vessels are per-
fused and the outflow measured, a diminution in the latter is found to
occur when epinephrine is added to the injection fluid — a result which
is, however, denied by certain investigators. Changes in the bloodflow
have not been observed to occur when the vagus or sympathetic nerve
fibers running to the lungs are stimulated. In short, the conclusion
which we must draw is much the same as that for the blood vessels
of the brain — namely, that although, as a result of the epinephrine ex-
periment, we must admit that a vasomotor supply may possibly be
present, yet it is one which can be of no significance under normal
conditions.

When there is obstruction to the outflow of blood from the left ven-
tricle, as, for example, in cases of high aortic pressure, the blood is not
entirely discharged with each beat of the left ventricle, and therefore
dams back through the left auricle into the lungs. On account of the
marked distensibility of the pulmonary capillaries, a large amount of
this blood may collect there and thus make the lungs serve as a kind of
reservoir of the heart. When the capacity of this reservoir has, how-
ever? been overstepped, an increased peripheral resistance will come to

PECULIARITIES IN BLOOD SUPPLY IN CERTAIN VISCERA 265

be offered to the movement of blood in the pulmonary arteries, the
pressure in which will consequently rise and sooner or later interfere
with the discharge from the right ventricle, causing as a result a stag-
nation of blood in the systemic veins, and a consequent increase in vol-
ume of such viscera as the liver and kidneys. The same changes will
obviously also supervene when there is regurgitation of blood from the
left ventricle to the left auricle, as in cases of mitral insufficiency.

CIRCULATION THROUGH THE LIVER

The liver is the only gland in the body receiving both venous and
arterial blood, the former being supplied to it at a very low pressure
by way of the capacious portal vein, and the latter at very high pressure
by the strikingly narrow hepatic artery. Except for the relatively
small amount of blood which is supplied to the walls of the blood vessels
and the biliary ducts, none of the hepatic artery blood mixes with that of
the portal vein until the vessels enter the hepatic lobules. Beyond this
point the two blood streams mix and the combined stream is drained
away by the sublobular and hepatic veins.

Methods of Investigation

To study the relative importance of these two sources of blood sup-
ply, and also to investigate the manner in which the latter is controlled,
the most satisfactory method has consisted in measurements of changes
in volume floAV rather than in those of changes in pressure. The vol-
ume-flow measurement has been made either by connecting stromuhrs
(page 207) to the hepatic artery or portal vein, or by measuring the out-
flow of blood from the hepatic vein into the vena cava, first with both
inflow vessels intact, and then with one of them ligated. An objec-
tion to the first (the stromuhr) method is the possible interference with
bloodflow or blood pressure produced by inserting the stromuhr into
the entering vessels, and also the fact that simultaneous measurement
of the flow in both vessels can not be made satisfactorily.

To measure the outflow from the hepatic veins, the aorta is- ligated below the celiae
axis and a wide cannula is inserted into the central end of the vena cava below the
level of the liver, a loose thread being placed around this vessel just above the dia-
phragm. By pulling on this thread the vena cava becomes obliterated, and the blood
from the hepatic veins is therefore diverted into the cannula, through which it flows
into one end of a vessel shaped somewhat like a sputum cup (the receiver), the other
end being connected by tubing with a piston recorder, from the movement of which
the volume of blood flowing into the receiver can readily be computed. To measure
the flow of blood, a clip on the tube of the receiver is removed at the same moment
that the thread around the vena cava above the diaphragm is tightened, and when the
receiypr has filled with blood, this thread is again loosened and the receiver tilted up

266 THE CIRCULATION OF THE BLOOD

so that the blood flows at low pressure back into the circulation. The receiver being
of known capacity, the length of time 'it takes the blood to fill it as determined by the
piston recorder, furnishes us with the necessary data from which to calculate the rate
of flow. The receiver is chosen of such a size that it takes only a few seconds to
fill, the diversion of blood into it not causing any material fall in arterial pressure.
The observations are repeated frequently.

Results. — By the use of these methods it has been found that the total
mass movement of blood to the liver of the dog varies between 1.46 and
2.40 c.c. per second for 100 grams of liver. Considerable changes may
occur in the arterial pressure without affecting the liver flow. When
the hepatic artery is occluded, the flow diminishes by about 30 per
cent, or conversely, when the portal vein is obstructed but the hepatic
artery left intact, by about 60 per cent, indicating that about one-third
of the total bloodflow through the liver is contributed by the hepatic
artery and two-thirds by the portal vein. Some blood, however, gains
the liver through anastomotic channels between it and the diaphrag-
matic veins.

The relative supply ~by the two vessels is subject to various condi-
tions. That through the hepatic artery, for example, may be very con-
siderably altered on account of vasoconstriction in this vessel, for its
walls can easily be shown to be liberally supplied with vasoconstrictor
fibers carried by the hepatic plexus. This can be demonstrated by
the rise in blood pressure which occurs in a branch of the hepatic artery
during stimulation of the plexus. On the other hand, alterations in the
bloodflow in the portal vein can not be brought about by active con-
striction or dilatation of the intrahepatic branches of this vessel, no
active vasomotor fibers having been demonstrated by stimulation of
the hepatic nerves, although, as in the case of the brain and lung blood
vessels, a certain amount of constriction may occur under the influence
of epinephrine.

The bloodflow through the portal vein is dependent on changes oc-
curring at either end of the distribution of the vessel, that is, changes
occurring in the liver itself or in the intestine. Of these factors the lat-
ter is no doubt the more important, an increase not only in portal blood
pressure but also in portal bloodflow being readily produced by dila-
tation of the splanchnic blood vessels; for example, as the result of sec-
tion of the splanchnic nerve. Alterations in portal bloodflow brought
about by changes in the caliber of the vessels in the liver itself are
partly dependent upon changes in the branches of the hepatic artery.
Let us consider briefly how this may be brought about. At the point
where the portal and hepatic arteries come together — that is, at the in-
trahepatic capillaries — the pressure of the blood in them must become
equal, which means that in its course through the interlobular connec-

PECULIARITIES IN BLOOD SUPPLY IN CERTAIN VISCERA 267

tive tissue, the branches of the hepatic artery must offer much resistance
to the blood flowing through them. This frictional resistance resides in
the hepatic arterioles, and since these are richly supplied with constric-
tor nerves, great variation in hepatic inflow becomes possible. These
changes will affect the degree of tension of the interlobular connective
tissue in which the arterioles lie. In this tissue, however, also lie the
thin-walled branches of the portal vein. When therefore the tension
of this tissue becomes greater, as a result, for example, of vasodilatation
in the hepatic artery, the portal vein radicles will become compressed
and the bloodflow along them impeded. Conversely, when vasocon-
striction occurs in the hepatic arteries, the congestion of the connective
tissue becomes diminished, the veins dilate, and the blood flows through
them more readily (Macleod and R. G. Pearce21). Experimental evi-
dence in support of the above view is furnished by observing the out-
flow of blood from the liver before and during stimulation of the he-
patic plexus. The first effect is an increase in the outflow, which very
soon returns to its original amount, even though the stimulation of the
plexus is kept up during the experiment. This return to the normal
flow must indicate either that the constriction of the hepatic artery has
not been maintained, or that it has been maintained but is accompanied
by a compensatory increase in the flow through the portal vein. As
a matter of fact, we know that the hepatic artery remains constricted
as long as the hepatic plexus is stimulated, indicating that the conges-
tion of the connective tissue in which the venules lie has become reduced
to such an extent, as a result of the constriction, that these open up and
permit the blood to flow through them more readily. The initial in-
crease in outflow immediately following upon stimulation of the hepatic
plexus, is no doubt caused by the squeezing out of the blood already in
the hepatic vessels, and it is a result which is often observed in other
organs during stimulation of vasoconstrictor nerve fibers.

THE CORONARY CIRCULATION

We have already studied the effect produced on the heartbeat by in-
terfering with the flow of blood in the coronary vessels, and it remains
for us to study: (1) peculiarities in the bloodflow through them, and
(2) whether this bloodflow can be altered by dilatation or constriction
of the vessels brought about through nerves. With regard to the pecu-
liarities of 'bloodflow, it may be stated that there are said to be two periods
in each cardiac cycle during which an increase takes place in the mass
movement of blood in the coronary vessels — namely, at the beginning
of systole, and again at the beginning of diastole. Nevertheless the

268 THE CIRCULATION OP THE BLOOD

pressure pulse has the same contour in the coronary as in the systemic
circulation. (W. T. Porter.22) During systole the intramural branches
of the coronary artery are compressed and the blood pressed out of
them. This emptying of the vessels favors the flow of blood through
the heart walls.

Regarding the presence of coronary vasomotor nerves, there is at pres-
ent a certain amount of doubt. When strips of the coronary artery are
suspended in a solution of epinephrine, they undergo relaxation instead
of contraction. On the assumption that the action of epinephrine on
blood vessels is the same as that of stimulation of the vasoconstrictor
fibers, this result has been taken as evidence of the absence of such
fibers and the possible presence of vasodilator fibers. A somewhat
similar type of experiment has been performed by injecting epineph-
rine into the fluid used to perfuse the excised mammalian heart,
with the result that, when such injections are made into a heart that
is not beating, evidence of vasoconstriction is obtained, whereas when
injected into a beating heart, dilatation occurs. This latter result
may, however, be owing to the action of the epinephrine in stimulating
the cardiac contractions. Other observers, however, deny that the in-
jection of epinephrine into the coronary circulation has any influence
upon the outflow of the perfusion fluid. Taking the result of these
observations as a whole, we may at least conclude that epinephrine
does not produce the same marked vasoconstriction that it produces in
other blood vessels — a fact, which, as already stated, may be taken
advantage of in bringing about the rise in coronary pressure that is
necessary for successful resuscitation of the heart.

Attempts to demonstrate the presence of vasomotor fibers by electrical
stimulation of the vagus or sympathetic nerve have yielded results which
are quite inconclusive, although some observers assert that the vagus
nerve carries vasoconstrictor fibers to the coronary vessels, and that
the sympathetic carries vasodilator.

Whatever may be the mechanism involved it is evident that adjust-
ment of bloodflow through the coronary arteries in order that this may
correspond, to the greatly varying activities of the heart must be very
close. Evans and Starling, working on the heart-lung preparations
(page 163), have shown that changes in coronary bloodflow depend in-
timately on changes in aortic blood pressure; for example, an increase
of fifty per cent in aortic pressure may cause the coronary flow to in-
crease three times. The tone of the vessels also becomes lowered when
more blood supply is required and this dilatation is probably effected
by an increase in CH of the blood (due to acid metabolic products) and

PECULIARITIES IN BLOOD SUPPLY IN CERTAIN VISCERA 269

possibly by the appearance in the blood of substances like histamine
that cause dilatation of the capillaries. It is computed that the blood-
flow through the heart of a man during rest is 140 c.c. per minute ; during
muscular exercise the flow may increase to 800 c.c. Under these condi-
tions the oxygen consumption of the heart is increased in greater pro-
portion than the increase of bloodflow, which indicates that the 02 must
be more thoroughly utilized, i.e., the coefficient utilization becomes
greater (page 410).

CHAPTER XXX

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL

METHODS*

In the following chapters a brief account will be offered of the clinical
use of the electrocardiogram, of polysphygmograms, and of bloodflow
measurements. This is done to show how physiological technic is being
employed for the accurate investigation of cardiovascular disease.

ELECTROCARDIOGRAMS

To observe the electrical change produced by the spread of the excita-
tion wave over the heart from auricles to ventricles, it is not necessary
to place the electrodes directly on the heart, but, as already hinted, we
may follow the electrical change by leading off from electrodes applied
to the surface of the body. From such electrocardiographic tracings
extremely important facts concerning the propagation of the heartbeat
may be ascertained. In order to make an observation the hands and the
left foot are each placed in a solution of sodium chloride contained in
porous jars, immersed in larger vessels containing a saturated solution of
ZnS04 and zinc terminals.! An arrangement like that in Fig. 81 may also
be used. By manipulation of suitable keys, the extremities may then be
connected with the electrocardiograph in the following manner: Lead 1,
right arm and left arm; lead 2, right arm and left leg; lead 3, left arm
and left leg. Through lead 1, the current acting on the galvanometer will
be that produced more especially at the base of the heart. Through lead
2, the current will pass through the long axis of the heart, and through
lead 3, it will pass mainly along its left border.

When any pair of leads is connected with the galvanometer, it is ob-
served that the string is deflected to one side owing to electrical cur-
rents arising from the skin. Before taking a record of the cardiac
movements of the string, it is necessary to compensate for this skin cur-
rent by introducing into the circuit in the opposite direction the re-
quired amount of current, called the compensating current, to bring the
string shadow back to the zero or midposition. In order that the rec-

*A certain amount of repetition of matter previously discussed has been found advisable in these
chapters for which the indulgence of the reader is requested.

tit is really unnecessary to use the so-called npnpolarizable electrodes. Glass vessels containing
20 per cent NaCl solution with the zinc plates dipping into them are quite satisfactory.

270

ELECTROCARDIOGRAMS

271

ord obtained may be quantitative in character, it is further necessary
that the movement of the string be standardized. This is done by as-
certaining to what extent the string moves when a current of known
voltage is sent through it and by altering the tension of the string so that
one millivolt of current causes an excursion of one centimeter of the
string shadow on the photographic plate. It would take us beyond the
confines of this volume to go in any greater detail into the technic in-
volved in taking electrocardiograms, but it may be said that this is by

Fig. 81. — Electrocardiographic apparatus as made by the Cambridge Scientific Materials Co. Con-
tact electrodes are shown, but the immersion electrodes described in the context are preferable.

no means difficult, provided the instructions which are supplied with
the instrument are carefully followed. In practice the taking of elec-
trocardiograms is indeed quite a simple matter, and the extremely im-
portant information which they give us concerning the mechanism of
the heartbeat and the evidence of myocardial disease should make their
employment a universal practice in all cardiac clinics. Some of these
clinical applications are described elsewhere (page 278).

What particularly interests us here is the contour of the electrocardio-
gram in a normal person (Fig. 82). It will be observed that there are

272 THE CIRCULATION OP THE BLOOD

three waves above the line of zero potential and two waves below it.
They have been lettered from before backward, P, Q, R, S, and T,
and in all such records when correctly obtained, the waves above the
line of zero potential indicate that the base of the heart is negative to
the apex. The exact cause of each wave has been ascertained by taking
simultaneously with the electrocardiogram a record of the mechanical
changes occurring in the heart during each cardiac cycle. Such records
have been secured by taking intracardiac pressure curves with the results
as shown in Fig. 83. The top curve represents auricular and the second

m m

ff» i T

^

m

«<*-

T *T T

Fig. 82.— Normal electrocardiogram. Leads 1, 2, 3. Note that the height of the R deflection in
lead 3 equals the difference between the height of RI and R2.

one ventricular pressure, whereas the lowest is an electrocardiogram.
It will be observed: (1) that the P-wave occurs just antecedent to con-
traction of the auricles; (2) that the small positive wave, Q, which is ab-
sent in these tracings, must occur just before the beginning of the con-
traction of the ventricles; (3) that the negative wave, R, occurs just be-
fore and during the early part of ventricular systole — that is, during
the presphygmic period; and (4) that the long upward wave, T, culmi-
nates at the moment the ventricle begins relaxing.

Although such comparisons give us considerable insight into the cause
of several of the waves, there yet remain certain peculiarities of the
electrocardiogram to be considered. These are: (1) the cause of the

ELECTROCARDIOGRAM

273

slight positive wave, Q; (2) the cause of the positive wave, S; (3) the
cause for the period of equal potential at the base and apex during ven-
tricular systole indicated by the portion of the curve between S and T ;
(4) the cause for the negative wave, T. To solve these problems it is
necessary to compare electrocardiograms taken from the surface of the
body with those from electrodes placed directly on the base or apex of
the ventricle of the exposed heart.

Fig. 83. — TClectrocardiogram (dog) taken simultaneously with curves from auricle and ven-
tricle. It will be observed that wave P slightly precedes auricular systole and that wave R occurs
just before the presphygmic period starts in the ventricle. (From Lev/is.)

The Ventricular Complex

In view of the nature of the electric change which occurs in a strip
of denervated muscle when a wave of contraction passes along it (page
188), the simplest interpretation of the ventricular part of the above
curve is that the contraction must pass into the ventricle at a little dis-
tance from the base, thus causing the latter, for a moment of time, to be
positive to the rest of the ventricle, and accounting for the slight down-
ward wave, Q. Immediately after this the base of the ventricle becomes
negative to the apex, giving us the marked upward wave, R, which
however lasts for but a short period of time, being folloAved by an inter-
val during which the base and apex are of the same electrical potential
(horizontal part of wave between R and T). Finally the base again be-
comes negative to the apex, thus accounting for the smaller upward
wave, T. The cause of the occasionally observed downward wave, S,
following R, is obscure.

The most significant fact in the electrocardiogram is therefore that

274 THE CIRCULATION OF THE BLOOD

the base is negative to the apex at the beginning (It-wave) and again at
the end (T-wave) of the ventricular contraction. How may this be ex-
plained? When electrocardiograms are taken through electrodes placed
directly on the base and apex of the ventricle of the exposed heart, it
has been found that the contour of the electrocardiogram is like that
which is obtained from a strip of muscle when a wave of contraction
passes along it: it is diphasic in character (page 188), a result which
may be interpreted as indicating that the wave of contraction starts at
the base and ends at the apex. This rules out the explanation, at one
time suggested for the T-wave, that the wave starts at the base, then
proceeds to the apex, and finally ends at the base, following the disposi-
tion of the muscular fibers of the ventricle in a folded or loop form,
with the bend of the loop at the apex and the free ends at the base. Al-
though the explanation seemed at first to conform with the embryo-
logical fact that the heart is developed from a folded tube, it can not hold
as has been shown by observing the course of the excitation wave se-
cured through electrodes placed at various points on the surface of the
exposed ventricle (page 194).

The explanation which is accepted by the majority of observers at the
present time is to the effect that the T-wave is caused by the longer con-
tinuance of the electric change at the base of the ventricle than at the
apex. To test this hypothesis the crucial experiment would evidently
be to see whether a T-wave could be induced in an electrocardiogram,
such as that of the frog ventricle, in which no T-wave exists, by hurry-
ing up the contraction process at the apex without affecting it at the
base. This can be done by local warming of the apex, or by applying
the ventricular electrode at varying parts of the ventricle in an excised
heart beating in Ringer's solution of relatively high H-ion concentra-
tion. Mines showed that under these conditions a typical T-wave ap-
pears in the electrocardiogram, as shown in Fig. 84.*

The existence of the small Q-wave, indicating that the contraction
does not really start from the base, conforms with the observation that
the Purkinje system of fibers ends about the papillary muscles, which
therefore would be the first to contract, and with the observations of
Lewis, already alluded to above, on the appearance of the negative vari-
ation on the surface of the exposed heart.

The most important clinical application of the electrocardiogram is
undoubtedly in connection with the determination of the rate of trans-
mission of the excitation wave from auricle to ventricle; thus, the P-R
interval, as it is called, indicates the time taken for the impulse to

*This tracing was found among those left by Professor Mines of McGill University, and for
permission to use it the author is indebted to the authorities of that institution.

ELECTROCARDIOGRAMS

275

A. — Normal

B. — Apex cooled

C. — Apex' warmed

Fig. 84. — Records of electrocardiogram and movement of ventricle of frog showing that when
the apex is warmed a typical T-wave appears in place of a wave in the opposite direction appear-
ing when the apex is cooled. (From Mines.)

276 THE CIRCULATION OF THE BLOOD

travel from the sinoauricular to the auriculoventricular node and bundle.
In delayed transmission this interval becomes abnormally long. Obvi-
ously also conditions of heart-block, of auricular fibrillation, or of auric-
ular flutter will be immediately revealed by the electrocardiogram. The
interpretation of abnormalities in the contour of the ventricular portion
of the curve is, however, not so easy a matter, and should never be
undertaken unless curves from the three leads have been secured, for it
will be found that the corresponding electrocardiograms differ from
one another in detail; for example, the R-wave is usually most prominent
in lead 2, although sometimes it is more prominent in lead 3. T is always
upright in normal individuals in curves taken from lead 2, but it is not
infrequently inverted in those of lead 3, and may show partial inversion
in those from lead 1. The Q-R-S group is often of peculiar contour in
curves from lead 3. These variations are possibly dependent upon the
relative preponderance of the musculature in the left and right ven-
tricles, for it is evident that the amount of muscle included in the path-
way between the two leads will vary.

Interpretation of Electrocardiograms by the Triangle Method

Much light can be thrown on the interpretation of electrocardiograms
by following the change of direction and magnitude of the vector rep-
resenting the potential difference in the heart.

An excellent account of the methods for working out these problems is given by
Fahr51 who has made use in a modified form of the equilateral triangle method of
Einthoven. The triangle is formed by lines joining leads I, II, and III used in elec-
trocardiography (i. e., the two hands and the left foot). When a potential difference
is created somewhere about the center of such a triangle (as in the heart) and we lead
off to galvanometers from it through the corners of the triangle, then the potential
difference between any two corners is to that between any other two corners ' ' as the
projection of a line having the direction of the potential difference at the center on
to the side of the triangle lying between the first two corners is to the projection on the
side of the triangle between the second pair of corners. ' ' By ascertaining synchronous
heights of the electrocardiograms from two leads, we can, by this method, ascertain
the real direction of the electrical tension and the magnitude of the potential differ-
ence in the heart at any phase of its activity. The latter is proportional to a value
called the ''manifest value" which is found as follows: an angle of 60° is constructed
and a distance C, in centimeters, equal to the tenths of millivolts observed in the
electrocardiogram from lead I, is measured off on the horizontal side; a distance D
similarly obtained from the synchronous point on the electrocardiogram of lead II, is also
measured on the other side. Perpendiculars DB and CB are dropped from the ends
of these lines and their point of intersection B is joined to the vertex of the angle A.
This line AB is the manifest value for this moment of the cardiac cycle, its length be-
ing proportional to the potential difference and its direction giving the direction of the
resultant electromotive force set up in the heart.

By ascertaining the manifest values at different phases of the cardiac

ELECTROCARDIOGRAMS 277

cycle Fahr has traced the manner of spread of the excitation wave over
the ventricles, and from the results considered along with our knowl-
edge of the course of the Purkinje system of conducting tissue, and the
rate of -conduction of the electrical disturbance through it and through
the muscle fibers, as well as the precise moment of onset of the first
sound and of the rise in intraventricular pressure, he has arrived at the
following conclusions: The excitation process begins in the Purkinje
system in the neighborhood of the papillary muscles, a little earlier in
the right than in the left ventricle and spreads to the apical region,
causing the Q wave. It is then conducted to the basal portions of the
system, causing the ascending limb of the R wave, and while this is go-
ing on at the base, the impulse is being conducted from the Purkinje
fibers into the muscle fibers at the apex. When as a result, the muscle
fibers have acquired sufficient negativity to neutralize the hitherto pre-
ponderating negativity in the Purkinje system at the base, the descend-
ing limb of R is formed, and S results. Soon thereafter the muscle fibers
are equally affected over the ventricle and S becomes obliterated and,
finally, the negativity dies out at first at the apex and later at the base,
thus causing the T wave. When one ventricle of the heart is hypertro-
phied the conduction path on this side becomes elongated so that the
other ventricle receives its negativity first and the electrocardiogram
becomes distorted. The position of lesions affecting one or other of the
main branches of the conducting system, can be determined by a study
of the electrocardiograms by the above methods. When the left branch
is affected R should be high in lead I and S deep in lead III, whereas in
those of the right branch S should be deep in lead I and R high in lead
III.

CHAPTER XXXI

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL
METHODS (Cont'd)

CLINICAL APPLICATIONS OF ELECTROCARDIOGRAPHY

The Electrocardiogram in the More Usual Forms of Cardiac

Irregularities

By R. W. SCOTT

The principle of the application of the string galvanometer to the
study of cardiac irregularities has been indicated. It is our object here
to outline some of the more common forms of irregular heart action,
with a brief description of the abnormalities in the electrocardiogram
resulting therefrom. For the sake of comparison a normal electrocar-
diogram is shown in Fig. 82. The cause and relationship of the various
deflections have been explained (page 272).

Sinus Arrhythmia. — This irregularity is seen commonly in children
and young adults, and is without pathologic significance. The electro-
cardiogram presents the normal deflections and shows by the varying
spaces between the P deflections that the cardiac impulse has been gen-
erated at slightly irregular intervals.

Sinus Bradycardia. — The electrocardiogram in a simple case of sinus
bradycardia is usually normal, except that the deflections occur at an
unusually slow rate (Fig. 85). This indicates that the cardiac impulse
is built up at a slow rate, but when generated it evokes a normal auric-
ular and ventricular contraction.

The Extrasystole. — The extrasystole may be either auricular or ven-
tricular in origin. Occasionally a rare type is seen in which the im-
pulse arises in the junctional tissues between the auricle and ventricle.
When the focus of impulse production is at or near the sinoauricular
node, the resulting electrocardiogram complexes are practically normal.
If, however, the seat of impulse formation is removed from the S-A
node, the P deflection may be distorted or actually inverted, followed
by a normal Q-R-S-T complex (Fig. 86).

In the case of ventricular extrasystole, the cardiac impulse originates
in either the right or the left ventricle. This abnormal site, together

278

CLINICAL APPLICATIONS OF ELECTROCARDIOGRAPHS

279

Fig. 85. — Sinus bradycardia. Rate 32 per minute. Note the normal appearance of the electro-
cardiogram. P-R interval = .17 seconds.

Fig. 86. — Auricular extrasystole. Two auricular extrasystoles following two normal complexes.
Note the ectopic origin of the extrasystoles indicated by the inversion of P.

I

Fig. 87. — Ventricular extrasystoles arising in the right ventricle.

Fig. 88. — Ventricular extrasystole arising in the left ventricle.

280

THE CIRCULATION OF THE BLOOD

with the path which the impulse takes, produces a much greater differ-
ence of electric potential than is seen in the normal electrocardiogram.
When the impulse arises in the right ventricle near the base, the prin-

L • ' : ...::. j : .. | ; ,., | ' ' • T

—]_ u~ — _j »— U — , —

! 1 1 — 1

m

t~

Fig> 89. — Paroxysmal tachycardia. Auricular origin. Note that the P deflection falls back on T.

Rate 200 per minute.

cipal R deflection is upwards in both leads 1 and 2. Arising near the
apex, the principal R deflection is up in lead 1 and down in lead 2. Two
extrasystoles both arising in the right ventricle are shown in Fig. 87.

Fig. 90. — Auricular fibrillation. Leads 1, 2, 3. Note the coarse fibrillation waves between the
7\' jieaks, and the absence of any P deflections in relation to R. Also the unequal spacing of the R
deflections.

In the case of the left ventricle, a basal impulse gives a downward
principal deflection in lead 1 and an upward in lead 2. When the aberrant
focus is located near the apex of the left ventricle, the principal deflec-

CLINICAL APPLICATIONS OF ELECTROCARDIOGRAPH^ 281

tion is down in both leads 1 and 2. Any one or several of the general
types of extrasystole may occur in the same patient. Fig. 88 shows
an extrasystole originating from the left ventricle.

Paroxysmal Tachycardia.— Electrocardiographic records taken in the
interval between the paroxysms may appear normal. During the tachy-
cardia the records normally show only two deflections, R and a combina-
tion of T and the succeeding P (Fig. 89). If the paroxysm is of auric-
ular origin, the P deflection may be inverted, indicating that the new
focus of impulse production is located at some other site than the sino-
auricular node. Rarely the new focus may be in the ventricles. Records
taken during the paroxysm may show a rapid succession of deflections,
simulating isolated ventricular extrasystoles.

Auricular Fibrillation, — The electrocardiogram in auricular fibrilla-
tion shows three distinctive features:

1. Absence of the P deflections typical of auricular contractions.

2. The ventricular complexes (Q-R-S-T waves) occur in irregular se-
quence and may vary in height.

3. The presence of small irregular oscillations best seen between the
ventricular complexes. A typical tracing of this condition is shown in
Fig. 90.

The dependence of the P-wave upon auricular contraction has been
indicated (page 272). Its absence in auricular fibrillation is accounted
for by the fact that the individual muscle fibers of the auricles contract
independently of one another, so that some fibers are in a state of con-
traction while others are relaxed. This renders impossible a coordinate
contraction of the auricle as a whole.

The multiple impulses from the fibrillating auricles reach the ventri-
cles and evoke a contraction provided the ventricle is not already in a
state of contraction (refractory period, page 178). These irregular
ventricular responses will of course produce unequal spacing of the
ventricular complexes in the electrocardiogram. The variations in the
height of the R deflections is thought to be due to the distortion caused
by the superimposition of the small waves representing auricular ac-
tivity. These small waves must occur throughout the whole cardiac
cycle, but are more or less masked by the ventricular complexes, appear-
ing as separate oscillations only during diastole.

Auricular Flutter. — Auricular flutter was discovered by the electro-
cardiograph, and it is practically impossible to make a diagnosis of this
condition without the use of the string galvanometer. The auricular
deflections are usually rhythmic and in the average case vary in rate
from 200 to 350 per minute. The initial deflection of P may be base
negative or apex negative — up or down — depending on the site of the

282

THE CIRCULATION OF THE BLOOD

origin of the auricular impulse (when arising from some other source
than the S-A node the impulse is said to be ectopic). Usually a regular
succession of P deflections can be traced throughout the record (Fig.
91).

Since it is impossible for the ventricle to respond to all the impulses
coming from the auricles, a condition of partial heart-block obtains
(2:1 — 3:1—4:1, etc.). The ventricular complexes will occur regularly
except when a 3:2 rhythm exists.

l?ig. 91. — Auricular flutter. Auricular rate 300. Ventricular rate 80. Note the inversion of the P

deflections.

Usually the ventricular complexes are such as to indicate that the
stimulus arose in the auricle (supraventricular). The height of the
individual deflections Q-R-S-T may vary, depending on the predominance
of a right or left ventricular hypertrophy.

Fig. 92. — Delayed conduction. Note the normal appearance of the electrocardiogram except for
the prolongation . of the P-R interval, which measures .23 seconds.

Heart-block. — There are three degrees of severity in heart-block: (1)
delayed conduction, (2) partial dissociation, and (3) complete dissocia-
tion.

Any one of these conditions may be present in the same patient at
successive intervals.

DELAYED CONDUCTION. — When the conducting tissues of the heart are
so affected as to cause an abnormal prolongation of the P-R interval,
the condition is called delayed conduction. The ventricles respond to
each stimulus originating at the sinus node, but the time required for the
impulse to pass through the conducting tissues is longer than normal.

CLINICAL APPLICATIONS OF ELECTROCARDIOGRAPHS

283

In a simple case the electrocardiogram may appear perfectly normal,
but when the P-R interval is measured accurately, it will be found to be
lengthened beyond the extreme limits of the normal (0.20 seconds) (Fig.

92).

PARTIAL DISSOCIATION. — In the typical case of partial dissociation the

Fig. 93. — Partial dissociation. Note the failure of ventricular response following the second P,
which has been preceded by two extrasystoles (x) of ventricular origin.

ventricles respond to the impulse coming from the auricle most of the
time, but occasionally fail to do so, when the condition is called "dropped
beat." The electrocardiogram records a P deflection but no ventricular
complex, showing that the auricles have contracted at their usual rate
but that the ventricles failed to respond to the stimulus coming from
the sinoauricular node (Fig. 93).

£

Fig. 94. — Complete dissociation. Note that the P wave spaces regularly and bears no definite re-
lation to the R wave of the ventricular complex. Auricular rate 72. Ventricular rate 40.

COMPLETE DISSOCIATION. — In a simple case of complete dissociation
the auricles beat independently of the ventricles; hence the P deflection
of the electrocardiograms bears no relation to the ventricular complex
(Q-R-S-T) (Fig. 94). The P deflections space regularly and are easily
made out when they fall during diastole of the ventricle. Occasionally

284 THE CIRCULATION OF THE BLOOD

the auricle will happen to contract during ventricular systole, causing a
distortion of the ventricular complex by the superimposition of a P
deflection. Except when this occurs the Q-R-S-T complex is the normal
supraventricular type. The P deflections occur more frequently than
the Q-K-S-T complex, showing that the auricles are beating more often
than the ventricles. The auricular rate in the average case of complete
heart-block is about 72, while the ventricular rate is much slower (35
to 40).

CHAPTER XXXII

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL
METHODS (Cont'd)

POLYSPHYGMOGRAMS

(Revised by DR. N. B. TAYLOR)

For purposes of more precise study and description of polysphygmo-
grams and in order that the events in the different pulse tracings (jug-
ular, carotid, apex beat, and radial) may be correlated accurately with
one another, in regard to time, the following method of standardization
has been employed (see Fig. 95). The tracings have been superimposed,
accurately, so that the commencement of each is in the same vertical
line (i.e., all the curves are made to start, as it were, at the same in-
stant). Perpendicular lines (6 in number) have then been drawn through
the tracings at certain important and easily recognizable points. Since
the tracings commence together and the intersecting lines are perpendic-
ular to them it is clear that the points in the different curves which are
cut by a given line will be synchronous, for example, line 2 cuts the
tracing of the apex beat at the commencement of its upstroke and falls
in the case of the venous tracing near the summit of the "A" wave.
These events in the respective curves, consequently, must be of simul-
taneous occurrence.

In the taking of polysphygmograms the following technique is usu-
ally employed:

Venous Pulse Tracing's. — The subject is directed to lie down with his
head slightly raised by a cushion and turned toward the right side. An
open tambour (one having no rubber membrane) is placed above the
inner end of the clavicle on the right side of the neck, that is, immedi-
ately overlying the jugular bulb.

Though the features of a normal and typical venous pulse tracing may be
recognized by inspection alone, it is very often impossible in diseased
conditions to identify the different waves of the curve Avithout the use
of a standard for comparison. For this purpose a simultaneous tracing
is taken from an artery, the features of which (primary and dicrotic

28o

286

THE CIRCULATION OF THE BLOOD

waves) can readily be defined. The receiving button of a second tam-
bour, therefore, is applied to the carotid (or radial) artery.

The writing points of the two tambours (venous and arterial) are then adjusted
to the recording surface, their points being so arranged that they lie approximately
in the same perpendicular line. Since it is practically impossible to adjust the two
styles so that they lie one precisely perpendicular to the other, obviously one style
must commence to describe its tracing a fraction of a second before or after the other
and vertical lines cutting the two records will not pass through synchronous points.
In order to correct for this difference in the time relations of the two curves, each

'/f SeeonJis I A 3V

Rex oil <xi

Fig. 95. — Tracings of the jugular pulse, apex beat, carotid and radial pulses. The perpen-
dicular lines represent the time of the following events: 1, The beginning of the auricular
systole; 2, The beginning of the ventricular systole; 3, The appearance of the pulse in the
carotid; 4, The appearance of the pulse in the radial; 5, The closing of the semilunar valves; 6,
The opening of the tricuspid valves. (Mackenzie.)

style (by a gentle tap of the finger while the paper is at a standstill) is made to
describe an upright mark. The lines so made are termed alignment marks, and by
their means the relative positions of the two writing points are recorded, thus enabling
subsequent time measurements to be made with accuracy. After adjusting a time
marker (one-fifth second), which should always be employed simultaneously with the
pulse tracings, the clockwork mechanism which carries the paper is started and al-
lowed to revolve at a moderate speed. (A convenient form of apparatus in clinical work
is shown in Fig. 95.)

The interpretation of the venous pulse tracing is obtained in the fol-
lowing way: The distance from the alignment mark of the carotid trac-
ing to the commencement of the upstroke of the latter (intersection of
line 3) is measured. The same distance is then laid off on the venous
tracing, commencing from the alignment mark of this tracing. If a

POLYSPHYGMOGRAMS 287

stroke be made through the point obtained by this measurement it
will be found to cut the venous curve at the beginning of a small wave
(c) which is produced by the bulging into the auricles of the closed au-
riculo-ventricular valves. Our measurements show that this "c" wave
of the venous tracing commences at the same instant that the upstroke
appears in the carotid tracing. That these events are simultaneous in
the respective curves may be shown in another way, for example, should
two such tracings be separated (by dividing the paper longitudinally
between them) and superimposed, so that their respective alignment
marks lay in the same straight line, we would find that line 3 drawn
from the upstroke of the carotid tracing would when continued through
the venous curve intersect the latter at the commencement of the "c"
wave. We would then have an arrangement identical with that of the
venous and carotid tracings in Fig. 95.

The auricular wave (a) of the venous pulse, which is due to the sys-
tole of the auricle, is determined by measuring approximately one-fifth
of a second in front of the "c" wave. Line 1 passes through the com-
mencement of this wave. In order to identify other waves in the venous
tracing similar procedures are carried out as in the case of the "c"
wave determination. If the distance from the alignment mark of the
carotid tracing to the commencement of the dicrotic notch of the latter
be measured and the same distance marked off on the venous tracing, a.
line drawn through the point so obtained will be found to fall upon
the upstroke of a large wave "v" close to its summit. In a similar
manner a measurement of the carotid curve from its alignment mark to
the termination of its dicrotic wave (intersection of line 6) would,
when transposed to the venous pulse tracing, indicate a point on the
down slope of "v" a short distance beyond its summit.

As the time consumed in the propagation of the pulse to the jugular
and to the carotid is approximately the same in either case, the carotid
tracing, in order to avoid confusion, has been used as the standard for
comparison in the foregoing calculations; but the radial curve is more
commonly employed for this purpose. When such is the case the time
required for the propagation of the pulse from the neck to the wrist
must be taken into our calculations. This is about one-tenth second, so
that when the radial tracing is employed we must measure to a point
one-tenth second in front of its upstroke (or dicrotic wave) and apply
this distance to the venous tracing in order to obtain synchronous points
in the two curves.

The respective factors responsible for the production of the "c" and
"a" waves have already been mentioned, the production of the other
features of the venous pulse tracing remains for consideration. The de-

288

THE CIRCULATION OF THE BLOOD

pression x is an indication of the fall in intraanricnlar pressure, refer-
ence to the intraauricular pressure curve (Fig. 91 -A) to which, as already
explained, the venous pulse tracing is qualitatively similar, will make
this clear. The factors producing this fall in pressure are as follows :
(1) relaxation of the auricular wall, (2) dragging down of the auricular
floor by the contracting ventricles (compare the jugular and apex curves
in Fig. 95), and (3) reduction of intrathoracic pressure consequent

Fig. 96. — Polysphygmograph. This instrument records in ink on glazed paper two simul-
taneous tracings, i. e., radial pulse and one other, such as carotid, jugular, apex beat, etc., in addi-
tion to the time tracing. The ink tracings are both more convenient and permanent than smoked
paper tracings. The clockwork operates at variable speeds, permitting the taking of protracted
records at different speeds.

Fig. 97. — 'Normal jugular tracing. The spacing below shows the duration of the n-c interval.

(From 15. P. Carter.)

upon the ejection of blood from the ventricle into the arterial system
(see page 215).

The slope from x to y is due to the rising intraauricular pressure as the
blood, flowing into the auricle from the great veins, is dammed back
by the closed auriculo-ventricular valves. A small wave, sometimes, is
seen on the upstroke of the "v" wave at the point where the latter is
intersected by line 5 ; this wave coincides with the closure of the semi-

lunar valves. At the summit of the

wave the auriculo-ventricular

valves open and the fall in intraauricular pressure which occurs, as

POLYSPHYGMOGRAMS

289

the blood escapes into the ventricle, is responsible for the downward
slope in the curve from v to y.

The Cardiogram (tracing of the apex beat). — In order to record and
interpret the cardiogram, tambours are applied to the apex beat and the

OF Se*]l(||o,,«H.

•A

**&•

L.NE I

u»»« *iA

Fig. 97-A. — Superimposed pressure curves from aorta, ventricle and auricle, along with elec-
trocardiogram and phonocardiogram. A, aorta; V, ventricle; Aur, auricle; E, electrocardiogram;
P, phonocardiogram.

carotid pulse in similar manner to that already described for the venous
tracing. An inspection of the tracings so obtained will reveal the fol-

290 THE CIRCULATION OF THE BLOOD

lowing features. A short distance (about one-tenth second) in front of
the upstroke of the cardiogram a small wave, sometimes, appears. This
is due to auricular systole and is termed the auricular (a) wave of the
apex curve: its commencement coincides with line 1. The main steep
rise in the curve is due to ventricular systole. Its commencement, which
coincides with the closure of the auriculo-ventrieular valves, is inter-
sected by line 2. Turning now to the carotid tracing it is found that
a measurement made from its alignment mark to the commencement of its
upstroke when transferred to the apex tracing in the usual way falls
near the upper part of the upstroke of the latter tracing. This point
marks the opening of the semilunar valves and is intersected by line 3.
Measuring again on the carotid tracing from its alignment mark to the

Fig. 98. — Polysphygmograms including jugular, apex and radial tracings. Line 4 on the radial
tracing is first of all located. It is then transferred (by measurement from the alignment mark on
the right edge of the tracing) to the jugular and 1/10 second subtracted from it, giving line 3.
When this is similarly transferred to the apex tracing, it falls somewhere on the upstroke the be-
ginning of which is line 2.

beginning of the dicrotic wave and applying this measurement to the
apex tracing a point is defined near the beginning of the downstroke
of the latter. This marks the time of closure of the semilunar valves
and is intersected by line 5. The termination of the downstroke in the
apex curve in the same way may be shown to be synchronous with the
termination of the dicrotic wave in the carotid tracing. This point in
the cardiogram, which is crossed by line 6, marks the time of opening of
the auriculo-ventrieular valves.

The intervals between the lines 2 and 3, 3 and 5, and 5 and 6 are
termed the presphygmic (space D), sphygmic (space E), and post-
sphygmic (space F) periods respectively (see page 150). The period

POLYSPHYGMOGRAMS

291

between lines 1 and 6 (space G) coincides with that part of the ventric-
ular diastole during which the ventricle is filling with blood, the auriculo-
ventricular valves being open and the semilunars closed.

Abnormal Pulses

The following is a brief description of the main characters of abnormal
pulses :

The Ventricular Form of Venous Pulse. — In this no "a" waves ap-
pear in the jugular tracing, but the "v" waves are unduly large and
dominate the curve. This type of venous pulse may depend upon any
one of the following circumstances: (1) onset of auricular fibrillation,
in which condition the pulse is usually, though not always, irregular,
(2) great increase in the rate of the heart, and (3) overfilling of the
right auricle.

Delayed Conduction and Heart-block. — This causes a change in the

1 LI

"r"rr±±:r

are regularly recurring "a"

Fig. 99. — Delayed conduction time. First stage of heart-block. The A-C intervals measure more
than 0.2 second. (From E. P. Carter.)

time relationship of the "a" and "c" waves in the jugular curve. When
the heart-block is of the first degree, the "a-c" interval merely becomes
lengthened, but when it is of such degree that the normal impulse some-
times fails to be conveyed along the auriculoventricular bundle, isolated
"a" waves can be detected. In the higher degrees of heart-block there

waves having no constant time relationship
waves. For the purpose of exact analysis of the curves in
suspected cases of delayed conduction, it is often advantageous to draw
vertical lines below the tracing representing the beginning of auricular
and ventricular systole. This has been done in the tracing reproduced
in Fig. 99.

The line joining these two verticals indicates the conduction time
or "a-c" interval. When it exceeds one-fifth of a second, there is
delay in the conduction time.

292

THE CIRCULATION OF THE BLOOD

A tracing showing a higher degree of heart-block is given in Fig. 100.

Sinus Arrhythmia. — In this disorder, Avhich occurs in children and
young adults, the heart as a whole is affected, so that the "a, " "c" and
"v" waves of the jugular tracing are in normal time relations with one
another. The pulse is markedly irregular, the irregularity very fre-
quently bearing a direct relation to the respirations. A disturbance of

tft

"I T

i r

Fig. 100. — Dropped beats. Second stage of heart-block. (From E. P. Carter.)

the vagal influence is believed to be concerned with the production of
this type of arrhythmia.

Sinus Bradycardia. — The beat originates at long intervals in the
sinus; the "a-c" interval is normal, and the radial pulse very slow but
practically regular.

Premature Beats. — These may be either ventricular or auricular in

Vy-mWu

I I M h-H I I h
K-K 4-* ^ M

Fig. 101. — Premature beats (extrasystoles) ventricular in origin at PB. Compare the duration of
the intervals marked A and B' with those marked C and D. (From E. P. Carter.)

origin. In the former case the "a" waves on the jugular tracing space
regularly throughout, but the "c" waves at the point of disturbance
coincide with the "a" waves, giving therefore a more pronounced wave.
This is due to a premature contraction of the ventricle occurring about

POLYSPHYGMOGRAMS 293

the time of the "a" wave, so that the latter finds the ventricle in a re-
fractory state (see page 178). The premature contraction is therefore
followed by a compensatory pause, which is evident on the tracing. An
example of such a case is given in Fig. 101. In doubtful cases the exact
site of origin of the premature beats can be determined only by careful
measurement of the distances between the various beats of the ventricle.
Whenever an irregularity repeats itself and the duration of one cycle
of the arrhythmia accurately corresponds to another, the irregularity
may be due to: (1) premature auricular or ventricular contractions;
(2) the occasional occurrence of dropped beats (a failure of ventricular
response) ; or (3) a high degree of heart-block with a wide variation in
the ventricular response. The important point to note here is that, no
matter how irregular such a tracing may appear, if the irregularity re-
peats itself it can not be due to auricular fibrillation.

Fig. 102. — Paroxysmal tachycardia. The paroxysms start at xx following normal beats and
lasting for seven beats. The clue to "a," which falls with "v" after the first premature contrac-
tions, is found in the initial beat of the new rhythm. (From E. P. Carter.)

Paroxysmal Tachycardia and Auricular Flutter. — These conditions are
characterized by a very great increase in the cardiac rate, the auricles
beating, in the case of paroxysmal tachycardia, at the rate of 150 to 200
per minute. In auricular flutter the rate is more rapid still, the auricles
attaining a speed of 200 to 400 beats per minute. (See Figs. 102, 103,
104.) There is no fundamental distinction to be made between these two
conditions; each is dependent upon impulses arising from an unusual
situation in the auricular muscle, the sinoauricular node having lost its
control over the auricular rate. The respective terms employed for. the
designation of the two conditions are more or less arbitrary ones based
upon the extent to which the auricular rate is increased; the term par-
oxysmal tachycardia being applied to cases with the slower rates (150
to 200 per minute) whilst the term auricular flutter is employed in in-
stances where the higher rates of auricular contraction prevail. In

294

THE CIRCULATION OF THE BLOOD

auricular flutter, however, on account of the extreme degree to which
the contractions of the auricles are increased, the ventricles are rarely
able to keep pace with the latter, so do not respond to every auricular
impulse. The failure of the ventricle is due partly to the refractory
phase of the conducting bundle and partly to the refractory phase of
the ventricular muscle itself. In some cases the ventricular response
fails at odd intervals only, but usually the missed beat recurs more
frequently. Two, three or even four auricular beats may occur before

Fig. 103. — Auricular flutter. In this case the ventricular rate varied from 82 to 98 per minute.

(From E. P. Carter.)

IvxMwMv.xl

Fig. 104. — Auricular flutter. Note the relative rates of A and V, and also that the ventricular
rate is regular. (From E. P. Carter.)

one appears in the ventricle, so that the ratio between the beats of the
auricles and the ventricles may be 2:1, 3:1, or 4:1. In extreme cases
the two chambers may be completely dissociated, the auricle beating at
a rate of 300-400 per minute while the ventricle continues at its own
inherent rate of 35-40 beats per minute.

Missed beats accompanying auricular flutter must not be confused
with true heart block; in this disorder the auricular beats are not
increased.

Paroxysmal tachycardia and auricular flutter are each characterized

POLYSPHYGMOGRAMS

295

by a sudden onset and an intermittent course. In the former condition
the paroxysm lasts for a period varying from a few minutes to several
days; in auricular flutter the attack, though it may be of brief duration,
more frequently lasts for months.

Auricular Fibrillation. — The contractions of the auricle, as already ex-
plained, are entirely irregular, and the jugular tracings show an en-
waves, the radial tracing being characterized by

^§L. V» k V 1. TV X Uv Uk k lv 1

Fig. 105. — Auricular fibrillation. Note the absence of all "a" waves from the jugular tracing, the
marked irregularity of the radial pulse, and the occurrence of "c" and "v" during the sphygmic
period. (From E. P. Carter.)

the complete absence of a dominant rhythm and by great variation in the
length of the individual beats from one cardiac cycle to the next. This
irregularity does not repeat itself, and the long- pauses are not simple
multiples of the shortest pause. Tracings from a case of auricular
fibrillation are shown in Fig. 105.

CHAPTER XXXIII

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL
METHODS (Cont'd)

THE MEASUREMENT OF THE MASS MOVEMENT OF THE BLOOD

Method. — The apparatus used for this purpose consists essentially of a vessel con-
taining a known quantity (3,000 c.c.) of water and a thermometer from which a change
of temperature of a hundredth of a degree centigrade can be read. In order to
diminish as much as possible the loss of heat between the vessel and the outside air, the
avails are double, the space between being stuffed with broken cork. The top of the
vessel is closed with a thick cork plate, having suitable openings in it for the hand or
foot and for the thermometer and a stirrer (feather) with which to keep the water in
constant motion. The apparatus is called a calorimeter.

After the hand or foot has been in the calorimeter, with the water a few degrees
below that of the body, for a certain time (ten minutes) the temperature of the water
will of course become raised, and the degree to which this occurs, multiplied by the
volume of water in cubic centimeters, will give in calories the amount of heat dissipated.
By the application of a very simple formula it is now an easy matter to calculate how
much blood must have passed through the blood vessels of the part in order to give out
the observed amount of heat; for, if we divide the calories by the difference in tempera-
ture between the inflowing and outflowing blood of the part, the result must indicate
the volume of blood, in cubic centimeters, that has passed through it (since by defini-
tion a calorie equals volume multiplied by difference in temperature). It remains to
explain the equation by which the results are arrived at. If Q equals the amount of
blood, E the calories of heat given out to the calorimeter, T the temperature of the
arterial blood and T' the temperature of the venous blood, then we have the equation:

H*

Q— — r It has been shown by Stewart that T may be taken as the same as that

of the mouth, or 0.5° C. below that of the rectum, and T' as the average temperature
of the water in the calorimeter during the observation. To allow for the specific heat

of blood, the result is multiplied by _ , the reciprocal of the specific heat of blood.

9

Theoretically, then, the method is very simple, and there are no un-
usual technical difficulties in applying it. The main precaution is that
the air surrounding the calorimeter should be kept constant in tempera-
ture, so that we may be enabled to allow in our calculations for the loss
of heat from the calorimeter itself, this value being obtained by observ-

*For the determination of H we must multiply the cubic centimeters of water plus the water
equivalent of the hand and calorimeter (because both of these will absorb some heat) by the dif-
ference in temperature plus the self-cooling of the calorimeter (because some heat is lost to the
air during the observation). The water equivalent of the hand is equal to its volume multiplied
by 0.8; that of the calorimeter must be determined for each instrument and is usually about 100 c.c.
The self-cooling of the calorimeter is determined by observing the fall in temperature for a period
equal to that of the actual observation without the hand in the calorimeter.

29Q

MEASUREMENT OF MASS MOVEMENT OF BLOOD 297

ing the change of temperature in the calorimeter for a certain period
of time after the hand has been removed from it.

The Normal Flow

The results are calculated on the basis of grams of blood flowing
through 100 c.c. of tissue in one minute. The volume of the hand or foot
is ascertained by placing it in water contained in a small-sized irrigation
can, the tube of which is connected with a burette. The height to which
the water rises in the burette is noted, and after withdrawing the hand,
water is added from a graduate to the irrigation can until the same
height is reached on the burette. The number of cubic centimeters re-
quired gives the volume of the hand. In a normal, healthy individual
the average flow in the hand is from 12 to 13 gm. for the right hand,
and about half a gram less for the left. This difference between the two
hands corresponds, of course, with their relative degree of development.
The average foot flow is much less, and varies according to whether the
patient is sitting up or lying down while the measurement is being made.
In a normal individual, while lying down, it was 5.11 gm. in the right
foot and 5.23 gm. in the left, per 100 c.c. of foot; but only 2.96 gm. for
the right and 4.1 gm. for the left foot, while sitting up. By extended ex-
perience with the method we have found that the bloodflow is very
greatly influenced by the average outside temperature. Although the
outside influence may be diminished somewhat by spending some time
indoors before the measurement is actually made, this does not entirely
remove the outside influence.

The Physiological Causes for Variations in Bloodflow. — As above indi-
cated, the most marked of these is probably the temperature of the
room. The temperature of the water in the calorimeter has likewise a
great influence, and for the comparison of different cases it is always
important that the room and calorimeter temperatures be stated along-
side the results. Muscular contractions, produced by compressing
a dynamometer by the fingers, cause a decided increase in flow. A
great diminution of flow results from constriction of the arm of sufficient
degree to obstruct the venous circulation; and when the constriction,
as that caused by a blood pressure armlet, is increased to between the
systolic and diastolic pressures, extremely little blood flows through the
hand.

By immersing the opposite hand or foot in hot or cold water, the blood-
flow through the observed hand increases or decreases, respectively.
The change may be of a temporary character, or it may persist through-
out the whole period of immersion of the hand. These reactions are due
to a vascular reflex, and observations of its sensitiveness are of value in

298 THE CIRCULATION OP THE BLOOD

the study of the effects of lesions either of the nerve or of the nerve
centers concerned in vascular reflexes. Massage of the hand prior to
placing it in the calorimeter does not affect the flow. Massage of the
opposite hand, however, appears to cause an increase in flow.

Clinical Conditions which Affect the Bloodflow

Even in cases where there is plenty of other evidence of curtailment
of flow, the measurement may be of importance either for detecting
an alteration in the vascular reflex or, by comparison of the two
hands, for demonstrating the relative degree of alteration in flow. In
acute inflammatory conditions affecting one hand, there is an increase
in flow on the affected side accompanied by a marked curtailment on
the other side. This indicates that an increased flow in the infected
area is accompanied by a reflex vasoconstriction elsewhere, particu-
larly in the symmetrically placed part of the opposite side of the
body. In cases of nonbacterial inflammation of the hand, as in gout.
no sign of vasoconstriction may be observed.

There are many clinical conditions in which Stewart's method re-
veals an alteration in bloodflow that would be unsuspected by the use
of ordinary clinical methods. It is for the investigation of these that
the method is of greatest value but it must be used with very great care
that the temperature conditions are always the same; otherwise the re-
sults are apt to be misleading. The most important findings are as
follows:

Anemia. — The bloodflow in the hand may be much less than normal
in pernicious anemia and secondary anemia, and distinctly curtailed
in chlorosis. Since the minute volume of the heart is also increased
in extreme degrees of these conditions, the vasoconstriction at the periph-
ery will assist in compelling more blood to pass through the lungs, so as
to make up for deficiency of blood.

Fever. — Since changes in the cutaneous circulation probably con-
stitute the chief factor in the derangement of the temperature-regu-
lating mechanism in fever (cf. page 742), it is evidently of great ad-
vantage to be able to measure such changes quantitatively. This has
been done by Stewart in several cases of typhoid fever and in one case
of pneumonia. In general it was found that the flow in the feet never
exceeded the normal flow, and was usually much below it. This ten-
dency to vasoconstriction seems to be carried into convalescence. For
practical reasons the handflow has not been so extensively studied.
This hyperexcitability of the vasoconstrictor mechanism at the periph-
ery is most naturally interpreted as a defensive reaction of the or-

MEASUREMENT OF MASS MOVEMENT OF BLOOD 299

ganism by which an increased supply of blood is imported to those
internal organs which bear the brunt of the infection. When we con-
sider that in spite of this constriction of the periphery the blood pres-
sure is low and the pulse dicrotic, we must conclude that there is con-
siderable 'dilatation of other vascular parts, especially the splanchnic
area. A very practical application of these facts presents itself in con-
sidering the rationale of the cold-bath treatment for fever. If, for
example, we conclude that the cutaneous constriction is in the inter-
ests of an increase in the bloodflow to the organ on which the stress
of the infection falls, it will evidently be more rational to lower the
temperature by methods which will not diminish, and may even in-
crease, the cutaneous constriction than to do so by causing the vessels
to dilate. In other words, the use of antipyretics seems to be contra-
indicated, since they diminish the body temperature by causing vaso-
dilatation at the periphery with a consequent withdrawal of blood
from the seat of infection.

Cardiovascular Diseases. — In cardiac cases the handflow is far more
apt to be markedly deficient where there is evidence of serious impair-
ment of the myocardium than in cases where a gross valvular lesion
exists but the heart action is strong and orderly. This indicates that
it is more serious for the force of the heart pump to be interfered
with than for its valves, particularly the mitral, to be leaky. Even
where there is considerable venous engorgement, the flow may be lit-
tle diminished. In untreated cases of auricular fibrillation the blood-
flow is subnormal. After the administration of digitalis the bloodflow
in such cases is often promptly and decidedly increased.

As would be expected, arteriosclerosis is associated with a small blood-
flow, arid the vasomotor reflexes are weaker than in normal persons.

In aortic aneurism, when the aneurism is of such a size as to cause
pressure on the subclavian artery or vein, there is a diminution in flow
of the corresponding hand, but aortic aneurism itself, although it' may
cause great changes in the character of the pulse beat, does not decid-
edly affect the mass movement of the blood. In aneurism of the sub-
clavian artery, the bloodflow may be much greater in the corresponding
than in the opposite hand, even though the amplitude of the pulse is
very obviously diminished and the difference between the systolic and
diastolic pressures (the pressure pulse) is much less on the affected
than on the normal side. By ordinary clinical measurements, there-
fore, false estimates of bloodflow are quite likely to be made. These
results are no doubt owing partly to vasodilatation brought about by
pressure of the aneurism on the brachial plexus and partly to the
lower resistance to the flow of blood into the dilated subclavian.

300 THE CIRCULATION OF THE BLOOD

In Raynaud's disease, as would be expected, the flow is small, the
diminution being more or less proportional to the duration of the
disease. The contralateral vasomotor reaction to cold is also pecu-
liarly intense.

In diabetic gangrene of the feet there is a very subnormal flow in both
the hands and the feet. The vasomotor reflexes are also feeble.

It is sometimes difficult to tell whether an observed curtailment of
flow is a nervous (reflex) effect or is due to some mechanical interfer-
ence. There are two ways by which the exact cause may be diagnosed:
(1) by observing the flow from day to day; if it remains unchanged,
any alteration must be dependent on mechanical causes; (2) by observ-
ing the change in flow brought about by altering the temperature of the
room or calorimeter and seeing whether the ratio between the two hands
remains unchanged or becomes altered. If the latter occurs, the in-
equality in flow must be due to nervous causes.

Diseases of the Nervous System. — The effect of neuritis on the flow
varies with the duration of the disease. In cases of early peripheral
unilateral neuritis there may be an increase of flow altering the ratio be-
tween the two hands with the greater flow on the diseased side. In
neuritis of long standing the flow is cut down, the greater flow occurring
on the healthy side. The changes here are probably due to anatomical
alterations in the lumen of the tube, perhaps a thickening of the intima.
In motor-neuron disease without any involvement of the sensory skin
nerves the flow seems to remain normal and the reflexes to be well-
marked. This indicates that involvement of the motor nerves does not
interfere with bloodflow to anything like the same degree as involvement
of the skin nerves.

Hemiplegia. — A deficiency of bloodflow of the paralyzed side is usually
observed, and the vasomotor reflexes are altered, the most usual change
being that vasoconstriction is more easily produced than vasodilatation.
In some cases an abnormal tendency to vasoconstriction is a conspicuous
feature.

Tabes Dorsalis.— The flow is distinctly diminished, especially in the
feet, although also in the hands, and the vasomotor reflexes are feeble.
Sometimes there is inequality in the flow of the two hands, which how-
ever need not necessarily indicate a unilateral lesion of the cord in the
cervical region.

CHAPTER XXXIV
SHOCK

Shock may be due to a variety of causes. In general it may be de-
scribed as a condition in which there is more or less paralysis of the
sensory and motor portions of the reflex arc, along with profound dis-
turbances in the circulatory system, subnormal temperature, and fre-
quent and shallow respiration. Certain of the symptoms may be consid-
ered as primary and others as secondary, an important step in the in-
vestigation of this difficult and important problem being to distinguish
between the two groups. Before attempting to do this, however, it will
be profitable to differentiate as sharply as possible the various conditions
in which one or another of the many varieties of shock is liable to occur.

Several varieties of shock have been described but it is particularly
that known as surgical or secondary shock that is important. The less
important varieties are as follows:

1. Gravity Shock. — This is caused by the stagnation of blood in the splanchnic ves-
sels and the consequent inadequate filling of the heart in diastole. It occurs, when the
erect position is assumed, in animals in which the mechanism which ordinarily compen-
sates for the tendency of gravity to make the blood flow to the dependent parts is
inadequate. Thus, when a domesticated rabbit with a large pendulous abdomen is
held in the vertical tail-down position for any length of time, the animal gradually
passes into a shocked condition and may die in a short time (20 to 30 minutes). Ob-
servation of the blood vessels of the ear or a record of arterial blood pressure will
show that the cause of shock in this case has been a great curtailment of the blood
supply to the upper part of the body, and therefore to the nerve centers. The shock
is entirely dependent upon the laxity of the abdominal musculature, for if a binder
is applied to the abdomen, or if the experiment is performed on a rabbit whose
abdominal musculature is in good condition, gravity shock does not develop. Nor can
fatal gravity shock be produced in a dog, although in a deeply anesthetized animal
a marked fall in arterial blood pressure occurs when the vertical tail-down position is
assumed. In man^ in whom compensation for the erect posture is highly developed,
shock from gravity occurs only when there has been some other considerable upset in
the circulatory mechanism (see also page 249).

2. Hemorrhagic Shock. — Free hemorrhage produces a typical condition of shock, but
the extent to which different individuals react to the same degree of hemorrhage
varies considerably. The essential factor in the production of hemorrhagie shock is
of course similar to that of gravity shock — namely, a deficient diastolic filling of the
heart with blood. Details concerning the effect of hemorrhage will be found elsewhere
(page 138).

In man hemorrhagie shock is often indistinguishable from surgical shock. This does

301

302 THE CIRCULATION OF THE BLOOD

not mean that every case of severe hemorrhage is necessarily also suffering from the
condition usually understood as surgical shock, but hemorrhage greatly predisposes t<
shock, and unfortunately it is often impossible to tell from the symptoms alone how
much of the latter is present. The diagnosis is clinched by the effect of transfusion;
the hemorrhagic case quickly recovers whereas that in shock only slowly, if at all.

3. Anesthetic Shock. — So far as blood-pressure reflexes are concerned, an animal can
be kept in a perfect condition when ether is administered in just sufficient amount to
produce light anesthesia. When larger quantities cf ether are employed, a typical con-
dition of shock may supervene after a time. In such instances the arterial blood pres-
sure remains low and cannot be restored even after an hour or two of artificial respira-
tion. The danger of anesthetic shock has been considerably diminished in the clinic
by the more careful administration of ether or by the use of other anesthetics, such
as nitrous oxide gas. A condition closely simulating shock may also be induced in
the earlier stages of the administration of anesthetics when these are badly given, but
paralysis of the heart or of the respiratory center is a usual cause.

In cases which have recovered from the shock which often follows immediately after
some severe accident, and which is usually called primary shock, the administration
of an anesthetic may bring on secondary shock. The danger is least when nitrous oxide
is used.

4. Spinal Shock. — Spinal shock is produced by section of the spinal cord, but it is
to be carefully distinguished from all other forms of shock because of its local charac-
ter, as it affects only those parts of the body which lie below the level of the lesion
in the cord. Above this level the animal may be in a perfectly normal condition, except
in cases where the section has been at so high a level that it has severed the vaso-
constrictor pathway and thereby produced a fall in blood pressure from vasodilatation.
Even when this has happened the part of the animal anterior to the spinal lesion is by
by no means in a condition of shock. Thus, Sherrington observed in a monkey whose
spinal cord had been cut far forward that, although the posterior part of the body was
in profound spinal shock and the blood pressure very low, the animal amused himself
by catching flies with his hands. A sufficient description of the condition of spinal
shock will be given elsewhere, but here it may be noted that it consists essentially
in a paralysis involving at first all of the reflex mechanisms, including the control of
the sphincters, in the part of the cord posterior to the section. In the course of a few
days or weeks, according to the position of the animal in the scale of development,
the reflexes gradually return, until ultimately in a couple of months — in a dog, for
example — they may all have reappeared. The cause of this shock is no doubt the
sudden interruption of the nervous pathways which reflex action ordinarily takes in
the higher animals (see page 924).

5. Toxic Shock. — The condition known as anaphylaxis and that which follows the in-
jection of histamine into normal animals furnish the best known examples of toxic
shock. There is also some strong evidence that a toxic factor is often involved in the
causation of clinical shock. The toxic substance may be liberated from a septic
process, as in septic peritonitis, or from bruised and mutilated tissue, as after a com-
pound fracture. Experience has shown that rapid amputation of a much mutilated
limb in a shocked patient has not infrequently ushered in striking changes for the
better. The shock which develops in intestinal obstruction has been shown by Whippl'-
and his coworkers to be due to a proteose absorbed from the obstructed loops . (see
page 538).

6. Nervous Shock; "Shell Shock." — Considerable attention has been paid to the
nervous shock that has frequently been observed in men who have been subjected to the
harrowing sights and the constant noise and nerve strain incurred in modern warfare.

SHOCK 303

The symptoms may appear suddenly at the front or they may develop in men whr.
have comported themselves in an apparently normal manner until removed to the rear,
when they pass into a condition more or less simulating that of shock. Severe con-
ditions may also result to soldiers from injuries which in normal individuals would
not in themselves be sufficient to produce surgical shock. The characteristic symptoms
in such cases are frequently different from those of other forms of shock, and, as
has been shown by Elliot-Smith25 and T. H. Pear,2^ the condition must be treated from
the neurologic or psychopathic point of view.

Sometimes however a profound condition of shock which yields to no treatment sets
in without any degree of injury that would adequately account for it.38

7. Surgical Shock. — It is this variety that is usually referred to when one speaks
of shock. It may be caused either by severe mechanical injury to a healthy person
or by extensive manipulation and rough handling on the operating table. It is a com-
mon sequela to war injuries and industrial accidents, especially where the destruction
of muscular tissue has been extensive. However produced, the symptoms of surgi-
cal shock are very much the same. The patient is restless and keenly alert mentally.
He complains of great thirst but if given water almost immediately vomits it. His
skin is a peculiar grey color and the lips and gums are more or less cyanotic; the skin
feels cold and is moist with sweat; the reflexes are greatly diminished, and it is
usually only after applying a very painful stimulus that any movement of defense is
elicited or resentment is shown on the part of the patient. The postural reflexes are
also abolished, so that if a limb is lifted it falls back limp and toneless. The pulse at
the wrist is very rapid, thin and almost imperceptible, and the arterial blood pressure
is usually abnormally low. The respirations are frequent and shallow. The rectal tem-
perature is 1° C. or more below normal. The pupils are dilated and react slowly to
light. The symptoms are thus not unlike those of cholera.

In shock observed in the trenches and clearing stations it came to be
recognized that there are two stages, primary and secondary. The con-
dition described in the preceding paragraph is that of secondary shock.
The primary shock comes on immediately the wound is received or
shortly after, when the patient sees his wound or realizes the gravity
of his condition. It may be analogous to the effect caused by the re-
ceipt of bad news, fright, etc. By free administration of fluids and by
keeping the body warm this primary shock is likely to be recovered
from ; but if the patient be left untreated it is apt to pass on to second-
ary shock, the factors producing which are several.

Although the above classification is convenient for descriptive pur-
poses it must be remembered that the clinical condition of shock is
usually due to the combined action of several causes, e.g., hemorrhage,
toxins, and anesthetics. Any one cause may be insufficient but if two
act together the effect will be greater than the sum of the two acting
separately, and this is particularly the case if they be allowed to act for
a long time. Since cold is a factor in the causation of shock, it is most
important to keep the patient warm from the moment at which the onset
of shock is feared.

3()4

THE CIRCULATION OF THE BLOOD

Experimental Investigations of Shock

In the investigation of a problem of this nature little real progress
can be made unless it is possible to reproduce the condition by experi-
mental means on laboratory animals. The various factors which con-
tribute to bring about the condition can then be investigated under con-
trolled conditions and a rational therapy evolved. It was only after
attacking the problem of shock in this manner that it became possible
to treat the condition in man with any measure of success. For inducing
shock experimentally several methods have been employed, of which the
following are important; 1, rough manipulation of the abdominal vis-
cera ; 2, repeated electrical stimulation of large afferent nerves ;
3, applying a clamp, off and on, for a little over two hours to the
inferior vena cava just above the liver, or to the aorta, to such a degree
that the arterial blood pressure is kept at about 40 mm. Hg.31 ; 4, mas-
sive injections of adrenaline. Since the experiments are usually per-
formed on anesthetized animals, the effect of the anesthetic is a contrib-
utory factor in producing the shock.

Having induced a condition of shock, the first step in an investiga-
tion into its cause consists in a differentiation of the symptoms into pri-
mary and secondary.

The earlier investigators were naturally attracted to the pronounced
fall in blood pressure as the most outstanding symptom in shock ; and
attention was directed to its cause. These might be either a lowering of
peripheral resistance or a diminished output of blood from the left ventri-
cle. It was believed by Criie that the former was the cause, and that it
developed because of a universal dilatation of the arterioles brought about
by exhaustion of the tone of the vasoconstrictor center. It has been
clearly shown, however, that the tone of this center is practically normal
in shock, and that the arterioles are maintained not in a dilated but in a
contracted state, indicating clearly therefore that the low blood pressure
must be dependent upon inadequate output of blood from the heart. The
evidence for this conclusion is as follows: (1) W. T. Porter26 and his col-
laborators have shown that both rjressor and depressor reflexes (page 243)
are perfectly normal in a rabbit that is in a condition of extreme shock. It
is particularly important that depressor effects are still obtained in shock,
since this indicates that tonic activity of the center must still be present.
(2) Morrison and Hooker 29 found that the outflow of blood from the or-
gans of a shocked animal, when these are perfused through their blood
vessels with the organ in situ, is less than that from the same organs under
normal conditions. Furthermore, severing of the nerve of such an organ
has the usual effect of causing an increased outflow. (3) This same fact has
been shown by Seelig and Joseph,27 who cut the vasomotor nerve proceeding

Fig. 106. — Illustration showing the appearance of the blood vessels in the ears of a rabbit
"in a state of deep shock." The marked vasoconstriction is very plain in the left ear, the ves-
sels of the right ear being dilated because the cervical sympathetic, which carries the constrictor
fibers, has been cut. (From Seelig and Joseph.)

to the vessels of one ear of a white rabbit and thus caused a local paralytic
dilatation of the vessels. Intense shock was then induced, after which
the blood pressure in the anterior part of the animal was suddenly raised
by applying a clamp to the abdominal aorta just below the diaphragm.
This increased blood pressure caused the vessels of the denervated ear to
become engorged with blood, but not those of the opposite normal ear,
which retained their tone (Fig. 106). (4) The volume of blood expelled
by the ventricles has been shown by Henderson28 to be distinctly diminished
in the early stages of shock, before there is a pronounced fall in blood
pressure indicating that there must be a compensatory constriction of the
arterioles.

To the foregoing evidence of a constricted condition of the arterioles
in shock, may be added the less direct evidence furnished by the. pallor
of the shocked patient and the indications that 'the sympathetic nervous
system, instead of being paralyzed, is in an excited state, as shown by
the sweating and the dilated pupils.

Furthermore, we know from the experiments of Pike, Guthrie and
Stewart30 that the vasomotor center can withstand complete anemia with-
out losing its tone or reflex activity, better than any of the other cardinal
centers.

Those who have maintained that a deficiency in the tone of the vaso-
constrictor and other nerve centers is responsible for shock have based
their evidence partly on histological examination of nerve cells of shocked
animals, it being assumed that the chromatolysis shown by these cells
indicates an exhausted condition. The assumption is, however, entirely
unwarranted, and no regard is given to the well-established fact that
similar histological changes may be produced by other conditions. It
is certainly safe to conclude that the changes in the nerve cells in shock
are the result and not the cause of this condition. It may be, as suggested
by Mott,38 that toxic substances liberated from damaged tissues are in
part, at least, responsible for the chromatolysis.

Since the fall in arterial blood pressure occurs with contracted ar-
terioles, it must be dependent on a diminished discharge of blood from
the heart. Interference with the heart action itself (independently of
the blood carried to this organ), or a deficiency in the filling of the ven-
tricles during diastole, are the possible causes for the diminished output.
The possibility that the heart action itself has been interfered with, as for
example, by paralysis of the vagus mechanism, causing a rapid beating
and consequent shortening of the filling (diastolic) period of the heart,
has been shown to be untenable by various experiments. Thus, when
the arterial blood pressure is artificially raised, either by epinephrine in-
jection or by cerebral compression, the heart promptly responds to the in-

306 THE CIRCULATION OF THE BLOOD

creased blood pressure by contracting more slowly and vigorously. Neither
is there evidence that the force of the heart beat is in itself diminished.
When the organ is exposed it is seen to beat vigorously. Evidently, there-
fore, as the cardiac mechanism itself is normal, the deficient discharge of
blood must be dependent upon improper diastolic fitting. After this con-
dition of oligemia has set in, it becomes progressively worse because of
weakening of the heart muscle, consequent upon the failing blood supply
through the coronary vessels, and this again upon a curtailment of the
amount of blood in actual circulation.

The Cause of the Oligemia. — In the first place it is important to recall
that mechanical obstruction of the inferior vena cava is followed ulti-
mately by the usual signs of shock. Such interference with the venous
return to the heart may also possibly be caused by excessive movements
of the thorax, as during artificial respiration. That this in itself may lead
to shock is known to all experimental investigators on the subject, although
the interpretation has not always been that which is given above. Yan-
dell Henderson,32 for example, thought the excessive ventilation to be
the factor responsible for the shock, by causing a blowing off of carbon
dioxide from the blood (see page 382) and a consequent low tension of
this gas in the blood (acapnia).

As in gravity shock, so in surgical shock, stagnation of blood in the
splanchnic area is common; the animal bleeds into his own (splanchnic)
blood vessels (capillaries and venules), because these have lost their tone.
As we have noted above, one of the most certain ways of producing
shock is by exposure and rough handling of the abdominal viscera. It
is therefore of importance to study the effects that can be noted on
the blood vessels of this area under such conditions. When the viscera
are first exposed to air, there may be a short period during which vaso-
constriction is evident. This is soon followed by a dilatation of the capil-
laries and veins as during the first stage of inflammation. The resulting
accumulation of blood in the mesenteric veins has been shown by Mor-
rison and Hooker to cause an increase in the weight of an isolated loop
of intestine as an animal passes into a state of shock. Erlanger and his
coworkers insist also on the constant appearance in shocked animals of
marked dilatation of the capillaries and venules of the intestinal villi.
In the milder forms, the congestion may be confined to the duodenum.31

Engorgement of the abdominal vessels alone does not, however, suffice
to explain all the curtailment of blood, and we are driven to the con-
clusion that much is lost in the capillaries of the tissues outside the abdo-
men. As a matter of fact, Cannon and others have found that concentra-
tion of the blood occurs in these capillaries, as indicated by comparisons
of the percentage of corpuscles and hemoglobin in blood drawn from veins

SHOCK 307

and from capillaries respectively. Normally the values are equal; in
shock on the other hand the capillary blood is much concentrated, which
indicates that plasma must have left the blood.

To understand the nature of the process by which this loss of blood occurs
in the capillaries, it is important to digress here to consider the results
obtained by H. H. Dale and A. N. Richards53 on the effects of histamine on
the circulation. It is by an application of the work of these investigators
that much light has been thrown on the shock problem in recent years.

Evidence Obtained by a Study of the Shock Produced by Histamine.—
Histamine is derived by removal of the carboxyl group, as Co2, from
histidine, one of the most important of the building stones of the pro-
tein molecule. Injected quickly into etherized animals in very minute
dosage (1 mg. per kg. body weight) histamine soon causes the arte-
rial blood pressure to fall to the shock level of 30-40 mm. Hg. For a brief
period preceding the fall there is a rise in pressure due to constriction of the
arterioles, and this constriction persists while the pressure is falling. So far
as the obvious vascular changes are concerned, therefore, the condition is
strictly comparable with those found in shock — low blood pressure and con-
stricted arterioles. By the time the pressure has fallen to near the shock
level the cardiac pulsations disappear from the tracing. The respirations
also cease, but if the animal be kept alive by artificial respiration and the
thorax opened for inspection of the heart this organ will be observed to be
beating quite vigorously, with, however, a pronounced deficiency of blood
in the auricles and in the large veins both of the thorax and abdomen.
This observation affords positive proof that in this form of shock at least
the fundamental cause for the condition is inadequate blood flow to the
heart. The question is, what becomes of the blood? Either it must pass
out of the blood vessels into the tissues, or the capacity of the former must
be increased. Loss of blood itself could scarcely occur short of hemorrhage
— of which there is no evidence in histamine shock — but the water with some
of the soluble constituents (plasma) might become extravasated, leaving in
the vessels blood excessively rich in corpuscles. Such extravasation ac-
tually occurs in acute histamine shock, as revealed by measurement either
of the concentration of hemoglobin or of the corpuscles, but this in itself
can not explain all of the loss in circulating blood, for if the histamine be
given slowly (over a period of 20-30 min.) it takes much longer for the
shock to become established, and the blood does not show any increase in
the percentage of hemoglobin or in the number of corpuscles. In these
cases we are driven to conclude that much of the blood must be withdrawn
from currency by stagnation in dilated vessels. Direct evidence for this
important conclusion has been secured by determination of the volume of

308 THE CIRCULATION OF THE BLOOD

circulating blood, by means of. the vital red method of Keith, Rowiitree and
Geraghty,52 described elsewhere (page 86).

Although the oligemia is due in great part to dilatation of the capillaries
and venules of the intestine, as can be shown by inspection, it is also partly
dependent upon dilatation of vessels elsewhere, since histamine shock can
be induced in animals from which all of the intestines have been removed.
The vessels of the skeletal muscles are probably the chief extraabdominal
vessels affected, for although 110 dilatation of these can ordinarily be seen
in histamine shock, it becomes quite evident in animals which have been
transfused before being shocked. The capillaries (and venules) in these
areas evidently lose their tone so that they become too roomy for the
available blood. As a matter of fact Dale and Richards53 have shown that
histamine abolishes the tone of capillaries at the same time that it in-
creases the permeability of the walls and so permits the plasma to -leak
through. It is on account of this latter action that histamine when it is
rubbed on the scarified skin soon causes the formation of a wheal like that
following the lash of a whip.54

When histamine is given to unanesthetized animals about ten times
as much can be withstood as in those that are anesthetized with ether.38
At first sight this result might seem to discount the observations on ether-
ized animals, but on the contrary they greatly enhance their importance.
They indicate that whereas the normal animal is able to combat the toxic
action of histamine, ether greatly depresses this power, an observation
which agrees remarkably with the clinical experience that administration
of ether is most dangerous in persons who are threatened with shock. The
poisoning effect of ether persists for some time after the anesthetic is re-
moved, and it is no doubt dependent upon a toxic action on the endothe-
lium of the capillaries, for it is particularly in such animals that concen-
tration of the blood is evident after histamine. It is of great significance
that histamine did not readily produce shock in nitrous oxide anesthesia.

Hemorrhage also greatly predisposes to histamine shock, but in this case
the blood is not nearly so concentrated as ordinarily because of the passage
of plasma from the tissue spaces into the vessels, which, it will be remem-
bered, is the natural reaction of an animal to hemorrhage alone. The
cause of shock in such animals is mainly the opening up of the vessels.

Many bacterial toxins, both when applied to scarified skin and when in-
jected intravenously, have effects very like those of histamine. It is also
well known that shock is peculiarly common after injuries in which there
has been extensive destruction of tissue. The facts warrant the suggestion
that shock may be due to liberation from damaged tissues, particularly
the muscles and the viscera, of toxic substances acting like histamine. This
conforms with the fact that shock is most common when there has been

SHOCK . 309

extensive destruction of muscle, or when the liver or intestines are roughly
handled. It is possible also that the shock of intestinal obstruction is fun-
damentally due to absorption into the blood of similar substances from the
closed loop of intestine. Whipple and Hooper's discoveries that absorp-
tion of a proteose is responsible for the shock-like symptoms of intestinal
obstruction are very suggestive in this connection (page 538).

The Possibility that Traumatic Toxemia is a Factor in Surgical Shock. —
Is it possible that surgical shock is dependent upon intoxication by hista-
rnine-like substances absorbed from greatly damaged tissues? To test this
hypothesis Cannon38 and others have investigated the effects of crushing
the muscles of the hind limbs, without external hemorrhage, by blows
from a heavy hammer. It was found that an immediate fall in blood pres-
sure occurred, followed by a more gradual decline to the shock level, with
a decrease in the C02-combining power and a marked concentration of
the blood. This result was not due to irritation of afferent nerves, caus-
ing excessive stimulation of the vasomotor centers, since it persisted in
animals in which all nerves of the limb had been cut; neither was it caused
by any local loss of circulating fluid (by dilatation of vessels or extra-
vasation). It was due to the discharge into the circulation of some toxic
material, since no shock resulted when the vessels of the damaged limb
were clamped. Removal of the clamp some time after the damage re-
sulted in the immediate appearance of the symptoms which could again be
caused to disappear somewhat by its reapplication. As to the nature
of the toxic material, the first possibility to be considered is that it is
unoxidized acid (lactic), which, it is well known, accumulates quickly in
muscular tissue whenever this is destroyed, or when the circulation
through the tissues is greatly curtailed. As a matter of fact it was found
that the C02-carrying power of the blood became greatly depressed when-
ever the toxic material was permitted to enter the circulation by removal
of the clamp, and it is well known that there is also a decided depres-
sion in the blood carbonates in surgical shock. Acid intoxication can
not, however, be the main factor, and for the following reasons: (1)
Injections of lactic acid intravenously do not cause shock, neither do they
predispose an animal to it. (2) Copious injections of bicarbonate solu-
tion do not prevent shock. (3) Extracts of damaged muscle made with
isotonic saline do have a shock-like effect, but this is just as great when
the lactic acid in the extracts is neutralized with bicarbonate, as when
they are unneutralized. Moreover the fall in the blood carbonate does not
coincide with, but rather precedes, the development of the shock symp-
toms. An excess of lactic acid in the blood has been noted in the later
stages of many cases of shock (Wiggers and Macleod), but this is a sec-

310 THE CIRCULATION OF THE BLOOD

ondary effect, and it is doubtful whether it is the only cause for the
depressed C02-carrying power of the blood.

In one or two cases the muscles were crushed in unanesthetized cats,
with the result that shock did not invariably follow, but this does not
invalidate the observations on anesthetized animals ; it only shows that,
as in histamine poisoning, the anesthetic weakens the resistance. When
the normal animals were bled before the crushing operation, shock super-
vened with certainty.

Taking the results as a whole, and comparing them with clinical ex-
perience a very strong case is made for the hypothesis that surgical shock
is essentially due to intoxication by materialls derived from damaged
tissue. Shock is particularly common after severe tissue damage; rough
handling of the wound greatly aggravates it, whereas rigid care to
render the wounded part immobile is a valuable safeguard ; the adminis-
tration of ordinary anesthesia, (ether) to a shock patient- is notoriously
dangerous, whereas rapid amputation under nitrous oxide often ushers
in a steady recovery. All these clinical facts conform admirably with
the experimental findings. The above conclusions are more or less con-
firmatory of those drawn several years ago by Turck,55 to whom credit
is due for being the first to suggest the toxemic element as a causative
factor in shock.

With regard to the diagnostic value of measurement of the blood vol-
ume, it has been shown by Erlanger, Gasser and Meek40' 41 that con-
centration of the blood becomes evident before the shock symptoms are
pronounced. This concentration is no doubt a most important factor
in causing curtailment of the volume of circulating fluid, not only be-
cause of loss of plasma, but also because it causes the corpuscles to be-
come contiguous so that they have a tendency to jam in the capillaries
and so lead to a progressively increasing under-nutritioii of the tissues
and the production of more toxic material.

Cause of Secondary Symptoms

It remains to consider the cause of some of the secondary conditions
developing in shock — namely, the disturbances in sensation and motion
and the fall in body temperature. All of these are undoubtedly depend-
ent upon the low arterial blood pressure, although some authors have
suggested that the loss of sensation may be dependent upon an increased
resistance or block at the synapses of the receptor neurons (page 854).
This suggestion depends on the fact, demonstrated by Sherrington, that
repeated stimulation of the receptors of a reflex arc produces fatigue
of that particular reflex, and that this fatigue must be resident in the
synapsis and not in the motor neuron, since the same motor neuron

SHOCK 311

that participated in the fatigue can still be called into activity by afferent
stimuli transmitted to its nerve cell through other sensory pathways
(see page 825). It is thought that in shock the frequent afferent stimula-
tion produces synaptic fatigue and therefore dulls the sensory responses
of the animal. The researches of Mann, in which he shows that shock
may occur without any demonstrable afferent stimuli in the brain stem,
would seem, however, to negative the above hypothesis.

The raised threshold of sensory stimulation is no doubt an effect of the
low blood pressure. It has been shown, for example, by E. L. Porter36
that when the arterial blood pressure is maintained at a uniform level,
the threshold stimulus for spinal cord reflexes remains practically uni-
form, but becomes promptly increased when the arterial blood pressure
is made to fall. Why a lower blood pressure should have this effect is,
however, difficult to understand in the light of the researches of Stewart
and his coworkers, who, as remarked above, found that the cells of the
central nervous system may endure total anemia for many minutes and
still recover their physiological condition. It may be, however, that the
low blood pressure affects the conductivity of the synapsis.

The muscular weakness is probably also dependent on low blood
pressure, for it has been found in animals that, when the arterial blood
pressure is lowered to about 90 mm. Hg, the muscles contract much less
efficiently than ordinarily. The fall in body temperature is dependent
upon the muscular inefficiency.

In conclusion, it should be pointed out that W. T. Porter, in the inves-
tigation of acute shock met with at the front, has found that, in many
cases at least, the circulatory disturbance is due to a condition of fat
embolism. The fat is derived from the marrow of long bones, such as
the femur, by injuries which smash the bones. Porter's observations
are at least very suggestive. That fat embolism may be at least a con-
tributory factor is made probable by the fact that fat emboli have been
observed by Mott in the medulla and the cortex of the brain.

The Treatment and Prognosis of Shock

It remains for us to show that the foregoing conclusions drawn from
observations made on laboratory animals are applicable to the clinical
condition known as surgical shock. It will then be advantageous to con-
sider the principles which determine successful treatment. The unusual
opportunity afforded at the front to study shock has led to a furtherance
of our knowledge of its causes, which might have taken many years of
investigation in time of peace, and by far the most important contribu-
tions have come from those who have been intimately familiar with the
experimental as well as the clinical aspect of the problem. N. M. Keith30

312 THE CIRCULATION OF THE BLOOD

estimated the total volume of circulating blood by the vital red method
and the relative amounts of plasma and corpuscles by measurement of
hemoglobin or by means of the hematocrit, and as a result of his inves-
tigations has divided the cases of secondary shock into three groups which
vary from one another with regard to: (1) The total volume of blood
in circulation and (2) the relative amounts of plasma and corpuscles in
the blood. The differentiation is not only of great prognostic value, but
also invaluable as a guide to the proper plan of treatment. In group 1 are
the compensated cases, in which the blood volume is reduced to not more
than 80 per cent of the normal, but in which the plasma is relatively
greater, being reduced only to 85 or 90 per cent of the normal. In other
Yords these cases have reacted like cases of hemorrhage, i. e., there has
bv?en a migration of fluid from the tissues into the blood. If kept warm and
gi\en fluid per rectum, the patients recover. In the second group, called
partially compensated, the blood volume is reduced to 65-75 per cent, with
little, if any, evidence of dilution of plasma (i. e., the plasma is also re-
duced to 65-75 per cent). Treatment by transfusion either with blood
(citrated blood by Bobertson's method, or with gum solutions (vide infra)
is necessary and in most cases, if the proper technic is followed in the
transfusion, recovery is likely. It is important, however, that the plasma
volume be measured a few hours after the transfusion to see whether the
desired reaction, namely, a migration of fluid into the plasma, has set in.
If not so, a second transfusion is indicated. In favorable cases the plasma
volume increases more rapidly than that of total blood, and pari passu the
a'rterial blood pressure rises.

In the third or uncompensated group— the blood volume is below 65 per
cent and the blood is more concentrated than normal, i. e., there is relatively
a greater decrease of plasma. Treatment must be energetic in these cases,
but the prognosis is unfavorable because the transfused fluid readily leaves
the vessels, causing the lungs and tissues to become edematous.

With regard to the rationale of the transfusions, it is clear that the
added fluid makes good the blood that is lost by stagnation, etc., and so
tends to maintain in the circulation a normal pressure for a sufficient
time to enable the organism to destroy the toxic bodies. If the shock con-
dition has existed for some time, so that the nerve centers are paralyzed,
the injections are of no avail. Since many cases of shock in man have
also suffered considerably from loss of blood, it is often difficult to decide
whether the shock really exists apart from the effects of hemorrhage, the
cardinal symptoms of the two conditions being very much alike. The test
is afforded by examination of the total blood and plasma volume, and by
the reaction to transfusion. After hemorrhage alone there is great migra-
tion of plasma into the blood, making this very dilute, and transfusion has

SHOCK 313

immediately beneficial results. In shock there is no migration of fluid into
the blood, indeed the reverse is usually the case, and transfusion does not
always succeed in reestablishing normal conditions.

Finally, with regard to the composition of the transfusion fluid, should
this be human blood, or can a reliable substitute be found in saline solutions
containing gum? There is much diversity of opinion over this question.
Keith sums up by stating that there does not appear to be any decided
advantage in blood over gum solutions, although the immediate restoration
of natural color to the patient, which occurs with blood but not with gum
solutions, may make the former appear to be the more satisfactory treat-
ment.

Much painstaking work has been done by Erlanger and Gasser41 to de-
termine the exact conditions for success in using gum solutions. As their
criterion for successful treatment, they did not merely see whether the
blood pressure was restored, but they allowed the animals to recover from
the effects of the anesthetic and then watched them to see whether they
became restored to normal. Many animals might appear to be recovering,
but nevertheless succumb within 24 hours. These workers point out that
strong gum solutions owe their efficacy to the fact that they slowly attract
water into the blood from the tissues, and once attracted the water re-
mains in the vessels. Hypertonic solutions of crystalloids on the other
hand, quickly attract water, but this is not retained long. These workers,
therefore, devised the scheme of combining the two factors, and they found
that success depended on how this was attempted. In the shock produced
by partial clamping of the vena cava about one-half of the animals died
within 48 hours. Neither weak gum (6 per cent) and weak alkali (2 per
cent) given in large amount (12 c.c. per kg.) nor strong gum (25 per cent)
in strong alkali (5 per cent) given in smaller dosage (5 c.c. per kg.) de-
creased the above mortality; but if strong gum (25 per cent) were given
along with strong glucose solutions (18 per cent) at the rate of 5 c.c. per
kg. an hour, many more animals survived. The alkali was chosen to fur-
nish the crystalloid, in many of the experiments, so that it might inciden-
tally combat any existing acidosis. We have already seen, however, that
there is no reason to believe that acidosis is an important factor in shock.
Two precautions are necessary to success in using the gum solutions, first
they must be properly prepared, and second they must not be injected so
rapidly that their high viscidity would slow the circulation and so embar-
ress the heart's action.

CIRCULATION REFERENCES

(Monographs)

Wiggers, C. J.: The Circulation in Health and Disease, Philadelphia, 1915.
Mackenzie, J.: Diseases of the Heart, Oxford Medical Publishers, ed. 2, 1910.

314 THE CIRCULATION OF THE BLOOD

Lewis, Thomas: Mechanism of the Heart Beat, 1911, Shaw & Son, Fetter Lane,

London.

Lewis, Thomas: Harvey Lectures, 1913-1914, J. B. Lippincott Co.
Lewis, Thomas: Clinical Disorders of the Heart Beat, P. B. Hoeber, New York, 1912.
Hill, Leonard: The Mechanism of the Circulation of the Blood, in Schafer's

Physiology, ii, 1900. Young J. Pentland.
Gaskell, W. H.: The Contraction of Cardiac Muscle, in Schafer's Physiology, ii,

1900, Young J. Pentland.
Flack, M.: Further Advances in Physiology, 1909. Ed. by Leonard Hill, E. Arnold,

London.
Porter, W. T.: American Text Book of Physiology, W. B. Saunders Co., 1900.

(Original Papers)

iMacWilliam, J. A., et al: Heart, 1913, iv, 393; ibid., 1914, v, 153; Brit. Med.
Journal, Nov., 1914; VII Internat. Congress of Medicine, London, 1913, Sec.
II, Physiology.
2Hill, Leonard, F. E. S., et al.: Proc. Boy. Soe., 1914, B, Ixxxvii, 344; ibid., 1915, B,

Ixxxviii, 508 and 516.

sErlanger, J.: Am. Jour. Physiol., 1916, xxxix, 401; ibid., 1916, xl, 82.
4Downs, A. W.: Am. Jour. Physiol., 1916, xl, 522.
sBayliss, W. M.: Proc. Roy. Soc., 1916, Ixxxix, B, 380.
GKnowlton, F. P.: Jour. Physiol., 1911, xliii, 219.
7Malroy, T. H.: Jour. Physiol., 1917, Ii, 259.
sEyster and Meek: Heart, 1914, v, 119) ibid., 194, v, 137; Am. Jour. Physiol., 1914,

xxxiv, 368.
^Porter, W. T. : Art. on Circulation in American Textbook of Physiology, W. B.

Saunders Co., 1900.

•toBrodie, T. G.: Proc. Physiol. Soc., 1905, Jour. Physiol., 1905, xxxii.
uStewart, G. N.: Heart, 1911, iii, 33.
i2Garrey, W.: Am. Jour. Physiol., 1912, xxx, 451.
isMines, G. R.: Jour. Physiol., 1913, xlvi, 188.
i^Cohn, A. E.: Jour. Exper. Med., 1912, xvi, 732; Robinson, G. Canby: Ibid., 1913,

xvii, 429; Cohn and Lewis, T.: Ibid., 1913, xviii, 739.
isMathison, G. C.: Jour. Physiol., 1910, xli, 416.

isPorter, W. T.: Am. Jour. Physiol., 1911, xxvii, 276; ibid., 1915, xxxvi, 418.
irMartin, E. G., and co-workers: Am. Jour. Physiol., 1914, xxxii, 212; xxxiv, 2L>0;

1915, xxxviii, 98; 1916, xl, 195.

isBayliss, W. M.: Proc. Roy. Soc., 1908, Ixxx, B, 339.
isHill, Leonard: The Physiology and Pathology of the Cerebral Circulation, J. and

A. Churchill, 1896. *

2QHill, L., and Macleod, J. J. R.: Jour. Physiol., 1900, xxvi, 394.
2iMacleod, and Pearce, R. G.: Am. Jour. Physiol., 1914, xxxv, 87.
22p0rter, W. T.: Am. Jour. Physiol., 1898, i, 144.
23Hill, L., and Barnard, H.: Jour. Physiol., 1887, xxi, 323.
24Carter, E. P.: Jour. Lab. and Clin. Med., 1916, i, 719.

25Elliot-Smith, G., and Pear, T. H.: Shell Shock, Longmans, Green & Co., 1917.
26p0rter, W. T.: Am. Jour. Physiol., 1907, xx, 399.
27Seelig, M. G., and Joseph, D. R.: Jour. Lab. and Clin. Med., 1916, i, 283; also See-

lig and Lyon, E. P.: Surg., Gynec., and Obst., 1910, ii, 146.

2sHenderson, Yandell: Am. Jour. Physiol., 1908, xxi, 155; also Mann: Bull. Johns
Hopkins Hosp., 1914, p. 210; Markwald, J., and Starling, E. P.: Jour. Physiol.,
1913, xlvii, 275.

29Morrison, R. A., and Hooker, I). R.: Am. Jour. Physiol., 1915, xxxvii, 86.
sopjke, F. H., Stewart, G. N., and Guthrie, C. C.: Jour. Exper. Med., 1908, x, 499;

see also Dolley, D. H.: Jour. Med. Research, 1909, p. 95, and 1910, p. 331.
siJaneway, H. H., and Jackson, H. C.: Proc. Soc. Exper. Biol. and Med., 1915, xii,
193; Erlanger, J.: Gesell, Gasser, Proc. Am. Physiol. Soc., Am. Jour. Physiol.,
1918, xlv.

SHOCK 315

ssHenderson, Y., and Haggard, W. H.: Jour. Biol. Chem., 1918, xxxiii, 333, 345-355-

365 (gives older references). See also Macleod, J. J. K.: Jour. Lab. and Clin.

Med., (editorial), 1918, iii.
ssShort, Eendel: Lancet, London, 1914, p. 131.
34Mann: Jour. Am. Med. Assn., 1918, Ixx, 611. Also Boston Med. and Surg. Jour.,

1917.
35Cannon, W. B.: Papers by Cannon and Collaborators in Jour. Am. Med. Assn., 1918,

Ixx, 520, 526, 531, 611, 618.

seporter, E. L.: Proc. Am. Physiol. Soc., Am. Jour. .Physiol., 1916, xlii, 606.
rf7Wigg.ers, C. J., and Dean, A. L.: Am. Jour. Physiol., 1916, xlii, 476; Am. Jour.

Med. Sc., 1917, clii, 666.

, Dale, Bayliss, Cannon, Keith, and others: cf. Eeport No. 26, Medical

Eesearch Committee, London,
ith, N. M. : Blood Volume Changes in Wound Shock and Primary Hemorrhage.

Eeport 27, Medical Eesearch Committee, London, 1919.
4oGasser, H. S., and Erlanger, J.: Am. Jour. Physiol., 1919, 1, 104.
4iErlanger, J., and Gasser, H. S. : Ann Surg., 1919, Ixviii, 389.
42Evans, C. L., and Starling, E. H. : Jour Physiol., 1913, xlvi, 413.
43Boothby, W. M.: Am. Jour. Physiol., 1915, xxxvii, 383.
44Krogh, A., and Lindhard, J. : Skand. Arch. f. Physiol., 1912, xxvii, 100.
45Wiggers, C. F.: Arc. Int. Med'., 1919, xxiv, 471.
46Lewis, T. : Quart. Jour. Med., 1913, iv, 241.

47Knowlton, F. P., and Starling, E. H.: Jour. Physiol., 1912, xlix, 206.
48Evans, Lovatt C.: Jour. Physiol., 1912, xlv. 214.

4»Patterson, S. W., Piper, A., and Starling, E. H. : Jour. Physiol., 1914, xlviii, 465.
soFahr, G.: Arch. Inf. Med., 1920, xxili, 146.

siKeith, N. M., Eowntree, and Geraghty: Arch. Int. Med., 1915, xvi, 547.
52Dale, H. H., and Eichards, A. N.: Jour. Physiol., 1918, Iii, 110.
ssSollmann, T., and Pilcher, J.: Jour. Pharm. and Exp. Therap., 1917, xix, 309.
s^Turck, F.B.: Jour. Am. Med. Assn., 1897 (June), p: 1160; Chicago Med. Eecordcr,

May, 1902, 450.

ssHooker, D. E. : Am. Jour. Physiol., 1911, xxviii, 235.
seKrogh, A.: Jour. Physiol., 1919, Iii, 409 and 457.

PART IV
THE RESPIRATION

CHAPTER XXXV
RESPIRATION

For convenience, the physiology of respiration may be considered un-
der its mechanics, its control, and its chemistry.

THE MECHANICS OF RESPIRATION

Of the many factors concerned in maintaining the normal functioning
of the animal body, the respiratory act is probably the most important.
On this account and also because we are conscious of the respiratory
movements, the physiology of respiration has been studied from the
earliest times. Much of the earlier work naturally concerned itself
with the study of the air that enters and leaves the lungs at each respi-
ration— the ventilation of the lungs, as it may be called. Two obvious
properties of the respired air are: (1) its pressure and (2) its volume.

The Pressure of the Air in the Respiratory Passages — the Pulmonary
or Intrapulmonic Pressure

This is readily measured "by inserting a tube into one nostril and con-
necting the tube with a manometer; at each normal inspiration the
manometer registers a negative pressure of 2 or 3 mm. Hg, and at each
expiration, a positive pressure of about the same degree. Although
normally of small magnitude, the intrapulmonic pressure may become
very great when any obstruction is offered to the free passage of the
air. The greatest possible expiratory pressure can be measured by sim-
ply blowing into a mercury manometer, when it will be equal to that
which all the muscles of the thorax and abdomen can exert in compress-
ing the lungs. In a strong man it may amount to more than 100 mm.
Hg. Similarly, the greatest possible negative pressure on inspiration
may be measured by attempting to inspire through a tube connected
with a manometer. It represents the force with which the musculature

316

RESPIRATION 317

of the thorax and abdomen can open up the thoracic cage, and may
equal -70 mm. Hg. These measurements in themselves are not of much
importance, except as a measure of muscular development.

Intrapulmonic pressures that are intermediate between the two ex-
tremes will be acquired in the lower air passages in cases in which there
is partial obstruction of the upper respiratory passages, as in bronchitis,
spasm of the glottis, diphtheria, etc. During coughing also, the intra-
pulmonic pressure may become very high. In this act the thorax is first
filled with air by a deep inspiration; the glottis is then closed, and a
forced expiration is made. "When a sufficiently high intrapulmonic pres-
sure is attained, the glottis opens and the sudden change in pressure
causes so forcible a blast of air that the offending foreign substance is
frequently carried with it out of the air passages. It is often assumed
that during coughing the sudden increase in pressure in the alveoli will
tend to cause their walls to rupture. This, however, is not the case.
The alveoli do not alone support the increase of pressure ; they merely
act as the inner layer, of a practically homogeneous structure cam-
posed of lung, pleura and thoracic cage. When the tissues of the lung
are partially degenerated or atrophied, as in old people, then it is pos-
sible that a rupture may take place, but under ordinary conditions it
is not likely to occur.

Amount of Air in the Lungs

Measurements of the amount of respired air have recently assumed a
considerable interest on account of the various applications which can
be made of them in the study of lung conditions. The tidal air is that
which enters and leaves the lungs with each respiration (about 500 c.c.) ;
the complement al air is that which we can take in over and above an
ordinary tidal respiration (about 1500 c.c.) ; and the supplemental air,
is that which we can give out after an ordinary tidal expiration (about
1500 c.c.). Taking these three together, we have what is known as the
vital capacity. It is usually about 3500 c.c., and is represented by the
amount of air which we can expel from the lungs after as deep an inspi-
ration as possible. The vital capacity is diminished in certain cardiac and
pulmonary diseases, (page 330). After all the supplemental air has been
expelled, there still remains in the lungs a large volume of air which
can not be voluntarily expelled. This is known as the residual air. To
measure it in a dead animal it is necessary to clamp the trachea, open
the thorax, remove the lungs to a vessel of water, and then allow the air
to collect from the opened trachea in an inverted graduated cylinder.
One part of the residual air is sometimes called the minimal air; it is
represented by that which is not expelled from the lungs of a dead

318

THE RESPIRATION

animal when the thorax is opened. In the collapse of the lungs thus
produced, the alveoli are not completely emptied of air, because some
becomes pocketed within them and is expelled only when the lungs are
compressed under water.

The volume of the residual air can readily be measured during life

Maximum inspiration -7 —

Complemental air ._

Ordijnary inspiration
TIDAL AIR
Ordinary expiration —

Supplemental air -

Maximum expiration -

Residual air -

. Vital capacity

Capacity of equilibrium

Fig. 107. — Amounts of air contained by the lungs in various phases of ordinary and of forced

respiration. (From Waller.)

Fig. 108. — Diagram to show manner of termination of bronchiole in the atria and air sacs.
I, Air sacs (respiratory epithelium) ; II, atria (respiratory epithelium) ; III, alveolar ducts (res-
piratory epithelium and occasional muscle fibers) ; IV, respiratory bronchioles (partly respiratory
and partly cuboidal epithelium and continuous muscle fibers) ; V, bronchiole (cuboidal epithelium
and muscle fibers). It is clear from this diagram that there is no definite position in the respira-
tory passages where the bronchiolar epithelium (cuboidal) ends and the respiratory epithelium
starts. There can therefore be no definite line of demarkation between the air of the dead space
and that of the alveoli. Redrawn from Miller (Journal of Morphology, 1913, XXIV, p. 459).

RESPIRATION 319

by causing a person, after a forced expiration, to take two or three
breaths in and out of a rubber bag containing a measured quantity of
an indifferent gas such as hydrogen. Suppose the bag to contain at
the start 4000 c.c. of hydrogen, and after a few breaths 3000 c.c. of
this gas and 1000 c.c. of other gases (the total volume of hydrogen and
expired air in the bag being still 4000 c.c.); then the residual air will
be 1333 c.c., for it is evident that after a few breaths the composition of
the expired air in the bag will be the same as that in the lungs. This
calculation is based upon the assumption that no hydrogen is absorbed
by the blood during the experiment, which is not strictly the case.
The amount absorbed is, however, so small in two or three breaths as to
make it permissible to disregard it. The measurement can also be made
by taking a few breaths in and out of a bag containing pure 02. By
ascertaining the proportion of nitrogen that collects in the bag, the
quantity of residual air can be calculated. We shall see later that the
measurement of the residual air during life has some practical impor-
tance in connection with the measurement of the bloodflow through the
lungs.

Alveolar and Dead Space Air

In addition to these moieties of respired air, we have to consider the
division of the air in the lungs into what is called alveolar air and
dead space air. The former is the air which comes in contact with the
epithelium through which gas diffusion between the blood and the air
occurs, the latter being the air which fills the respiratory passages. The
dead space can not be defined anatomically with exactitude ; it is func-
tional rather than morphologic.

Measurement of the volume of the alveolar and dead space air can be made
by taking advantage of the fact that, while it is in the lungs, the air has
added to it C02 gas, which is present in the inspired air only in negligible
traces. The necessary data are : (1) the volume of the tidal respiration ; (2)
the percentage of C02 in alveolar air ; (3) the percentage of C02 in the tidal

air. Suppose the values to be 500 c.c., 6 per cent and 4 per cent, re-

4.
spectively; then the volume of alveolar air must be 500x^=333 c.c.,

and the dead space 167 c.c. The measurement so made is accurate only
when certain precautions are taken. Because of the practical impor-
tance of this part of our subject we shall, however, defer its further
consideration until we have become familiar with the general features
of pulmonary physiology. Since the first air to move into the alveoli
at the beginning of inspiration is that present in the dead space, — the
last air expelled from the alveoli on the previous expiration, — it is of

320 THE RESPIRATION

no value in purifying the air already present in the alveoli. If we take
a tidal inspiration as amounting to 500 c.c. and the functional dead space
as 150 c.c., it is plain that only 350 c.c. of the outside air gains the
alveoli, and that the subsequent expiration is composed of 150 c.c. of
outside air that had lodged in the dead space plus 350 c.c. of alveolar air.

These facts deserve a certain amount of emphasis because of their
practical importance in many phenomena connected with respiration.
One seldom thinks, for example, that out of the 500 c.c. of air inspired
with each breath, only 350 c.c. reaches the alveoli, where it comes in
contact with the 2500-3000 c.c. of air already present in this part of the
lungs.

There must therefore be a sort of interface somewhere in the alveoli
between the fresh outside air that comes in with each breath through
the bronchioles and the air which is more or less stagnant in the alveoli.
This interface must move backward and forward somewhat with each
breath, and a rapid diffusion of oxygen and of C02 must take place
across it between the inspired air and that in the alveoli. It is impossible
to fix any anatomical point at which the interface occurs.

The above described mechanism for the ventilation of the alveoli in-
sures the maintenance of slight but constant changes in the composition
of the air next the alveolar epithelium. It helps to prevent sudden varia-
tions in the amount of gases in the blood, particularly of C02. Should
such variations occur, irregular stimulation of the respiratory and other
important centers that are influenced by the amount of this gas present
in simple solution in the blood, would be the result. The mechanism
serves as a sort of mechanical buffer by diminishing the sudden changes,
in gas concentration produced by inspiration and expiration.

Respiratory Tracings

The measurements of air for the determination of the foregoing val-
ues are made by the use of meters of various types. Sometimes, how-
ever, it is necessary to obtain an, inscribed record of the respirations.
This may be either qualitative or quantitative. A qualitative record is
taken by attaching some sort of receiving tambour to the thoracic wall
(the best type is shown in Fig. 109), and connecting this with a record-
ing tambour arranged to write on a blackened surface. When it is
desired merely to count the respirations or to observe their regularity,
such a tracing is all that is required, but obviously it does not tell us
hoiv much air has entered and left the lungs at each respiration. To
obtain a quantitative tracing, we must either connect a recording instru-
ment with the trachea or inclose the body of the animal in what is
known as a body plethysmograph. In observations on laboratory an-

RESPIRATION 321

imals the best type of recording instrument to connect with the respira-
tory passages is the Gad or Krogh pnenmograph. All these instruments
must of course lie calibrated, which is done by pouring a definite num-

Fig. 109. — Fneumograph. The straps (b, b) are held around the thorax, and the tube of the
tambour connected by rubber tubing with a recording tambour.

ber of c.c. of water from a graduate into a bottle with which the record-
ing instrument is connected by tubing. The displacement of the writing
point gives us the necessary data for standardization.

The Intrapleural Pressure

The air which we have just been considering depends for its move-
ment in and out of the air passages upon changes occurring on the outer
aspect of the lungs in the space between them and the thoracic wall.
This is called the intrapleural space. It does not really exist as an
actual space in the living animal, for the visceral pleura which covers
the lungs is in accurate and intimate apposition with the parietal pleura
on the inner aspect of the thorax.

If the thoracic walls are punctured in a living animal or in one which
has recently died, the air will rush into the thorax, the two layers
of pleura separate, and the lungs collapse, causing temporarily a space
to be formed between the two layers of pleura and indicating that a
certain subatmospheric or negative pressure must exist in the intact
thorax to prevent the lungs from collapsing. The degree of this nega-
tive pressure may be measured by connecting a tube and a manometer
with the thoracic cavity. While the thorax is at rest, as in expiration
or immediately after death, this pressure amounts to about -5 milli-
meters.* On inspiration it increases to -10 millimeters. There are there-
fore two problems to be considered: (1) the cause of the negative pres-
sure in the quiescent thorax, and (2) the cause of the increase of the
negative pressure during inspiration.

*The minus sign indicates that the pressure is negative or subatmospheric. It is a suction pressure,
angle.

322 THE RESPIRATION

The Permanent Negative Pressure.— Let us start with the changes
that occur in the thorax when the first breath is drawn. While the an-
imal is still in utero, the lungs completely fill the thorax. When the
first breath is 'drawn the thoracic cage expands more quickly than the
lungs, so that the latter become stretched, the stretching force being
the air that is introduced into them from the outside through the tra-
chea and bronchial tubes. On becoming stretched the lungs fill the
increased space created in the thorax by the greater expansion of the
thoracic cage. This in itself, however, would not explain the cause of a
subatmospheric pressure in the intrapleural space. Another factor must
come into play — namely, the elastic tissue of the lungs, which by the
expansion will become stretched and, therefore, tend constantly to re-
lax to its previous condition and so exert a pull on the structures be-
tween it and the thoracic wall. It is this elastic recoil which we really
measure when we connect a manometer with the intrapleural space.
Throughout life the lungs remain of smaller size than the thoracic wall,
and therefore to fill the thoracic cavity they are constantly more or
less distended and the elastic tissue somewhat stretched. The lungs
are, however, not the only structures in the thorax which become ex-
panded; all thin-walled vessels and viscera, like the veins, the esopha-
gus, the auricles, etc., must also become opened out a little.

When the thoracic wall is punctured and the outside air allowed free
entry to the intrapleural space, differences in pressure no longer exist
on the inner and outer aspects of the lungs, so that they collapse into
the postmortem condition on account of the elastic recoil. If a puncture
in the thoracic wall of a living animal is immediately occluded, the
lungs will expand again, because the blood absorbs the gases from the
intrapleural space and recreates the partial vacuum required to expand
the lungs. This absorption of gas in the pleural cavity is usually quite
rapid; but if the pneumothorax, as the condition is called, is allowed to
persist for any length of time, the lungs will not become properly ex-
panded again.

The Greater Negative Pressure on Inspiration.— The cavity of the tho-
rax becomes increased in all diameters during inspiration, with the re-
sult that a greater space in the pleural cavity has to be filled. All the
thin-walled structures in the thorax therefore become still more stretched,
the lungs of course participating to the greatest extent because of the
entrance of outside air. The stretching of the elastic structures causes
a greater pull, or negative pressure, to be exerted in the pleural cavity.
Instead of being -5 mm. Hg, as in expiration, the intrathoracic pressure
now comes to be above -10 mm. Hg.

When any obstruction exists in the air passages, the changes in intra-

RESPIRATION 323

thoracic pressure produced by the movements of respiration become
more pronounced than under normal conditions. When the thorax ex-
pands with the trachea blocked, the lungs are not able to open up suffi-
ciently to fill all the space so that there is excessive dilatation of the
veins, auricles and esophagus, as well as drawing in of the intercostal
spaces and bulging upwards of the diaphragm. If a manometer is con-
nected with the pleural space under these conditions, a very large
negative or suction pressure will be observed, amounting often to -70
or -80 mm. Hg. In the opposite condition, in which the respiratory passages
are blocked and a forced expiration is made, as for example in the first stage
of coughing or during such acts as defecation and parturition, the thoracic
cage is compressed upon the viscera, with the result that the air in the lungs
assumes a positive pressure, amounting often to nearly 100 mm. Hg. If a
puncture wound is made in the thorax under these conditions, the lungs in-
stead of collapsing will bulge out of the wound, for what is really occurring
is that the thorax is forcibly contracting on occluded sacs of air.

It is the alternating changes in intrapleural pressure that are respon-
sible for the changes in intrapulmonic pressure and these for the iriove-
ment of air in and out of the lungs with each respiration. In other
words, the thorax does not expand on inspiration because air rushes
in, as the uninitiated imagine, but air rushes in because the thorax
expands.

The Influence of Intrapleural Pressure on the Blood Pressure. — The
movements of respiration produce effects on the vascular system that
are of considerable importance in maintaining the circulation of the
blood. If an arterial blood-pressure tracing is examined, it will be
observed that aside from the cardiac pulsations large waves exist on it that
are approximately synchronous with the respiratory movements, the
upstroke of each of these waves corresponding in general with inspira-
tion, and the downstroke with expiration (Fig. 22). These respiratory
variations in blood pressure might be due either to changes in heart
rhythm or to a purely mechanical cause. Kegarding the first possi-
bility, it is indeed the case in most animals that the pulse is quicker on
inspiration than on expiration, but that this alone is not an adequate
explanation of the rise is shown by the fact that it still persists after
the vagus control of the heart has been eliminated, either by cutting
the nerve or by the action of atropine.

The cause must therefore be a mechanical one. Bearing in mind the
effects which we have seen are produced on the movement of air in and
out of the lungs by the changes in capacity of the thorax with each res-
piration, we naturally assume that the increase in blood pressure may
be due to the fact that on inspiration more blood is sucked out of the

324 TTTE RESPIRATION

systemic veins into those of the thorax, that this excess when it is pro
pelled by the heart into the arteries raises the blood pressure, and that
on expiration the opposite condition obtains. That the movements of
the thorax on inspiration do accelerate the speed with which the venous
blood is traveling towards the heart can easily be shown by measure-
ments of bloodflow.

This explanation, however, does not suffice to account for all the
changes of blood pressure which occur in respiration, for if we take
very accurate tracings of blood pressure and of the respiratory move-
ments side by side, we shall find that, although, in general, the blood
pressure rises with inspiration, yet the beginning of the rise is consid-
erably delayed; that is, immediately following the beginning of the
inspiratory act the arterial blood pressure continues for some time to
fall, and at the beginning of expiration it continues for some time to
rise (Fig. 22). Moreover, it will be found, if tracings taken from dif-
ferent animals are compared, that frequently the general effect of ex-
piration is to cause more rise than fall, and of inspiration more fall
than rise. It will be found that these differences are dependent largely
on the type of respiration, whether thoracic or abdominal (Lewis).11

Let us consider first of all exactly what will happen in an animal
breathing entirely by the thorax (e.g., the rabbit). The first effect of
the inspiration is to cause the veins leading to the auricles, the auricles
themselves and the blood vessels of the lungs to become suddenly ex-
panded. More blood therefore will flow into them. For a moment or
two this blood will, however, tend to stagnate in the more capacious
vessels, and it will be some time until it finds its way to the left side
of the heart; therefore the initial effect of inspiration is a distinct fall
in arterial blood pressure. When the extra space created in the blood
vessels has been filled with blood, — that is, when inspiration has prac-
tically ceased, — the blood will flow on in increased volume to the left
side of the heart, and, therefore, raise the arterial blood pressure. On
expiration the first effect is that the diminishing negative pressure will
cause the thin-walled vessels mentioned above to constrict and thus
squeeze the blood inside them into the left side of the heart and raise
the pressure; but the ultimate effect in the later stages of expiration
will be that the vessels, being constricted, will allow less blood through
them and the arterial blood pressure will fall.

Take now the case of abdominal respiration. In inspiration the dia-
phragm descends and crowds the viscera against the vena cava, with
the result that at first more blood is squeezed into the thorax and the
blood pressure tends slightly to rise. After this initial effect, how-
ever, the compression of the vena cava causes less blood to reach the

RESPIRATION

325

thorax, and the arterial blood pressure falls. The conditions will be
exactly reversed on expiration. The initial effect of thoracic inspira-
tion is, therefore, to make the arterial blood pressure fall, and the in-
itial effect of abdominal inspiration, to make it rise. The net effect
produced will be the algebraic sum of these two opposing influences
(see Fig. 110).

Another factor that comes into play in determining the effect of the
respiratory movements on the cardiac output acts through the changes
in the pericardial pressure. When this is lowered, as early in inspira-

Fig. 110. — Effect of abdominal and chest breathing on the pulse and blood pressure of man.
Abdominal inspiration raises the pressure and diminishes the amplitude of the pulse curve. Thoracic
inspiration less clearly lowers the pressure. Expiration has the opposite effects. (From Lewis.)

tion, it encourages diastole, thus causing better filling and therefore
better discharge from the heart.

These considerations taken together make it easy to understand the
changes in blood pressure, particularly in the veins, which occur when
a forced inspiratory or expiratory movement is made with the glottis
closed. A forced expiration of this nature occurs during the acts of
defecation and parturition, as well as in the first stages of coughing; it
is also produced by blowing into a tube, or against some resistance.
On account of the positive pressure that is brought to bear on the veins
as they enter the thorax, the venous pressure suddenly rises, slowing

326 THE RESPIRATION

down the flow of blood through the capillaries and causing bulging of
the veins and, if the effect is sustained, cyanosis. On the arterial
side of the vascular system, after a momentary rise caused by the
squeezing out into the left side of the heart of the blood in the capil-
laries of the lungs, there is a more permanent fall in pressure due to
the fact that less blood is now getting from the right side to the left
side of the heart. After some time the pressure begins to rise again,
partly on account of the back pressure through the capillary vessels
and partly because of vasoconstriction as a result of asphyxial
conditions.

In the opposite condition, during a forced inspiratory movement with
the glottis closed or with the mouth attached to some tube through
which the attempt is made to suck air, the thoracic cavities open up
without the lungs being able to occupy completely the extra space.
The dilatation of the veins and other thin-walled structures in the tho-
rax thus causes an immediate fall in both the venous and the arterial
pressure — in the venous, because the blood is sucked toward the large
vessels in the thorax and lungs, and in the arterial, because the blood is
now delayed in its passage from the right to the left side of the heart.
If this condition is maintained, the arterial pressure may recover some-
what, but that in the veins is permanently lowered.

CHAPTER XXXVI
THE MECHANICS OF RESPIRATION (Cont'd)*

VARIATIONS IN THE DEAD SPACE, THE RESIDUAL AIR AND
MID-CAPACITY, AND THE VITAL CAPACITY IN VARI-
OUS PHYSIOLOGICAL AND PATHOLOGICAL
CONDITIONS

Dead Space

Under ordinary conditions of breathing the dead space is fairly con-
stant in volume. Haldane5 and Henderson6 believe that it may be in-
creased by 400 per cent in maximal deep breathing, and that the in-
crease is due to the passive stretching of the lower air sacs. Although
such large variations in the capacity of the dead space has not been ob-
served by Krogh and Lindhard7 or by R. G. Pearce,8 it is undoubted
that moderate rhythmic variations may occur. Even in deeper breath-
ing (1500 c.c. or over), a slight increase, which with maximum breaths
may amount to 100 c.c., can be demonstrated. This is not surprising
when we remember that the walls of the bronchi and bronchioles are
made up largely of readily expansible tissue (elastic and smooth-muscle
fibers). As the respirations become deeper and the expanding force of
the inspiratory movements of the thorax becomes more pronounced, the
diameter of the bronchi and bronchioles will enlarge proportionately—
that is, the diameter or circumference will increase in direct proportion
to this force; but the area of the cross section of the bronchi (i. e., the
capacity) will increase as the square of the diameter. This depends on
the fact that the area of a circle is increased by 125 per cent when the
diameter is increased by 50 per cent, and by about 300 per cent when
the diameter is increased by 100 per cent.

The capacity of the dead space has a certain clinical significance.
Siebeck9 has estimated that the dead space may increase by 100 c.c. in
asthma, but others believe that the increase may be greater. One rea-
son for the discordant results lies in the fact that the percentage of
C02 found in the alveolar air obtained by the Haldane-Priestley method
has been used as one of the basic figures in the determination of the

*Most of this chapter was written by R. G. Pearce, M. D.

327

328 THE RESPIRATION

capacity of the air passages. As explained elsewhere (page 361), the pro-
longation of expiration required to obtain the sample of alveolar air by this
method gives figures that are too high even under normal conditions,
and it is plain that this error will be exaggerated in asthma, where the
expiration is greatly prolonged. An increase in the capacity of the
dead space must be accompanied by an increase in the respiratory vol-
ume if the alveoli are to be adequately ventilated. It has been thought
by some clinicians that the difficulty in asthma, emphysema and car-
diac decompensation may lie in part in an increase in the dead space.
Careful estimations of the dead space in these conditions, however,
fail to demonstrate any great variation.

An explanation of the fact that the dead space in einphysrmatous patients has been
found to be generally large when determined by the Haldane-Priestley method (sec
page 357), and also for some of the clinical phenomena accompanying the condition,
may be as follows: In emphysema the Avails of the alveoli, especially about the lateral
and lower borders of the lungs, have lost their elasticity and fail to expand or relax
properly during the respiratory cycle. As a result the air in these alveoli remains
relatively unchanged except when forced respirations are made. When a sample of
alveolar air is taken directly, this dead air is pushed out of the distended and diseased
alveoli by the forced respiration required in the direct sampling of the alveolar air.
Since the air in these alveoli has been in contact with the blood entering the lungs, it
has a high CO content, which results, when compared with the uniformly low COo content
found in the tidal air, in giving a large figure for the dead space. Since the capacity of
the dead space is not increased, the blood in the normal alveoli is probably being
superventilated in order to compensate for the high CO^ tension in the blood entering
the left heart from the diseased alveoli. However, the O content of the blood leaving
the sound alveoli is practically normal (because superventilation can not cause it to
take up more), and can not compensate for the low O} content in the blood coming from
the diseased alveoli, the net effect being therefore a low tension of Oo in the blood
leaving the heart, which accounts for the cyanosis often seen in emphysema (Pearce).
A somewhat similar explanation can he given for the cyanosis present in pulmonary
edema, if we assume that all the alveoli in this condition do not share alike in the
edema (Hoover).

The Residual Air and Mid-capacity of the Lung's

During muscular exercise the residual air of the lungs is increased,
and the vital capacity decreased (Bohr). This causes the lungs to as-
sume a more inflated condition between breaths or, as it has been clum-
sily styled, a greater mid-capacity. These changes may serve as a
physiological method for increasing the efficiency of alveolar ventilation
so as to meet the greater needs of the body. This is partly because the
pulmonary vessels become dilated and the bloodflow through the lungs
is favored, and partly because of the influence of the reserve and sup-
plemental airs on the tension of the arterial blood gases during the res-
piratory cycle. For example, if the lungs were completely depleted
of nil' during expiration, the blood leaving them at the end of this act

THE MECHANICS OF RESPIRATION

329

would be entirely venous. On the other hand, if the amount of air left
in the lungs at the end of. expiration were above the normal amount,
each increment of C02 given off from the blood, or of 02 absorbed by
it would produce less change in the pressure of the C02 or 02.

Patients suffering from dyspnea, particularly those suffering from
cardiac dyspnea, can not breathe as comfortably when lying as when
sitting. This condition is known as orthopnea. The advantage of the sit-
ting over the lying position for breathing can not be satisfactorily ex-
plained. The greater vital capacity in the upright position; the favor-
ing of the return of the venous blood from the cerebral vessels by
gravity; the increased caliber of the pulmonary vessels because of the
enlarged thoracic cavity (see page 335) ; and the increase in the reserve
air of the lungs — are all factors to be considered.

The Vital Capacity. — At one time it was thought that the vital capacity
of the lungs was related to their ventilatory capabilities, but for years
the determination of this value in patients has been considered unimpor-
tant. Recently Peabody and Wentworth10 have called attention to the
fact that patients with heart disease become dyspneic more readily than
do healthy subjects, and that this tendency seems to depend largely
on their inability to increase the depth of the respiration in a normal
manner. They find that this inability to breathe deeply corresponds to
a diminished vital capacity of the lungs as measured in a spirometer,
by the volume of the greatest possible expiration after the deepest in-
spiration. They believe that any condition which limits the possibility
of increasing the minute volume of air breathed must be an important
factor in the production of dyspnea.

In normal adults the following averages (Table I), were secured from
a large series of clinical cases. The subjects are grouped into two
classes, each group being subdivided according to height.

TABLE I
THE VITAL CAPACITY OF THE I,UNGS OF NORMAL, MALES

GROUP

NUMBER
STUDIED

HEIGHT IN
FEET AND
INCHES

NORMAL
VITAL
CAPACITY
C.C.

NUMBER
WITHIN
10% OF
NORMAL

HIGHEST
VITAL
CAPACITY

LOWEST
VITAL
CAPACITY

HIGH-
EST

%

LOWEST

%

NUMBER
BELOW
90% OF
NORMAL

I
II

III

14

44
38

6' +

Over 5'
8l/2" to 6'
5' 3" to
5' BY*"

5,100
4,800

4,000

9

41

31

7,180-
5,800

5,080

5,030
4,300

3,450

141
121

127

99
90

86

0

0

1

THE VITAL CAPACITY OF THE LUNGS OF NORMAL FEMALES

I

10

Over 5'

3,275

5

4,075

2,800

124

86

2

6'

II

13

Over 5'

3,050

9

3,425

2,660

112

88

2

4" to 5'

6"

III

21

5' 4" or

2,825

16

3,820

2,500

135

89

1

less

(Peabody and Wentworth.)

330

THE RESPIRATION

It would appear that in normal people the vital capacity is at least
85 per cent, and almost always 90 per cent or more, of the standard
adopted for each group. In elderly persons a slight decrease from these
standards may be expected.

TABLE II

THE RELATION OF THE VITAL CAPACITY OF THE LUNGS TO THE CLINICAL CONDITION IN
PATIENTS WITH HEART DISEASE*

GROUP

VITAL

NUM-

MOR-

SYMPTOMS

WORK-

REMARKS

CAPACITY

BER OF

TALITY

OF DECOM-

ING

%

CASES

%

PENSATION

%

I

90 -

25

0

0

92

Few symptoms ref-

erable to heart.

II

70 to 90

41

5

2

54

History of dyspnea

with exertion, yet

able to do moder-

ate work.

III

40 to 70

67

17

89

7

Dyspnea with mod-

e r a t e exercise.

Few able to work.

IV

Under 40

23

61

100

0

Bedridden, with

marked signs of

cardiac insuf-

ficiency.

(Peabody and Wentworth.)

*Certain cases were tested several times and, owing to changes in the vital capacity they appear
in more than one group. In the "mortality" column they are included only in the lowest group into
which they fell. "Symptoms of decompensation" indicate dyspnea while at rest in bed or on very
slight exertion. Under "working" are included only those actually at work, and able to continue.
Many other patients in Group II were able to work, but they are not included as they were still in
the hospital.

Table II shows that there is a remarkably close relationship between
the clinical condition of cardiac patients, particularly as regards the
tendency to dyspnea, and the vital capacity of the lungs. Peabody and
Wentworth believe that the determination of the vital capacity affords
a clinical test as to the functional condition of the heart, since compen-
sated patients who do not complain of dyspnea on exertion have a nor-
mal vital capacity. Patients with more serious disease in whom dyspnea
is a prominent symptom, have a low vital capacity; and the decrease in
vital capacity runs parallel with the clinical condition. As a patient
improves, his vital capacity tends to rise ; as he becomes worse, it tends
to fall. In other diseases in which mechanical conditions interfere with
the movements of the lungs, the tendency to dyspnea corresponds closely
to the decrease in the vital capacity. The cause of the decrease in the
vital capacity of the lung in cardiac decompensation is difficult to ex-
plain satisfactorily. It may be the limitation in the movements of the
lungs produced by engorgement of the pulmonary vessels, by the weak1-
ness of the intercostal muscles, the rigidity of the bony thorax,
emphysema, or accumulation of fluid in the pleural cavities.

THE MECHANICS OF RESPIRATION 331

In cardiac disease the air in the lungs at the end of a normal expiration
is usually increased. This is similar to the condition which attends exer-
cise, and is probably a physiological adaptation to give optimum aeration
to the blood, as explained above.

It has become more and more evident, since Peabody and Wentworth's
researches, that a determination of the vital capacity is of great importance
in the diagnosis and prognosis of several diseases, including heart disease
and tuberculosis. It is also important in guaging the effects of treatment.
In order that the value actually found in a given patient may be compared
with the value which a healthy individual of the same body build would
give, it is necessary for clinical purposes that some reliable and yet simple
method be available from which the normal value may be computed.
Lundsgaard and Van Slyke51 and Dreyer52 have worked out several ratios
for this purpose, and West50 has shown, by observations on 129 persons,
the most useful of these is one based on the body surface. The body sur-
face is determined from measurement of height and weight by the graphic
chart of DuBois, the use of which is explained on page 576.

The vital capacity can be satisfactorily measured by using a simple
spirometer of about 8 liters capacity and three trials should be allowed, the
largest expiration being recorded. The average value for vital capacity
(in liters divided by the body surface (in square meters) is 2.61 1. per sq.
m. and for women 2.07 (e.g., vital capacity = 5,300 1. ; body surface 2.01,
therefore, ratio =2.63). The deviation from the values should not be be-
yond 15 per cent, the great proportion of normal individuals being within
10 per cent of the above averages. Athletes give decidedly higher values
and old people give lower ones.

CHAPTER XXXVII
THE MECHANICS OF RESPIRATION (Cont'd)

THE MECHANISM BY WHICH THE CHANGES IN CAPACITY OF
THE THORAX AND LUNGS ARE BROUGHT ABOUT

By R. G. PEARCE, B.A., M.D.

The changes that take place in the form and the dimensions of the
thorax during respiration are brought about by movements of the ribs,
diaphragm, sternum, and vertebrae. The share which each plays must
be considered separately.

The Movements of the Ribs

The first seven pairs of ribs progressively increase in length, and are
attached directly to the sternum by cartilaginous bands. The eighth to
the twelfth pairs progressively decrease in length, and as far as the
tenth they are indirectly attached to the sternum by cartilages which join
the seventh. The eleventh and twelfth have their anterior ends free, and
may be considered a part of the abdominal wall and not an intrinsic part
of the thoracic cage.

Each pair of ribs, together with its articulating cartilage and vertebrae,
forms a ring, the plane of which is directed fonvard and downward.
The spinal articulations of the upper ribs differ from those of the lower
ones. In the former the articulations on the tubercle exist as convex
ovoid facets, which fit into corresponding hollow facets on the transverse
processes of the vertebras, while the corresponding facets of the lower
ribs are flat. Each transverse process from above downward is tilted a
little more backAvard than the one above, so that the angle at Avhich the
ribs are set to the spine increases from above downward. This manner
of articulation of the upper ribs with the vertebrae prevents any rotation
in the spinosternal axis, so that there can be no so-called bucket-handle
movement in this region (Keith). The articulation, however, allows the
neck of the rib to rotate in an axis approximately transverse to the body.
The angle which the shaft of the rib makes near its neck, together with
the arch of the shaft, which is directed downward and forward, has the
effect of causing the transverse rotation of the neck of the rib to be

TI7E MECHANICS OF RESPIRATION

converted into an upward movement, which is greatest in that part of the
shaft lying parallel to the axis of rotation of the neck (Fig. 111).

The upper ribs from the first to the fifth form a cone-shaped top to the
thorax, wrhereas the lower ones form a vertical series, each being situated
almost directly above its neighbor. The upper set is arranged for the
expansion of the conical upper lobe of the lungs, the lower for the ex-
pansion of the more or less cylindrical lower lobes. During inspiration
the anteroposterior diameter of the conical portion of the thorax, in-
creases, because the ribs, together with the sternal connections, move
through progressively increasing arches, and each lower rib tends to over-
ride the rib just above. The maximal rise of the ribs from the first to the
tenth during inspiration shifts more and more from the anterior to the

Fig. 111. — A, first dorsal vertebra; B, sixth dorsal vertebra and rib. Axis of rotation shown in

each case.

lateral aspects of the thorax, because the angle formed by the shaft near
the neck of the rib approaches nearer to the articulating joints on the
vertebrae.

An examination of the shape of the first rib, its relationship to adjacent
structures and its movements, shows that it differs from the others in
its respiratory function. The first pair of ribs and the manubrium sterni
are bound closely together by short, wide costal cartilages, and form a
structural unit which Keith1 calls the thoracic operculum. This lid is
articulated behind with the first thoracic vertebra by a joint, which is
more nearly transverse than that of the rest of the costal series ; and in
front with the manubrium, which is also articulated with the clavicles

334 THE RESPIRATION

above and with the body of the sternum below. The freedom of move-
ment at the angle which the manubrium makes with the sternum at this
joint is related to the type of breathing. When the lower portion of the
sternum is elevated during inspiration, the movement of the joint is not
free, but when the sternum is retracted, the movement at the angle may
amount to 16°. Lack of movement of the sterno-manubrial joint has
been considered by some physicians as one of the predisposing causes of
pulmonary tuberculosis. During inspiration, the first rib and its anterior
attachments are raised by the scaleni, and serve as a point towards which
the second, third, fourth and fifth ribs are elevated. During expiration,
they are depressed toward the lower ribs, which form a more or less
fixed base.

The combined effect of these influences is to produce a motion of the
upper ribs which is described by the clinician as being undulatory. This
movement is more apparent in the upper part of the thorax, because
here the relative difference in the length of the ribs is greatest. Hoover
attributes a certain diagnostic significance to loss of the undulatory
movement, diminution in the extensibility of the underlying lungs causing
it to become less or to disappear. The phenomenon is elicited by placing
the tip of the ring finger on the second rib in the midclavicular line, the
tip of the middle finger on the third rib midway between the midclavicu-
lar and anteroaxillary line, and the tip of the index finger on the fourth
rib in the midaxillary line. The patient is then instructed to make a
moderately rapid and deep inspiration. The finger on the third rib will
be observed to move farther than that on the second rib, and the finger
on the fourth rib will move farther than that on the third. The move-
ment of each rib from above downward succeeds and exceeds that of
the rib just above.

When there is a moderate degree of impairment in the ventilation of
the upper lobe, the three ribs move in unison and through the same dis-
tance, so that the undulatory movement is lost although the ribs involved
may exhibit a considerable excursion. The undulatory movement is also
impaired by any disease which encroaches on the air spaces, invades the
interstitial tissue of the lung, or displaces the lung as in the case of an
enlarged heart or a distended pericardial sac. Another possible factor
in this phenomenon is that any inflammatory process in the lung or adr
jacent tissue will produce a reflex inhibition of the muscles of the ribs,
and thus limit the expansion of the thorax.

The axis of movement of the lower ribs, as of the upper ribs, accurately
corresponds with that indicated by their articulation with the vertebrae,
because the muscles attached to them, as well as the diaphragm, influence
their movements to a large extent. Anteriorly the lower ribs from the

THE MECHANICS OF RESPIRATION

335

sixth to the tenth are joined to the sternum by the cartilages which unite
the sixth, seventh, eighth, ninth, and tenth, so that any movement in
which the ribs are raised is accompanied by an anterior movement of the
sternum (Fig. 112). The ribs are so articulated to the spinal column that
the inspiratory act causes the lateral and anterior part of each rib arch
to move forward and outward more than the one above it.

In natural breathing in the standing or sitting posture there is a
slight extension of the spine during inspiration. This serves to increase
all diameters of the thorax and its absence is undoubtedly an important

Fig. 112. — Lower half of the thorax from the 6th dorsal to the 4th vertebra, seen from the
front, c, ensiform process; d, d' , aorta; e, esophagus; /, aperture in tendon of diaphragm for
passage of vena cava inferior; /, 2, 3, trilobate expansions of tendinous center of diaphragm; 4, 5,
costal portions, right and left, of diaphragm muscle; 6, right crus of diaphragm; 8, 9, internal
intercostal muscles, which are absent near the vertebral column, where it joins 9 and 9, the ex-
ternal intercostals; 10, 10, subcostal muscles of left side. (From L,uschka.)

contributory factor in reducing the vital capacity of an individual when
lying on the back. Figures given by Hutchinson for the effect which
posture has on the vital capacity are of interest because of their bearing
on the cause of orthopnea. In the same individual he found the following
vital capacities:

Standing 4300 c.c.

Sitting 4200 c.c.

Supine 3800 c.c.

Prone 3620 c.c.

336 THE RESPIRATION

The Action of the Musculature of the Ribs

In a general way, the external intercostal muscles may be considered
as a broad extension of the scalene muscles over the thoracic walls, with
the ribs as intersections. The scaleni serve to fix the position of the

Fig. 113. — Intercostal muscles of 5th and 6th spaces. A, side view; B, back view; JV, 4th
dorsal vertebra; V, 5th rib and cartilage; I, i, M. levatores costarum, 2, 2, external intercostals;
3, 3, internal intercostals, exposed by removal of the external muscles. In A, there are no external
intercostals in the intercartilaginous spaces; in B there are no intercostals near the .vertebral
column. (From Allen Thomson.)

first rib so that it forms an anchorage for the action of the external
intercostal muscles in raising the lower ribs. They also raise the upper
three pairs of ribs along with the manubrium and sternum.

The function of the intercostal muscles has been the subject of much

Fig. 114. — Hamberger's schema to demonstrate the functional antagonism of internal and ex-
ternal intercostals.

When the ribs ac and bd pass into the inspiratory positions ag and bf, the intercostal space
dilates (bh is greater than a&) ; the sternum gf moves away from the vertebral column ab (bf is
greater than be) ; the fibers of the external intercostals ak shorten (ak is greater than a/) ; and
those of the internal intercostals ck lengthen (ck is greater than /#). The reverse occurs when
the inspiratory position is taken. (From Luciani's Human Physiology.)

THE MECHANICS OF RESPIRATION

337

debate, and can not be said to be definitely settled. The direction of the
fibers in the internal intercostals indicates that they are expiratory in
function, since they can not shorten in the inspiratory position; while,
on the other hand, the fibers of the external intercostals can not shorten
in the expiratory position, and hence must be considered inspiratory in
character (Fig. 113). In 1751 Hamberger showed that mechanically this
is the case, and gave the schema shown in Fig. 114.

The function of the intercartilaginous muscles, however, must be
inspiratory, as is shown in Fig. 115.

Fig. 115. — Schema to demonstrate that the function of the internal intercartilaginous intercos-
tals is identical with that of the external interosseous intercostals.

The ribs and costal cartilage may be regarded as rods bent at the angles acd and bef, in
which the articular points c and e represent the symphysis between the bony and the cartilaginous
parts on which traction is made. During inspiration the fibers of the intercartilaginous muscles,
which have the direction gh, move the sternum df away from the vertebral column ab, like the
libers of the external intercostals, which run in the direction kl. During this double action the
angles c and e must be decreased, because the muscles of the upper intercostal spaces work simul-
taneously, and the entire thorax is slightly elevated during inspiration. From this scheme it is
apparent that the external intercostals and the intercartilaginous muscles must be the same. (From
Luciani's Hitman Physiology.)

The Action of the Diaphragm

It is possible, however, that the main function of both the intercostal
muscles is to regulate the tone of the intercostal spaces and so prevent
their suction inwards when the negative pressure in the thorax increases
(i. e., suction becomes greater) . The ascent of the ribs, while producing an
increase in the anteroposterior and transverse diameters of the thorax,
would decrease the vertical diameter if this was not counteracted by the
fixation of the lower ribs and the descent of the diaphragm. The periph-
eral edges of the diaphragm are attached behind to the lumbar vertebrae,
laterally to the lower edges of the six lower ribs and their cartilages,
and in front to the tip of the ensiform cartilage. The fibers converge to

338 THE RESPIRATION

enter the central tendon, and the lateral sheets are pressed upward by
the intraabdominal positive and intrathoracic negative pressures, so that
they form a dome-shaped vault, with the liver in the right side and the
stomach and the spleen in the left.

During expiration the lateral edges of the diaphragm are in contact
with the parietal pleura of the thoracic cavity, forming what are known
as the pleural sinuses. During inspiration the fibers of the diaphragm
shorten; this straightens out the arch of the diaphragm and pulls the
lateral edges of the diaphragm away from the parietal pleura, thus open-
ing up the pleural sinuses, into which the lungs descend. Usually the
opening up of the sinuses is accompanied by a slight retraction of the
external chest wall, which is known as Litten's diaphragm phenomenon.
The descent of the diaphragm may produce a movement of from 10 to
15 mm. on each side, which accounts for a rather important fraction of
the volume of air exchange by the lungs. The central portion of the
diaphragm does not move much in normal respiration, but in forced
respiration its movement may be considerable.

Because of its attachments to the lower six ribs, the contraction of the
diaphragm tends to pull the margins of the ribs towards the median line,
but under normal conditions this movement is opposed by the action of
the external intercostals in raising the ribs and expanding the horizontal
diameters of the thorax, and by the lower vertebral muscles, which fix
the position of the lower ribs.

The relative part which the diaphragm and the external intercostal
muscles play in the widening of the lower part of the thorax is of som&
importance from the standpoint of diagnosis. It has generally been held
that the contraction of the diaphragm produces a widening of the lower
part of the thorax, because in its descent it presses upon the abdominal
viscera and so distends the abdomen and pushes out the lower ribs.
That this might occur seems not improbable, but Hoover2 has recently
shown by experimental and clinical observations that the flaring in the
costal margins seen in normal inspiration depends on other factors. He
calls attention to the fact that the contraction of the intercostals raises
the ribs and increases the angular divergence of the subcostal borders.
This widening of the angle made by the costal margins at the tip of the
sternum is very pronounced in paralysis of the diaphragm while in
paralysis of the intercostal muscles, the costal borders are drawn towards
the median line and the subcostal angle is decreased. This shows that
the diaphragm must tend to diminish the angle.

The line of traction of the diaphragm is a straight one joining the cen-
tral tendon with the edge of the ribs. When the diaphragm forms a
well-defined arch, it exerts its traction at a disadvantage, and the ex-

THE MECHANICS OF RESPIRATION

339

Fig. 116. — Diagram to show the effect of high and low positions of the diaphragm on the
costal angle.

Line 1. Normal position of diaphragm Costal margins move out during inspiration.

Line 2. High position of diaphragm. Normal outward movement of costal margins accentuated.

Line 3. Low position of diaphragm. Costal margins move in during inspiration.

Line 4. Very low position of diaphragm. Costal margins move out during inspiration.

Line 5. Actual line of traction of diaphragm. (From T. Wingate Todd.)

340

THE RESPIRATION

Fig. 117. — Diagram to show the effect of clinical displacements of the diaphragm on the costal

angle.

Line 1. Normal position of diaphragm. Costal margins move out during inspiration.
Line 2. Position of diaphragm in general cardiac enlargement. Costal margin from ensiform to

ninth rib moves toward median line.
Line 3. Position of diaphragm in left-sided cardiac enlargement. Left costal margin is fixed or

moves in during inspiration.
Line 4. Position of diaphragm in right-sided cardiac enlargement. Right costal margin is fixed

or moves in during inspiration.
Line 5. Costal margin. (From T. Wingate Todd.)

THE MECHANICS OF RESPIRATION 341

ternal intercostals have the mastery and cause the costal borders to
spread. When the arch of the diaphragm is depressed, as in pleurisy
with effusion, emphysema, and empyema, the line of traction and the
line of the muscular fibers of the diaphragm correspond more closely,
so that the diaphragm is able to use its full force against the intercostal
muscles, with the result that the costal border moves towards the median
line. The curves of the different fibers of the diaphragm vary greatly;
the arch is much less marked in the portion attached to the costal margin
near the median line than in that attached in the axillary line. For this
reason the anterolateral part of the diaphragm requires less depression
to give it a horizontal position than is required for parts occupying a
more lateral position. A small pericardial effusion or an increase in the
size of the heart may therefore depress the diaphragm sufficiently to give
it mastery over the intercostals in the front portion, so that the costal
border may here move towards the midline, while the lower borders
move in a perfectly normal manner (see Figs. 116 and 117).

During forced breathing several muscles are brought into play, among
the most important of which are the scaleni, sternomastoid, trapezius,
pectorals, rhomboids, and serratus magnus.

There has been considerable debate as to whether expiration is normally
an active or a passive process. Undoubtedly the expiratory phase under
normal conditions does not require the same muscular effort as does that
of inspiration, but there are many observations which indicate that ex-
piration is partly under muscular control. The abdominal musculature,
for example, increases in tone during expiration, so as to bring about a
rise in the abdominal pressure, with the result that the relaxed diaphragm
is pushed up into the thoracic cavity. To this extent at least, expiration
is accompanied by increased muscular activity.

Before leaving the subject of the diaphragmatic movements, reference
must be made to the recent observations of Lee, Guenther and Meleney3
bearing on the general physiological properties of the diaphragmatic
muscle. They point out that most skeletal muscles in the living body
contract with varying degrees of intensity and at irregular intervals,
between which relatively long periods of rest occur, but the diaphragm
from birth to death performs a continuous succession of brief contrac-
tions of fairly regular rhythm and uniform extent, alternating with brief
periods of rest. Its muscle fibers, together with those of the other
respiratory muscles, therefore hold a unique position among skeletal
muscles, which suggests a crude analogy with that of the heart. They
have compared the physiological properties of the diaphragm with those
of the extensor longus digitorum, the sartorius, and the soleus, and found

342 THE RESPIRATION

that the diaphragm is composed of a much more efficient muscular tissue
than that of the other muscles.

The Effects of the Respiratory Movements on the Lungs. — The changes
produced in the dimensions of the lungs by the inspiratory expansion of
the thoracic cavity are not uniform, since different parts of these struc-
tures are not equally extensible. From an anatomical standpoint, the
lungs may be divided into three zones: (1) The inner or root zone contain-
ing the bronchus, artery and vein, and their main subdivisions. The
large amount of fibrous tissue in this region offers great resistance to
any expanding force. (2) The intermediate zone, containing the vascular
and bronchial ramifications radiating towards the surface of the lungs,
with pulmonary tissue implanted between the rays. This part of the
lungs has varying degrees of extensibility, the pulmonary tissue having
the most and the vascular and bronchial the least. (3) The outer zone,
perhaps 25 to 30 mm. in depth, composed of pulmonary tissue and
equally extensible throughout (Keith1). The expansion of the lung is
accomplished by a moving apart of the less extensible rays of tissue so
as to permit the expansion of the more extensible pulmonary tissue be-
tween them. Keith compares the mechanism to that seen in the opening
of a Japanese fan.

Because the lung expands in the direction of least resistance, study
of the inflated dead lung does not reveal the normal expansion brought
about by the thoracic movements. In the living body expansion is more
limited in some regions than in others. Of the five areas which may be
distinguished on the surface of the lungs, three are in contact with rela-
tively immovable parts of the chest wall, and therefore can not be ex-
panded directly. These are: the mediastinal, in contact with the pericar-
dium and the structures of the mediastinum ; the dorsal surface, in contact
with the spinal column and the posterior aspect of the thoracic cage, and
the apical surface. The motions of the first pair of ribs and the manu-
brium expand chiefly the anterior and ventrolateral part of the apex
of the lung, and have only an indirect influence on the dorsal part of the
apex — i. e., the part lying directly in front of the necks of the first and
second ribs, the most common site of pulmonary tuberculosis. The two
surfaces of the lungs which are directly expanded are the diaphragmatic
and the ventrolateral or sternocostal. Meltzer4 found that the negative
pressure in the thorax during inspiration was least along the relatively
stationary walls of the thorax, and greatest in the regions nearest the
diaphragm. From this he concludes that some of the expanding force
is lost as it passes through the lungs to the surfaces of indirect expansion.
Many observers have claimed that the expansion of the lung does not
take place throughout instantaneously and equally. This is illustrated

THE MECHANICS OF RESPIRATION 343

by the fact that, in the region immediately surrounding a localized con-
solidation, a fluid has increased resonance, which would not be the case
if the relaxation produced was equally distributed throughout the lung.
The root of the lung, which has generally been regarded as more or
less fixed, undergoes in normal breathing a definite forward, downward
and outward movement, and the heart shares in this movement (Keith).
The movements of .the lower ribs and diaphragm are responsible for the
expansion of the lower lobes and dorsal portion of the upper lobes of the
lungs, whereas the movement of the upper five ribs expands the anterior
portion of the upper lobes. The relative infrequency of pleuritic fric-
tion-sounds and pain over the upper lobes as compared with their fre-
quency over the lower lobes is explained by the fact that the expansion
of the upper lobes is accomplished with little displacement of the pleural
surfaces, whereas in the lower lobes expansion is accompanied by a glid-
ing of the lungs across the ribs.

CHAPTER XXXVIII
THE CONTROL OF THE RESPIRATION

The participation of such widespread groups of muscles in the respira-
tory act demands that some mechanism be provided to insure its adequate
control. With every inspiration, for example, the muscles of the ala>
nasi act so as to cause dilatation of the nares, the vocal cords are ab-
ducted, and the intercostal muscles, along with the scalenes and the
diaphragm are contracting while the muscles of the abdominal wall are
relaxing; and all these events occur at exactly the proper time so as to
bring about the most efficient opening up of the thoracic cavity. Evi-
dently there must be some mechanism to insure this perfect control. This
is effected through the nervous system.

THE RESPIRATORY NERVE CENTERS

The efferent fibers to the various groups of muscle originate in their
respective motor neurons, which in most cases are situated in the gray
matter of the spinal cord. The harmonious action of these motor neu-
rons, or subsidiary centers, is brought about by the transmission to them
of impulses from a higher or master center placed in the medulla ob-
longata, the pathway of transmission between this master center and the
subsidiary centers being in the lateral columns of the spinal cord.

The evidence that the chief respiratory center is in the medulla is fur-
nished by observing the effects produced on the respiratory movements
by serial destruction of the cerebrospinal axis from above downward.
By this method the approximate position of the center is found, its exact
location being then determined by punctiform destruction or stimulation
of the supposed locus of the center. If we destroy the cerebrum from
before backward, piece by piece, we shall find that no marked effect is
produced on the respirations until we arrive at about the middle of the
medulla, when immediate paralysis of the respiratory movements occurs.
If we now proceed to puncture various areas on the floor of the fourth
ventricle in another animal, we shall find an area called the noeud vital,
located about the tip of the calamus scriptorius, destruction of which
causes immediate cessation of respiration. It is believed that the center
resides in the group of nerve cells known to neurologists as the fasciculus
solitarius. It is bilateral.

344

THE CONTROL OF THE RESPIRATION

345

The subsidiary centers are entirely dependent upon the master center
for their harmonious action, as is shown by the fact, that if the phrenic
motor neuron — which is situated in the cervical spinal cord between the
fourth and sixth spinal segments — is isolated from the medulla by a
lateral hemisection of the cord just above the fourth segment and by
mesial section of the cord opposite the center, the corresponding half of
the diaphragm no longer participates in the inspiratory act (see Fig. 118).

The chief center on either side of the midline of the medulla is con-
nected with the motor neurons of both sides of the spinal cord, as is
proved by the following experiment. When the central end of the vagus
nerve is stimulated, the respiratory center becomes excited and the respi-
rations more pronounced, the participation of the muscles on both sides
of the body being equal in extent. If now we bisect the medulla down the

Fig. 118. — Diagram to show cuts required for isolation of the phrenic center.

midline and repeat the stimulation of one vagus, the muscles on both sides
will still participate in the increased respiration, which they will likewise do
if the cervical cord is bisected or hemisected but the medulla left intact
(Fig. 119). The simplest interpretation of these results is that commis-
sural fibers connect both halves of the respiratory center in the medulla
and that each half is also connected with the motor neurons of both sides
of the spinal cord. Often, especially in young animals, a hemisection of
the cord causes cessation of the movements of the diaphragm on the same
side; but this paralyzed side at once begins to contract again when the
phrenic of the opposite side is cut, probably because the respiratory
impulse descending from the chief center, on finding its way along the
motor center of the same side of the cord blocked, is forced to follow the
crossed path. The crossing in the cord is believed to take place at the
same level as that at which the subsidiary center is located (W. T.
Porter12).

346

THE RESPIRATION

The question now arises as to 'how the chief center functionates. Is it
purely reflex in the sense that it depends for its activity entirely on the
transmission to it of nervous impulses from elsewhere, or is it automatic
in the sense that it can work independently of such impulses? The au-
tomaticity of the heart makes it seem not improbable that the center
which controls the co-ordinate action of the respiratory muscles would
also have an inherent or automatic power. The activity of such an auto-
matic respiratory center would, of course, be subject to great variation
as a result of changes in the composition of the blood supplying it, and
the fact that it was automatic would not remove it from the influence of
nervous impulses. Indeed it is possible to conceive of the automaticity
of the center as being of a low order, with its normal functioning
dependent upon afferent nerve impulses. Its automaticity might, then,

Medulla

Fig. 119. — Diagram to show certain positions in the medulla and upper cervical cord, where
sections may be made without seriously disturbing the respirations. Sections made separately will
not disturb the respiration, nor interfere with the effect of vagus stimulation. If both sections
are made at once, however, breathing will be seriously interfered with on the side of the
hemisection, and this side will not respond to vagus stimulation.

be merely a factor of safety called into play only when the influences
ordinarily controlling the center were for some reason removed.

The question which at present confronts us, however, is whether the
center may or may not act automatically. Many experiments have been
undertaken to test this point, the nature of all of them depending upon
the isolation of the center as completely as possible from afferent nerve
paths. The most successful experiment has been performed as follows:
The influence of the higher nerve centers was removed by cutting across
the peduncles of the cerebrum or the pons. The influence of afferent im-
pulses traveling up the spinal cord was removed by completely severing
the spinal cord below the level of the phrenic nerves and sectioning all
the posterior or sensory spinal roots of the cervical cord above the level
of this section. The vagi were also cut to remove the impulses traveling

THE CONTROL OF THE RESPIRATION

347

by them to the respiratory center. By such an operation the only lower
respiratory neurons left intact are those of the phrenic nerve, so that the
respiratory movements that alone are possible are those in which the
diaphragm participates and the muscles of the alaa nasi and larynx. It
was found that the animal after the operation went on breathing, though
imperfectly, and that the respirations soon became more marked and
asphyxial in character, indicating that the blood was not becoming

Vagus,!.

Diaphragm.

Fig. 120. — Diagram to show where cuts are made to isolate the chief respiratory center from

afferent impulses.

properly aerated and that the chemical changes occurring in it were
acting directly on the center, stimulating it to greater activity. The
conclusion seems warranted that the respiratory center can act auto-
matically, for the only possible afferent nerves left in the above prepara-
tion were those carried to the center by the fifth nerve (Fig. 120).

That the respiratory center is extraordinarily sensitive to changes in
the composition of the blood flowing through it is a fact that has been
known for a long time, but it is only within recent years that the exact

348 THE RESPIRATION

nature of this control and the remarkable sensitivity of the center towards
it have been thoroughly established. We shall return to this important
subject later. Meanwhile we shall proceed to examine the manner in
which the center is affected by sensory impulses transmitted to it.

THE REFLEX CONTROL OF THE RESPIRATORY CENTER

The afferent nerve fibers going to the respiratory center may conven-
iently be divided into two groups: those coming from the respiratory or-
gans and those coming from other parts of the body.

Afferent Impulses from the Respiratory Organs

If the vagus nerves are cut or their continuity severed by freezing
a portion of them, the respiratory movements become markedly slower.
Evidently, the vagus nerves in some way hurry up the respiratory
movements. Again, if the central end of either vagus is stimulated
with the ordinary interrupted faradic current, a profound effect on
the respiratory movements is usually observed. This effect is how-
ever not strictly predictable. Usually there is a quickening of respira-
tion, and if the stimulus is a strong one, there may be a standstill of the
thorax in the inspiratory position. On the other hand, if the central
end of the nerve is stimulated with other types of stimuli, as by slow,
weak faradic shocks or by the stimulus produced by the closure of an
ascending voltaic current, the effect may be to stimulate expiration
rather than inspiration. Such results would seem to indicate that the
vagus contains two kinds of afferent fibers to the respiratory center, one
kind stimulating inspiration, the other, stimulating expiration.

Supposing that such fibers exist, the next question is, how do they
become stimulated at their terminations in the lungs? The most nat-
ural assumption is that the mechanical distention and collapse of the
alveoli which occurs with each respiratory act, serves as the stimulus —
an hypothesis to which support is offered by the observation that, when
air is blown into the lungs so as to distend the alveoli, the animal im-
mediately makes a forced expiratory movement, whereas when the air
is sucke.d out, the thorax assumes the inspiratory position.

Of the many methods that have been employed to produce disten-
tion of the alveoli, the best is undoubtedly that recently employed by
Ilaldane13 and Boothby.14 The person or animal is made to respire through
a tube in which is inserted a three-way stopcock, which communicates
either with the outside air or Avith a side-tube leading to a spirometer
or bag containing air under slight pressure, so that when the stopcock
is turned breathing takes place against a definite positive pressure.

THE CONTROL OF THE RESPIRATION 349

Such a method is obviously much more physiological than one in which
the air-tube is suddenly clamped at the end of inspiration and the lungs
left in a distended condition.

The term used to designate the cessation of breathing is called apnea.
The extent to which it occurs varies very considerably in different an-
imals and, in the case of man, in different individuals. Thus, when a
man is made suddenly to breathe into compressed air, the apnea often
lasts for about half a minute, the pause being then broken by a deep ex-
piration followed by a further pause, then again an expiration, and so
on with progressively shorter pauses. Disregarding for the present
any influences which changes in the composition of the air in the lungs
or of the gases in the blood might have in producing the apnea, Ave may
consider the possibility that it is the result of afferent fibers in the
vagus. This is an old view, but the most recent experimental evidence
does not lend support to it. It was shown by Boothby and Berry,14 for
example, that a similar apnea, though indeed of shorter duration, could
be produced in dogs in which the pulmonary branches of both vagus
nerves had been severed two months previously. The apnea is, there-
fore, not a reflex of the vagus, and must be interpreted as due to nerv-
ous impulses passing to the respiratory center from some other part of
the nervous system, perhaps from centers higher up, or to stimuli trans-
mitted to the respiratory center possibly through afferent fibers in the
respiratory muscles.

It has usually been taught that section of the vagus nerves of both
sides results in death from pneumonia within a few days. E. A. Schafer
has shown that this is not the case but that animals (cats) can be kept
alive practically indefinitely if precautions are taken to prevent the
obstruction of the larynx which supervenes, through paralysis of the
laryngeal muscles, or when the inferior laryngeal nerves are cut. The
obstruction causes asphyxia followed by congestion and edema of the
lungs. If the larynx be cauterized so as to prevent obstruction double
vagotomy even in the neck has no greater influence on breathing than
perhaps a slight and often transitory slowing.53

The formerly very popular theory that respiration is controlled au-
tomatically by alternate distention and collapse of the alveoli, acting
through the afferent fibers of the vagus nerve on the respiratory center
in such a way as to bring the opposite act with each expiration and
inspiration, must, therefore, be abandoned. But we can not deny that
the vagus plays a most important role in the control of the function of
the respiratory center, for apart from the effect which we have seen to
follow the severence of continuity of the nerve, there is the important
observation of Alcock and others15 that when nonpolarizable electrodes

350 THE RESPIRATION

are placed 'on the vagus nerve and connected with a galvanometer, a
current of action occurs toward the end of each inspiration in quiet
breathing; and when the respirations are forced, a current of action
appears during both inspiration and expiration. Another reason for
believing that the vagi have some important function to perform in con-
nection with the control of respiration is the fact, observed by F. H. Scott,16
that in an intact animal, when atmospheres containing increasing percent-
ages of carbon dioxide are respired, the respirations become both deeper
and quicker, whereas in one whose vagi have been cut the carbon diox-
ide causes only a deepening of the respirations. From this result it
would appear that the vagi exert an influence on the rate of the respira-
tions but not on their depth, this effect, as we shall see later, being de-
pendent primarily on changes in the composition of the blood supplying
the respiratory center. It is probable that both controlling agencies act
together, the one serving to maintain the center in a proper state of
excitability, and being active to a greater or less extent all the time;
while the other acts only occasionally on the " tuned up" center. There
is, of course, no doubt that it is through the nerves that the occasional
alterations of respiration occur. They appear also to have a certain
influence on the rhythm, for Stewart, Pike and Guthrie17 observed that,
after resuscitation from acute brain anemia, the respirations when they
returned were of the same rhythm as that of the artificial respirations
employed during the resuscitation.

Afferent Impulses from Other Parts of the Body

To the first group belong afferent nerves from practically every part of
the body. That impressions from the skin affect the respiratory center
is well known by the increased breathing caused by applications of cold
water. The influence of these afferent impulses is often very marked,
and is frequently taken advantage of in stimulating a newborn infant to
take the first breath. Stimulation of the terminations of the fifth nerve
in the mucous membrane of the nose, as by inhaling a pungent odor,
immediately inhibits respiration. To these occasionally acting afferent
impulses may be added the impulses that are conveyed to the respiratory
center from the higher nerve centers of the cerebrum. These impulses
are largely voluntary in nature, and enable us to hold our breath at will.
Some of the cerebral impulses are however also involuntary, their exist-
ence being seen by observing the respirations of an animal before and
after sectioning the pons or peduncles. The respirations for a time at least
become distinctly affected, but they later return with perfect regularity.
They may become very irregular, however, if the vagi as well as the pons
are cut. Other experimental evidence of the existence of cerebral respir-

THE CONTROL OF THE RESPIRATION 351

atory fibers is furnished by cerebral localization experiments. During
stimulation of the cerebral cortex, for example, a marked effect on the
respiratory movements is often noted.

Respiratory rhythm, unlike that of the heart, has often to be modified
in order that the respiratory mechanism may be used for other purposes
than the ventilation of the lungs. This alteration in rhythm may take
the form of a mere inhibition, such as the act of swallowing; or the
respiration may be altered, as in phonation and singing. More consid-
erable alteration in the expiratory discharge occurs in coughing and
sneezing, and still more in the acts of micturition, defecation, and parturi-
tion. We must conclude therefore that the rhythmic stimuli sent out
from the respiratory center are so weak that stimuli from other sources
may instantly inhibit or change their form at any stage of the cycle.

Stimulation of the endings of the glossopharyngeal nerve inhibits res-
piration, which explains the holding of the breath that occurs in swal-
lowing.

The superior laryngeal branch of the vagus has an occasional influence
on the respiratory center, its particular function being in connection with
the act of coughing. When a foreign body irritates the mucous membrane of
the larynx, the nerve fibers transmit impulses to the respiratory center
which excite a violent expiration and at the same time cause the glottis to
close. The closure of the glottis lasts, however, only during the first part of
the expiration; it then opens, with the result that the sudden release of
intrapulmonic pressure causes the expulsion of the foreign substance
from the air passages.

CHAPTER XXXIX
THE CONTROL OF RESPIRATION (Cont'd)

THE HORMONE CONTROL OF THE RESPIRATORY CENTER

Just as the rhythmical activity of the heart is readily influenced by
changes in the composition of the blood supplying it, so also is that of
the respiratory center. In the case of the heart it is the cations — cal-
cium, potassium and sodium — that have the most pronounced effect,
whereas in the case of the respiratory center it is largely the relative con-
centration of hydrogen and hydroxyl ions — the H-ion concentration
(CH) of the blood. This influence can be shown in a general way by
injecting acid or alkaline solutions into the peripheral end of the carotid
artery of an anesthetized animal, or better still of one that has been
decerebrated. Acid injections stimulate the respiratory activity; alka-
line injections tend to depress it. When the acid or alkaline solutions
are injected intravenously in other parts of the body, so that they be-
come thoroughly mixed with the blood before the respiratory center is
reached, the effects are not nearly so pronounced, because the buffer in-
fluence of the blood has time to develop (see page 36).

From the results of such injection experiments, however, one could
not draw the conclusion that under normal conditions the activity of
the respiratory center is affected by measurable changes in CH of the
blood, for, as we have seen, constancy of CH is one of the most remark-
able properties of the animal fluids. To justify the conclusion that the
respiratory center is affected by changes in CH, it is necessary to observe
the behavior of some easily measurable acid or alkaline constituent of
the blood that undergoes changes in amount that are proportional to an
alteration in CH. In order to understand what this acid or basic
substance may be, it will be advisable to recapitulate the main factors
concerned in maintaining CH at a constant level. This value is obviously
dependent upon the balance between basic and acid substances, so that-
any variations which it undergoes must be caused by changes in the
relative amount of one of these. Changes in "base may occur, exoge-
nously, by altering the alkali content of the food, or, endogenously, in
various ways but particularly by variations in the amount of ammonia
produced during the course of metabolism of protein. Thus, when sud-
den demands are made by the organism for an increased amount of base,

352

THE CONTROL OF THE RESPIRATION 353

the amino groups — split off from the amino bodies — become converted
into ammonia instead of into the neutral substance, urea. But the chief
variations seem to concern acids rather than the basic substances. These
acids may be divided into three groups: fixed inorganic acids, represented
by phosphoric; fixed organic acids, represented by lactic; and volatile
acids, represented by carbon dioxide. Of these three groups, the first
shows the least tendency to change, and the third, the greatest. Changes
in the second group (fixed organic acids) are effected partly by excretion
through the urine and partly by oxidation into volatile acid. The sud-
den and rapid changes in the third group are brought about by the dif-
fusion of the C02 of the blood into the alveolar air. Gross changes in
the acid content of the blood are therefore mainly effected through al-
teration in the excretion of the fixed acids, whereas sudden changes are
effected by excretion of the volatile acid. It is important to note here
that the fixed organic acids do not participate to any great extent in
the makeup of the acid content of normal blood: they appear only under
unusual conditions, as in dyspnea. The variations in CH that ordinarily
affect the activity of the respiratory center are therefore dependent
upon changes in the volatile acid, a direct measure of which is found
in the tension of CQ2 in the blood. The correlation between CH of the
blood and respiratory activity must be a very close one if CH is to be
maintained.

The Laws of Gases, — In order to understand the principles upon which
alterations in C02 tension are dependent, it will be necessary for us to
review briefly some of the gas laws. Among these laws the first in im-
portance is the law of pressure, which states that, other things being
equal, the pressure of a gas is inversely proportional to its volume; if
a gas occupying a certain volume is compressed by a pump so that it oc-
cupies one-half of its previous volume, its pressure will become doubled.
The second is the law of partial pressure, which states that the partial
pressure of a gas in a mixture of gases, having no action on one another,
is equal to that which this particular gas would exert were it alone present
in the space occupied by the mixture. Thus, atmospheric air consists
roughly of 79 volumes per cent of nitrogen and 21 of oxygen; the par-

21
tial pressure of the oxygen is therefore equal to -rr X 760 mm. Hg,

this last figure being the barometric pressure of air at sea level. The
third is the law of solution of gases, which is to the effect that the amount
of gas which goes into solution in a liquid having no chemical attraction
for the gas, is proportional to the partial pressure of gas. If water is
exposed to air, the amount of oxygen which it dissolves will be the same
as if the water had been exposed to oxygen at a pressure equal to that

354 THE RESPIRATION

of the partial pressure which it produces in air. The same will be
the case with the nitrogen of the air. The actual amount of gas which
becomes dissolved in the fluid, pressure and temperature being constant,
depends partly on the nature of the gas and partly on the nature of the
fluid. For example, the solubility of oxygen in water is considerably
different from that in a neutral oil; or, taking the same solvent, nitro-
gen and C02 do not dissolve to the same extent in water. It becomes
necessary, therefore, in calculating what amount of a particular gas
will dissolve in a particular fluid to use a figure known as the coefficient
of solubility of the gas — that is, the amount of gas taken up by a unit
volume of fluid at standard temperature and pressure; for example, to
say that the coefficient of absorption of nitrogen in water at 0° C. is
0.0239 means that, at this temperature and at normal barometric pres-
sure, 1 c.c. of water will dissolve 0.0239 c.c. of nitrogen when exposed to
a pure atmosphere of this gas. Obviously, then, if water were exposed
to 79 per cent of an atmosphere of nitrogen (as in air) the amount which

79
would become dissolved in each c.c. would be -7777: x 0.0239 = 0.0189 c.c.

In solutions containing no chemical substances with which the gas can
enter into combination, it is evident that the tension of the gas will be
proportional to the amount of gas that can be displaced or pumped out
from the fluid. On the other hand, when a chemical compound is formed,
the combined gas will exercise no direct influence on the tension, so that
this will be independent of the amount; in suck cases separate methods
will have to be used for the determination of amount and tension. Let
us take the case of pure water exposed to an atmosphere of C02: the
amount of C02 which goes into solution will depend entirely on the
pressure. If a trace of alkali is dissolved in the water, however, some
of the C02 will become combined to form carbonate, so that a much
larger quantity of C02 will be displaceable from the solution (as by
adding a mineral acid to it) than corresponds to the tension of C02 in
the atmosphere surrounding it. Since blood contains alkali the condi-
tions are analogous with those of a weak alkaline solution.

The Tension of C02 and 02 in the Arterial Blood. — If we were to
pass blood at body temperature in a very thin film over the walls of a
confined space containing a mixture of gases one of which was C02, it
is evident that the percentage of C02 in the atmosphere contained in
this space would remain unchanged only when the tension of this gas in
the blood was the same as that in the confined atmosphere. If, on the
other hand, the tension of C02 in the blood should correspond to a per-
centage that is higher than that in the atmosphere, then C02 would dif-
fuse from the blood, and at the end of the experiment an analysis of the

THE CONTROL OF THE RESPIRATION

355

atmosphere in the space would show that the C02 percentage had been
raised. If the blood contained a lower tension than that corresponding
to the percentage of C02 in the space, some of the C02 would diffuse
into the blood, and its percentage in the atmosphere would be lowered.
By successively exposing blood to gas mixtures that contain slightly
different percentages of C02, we should ultimately find one with which
the free C02 in the blood was in perfect equilibrium, and we should be
able to state that the tension of this gas in the blood was equal to a
certain percentage in the atmosphere surrounding the blood (see Fig.
121).

Many forms of apparatus based on the above principle have been in-
vented for the examination of the tension of the gases in the blood.
The most accurate is that devised by Krogh,18 the principle of which

CO,

J.1.5 at and

Fig. 121. — Diagram to show principle for measurement of the tension of CO2 in blood.
COs tension of blood is supposed to be 5.75.

The

differs slightly from that just described in that a bubble of air is
exposed -to a relatively large quantity of blood, so that after a time
actual equilibrium of gas tension becomes established between the bub-
ble and the gases of the blood. This apparatus is shown in Figs. 122
and 123. It consists of a graduated tube of narrow bore sur-
rounded by a water jacket. To the upper end of the graduated tube,
a small syringe is attached. The lower end of the graduated tube ex-
pands into a thistle-shaped bulb, closed below by a cork, through which
is inserted a tube (inflow tube) ending near the top of the bulb in a
fine opening and connected outside with an artery. An outflow tube is
also connected with the thistle-shaped bulb.

At the beginning of the experiment the thistle-shaped bulb and the
graduated tube are filled with physiological saline. By means of the
syringe a small bubble of air is then introduced, so that it lies at the

356

THE RESPIRATION

junction of the thistle-shaped bulb and the graduated tube. As the blood
is allowed to enter through the inflow tube, it is ejected in a fine stream
around the bubble of air, which moves about in the stream. The blood
displaces the saline out of the bulb into the side tube. After the bub-
ble has been subjected to the influence of the blood for some minutes,
the gases in it come into perfect equilibrium with those in the blood.
The percentage of 02 and C02 in the bubble will therefore correspond
to the tension of these gases in the blood. The analysis is effected by
drawing the bubble into the graduated tube by means of the syringe,

A

Fig. 122.

/o\

Fig. 123.

Fig. 122. — The gas analysis pipette for the. microtonometer shown in Fig. 123. For description
see context. (From A. Krogh.)

Fig. 123. — Microtonometer, to be inserted into a blood vessel. The small circle represents the
bubble of air. For further description see context. (From A. Krogh.)

measuring its capacity, transferring it into a bulb containing KOH,
which absorbs the C02, then taking it back into the capillary tube and
again measuring. The shrinkage obviously corresponds to the amount
of C02. The bubble is then transferred into potassium pyrogallate solu-
tion, where the 02 is absorbed.*

The Tension of C02 and 02 in Alveolar Air. — Having seen how we
may determine the tension of the gases in blood, we must now consider

*Since the above was written, a more efficient tonometer devised by the late T. G. Brodie has
been described by O'Sullivan (Am. Jour. Physiol., Sept., 1918).

THE CONTROL OF THE RESPIRATION 357

the method by which the tensions of these gases in alveolar air can be
determined. The simplest and until recently the most accurate method
is that of Haldane and Priestley.19 This consists in having an individual,
with his nostrils clamped, breathe quietly through a piece of hose pipe
about a meter long, which has at the mouth end a short side-tube lead-
ing to an evacuated gas-sampling bulb of about 50 c.c. capacity.* (Fig.
124). After the subject has become accustomed to breathing through the
tube, he is asked to make a forced expiration and at the end of it to close
the mouthpiece with his tongue. At this moment the operator opens the
tap of the sampling tube, allowing the air from the tubing through
which the individual has made the forced expiration to rush in and fill
it. This sample represents the air from the alveoli (see page 319), and
is analyzed for percentages of C02 and 02. Since each normal inspira-
tion dilutes the alveolar air somewhat, it is necessary, for constant re-

Fig. 124. — Apparatus for collection of a sample of alveolar air by Haldane's method. It is
better to use a mouthpiece than a mask.

suits, to make two analyses of alveolar air from each subject, one taken
at the end of a normal inspiration and the other at the end of normal
expiration. The average of the two results is taken as the composition
of the alveolar air.

On account of the difficulty in securing intelligent cooperation in the
application of this method, particularly with children, other methods have
been devised. One of the simplest is that of Fridericia, which is a modifica-
tion of the Haldane-Priestley method, the apparatus for which is shown
in the figure (Fig. 125), and the manipulation of which is outlined in
the legend. Another is to take a mixed sample of the very last portion
of several normal expirations. On account of the extended use which is
being made of measurements of alveolar air composition, both in lab-

*In place of the gas-sampling tube it is much more convenient and equally accurate to employ one
of the modern ground glass piston syringes (Luer). The piston should, of course, be well smeared
with a good mineral grease.

358

THE RESPIRATION

Fig. 125. — Fridericia's apparatus for measuring the CO* in alveolar air. The person expires
forcibly through the tube with the stopcocks as in I. A is closed and the tube placed in water to
cool the air, after which B is turned as in II. The entrapped column of air equals 100 c.c. A
solution of caustic alkali is now sucked into C with stopcocks as in II. B is then turned as in
I but with A still closed, and the alkali solution allowed to enter b, after which B is turned off,
the excess of alkali solution in C allowed to run out and the burette shaken. The burette is
then submersed up to a in a cylinder of water, with B as in III. After allowing for cooling,
the level at which the water stands gives the per cent of COu.

in inspired
air

ISO

fO 20 00 W 50

Fig. 126. — Curves to show the relationship between the Oo and COa tensions in alveolar air
(dotted lines) and arterial blood (continuous lines). It will be observed that the tension of CO2
in blood is slightly above that in alveolar air, but that the reverse relationship obtains for Os. In
the upper part of the curve the O2 tension in the alveolar air was experimentally altered, causing
a corresponding alteration in the O| tension of the blood. This result is of practical significance
in connection with On alterations in gas poisoning, pneumonia, etc. (From A. and M. Krogh.)

THE CONTROL OF THE RESPIRATION

359

oratory and in clinical work, a special chapter has been devoted to the
subject, giving in detail the more recent methods devised by R. G. Pearce.

Lastly, it should be noted that several observers believe that a more
reliable estimate of the alveolar tension of C02 (and of 02) can be made
by analyzing a sample of ordinary expired, air and calculating the per-
centages of C02 and 02 in the alveolar air by allowing a constant dead-
space capacity of 140 c.c. (Krogh, etc.).

If we compare the C02 tension of arterial blood, as measured by the
Krogh method, with that of alveolar air, we shall find that there is a
remarkable correspondence, indicating, therefore, that, when the arterial

^ •£ % €02 in. it spired &ir

£20 30 itO SO

20 30 40

Fig. 127. — Same as Fig. 126, except that in this case the tension of CO2 in the alveolar air was
experimentally altered. (From A. and M. Krogh.)

blood leaves the alveoli, its partial pressure or tension of C02 is exactly
equal to that in the alveolar air. This is shown in the accompanying
curves of experiments performed by Krogh. The dotted line in these
curves represents the tension of C02 or 02 in alveolar air, and the con-
tinuous line, these tensions in arterial blood. Close correspondence
will be observed between the C02 curves even when sudden changes in
alveolar C02 w^ere induced by artificial means. In the case of the 02
tensions, however, that of the blood is always lower than that of the
alveolar air, the differences being especially marked when the 02 ten-
sion in the alveoli is raised (Figs. 126 and 127).

Tension of C02 in Venous Blood, — If we examine the C02 tension of
the venous blood coming to the lungs, we shall find that it is distinctly

360 THE RESPIRATION

higher than that in the alveolar air. The earliest method for measuring
it consisted in passing a lung catheter into the right bronchus and then
blocking the passage above the open end of the catheter by inflating a
rubber collar or ampulla. The renewal of air in the right lung is thereby
prevented, and a sample of the stagnant air can be removed and analyzed.
In such a case, however, the blood will have circulated several times
round the body, and with only one lung operating the risk is incurred
that more C02 is being discharged into the blocked lung than cor-
responds to the tension of C02 of venous blood under normal conditions.

Much more practical methods are those of Haldane, Yandell Hender-
son and R. G. Pearce, which are much the same in principle. In Pearce 's
method, the person first of all inspires from a gas meter containing a
gaseous mixture with about 10 per cent of C02. Immediately after fill-
ing the lungs, he makes a rapid forced expiration into a tube provided
with a valve having four openings. This valve is turned through a
complete circuit during the expiration, so that four fractions of the ex-
pired air can be collected in rubber bags connected with side tubes
opening opposite the four openings in the valve. The first fraction will
contain a little less than 10 per cent C02, the second distinctly less,
while the fourth will contain the same as the third, indicating that equi-
librium between the C02 of the alveolar air and the blood must have been
attained. This figure therefore gives us the tension of C02 in the venous
blood of the lungs. In Henderson's method the rebreathing is per-
formed into gas receivers containing 6 per cent C02.

These results then indicate that the whole process by which C02 is
exchanged in the lungs is dependent on the law of gas diffusion ; the gas
diffuses from a place of higher to a place of lower pressure, and does
so until equilibrium is attained.

CHAPTER XL
THE CONTROL OF RESPIRATION (Cont'd)

THE ESTIMATION OF ALVEOLAR GASES
BY R. G. PEARCE, B.A., M.D.

Methods such as that of Haldane and Priestley, which calculate the
mean percentage composition of the alveolar air by analysis of a sample
taken from the end of a prolonged forced expiration, give values which
are too high for C02 and too low for 02. There are several reasons
for this: (1) In the time taken for the prolonged deep expiration an
appreciable amount of C02 will be given off by the blood to the alveolar
air, and oxygen will be absorbed — that is, the sample will not contain
the same percentages of C02 and 02 at different stages of expiration.
(2) The portion of the tidal air which reaches the alveoli dilutes the
alveolar air and thus causes the amount of C02 given off by the blood to
vary during the different phases of respiration. If we bear in mind that
the tensions of C02 in the alveolar air and in the blood leaving the lungs
are always the same (page 360), and that the entire fall in CO2 tension
in the alveolar air occurs during inspiration, then it is clear that the
blood in the pulmonary capillaries must have a maximum tension and
load of C02 at the end of expiration, and a minimum tension and load
of C02 at the end of inspiration. Accordingly, the average of the per-
centage of C02 and 02 at the end of inspiration and expiration, as de-
termined by the Haldane-Priestley method or by any of its modifications,
must fail to give the correct mean tension of these gases in the alveolar
air during expiration. The error which makes the C02 higher than it
should be, makes the percentage of 02 less than it should be. These in-
fluences taken along with the fact, which will be shown later, that the
evolution of C02 from the blood is relatively more rapid at low than at
high tension of C02, indicates that the blood in the pulmonary capil-
laries during inspiration must contribute a greater part of the C02
excreted during a respiratory cycle than that in the pulmonary capil-
laries during expiration, and moreover that a greater part of the C02
excreted must be evolved at a tension which is below the mean tension
of the C02 present in the entire time of the expiration. We conclude,
therefore, that the average tension of C02 in the alveolar air, determined

361

362 THE RESPIRATION

by the actual tension under which the gas is evolved from the blood, is
less than the average tension of C02 in the alveolar air during the time
of a respiratory cycle.

In the case of 02 the conditions are different. While the diluting
effect of the alveolar tidal air is marked in altering the amount of C02
given off during the different phases of a respiration, it can have little
influence on the amount of 02 taken up by the blood under normal con-
ditions. This is evident from a study of the dissociation curve of hemo-
globin (page 396), which shows that at tensions above 65 mm. Hg the
hemoglobin is practically saturated with 02. Since the tension of 02
in the alveolar air under normal conditions is greater than 65 mm.
(95-100 mm.), the rate of absorption of 02 must be practically maximal
during the respiratory cycle — that is, it will not change at different
phases of it.

While the relationship of the alveolar gases is continually changing
at different stages of the respiratory cycle, their mean relationship for
periods including several respirations or for complete respirations is
more or less constant, being controlled by the type of the metabolism,
and mathematically expressed by the respiratory quotient (page 582).
The average relative percentages of the two gases in the alveolar air
must therefore be the same as in the tidal air. In the alveolar air col-
lected by the Haldane method, however, the above factors cause the
respiratory quotient to be less than that in the tidal air.

These points have been insisted upon because much of the knowledge
of the gaseous exchange between the blood and the air in the lungs, as
well as the control of respiration, has been built upon data obtained by
the Haldane-Priestly method, and in considering this work, which we
shall do in subsequent pages, it is advisable that we be aware of the
limitations of the method employed. The method has been an invaluable
one for opening up a hitherto entirely unexplored field of research, but
now, the pioneer work having been done, we must employ methods
which will enable us to explore more exactly.

An Accurate Standard Method for Normal Subjects. — The most accu-
rate method, and one free from many of the theoretical errors present in
the others, depends on the relationship found to exist between the dilut-
ing effect of the air in the dead space (see page 319) and the known per-
centage composition of the alveolar air in expirations which are of vary-
ing depths but of equal and normal duration and which follow normal
inspirations (R. G. Pearce).

In this method the subject is made to breathe through valves, which automatically
separate the inspired from the expired air. The expired air is led into a tube con-
nected with two spirometers by two three-way stopcocks. The spirometers are of the
Gad-Krogh type, one being capable of holding ten liters, and the other one and a half.

THE CONTROL OF THE RESPIRATION

363

The exact time during which air enters is recorded by the small spirometer by means of
a grooved dial on the axis of the lid, on, which a thread works over a system of pulleys,
and any movement is accurately recorded by a writing point on the smoked paper of a
drum. The spirometers are connected so that the air current may be directed in the
three following ways: (1) through Cocks 1 and 2 outside; (2) directly through both
cocks into the large spirometer for the purpose of collecting a series of expirations;
and (3) through Cock 1 directly into the small spirometer for catching a single expira-
tion. In all experiments the first filling of the spirometer is rejected, so that the dead
space of the spirometers is filled with air of approximately the same composition as in
the succeeding expirations. The time is marked in seconds by a time clock. The respira-
tory movements are recorded by a pneumograph. (Fig. 128.)

The subject is brought into respiratory equilibrium by having him breathe through
the valves for a period of time before the observation. The respiratory movements
during this time are recorded while the cocks are in Position 1. When the observation
is started, the cocks are turned into Position X during the time an inspiration is being-

Fig. 128. — Arrangement of meters and connections of Pearce's method for measurement of CO*

of alveolar air in normal subjects.

made, so that the expirations which follow may be collected in the large spirometer.
After about ten respirations (a counted number) have -been collected, the cocks are
turned to Position 3 during an inspiration, and a single deep expiration is collected
in the small spirometer. In order that the time of this may be the same as the normal
expiration, it is necessary to quicken it. This is more or less a chance procedure, but
with a little training, the operator can close the stopcock with sufficient accuracy to
interrupt the deep expiration, at the end of the normal expiratory time. Should
there be any gross variation from the normal expiratory time, the sample must be col-
lected again. Not infrequently the inspiration immediately preceding the expiration
into the small spirometer is varied involuntarily by the subject on account of his being
aware that the following expiration has to be deepened and quickened; this can be
partially overcome by giving him the signal to breathe out deeply after he has actually
begun to expire.

Determinations are made of the average volume of the tidal air (c.c. air in large
spirometer divided by number of breaths), of the volume collected from the deep ex-
piration, and of the percentage composition of the tidal air and that of the deep
expiration. A criterion for determining whether or not the procedure has been carried
out correctly is the respiratory quotient (ratio of CO2 excreted to O2 absorbed). For

364 THE RESPIRATION

reasons which are set forth above, the quotients should be approximately equal in the
air collected in the large and in the small spirometers; if they are not so, the condi-
tions of the method have not been correctly carried out.

Since the dead space and the average composition of the alveolar air under these
conditions may be considered constant, the percentage composition of the deep expira-
tion will differ from that of the mixed sample of several normal expirations in propor-
tion as the dead space exerts a greater diluting effect in the small than in the large
expiration. This being the case, the data obtained can be combined algebraically to
give either the capacity of the air passages or the percentage composition of the
alveolar air. .

Let A = amount of air in large expiration (small spirometer),
Ai = amount of air in small or normal, expiration (tidal air),

B = the percentage of CO2 or O2 in the expired air of large expiration,

Bi = the percentage of CO2 or O2 in the expired air of small expiration,

x — the capacity of the dead space,

y = the average percentage of CO2 or O2 in the alveolar air; then,

A x B = (A - x)y and Ai x Bi = (Ai - x)y.
Solving this for x, y remaining constant under the same physiological conditions, we

A x Ai x (R-Bi)
have: x -- ^ — , the dead space. Or solving for y, we have:

y — A x B ~ Al x Bl the mean percentage of CO., in the alveolar air. In case the

A — Ai
dead space for O2 is desired, B and Bi must be made to equal the O2 absorbed.

Clinical Method. — The use of the kymograph and pneumo graph, and
other complicating factors, make the method as just described quite im-
practicable for clinical procedure, but the use of the same apparatus
with the following modification will yield satisfactory results for most
clinical purposes.

The patient is made to respire through the valves for a short time, after which the
observer collects a single expiration in a small spirometer by turning the stopcock from
Position 1 to 2. A sample of this is taken for analysis, and the spirometer is again
emptied and a series of successive samples of deeper expirations taken. This is done
by directing the patient, after he has started to breathe normally into the spirometer,
to breathe more deeply. The amount of air collected in each expiration is controlled by
the observer by closing the stopcock when the desired volume is obtained. By this
means one can collect several expirations differing from one another by increasing
amounts but all occupying the same time. The samples of the various expirations
are collected in a series of numbered sampling syringes, and the gaseous composition
of each is determined. When the percentage of CO or Ot in each expiration is
plotted on cross section paper on the ordinates, with the volume of the expirations in
c.c. on the abscisste, a hyperbolic curve should be obtained. Any marked deviation
from such a curve indicates that some error has been made in taking a sample, and
this observation should be discarded. The different observations are then combined in
the formula given above. The determination of the CO., percentage of expired
air is so simple that a number of specimens of varying depths of expiration can be
taken and thus many points on the curve determined. For the most accurate results
it is in general best to compare only those expirations which differ from one another
by at least 0.3 per cent in CO., and by at least 200 c.c. in volume. This depends on
the fact that the diluting effect of the dead space in reducing the percentage of CO^

THE CONTROL OF TfiE RESPIRATION

365

in the expired air from that in the alveolar air is greater in relatively small expira-
tions. If more exact work is desired, the O content can be determined on each
specimen, the respiratory quotient calculated, and only those expirations which show
the same respiratory quotient combined.

In the table each observation is compared with each of the others in all possible
combinations.

NO. OF
OBSERVA-
TION

1

2
3
4
5
6

TOTAL
EXPIRED
AIR

PVR CENT
CO2 IN
EXPIRED

AIR

ALVEOLAR C02

DEAD SPACE

1

2

3

1

2

3

450
637
750
960
1120
1440

3.10
3.66
4.00
4.28
4.30
4.40

4.99
5.34
5.30
5.11
5.16

5.48
5.15

4.98

5.27
4.92

4.82

170
189
189
161
171

183
140
127

214

184
171

General average for CO2 in alveolar air, 5.13.

General average for dead space, 172: Dead space in valves in this experiment was
about 30 c.c.

Another method which has been suggested for clinical purposes is that of Plesch; this
consists in having the subject breathe several times in and out of a small bag. It is
assumed that after such respiration the composition of the air in the bag will become
the same as that in the alveoli. Although this is no doubt true, it has been shown
that the method is fallacious, because the COo tension determined in this way is not
that of the arterial blood alone, but is the average between it and that of the venous
blood.

CHAPTER XLI
THE CONTROL OF RESPIRATION (Cont'd)

THE NATURE OF THE RESPIRATORY HORMONE

The practical importance of the observations described in the foregoing
chapters in the investigation of the relationship between CH of the
blood and respiratory activity will now be plain, and it remains for us
to consider the physiological evidence that such a relationship exists. In
the first place, let us consider the behavior of the acid-base equilibrium
during conditions of abnormal breathing — hyperpnea and dyspnea."

As C02 accumulates and 02 becomes used up in a confined space, the
breathing becomes intensified. In searching for the exact cause of this
effect, we must first of all ascertain whether the hyperpnea is due to the
deficiency of 02 or to the accumulation of C02 or to both acting to-
gether. Many of the experiments bearing on these problems can be
more satisfactorily performed on man than on laboratory animals, be-
cause anesthesia is not necessary and the subjective symptoms experi-
enced are of great value in the interpretation of the results. If an in-
dividual is placed in a large air-tight chamber (2000 liters' capacity),
and the depth and rate of breathing observed as the C02 accumulates and
the 02 becomes used up in the air of the chamber, no distinct change in
respiration will be observed by the person himself until the C02 per-
centage of the air has risen to almost 3. Above this point, however, the
hyperpnea becomes more and more pronounced, until finally, when the
C02 percentage has risen to about 6 and the 02 percentage has fallen to
13.5, it becomes unbearable (dyspnea). From the results of the fore-
going observation alone we could not, however, decide whether the
excitation of the respiratory center is due to the deficiency of 02 or to
the increase of C02. If the experiment is repeated with the difference
that the C02 as it accumulates is absorbed by soda lime, no perceptible
hyperpnea will develop even when the 02 is as low as in the previous
experiment. We may conclude, therefore, that in the first experiment
C02 accumulation must have acted as the main respiratory stimulus, and
that oxygen deficiency, if it stimulates at all, must do so to a less degree
than increase in C02.

*Hyperpnea means slightly increased breathing; dyspnea, labored breathing, but yet with suffi-
cient ventilation to maintain life; asphyxia, the results of insufficient breathing.

366

THE CONTROL OF THE RESPIRATION 367

There is an obvious reason why the adjustment of pulmonic ventilation
should not depend primarily upon changes in 02 supply to the respira-
tory center. If it were so, many other tissue activities and other nerve cen-
ters would suffer from the 02 deficiency before there was time for the
breathing to become stimulated sufficiently to make good the loss of 02. As a
matter of fact, headache, dizziness, nausea and even fainting are almost
certain to be caused whenever any muscular exercise is attempted in an
atmosphere containing a deficiency of 02 but no excess of C02 (cf. moun-
tain sickness). An adequate 02 supply of the body is, therefore, insured
by changes in C02 tension of the blood.

Quantitative Relationship between C02 of Inspired Air and Pulmonary
Ventilation. — These results suggest, as the next step in the investigation
of our problem, the determination of the quantitative relationship be-
tween the C02 percentage of the respired air and the amount of air
breathed (pulmonic ventilation).* That there is such a relationship has
been most successfully demonstrated by R. W. Scott,20 who used for his
purpose decerebrate cats.f The trachea was connected, through a T-tube
provided with valves, with tubing leading to a large bottle and a Gad-Krogh
spirometer, so that the animal breathed out of the bottle into the
spirometer, these two being also connected together. The spirom-
eter was made to record its movements on a drum, so that an accurate
record of the depth and frequency of the respirations was secured. Sam-
ples of air were removed from the bottle by ground-glass plunger syringes
at frequent intervals during the time that the animal was respiring into
the tubing.

The results are given in the accompanying curve (Fig. 129), which shows
that there is a perfect correspondence between the C02 percentage in the
air of the bottle and the pulmonary ventilation. Moreover, when the
bottle was filled with 02 instead of air to start with, the same results
were obtained, showing that the C02 accumulation alone was responsible
for the hyperpnea. In these cases the percentage of 02 remaining in the
system after hyperpnea had become extreme, was far above that at which
excitation of the center as a result of 02 deficiency is possible.

Experiments of a similar type had previously been performed by Por-
ter and his pupils,21 but their object was not so much to show the close
parallelism between the C02 content of the respired air and the pulmonic

*A distinction is somewhere drawn between pulmonic ventilation and alveolar ventilation, the
former being the total amount of air that enters and leaves the lungs, and the latter, that which en-
ters and leaves the alveoli. This distinction is based on the assumption that the capacity of the dead
space may vary considerably from time to time, which, as pointed out elsewhere, is erroneous. For
practical purposes pulmonic ventilation is the safer value to give.

fDecerebrate animals must be used in these experiments, since anesthetics markedly depress the
activity of the respiratory center.

368

THE RESPIRATION

ventilation as to demonstrate the changes produced in the sensitivity of
the respiratory center in pneumonia.

Possibility that C02 Specifically Stimulates Center. — After showing
that C02 acts as an excitant of the respiratory center, the question arises
as to whether the action depends on the raising of the CH of the blood, or
whether it may be a specific action of the CO2. Many attempts have

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air. Ordinates = the percentile increase the tidal air per minute. (From R. W. Scott.)

been made to decide this question experimentally, the general principle
of the experiments being to determine whether CH of the blood runs
parallel with the C02 content of the respired air and with the hyperpnea.
Using the gas-chain method (page 31), Hasselbalch and Lundsgaard22
found that the hyperpnea produced in rabbits by breathing in C02-rich

THE CONTROL OF THE RESPIRATION

369

air runs approximately parallel with the increase in the CH of the blood,
but on account of the experimental difficulties encountered they could not
decide whether changes in CH are alone responsible for the effect. These
authors had previously demonstrated that changes in CH can be induced
in blood removed from the body by alterations in the C02 tension within
the physiological limits. An increase of one millimeter in C02 tension
was found to cause an increase in CH of 0.0065 x 10'7 (see page 27).

R. W. Scott's experiments, above referred to, have, however, yielded
more definite results. By using the colorimetric method for determining
CH of the blood (see page 32), it could be readily shown, as is evident

THE EFFECT OF REBREATHING CARBON DIOXIDE ON THE MINUTE VOLUME AND ON THE

H-ION CONCENTRATION AND TOTAL CARBONATE CONTENT OF THE ARTERIAL

BLOOD IN THE DECEREBRATE CAT

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*PH is the actual value given in the table. This is inversely proportional to CH.

from the table (col. 8 in table), that a marked rise in CH became evident
when the inspired air contained 5 per cent or more of C02. That this
rise was due to increase in the C02 tension was shown not only by finding
a greater percentage of C02 (col. 15) in the blood, but also by being able
to demonstrate that when C02-free air was bubbled through the blood
removed during the dyspnea, CH immediately returned to the normal,
which it also did when the blood removed after the animal had breathed
for a few minutes in outside air (col. 16). The C02 content likewise re-
turned (col. 17). Had the increase in acidity been caused by nonvolatile
acids — lactic, for example — these results, particularly the latter, could
not have been obtained.

370 THE RESPIRATION

Although there is therefore no doubt that the CH of the blood may
be raised because of an increase in C02 in solution in the blood plasma —
a C02 acidosis, as we may call it (see page 371) — this does not prove that
the stimulation of the respiratory center is brought about solely by CH.
The increase in C02 might in itself also serve as a stimulus. That such
is actually the case was demonstrated by finding that, if CH of the blood
was first of all lowered by injecting alkali intravenously, hyperpnea still
developed in proportion as the C02 accumulated in the inspired air; and
that CH of the blood, when the hyperpnea was at its highest, was below
that of normal blood. Some other factor than CH must obviously be
responsible for this result. This is undoubtedly dependent on the C02.

Further corroboration of the claim that C02 has a specific stimu-
lating effect on th'e respiratory center that is independent of CH, has
been furnished by Hooker, Wilson and Connett.23 These authors suc-
ceeded in keeping the centers of the medulla alive by perfusion with
defibrinated blood through the blood vessels of the brain, and found
that, although the respiratory movements of the diaphragm became de-
pressed with a decrease and excited with an increase in CH of the per-
fusion fluid, a greater activity of the center was produced when the fluid
contained a high tension of C02 than with another fluid of the same CH
but with a low tension of C02. We conclude that, although the <7H is the
important respiratory hormone, carbon dioxide per se also has a stimu-
lating influence.

A similar conclusion had previously been arrived at by Lacquer and
Verzar54 who studied the activity of the respiratory center in young rab-
bits perfused through the aorta with isotonic solutions in which the CH was
caused to vary by the addition of different acids. It was found that when
CH was about the neutral point (even slightly on the alkaline side), but
the solution contained C02, much more marked stimulation occurred than
when CH was raised by adding some other acid.

These conclusions are confirmed by observations on the influence of
C02 on other living cells than those of the respiratory center. Rona and
Neukirch55 found that the isolated intestine when made to beat in oxy-
genated saline solution (page 497) is very sensitive to C02, and Jacobs56
has more recently made some very interesting observations on the toxic
effects of C02 as compared with that of other acids, on the tadpoles of
the toad, and on several species of protozoa. It was found that a saturated
solution of C02 is incomparably more toxic than are solutions of various
inorganic and organic acids of the same CH as the C02 solution. On the
other hand neutral solutions of NaHC03 are nontoxic, which indicates
that it can not be the HCOs-anion as some have supposed) that is the toxic
agent. The order of resistance of various protozoa to C02 was found to

THE CONTROL OF THE RESPIRATION 371

bear no relation to that which they bear to other acids. It may be, however,
that the more toxic effect of the C02 is dependent upon the greater rate
at which it penetrates cell membranes than other acids. It would there-
fore enter the cells of the respiratory center and by dissociation cause
alteration of CH in the protoplasm. In the light of this possibility it is of
interest that whereas other acids cause cessation of the movements of flag-
ella in protozoa with no visible changes in the interior of the cells, C02
has little effect on the flagella but causes marked alterations in the intra-
cellular activities.

Relationship Between Alveolar C02 and Respiratory Activity.— Vari-
ations in the respiratory hormone, whatever this may be, are associated
with changes in the C02 content of the alveolar air. Increase in the
alveolar C02 immediately stimulates respiration unless under certain
conditions which will be discussed later. Indeed the respiratory center
is so very sensitive towards this stimulus that whenever the percentage
•of C02 in the inspired air tends to rise, pulmonary ventilation is excited to
a degree which is just sufficient to maintain the tension of* C02 in the
alveolar air at the normal level. There is therefore, no better method for
testing the excitability of the center than to observe the magnitude of
pulmonary ventilation, when known percentages of C02 are added to the
inspired air. If the amount of C02 in the inspired air is sufficient to raise
the C02 in the alveoli, in spite of the greater breathing ; thus, it has been
found that an increase of from 0.2-0.3 per cent in alveolar C02 in man
causes a doubling in the alveolar ventilation, or, more precisely stated, an
increase of ten liters in the air entering and leaving the alveoli per minute
results from raising the alveolar C02 tension by 2.2 to 3.1 mm. Hg (Doug-
las24).

The relationship between breathing and alveolar C02 is by no means al-
ways so simple as in the instances just described. In these hyperpnea is sec-
ondary to an increase in alveolar C02 but there are many cases where the
reverse relationship obtains — namely, where decreased alveolar C02 is sec-
ondary to hyperpnea caused by stimulation of the respiratory center by
some other agency than increase in C02 tension of the blood. These agen-
cies include afferent nerve stimulation, lowering of the 02-tension, or in-
crease in CH of the blood brought about by other acids than C02 such
as occurs in clinical cases of acidosis (see page 654).

The whole question is very closely linked with that of the control of the
reaction of the body fluids and with the etiological factors in acidosis.
When it is fully answered, many obscure clinical conditions in which respi-
ratory disturbances occur will be much better understood than they are at
present. On account of the great importance of the subject, considerable

*The tension is found by the equation given on page 374.

372 THE RESPIRATION

attention will be devoted in the next few pages to some of the researches
which have been made bearing on the relationship between the C02 of
the alveolar air and the various modified types of breathing that can be
produced experimentally or which become developed under altered physi-
ological conditions.

As we have seen, much work concerning the physicochemical principles
involved in the control of the reaction of the blood has been contributed
during recent years by physical and biological chemists, but much of this
work in our judgment fails to pay sufficient regard to the extraordinarily
complicated conditions existing in the animal body, and more particu-
larly, to correlate the purely physicochemical data with the numerous
observations that have from time to time been recorded by physiologists
regarding the behavior of the respiratory center. Physical chemists have
recently, for example, gone so far as to define acidosis as a condition in
which there is a diminution in the bicarbonate content of the blood in-
duced by the discharge into it of fixed acids. This is going too far, for
it fails to recognize acidosis due to an increase in the C02 of the blood.

It is the molecular ratio XT* which determines the tension of C02.

LJNa-ti.v_/O3 J

When C02 is added to the blood, either experimentally by respiring the
gas, or naturally. owing to muscular exercise or to pathological conditions in
which there is a deficient excretion of C02, as in heart disease, the ten-
dency of the equation to change, by increase of the numerator, is pre-
vented partly by stimulation -of the respiratory center, which gets rid of
C02, and partly by an increase in the denominator. The respiratory
center is so sensitive to slight increases in CH that it becomes excited

before a sufficient increase in H2C03 has occurred to disturb the normal

rTT r<f\ -i
w ^rnA • When fixed acids are added to the blood the denom-

L iNa-biGUs. J

inator of the equation, NaHC03, is lowered and consequently CH rises,
and increased respiration occurs, lowering H2C03 and thus reestablishing
the ratio.

CHAPTER XLII

THE CONTROL OF RESPIRATION (Cont'd)
THE ALVEOLAR C02-TENSION. ANOXEMIA.

The Constancy of the Alveolar C0,-Tension Under Normal Conditions

Since a close relationship exists between the alveolar C02-tension and
the respiratory activity, it is to be expected that the two would bear a
strict proportionality to each other, and since the breathing under normal
conditions does not vary much, the C02-tension should also be constant.
Many observations show this to be the case. The tension is remarkably
constant from day to day and even from month to month in the same
individual, provided the physiological conditions, are the same. A slight
seasonal variation is said to exist, a rise in the temperature of the en-
vironment of the individual causing a slight depression in the C02-ten-
sion, while a fall in temperature causes a slight rise (Haldane). These
changes are independent of any demonstrable change in rectal temper-
ature and, therefore, are probably due to the influence of the temperature
on the skin.

Since it is the number of molecules of C02 in a given volume of alve-
olar air (i.e., the partial pressure or tension) that is of importance, it
is only when the barometric pressure is the same that the percentage of
C02 in the sample of alveolar air can be constant. To allow for this,
all results are reduced to standard barometric pressure (760 mm. Hg).
If the barometric pressure is lowered, there will have to be a higher
percentage of C02 in the sample in order that there may be the same
tension of this gas in the air of the alveoli ; and vice versa when the bar-
ometric pressure is raised. The equation by which this tension, ex-
pressed in millimeters of mercury, is determined is: 100:760::a:p, where
a is the percentage actually found in the air of the sampling tube and p
the tension. A correction must also be introduced in this equation to
allow for the vapor tension of the air in the alveoli, for of course H20
molecules will behave like C02 molecules in causing a partial pressure.

When reduced to this standard, it has been found that the tension of
CO2 in the alveolar air tends to remain constant under the varying baro-
metric conditions that obtain at sea level or at moderate departures from
this. This is shown in the following table :

373

374 THE RESPIRATION

(1)

(2)

(3)

BAROMETRIC

C02 ACTUALLY FOUND

PARTIAL PRESSURE

PRESSURE

IN DRY ALVEOLAR

OF C02 IN MOIST

(MM. HG)

AIR

ALVEOLAR AIR AFTER

(PER CENT)

CALCULATING FOR

BAROMETRIC PRESSURE

Top of Ben Nevis

646.5

6.62

5.23*

Oxford

755

5.95

5.53

Foot of Dolcoath Mine

832

5.29

5.48

Compressed air cabinet

1260

3.52

5.64

•

B' - A x P'

P. when P — fieures in

JL X1C liguica ill Liiia \*viu*Aiii die eiiiivtva ai- uj nn~ *v/i 11114*0 .

last column; B' ~ figures in first column; A = • aqueous tension of alveolar air; P' — figures of
second column; B = barometric pressure at sea level. A is obtained from tables giving the aqueous
tension at different temperatures.

The Alveolar C02-Tension in Conditions of Anoxemia

The foregoing observations have shown that the respiratory hormone
is related to the tension of C02 in the blood supplying the respiratory
center, and that this tension acts partly by causing alteration in CH
of the blood, and partly because C02 has direct effect on the center. These
conclusions do not imply that other changes in the composition of the
blood may not act on the respiratory center, indeed there is plenty of
evidence to show that deficiency of oxygen in the arterial blood or anoxe-
mia also acts. This influence is, however, less evident than that of changes
in CH or C02 and it varies with the degree of deficiency, being stimulatory
when the deficiency is moderate, and inhibitory when it is extreme. It is
not surprising, therefore, that some considerable confusion should have
existed as to the precise role of 02 deficiency in its effect on the respira-
tions and it is only within the last year or two that the problem has been
satisfactorily elucidated.

The most important indication that alterations in the C02-tensioii of the
blood cannot alone be responsible for changes in respiratory activity is
afforded by the observation that the alveolar C02 does not always, as in
the cases described in the previous chapter, run parallel with alveolar ven-
tilation. The opposite relationship often obtains, namely, decreased al-
veolar CO2 and hyperpnea (see page 379), and it is our purpose in the
present chapter to show how this is often associated with a condition of
oxygen deficiency. It is most important that we consider this phase of the
subject in some detail because of the application which it has in the eluci-
dation of many problems of respiratory disturbance, as met with in the
clinic. The disturbances in respiratory function which can be brought
about experimentally in normal animals are in many cases exactly like those
which are met with in various diseases, particularly those which depend
on inadequate absorption of oxygen by the blood.

The General Effects of Deficiency of Oxygen, or Anoxemia. — Various

THE CONTROL OF THE RESPIRATION 375

methods have been employed in the investigation of this subject. The
most important of these are as follows: (1) Breathing from a tank con-
taining varying mixtures of oxygen and nitrogen (Dreyer apparatus).
This apparatus was used extensively in the British Army in testing the
ability of candidates for the aviation service to withstand low oxygen.
Its greatest value is that the alteration in oxygen content of the inspired
air can be made either gradually or quickly. (2) Breathing from a
tank, through valves which direct the expired air to pass through
an apparatus for absorption of the C02, after which it re-enters the tank.
The subject, therefore, re-breathes the air of the tank from which he
gradually absorbs the oxygen. In this method the 02-content of the
inspired air falls gradually, and effects are produced which must be
similar to those which would be caused by slow ascent to higher alti-
tudes. The rate at which the 02 falls can be varied by altering the size
of the tank. When a very rapid fall is desired rubber bags can be used
in place of tanks. An apparatus on this principle was employed for
testing aviators particularly in the United States Army. (3) Breathing
in an air-tight cabinet containing properly arranged soda lime absorbers
to take up the C02, the oxygen decreases at a rate which is inversely
proportional to the size of the cabinet. (4) Breathing in a strongly
built steel chamber connected with a powerful pump by means of which
the chamber can be partially evacuated and the pressure maintained at
any desired level. Such a chamber has been used by Haldane, Kellas
and Kennaway in important experiments, the results of which we shall
consider immediately. (5) Adding a sufficient percentage of carbon mon-
oxide gas to the inspired air. This combines with the hemoglobin of the
blood and renders this incapable of carrying the oxygen.

The observations made by the use of these methods have been com-
pared with those made during life at high altitudes, particularly in con-
nection with mountaineering. The latter observations are of particular
importance in the study of the adaptive processes which come into play
to render persons who have become accustomed to high altitudes immune
to the distressing symptoms from which others suffer.

There is considerable variability in the reactions of different persons to
decreased oxygen. These symptoms are partly subjective and partly ob-
jective in nature and they show slight differences according to whether the
anoxemia is produced by a lowering of barometric pressure (decom-
pression), or by simply reducing the percentage of oxygen in the inspired
air. In the former case there is also a slight difference between the symp-
toms following decompression in an experimental chamber, and those
observed on a high mountain. In a general way the symptoms are less

376

THE RESPIRATION

marked when the barometric pressure is reduced than when the oxygen
percentage is simply diminished.

The Symptoms During Gradual Reduction of the Percentage of Oxy-
gen.— Measurements have been made of a number of physiological func-
tions in a large number of healthy young men who were condidates for
the flying corps of the various armies participating in the recent war.

LEGEND
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Fig. 130. — The behavior of the respiratory volume, the blood pressure, and the pulse during
progressive anoxemia.

The results are of value in showing to what extent the candidates can be
expected to withstand the rarefied air met with at great elevations. The
accompanying chart (Fig. 130) taken from the "Air Service Manual"
of the United States Army depicts the results obtained on a perfectly
normal individual. The percentage of 02 in the air breathed at var-
ious stages of the test is read on the right edge of the chart by find-

THE CONTROL OF THE RESPIRATION 377

ing the ordinate which is crossed by the thick continuous line. In
this observation the subject withstood oxygen deficiency without alarm-
ing symptoms until a percentage of nearly six was reached. These
symptoms are giddiness and then fainting along with various psy-
chological effects. The respiratory volume, the pulse rate and the
systolic and diastolic blood pressures are also shown (see legend of
figure for details) and it will be observed that the respiratory vol-
ume did not change greatly until the oxygen percentage had fallen
to below twelve. Usually, however, the volume is slightly increased
even with a slight reduction in the oxygen, the depth rather than the
rate of the breathing being responsible for the change. Ellis57 has more
particularly investigated the precise percentage of oxygen at which the
respiratory volume becomes increased and found it to be somewhat above
eighteen. By the time 8 per cent 02 is reached the majority of men
show about a doubling in the amount of air breathed. If they do not
respond in this way, they are almost certain to break down by fainting,
because the increased respiration is the mechanism by which the de-
ficiency of oxygen is compensated for. There is usually little change
in the pulse rate until the oxygen has fallen below fifteen per cent. A
total acceleration of 15-40 beats per minute is normal when the 02 is
lowered to seven per cent. The systolic blood pressure usually remains
unchanged down to a partial pressure corresponding to 14 or even 9 per
cent of oxygen. Below these levels the systolic pressure rises 15-20 mm.
Hg. above normal. If it rises more than this it is considered unfavora-
ble, since it indicates that vasodilatation has not occurred as it ought
to — as a result of the low- oxygen. A sudden fall in systolic pressure
precedes fainting. The diastolic pressure remains practically unchanged
throughout the test, but it ought to show a slight decline as the systolic
pressure rises. The decline shows that vasodilatation is occurring.

When the anoxemia is continued for a time, the pulse usually returns
towards the normal rate and the systolic and diastolic pressures, if
they were affected, also tend to return to the normal levels (Lutz and
Schneider58). These authors found the same results whether the 02
was reduced by lowering of the barometric pressure or reduction of the
percentage of the gas.

Cyanosis is a normal reaction but it should be delayed in its onset.
In some cases a pale and death-like color develops in place of cyanosis.
This is an unfavorable sign.

The actual time taken to reach the limit of endurance in the test de-
pends of course on the capacity of the spirometer. This is usually chosen
so that a test occupies from 20 to 30 minutes.

The Symptoms During Lowering of the Barometric Pressure in a Pneu-

378 THE RESPIRATION

matic Chamber. — These have been carefully described by Haldane, Kellas
and Kennaway,59 who exposed themselves and others to 380 mm. baro-
metric pressure (corresponding to about 19,000 feet above sea level) for
at least an hour on several successive days, the pressure being. lowered to
this level very quickly (5 minutes). The symptoms varied somewhat in
the different subjects. The respirations increased in depth and frequency
at first but then returned more or less to normal in four out of six of the
observed persons. In one it remained very rapid, and in another it readily
became periodic subsequent to holding the breath for a time. The pulse
always increased at first and then returned almost to normal. Cyanosis
was always present but did not diminish with continued exposure. Al-
though mental and sensory symptoms were not perceived, the sudden raising
of the oxygen percentage caused the light to become brighter and sounds
to become louder. Vigorous muscular work caused marked hyperpnea,
quick pulse, increased cyanosis and mental confusion. There were none
of the symptoms of mountain sickness (page 415) and no ill-effects were
experienced on leaving the chamber.

At still lower pressures the above mentioned changes in pulse and respira-
tions became much more pronounced and decided mental symptoms ap-
peared, for example it became very difficult to count the pulse, or to
record the other observations. Loss of memory was common, but there was
no loss of consciousness. A most interesting mental symptom sometimes
observed was fixedness of ideas. This has also been noted in coal gas poison-
ing, and in high balloon ascensions. Thus, in one experiment the sub-
ject persisted in having the pressure held at a certain (very low) level
for no evident reason, just as those exposed to carbon monoxide can not
be diverted from remaining exposed to the gas.

These symptoms have been described in some detail since it is im-
portant that they be compared with those in clinical cases in which
oxygen deficiency exists. They constitute the reactions of healthy in-
dividuals to conditions which may become established as a result of
disease, and it is obviously most important in such cases that they be
distinguished from the more definitely pathological symptoms.

On comparing the above symptoms to those of mountain sickness it
will be noted that there is a marked difference (see page 415). One pe-
culiarity of the latter condition is that prolonged stay in the rarefied air
brings about an acclimatization, so that after some days the person is
practically normal. The attempt was made in the above experiments
to bring about a similar acclimatization with partial success.

The Nature of the Changes Produced in the Body in Anoxemia. — A
careful study of this aspect of the problem is most important, not only
because it throws much light on the manner of control of the respiratory

THE CONTROL OF THE RESPIRATION 379

center, but also because it helps us to explain the nature of the altera-
tions which occur in the acid-base equilibrium of the body in all condi-
tions which tend to bring about anoxemia. The immediate increase in
breathing is the first of the symptoms which demands attention. Ob-
viously it cannot be due to the excitation of the respiratory center by an
increase in the free C02 of the arterial blood (see page 366). Two possi-
bilities remain — either the reduction of free oxygen in the blood per se
excites the center, or this reduction in oxygen causes incompletely oxi-
dized acid substances — such as lactic acid — to appear in the blood so
as to raise CH. A clue as to which of these causes is responsible is fur-
nished by observation of the C02 tension of the alveolar air. It will be
recalled that this does not change when the barometric pressure is
slightly altered (page 373), but it is otherwise when the reduction is
extreme; a progressive decrease occurs. Thus, in one of the experiments,
the alveolar C02 tension to start with was 40.7 mm. Hg. After lowering
the barometric pressure to about 500 mm., the alveolar tensions were : after
25 minutes, 36 mm. ; after 90 minutes, 36.8 mm. ; after 175 minutes, 25.7 ;
after 465 minutes, 34.9 mm. This shows clearly that increase of free CO.,
in the blood cannot be the cause for the hyperpnea. Further evidence for
this conclusion is afforded by the fact that the breathing after some time
returns towards the normal although the alveolar C02 tension remains low.
Increase in CH of the arterial blood on account of the appearance of
unoxidized acids, has been considered as the possible cause for the symp-
toms of anoxemia. This hypothesis demands close attention because it
has been very widely accepted and has seemed to be supported by nu-
merous observations, both physiological and clinical. Physiologists,
for example, have known for long that lactic acid accumulates in the
blood and appears in the urine in all conditions in which there is de-
ficient oxidation in the tissues. Thus, Araki found it in the urine after
asphyxia produced either by obstruction to breathing or by inspiring
coal gas. Hopkins and Fletcher showed that it appears in muscle when-
ever this is made to contract in deficiency of oxygen, and Ryffle found
it increased in the blood and was present in the urine excreted after vigor-
ous muscular exercise. From the clinical side the evidence has been fur-
nished by observing the behavior of patients suffering from acidosis
due to the appearance of oxybutyric acid (page 737), as in diabetes, or
of other acids, as in certain cases of nephritis. In these cases hyperp-
nea is accompanied by a lowered tension of alveolar C02 and by a lowered
capacity of the blood to combine with C02, that is a lowered alkaline
reserve (page 38). If the alkaline reserve of the blood be determined
after exposure of an animal (man) to low oxygen, it has also been found
to be decreased.

380 THE RESPIRATION

Taking all these facts together, a strong case appeared to be made
for the acidosis hypothesis and this seemed to be almost established since
Haldane and his collaborators were apparently able to apply it in ex-
plaining the results of their numerous investigations of the respiratory
function. It will be observed, however, that all of the evidence is cir-
cumstantial in nature, and that the changes observed in anoxemia may
be due to entirely different causes. Lowering of the alkaline reserve of
the blood, lowering of the tension of C02 in the alveolar air, and hyperp-
nea can undoubtedly all result from deficiency of oxygen-supply to the
tissues, but the sequence in which the changes occur may be exactly the
opposite to that which is assumed in the acidosis hypothesis; it is pos-
sible, namely, that the deficiency in oxygen first excites the respiratory
center, the increased breathing then causes a blowing off of the free CO2
from the blood, and the alkali is then excreted from the blood in the en-
deavor to hold CH at a constant level. If some method were available for
precise measurements of CH of the arterial blood at frequent intervals it
would be possible to settle this question once and for all, but such is not
the case, and we must seek for proof for the new hypothesis by indirect
means.* Assuming then that the respiratory center is excited by a slight
degree of anoxemia, let us see how the known facts fit in. The diminution
in oxygen in the blood excites the respiratory center and causes increased
breathing. This results in a blowing off of C02 from the blood into the al-
veolar air, so that there comes to be relatively more C02 excreted than 02
absorbed, and the respiratory quotient becomes raised. We have shown
this very clearly in experiments on decerebrated cats breathing in oxy-
gen-poor atmospheres; even when the oxygen percentage was only slightly
reduced, R.Q. had already risen to over unity. As a result of this blow-
ing-off of C02, CH of the blood must tend to fall and this may explain
the tendency for the breathing to return towards the normal. It is impor-
tant for practical reasons to realize that when this condition becomes
established (i. e., slight anoxemia along with diminished CH, increased
breathing will not compensate for the anoxemia, for the advantage gained
by higher saturation of the blood with oxygen is counteracted by the al-
kalosis produced because the oxygen-carrying power of the hemoglobin has
become altered. Under such conditions as pointed out on page 401 the
hemoglobin holds on more tightly to the oxygen and does not give it up to
the tissues. Under these conditions neither increased breathing nor in-
creased bloodflow can force more oxygen into the tissues, so that both
the respirations and the pulse become less rapid after the initial accel-
eration. It is this prolonged anoxemia that causes the symptoms of

*It may be stated, however, that Cn of the blood of man after he has been for some time in
rarefied air is still normal as judged by determination of the dissociation curve of his blood (page
402) in a partial pressure of COo equal to that of his alveolar air (Barcroft). This result shows
at least that the acid-base equilibrium is ultimately restored under the altered conditions.

THE CONTROL OP THE RESPIRATION 381

mountain sickness and many of these of pathological conditions such as
pneumonia or CO-poisoning. The only .opssible treatment is to raise the
tension of oxygen in the alveolar air sufficiently to force some into solu-
tion in the plasma (see page 445).

After a time acclimatization to anoxemia occurs because of adjustments
which bring CH back to its normal value. These depend on excretion of
the excess of alkali by the kidneys and the conversion of a greater pro-
portion of ammonia into urea (page 650). Hasselbach and Lindhard™ were
the first to show that CH of the urine becomes reduced early in anoxemia,
but returns to the normal after acclimatization is established, and that
the excretion of ammonia is also relatively decreased but remains low
even after acclimatization. Haldane, Kellas and Kennawayr'9 have con-
firmed these observations by showing that the titrable acid of the urine
(titration with No. 1 alkali to the neutral point with phenolphthalein be-
fore and after addition of formalin — Folin's method) is reduced by one-
half, or more. The diminution in the NH3 excretion found by both groups
of workers is always observed when the excretion of fixed alkali is in-
creased in proportion to the acid and it indicates that the function of the
liver and other organs which are responsible for conversion of NH3 to
neutral urea, must become stimulated as a protection against the alkalosis.
The question therefore arises whether the relative decrease in the acid ex-
cretion by the kidneys, rendering the urine more alkaline, runs parallel
with the diminished production. To answer this question the ratio of
ammonia to acid was calculated in the experiments of Haldane, etc. (i. e.,
the percentage of the total NH3 and acid that is represented by NH3
alone) and found to rise markedly. Therefore, the conversion of NH3
into urea did not occur as promptly as the increased excretion of alkali
by the kidney. Part of its delay is no doubt dependent upon the time
required for the ammonia already present in the blood and tissue fluids
to be excreted before the increased urea formation could become evident
in the urine. The results as a whole show that the kidneys and liver on
the one hand, and the respiratory center on the other, respond to changes
in CH of the blood which are far below those that can be detected by
existing physical or chemical methods of measurement (Haldane). The
respiratory center constitutes the first line of defence against any change in
CH by increasing or decreasing the rate at which C02 is blown off from the
blood. The kidneys constitute a second defence by altering the ratio of
acid base which they allow to pass into the urine, and the liver and other
organs form a third line of defence by altering the amount of free NH3
which they permit to enter the blood. The readjustment of the alveolar
C02 and of the acid and ammonia excretions do not return to the normal
until some time after the subject has been breathing at normal barometric
pressure. This will be made evident by consulting Fig. 142-A.

CHAPTER XLIII

THE CONTROL OF RESPIRATION (Cont'd)
APNEA— PERIODIC BREATHING

Apnea

If a man breathes forcibly and quickly for about two minutes, he
will experience no desire to breathe for a further period of about the
same duration — lie becomes apneic. When the desire to breathe returns,
the breathing is at first very shallow, and frequently periodic in type,
but gradually it becomes more marked, until at last normal respiration
is reestablished. How may the results be explained? The cause for the
absence of breathing is lowering of the C02-tension in blood. This re-
moves the natural stimulus to the respiratory center because a temporary
condition of alkalosis with low C02-tension is induced. Evidence of the
establishment of alkalosis by forced breathing has been obtained by ex-
amination of the acid excretion in the urine, (see page 381). The C02-
tension is lowered because this gas has been "washed out" or "blown
off" from the blood into the overventilated alveoli. Although this over-
ventilation also raises the pressure (tension) of oxygen in the alveoli,
little, if any, more of this gas can be absorbed into the blood because
even at the normal alveolar tension, the blood takes up at least 95 per
cent of its possible load, in consequence of the dissociation curve. These
differences in the rate of C02-loss and 02-gain cause the respiratory quo-
tient to become very high during the forced breathing ; it may indeed rise
nearly to 2. During the apneic period the person by an effort can expire
some alveolar air, and if this be analyzed it will be found that very little
C02 is being expelled from the blood though the 02 is being absorbed as
usual. Consequently R.Q. becomes very low (0.2 has been observed).
Gradually, however, the C02 rises again in the blood and the alkalosis
disappears so that the respiratory center becomes excited, although at
first only feebly and irregularly. If alveolar air be analyzed when the
first indication of breathing returns it is said by Haldane that the C02
tension is not yet back to the normal level (see Fig. 131). This indi-
cates that some other influence is helping to excite the respiratory center
and this no doubt is anoxemia for the percentage of 02 in the alveolar
air has now fallen to a very low level.

382

THE CONTROL OF THE RESPIRATION

383

Fig. 131. — Curves showing variations in alveolar gas tensions after forced breathing for two
minutes. Thin line = O2 tension; thick line = CO2 tension. Double line = normal alveolar
CO2 tension. Dotted line shows the alveolar CO2 tension at which breathing would recommence
at the end of apnea with the alveolar O2 pressures shown by the thin line. The actual breathing
is indicated at the lower part of the figure. It is periodic to start with. (From Douglas, and
Haldane.)

384 THE RESPIRATION

In agreement Avith this explanation it has been found that, if the
last two or three forced respirations preceding the apnea are made in
an atmosphere of 02 instead of air, so as to. fill the alveoli with 02, the
apnea can be maintained for a very much longer period; and when the
natural desire to breathe returns, the C02 tension of the alveolar air,
instead of being below the normal, is above it. The effect of 02 in pro-
longing apnea, must, therefore, be dependent on the fact that it prevents
anoxemia. By this means the period during which the breath can be
held after breathing 02 is sometimes phenomenal; in one individual, for
example, after breathing forcibly for a few minutes and then filling the
lungs with 02, apnea lasted for eight minutes and seventeen seconds.
The excess of' 02 also serves to drive out considerably more CO2 from
the blood in the alveolar capillaries.

THE SUPPOSED NERVOUS ELEMENT IN APNEA

It is necessary to point out that, prior to the elaboration of accurate
methods for the investigation of the chemistry of respiration, many
physiologists interpreted the apnea following forced breathing as the
result of a sort of inhibition of the respiratory center brought about by
its repeated stimulation by afferent nervous impulses transmitted to it
along the vagus nerves, these impulses being set up by the frequent col-
lapse and distention of the alveoli acting on the terminations of the
nerve. In justification for the nervous interpretation of apnea, it was
claimed by the earlier observers that it could not readily be produced
in animals after severing both vagus nerves. More recent work has
shown that this is not an accurate observation, for if the severing of
the vagi is accomplished not by cutting but by freezing, then apnea is
as readily produced as in an intact animal (Milroy).28

That chemical and not nervous factors cause the apnea is further
demonstrated by the well-known experiment of Fredericq, who, after
ligating the vertebral and one of the carotid arteries in two dogs, anas-
tomosed the central end of the remaining carotid of the one to the
peripheral end of the carotid of the other animal, thus establishing a
crossed circulation. He then found that by applying forced artificial
respiration to the one animal, the apnea which supervened affected the
other animal and not that to which the artificial respiration had
actually .been applied. Another proof of the chemical theory of
apnea is furnished by the observation that if forced breathing is per-
formed in an atmosphere containing C02 in about the same partial pres-
sure as in the alveolar air, no apnea supervenes, and if the experiment
is repeated several times with progressively declining percentage of

fHE CONTROL OF THE RESPIRATION 385

C02 in the air each time, the length of the apneic pause proportionally
increases as the C02 pressure in the inspired air diminishes.

Periodic Breathing

TYPES OF PERIODIC BREATHING

In the best known of these, called Cheyne-Stokes respiration, a period
of hyperpnea supervenes upon one of apnea, each period following in
regular sequence. After an apneic period, the breathing begins at first

Fig. 132. — Various types of periodic breathing. (From Mosso's "Life of Man in the High Alps.")

faintly, gradually becomes more pronounced until it is markedly exag-
gerated, and then fades off again to the apneic pause. Sometimes the
apneic period is immediately followed by one of intense hyperpnea, there
being no gradual increase in the respiratory movements. Between these
two types all varieties of the condition are met (Fig. 132).

The conditions in which periodic breathing occurs may be divided into

386 THE RESPIRATION

physiological and pathological groups. Of the physiological conditions the
following may be taken as examples: (1) Breathing in an atmosphere
containing a deficiency of 02 ; thus, periodic breathing is very readily pro-
duced in persons living in rarefied air. It is often more particularly after
returning to air at normal barometric pressure, that the periodic breathing
sets in. (2) Breathing through a long tube having a small vessel contain-
ing soda lime inserted between the tube and the mouth, the whole capacity
of this vessel and tubing being about a liter. This will cause periodic
breathing in persons that are susceptible to oxygen deficiency. Even
breathing through the tube without soda lime will sometimes cause a periodic
type of breathing in such individuals. (3) The initial breathing follow-
ing an apnea induced by forced ventilation of the lungs. In this post-
apneic periodicity, the apneic periods may at first be quite marked, but as
breathing returns they become gradually shorter and the breathing in-
tervals gradually longer, until normal respiration is restored (Fig. 131).
(4) Restricted breathing, brought about either by limiting the quantity
of inspired air or by restricting the respiratory movements by corsets.

The pafhological conditions in which periodic breathing becomes devel-
oped are particularly those associated with renal disease and cerebral
hemorrhage. In many of these cases, the periodic breathing does not
appear to depend on the same factors as are concerned in the experi-
mental types. The symptoms would rather appear to depend on some
influence of the higher cerebral (supranuclear) centers on the respiratory
center. At least some other evidence of disturbance of the cerebral func-
tions is always forthcoming, such as a slight paralytic stroke, and the
periodic breathing is nearly always aggravated during sleep. Many of
these cases are greatly benefited by administration of caffeine.

In both the physiological and the pathological groups, the breathing may
develop a periodic character only when the person is asleep, during which
infants or very old people, may exhibit it to a certain degree, apart from any
of the above mentioned causative factors.

CAUSES OF PERIODIC BREATHING

Great interest attaches to an investigation of the causes of periodic
breathing, but it can not be claimed that any perfectly satisfactory ex-
planation has as yet been offered. Pembrey31 attributes it to a diminished
excitability (a raised threshold) of the respiratory center due to faulty
blood supply, the supposition being that, when thus suppressed, the
normal CH of the blood is unable to excite the center, so that breathing
stops. During the resulting apnea, C02 again accumulates until it has
raised the CH sufficiently to excite the depressed center. Hyperpnea
follows, causing a washing out of the C02 and a resulting diminution of

THE CONTROL OF THE RESPIRATION 387

the effective stimulus, so that again the center fails to be stimulated and
apnea supervenes, and so on. Support for this explanation would appear
to be furnished by the fact that, when patients exhibiting periodic breath-
ing are made to breathe an atmosphere containing a high percentage of
C02, the periodicity of the breathing may give place to regular breath-
ing ; a result which may also be obtained by making such patients
breathe in atmospheres rich in oxygen. In the former case, the stimulus is
raised to meet the depressed excitability of the center; in the latter, the
excitability of the center is increased because of better oxygen supply
so that it is enabled to react to the diminished stimulus.. But even
granted that the excitability of the center is depressed, it is difficult to
see why this should occasion a periodic type of breathing unless we as-
sume that it is only when stimulus (i. e., CH of blood) and threshold of
excitability of the center are adjusted at a certain physiological level that
smooth and continuous action can go on.

The fact that alterations in the excitability of the respiratory center
in clinical conditions are very commonly associated with periodic breath-
ing, suggests that similar alterations must be responsible for the experi-
mental forms. Support for this view is found in the fact that most of
these latter are produced under conditions where there must be a cer-
tain degree of anoxemia. Apparently when the oxygen tension of the
blood falls to a certain degree the excitability of the center becomes
altered and when it is so, the respiratory hormone, afforded by the ten-
sion of C02, causes an irregular stimulation, but why it should do so
is impossible to explain. A further factor that may come into play
is dependent on the time taken for blood to travel between the pulmo-
nary alveoli and the medulla. This may explain the gradual rather
than sudden development of the apneic and hyperpne;ic phases. At
present all we can do in attempting to explain this mysterious phenom-
enon is to examine the exact conditions under which it occurs.

The most simple to consider first is the periodic breathing that is
produced in a person susceptible to 02 want, by breathing through
a tube and bottle (of a total capacity of 1 liter), containing soda lime.
In such a case no outside air enters the lungs, for what we have really
done, besides providing for the absorption of C02, is to prolong the
dead space greatly. The oxygen tension of the rebreathed air, therefore,
quickly falls, until at last a point is reached at which the respiratory
center is directly stimulated by anoxemia (see page 374). The deep
breaths (hyperpnea) which follow, being of greater volume, cause some
outside air to be inspired so that the 02 want is made good and the hy-
perpnea again disappears, possibly to the extent of apnea, for now in
consequence of a coincident " washing out" of C02, there has been a

388 THE RESPIRATION

lowering of the C02-tension of the blood below the threshold value.
During the apnea the 02 is rapidly used up, till a point is reached at
which the center again becomes excited. In such an experiment the
effects of anoxemia such as cyanosis may show themselves. That breath-
ing under these conditions should be periodic and not merely show a
steadily increasing hyperpnea is probably due as we have seen, to the un-
equal rates at which the 02 and C02 tensions change in the blood. Be-
cause of a " buffer action" the latter fluctuates much less than the for-
mer. Another cause for the periodicity is no doubt the delay between
the gas exchange in the lungs and the arrival of the arterialized blood in
the brain. When the 02 tension of the blood supplying the respiratory cen-
ter falls to so low a level that excitation of the center occurs, the resulting
increased breathing aspirates outside 02 into the alveoli. After a moment
or so, the 02 is carried by the blood to the center, so that its stimula-
tion by 02 deficiency is removed, and it is left in a condition in which

Fig. 133. — Quantitative record of breathing air through a tube 260 cm. long and 2 cm. in diameter.

(From Douglas and Haldane.)

it fails to discharge any impulses, since there is a subnormal CH of the
blood as a consequence of the lowering of the C02 tension produced by
the hyperpnea. A little time must now elapse before the C02 again
rises or the 02 falls sufficiently to excite the center.

Periodic breathing can. be brought about by this method in decerebrate
cats, the animals being caused to respire through a tube and small flask
containing soda lime, the total capacity being about 80-100 c.c. That 02
deficiency is responsible for the result is indicated by the fact that adminis-
tration of 02 through a catheter inserted in the trachea brings about normal
breathing.

A similar although less marked degree of periodic breathing can
sometimes be induced by merely respiring through a long tube without
any provision for the absorption of C02. In this case it is more difficult
to explain the cause of the periodic breathing, but that the main factor
concerned is one of 02 deprivation is evidenced by the fact that in this,

THE CONTROL OF THE RESPIRATION 389

as in the previous experiment, the periodic nature of the respiration is
immediately changed to the regular breathing if 02 is introduced into
the tube. The interest of the experiment lies in the fact that a similar
relative elongation of the dead space is probably accountable for the
periodic breathing seen in the winter sleep of hibernating animals. Dur-
ing this condition, on account of the depression of metabolism less 02
is required and less C02 is produced, so that the exchange of gases
through the pulmonary endothelium is greatly diminished. The dead
space, however, remains of the same capacity, which amounts to the
same thing as if the latter had been prolonged under unchanged con-
ditions of pulmonary gas exchange.

Important evidence that changes occurring in the tensions of 02
and C02 in the alveolar air, and therefore in the arterial blood of
the respiratory center, are largely responsible for periodic breathing
has been secured by studying the condition that develops after a period
•of apnea produced by voluntary forced breathing. The results of such
observations are given in the curve shown in Fig. 131.

The thin line represents the 02 tension of the alveolar air, the thick
line the C02 tension. The double line running across the chart repre-
sents the average tension of C02 during quiet normal breathing. The
respiratory movements are represented by the tracing at the foot of
the curve along the abscissa. It will be observed that the oxygen ten-
sion falls very rapidly during the apneic period, until just before breath-
ing recommences it may be as low as 30-35 mm. Hg instead of the nor-
mal of about 95. Meanwhile the C02 tension rises from the very low
level of 12 mm., at first very rapidly, then more gradually, although,
when breathing recommences, it has not yet gained the normal level.
As a result of the first periods of breathing, the 02 tension suddenly
increases, but the C02 falls only slightly. During the next apneic stage
the 02 quickly comes down again, and the C02 rises so as almost to at-
tain normal tension before breathing again supervenes. As the apneic
periods subsequently become less pronounced, the C02 tension comes to
stand almost at its normal level, whereas considerable variations in the
02 tension continue to occur. If the lungs are filled with oxygen by in-
haling the gas with the last few deep breaths the return of breathing
is delayed and it is not periodic in character.

Besides affording substantial support to the hypothesis which was
stated above, there are several other interesting features of these results
which demand attention. In the first place, it is plain that the body
is possessed of some mechanism by which it can prevent great fluctua-
tions in the C02 tension of the blood, whereas towards 02 no such
"buffer action" is displayed. It will further be observed that the CO,

390 THE RESPIRATION

tension of the alveolar air rises very rapidly during the firsJb part of
the apneic period, and then more gradually, the explanation being that
during the forced breathing the C02 has been washed out from the blood
but not from the body as a whole.

As the C02 tension becomes lowered in the blood, C02 will diffuse
out of the tissues to maintain equilibrium between blood and tissues.
There must be some considerable lag in this process however, so that
when the forced breathing ceases a much lower tension exists in the
blood than in the tissues. The rapid rise in alveolar C02 early in the
apnea is therefore due to diffusion from the tissues up to the equi-
librium point.

Periodic breathing is produced by forced respiration more readily in
rarefied air than at sea level. It was found by Douglas,26 after breath-
ing forcibly for one minute at sea level, that the breathing when it
returned showed 8 to 10 different periods of apnea and hyperpnea. On
repetition of the experiment at an altitude giving a barometric pres-
sure of 600 mm., 25 such periods followed the apnea; at a height cor-
responding to 520 mm., 40 periods. Indeed, at high altitudes periodic
breathing may be brought about by the slightest alteration in normal
respiration ; even taking a deep breath may be sufficient to cause distinct
periodicity in the succeeding respirations, and in many persons living
at high altitudes periodic breathing is very apt to occur during sleep.
As in pathological cases exhibiting Cheyne-Stokes respiration, the peri-
odic breathing at high altitudes can be immediately removed by inspir-
ing oxygen.

CHAPTER XLIV
RESPIRATION BEYOND THE LUNGS

Up to the present our studies in respiration have concerned the various
mechanisms involved in bringing about a constant change in the com-
position of the alveolar air. We must now consider the nature of the
means by which the oxygen is conveyed to the tissues and the carbon di-
oxide removed from them.

In the first place, it is important to note that it is not for purposes
of oxidation in the blood itself that the 02 is required. In its respiratory
function this fluid serves as a transporting agency between the lungs
and the tissues, in which reside the furnaces of the body that con-
sume the 02 and produce the C02. This does not imply that there is no
oxidation in the blood itself; indeed, we should expect a certain degree
of oxidation because of the fact that the blood contains some living
cells — the leucocytes. It is scarcely necessary nowadays to offer evi-
dence for the foregoing conclusion. One well-known experimental proof
consists in replacing the blood in a frog with physiological saline solution
and then subjecting the frog with the saline in its blood vessels to an
atmosphere of pure 02, when it will be found that the animal continues
to absorb the normal amount of 02 and exhale the normal amount of
C02. It respires normally without any blood in the blood vessels.

In order that this transportation of gases between the lungs and the
tissues may be efficiently performed, the blood must be provided with
means for carrying adequate amounts of gases to supply the requirements
of the tissues, both during rest and during their varying degrees of
activity. Not only, therefore, must the 02 and C02 capacity of the
blood be very considerable, but it must be capable of very rapid adjust-
ment from time to time.

Our problem naturally resolves itself into three parts: (1) the call
of the tissues for oxygen (Barcroft) ; or, as it is stylecl, tissue or internal
respiration; (2) the mechanism by which the blood transports the proper
amounts of gases to meet the requirements of the tissues; and (3) the
mechanism by which the blood gases are exchanged in the lungs — ex-
ternal respiration. For convenience, however, we shall change this nat-
ural order and consider the transportation of the gases first.

391

392 THE RESPIRATION

THE TRANSPORTATION OF GASES BY THE BLOOD

The Transportation of Oxygen

It is plainly not by mere solution in the plasma of the blood that the
transportation of 02 occurs, for at the partial pressure of this gas ex-
isting in the alveolar air at the temperature of the body the amount that
could be dissolved in the blood would be only one-fortieth of that which
is actually found to be present. If there were only plasma in the blood
vessels, it would require a volume of fluid amounting to 150 kilograms
or more in order to convey the necessary amount of 02 from the lungs
to the tissues; that is, the contents of the vascular system would weigh
twice as much as the average weight of a man.

The substance that carries the 02 in the blood is the hemoglobin, which
may be described as a highly complex iron compound of protein espe-
cially evolved for the purpose of transporting 02. In some of the lower
animals other compounds exist in the blood for this purpose, but none
of them is to be compared in its efficiency with hemoglobin. They are
merely poor imitations of it.

Regarding the conditions under which hemoglobin combines with or
delivers up 02, the first question that presents itself is whether or not
the reaction is a strictly chemical one. If so, a definite amount of 02
must be capable of combining with a definite amount of hemoglobin. It
is impossible to secure hemoglobin of sufficient purity to test this rela-
tionship directly on hemoglobin itself, so that we must test it indirectly
by examining the combining equivalent between 02 and that portion of
the hemoglobin molecule upon which the combining power depends. This
is the part of the molecule containing iron. Now, if we compare the
amount of 02 which hemoglobin can take up with the amount of iron
present in the hemoglobin, we shall find that one atom of iron becomes
combined with two atom,s of 02. Evidently, then, we are here dealing
with a definite chemical reaction occurring between the 02 and the iron
of the hematin portion of the hemoglobin. This relationship is known
as "the specific oxygen capacity of hemoglobin. ",

In showing that the union of 02 and hemoglobin occurs according to
chemical laws, we throw into prominence consideration of the mechanism
by which the 02, combined with hemoglobin in the blood, is rapidly de-
livered up in the capillaries so as to supply the tissues with their require-
ment, and is then as rapidly recombined again in the lungs. Moreover,
we must reconcile the idea of a specific 02 capacity with the well-
known observation that the hemoglobin in the circulation may be united
with considerably less 02 than the total amount possible. In other words,
we must recognize that, although it is essentially a chemical reaction,

RESPIRATION BEYOND THE LUNGS 393

the combination of 02 with hemoglobin is greatly influenced by other
factors, and that it is these that are likely to be of physiological impor-
tance.

In order to understand the conditions under which hemoglobin will
take up and give off 02 in the animal body, we must study the combining
power of hemoglobin when it is exposed to different partial pressures
of 02 (for laws governing this, see page 353). In the blood, the ex-
tremes of the partial pressure of 02 are represented, at the one end, by
that in the alveolar air, which we have seen to be about 100 mm. Hg,
and at the other, by that existing in the tissues, such as muscle, which
has been shown to be not more than 19 or 20 mm. Hg. We must further
bear in mind that the 02 in its passage from the alveolar air to the hemo-
globin and from the hemoglobin to the tissues, is transmitted in solution
through the plasma; that is, so far as the supply of 02 to the tissue cells
is concerned, the plasma serves as the immediate source. Since the tis-
sues are using up 02 at a very great speed, especially when active, and
are thus tending to lower the tension of 02 in the plasma, favorable con-
ditions have to be created whereby the hemoglobin liberates 02 at the
same rate as that at which it is leaving the plasma. In brief, it is the
02 tension of the plasma in the tissue capillaries that is the important
factor, the hemoglobin merely serving as a storehouse, which delivers
its 02 at just such a rate as to maintain the plasma-oxygen tension at
a constant level. It is obviously of the greatest importance that we
should understand how this mechanism of an adequate plasma-oxygen
tension is maintained.

Methods of Investigation. — We must remember that the combination
of 02 and hemoglobin, being a definite chemical reaction, will be re-
versible, and must, therefore, obey the laws of mass action (see page
23) according to the equation: Hb + 02^±Hb02. In order to ascertain
the position of the balance of this equation at different partial pressures
of 02, — that is, the relative quantities of oxy- and reduced hemoglobin
formed in a solution of hemoglobin when this is shaken with 02 at differ-
ent pressures, — we may proceed as follows: A few c.c. of the hemoglobin
solution are placed in each of a series of vessels called tonometers, like
those shown in Fig. 134. In addition to the hemoglobin solution, each
tonometer contains a mixture of nitrogen and 02 in different propor-
tions. Suppose we use six vessels and in No. 1 have pure nitrogen; in
No. 2, nitrogen containing 5 mm. partial pressure of 02; in No. 3, 10
mm. ; in No. 4, 20 ; in No. 5, 50 ; and in No. 6, 100. We now rotate the
tonometers in a water-bath at body temperature for about twenty min-
utes, so that, by the formation of a thin film of hemoglobin solution over
the walls of the vessel, perfect equilibrium between the atmosphere and

394 THE RESPIRATION

the fluid may be attained (see page 355). A measured quantity of hemo-
globin solution (0.1 or 1.0 c.c.) is then removed from each tonometer
and placed, together with some very dilute ammonia to lake the blood,
in one of the small bottles of the differential manometer, shown in Fig.

Fig. 134. — Barcroft's tonometer for determining the curve of absorption of oxygen by hemoglobin
or blood. (From Starling's Physiology.)

135.* This manometer consists in principle of a graduated U-shaped
tube of narrow bore, containing clove oil, the free end of the U-tube
being connected with small bottles provided with some device so that

Fig. 135. — Karcroft's differential blcod gas manometer. The capillary U-tube contains clove oil.
The pockets on the sides of the blood bottles should be deeper. For manipulation see context.

two fluids can be placed in each of them but kept unmixed until the
bottle is violently shaken. The' three-way stopcock between the small
bottles and the manometer serves to permit communication of the
manometer with the outside air.

*The blood-gas manometers are made in two sizes for use with 1 c.c. and 0.1 c.c. quantities of
blood, respectively. The results with these small quantities are as accurate as with larger amounts.

RESPIRATION BEYOND THE LUNGS

395

An equal quantity of hemoglobin solution that has been saturated
with oxygen — i. e., oxyhemoglobin — is placed in the bottle on the other
end of the manometer tube from that containing the bottle with the un-
saturated hemoglobin solution. The bottles having been attached to
the manometer with the stopcocks open to the outside, the apparatus
is placed in a water-bath until the temperature conditions are constant.
The manometers are then closed to the outside air and the bottles are
shaken in order that the hemoglobin solution that is unsaturated with
02 may take up 02 from the atmosphere in the bottle until it becomes
saturated. The resulting shrinkage in the volume of the atmosphere
on the side of the unknown hemoglobin solution causes the clove oil

Fig. 136. — Barcroft blood gas manometer. This form can be used either as a differential
manometer (page 403) or for direct measurement of pressure. For the latter purpose one bottle
is removed and the pressure of gas generated in the other bottle is measured by the height to
which it raises the clove oil in the distal tube of the manometer, the meniscus in the proximal
limb being readjusted to its original level by compression with the brass screw of the rubber tube
shown in the center.

meniscus to move towards that side, the degree of movement being pro-
portional to the initial unsaturation of the hemoglobin. The manometer
tubes are then again brought into communication with the atmosphere
so that the meniscus of clove oil may move back to its old level, and the
bottle with saturated hemoglobin is removed from the manometer and a
drop or two of a saturated solution of potassium ferricyanide placed
in the separate compartment of the bottle without allowing it to mix
with the hemoglobin. The bottle is then reattached, the temperature
conditions readjusted, the manometer closed off from the ouside air,
and the apparatus again shaken so that the ferricyanide mixes with the

396 THE RESPIRATION

hemoglobin solution. This drives off all the 02 from the oxyhemoglobin
solution, and, therefore, raises the pressure in the atmosphere of that
bottle so that the clove oil moves to the opposite side of the manom-
eter, the degree of displacement being proportional to the amount of
oxyhemoglobin.

We have now all the necessary data for estimating the relative amounts
of reduced hemoglobin in the hemoglobin solution as removed from the
tonometers, for it is plain that the second estimation,, as described above,
tells us how much oxyhemoglobin might have been formed had all the
hemoglobin been saturated and the first one, how much 02 had yet to be
taken up by the original hemoglobin solution to produce saturation.

The Dissociation Curve. — The next step is to plot the results obtained
from the various hemoglobin solutions in the form of a curve. This is
known as the dissociation curve of hemoglobin. It is plotted with the
relative percentages of reduced and oxyhemoglobin in each of the solu-
tions along the ordinates, and the partial pressures of 02 in millimeters
of mercury to which they were exposed along the abscissae. The curve
thus drawn is exactly of the same shape as that which would be pro-
duced if we were to place. the tonometers in a row at distances from one
another corresponding to the partial pressure of 02 which each con-
tained, and then to mark on each tonometer the relative amounts of
reduced and oxyhemoglobin found in the solutions after shaking. A
line joining these marks on the tonometers would then exactly corre-
spond to the curve drawn by the method described above. This will be
clear from the accompanying figure from Barcroft's book (Fig. 137).

In such a chart the space below the curve can be taken to represent
the percentage of oxyhemoglobin (red in chart), and that above it of
reduced hemoglobin (blue in chart), at the varying partial pressures of
02 which are indicated along the abscissae as being contained in the at-
mosphere of the tonometers, and which must be proportional to the
partial pressure of 02 in the solution in which the hemoglobin is dis-
solved.

Difference between Curves of Blood and Hemoglobin Solutions. — The
curve obtained from pure hemoglobin solutions is very far, however,
from clearing up the problem as to how the blood absorbs and
discharges 02. On the contrary, it makes this problem appear all the
more difficult, for, according to the curve (Pig. 138-Curve A) the hemo-
globin is already more than half combined with 02 at a partial pressure
of this gas of no more than 10 mm. Hg, which means that in the low
partial pressure of 02 existing in the capillaries the oxyhemoglobin, in-
stead of readily yielding up its load of 02, would greedily retain prac-
tically the whole of it. The curve, in other words, would satisfactorily

10 20

40

1OO V

mm. pressure

Percentage saturation
with oxygen

100

0 10 20 30 40 50 50 70 80 90 100

Oxygen pressure
mm.

Fig. 137. — Upper left hznd, percentage saturation of hemoglobin with oxygen at 37° C. cor-
responding to oxygen pressures of 0, 10, 20, 40 and 100 mm. of oxygen, respectively.

Upper right hand, the same spaced with the oxygen pressure as the abscissae.
j^°Weir figure' dissociation curve representing the equilibrium between oxygen, oxyhemoglobin
(.red) and reduced hemoglobin (purple). (From Joseph Barcroft.)

RESPIRATION BEYOND THE LUNGS

397

explain why hemoglobin should readily absorb 02 from the alveolar air,
but would fall far short of explaining how this 02 is readily released
when it is required in the tissues. Obviously there is some artificial con-
dition present in the above experiment which can not obtain in the nat-
ural environment of the blood.

Since hemoglobin takes up 02 in proportion to its iron, it can not be

10 2.0 30 W 50 60 70 80 <iO 100

Fig. 138. — Average dissociation curves.

Ordinates — Percentage saturation of hemoglobin with oxygen.

Abscissae — Tension of oxygen in mm. of mercury.

Curve A — Degree of saturation of pure hemoglobin solutions at varying pressures.

Curve B — Disregard this curve.

Curve C — Effect of 20 mm. CO2 pressure on above solution.

Curve D — The saturation curve in normal blood at 40 mm. carbon dioxide pressure.

because of changes in the 02 combining part of the hemoglobin itself
that blood and pure hemoglobin solutions have dissimilar dissociation
curves, but rather because of differences in the environment in which the
hemoglobin acts. That this is so can be readily shown by plotting the
dissociation curve, not for a hemoglobin solution, but for Mood itself
(D in Fig. 138). The results are very different. At a partial pressure
of 02 of about 60 mm. Hg — that is, a* lower pressure than exists in the

398

THE RESPIRATION

lung alveoli (100 mm.)— the blood becomes nearly saturated with 02,
whereas at pressures below 50 mm. it readily loses 02, so that at 10 mm!
there is nearly complete reduction.

The question is: What are the environmental conditions under which
the hemoglobin in the blood so alters its combining power for 02 as to
produce such a difference in the dissociation curve? By experimenting
with hemoglobin solutions, three such factors have been found to come

>00

90

80

70

60

50

40

30

20

10

100

10 20 30 40 50 60 70 80 i

Fig. 139. — Dissociation curves of hemoglobin.

; Ordinates — Percentage saturation of hemoglobin.
Abscissa — Tension of oxygen in mm. of mercury.

I. Dissociation curve of hemoglobin dissolved in water.

II. Dissociation curve of hemoglobin dissolved in 7% NaCl.

III. Dissociation curve of hemoglobin dissolved in 9% KC1
Temperature 37-38° C. (From Joseph Barcroft.)

into play: (1) the presence of inorganic salts, (2) the hydrogen-ion con-
centration (C02 tension) of the solution, and (3) the temperature. If
hemoglobin is dissolved in water containing the various salts of plasma
in the same proportion as in blood (artificial plasma), the dissociation
curve will be found to change so as to resemble that of blood (Fig. 139).
Since the plasmas of different animals contain different proportions of
salts, the artificial plasma required to secure the result is not always the

K'KSI'I RATION BEYOND THE LUNGS

399

same. It differs, for example, for the dog and man. Potassium salts
are particularly efficient in causing hemoglobin to absorb 02. The in-
fluence of varying hydrogen-ion concentrations of the solution may
be conveniently studied by adding varying percentages of C02 to the
gas mixture in the tonometers, when it will be found that the curve be-
comes lowered in proportion to the amount of C02 present. This is shown
in Fig. 140.

The effect of temperature on the dissociation curve is twofold: (1) on
the rate with which equilibrium is established at the given partial pres-
sure of 02, and (2) on the position of the curve; the lower the tempera-
ture, the higher the curve.

100
90
80
70
60
50
40
30
20
10

0 10 20 30 40 50 GO 70 80 90 100

Fig. 140 — Dissociation curves of human blood, exposed to 0, 3, 20, 40 and 90 mm. COs- Ordinate,
percentage saturation. Abscissa, oxygen pressure. (From Joseph Barcroft.)

The Rate of Dissociation. — Though it is now clear that the three con-
ditions— namely, saline content, CH, and temperature — are capable of
altering the dissociation curve of a pure hemoglobin solution so as to
make it correspond with that of blood, this does not entirely solve our
problem, for we have yet to show how the cooperation of these forces
renders it possible for the rate at which hemoglobin takes up 02 in
the lungs to correspond exactly with that at which it gives up its O2
to the tissues. To study this problem a somewhat different kind of
experiment must be undertaken. The hemoglobin solution is placed in
a tube and the gas mixture slowly bubbled through it, samples of the
solution being removed at intervals for analysis in the differential blood-
gas apparatus. To obtain the rate of oxidation, a mixture of N2 or H2
and 02 is bubbled through the blood with the partial pressure of the

400

THE RESPIRATION

0, the same as that which obtains in alveolar air — namely, about 95-100
mm. Hg; and to obtain the rate of reduction pure N2 or H2 gas is bub-
bled through.

10 2O 30 40 50 60 70 80 SO 10oQiidatiOD

17-5° C. no COo

Induction

100f

Oxidation

37-5° C. no C02

Keduction

100

Oxidation

E

^

^^

37-5° C.

•f 40 mm. pressure
of C02

Reduction

\

/

\/

V

c

A

7

\

/

\

0

/

\

1

"^-,

Fig. 141. — Curves showing relative rates of oxidation and reduction of blood as influenced by
temperature and tension of COo.
Ordinates — Percentage saturation.
Abscissae. — Time in minutes.
Reducing gas, hydrogen.
Oxidizing gas, oxygen.

A, temperature 17.5° C., with no CO2.

B, temperature 37.5° C., with no CO2.

C, temperature 37.5° C., but the On and H contained 40 mm. Hg pressure of COa. (From
Joseph Barcroft.)

The rates of reduction or of oxidation as thus determined are then
plotted in curves constructed with the percentage saturation of the
hemoglobin on the ordinates and the time in minutes along the abscissa?
(Fig. 141). Even if we use blood in this experiment and therefore make

RESPIRATION BEYOND THE LUNGS 401

certain that the hemoglobin is acting in the presence of the proper pro-
portion of salts, we shall find, as curve A shows, that at room temperature
the rate of oxidation is very much greater than the rate of reduction.
If now we repeat the observation at a temperature of 37° C., the two
curves come more nearly to correspond, but still the rate of reduction is
slower than that of oxidation. If in a third experiment, besides having
proper temperature and chemical conditions, we produce the oxidation
and reduction in the presence of a partial pressure of C02 of 40 mm.,
which corresponds to that of the arterial blood, we shall find that oxida-
tion becomes a little slower, whereas reduction is further quickened.
Indeed the two curves, as seen in C in the figure, come practically to
correspond, indicating that the environmental conditions under which
hemoglobin combines and gives off 02 in the blood are exactly adjusted.

One word more with regard to the influence of CH. Its effect in flat-
tening out the curve, especially at the lower partial pressures of 02,
indicates that when a high CH is present, the blood will very readily part
with its 02 supply. Now, the most significant application of this fact
is that high concentrations of H ion will occur just exactly where it
will be of benefit — namely, in the capillaries (because of the C02 and
lactic acid produced by the tissues). Some doubt has, however, recently
been thrown on the importance of this factor.

Since, as we have seen, hemoglobin absorbs 02 according to chemical
laws, it will naturally be asked not only why the dissociation curve flat-
tens out while yet maintaining the shape of a right-angled hyperbola,
as by the action of acids or an increase in temperature, but also why it
should change its shape when salts are also present. The explanation
offered by Barcroft and his pupils is that the changes depend on the fact
that since hemoglobin is a colloidal substance, its molecules undergo
processes of aggregation under the conditions referred to abo.ve, and
therefore cause the reaction to become of a different type from that
represented by the equation Hb02 +± Hb + 02. As has been pointed out
by Bayliss, although such an explanation might suffice to explain the
flattening out of the curve, it fails to explain the change in its shape ;
for, according to the laws of mass action, such a change could occur
only if molecules of a different type came to take part in the reaction.

Dissociation Constant. — Notwithstanding these criticisms, it is of con-
siderable practical importance to know that an equation exists from
which the entire dissociation curve can be plotted by making only one
determination of the relative amounts of oxy- and reduced hemoglobin
at a particular tension or partial pressure of oxygen. This equation is as

y Kxn

follows: -r- = — — n , where y equals the percentage saturation of

hemoglobin with 02, x the 02 tension, and K and n are constants, K

402 THE RESPIRATION

being the equilibrium constant and n the average number of molecules
of hemoglobin supposed to exist in each aggregate.

When this equation is applied to human blood, the value of n remains
unchanged and is given as 2.5, so that by transposition we are enabled

•y

to find the value of K as follows: K = — n/inn — — . If we find the value

of K by measuring the relative saturation of the blood with 02 at one pres-
sure of this gas, then by changing the value of x to correspond to other
02 pressures, we can find all positions of the curve for a given sample of
blood.

An important practical application of this method is found in the
determination of the CH of ~blood, for, as we have seen, the dissociation
curve becomes lowered in proportion to the concentration of hydrogen
ions. The acidity of a sample of blood can therefore be found by com-
parison of its dissociation curve, as plotted from the values found for
K, with that of normal blood to which known quantities of acid have
been added. When the curves correspond, the bloods must contain the
same amounts of acid, other things being equal. In brief, then, the re-
action of the Nood is proportional to the value of K. When this is low,
it indicates that the blood is taking up an abnormally low percentage
of its possible load of 02 at a given pressure of 02, and that the acidity
is greater than normal ; when K is high, for the same reason the acidity
must be low.

In determining K for the blood as it exists in the body, it is necessary
that it should be subjected to the same tension of C02 as obtains in the
blood vessels. K will then be proportional to the CH of the living blood.
This condition would be impossible to fulfil in drawn samples were it
not for the fact that we can place in the tonometer an atmosphere con-
taining the same partial pressure of C02 as is found in the alveolar air.
S.ince this value varies in different individuals, it must be separately
ascertained in each case (see page 361). As determined with these
modifications, K has been found to vary in healthy men between
0.000212 and 0.000363 (ten individuals). When acid substances appear
in the blood, as in acidosis, K becomes extremely low; thus, in one case
suffering from acidosis with dyspnea, it was found a few hours before
death to be only from 0.000082 to 0.00011. It is said to be raised after
taking food that is rich in alkali.*

*When K is found to be normal, the blood is said to be mesertic; where K is low, it is said to
be myonectic; and when K is high and the acidity is therefore small, it is said to be pleonectic.

CHAPTER XLV
RESPIRATION BEYOND THE LUNGS— Cont'd

THE MEANS BY WHICH THE BLOOD CARRIES THE GASES

In the foregoing account of the physiology of the blood gases, empha-
sis is placed on the tension under which the gases exist rather than on
the total amount of each gas present in the blood. This has been done
because the exchange of gases between alveolar air and blood and be-
tween blood and tissues proceeds according to the laws of gas diffusion,
which are of course dependent upon differences in gas pressure or
tension.

Something must now be said regarding the amount of the gases. This
may be measured either by physical or by chemical methods. In the
former, a measured quantity of blood is received into an evacuated glass
vessel, which is then attached to a mercury pump, by which the gases
are sucked out of the blood and transferred, by suitable manipulations
of stopcocks, to a graduated tube, in which they are then analyzed by
chemical means. The principle of the chemical method has already been
described in connection with the measurement of oxygen in hemoglobin
solutions (see page 393). A measured quantity of blood, kept free from
contact with the air, is transferred under some weak ammonia solution
to one of the blood-gas bottles of the blood-gas differential manometer,
and a few drops of a saturated solution of potassium ferricyanide are
placed in the pocket of the bottle. After the blood has been laked and
temperature conditions adjusted, the ferricyanide is mixed with the
blood solution, thus causing the 02 to be quantitatively displaced. From
the increased pressure produced in the manometer the amount of 02 can
readily be computed. To determine the C02 of the blood, the bottle is
now removed from the manometer and a few drops of a saturated solu-
tion of tartaric acid placed in the pocket. When this is mixed with the
deoxygenated blood mixture, after the usual adjustment for tempera-
ture, the pressure caused by the evolved C02 is recorded and the amount
present calculated.

The results of the analysis are expressed as the number of cubic centi-
meters of gas present in 100 c.c. of blood — the volume percentage, as it
is called. The following are approximate percentage values:

403

404 THE RESPIRATION

OXYGEN CARBON DIOXIDE TOTAL GAS

Venous blood 12 48 60

Arterial blood 20 40 60

The estimation of the amounts of the gases, although of little value
in connection with the physiology of gas exchange, is very important in
supplying information regarding the respiratory activities of the various
organs and tissues. Just as we determine the total respiratory exchange
of an animal by measuring the differences in 02 and C02 in inspired and
expired air, so may we determine the local respiratory exchange of the
tissues by analysis of the gasses in blood removed from the artery and
vein of the tissue. It should be clearly understood, however, that it is
not the percentage but the total amount of the gases that must be con-
sidered, and that it is therefore necessary to know the volumes of blood-
flow as well as the percentage of the gases. Something will be said later
of the results of 'such investigations (see page 408).

At present we are concerned with the manner in which the gases are
carried in the blood. The 02, as we have seen is carried by the hemo-
globin, some being also in a state of simple solution in the plasma. The
C02, to which we must now pay attention and which it will be noted
is present even in arterial blood in considerably greater amount than
the 02, is carried by various agencies, the relative importance of each
of which is not as yet clearly understood. A most important feature
of the mechanism is that there is a considerable degree of interdependence
between the carrying agencies for C02 and 02, an increase in the one
causing a decrease of the other. By comparison of the dissociation curve
of blood for oxygen at varying pressures of C02 we have already studied
this relationship in so far as C02 influences the 02-carrying power of
blood. By adopting the same method but in the reverse way we may
also investigate the influence of varying tensions of 02 on the C02 carry-
ing power.

The C02-Dissociation Curve of Blood. — This is constructed by expos-
ing defibrinated blood in a flask at body temperature to atmospheres
containing known percentages of C02 and then removing samples and
analyzing them for C'02 in Barcroft's or Van Slyke's apparatus. The
results are plotted as shown in Fig. 142 by placing the tensions (calculated
from the percentages) of C02 in mm. Hg on the abscissae and the vol-
umes per cent of C02 absorbed on the ordinates.. When the atmosphere
writh which the C02 is mixed is a neutral gas such as hydrogen, the upper
curve (B) is obtained; when the atmosphere is air, the lower curve (A).
Clearly, reduced blood can carry considerably more C02 at all pressures
of this gas, than oxygenated blood. Disregarding for the moment the
agency by which the C02 is carried, it is important to note that the

RESPIRATION BEYOND THE LUNGS

405

height of the curve at any given tension of C02 varies somewhat for
different individuals, but not in proportion to the tension of C02 in the
alveolar air ; that is, a person with a low C02-dissociation curve may have
a high alveolar C02-tension and vice versa. On the other hand in a given
individual if the one of these be lowered by some physiological condition,
the other will become altered in the same direction. Thus in muscular
exercise the C02-dissociatioii curve and the alveolar tension of C02 both
decline.

It can be shown that it is the degree of reduction of hemoglobin which
is responsible for the alteration in C02-carrying power. Thus, the dis-

70

65

50

y*A

30 40

50

60 70

vrv rrvm.

80

90

Fig. 142. — Curve of CO2 tension in blood. For description, see text. (From Christiansen, Doug-
las and Haldane.)

sociation curve is the same whether pure oxygen or air is used as the
diluting gas. Did 02 per se have an influence these results should be
different. Another indication that it is the amount of reduced hemoglobin
that is the determining factor is that the curve is the same in the presence
of coal gas as in oxygen.

When we were considering the unloading of 02 from the blood in the
tissues we saw that the local increase in CO2-tension must encourage it
because of depression of the dissociation curve for 02 (page 399). Of much
greater physiological importance, however, is the opposite relationship be-
tween the unloading of CO2 from the blood in the lungs and the increase
in oxyhemoglobin due to the oxygen taken up from the alveoli. This will

4:06 THE RESPIRATION

be evident by studying the curves in Fig. 142 more minutely. Let us
suppose that all of the 18.1 volumes per cent of 02 in arterial blood be-
comes used up in the tissues. With the respiratory quotient of 0.8 (page
582) this will mean that 15 c.c. of C02 are carried away from the tissues in
every 100 c.c. of blood. If the blood when it -gained the lungs remained
completely unoxygenated it will be seen by examination of curve B
that to discharge this 15 c.c. C02, the C02-tension would have to fall
through 40 mm. e.g., from 80 mm. to 40 mm., or in other words, the al-
veolar C02-tension would rise to this extent. But we know by actual
measurement of alveolar tension that no such change occurs. The ex-
planation is that the absorbed 02 forms oxyhemoglobin so that to find
the pressure difference necessary to drive out the 00 2 we must shift to
curve A, when we find that 22 mm. Hg. difference in tension is sufficient
to expel the 15 c.c. of C02, as is shown in the curve by the straight line
joining A and B. Now we know that blood only yields up about one-
third of its oxygen during a circuit of the circulation; therefore, since
only 5 c.c. of C02 will be added to every 100 c.c. of blood, the necessary
difference in tension in the alveoli will require to be only a little over
7 mm. Hg., a difference which is not far removed from that actually
observed. Even when the pressure of C02 in the venous blood entering
the lungs is the same, or even somewhat less than that in the alveolar
air, some of the C02 will be discharged because of the arterialization of
the blood.

How the C02 is Carried in the Blood. — As already remarked this is
not fully understood. There are several conflicting observations for
which no satisfactory explanation can be given. If blood be separated
into corpuscles and serum and each exposed to atmospheres containing
equal percentages of C02, the serum will absorb somewhat more C02
than the corpuscles. In both fractions it is carried, partly in simple so-
lution, its coefficient of solubility being relatively high (see page 354),
and partly combined with alkali to form bicarbonate. The bicarbonate
in the plasma of living blood is, as we have seen, the most important
regulator of the H-concentration, and indeed some recent work goes to
show that the bicarbonate is present for this specific purpose only and
not because it is an important carrier of 002 (Bayliss). In other words,
the CO, produced by metabolism in the tissues is carried by the blood
to the lungs mainly in combination with other things than alkali ; only
a small proportion of it becoming united with alkali to form bicarbonate
for the purpose of serving as a buffer substance. As to how the main
bulk of C02 is carried in the plasma cannot be said. It has been supposed
that it might be united with protein but there is incontrovertible evi-
dence to show that this is not the case; for example, Bayliss has found

RESPIRATION BEYOND THE LUNGS 407

that serum absorbs practically the same amount of C02 as a solution
of bicarbonate of the same concentration, and also that the addition of
egg albumin or of dialysed serum to a bicarbonate solution does not
change its reaction towards neutral red, which it should certainly do if
the protein absorbed any of the C02. With regard to the C02 carried in the
corpuscles, there is no doubt that the greater bulk is united with hemo-
globin, the remainder being combined with alkali and in simple solution.
The behavior of the dissociation curves both of 02 and C02 in blood afford
weighty evidence for this conclusion and it is further supported by the fact
that a watery solution of pure hemoglobin absorbs much more C02 than
water alone when exposed to atmospheres containing the same partial
pressures of C02.

Alterations in C0,-Content of the Blood in Certain Respiratory and
Circulatory Diseases. — There is a difference of three to eight volumes
per cent in the C02-content of the plasma of arterial and venous blood in
man during complete muscular rest. After exercise, such as walking,
the difference becomes much greater (12 to 15 per cent). The average
for arterial plasma is 56 volumes per cent, the deviations from the aver-
age being about - 5 (R. W. Scott75).

In chronic cardiac disease (rheumatic myocarditis and valvulitis), with-
out vascular or renal complication, the carbonate of the plasma of both
arterial and venous blood (taken while the patient is at rest) is very de-
cidedly below the normal, the arterial C02 being also much more variable
than usual, and the discrepancy between venous and arterial bloods more
marked. The lowest values were found by R. W. Scott to occur in cases
in which dyspnea was a marked symptom, which indicates that the cause
for the low C02 value must be increased alveolar ventilation due to excite-
ment of the respiratory center by inadequate oxygenation of the blood
(anoxemia). When the condition is treated by rest in bed and the circula-
tion becomes restored to normal, the OCX-content of the arterial blood re-
turns towards the normal.

In cases of chronic pulmonary emphysema without circulatory or renal
complications the C02-content of arterial and of venous blood plasma is
markedly raised (values such as 80.2 for arterial plasma and 88.4 for
venous having been obtained). These patients show another remark-
able peculiarity, namely a great tolerance towards C02 in the inspired
air: thus, in one case, inspiration of air containing 11.4 per cent C02 only
served to increase the minute volume of air breathed from 10 to 14 liters,
with mild symptoms of dizziness and nausea (R. W. Scott). In a normal
person a much lower percentage of C02 would increase the pulmonary
ventilation several times over the normal and the symptoms would soon
become intolerable. The most probable explanation for the existence

408

THE RESPIRATION

of these conditions is that the interference with the pulmonary func-
tion has prevented proper removal of free C02 from the blood, to com-
bine with which the alkali has increased probably by diminution in its
excretion by the kidney. The increase in alkali will raise the buffer
action of the blood for C02.

THE OXYGEN REQUIREMENT OF THE TISSUES

In order to ascertain the average 02 requirement of the different tis-
sues of the body, it is necessary to adopt as a standard of measurement
the amount of 02 in c.c. absorbed per gram of tissue per minute. To ob-
tain it we must know: (1) the weight of the particular organ or tissue
under investigation; (2) the bloodflow through the vessels of the organ
in c.c. per minute; and (3) the different percentages of 02 in the arterial
and venous blood of the tissue. It would be beyond the scope of this
book to review in any detail the many experimental investigations which
have been undertaken in this connection. A iew of the most recent
and important results are given in the accompanying table from Halli-
burton's Physiology:

ORGAN

CONDITION OF REST

OXYGEN USED
PER MINUTE
PER GRAM
OF ORGAN

CONDITION OF ACTIVITY

OXYGEN
USED PER
MINUTE
PER GRAM
OF ORGAN

Voluntary
muscle

Nerves cut. Tone
absent

0.003 C.C.

Tone existing in rest
Gentle contraction

0.006 C.C.

0.020 c.c.

Active contraction

0.080 c.c.

Unstriped
muscle

Eesting

0.004 c.c.

Contracting

0.007 c.c.

Heart

Very slow and

0.007 c.c.

Normal contractions

0.05 c.c.

feeble contractions

Very active

0.08 c.c.

Submaxillary
gland

Nerves cut

0.03 c.c.

Chorda stimulations

0.10 c.c.

Pancreas

Not secreting

0.03 c.c.

Secretion after injec-
tion of sccretin

0.10 c.c,

Kidney

Scanty secretion

0.03 c.c.

After injection of
diuretic

0.10 c.c.

Intestines

Not absorbing

0.02 c.c.

Absorbing peptone

0.03 c.c.

Liver

Suprarenal
gland

In fasting animal
Normal

0.01 to
0.02 c.c.

0.045 c.c.

In fed animals

0.03 to
0.05 c.c.

In the order of their oxygen requirements, or the coefficient of oxida-
tion, as it is called, the tissues may be divided into four groups ; glandular,
muscular, connective, and nervous. The nervous tissues should possibly

RESPIRATION BEYOND THE LUNGS 409

stand above the connective, but very little is known regarding their
oxygen consumption, although it appears that this is quite low (Hill and
Nabarro). It is of course necessary in making these comparisons to
secure the coefficient of oxidation both when the tissue is at rest and
when it is thrown into varying degrees of activity. Special attention
has been devoted to the requirements of skeletal muscle, heart muscle
and the salivary glands.

Skeletal Muscle. — It will be seen from the table that a resting muscle
while still connected with the nervous system consumes about 0.006 c.c.
02 per gram per minute; a small amount when compared with other
tissues. The consumption increases by from ten to fifteen times during
muscular exercise. This increase depends partly on increased blood
flow, and partly upon the active muscles taking up the oxygen more
thoroughly from the blood flowing through them.

As a type of the experimental method by which these values are ob-
tained and to show for what purpose the muscle requires the extra oxy-
gen when it contracts it will be of interest to consider the observations
of Verzar47. This worker isolated the gastrocnemius muscle of the cat,
and without disturbing its blood supply collected samples of blood by
introducing a 1 c.c. pipette into a branch of the saphenous vein. Activ-
ity was induced by throwing the muscle into brief tetanus by the ap-
plication of an electrical stimulus to the sciatic nerve. During its con-
traction the muscle lifted a weight, so that it did about 70 gram-centi-
meters of work at the beginning of each period of tetanus. The velocity
of bloodflow was determined by the rate at which the blood flowed along
the pipette, and the 02-consumption, by the difference in percentage of
02 in the venous and the arterial blood. These measurements were made:
(1) before contraction, (2) during contraction, and (3) after contraction.
It was found that although the 02 consumption was usually somewhat
greater during the tetanus than during rest, the most outstanding and
significant result was that a great increase occurred immediately fol-
lowing the tetanus — that is, the call for 02 continues for some time after
the actual work has been performed. This result shows that the con-
traction is not dependent upon oxidation, but that the oxidation occurs,
mainly after the contraction is over. The mechanism involved in mus-
cular contraction can not therefore be analogous with that by which
energy is liberated in a steam engine by the oxidation of the fuel.

Interesting results corroborative of these conclusions have been se-
cured by observations on the heat production of isolated muscles. It
was found that heat production occurred after a single shock to the

410 THE RESPIRATION

muscles, not only during the contraction, but for a considerable period
after it, provided 02 was present. In the absence of 02 this recovery
was either greatly delayed or entirely abolished. Such results favor
the view that 02 is used largely in the processes whereby the muscles,
"like an engine charging an accumulator, synthetize substances con-
taining a considerable amount of potential energy, which again, like the
accumulator, it discharges when appropriate stimuli are applied" — (L.
V. Hill48). One immediately thinks of lactic acid in connection
with these interesting results, for, as has already been stated, Hopkins
and Fletcher29 have shown that this acid is produced in the absence of
02 in excised frog muscles, but when 02 is present, it is either not pro-
duced or, if so, quickly disappears. •

These important results lead to the further question as to whether
the increase in l)loodflow accompanying activity is in itself sufficient to
account for the increased uptake of oxygen. This question is answered
by finding whether the increase in total oxygen consumption during mus-
cular exercise (in man) is proportional to the increase in bloodflow which
can be determined by measurement of the output of the heart (page
216). Krogh44 calls the ratio between the two the coefficient of utilization,
and it is obtained by dividing the amount of oxygen taken up from one
liter of blood during its passage round the body by the oxygen capacity
of the blood (per liter). The former value is ascertained by analysis of
the respired air and measurement of the minute volume of the heart (page
218). Thus, suppose 270 c.c. of O2 is absorbed by the body in one minute
and the minute-volume of the heart is 4.800 c.c. (and the oxygen capacity

°70 ^fi 9^

of the blood 18.5 per cent then =-= 56.25 and ^ nr = 0.03.

*.o 1.85

The coefficient increases markedly during exercise, showing that other
factors besides increased blood flow come into play. This is shown in
the accompanying tables.

O, CONSUMPTION OUTPUT OF HEART COEFFICIENT OF

C. C. PER MIN. LITERS PER MIN. UTILIZATION

1 Eest 310 5 0.30
a 1630 17.05 0.47
°rk b 2089 19.65 0.55

The unknown factors may reside in the blood itself or in the tissues.
In the former, the increase in CH due to the passage of acids into the
blood would greatly increase the rate at which oxyhemoglobin dissociates
(see Fig. 141) this being further assisted by the slight rise in temperature
which accompanies the contraction. With regard to a possible increased
avidity of the tissues, the recent work of Krogh, referred to elsewhere
(pages 252 and 414) would not seem to lend support.

RESPIRATION BEYOND THE LUNGS 411

Heart Muscle. — The gaseous exchange of the heart has been studied
both on isolated heart preparations and by examining the exchange
in the lungs of a combined lung and heart preparation. The most
important investigations by the first of these methods are those of
a known pressure. By altering the initial pressure it was found that the
02 used by the heart depends on the product of the pulse frequency and
the maximal increase in pressure produced by each cardiac contraction;

or, in the form of an equation : = a co-nstant quantity ; where Q is

the oxygen used, T the maximal increase of pressure at each beat, and N
the frequency of the pulse.

It should be pointed out, however, that constancy in the product of
the above equation does not hold under abnormal conditions of the heart-
beat. For example, when the pressure in the heart is very high, the
amount of 02 required begins to go up out of proportion, indicating that
the heart is becoming overtaxed — that it is losing its efficiency. The
same result occurs when the heart is dying, and when depressing drugs
are used, such as chloral hydrate, potassium cyanide, veratrine, etc.
Some other drugs, however, such as epinephrine, do not cause altera-
tion in the ratio, nor does vagus stimulation. Of course when the vagus
is stimulated, the 02 consumption in a given period decreases because
the heartbeats are slowed ; but the absorption of 02 is not increased rela-
tively to the slowing of the heart.

The oxygen consumption of the heart in a heart-lung preparation (page
163) has been investigated particularly by Evans49 with the object of de-
termining the mechanical efficiency of the heart. This involves a com-
parison of the actual mechanical work done with the energy expenditure
calculated on the basis that 1 c.c. 02 consumed = 2.07 kilo-grammeters
of work. It was found that when the pulse-rate is constant and rapid
(as it would be in a heart deprived of nerve control), the efficiency be-
came greater as the venous inflow was increased. This conforms with the
principles laid down elsewhere concerning the so-called law of the heart
(page 216). There is every reason for believing that alterations in pulse-
rate produced through the nerve control would also influence the effi-
ciency, that is, the consumption of 02 is less for a given output of blood
per minute when maintained by a slow beat than by a fast one. In the
heart-lung preparation alteration in the rate by changing the tempera-
ture had this effect. Under the most favorable conditions the mechanical
efficiency of the heart was found to be 28 per cent, which is greater than
that reached by the body as a whole under the most favorable conditions.

Glands. — Most work has naturally been done on the most accessible
gland— the submaxillary. By stimulating the secretory nerve of this

412 THE RESPIRATION

gland (the chorda tympani) in the dog, it has been found that, whereas
the more abundant secretion lasts only so long as the stimulus is ap-
plied to the nerve, the 02 consumption is increased to several times that
of rest, and remains increased for a considerable period after the stimulus
has been removed. Accompanying the increased functional activity
there is a very marked increase in bloodflow due to vasodilatation, which,
in part at least, is dependent upon the secretion into the blood of some
substances resulting from the glandular activities, and is not entirely
due to the action of vasodilator nerve fibers.

Similar results have been obtained in the case of the pancreas when
excited to secrete by the injection of secretin (see page 460). Under
such conditions, the oxygen consumption has been observed to increase
about fourfold and to be accompanied by a dilatation of the gland.

The work on the kidney has been especially interesting, because it
has been found that increased activity, which of course is measured by
the rate of urine excretion, is not always accompanied by increased
consumption of oxygen. When diuresis is caused by injecting Ring-
er's solution into the circulation, a great increase in urine outflow may
occur without any change in oxygen consumption ; whereas, on the other
hand, when a diuretic such as sodium sulphate or caffeine is used, the
oxygen consumption increases enormously.

Regarding the other tissues and organs, the 02 consumption of the
lungs and brain appears to be small. It is a very significant fact, how-
ever, that the higher cerebral centers are extremely sensitive to depri-
vation of 02.

The Blood. — In the blood itself, a certain amount of oxidation goes
on because of the presence of living cells such as the blood corpuscles.
This oxidation becomes considerable in the blood of animals rendered
anemic by the injection of phenyl hydrazin. A thorough investigation
of the cause of this greater oxidation has shown it to be owing, not to
an increase in nucleated erythrocytes, but to the presence of the young
unnucleated red blood corpuscles, which appear in large numbers in the
blood under these conditions. A similar increase in blood oxidation oc-
curs during posthemorrhagic anemia the rate of oxidation running paral-
lel with the rate of regeneration of the red corpuscles.

The Mechanism by Which the Demands of the Tissues for
Oxygen Are Met

There are two possible methods by which this may be brought about:
(1) by a change in the CH or the saline constituents or the temperature of
the plasma, so that the hemoglobin more readily delivers up its load

RESPIRATION BEYOND THE LUNGS 413

of 02; and (2) by an increase in the mass movement of blood through
the vessels of the acting tissue.

Regarding the first of these possibilities, there is no doubt that acids
are produced during metabolism of acting tissues. As we have seen,
when muscles contract in the presence of an abundance of 02, C02 is
produced in large amounts, and when they contract in a deficiency of 02,
sarcolactic acid. In the submaxillary gland, too, it has been possible to
show that the CH of the venous blood, as measured by the value of K of
the dissociation curve of hemoglobin, becomes distinctly increased dur-
ing glandular activity. That this increase in CH will dislodge 02 we have
already seen (page 401).

That it should have been impossible by direct methods to show any
change in CH of the blood as a whole during muscular exercise (cf. page
410) does not necessarily indicate that such may not occur in the capillary
blood of the muscles themselves. There is considerable indirect evi-
dence that CH rises in the blood circulating through the muscles. This
increased acidity will greatly facilitate the unloading of 02 from the
blood; not so much because it depresses the level of the dissociation
curve as that it accelerates the rate of dissociation (page 399). This
acceleration will be further encouraged by the rise in temperature of
the blood (pages 409 and 433).

In connection with dilatation of the blood vessels of the active tis-
sue it is most important to bear in mind that this may occur either
in the arterioles or in the capillaries or, of course, in both together.
Krogh42 has conclusively demonstrated that the capillaries of muscles
can become dilated during activity quite independently of dilatation
of their contributory arterioles and it has been shown by Dale and
Richards43 that histamine causes capillary dilatation accompanied by
arteriole constriction. The application of this discovery in the patho-
genesis of shock has already been referred to (page 307) and it is pos-
sible that histamine, or a similar substance, may be the cause of the
capillary dilatation during muscular activity.

But before such an hypothesis can be entertained, it is necessary to
show that, independently of nerve impulses, the blood vessels of an acting
organ may dilate. The best evidence has been secured by studying the
effects of stimulating with epinephrine the cervical sympathetic nerve to
the submaxillary gland of a cat. The gland cells become more active,
and dilatation of the artery occurs, although on blood vessels alone
epinephrine in similar dosage produces constriction. Of course in show-
ing that local chemical products of activity serve as the excitant of local
dilatation, we do not mean to imply that the vasodilator fibers going to
the blood vessels are of no use. Indeed we know that such fibers do be-

414 THE RESPIRATION

come active in the case of a salivary gland whose cells have been para-
lyzed by atropine, but it is a significant fact that this dilatation is of rela-
tively short duration, whereas that produced by glandular activity lasts
for some time. The suggestion seems therefore not out of place that un-
der normal conditions the initial dilatation of an acting gland may be
brought about through nervous stimuli, but the later dilatation is main-
tained by metabolic products, and by rise in temperature.

It is probable that the increased blood flow acting along with the
accelerated dissociation of oxyhemoglobin is adequate to account for
all of the increased consumption of oxygen by the active muscles. The
oxygen simply diffuses into the muscle fibers from the blood plasma.
It has commonly been supposed that the avidity of the muscle for oxygen
is so great that the tension within the fiber immediately falls to zero
but Krogh has brought forward evidence to show that this is not neces-
sarily the case. This worker has shown, by microscopic examination, that
'the capillaries containing blood are relatively scanty in a resting muscle
being, however, uniformly distributed around the fibers, but that many
additional capillaries become filled with blood and make their appearance
during activity. That is to say many capillaries that are empty during
rest open up and fill with blood when the muscle becomes active. He has
also shown by mathematical calculations that every part of the muscle
fiber must be readily accessible to oxygen molecules conveyed into them
purely by physical processes.

CHAPTER XLVI

THE PHYSIOLOGY OF. BREATHING IN RAREFIED AND COM-
PRESSED AIR

In the application of a knowledge of the physiology of respiration to
the investigation of disease, a group of conditions arises in which con-
siderable interference with physiological mechanisms occurs, not as a result
of disease, but of changes in the atmospheric environment. The regula-
tion of the functions of respiration depends very largely on changes in
the physical and chemical properties of the alveolar air, so that it is to
be expected that similar changes in the atmosphere will have a marked
influence on the respiratory activity and on .the general well-being of
the animal.

Man subjects himself to the influence of these conditions by living
at high altitudes and by work in caissons and diving suits. Although it
has been necessary, in explaining the functions of the respiratory center,
to refer in previous chapters to the influence of deficiency of oxygen,
it is important that wre pay some attention to the subject of mountain
sickness as a whole, because of the more lasting physiological alterations
which become established during it. We will then consider the opposite
condition of caisson sickness or diver's palsy.

MOUNTAIN SICKNESS

This condition depends primarily on disturbances in the control of the
respiratory function, and it is on account of the useful information con-
cerning the nature of these functions, rather than because of the so-called
disease itself, that so much attention has been devoted to its investiga-
tion during recent years. Tho disturbances produced by the rarefied
atmosphere develop rather quickly, but after some time they gradually
disappear, indicating that the organism has acclimated itself — that is,
the compensatory mechanisms have come into play to bring the respira-
tory control back to normal. When animals are placed in pneumatic
cabinets from which some of the air is pumped out, most of the imme-
diate symptoms observed in mountain sickness occur, but it is usually
impracticable to continue the observations for a sufficient length of
time to allow the compensating mechanisms to develop.

More or less hyperpnea, especially on exertion, soon appears in a

415

41 6 THE RESPIRATION

rarefied atmosphere, and the alveolar C02 tension assumes a value con-
siderably below the normal. For example, at sea level the minute vol-
ume of air breathed in one individual was 10.4 liters, and the alveolar
C02 tension 39.6 mm. Hg. After being some time on Pike's Peak, where
the barometer registers only 459 mm. Hg, Douglas26 found the minute
volume of air to be 14.9 liters, and the alveolar C02 tension 27.1 mm. Hg.
At first sight the above statement may seem to contradict one pre-
viously made, to the effect that the alveolar C02 tension tends to remain
constant at varying barometric pressures. This applies, however, to
the slight variations occurring at ordinary elevations. It is important
to consider the significance of these changes because it will assist us
in the investigation of the clinical conditions of hyperpnea, in which
likewise a diminished C02 alveolar tension is often observed. Mountain
sickness may indeed ~be considered as an intermediate condition between
the physiological and the pathological.

From what we have learned we should expect the above result to be
dependent upon stimulation of the respiratory center by deficiency of
oxygen, that is anoxemia (page 374). This excitation may be aggravated
by a hyperexcitability of the center due to constant irritation of the
sensory nerve terminations in the skin by a greater chemical activity of
the light rays at high altitudes. The erythema of the skin observed at
high altitudes is cited as evidence for this irritative action of light rays.
A similar increase in respiratory activity has been observed by Lindhard03
to be produced by light baths. This author believes that this action
of light is the main cause for a demonstrably greater excitability of
the respiratory center during summer than winter.

.The increased breathing brings about a blowing off of C02 from the
blood with a consequent decrease of alveolar C02-tension, and, to com-
pensate for the resulting tendency to a lowering of CH, the kidney ex-
cretes less acid and ammonia (page 381). This compensation has been
found by Barcroft to be adequate to maintain CH at its normal value,
as judged by the magnitude of the dissociation constant for hemoglobin
(page 402) when the blood is exposed to a tension of C02 equal to that of
the alveolar air. Since the adjustment of the acid-base equilibrium by
means of alteration in the acid excretion by the kidneys must take some
time it is to be expected that the alveolar C02 will gradually attain its
new levels both on the mountain and after returning to sea level. That
this is actually the case is shown in Fig. 142- A.

Thus, on Pike's Peak, where the barometric pressure is 459 mm. Hg.,
the C02-tension after an initial fall took about seven days before it came
to its permanent level for that barometric pressure, and fourteen days
elapsed after descending from the mountain before the sea level tension
had been regained.

BREATHING IN RAREFIED AND COMPRESSED AIR

417

The anoxemia acts on the various nerve centers, producing symptoms
which vary in different individuals according to their relative susceptibili-
ties. In some, the digestive centers are affected and nausea and vomiting oc-
cur; in others, the higher cerebral centers are affected, causing depression

Fig. 142-A. — CO2-tension at various altitudes. The horizontal interrupted lines represent the
mean normal alveolar CO2 and O2 pressures at sea level (i.e., Oxford and New Haven); the thick
line, alveolar CO2 pressure; and the thin line, alveolar O2 pressure. (From Douglas, Haldane,
Henderson, and Schneider.)

and general mental apathy, great drowsiness, muscular weakness, or it may
be mental excitement and loss of self-control. As to whether it is the anoxe-

418 THE RESPIRATION

mia itself or the slight degree of alkalosis induced by the lowered C02-
tension that is the cause for these symptoms cannot at present be said.

The susceptibility of different individuals also varies according to the
amount of previous experience in mountaineering and the type of breath-
ing. Much of the value of previous experience and training depends on
the ability to perform muscular effort economically; to adjust the effort
to the available oxygen supply without causing aggravation of the symp-
toms of anoxemia. It often happens that no symptoms appear so long as
the person is at rest, but immediately do so whenever any muscular
effort is attempted.

The type of breathing that best withstands the rarefied air is slow and
deep, rather than rapid and shallow. The reason for this is of course
that much more of the outside oxygen gets into the alveoli in the former
case than in the latter, the dead space being practically constant. The
following figures taken from observations on three different individuals
will illustrate the importance of this factor.

C.C. PER

NO. OF RES-

HEIGHT IN METERS

RESPIRATION

PIRATIONS

AT WHICH SYMP-

PER MINUTE

TOMS OCCURRED

Subject 1

270

20

3300

" 2

440

14

6000

" 3

700

8

6500

(From Halliburton.)

After living for some time in the rarefied air and quite independently
of training in the efficient performance of muscular work, adaptation
occurs, so that the symptoms pass off. The essential feature of this adap-
tation is increased absorption of 02 into the blood. Three mechanisms
have been described as responsible for this effect: (1) increase in the ten-
sion of 02 in the alveolar air; (2) assumption by the pulmonary epithelium
of the power of secreting 02 into the blood; (3) increase in the erythrocytes
and hemoglobin of the blood. The increased alveolar 02 tension is a result
of the increase in pulmonary ventilation. If no adaptation occurred, the
02 tension at 10,000 feet would be 59 mm. and at 15,000 feet, 33.8 mm.
Actual observations on men, however, gave at 10,000 feet a tension of 65
mm. and at 15,000 feet, 52 mm.

The evidence for an increased secretory activity of the pulmonary
epithelium depends on observations made by Haldane and his cowork-
ers,33 who found that blood collected from the finger of a man living on
a high mountain is brightly arterial, whereas if this same blood is
shaken in a flask with alveolar air from the man from whom it was
taken, it will become darkly venous. To account for this difference it is

BREATHING IN RAREFIED AND COMPRESSED AIR • 419

believed that the pulmonary epithelium forces 02 into the blood contrary
to the laws of diffusion.

A more exact proof was sought for by comparing the relative amounts
of 02 and CO that blood would take up (1) when exposed outside the
body and (2) while in the blood vessels. Carbon monoxide has a very
great avidity for hemoglobin, so that if blood is shaken in a flask with
air containing 0.07 per cent of this gas, colorimetric measurement will
show an equal mixture of oxy- and carboxy-hemoglobin. Since carbon
monoxide is destroyed with extreme slowness in the body, it is possible
by causing a man to breathe a mixture of it in air to determine, in a
sample of drawn blood, whether as much carboxy-hemoglobin has been
formed as in vitro. If so, the 02 tension in the blood must equal that in
the alveoli; if less carboxy-hemoglobin should be formed, it would indi-
cate that a higher tension of 02 existed in the blood. This latter is the re-
sult which Haldane states he has secured. In one experiment, for ex-
ample, when blood was shaken outside the body with 0.04 per cent CO
the amount of carboxy-hemoglobin formed was 31 per cent of the whole
hemoglobin. When the same mixture was inhaled for three or four hours
the percentage of carboxy-hemoglobin in the blood rose only to 26 per
cent, which would correspond to an 02 tension of 25 per cent of an atmos-
phere, whereas even at sea level the tension of 02 in the alveolar
air cannot be above 15 per cent of an atmosphere. (Cf. Douglas and
Haldane: Jour. Physiol., 1912, xliv, 305.)

It is possible that during muscular training the function by which the
alveolar epithelium secretes oxygen into the blood is enhanced and that
it is on account of this effect that such training renders a person less sus-
ceptible to mountain sickness.

The constantly low tension of 02 in the plasma causes the red blood
corpuscles and the percentage of hemoglobin to become markedly in-
creased after residence for some time in high altitudes. At first this is
due to a concentration of the blood by a diminution in plasma, but grad-
ually the blood-forming organs become excited and an actual increase
in the total amount of hemoglobin occurs. In the light of these facts it
is interesting to compare the average number of red corpuscles in the
blood of inhabitants of different altitudes.

HEIGHT ABOVE SEA RED CORPUSCLES
(METERS) (PER C.MM. BLOOD)

Christiania
Zurich
Davos
Arosa
Cordilleras

0
412
1560
1800
4392

4,970,000
5,752,000
6,551,000
7,000,000
8,000,000

(From Starling.)

420 THE KF.S1 >I RATION

As has been pointed out elsewhere the increase in the percentage of
hemoglobin starts very soon after the rarefied air begins to be breathed,
and in confirmation of this it is of interest to note that even at relatively
low altitudes Miss Fitzgerald found that changes in the concentration
of blood pigment are distinct. The purpose of these changes is no doubt
Hint there may be a larger storehouse of oxygen in the blood from which
the necessary tension may be maintained in the plasma. The most im-
portant work that remains to be done in mountain sickness is measurement
of the acid and ammonia excretion by the kidneys so as to see in how far
the observations made in pneumatic .cabinets can be confirmed (see page
381).

COMPRESSED-AIR SICKNESS; CAISSON DISEASE;
DIVER'S PALSY

Divers and caisson workers are susceptible to peculiar symptoms.
These are frequently of sufficient severity to cause death, but may be so
mild as almost to escape notice. They first appear, not when the worker
is subjected to the high pressure, but after he has come back to atmos-
pheric pressure.*

While in the compressed air the worker as a rule suffers no discom-
fort. A stuffiness may be felt in the ears and temporary giddiness; the
respiration and pulse rate may become slowr and frequency of micturition
may be noticed, but none of the symptoms of disease appear until after
the caissonier or diver has been decompressed (after he has returned to
atmospheric pressure), the exact time of their onset being either imme-
diately after decompression or at the end of several hours. The worker
may have returned home and spent the evening feeling perfectly well
until he went to bed, when symptoms supervened which may include mus-
cular and joint pains, vertigo, embarrassed breathing, subcutaneous em-
physema and hemorrhages, pains in the ears and deafness, vomiting,
perhaps hemoptysis and epigastric pain. These symptoms usually pass
off after some hours but the arthralgia and myalgia sometimes persist
for a considerable time.

In the more severe cases the first symptom is severe pain in the mus-
cles and joints, quickly followed by motor paralysis, so that the patient
falls and is likely to become unconscious. The pulse is almost imper-
ceptible, the respiration is labored, sometimes even asphyxial, the face

*A caisson is a steel or wooden chamber sunk in water and prevented from filling by means of
compressed air. For the passage of the workmen and of material, into and out of the caisson, the
latter is connected with a second smaller chamber fitted with air-locks and decompressing cocks. A
diver works in a waterproof suit, the head being enclosed in a copper helmet connected by hose with
air pumps. Every 10 meters or 33 feet of water corresponds to one atmosphere pressure (15 pounds
to the square inch), so that at this depth the total air pressure in a caisson, or in a diver's helmet,
would amount to 30 pounds to the square inch, that is, + 1 atmosphere.

BREATHING IN RAREFIED AND COMPRESSED AIR 421

cyanosed, and the surface of the body cold. Many of the cases are fatal ;
indeed, death may be almost instantaneous. Such cases are common in
careless diving when the divers, to return the more quickly, screw up the
outlet valve in their helmets so as to fill their suits with air, which car-
ries them to the surface, where they decompress themselves by opening
the valve.

Autopsies of persons dead of caisson disease have shown, as a rule,
intense congestion of the viscera, hemorrhages in the spinal cord and
brain, and ecchymoses on the pleura and pericardium. In some cases
interlobar emphysema of the lungs and laceration of the spinal cord and
brain have been noted.

The Cause of the Symptoms

The cause for the symptoms is not, as was at one time supposed, that
the pressure drives the blood from the peripheral into the deep regions
of the body, including the nerve centers. Such a process is impossible,
because the fluids of the body — and all tissues, even the bones, are full
of fluid — are incompressible. Pressure applied to any part of the body
will be immediately distributed equally to every other part. If this were
not so, life would be impossible during any variation of atmospheric pres-
sure. It is now clearly established that all the symptoms of caisson disease
are due to decompression, and not, in the slightest degree, to the mechan-
ical effect of the pressure itself (Paul Bert, Leonard Hill and Macleod34).

When an animal is under pressure, its tissue fluids dissolve a large
amount of gas. They absorb it in obedience to the law of solution of a
gas in a fluid, which states that the amount of gas dissolved in water is
directly proportional to the partial pressure of that gas in the atmos-
phere; at two atmospheric pressures twice as much gas will pass into
solution as at zero pressure (Dalton's law). So long as the gas is in
simple solution, it does not in any way change the physical condition of
the blood and tissue fluids. If, however, the animal is suddenly decom-
pressed (i. e., the pressure of air surrounding it is reduced to zero), the
dissolved gas will be so quickly thrown out of solution that bubbles of
it are set free. These bubbles act as air emboli, sticking in the pulmonic
capillaries or blocking up a terminal artery in the brain; or they may be
large and tear the capillary wall and so lead to hemorrhage. If these
bubbles are produced in the posterior spinal roots, intense pain results;
if in the anterior, motor paralysis. Frothing of the blood in the heart im-
pedes the action of the organ and death soon follows.

The following experiments furnish proof of this explanation: A frog
was placed in a small steel chamber connected with, a cylinder of com-
pressed air and provided with two windows by which a strong arc light

422 THE RESPIRATION

could be passed through the chamber. The web of the foot was stretched
on a wire and fixed so that the small blood-vessels could be seen by apply-
ing a microscope to the outside of the window. After carefully observing
the circulation of the blood in the vessels at atmospheric pressure, a posi-
tive pressure, amounting in some experiments to + 50 atmospheres, was
introduced but no effect could be noted on the circulating blood. By
opening a tap in the chamber, decompression to zero pressure was quickly
effected and, immediately, large bubbles were seen to develop in the
blood, blocking the vessels and producing stasis. The bubbles were de-
rived from the gas that had gone into solution under pressure. On re-
applying the pressure the bubbles of gas again went into solution and
the blood circulated normally. When the pressure was subsequently very
gradually lowered to zero, the circulation went on undisturbed, and the
frog was removed from the chamber in normal condition.

The process involved in causing caisson disease is evidently the same as
that which can be observed in a bottle of aerated water; if the cork in
such a bottle is drawn, the dissolved gas escapes as bubbles and effer-
vescence results ; if the bottle is recorked, the gas reenters solution and
the fluid becomes quiet. If a pin hole is made in the cork, the gas will
gradually escape and no effervescence will result.

Confirmatory results have been secured by observations on mammals.
The arterial blood pressure of rabbits was not found to become altered
by exposure to compressed air, and various animals placed in a large,
strong steel chamber at pressures far in excess of those to which man
ever subjects himself did not show any symptoms like those of caisson
sickness, unless the pressure was suddenly lowered. Many times also, if
symptoms had appeared they could be removed by again subjecting the
animals to the compressed air.

Investigations were also carried out to determine exactly how much
gas the blood of an animal subjected to high pressures contains, and how
long it takes to absorb the maximal amount of gas and to release it. It
was found that the gases that increased in amount were nitrogen and
oxygen, and that these become dissolved in the blood according to Dai-
ton's law.

The Prevention of the Symptoms

The most important practical application of these observations con-
cerns the length of time required for the saturation and desaturation to
occur, for the results serve as a basis upon which the safe regulation of
work in compressed air by man can be conducted. The most significant
outcome of the above experiments from this standpoint is that it takes
considerable time for the blood to absorb its full quota of gas at a given

BREATHING IN RAREFIED AND COMPRESSED AIR 423

atmospheric pressure and to liberate it again when the animal is decom-
pressed. The cause of delay is that the tissue fluids other than the blood
take much longer than would be expected to reach equilibrium with the
partial pressure of gas in the blood plasma.

To understand why this delay should occur, let us suppose that the
only gas concerned is nitrogen. As the pressure rises, the blood in the
capillaries of the lungs must dissolve nitrogen in proportion to the pres-
sure of this gas in the alveoli; the blood carries the dissolved gas to the
tissues and these dissolve it until the pressure is again equalized between
them and the blood. The blood, after giving up its excess of dissolved
nitrogen, returns to the lungs and again becomes saturated and this goes
on until blood and tissue have become saturated with gas at the external
pressure. The tissues are two-thirds water and .they contain (in man)
from 15 to 20 per cent of fat. Fat, however, dissolves five times more
nitrogen than water (Vernon) ; consequently, it takes longer for a given
volume of tissue than of blood to become saturated at a given pressure.

The blood in man constitutes one-twentieth of the body weight; so
that if the tissues were all liquid they would dissolve 20 times as much
nitrogen as the blood. On account of the fat which they contain, however,
the tissues take up more than this proportion — namely, in an average
man about 35 times more than the blood. All the blood in the body takes
about one minute to complete a round of the circulation, so that in this
time, after being suddenly subjected to an increased pressure — assuming
that the blood circulates equally throughout the body — the tissues will
be one-thirty-fifth saturated; in the next minute another thirty-fifth of
thirty-four thirty-fifths will be saturated, and so on. After five minutes
the body will be about 22 per cent, and in 25 minutes about one-half,
saturated; but it will take about two hours before saturation is complete.
These calculations assume that the blood is evenly distributed through-
out the body; but this is not the case, for its mass movement varies
considerably in different parts, being much greater in the active muscles
and in the glands than in passive structures, such as fat. These less vas-
cular parts will therefore lag behind the others in taking up their full
quota of gas, and therefore prolong the time necessary for complete
saturation of the body as a whole.

We see therefore that, after -some time in compressed air, the blood
and active tissues will be saturated and contain volumes of dissolved
gas in proportion to their relative bulks ; the fat, although not saturated,
will yet contain up to five times more gas than an equal volume of
blood, and the passive tissues will be incompletely saturated.

These considerations regarding the saturation of the different parts
of the body apply also to its desaturation. Suppose, for example, that

424 THE RESPIRATION

the external pressure is suddenly lowered: the blood, on leaving the
lungs, will contain no excess of gas; when it reaches the tissues it will
remove gas until the pressure is equalized, discharge this into the alveoli
and return again for more. Other things being equal, it 'will take the
same number of minutes to desaturate that it took to saturate, and the
parts of the body that will lag behind the others, in being desaturated,
are those with a sluggish circulation.

When the mass movement of the blood is increased by muscular exer-
cise, the rate of saturation and desaturation with nitrogen is increased
in proportion. During active work the increase in movement of the
blood may be four or five times over the normal, so that the tissues of
the caisson worker become much more quickly desaturated during decom-
pression than the above figures would lead one to expect.

Application of Foregoing Laws in Practice

With regard to the application of these principles in the decompression of caisson
workers, it is impracticable to occupy as much time as it takes to saturate the body
even at comparatively low pressures. If the great dangers attending work in com-
pressed air are to be avoided, we must either insist on very gradual decompression
or we must show how the dissolved gases may be got rid of by some modification in
the decompression procedure. With this object in view, we must determine what
difference of pressure may be allowed between the external air and the body without
the formation of bubbles. Actual experience shows that there is no risk of bubble-
formation, however quick the decompression, after exposure to + 15 pounds pressure
(i. e., 2 atmospheres absolute). "Now, the volume of gas capable of being liberated
on decompression to any given pressure is the same, if the relative diminution of
pressure is the same" — (Haldane3s). On reduction from 4 to 2 atmospheres, -the same
volume of gas will tend to be liberated as on reduction from 2 to 1 atmospheres — that
is to say, no bubbles will form. The practical conclusion is "that the absolute air
pressure can always be reduced to half the absolute pressure at which the tissues arc
saturated without risk." Thus, after saturation at 90 pounds absolute pressure (+5
atmospheres), a man can be immediately decompressed to 45 pounds (+2 atmospheres)
in a few minutes without risk, but from this point on the decompression must be
conducted slowly, so as to insure that the nitrogen pressure in the tissues is never
more than twice the air pressure. The great advantage of this method is that it makes
the greatest possible use of difference of pressure between tissues and blood in order
to get rid of the gas that these contain.

When the decompression from the start is gradual, the desaturation of the tissues
will progressively lag behind that of the blood, and the tendency to the liberation of
free gas will become greater. In such a case the decompression is far too slow at first
and far too rapid later. Theoretically, therefore, the decompression should' be rapid
at first and very slow later.

Before recommending the adoption of this principle of stage decompression in
caisson work, Haldane and his coworkers made numerous observations on the incidence
of decompression symptoms in laboratory animals. They assert that the stage method
is decidedly safer than the uniform method, the advantage being particularly after
short exposures. On the other hand, Leonard Hill could make out no definite advan-
tage for the stage method. The two methods have also been compared in actual caisson

BREATHING IN RAREFIED AND COMPRESSED AIR 425

work -at the Elbe Tunnel, where the pressure was + 2 atmospheres. Very little advan-
tage could be demonstrated for the stage as compared with the uniform method at this
comparatively low pressure. The general conclusion which we may draw is that the
stage method should be employed, although it is not to be expected that it will ab-
solutely insure absence of decompression symptoms. Of course the great advantage
of the stage method is the saving of time, making it possible to persuade the workmen
to adopt it. ,

There are two other factors that are to be considered in hastening the desaturation
of the tissues; these are muscular exercise, and the breathing of an indifferent gas.

It is clear, from what has already been said, that the gas dissolved in the tissues
will become removed in proportion to the mass movement of the blood, and it is prob-
ably true that muscular exercise, performed in the decompression chamber, is of as
great importance in preventing the subsequent development of symptoms as a much
prolonged decompression. In a man at rest, the circulation through the central nervous
system and the viscera is constantly influenced by the pumping action of the respiratory
movements, but in the capillaries of the muscles, joints, fat, etc., this influence is not
felt and the blood flows more slowly. It is consequently in these parts that bubble
formation is likely to occur, especially some time after decompression. The bubbles
cause the neuralgic pains — the "bends" and "screws" so well known to caisson
workers. These could no doubt be entirely prevented by muscular exercise and massage
of the limbs during decompression. In illustration of these facts the following experi-
ment by Greenwood may be cited : During decompression from +75 pounds pressure in 95
minutes ' ' Greenwood flexed and extended all the limb joints at frequent intervals,
with the exception of the knees. Subsequently pain and stiffness were experienced in
t'he knees and nowhere else." In another experiment the knees also Avere flexed and
no pain was felt.

But even in the parts with active circulation, the gas in the tissues may lag con-
siderably behind that in the blood, although the decompression has been properly
controlled. This has been shown by Leonard Hill in the case of the kidney. The
1 ' tissue ' ' gas in this case can be taken as the gas dissolved in the urine, by analyzing
which, therefore, at different stages of decompression, the excess of nitrogen over what
it should be at the external pressure, can be ascertained. On decompression from +30
pounds by two stages to zero, a considerable super-saturation was found to exist. The
excess of nitrogen can, however, be cleared out of the kidneys rapidly and completely
by breathing oxygen, which should therefore be administered during decompression in
cases where great care has to be exercised (Leonard Hill).

When symptoms do appear, they can, in most cases, be relieved by recomprcssion,
and all modern caisson works are provided with a special chamber for this purpose.
We need scarcely say anything about this treatment here, as its value is so well known.
Suffice it to say that, although it is most likely to afford relief when applied as soon as
possible after the appearance of the symptoms, yet it is often efficacious when applied
several days after their onset.

Quite apart from the dangers of decompression, it must of course be remembered
that the working conditions in a caisson are somewhat different from those at atmos-
pheric pressure, as the air, owing to its compression, is warmer and is loaded to satura-
tion point with moisture. This hot, wet air interferes with the heat-regulating
mechanism of the body, making hard muscular work very uncomfortable because of the
tendency of the body temperature to rise. The reaction of the body against this
tendency to hyperthermia consists in dilatation of the superficial capillaries and in-
creased heart action.

When such working conditions are repeated day by day, the appetite is likely to

426 THE RESPIRATION

fail, partly because of the tendency of the body to suppress the activity of the metabolic
processes, so as to keep down heat production, and partly, no doubt, because the di-
gestive processes are working below par on account of there being less blood circulating
through the visceral blood vessels, it having been sent to the surface of the body to
be cooled off. The worker therefore tends to take less food, his metabolism becomes
depressed, and his factors of safety against bacterial infections become lessened.

The risk of the appearance of symptoms on decompression is also greater when the
air in the caisson has been moist and hot, for the heart has been overworking to main-
tain the bloodflow in the dilated vessels; it gets fatigued and is consequently unable
to maintain, during decompression, a rate of bloodflow that is adequate for carrying
the gas-saturated blood to the lungs, where the excess of gas becomes dissipated.

The criterion of proper working conditions in the caisson is therefore the wet -bulb
temperature. This should stand below 75 °F. To maintain this condition it is necessary
to ventilate the caisson, preferably with air that has been cooled by cold-water radiators ;
ir any case, the ventilation should be adequate to keep down the wet-bulb temperature.
The increased expense of ventilation with cooled air would soon be balanced by the
greater working efficiency of the men. Constant circulation of the air in the caissons
by means of fans assists also in improving the conditions, for it helps to increase
dissipation of heat from the body.

CHAPTER XL VII

THE ADAPTATIONS OF THE CIRCULATORY AND RESPIRATORY
SYSTEMS DURING MUSCULAR EXERCISE

There is probably no field of physiological research in which more
important results have been obtained during the past few years than in
that pertaining to the effects of muscular exercise on the bodily func-
tions. The adaptations in the circulation are particularly important
because they can be properly carried out only when this system is in
perfect working order, so that a study of them affords us a most valuable
method for estimating the reserve power of the heart and the efficiency
of the peripheral circulation. We shall first of all consider the adjust-
ments of the circulatory and respiratory systems that accompany muscu-
lar exercise and then proceed to see how the knowledge may be used in
clinical diagnosis.

The Circulatory Changes Accompanying Muscular Exercise*

During activity the muscles require many times more blood than dur-
ing rest. When the activity is widespread the greater blood supply is
provided by increased heart action accompanied by dilatation of the
muscular arterioles and capillaries and constriction of those of the
splanchnic area so that the entire available blood supply of the body is
made to circulate more rapidly.

If we take as a measure of the extent of muscular activity, the con-
sumption of oxygen, it has been found that this runs practically parallel
with the output of the heart and with the volume of air breathed. The
output of the heart varies between 3 and 6 liters per minute, in the resting
individual; during moderate muscular work it becomes 8 or 9 liters, and
during very heavy work it may rise to 20 liters or more (Krogh).

When the activity is confined to a limited group of muscles, the in-
creased blood supply is mainly provided by a local dilatation of the
blood vessels of the active muscles accompanied by a reciprocal constric-
tion of those inactive parts. Under these conditions there may therefore
be no quickening of the bloodflow as a whole. In order that this accurate
adjustment of blood supply to tissue demands may be promptly and ade-
quately brought about, all available types of coordinating mechanism are

*This chapter is placed here rather than following circulation because of the interdependence of
the circulatory and respiratory adjustments.

427

428 THE RESPIRATION

called into play ; that is to say, mechanical, nervous and hormone factors
cooperate to an extent which is dependent upon the type of work being
performed.

Besides the changes in pulse rate and blood pressure which are evi-
dently designed to supply more blood to the acting muscles, changes
dependent upon a secondary effect of the muscular movements have also
to be considered. Although the various factors work together and are
more or less interdependent, the final effect can be understood only after
we have studied the relative influence of each separately.

The Mechanical Factor. — It is particularly with regard to this factor
that the circulatory changes may be an unavoidable consequence of,
rather than a useful adjustment to, the muscular effort. The effects vary
with the type of exercise performed. In repeatedly lifting and lowering
dumbbells from the floor to above the head, the contracting muscles of
the back and extremities and of the abdomen compress the veins and
cause the blood to flow more rapidly into the heart, so that the arterial
pressure suddenly rises. So long as this compression exists, the veins
remain relatively empty and the arteries overfilled, but whenever it
-ceases and the muscles relax, the veins fill up again and the arterial pres-
sure markedly falls, until the extra space in the veins has been occupied
by blood. It is for this reason that the arterial blood pressure is always
found to be little, if any, above normal when taken within a few seconds
after such exercise. It subsequently rises because the other factors
responsible for the increased pressure (quick heart and arteriole constric-
tion) are still in operation at the time the veins again become filled with
blood. The purely mechanical influence outlasts the exercise for a com-
paratively short time, whereas the nervous and hormone influences con-
tinue acting. This interpretation is supported by the observation that
the fall of blood pressure is greater when the subject is left standing
after a given amount of dumbbell exercise than when he is allowed to sit
with his elbows resting on his knees. In the standing position the pres-
sure on the abdominal veins is less and the hydrostatic effect of gravity
causes more blood to collect in the large veins (Cotton, Rapport and
Lewis36). Being purely mechanical in its causation, the preliminary fall
following dumbbell exercise can always be demonstrated if the observa-
tions are made at close enough intervals of time.

The mechanical response of the circulation to exercise acts therefore
through the rate of filling of the right heart with blood, and if this organ is
in a healthy condition, it will respond to the greater inflow by correspond-
ingly increased discharge. Like every other physiological mechanism, the
heart, therefore, works with a large, factor of safety — a reserve power — and
it is the rate of venous filling that determines how much of this reserve must

CHANGES ACCOMPANYING MUSCULAR EXERCISE 429

be called upon to maintain the circulation. In isolated heart-lung prep-
arations Starling and his coworkers have very clearly demonstrated the
close dependence of cardiac output upon rate of venous filling and the
enormous range through which the systolic discharge can be made to
vary by altering this factor. As explained elsewhere (page 441), when the
reserve power of the heart is lessened, the rise in blood pressure following
exercise is longer in attaining its maximum, which is set at a higher level
and persists for a longer time. Observation of the extent of these changes
furnishes a most useful functional test of cardiac efficiency.

Other mechanical factors that augment the cardiac output depend on
the increased respiratory movements. During each respiration the in-
crease in capacity in the thorax causes both an opening up of the thin-
walled veins, so that blood is aspirated towards them from the extra-
thoracic venous system, and a dilatation of the blood vessels of the lungs,
so that the blood finds its way from right to left heart more readily.
Although this dilatation will at first tend to cause more blood to collect
in the intrathoracic vessels and less to be pumped out of them, the expira-
tory act when it supervenes will, by compressing the veins, cause the
extra blood to be expelled into the left ventricle and thence into the
arteries. It is obvious that increased depth and frequency of the respira-
tory movements will accelerate the bloodflow and tend to raise the arte-
rial blood pressure.

The above factors will come into play during most kinds of muscular
exercise such as walking, running, or swinging dumbbells, etc. There
are certain types of muscular effort, however, in which the mechanical
factors produce decidedly disturbing effects on the circulation. During
a sustained effort as, for example, in pulling against a resistance or in
attempting to lift a heavy load, the respirations are suspended, often after
a deep inspiration, and the contracted abdominal muscles press the dia-
phragm up into the thoracic cavity. After a preliminary squeezing out
of blood first of all from the veins of the abdomen into the thorax and
then from those of the latter into the systemic arteries, with a consequent
rise in arterial pressure, there comes to be a damming back of blood into
the peripheral veins, causing them to swell and, if continued, marked
cyanosis may develop. When such efforts are maintained for long, the
arterial pressure begins to fall, and this fall is very pronounced indeed
at the end of the effort, because, the compression being removed from the
abdominal and thoracic veins, these open up and form a large unfilled
blood reservoir.

A similar mechanism comes into play during expulsive acts such as
defecation, parturition, etc. In these the glottis is closed, usually after
a preliminary inspiration, and a powerful expiratory movement is per-

430 THE RESPIRATION

formed, with the consequence that the intrathoracic and intraabdominal
pressures rise considerably, greatly augmenting the systolic discharge
and causing the blood pressure to rise. Because of the obstruction to
the bloodflow in the large veins of the abdomen and thorax, however,
the later effect of the effort is to diminish the systolic discharge, but the
fall in blood pressure which this would be expected to occasion is masked.
The pressure remains high because other factors increasing the peripheral
resistance come into play. The fall in blood pressure following these acts
may be very marked indeed. It may be so marked that fainting occurs
because of curtailment of intracranial circulation. Similar mechanical
effects are produced in the acts of coughing, sneezing, etc.

The capacity of the veins varies considerably with the position of the
body, and it is in order that we may cause alterations in this capacity
and therefore encourage a more rapid bloodflow that we stretch the body
after sitting for some time in a cramped positio.n.

The Nervous Factor. — The activity of the vagosympathetic, vasomotor
and respiratory centers becomes greatly altered during muscular effort.
In the earlier stages the alteration depends on nervous impulses trans-
mitted to the centers, but later it also depends on changes in composition
and temperature of the blood flowing through them — the hormone factor.
The stimuli which first act on the centers are derived from the cerebral
cortex. They are believed to irradiate on the medullary centers from
the motor pathways along which impulses are passing, on their way down
from the cortex to the spinal cord. The most weighty evidence favoring
this belief is that increase in the rate of the pulse and respirations may
occur at the moment a muscular effort is attempted, before there is any
time for hormones to become developed, or for reflexes from the muscles
themselves to be set up. Moreover, the degree of alteration of the me-
dullary centers is not at first proportional to the actual amount of work
done ; if a person expects that much effort will be required to do a piece
of work, the pulse and respirations will increase immediately he starts
the work, even although this, after all, is trivial. These impulses are,
however, incapable of stimulating the respiratory center unless the C02-
tension of the blood is normal. After forced breathing, for example,
muscular effort does not cause increased breathing. During the progress
of the work the cortical influences continue to act on the centers which
now are said to be also affected by afferent impulses from the periphery,
as well as by hormones. These afferent impulses acting on the pulse rate
are supposed by Bainbridge to come from the wall of the ventricle where
they are set up by the diastolic tension due to venous inflow. It is
difficult to reconcile this view with the slowing of the pulse that occurs
in asphyxial and epinephrine hypertension (page 774).

CHANGES ACCOMPANYING MUSCULAR EXERCISE 431

The Hormone Factor. — We have to consider first the nature of the
hormone, and secondly the mode of its action.

The Nature of the Hormones. — The most important hormone is car-
bonic acid, but when the exercise is strenuous and continued, or from
the very start is of such a nature that it uses up oxygen more quickly
than the blood can supply it to the muscles, lactic acid also appears.
It is probable also that depression of the tension of oxygen in the blood
supplying the medullary respiratory centers is in itself an important cause
for their excitation. Evidence for these statements can readily be supplied
in man by analysis of the expired air (for carbon dioxide) and of the urine
(for lactic acid) before and during muscular work. The carbonic and lactic
acid are believed by many to act by causing an increase in the H-ion concen-
tration of the blood. There is, however, no direct proof for this belief, al-
though it has been shown by determination of the tension of C02 in the
alveolar air and calculation therefrom of the PH of the blood, that a
decrease of 0.02 occurs. (Campbell, Douglas and Hobson39). Barcroft27
by measuring the dissociation constant of his own blood (see page 401)
before and after climbing 1,000 feet in half an hour, estimated that PH
changed from 7.29 to 7.09. It is possible, however, that these estimations
are unreliable since they may not have included all the factors that are
involved.

Another view is that the effective hormone is an increase in the free car-
bonic acid itself (see page 368). In the earlier stages of muscular work,
the greater production of C02 by the active muscles would raise the
tension of this gas in the plasma, and later, especially when the work
was strenuous, lactic acid would also come into play by decomposing the
NaHC03 of the blood, and liberating C02. As the NaBC03 (buffer sub-
stance) became gradually used up, a relatively greater and greater pro-
portion of C02 would come to exist in a free state in the plasma, so that
its stimulating effect became progressively greater.

One serious difficulty in accepting the free C02 as the exciting hormone
of the nerve centers during muscular exercise depends on the observation
that the alveolar C02 after some time is lower than normal. If we ac-
cept Haldane's teaching that there is accurate correspondence between
the tensions of C02 in arterial blood and alveolar air, not only during
rest, but also during muscular activity, then obviously we must discard
the C02 hypothesis. But this assumption is unwarranted, for Leonard
Hill and Flack46 have shown quite clearly both in experimental animals
and in man that equilibrium between the blood and alveolar tensions of
CO, may fail to occur. When blood with excess of C02 is injected into the
jugular vein of dogs, the respiratory center is stimulated, as shown by
the increased breathing, which indicates that the CO2-rich blood must

432 THE RESPIRATION

have passed through the lungs without all of the excess of C02 being re-
moved from it. Hill believes that the diffusion of C02 out of the blood
into the alveolar air may be depressed in muscular exercise, and that
this, rather than the appearance of lactic acid in the blood, is responsi-
ble for the low C02 tensions usually found present as illustrated by the
results given in the table on page 336. He points out in support of
this view that a person after exercise can hold his breath for a much
shorter time than is usual, and the C02 meanwhile mounts in the alveo-
lar air very rapidly.

In view of the fact that the respiratory center also becomes excited
when there is a lowering of the tension of oxygen in the plasma (page
374) a contributory cause for its maintained stimulation during exer-
cise may depend on the great demands of the active muscles for this
gas. In its passage through the lungs the blood under these circumstances
may not succeed in taking on its full load of oxygen. That such is
the case during muscular exercise has been suggested by Barcroft.

It is well known that an animal under emotional stress may perform an
amount of muscular work that is much greater than the usual, and Can-
non has brought forward evidence to show that this may be associated with
an increase in the concentration of adrenin in the Mood. The adrenin as-
sists in facilitating the action of the autonomic nervous system and perhaps
by improving muscular contraction (see page 778).

The Effects of the Hormone. — These may be classified as follows: (1)
strictly local effects on the muscles themselves; (2) effects on the heart;
and (3) effects on the nerve centers. The local production of acids in
the muscles will cause dilatation of the arterioles, for it has been shown
by various observers that acids cause relaxation of vascular muscle.
Independently of changes in the arterioles, the capillaries themselves are
also altered in tone during muscular activity (see page 252). For the
maintenance of capillary tone an adequate supply of oxygen is essential
so that when this is rapidly used up by exercise capillary dilatation
occurs. This is no doubt further assisted by the appearance of the blood
of certain products of the metabolism of the muscles. These are proba-
bly in part related to histamine (see page 307) and in part are acids,
such as C02 and lactic. The effects produced by changes in H-ion con-
centration of the blood on the heart have been particularly studied by
Starling and Patterson,38 who, working on isolated heart-lung prepara-
tions, have shown that the heart relaxes more and more and discharges
less blood as the H-ion concentration of the perfusion fluid is increased
by adding C02 to the air ventilating the lungs.

It is unlikely that CH in the blood is raised to the extent of causing
these changes in the heart during muscular exercise. It is possible, how-

CHANGES ACCOMPANYING MUSCULAR EXERCISE 433

ever, that sufficient change occurs in the heart to cause dilatation of
the coronary arteries, and thus improve the bloodflow (page 267). It
should be pointed out here, however, that a much more important factor
determining the coronary bloodfloAV is the pressure in the aorta. When
this is lower than 90 mm. adequate circulation in the coronary arteries is
difficult to maintain even though these vessels be dilated to the full.
Above 90 mm. slight further elevations in aortic blood pressure cause
disproportionate increase in coronary flow. The blood supply of the
heart itself depends much more upon arterial blood pressure than upon
any other factor (Markwalder and Starling40). Indeed the heart is not
the only organ in which a similar relationship between blood pressure
and bloodflow exists. The same is true for glands, for Gesell41 has found
that a trivial fall in general pressure causes a marked curtailment in
bloodflow.

The known influence of chang.es in H-ion concentration of the blood on
the vasomotor centers is difficult to correlate with the changes which ac-
tually occur in muscular exercise. There is no doubt that an increase in
CH stimulates the vasoconstrictor centers, not only of the medulla, but
also although much more feebly, of the spinal cord, but this action, if
it occurs during exercise, must be confined to the splanchnic area, where
it would have the effect of bringing about a redistribution of the total
available blood by expressing it from the viscera and sending it to the
active muscles.

The effect of increased H-ion concentration on the vagus center must
be insignificant. It is commonly believed that it would cause not what is
actually observed, a quickening, but rather a slowing of the heart rate.
But even this is doubtful. If increase in the H-ion concentration does
affect the heart during muscular exercise, it must act by inhibiting the
vagus tone, which is opposite to the action which it is usually believed
to have.

The activity of the respiratory center is of course excited by in-
crease in H-ion concentration (page 352) and the resulting greater ac-
tivity of the respiratory pump will cause important changes in the cir-
culation. To this extent alterations in CH of the blood will assist in
bringing about a greater mass movement of blood during muscular ex-
ercise.

In this connection we must consider the effect of change in the tem-
perature of the Hood. The extent of this rise in temperature apart from
the amount of exercise depends on several factors such as the cooling
effect of the 'environment, the amount of subcutaneous fat, and whether
or not the person is- in training. By observations on the temperature of
the urine in a group of soldiers Pembrey found that a march of seven

434 THE RESPIRATION

miles caused an average rise of 0.8° F. on a cool day, and of 1.4° F. on
a hot day. The temperature returns to normal very quickly after the
exercise, and while it is raised there is by no means the upset in the
bodily functions that is observed in fever. For one thing, the metab-
olism in the two cases is quite different; in fever, protein catabolism is
abnormally great, whereas in muscular exercise this is not the case,
oxidation of carbohydrates and fat being the source of the energy. It
is very likely that rise in blood temperature is in part responsible for
the acceleration of the heart that occurs during exercise, and for in-
creased excitability of the medullary nerve centers. It probably also as-
sists in hurrying the oxidative changes in the active muscles, and, by
lessening the affinity of hemoglobin for oxygen, facilitates the liberation
of this gas to the plasma.

CHAPTER XL VIII

THE ADAPTATIONS OF THE CIRCULATORY AND RESPIRATORY
MECHANISMS DURING MUSCULAR EXERCISE (Cont'd)

THE EFFECT OF MUSCULAR EXERCISE ON THE
COMPOSITION OF THE ALVEOLAR AIR

During muscular exercise the pulmonic ventilation increases ito an
extraordinary extent. At rest an average man respires 6 to 8 liters of
air per minute, but during walking on the level at the rate of 5 kilometers
an hour, this figure may increase to about 20 liters.

The first investigations as to the cause of the relationship between muscular activity
and pulmonic ventilation were made by animal experiments in which tetanus of the
muscles of the hind limbs was produced by electric stimulation of the spinal cord. The
problem was to find out what serves as the means of correlation (nerve reflex or hor-
mone control) between the muscular activity and the respiratory activity. By cutting
the spinal cord above the point of stimulation, it was found that the tetanus was still
accompanied by hyperpnea. On the other hand, when the spinal cord was left intact
but the blood vessels of the limb were ligated, no hyperpnea followed the tetanus.
Evidently therefore the pathway of communication is the blood.

The next step was to seek in the blood for the substance or hormone that acted as
the respiratory excitant, and naturally the first possibility considered was a change in
the gases of the blood,, either a deficiency of O^ or an increase in CO . Direct exami-
nation of the blood for the quantity of these gases, however, yielded results which
were quite contrary to such an hypothesis. It was found that the percentage of O2,
if anything, was slightly increased, and. that of the CO2, if anything, diminished.
Moreover, when the expired air was analyzed during the hyperpnea, the p&rcentage
of CO contained in it was distinctly below the normal average, and the percentage of
Or above it. Evidently, therefore, the amount of gases in the blood has nothing to do
with the excitation of the respiratory center, and the conclusion drawn by the earlier
investigators was to the effect that the exciting substance carried from the active
muscles to the respiratory center must be some unusual metabolic product, possibly
the lactic acid produced by contraction.

It was further found, by examination of the respiratory quotient, that an excess of
CO2 was being expired during the work and immediately after it, but that this was
subsequently followed by a much lower quotient, indicating that CO2 was being re-
truned. Such a result would be in conformity with the view that an acid such as lactic
is discharged into the blood, on the carbonates of which it would act as explained on
page 372. Breathing in and out of a small rubber bag causes the same alterations
in the respiratory quotient (see page 582).

That lactic acid is actually produced by contracting muscle could not, however, be
shown by all investigators, and it was not until some years later that Fletcher and
Hopkins29 clearly demonstrated the conditions under which it may appear in active

435

436

THE RESPIRATION

isolated muscle. These observers found that lactic acid is produced in excised muscles
only when the muscular contraction occurs in a deficiency of O . When it occurs in
an adequate supply of Ot>, CO2 instead of lactic acid is produced.

Much light has been thrown on the physiology of muscular exercise
by studying the alveolar C02 tension and the respiratory quotient. The
results of such observations are given in the accompanying table.

(1)

(2)

(3)

(4)

(5)

O2 used

CO, pro-

E.Q.

CO2in

Total alveolar

in c.c.

duced in c.c.

vol. C02

alveolar

ventilation in

per min.

per min.

vol. O2

air

liters per min.

I.

During rest, standing 328

264

0.804

5.70

5.80

2.

Walking at the rate of

3 kilometers per hour 780

662

0.849

6.04

13.6

3.

Walking at the rate of

5 kilometers per hour 1065

922

0.866

6.10

18.8

1.

Walking at the rate of

6 kilometers per hour 1595

1398

0.876

6.36

27.6

5.

Walking at the rate of

7 kilometers per hour 2005

1788

0.891

6.20

35.6

6.

Walking at the rate of

8 kilometers per hour 2543

2386

0.938

6.10

48.2

In the first column is given the 02 used in c.c. per minute. Among other
things these figures indicate the actual amount of work done. In the
second column is given the C02 production in c.c. per minute. By divid-
ing the figures of the second column by those of the first, we obtain the
figures of the third column, representing the respiratory quotient. The
fourth column gives the C02 content of the alveolar air, and the last
column the total alveolar ventilation in liters per minute.

Taking for the present the figures in the first and fourth columns it will
be noted that, as the muscular work increases up to a total consumption of
about 1600 c.c. of 02 per minute, the C02 percentage in the alveolar air
steadily increases. The question arises, does the alveolar ventilation
increase in proportion to the increase in C02 tension? If it does so,
increase in C02 tension in the blood can be held solely responsible for
the hyperpnea (i. e., a pure C02 acidosis) ; whereas if the hyperpnea is
greater than can be accounted for by the increase in C02 tension, other
factors must be acting to excite the respiratory center. By making this
same individual breathe atmospheres containing different percentages of
C02 it -was found that to produce a doubling of the alveolar ventilation it
required an increase amounting to 0.33 per cent of an atmosphere of CO.,
in the alveolar air (see also page 366). When we examine the above
figures during muscular exercise, however, we find that a rise in alveolar
C02 from 5.70 to 6.36 (i. e., 0.66 per cent) caused the alveolar ventilation
to increase by considerably more than four times, whereas had it been

CHANGES ACCOMPANYING MUSCULAR EXERCISE 437

entirely due to an increase in C02, it should not have been more than
three times as much. Evidently therefore, some other factor than C02-ten-
sion must have been responsible for the increased respiratory activity. This
conclusion is further confirmed by examination of the alveolar C02
during very strenuous muscular effort, when a relative decrease in the
C02 percentage becomes apparent.

If it is true that the exciting agency has been only partly dependent 011
an increase in the C(X -'tension of the blood, we should expect that imme-
diately after discontinuing the muscular exercise the C02-tension of the
alveolar air would fall to a level distinctly below normal, that it would
only slowly recover thereafter, and that further exercise before the re-
covery had occurred would produce a less marked increase in alveolar
CO2. These results we should expect because the store of C02 in the body
must have been depleted by the hyperpnea. By actual experiment these
suppositions have been found to be correct, as is shown in the following
table.

TIME AFTER DISCONTINUING ALVEOLAR C02 TENSION

A BRIEF PERIOD OF IN MM. HG

MUSCULAR EXERCISE

1st Period:

10"

49.2

3' 0"

35.4

6' 30"

35.3

12' 30"

35.8

2nd Period:

10"

38.9

3' 0"

33-7

t

6' 30"

34.4

3rd Period:

10"

36.9

3' 0"

34.4

8' 30"

32.4

18' 30"

33.7

24' 0"

36.2

Normal resting:

39.0

(Douglas.)

In this table the figures of Period 1 represent the alveolar C02
tension in mm. Hg. immediately following a period of strenuous work.
The figures in Period 2 .are for the same individual again performing
the same amount of work with, however, only a short period. of rest in-
tervening, and the figures of the third period are a repetition of the same
conditions. It will be observed that the muscular exercise at first raised
the alveolar tension of C02 from the normal of 39 mm. to 49.2 mm., but
that in three minutes after the work had been discontinued the tension
was considerably below the normal. During the second period of mus-
cular exercise the C02 in the alveolar air collected immediately after the
effort did not increase above the normal level, and in the third period
the increase was still less.

The other factors besides increase in C02-tension may be appearance of

438 THE RESPIRATION

acids, such as lactic, decrease in the oxygen tension of the plasma and
irradiation of impulses on the respiratory center from the cerebrospinal
pathways in the medulla.

Direct evidence that lactic acid is formed during strenuous muscular
exercise in man has been furnished by Ryffel.30 Blood removed from a
person immediately after running at full speed for about three minutes
contained 70.8 milligrams of lactic acid per 100 c.c. of blood, the normal
amount being 12.5 milligrams. Much of the lactic acid accumulating in
the blood is no doubt got rid of by oxidation, but a large part of it is
also excreted by the urine, in which it was found by Ryffel in consider-
able amount after strenuous muscular exertion.

The accumulation of lactic acid in the blood must tend to raise CH as
well as to increase the C02-tension by decomposing bicarbonates.

With regard to the stimulation of the respiratory center by irradia-
tion, it is altogether likely that this can only occur provided that the
excitability of the center is being maintained at a certain level through the
existence of a proper degree of hormone stimulation, that is, by a proper
CH or C02-tension.

Finally, let us consider for a moment the behavior of the respiratory
quotient. This ratio rises early in the muscle work (Table on page 436),
indicating that more C02 is being excreted than 02 absorbed. After the
work is discontinued, it usually falls below the normal because of retention
of C02 to take the place of that removed by the hyperpnea excited by
the other factors than increase in OCX-tension. A similar fall in the res-
piratory quotient may sometimes occur during muscular exercise, if this
is continued for a long time.

Second-Wind

When strenuous exercise is maintained, it is usually the case that the
breathlessness, which is severe soon after the start, more or less gradually
passes away, and the person feels better able to continue the effort. He
gets his " second- wind." Not only does the breathing become easier, but
any cardiac distress that may have been present is likely to disappear,
and usually sweating sets in. The pulse rate does not change. It is
difficult to explain the cause for the phenomenon, but a clue is afforded
by the discovery made by Pembrey and Cooke64 that the percentage
of C02 in the alveolar air is less after the second-wind has been ac-
quired than it was before it. This probably indicates that something
has occurred to cause a lowering of CH of the blood supplying the res-
piratory center,* and it becomes of interest to speculate as to the nature

*It is highly improbable that the lessened breathing could be due to a lowering of the excitability
of the center.

CHANGES ACCOMPANYING MUSCULAR EXERCISE 439

of the adjustment which might be responsible for this. Since we know
that lactic a«id is produced in vigorous exercise at such a rate that it
accumulates in the blood, but that it does not do so when the oxygen sup-
ply to the muscles is commensurate with the rate of production of the
acid, it is likely that "second-wind" coincides with a readjustment of
the chemical processes in the muscles leading to a more thorough elim-
ination of this metabolic product. The readjustment may depend, first,
on an increase in temperature in the muscles, stimulating the chemical
processes, and secondly, on increased bloodflow due to the opening up
of capillaries. The appearance of sweating is another effect of the rising
temperature. Beside the more adequate elimination of lactic acid, it is
also possible that changes occur in the blood, increasing its alkaline re-
serve by migration of basic radicles into the plasma from the erythro-

cytes and tissues (see page 40). This will, of course, enable the plasma

TT r*r\ -i

to take up more acid without change of the normal ratio xr^r/s,^ -= —

20

The Influence of Oxygen Inhalations on the Effects of Muscular Exercise

The most important work in this connection is that of Leonard Hill
and his pupils46 who have found that the inhalation of pure oxygen for
a few minutes renders a person capable of greater exertion, and decidedly
lessons the degree of breathlessness and the various symptoms of cardiac
distress. That the improvement of the circulation does actually occur
is indicated objectively, by the fact that the pulse is slower, and the
blood pressure higher for a given degree of exercise after oxygen than
without it. Symptoms of cerebral anemia such as dizziness, blurring of
vision, etc., are also much less common during very strenuous work, if
oxygen has been inspired prior to the effort. There are at least two
ways by which the excess of oxygen may bring about these effects: either
it becomes stored and prevents incompletely oxidized acids from accu-
mulating or retards a fall in 02-tensioii, or it increases the power of the
blood to carry away the oxidation products (C02). Regarding the sec-
ond possibility it is now well known that increase in oxygen in the blood
lowers the dissociation curve for C02 because the oxygen displaces CO2 from
hemoglobin (page 404). The preliminary inhalations of O2 will drive out
C02 from the blood and therefore make more room, as it were for the extra
load of this gas which the blood must carry during exercise. Experimental
evidence that these changes actually occur is afforded by measurement of
the breaking point when the breath is held, that is the time during which
the breath can be held before an irresistible stimulus to breathe is expe-
rienced. After inhalation of oxygen the breaking point is materially pro-
longed because the oxygen, by removing C02 from the hemoglobin, has
enabled it to take up more of the gas while the breath was held.

440

THE RESPIRATION

The value of oxygen inhalations is most marked in the early stages of
great exertion, rather than later, and it is no doubt particularly by
maintaining the vigor of the heart beat, that it acts. From what has
been said in the foregoing paragraphs of this chapter, it must be clear
that the limitations to muscular work are set by the ability of the heart
to maintain a circulation rate that is proportionate to the demands of
the muscles for oxygen, and the output of the heart depends on the oxy-
gen carried to it by its blood supply. It is probable also that the heart
does not require to perform as much work in order to maintain an ade-
quate oxygen supply to the tissues when these can use some of the ex-
cess stored in them, if such storage occurs. In this way its expenditure
of energy will be conserved.

The After-effects of Exercise

Much attention has been given in recent years to the study of the
after-effects of exercise, because of the valuable information concern-
ing the reserve power of the heart which can thereby be obtained. In a
normal person the blood pressure and pulse rate, as we have seen, are
both materially raised during the exercise, but they promptly return
to normal after it is terminated, unless the exercise has been both severe
and prolonged, when the pulse rate may decline fairly rapidly at first,
but later only slowly, so that it still remains excessive even after an
hour. This delay in return to the normal pulse rate is possibly asso-
ciated with the prolonged increase in energy metabolism, which a bout
of strenuous exercise always stimulates, Benedict and Cathcart,65. In
order to standardize methods for testing these effects in the clinic,
Cotton, Rapport and Lewis36 have adopted the practice of causing the
patients to lift dumbbells of 20 Ib. weight from the floor to the shoulders
at a rate of every 2 seconds for periods of time varying between 20 and
80 seconds. The pulse rate and blood pressure are taken immediately
before and at varying periods after the exercise, and the results are
tabulated as shown in the accompanying table.

WORK

PULSE

SYSTOLIC BLOOD PRESSURE

Lifts 20 Ib. dumb-
bells every 2 sec.
for:

Before

Maximum

After

Before

Maximum

After

Time re-
quired to
fall to
normal

Time re-
quired to
fall to
normal

80 sees.
60 "
40 "
20 "

78

72
74
80

170
127+
118
112

280+
280+
160
60

121
119
116
119

162
145
137
128

230
220
120
50

CHANGES ACCOMPANYING MUSCULAR EXERCISE 441

The respiratory rate after such exercise usually returns to normal
earlier than the pulse, but the percentage of alveolar C02, which is
raised shortly after the beginning of the exercise and depressed imme-
diately after its termination, (page 436), may continue subnormal for
the best part of an hour. The occurrence of normal breathing with a
subnormal alveolar tension of C02 indicates that a state of so-called
compensated acidosis (page 39) must exist. When the exercise is
more prolonged, the alveolar C02 may remain subnormal for hours. If
the exercise is sufficient to raise the body temperature, this usually
returns to normal in about an hour, and may even become subnormal for
a time.

Effort Syndrome

In a perfectly healthy person violent exertion, or a course of athletic
training, leaves no harmful effects. If the heart be unequal to the strain,
however, a lessened capacity to perform muscular work may become
established and may persist for weeks or months. Its lessened capacity
.is shown by the fact that the changes in blood pressure, in pulse rate and
in breathing are greater and last after the exercise for a much longer
time than they ought to. Distressing subjective symptoms such as giddi-
ness, palpitation, breathlessness. and precordial pain are also brought
on even by moderate effort. The condition in which exercise has these
unfavorable results has been called "irritable heart," or "effort syn-
drome," and it is important to remember that the symptoms may be
entirely absent while the person is at rest and only appear when muscular
exercise is attempted. There has been considerable debate as to the
etiological factors involved in this condition, some maintaining that these
are dependent on a hyperexcitability of the central nervous system,
while others believe that they are due to toxic products, either bacterial,
or derived from some faulty metabolism. (Lewis66.) There does not
appear to be any justification for the hypothesis that the condition may
depend on prolonged lowering of the alkaline reserve of the blood (Bain-
bridge).

It seerns probable that it is the cardiac function that is fundamentally
upset in this condition. Because of toxic processes the supply of oxy-
gen to the cardiac muscle does not adapt itself to the extra strain put
upon it, so that the heart fails to beat powerfully enough to maintain
sufficient blood supply to the tissues, especially the nerve centers. The
latter then also suffer from lack of oxygen, and the whole complicated
mechanism of adjustment of the body to the extra demands put upon
it, fails to be properly coordinated. In support of this view it is note-
worthy that the cardiac muscle is very susceptible to bacterial and other

442 THE RESPIRATION

toxins, and that evidence of preexisting infectious disease is very common
in those suffering from effort syndrome (Lewis). It is also interesting,
as Bainbridge points out, that "as regards their response to exercise a
man suffering from effort syndrome bears almost the same relation to
a healthy untrained man that the latter does to a trained man. ' ' Since
training affects the cardiac function, primarily, the above analogy
would lend support to the view that the cause for effort syndrome is a
great depression in cardiac function. Under suitable treatment, rest
followed by exercises that are graded to the capacity of the individual, —
the condition of effort syndrome often disappears (remedial dilatation),
but sometimes this is not the case, and the heart remains permanently
dilated (irremedial dilatation) ("over stress" of the heart). It has
been assumed by clinical investigators that in the latter group of cases
the cardiac muscle fibers have become mechanically stretched beyond
their limits of elasticity by the exertion which was responsible for the
establishment of the effort syndrome.

It has been shown by Wearn and Sturgis76 that intramuscular injec-
tions of 0.5 c.c. 1-1000 epinephrin in normal men cause only a slight rise
in blood pressure and 'pulse rate, and only transient and trivial subjec-
tive symptoms. In those suffering from the condition known as irrita-
ble heart or effort syndrome, however, the blood pressure rises decidedly
(by more than 25 mm.), the pulse accelerates (by about 26 beats per
minute) and marked objective symptoms of tremor, pallor or flushing,
sweating, etc., are noted soon after the injection is made (in about 12
minutes,). The patient also complains of great discomfort. It has also
been found by Tompkins, Sturgis and Wearn* that these injections in-
crease the basal metabolism, the pulmonary ventilation and the respiratory
quotient in patients with irritable heart to a greater extent than in normal
persons.

*Tompkins, E. H., Sturgis, C. C., and Wearn, J. T.: Ibid., 1919, xxiv, 269.

CHAPTER XLIX

OXYGEN UNSATURATION OF THE BLOOD. CYANOSIS THE
THERAPEUTIC VALUE OF OXYGEN

OXYGEN UNSATURATION OF THE BLOOD

The blood leaving the lungs, i. e., arterial blood, is 95 per cent satu-
rated with oxygen. Its oxygen unsaturation is therefore said to amount
to 5 per cent. The venous blood is, of course, unsaturated with oxygen
to a greater degree, which varies between 22.7 and 3.3 per cent, depend-
ing on the activity of the tissues.*

The blood is transferred under albolene to prevent contact with air,
and is mixed with neutral oxalate. Samples are analysed immediately
for the percentage of oxygen actually present. Another sample is re-
moved from under the albolene and saturated with oxygen by exposing
it to air, after which it is also analysed. The analyses are performed by
the method of Van Slyke. Suppose it is found that the venous blood
gives 14 per cent 02 and the total 02 capacity is 20, then the venous
oxygen unsaturation is 30 per cent. The hemoglobin content may also be
used to determine the total 02 capacity.

The determinations can also be made by using the differential manometer of Bar-
croft (page 395). In Ihis case a sample of the blood is removed by means of a pipette
from the albolene and discharged under weak ammonia water in the bottle of the dif-
ferential manometer. After allowing for temperature changes the bottle is shaken,
Avhich causes the blood to become laked and saturated with oxygen, which it takes from
the confined atmosphere in the bottle and manometer. This causes shrinkage, the de-
gree of which is noted on the manometer. After readjusting the levels in the manom-
eter a few drops of a saturated solution of potassium ferricyanide is then mixed with
the laked blood (without opening the bottle, see page 403). This expels the O2 and
creates a pressure which is measured in the manometer. The ratio between the first
and second readings equals the unsaturation of the blood, and the second reading, mul-
tiplied by a factor for the apparatus, gives the oxygen content.!

Suppose the shrinkage of the manometer in the first operation is 25 mm. and the
positive pressure in the second, is 150, and the factor for the instrument is 0.13, then,

100 x 25
•ation is

per cent (150 X 0.13).

the percentage unsaturation is — "' = 16.6 per cent and the total O2 capacity 19.5

loO

*The sample of arterial blood is collected by the method of Hurter, which is described in suf-
ficient detail by Stadie;88 the venous blood must be collected without causing stasis.

tThe method is that described by Barcroft for obtaining data from which the dissociation curve
may be plotted (page 396). It will be found described in simplified form in the Jour. Lab. and
Clin. Med., 1919, iv, No. 9.

443

444 THE RESPIRATION

Much important information is being collected concerning these values
in various abnormal conditions. When the percentage of hemoglobin is
increased or. decreased the oxygen consumption by the tissues remains
within the normal limits unless the percentage of hemoglobin is reduced
below 30. Thus Luiidsgaard67 found in a polycythemic patient with 33.4
volumes per cent oxygen capacity (corresponding to 181 per cent
hemoglobin) a venous 02 content of 28 vols. per cent, giving a differ-
ence of 5.4 vols. per cent or 16.1 per cent unsaturation ; and in an anemic
patient with only 6.7 vols. per cent oxygen capacity (36 per cent hemo-
globin) he found the venous oxygen to be 1.5, a difference of 5.2 vols.
per cent or 77.6 per cent unsaturation. This result is significant, since
it shows that the tissues are efficiently oxygenated whether or no the
arterial blood carries a great reserve or no reserve at all of oxygen.
When the arterial oxygen falls below the minimum (which is about 30 per
.cent hemoglobin), the bloodflow must become increased in order to sup-
ply the tissues with the normal amount of oxygen. The observations on
the mass movement of the blood in the hands and the viscera referred
to elsewhere in this volume (page 208) are of interest in this connection.

Cyanosis. — Before considering the fundamental causes for cyanosis it
is important to note that a condition not unlike it may be due to marked
polycythemia (erythrosis or false cyanosis). In this condition the oxy-
gen unsaturation of the venous blood is normal. Cyanosis itself is prob-
ably always due to an excessive degree of oxygen unsaturation of the
blood, although sometimes, as in poisoning by certain drugs, it is caused
by conversion of oxyhemoglobin into methemoglobin. The unsaturation
may be due to excessive reduction of the blood in the tissues, in which
case the arterial blood remains normal, or it may depend on inadequate
aeration of the blood in the lungs when both venous and arterial blood
will give high unsaturation values.

Excessive reduction in the tissues may result either from increased
activity, as in vigorous muscular exercise, or from a sluggish circula-
tion, so that, although the rate of reduction itself is not altered, the blood
loses too much of its oxygen. This sluggish state of the capillary circu-
lation may be due to venous obstruction, to independent dilatation of
the capillaries (see page 252), or to a slow circulation "time of the blood
as a whole. Faulty aeration of the blood in the lungs may be the result
of interference with the ventilation of the alveoli from pneumonia,
bronchitis, edema, etc., or it may be due to disturbances in the lesser
.circulation, as in valvular or congenital heart disease.

Lundsgaard67 has furnished some interesting figures to show the de-
gree to which the unsaturation of the venous blood must occur to cause
cyanosis. The practical yalue which such information has already af-

OXYGEN UNSATURATION OF THE BLOOD 445

forded in following the treatment of pneumonia indicates the lines along
which future progress is likely to take place.

THE THERAPEUTIC VALUE OF OXYGEN

There is no therapeutic measure that is less efficiently put into prac-
tice than the administration of oxygen, and as a consequence, most phy-
sicians have little faith in its value. There are several reasons for this
state of affairs : in the first place, the physiological mechanism by which
added oxygen could assist in the respiratory functions is not understood;
in the second, an insufficient amount of the gas is usually given and in
the third, it is usually given too late. On the other hand, when oxygen
is properly administered in suitable cases before the patient has become
moribund, much evidence has accumulated to show that very great bene-
fit indeed results from the treatment, and as far as can be told a fatal
termination is often averted.

Theoretical Considerations. — In order to understand the physiological
principles involved in this treatment, it is important to remember that
although forty to fifty times as much oxygen is combined with hemo-
globin as is in simple solution in the blood plasma, yet it is the latter
which really diffuses into the tissues. The pressure of oxygen in the
plasma, in other words, the diffusion pressure of oxygen, is the deter-
mining factor in causing it to permeate the tissues, and whenever this
pressure begins to fall under normal conditions, more is added to the
plasma by dissociation from the oxyhemoglobin of the corpuscles. The
plasma retails the oxygen to the tissues, and the corpuscles are the
wholesale warehouses from which the plasma replenishes its stock. The
unloading of oxygen from the oxyhemoglobin to the plasma is assisted
by various chemical changes that take place while the blood is in the
capillaries. From these considerations it follows that an efficient sup-
ply of oxygen to the tissues could be maintained without any hemoglobin
if we were to put an excess of the gas into simple solution in the plasma ;
that is, if enough were forced into solution in the plasma in the lungs so
that the tissue requirements could be met without any local addition
from oxyhemoglobin. Two experiments may be quoted to show that it is
possible to fulfil these conditions.

1. After replacing all the blood from the blood vessels of a frog by
artificial plasma (Ringer's solution) the animal can be kept alive for
days in a vessel containing pure oxygen (i. e., five times the amount
present in air) and during this time the rate of 02 consumption and CO,
production are practically the same as normally.

2. Animals (mice) exposed to air containing more than 0.5 per cent of

446 THE RESPIRATION

carbon monoxide (contained in coal gas) soon become moribund, because
the oxygen carrying power of the hemoglobin is entirely abolished by the
formation of carboxy hemoglobin. If the animals are now transferred
to pure oxygen under two atmospheres pressure (i. e., 10 times the
amount in air) they quickly recover.

Both experiments show clearly that if we succeed in getting sufficient
oxygen into simple solution in the plasma, the oxyhemoglobin is not nec-
essary to supply the tissues with this gas.

It is evident, therefore, that oxygen administration can be of no 'avail
in poisoning by coal gas, or any other substance, which destroys the
02-carrying power of hemoglobin, unless it is forced into the alveoli so
as greatly to increase the partial pressure.*

In pulmonary edema, in " gassed" cases, in bronchitis, and in decom-
pensated cardiac cases, oxygen is also of undoubted value, when it is
properly administered. Many cases of pneumonia are also benefited by
such treatment, but there are others in which the heart is so profoundly
affected by toxic substances that oxygen may perhaps be of little use.
Evidence of this benefit is afforded by the easier and deeper breathing,
the slowing of the pulse, the disappearance of cyanosis and the greater
ease and' comfort experienced by the patient. Not only do these effects
persist as long as the gas is given, and thereby serve to tide over a crisis
and permit the natural defensive agencies of the body more successfully
to combat the abnormal condition, but they often outlast the administra-
tion.

Quantitative evidence that in pneumonia the arterial blood is improp-
erly saturated with oxygen in proportion to the degree of cyanosis, and
therefore of the condition of the patient, has been furnished by Stadie.68
In a normal person the arterial blood carries 95 per cent of its full load
of oxygen, but in pneumonia only a little over 80 per cent. Meakins72
has confirmed these findings, and has added most important observations
on the effect of oxygen inhalations by the Haldane method. In a case
of pneumonia the oxygen unsaturation on the eighth day of the disease
was 17.9 per cent. After two hours of oxygen treatment (at a rate of
delivery of 2.5 liters 02 per minute) the unsaturation percentage fell
to 9.08, and after 18 hours (at 1 liter per minute) it was 9.0. The
02 was then discontinued and in 4 hours the unsaturation percentage
had risen to 15.5. It fell subsequently to 3.05 after 24 hours, during
which 3 liters 02 per minute was administered. Shortly after this the
crisis occurred. Similar results were obtained in a case of chronic bron-
chitis, and even in normal men it was found that inspiration of 3 liters

*Hemoglobin becomes converted into methemoglobin and incapable of carrying labile O2 in vari-
ous types of poisoning, e. g., acetanilide, nitrobenzol.

OXYGEN UNSATTTRATION OF THE BLOOD 447

of 02 per minute for 100 minutes changed the arterial blood from 4.4 per
cent unsaturation to 1.87 per cent. To explain exactly how the oxygen
acts in this group of cases several possibilities must be considered. In
the first place we must suppose that the respiratory membrane has become
greatly reduced in extent because the alveoli in certain parts of the lungs,
have become more or less filled with fluid or exudate. Under these cir-
cumstances the blood circulating in the vessels of the affected portion
of lung cannot be reached by a sufficient amount of oxygen to saturate
its hemoglobin fully, because there is an inadequate diffusion pressure of
oxygen to penetrate the thick layer of fluid between the alveolar air
and blood. When the exudation completely fills the alveoli the blood
ceases to circulate through the capillaries of the affected part, so that
all the blood is passing through the capillaries of healthy parts. This
explains why the arterial blood may remain of a bright red color in cases
where there is entire consolidation or collapse of considerable areas
of lung. So long as the hemoglobin is not fully saturated the tension
of oxygen in the plasma must become very low and little can be avail-
able for the tissues when the blood arrives at them. When excess oxy-
gen is breathed the amount which goes into solution in the fluid will
become proportionately raised so that there will be a much better chance
for a sufficient amount to reach the plasma, so as to saturate the hemo-
globin and create a proper tension in the plasma.

The blood which leaves the lungs as a whole is a mixture of blood,
still more or less venous from the blocked portions, and of arterial blood
from the healthy portions, and it may be considered that the mixture is
just on the border line of being adequate to supply the oxygen require-
ments of the tissues and nerve centers — otherwise the animal could
not live. A very little improvement in the oxygen supply will therefore
suffice to turn the tide and it is possible that this may reach it by diffu-
sion through the fluid that has collected in the alveoli. By increasing
the pressure of oxygen in the inspired air, more will become dissolved
in the fluid (by Henry's law, page 353) so that the pressure gradient from
air to blood through the fluid will become steeper. But another fac-
tor must be considered, namely, that the increased partial pressure in
the healthy alveoli has caused more 02 to go into simple solution in the
plasma of the blood circulating in these portions, and although this
cannot cause the hemoglobin of the blood to carry away any greater
load of the gas, yet when this blood is mixed with that from the patho-

*The coefficient of solubility of oxygen in water at 20° C. is 0.34., i. e., 0.34 c.c. O2 will diffuse
through l/t (.001 mm.) of water in 1 minute when 1 sq. cm. of the water is exposed to 1 atmosphere
of the gas. (Krogh, A.73). The amount which will diffuse through fluid is proportional to the
thickness of the layer of fluid.

448 THE RESPIRATION

logical lobes, the dissolved oxygen will assist in bringing the hemoglobin
up to its proper degree of saturation with oxygen.

It has been imagined by some that it is useless to give oxygen because
the dissociation curve of the blood at varying pressures of the gas (page
396) shows even after reducing the partial pressure of oxygen to one half
that obtaining in normal alveolar air, the blood still takes up 80 per cent
of its full load. It is argued that it is therefore futile to attempt to
increase the oxygen carried by the blood by raising the partial pressure
in the air which is inspired into the still healthy alveoli. From what
has been said above, however, it is clear that this viewpoint does not
take into account two important effects which follow when the partial
pressure of the oxygen is increased, namely, that under this condition
oxygen diffuses much more rapidly through the fluid in the pathological
portions of the lung, and at the same time that more goes into simple
solution in the plasma that is circulating in the healthy portions.

Principles in Method of Administration. — The success of any treat-
ment with oxygen must depend on several factors, the most important
of which are: (1) to get as much of the gas into the alveoli as possible;
(2) to start the treatment early before irreparable damage has been done
because of anoxemia; and (3) to maintain the administration until cyanosis
disappears. With regard to the first of these, factors, it has sometimes
been thought that there is an element of danger in giving too much
oxygen. This depends on the observations made by several investiga-
tors that animals that have been caused to live in more than one atmos-
phere of the pure gas for some time develop symptoms of pulmonary
irritation, leading on to pneumonia. Even by the best methods of ad-
ministration, however, not more than 85 per cent of the gas can be got
into the alveoli and it takes three or four days for this percentage to
cause pneumonia, even in small animals. (Lorrain Smith.) Karsner
has also shown that there is no danger in administration of pure oxygen,
even for long periods of time.

The importance of early administration is evident when we realize
that the damage of oxygen deficiency on the nerve centers and the tis-
sues usually develops insidiously, and that once started the damage
must lead to a progressive deterioration of the vital functions of the
body. The respiratory center is among the first to suffer from the anox-
emia. The result is shallow and rapid breathing. Such breathing does
not, however, properly ventilate the alveoli (page 418), so that the anox-
emia becomes aggravated, and a vicious respiratory circle becomes es-
tablished. The defensive agencies of the body against toxins and bac-
teria are also depressed by the anoxemia so that resistance to the fur-
ther progress of the disease is deteriorated. It is also posible that pro-

OXYGEN UNSATFRATIOX OF THE BLOOD 449

longed oxygon deficiency, or it may be some toxic substance appearing
in the blood as a result, renders the hemoglobin less capable of carrying
oxygen by changing some of it into methemoglobin. It is at least sig-
nificant that this compound, is formed in animals after massive injections
of streptococci (Peabody74). The maintenance of an adequate tension
of oxygen in the plasma, by administration of oxygen by the lungs,
may retard the development of toxic substances.

For similar reasons, the administration should be maintained until
all signs of deficient oxidation are removed, the best index of this being
the color of the face. So long as there is any anoxemia this is of a char-
acteristic pale ashen hue, different from that of ordinary capillary con-
gestion.

Methods of Administration. — It may be said at once that the common
clinical practice of placing a funnel connected with an oxygen tank
in front of the patient's face is worse than useless. At the rate at which
the oxygen is usually applied by this method, it is inconceivable how
any measurable increase in the percentage of oxygen in the alveolar
air could be attained, and if enough gas is turned on really to have some
influence, the waste due to diffusion into the air is prohibitive.

Where no special apparatus is obtainable for the administration, the
best method is to pass a wide gum elastic catheter into one nostril,
through which the gas, after bubbling through water in a flask, is
passed as quickly as is comfortable for the patient. The method is ren-
dered much more efficient if the open nostril is closed by the attendant
during each inspiratory act. Dr. Rudolf and I have found by this lat-
ter method that the concentration of oxygen in the alveolar air can be
raised to 35 per cent, With the opposite nostril open, this percentage
was much less.

When special appliances are available, a choice may be made between
a face mask, such as that devised for the purpose by J. S. Haldane,70 and
which was extensively used in the treatment of gassed men, or an anes-
thetic mask may be employed. The oxygen is discharged from a cylin-
der of the gas, (provided with a reducing valve) through tubing con-
nected with a T-piece. To one limb of the T a small rubber bag is at-
tached, and the other is furnished Avith a small mica valve and ends
in the face mask. The valve does not open on expiration, so that oxy-
gen only collects in the bag, and it is inhaled on inspiration. The ap-
pliance is simple and saves oxygen, but patients not infrequently ob-
ject to covering up of the face with the mask.

A very satisfactory method is that of S. J. Meltzer,71 in which a flat
metal tube (hollow tongue depressor) is connected by wide rubber tub-
ing to a very easily manipulated respiratory valve, beyond which is a

450 THE RESPIRATION

strong rubber bag attached to the rubber tubing coming from an oxygen
cylinder. When the valve is in the inspiratory position, the gas passes
through the bag into the tongue depressor; when in the expiratory
position it fills the bag and none gets beyond the valve. The tongue
depressor is inserted in the mouth not much farther than the middle of
the tongue, so that there may be no gagging or other discomfort, and
the lips are kept closed. The valve is manipulated by the attendant
about 10 to 12 times a minute.

By this method, with the nose clamped, we have been able to raise
the percentage of oxygen in the alveolar air to eighty-five.

Of course by- far the most satisfactory method is to place the patient
in a respiratory cabinet filled with oxygen. Such cabinets are being
tried in England, and there is no doubt that they will soon come into
extensive use.

RESPIRATION REFERENCES

(Monographs)

Bainbridge, F. A.: The Physiology of Muscular Exercise (Monographs on Physiology)
Longmanns, Green & Co., London, 1919.

Barcroft, J.: The Eespiratory Function of the Blood, University Press, Cambridge,
1914.

Borrutau, H.: Nagel's Handbuch der Physiologic, 1905, i, 29.

Douglas, C. G.: Die Eegulation der Atmuiig beim Menschen, Ergebnisse der Physiol-
ogic, 1914, p. 338.

Hill, Leonard: Caisson Sickness, International Medical Monographs, E. Arnold,
London, 1912.

Keith, Arthur: The Mechanism of Eespiration in Man, Further Advances in Physi-
ology, E. Arnold, London, 1909.

Schenek, F.: Innervation der Atmung, Ergebnisse der Physiologic, 1908, p. 65.

(Original Articles)

iKeith, Arthur: Cf. Further Advances.

^Hoover, C. F.: Arch. Int. Med., 1913, xii, 214; ibid., 1917, xx, 701.

3Lee. F. S., Guenther, A. E., and Meleney, H. F.: Am. Jour. Physiol., 191 G, xl, 44(5.

<Meltzer, S. J.: Jour. Physiol., 1892, xiii, 218.

sHaldane, J. S., and Priestley, J. G.: Jour. Physiol., 1905, xxxii, 225.

Haldane and Douglas: Ibid., 1913, xlv, 235.
eHenderson, Y., Chillingworth and Whitney: Am. Jour. Physiol., 1915, xxxviii, 1.

Henderson and Morriss: Jour. Biol. Chem., 1917, xxx, 217.
7Krogh, A., and Lindhard: Jour. Physiol., 1913, xlvii, 30; ibid., 3917, li, 59.
sPearce, E. G.: Am. Jour. Physiol., 1917, xliii, 73; ibid., 1917, xliv, 369.
sSiebeck, E.: Skand. Arch. f. Physiol., 1911, xxv, 87; Carter, E. P.: Jour. Exper.

Med., 1914, xx, 21.

loPeabody, F. W., and Wentworth, J. A.: Arch. Int. Med., 1917, xx, 443.
uLewis, T.: Jour. Physiol., 1908, xxxiv, 213, 233.
isPorter, W. T.: Jour. Physiol., 1895, xvii, 455.
isChristiansen and Haldane, J.: Jour. Physiol., 1914, xlviii, 272.

i^Boothby, W. M., and Berry, F. B.: Am. Jour. Physiol., 1915, xxxvii, 433; also
Boothby, W. M., and Shamoff, V. N.: Ibid., p. 418.

OXYGEN UNSATU&ATION OF THE BLOOD 451

isAlcock, N. H., and Seemann, J.: Jour. Physiol., 1905, xxxii, 30.

"Scott, F. H.: Jour. Physiol., 1908, xxxvii, 301.

"Stewart, G. N., and Pike, F. H.: Jour. Physiol., 1907, xx, 61.

"aCoombs, H. C., and Pike, F. H.: Proc. Soc. Exper. Biol. Med., 1918, xv, 55.

isKrogh, A.: Skand. Arch. f. Physiol., 1910, xxiii, 248; and A. Krogh with Marie

Krogh, ibid., 179.

isllaldane, J. S., and Priestley, J. G.: Jour. Physiol., 1905, xxxii, 225.
soScott, K. W.: Am. Jour. Physiol., 1917, xliv, 196.

siNewburg, Means, and Porter, W. T. : Jour. Exper. Med., 1916, xxiv, 583.
22Hasselbalch, K. A., and Lundsgaard, Chr. : Biochem. Ztschr., 1912, xxxviii, 77, and

Skand. Arch. f. Physiol., 1912, xxvii, 13.

ssHooker, D. E., Wilson, D. W., and Connett, H.: Am. Jour. Physiol., 1917, xliii, 357.
24C'ampbell, J. M. H., Douglas, C. G., and Hobson, F. G.: Jour. Physiol., 1914/xlviii,

303.
25Lindhard, J.: Jour. Physiol., 1911, xxxviii, 337; Haldane, J. S., and Douglas, C. G.:

Ibid., 1913, xlvi.

26Douglas, C. G. : Art, Ergebnisse der Physiologie, see Monographs.
27Barcrof t, J. : see Respiratory Function of Blood.
28Milroy, T. H.: Quart. Jour. Physiol., 1913, vi, 373.
29Fletcher, W. M., and Hopkins, F. G. : Jour. Physiol., 1907, xxxv, 247 ; also Fletcher,

W. M.: Jour. Physiol., 1913, xlvii, 361.

soRyffel, J. H.: Proc. Physiol. Soc. in Jour. Physiol., 1909, xxxix, 29.
siPembrey, M. S., and Allen, E. W.: Jour. Physiol., 1909, xxxii, 18.
32Buckmaster, G. A.: Jour. Physiol., 1917, li, 105.
ssDouglas, C. G., Haldane, J. S., Henderson, Y., and Schneider, E. C.: Phil. Trans.

Roy. Soc., 1913, 203, B, 185.
3'*Hill, Leonard, Macleod, J. J. R.: Jour. Physiol., 1903, xxix, 507; Hill, Leonard,

Greenwood, M., Flack, M., etc. : see Hill 's Caisson Sickness.
3-r>Haldane, J. S. : Deep Water Diving, Committee of the Admiralty (British), see

Hill's Caisson Sickness.

sfiCotton, T. F., Rapport, and Lewis, T.: Heart, 1917, vi, 269.
3f Hill, Leonard, and Macleod, J. J. R. : Jour. Physiol., 1908, xxxvii, 77.
sspatterson, S. W., Piper, H., and Starling, E. H.: Jour. Physiol., 1914, xlviii, 465.
39Campbell, J. M. H., Douglas, C. G., and Hobson, F. G.: Jour. Physiol., 1914, xlvi, 301.
4oMarkwalder and Starling: Jour. Physiol., 1913, xlvii, 275.
4iGesell, R.: Proc. Am. Physiol. Soc., Am. Jour. Physiol., 1918, xlv.
42Rrogh, A.: Jour. Physiol., 1919, lii, pp. 409, 457.
43Dale, H. H., Richards, A. N.: Jour. Physiol., 1918, lii, 110.
44Krogh, A.: Skand. Arch. f. Physiol., 1912, xxvii, 126.
4r.Lindliard, J. : Arch. f. d. ges. Physiol. (Pfluger) 1915, clxi, 2,°,3.
4«Hill, Leonard, and Flack, M. : Jour. Physiol, 1910, xl, 347.
47Verzar, F. : Jour. Physiol., 1912, xliv, 243.

4&Hill, A. V. : Jour. Physiol., 1911, xlii, 1 ; ibid., 1913, xlvi, 435.
49Evans, C. L.: Jour. Physiol., 1912, xlv, 213; ibid., 1918, lii, 6.
soWest, H. F.: Arch. Int. Med., 1920, xxv, 306.

siLundsgaard, C., and- Van Slyke, D. D. : Jour. Exper. Med., 1918, xxvii, 65.
52Dreyer, G. : Lancet, 1919, August, 227.
ssSchaffer, E. S. : Quart. Jour. Physiol., 1919, xii, 231.

5*Lacquer, E., and Verzar. F.: Arch. f. d. ges. Physiol. (Pfluger), 1912, cxliii, 395.
-r«5Rona, P., and Neukirch, P.: Arch. f. d. ges. Physiol. (Pfliiger), 1912, cxlviii, 273.
se Jacobs, M. H.: Am. Jour. Physiol., 1920, li, 321.
"Ellis, M. M.: Am. Jour. Physiol., 1919, 1, 267.
ssLutz, B. R., and Schneider, E. C. : Ibid., 1919, 1, 228.

59Haldane, J. S., Kellas, A. M., and Kennaway, E. L. : Jour. Physiol., 1919, liii, 181.
eoHasselbach, K. A., and Lindhard, J.: Biochem. Ztschr., 1915, pp. 1 and 48.
6iHaldane7 J. S., Meakins, J. C., and Priestley, J. G. : Jour. Physiol., 1919, lii, 433.
62Bayliss, W. M. : Jour. Physiol., 1919, liii, 162.
63Lindhard, J.: Skand. Archiv. f. Physiol., 1912, xxvi, 289, and Jour. Physiol., 1911,

xlii, 337.
64pembrey, M. S., and Cook, F. : Proc. Physiol. Soc., 1908, in Jour. Physiol., xxxvii,

p. xli.
esBenedict, F. G., and Cathcart, E. P.: Report 187 Carnegie Institution of Washington.

452 Till-: RESPIRATION

is, T.: Special Eeport Series No. 8 issued by Medical Research Committee, Lon-

don, 1917.
67Lundsgaarcl, C.: Jour. Biol. Chem., 1918, xxxiii, 133; and Jour. Exper. Med., 1918,

xxvii, pp. 179, 199, 219; Ibid., 1919, xxx, pp. 147, 258, 269 and 295.
fisStadie, W. C.: Jour. Exper. Med., 1919, xxx, 215.
«»Van Slyke, D. D.: Jour. Biol. Chem., 1918, xxxiii, 127.
ToHaldane, J. S.: Brit. Med. Jour., 1919, July, p. 64.
TiMeltzer, S. J.: Jour. Am. Med. Assn., 1917, Ixix, 1150.
v2Meakins, J. C.: Brit. Med. Jour., March 1920, p. 324.
"Krogh, A.: Jour. Physiol., 1919, Hi, 391.
74Feabody, F. W.: Jour. Exper. Med., 1913, xviii, 1.

"Scott, K. W.: Proc. Soc. Exper. Biol. and Med., 1919, xvii, pp. 18, 19 and 21.
™Wearn, J. T., and Sturgis, C. C.: Arch. Int. Med., 1919, xxiv, 247.

PART V
DIGESTION

CHAPTER L

GENERAL PHYSIOLOGY OF THE DIGESTIVE GLANDS

The function of digestion is to bring the food into such a condition
that it can be absorbed through the intestinal epithelium into the blood
and lymph. Carbohydrates are broken down as far as monosaccharides ;
neutral fats are split into fatty acids and glycerine; and proteins are
broken down into the ammo acids. The agencies which effect these
decompositions are the digestive enzymes, or ferments, contained in the
various digestive fluids or juices. The digestive juices are produced by
glands, which are most numerous in the upper levels of the gastro-
intestinal tract, the lower levels having as their main function that of
absorption of the digested products. In order that the masses of food
may be kept in a state of proper consistency, and that they may move
readily along the digestive canal, numerous mucous glands are also
scattered along the whole extent of the canal. Some of the digestive
glands, such as the main salivary glands, the pancreas, and the liver,
discharge their secretions into the digestive canal by special ducts,
whereas others, such as the isolated salivary gland follicles in the mouth,
the gastric glands and the crypts of Lieberkiihn in the intestine, do not
have an anatomically distinct duct, but discharge their secretions directly
into the digestive tube.

It will be convenient to consider, first of all, certain properties that are
common to the digestive glands, and then, the conditions under which
each gland functionates during digestion.

MICROSCOPIC CHANGES DURING ACTIVITY

Structurally the active part of the glands, represented by the acinus
or tubule, is composed of a basement membrane lined internally with the
secreting epithelium. Outside the basal membrane are the lymph spaces
and blood capillaries. After the gland has been at rest, the cells become

453

454

DIGESTION

filled with granules or small globules, which are often so numerous as
almost entirely to obliterate the nucleus. When the gland becomes active,
on the other hand, the granules or globules leave the cells, except for a
few which remain toward the lumen border. (Figs. 143 and 144.)

A.'

Fig. 143.— Cells of parotid gland s.hpwing zymogen granules: A, after prolonged rest; B, after a
moderate secretion; C, after prolonged secretion. (From Langley.)

These observations indicate that the granular or globular material must
represent part at least of the secretion of the glands. Sometimes, even
before they are extruded, the granules become changed into some differ-
ent material, as is indicated by the fact that they stain differently from

D.

Fig. 144. — Parotid gland of rabbit in varying states of activity examined in fresh state. The
upper left-hand acini are resting. The upper right-hand acini are from a gland stimulated to
activity by injecting pilocarpine, and the two lower acini from one after stimulation of its sym-
pathetic nerve. (After Langley.)

those of the resting gland. It must not be thought, however, that an
extrusion of granules necessarily accompanies secretory activity, for
under certain conditions a copious secretion of water and inorganic salts,
as well as a certain amount of organic material, may be produced with-

PHYSIOLOGY OF THE DIGESTIVE GLANDS 455

out any change in the arrangement of the granules. In such cases it has
been observed, as in the pancreas, that fine channels develop in the
protoplasm of the cell (see page 464).

From this histological evidence it would appear that the gland cell
during rest is endowed with the property of building up out of the pro-
toplasm, as granules or globules, the material which is to serve as one of
the main organic constituents of the secretion. It is commonly believed
that this is the precursor of the active ferment of the secretion ; hence its
name, zymogen. It has been shown that the process of separation of the
zymogen granules starts around the nucleus with the production of a
basophile substance, which in hardened specimens sometimes takes the
form of filaments. From this basophilic ergastoplasm, as it is called, the
granules are gradually formed,, and then for some time continue to
undergo slight further changes, as is evidenced by the fact that the
staining reaction of those near the base of the cells differs from that of
those at the free margin. When the gland cell is excited to secrete,
the granules before being extruded, as noted above, often undergo a
definite change, becoming swollen and more globular in shape.

MECHANISM OF SECRETION

These microscopic studies merely tell us that active changes, associated
with the production and liberation of certain of the constituents of its
secretion, are occurring in the gland cell, but they throw no light on the
mechanism whereby the gland cells secrete water and inorganic salts.
This may be dependent, to a certain extent at least, on differences in
osmotic pressure (see page 11). A possible explanation of the flow of
water is as follows: If a watery solution of some osmotically active sub-
stance is put in a tube, which is closed at one end by a membrane
impermeable to this substance and at the other by one permeable to it,
and the tube immersed in water, a continuous current will be
found to issue from the permeable end so long as there remains any
osmotically active substance in the tube. If we assume, then, that the
membranes at the two ends of the secreting cell are of such a nature that
the one next the basement membrane is impermeable to some osmotically
active substance manufactured by the cell, and the other toward the
lumen is permeable, it will be clear that, so long as this substance
exists in the cell, it will attract water from the blood, and the water
together with the osmotically active substance will be discharged into
the lumen.

It is possible that when anything excites the cell to secretory activity,
such as a nerve impulse or hormone, it does so by causing a change in

456 DIGESTION

the permeability of the lumen border of the cell. This change in permea-
bility may be dependent upon alterations in surface tension brought
about by the migration of electrolytes to the border. That such a migra-
tion of electrolytes does actually occur has been demonstrated by A. B.
Macallum0 who developed a microchemical test for potassium, by the use
of which he was able to show that this electrolyte accumulates at the lumen
border of the cell during secretory activity, that is, at the border of the
cell through which the secretion takes place. Potassium may be taken
as a prototype of electrolytes in general. In the epithelium of the small
intestine, where the current goes in the opposite direction to that in
gland cells, the accumulation of potassium occurs at the portion of the
cell next the basement membrane.

Other observers believe that, when the gland becomes more active, the
molecules present in the cell become broken down into smaller molecules
and so raise the osmotic pressure of the cell content, with the result that
water is attracted from the blood and is then transferred to the lumen.
When the gland is excited so that the zymogen granules, as well as
water and salts, are secreted, the primary change appears to involve the
granules only. Those near the lumen swell up by absorbing water, and
become converted into spheres in which salts are dissolved in smaller
proportions than exist in the lymph bathing the cells. These swollen
structures are then ruptured at the periphery of the cell and discharged
into the lumen. This discharge of a fluid containing fewer saline con-
stituents than the cell or surrounding blood plasma brings about in-
creased concentration in the remaining parts of the cell, a process which
possibly is assisted by a breaking up of molecules in the protoplasm itself,
and which causes an increase in osmotic pressure with a consequent
flow of water from the lymph to the cells and therefore from the blood
to the lymph.

OTHER CHANGES DURING ACTIVITY

Whatever may be the nature of the physiological changes that
are responsible for the secretory activity of the cell, the fact stands out
prominently that a considerable expenditure of energy is entailed. This
is indicated by the fact that considerably larger quantities of oxygen
are taken up by the gland when it is in an active state than when at
rest. Thus, the oxygen consumption of the resting submaxillary gland
of the cat may be increased five times during active secretion. On
account of this increased oxygen consumption it is not surprising that
it should be found that the secretory activity of the cell is greatly im-
paired by a deficiency in oxygen.

PHYSIOLOGY OF THE DIGESTIVE GLANDS 457

These active processes occurring in the gland when it is excited to
secrete are associated with changes in electric reaction and in the
volume of the gland. The electric changes have been most extensively
studied in connection with the salivary gland. Cannon and Cattel,7 by
connecting a galvanometer with nonpolarizable electrodes, one placed
on the gland and the other on neighboring connective tissue, were able
to show that with each period of active secretion a current of action was
set up. This was first discovered by Rose Bradford and Bayliss, and
has been carefully studied by Gesell.8 That the electric current is
definitely associated with the secretion of saliva and is not caused by
the vascular changes which usually accompany this act was shown by
its occurrence when the blood supply was shut off from the gland,
and by its absence when there was no secretion even though the vascular
changes were brought about; neither is the electric change due to the
movement of fluid along the duct, as evidenced by its persistence after
ligation of the duct.

With regard to change in volume, it might be expected, on account of
the greater vascularity of the gland accompanying activity, that this
would increase. On the contrary, however, it has been shown to de-
crease, because of the large quantity of fluid secreted from the gland cells.

The action of two drugs on the gland cells is of considerable physio-
logic importance: that of atropine, which paralyzes the secretion, and
that of pilocarpine, wrhich stimulates it. We shall see later how this
information may be used in working out the exact mechanism of the
different glands.

Important observations concerning the relationship of glandular activ-
ity to the 'blood supply have been made by experiments in which glands
were artificially perfused outside the body. When the submaxillary
gland of the dog is perfused with oxygenated Ringer's solution, stimula-
tion of its nerve supply does not produce the usual secretion, but if the
Ringer's solution is mixed with blood plasma, the nerve stimulation has its
usual effect for a short time. Although no secretion occurs when
oxygenated Ringer's solution is perfused alone, the usual vascular
changes still occur in the gland. The results seem to indicate that the
presence of some constituent of the blood plasma is essential for the
change in the permeability of the cell wall necessary for the process of
secretion. Similar results have been obtained during artificial perfusion
of the pancreas when secretin was used as the stimulus.

CONTROL OF GLANDULAR ACTIVITY

Having outlined the general nature of the changes occurring in gland
cells during their activity, we may now proceed to study the nature of

458 DIGESTION

the process by which this glandular activity is controlled. Two mechan-
isms of control are known: (1) by the nervous system, and (2) by means
of hormones.

Nervous Control. — Control through the nervous system is most marked
— indeed it may be the only means of control — in glands which have to
produce their secretion promptly, whereas hormone control pre-
dominates in those in which prompt changes in secretory activity are not
required. Thus, nervous control alone is present in the salivary glands,
whereas hormone control is predominant in the pancreas, intestinal
glands and liver. The gastric glands are partly under nervous control,
and partly under hormone control. It should be pointed out here that
the glands of the body other than the digestive glands are also subject to
nervous or hormone control according to the promptness with which they
are required to secrete. The lachrymal and sweat glands, and the venom
glands of reptiles, for example, are practically entirely under -nervous
control, whereas most of the ductless glands, with the exception of the
adrenals, are mainly under the influence of hormones.

The exact nature of the nervous control of glandular function has,
therefore, been most extensively studied in the salivary glands, and that
of the hormonic in the pancreas. With regard to the salivary glands,
the following points are of importance: Their nerve supply comes from
two sources : the bulbar autonomic, and the sympathetic autonomic
(see page 893). These two nerve supplies have usually an opposite influ-
ence on the secretory activity of the glands, and very frequently also on
the vascular changes that accompany secretory activity.

.On account of its ready accessibility, the submaxillary gland in the
dog and cat has been most thoroughly investigated. The cerebral auto-
nomic nerve in this case is represented by the chorda tympani, and the
sympathetic autonomic by postganglionic fibers that run from the
superior cervical ganglion to the gland along its blood vessels (Fig. 145).
After tying a cannula into the duct of the gland, it will be found in the
dog that stimulation of the chorda tympani produces an immediate and
abundant secretion of thin watery saliva accompanied by a marked
dilatation of the blood vessels of the gland.

That this secretion is not dependent on the vasodilatation is easily
shown by repeating the experiment after administering a sufficient dose
of atropine to paralyze the secreting cells. Stimulation of the nerve then
produces a vasodilatation but no secretion. The same conclusion is
arrived at by an experiment of an entirely different nature ; namely, by
observing the pressure produced in the duct when the chorda tympani is
stimulated. This pressure rises considerably above that in the arteries,
so that no such physical process as mere filtration can be held accountable

m a ^BK T*»

:^S 3&''.- Center for ••ii^
cenfer for^fH. '^^/Masodilator nerj^T
cran/j/ i^cr^^^ft^^^^j^^^^gflc ganglion

i^V-T

Facial nerve

Cerebellum,

Clossopharynqea

(N.IK) €

Medulla oblong ata^

Parotid gland

/?orc/a tympani nerve^
mall superficial
petrosal nerve-
Inf. max. dlv. N.V ^ (Sten son's)

Submaxillary
duct(Wharton's)

ducf

Efpra (Bartholin's)
Lingual nerve

Electrodes

(Small amount of thkk saliva
vaso-constnction

fil/eck

ChordO'lingual

triangle

Electrodes
( Large amount of thin

vaso-dilatation
Sub lingual gland

constrictor fibers
sympathetic secretory fibers

Outgoing sympathetic
rami communicantes

Post ganglionic fibers are
dotted thus — •

?. 145. — Diagrammatic representation of the innervation of the salivary glands in the dog. (From

Jackson.)

PHYSIOLOGY OF THE DIGESTIVE GLANDS 459

for the secretion, and therefore vasodilatation alone can not be respon-
sible for it. If the sympathetic nerve supply is stimulated, a very scanty,
thick secretion takes place accompanied by vasoconstriction.

Eepetition of these experiments in the cat yields different results,
particularly with regard to the influence of the sympathetic, a copious
secretion being produced by stimulation of this nerve. The histological
changes produced in the gland cells are marked after sympathetic stimula-
tion, but very slight, if present at all, after chorda stimulation.

The outstanding conclusion which may be drawn from these results
is that two kinds of secretory activity are mediated through the nerves;
one causing a thin watery secretion, containing only a small percentage
of organic matter, and the other, a thick viscid secretion with a large
amount of organic material. To explain these differences the hypothe-
sis has been advanced that , there are really two kinds of secretory
fibers, called secretory and trophic, the former having to do with the
secretion of water and inorganic salts, and the latter with the secretion
of organic matter ; i. e., with the extrusion of the zymogen granules.
Certain authors (Langley) believe that such an hypothesis is unneces-
sary, and that the different results are dependent upon the concomitant
changes in the blood supply produced by stimulating one or other nerve.

That there are really different kinds of true secretory fibers is, however,
evident from the following experiment. If the duct of the gland is
made to open on the surface of the cheek, secretion of saliva through
the fistula can be induced by placing various substances in the mouth, such
as meat powder or weak solutions of acid. When the experiment is per-
formed in such a way that the bloodflow through the gland can be observed,
it has been found that the saliva produced by the stimulation with the meat
powder contains a very much higher percentage of organic material than
that produced when hydrochloric acid is the stimulant, whereas the vascular
changes in the gland and the inorganic constituents of the saliva are the
same in both cases. Since stimulation of the chorda tympani causes the
secretion of a watery saliva, while that caused by stimulation of the
sympathetic is thick, it might be thought that the secretory fibers are
contained in the former and the trophic fibers in the latter nerve; that
this is not the case can be shown by a repetition of the above experiment
in animals from which the superior cervical ganglion has been removed.
The same results are obtained, indicating that the chorda tympani con-
tains both secretory and trophic fibers.

CHAPTER LI
PHYSIOLOGY OF THE DIGESTIVE GLANDS (Cont'd)

THE HORMONE CONTROL

Hormone control is exhibited best in the case of the pancreas. The crucial
experiment demonstrating that this gland is not primarily dependent upon
nervous impulses for the control of its activity was performed by Bay-
liss and Starling.2 Starting with the well-known fact that the application
of weak acid to the duodenal mucous membrane excites secretion of pan-
creatic juice, these workers carefully severed all the nerve connections of
a portion of the duodenum, and found on again applying acid to the mucous
membrane that the secretion persisted. To explain this result they postu-
lated that the acid must cause some substance to be liberated into the
blood stream, which carries it to the pancreas, the cells of which it then
excites to activity. To test this hypothesis they scraped off the mucous
membrane of the duodenum and ground it in a mortar with weak hydro-
chloric acid (0.6 per cent), and, after boiling the solution so as to coagulate
the protein, nearly neutralizing and filtering, they obtained a fluid which
immediately caused a copious secretion of pancreatic juice when injected
intravenously.

Accompanying the secretion, however, a marked fall in arterial blood
pressure was observed, making it possible that the secretion might have
been due to a vasodilatation occurring in the pancreatic blood vessels. To
eliminate this possibility they prepared an extract that was free of the
depressor substances by extracting intestinal epithelium without any of the
submucous tissue. The resulting extract had merely the secretory effect
and produced no fall in blood pressure. This secretagoguary substance
they named secretin.

Further evidence that the action of secretin is independent of the
depressor substances has been obtained by taking advantage of the fact
that the depressor substance is more soluble in alcohol than the secretin.
If an acid decoction of duodenal mucous membrane is poured into abso-
lute alcohol, a precipitate is formed. If this precipitate is redissolved
in water and reprecipitated several times by absolute alcohol, then after
drying, a white powder is obtained, which is easily soluble in water The
resulting solution injected intravenously has a powerful secretory action,
but produces no effect on blood pressure. The concentrated alcoholic

460

PHYSIOLOGY OF THE DIGESTIVE GLANDS 461

liquor, on the other hand, when similarly injected produces a marked fall in
blood pressure. It is believed that this effect is due to the action of histamine
(/Mmidazolylethylamine). A very strong preparation of secretin can also
be prepared by the method of Dale and Laidlaw, which depends on pre-
cipitation by mercuric chloride.9

Secretin does not exist preformed in the epithelial cells, as is shown by
the fact that an extract, made with neutral saline solution, does not as a
rule, have any secretory action when injected intravenously. Sometimes
a slight secretion may be produced, but this is probably to be explained
by the fact that some secretin remains behind in the cells as a result of a
preceding phase of activity. If, on the other hand, the above neutral or
slightly alkaline opalescent solution of the mucous membrane is boiled
with acid, secretin may become developed in it. The interpretation put
upon these results is that a substance, called prosecretin, exists in the
epithelial cells, and that this becomes converted into secretin by the action
of acid on the cells. The secretin thus produced is then taken up by the
blood, none of it passing into the intestinal canal, because the free borders
of the cells are impervious to secretin. That this is actually the case has
been shown by finding that the introduction of neutralized secretin solu-
tion into the duodenum, or other parts of the small intestine, does not
cause a secretion of piancreatic juice.

We know practically nothing concerning the chemical nature of secretin.
Being soluble in about 90 per cent alcohol and in fairly weak acids, it can
not belong to any of the better known groups of proteins. As it is
readily diffusible through parchment membrane, it can not be of very
complex structure, and as it withstands heat, it can not be an enzyme.
It rapidly deteriorates in strength in the presence of alkalies.

Any acid when applied to the mucous membrane is capable of producing
secretin, and so are certain other substances, such as mustard oil. Watery
solutions of saccharose or urea, when rubbed up with the duodenal mucosa
in a mortar, produce secretin solutions of varying activity, but they do
not in the living animal excite pancreatic secretion when applied to the
.duodenum. Secretin is very susceptible to destruction by such digestive
enzymes as those present in the pancreatic, gastric, and intestinal juices.
That secretin is present in the blood when acid is in contact with the
duodenal mucosa has been shown by the fact that injection into a normal
dog of blood from one in which secretin formation is going on (as a
result of acid in the duodenum), excites pancreatic secretion.

The pancreatic juice produced by the injection of secretin, like that
which is produced under normal conditions, does not contain any active
trypsin, but instead contains its precursor, trypsinogen. This becomes
converted into trypsin in the intestine, being activated by contact with

462

DIGESTION

enterokinase, an enzyme present in the intestinal juice. By such a mechan-
ism the mucosa of the pancreatic duct is protected against autodigestion
by trypsin.

NERVOUS CONTROL OF PANCREAS

Prior to the discovery of secretin, Pavlov1 and his pupils had published
numerous experiments purporting to show that the secretion of pancreatic

Fig. 146. — Pancreatic acini stained with hematoxylin. The acini at the top and to the left
of the figure are from a resting gland, those to the right being from one that had been secreting
for over three hours as a result of acid in the duodenum. The lowermost figure is from a gland
the vagus nerve supply of which had been stimulated off and on for several hours. Note that
the zymogen granules are extruded only after vagus activity but not after secretin activity. (From
Babkin, Rubaschkin and Ssawitsch.)

juice is controlled through the vagus nerve. The amount of secretion
produced by nervous stimulation was, however, never found to be so large
as that produced by secretin, and for several years after the discovery of

PHYSIOLOGY OF THE DIGESTIVE GLANDS

463

the latter hormone, much doubt existed as to the correctness of Pavlov's
claim. As in many other fields of physiological science, investigators at-
tempted to show that one or the other mechanism obtained, and they were
not inclined to consider the possibility that both mechanisms might exist
side by side. That such is the case, however, is clear from the most recent
work, in which it has been found that if proper precautions are taken,
repeated stimulation of the vagus nerve does call forth a secretion of
pancreatic juice which, besides being less copious than that following

II. III.

Fig. 147. — Three preparations of pancreatic acini stained by eosin orange toluidin blue. The
acini of Fig. I were from a gland after vagus stimulation, and it is noted that besides free ex-
trusion of the granules, globules staining with orange (and appearing in deep black in the photo-
graph) have formed and may be present in the ductules. Some of the globules, however, change
in their staining properties, becoming light red (dark gray in photograph). The acini in II and III
were from glands excited by secretin. No globules appear; the granules remain, and fine canaliculi
appear in the clear protoplasm. (From Babkin, Rubaschkin and Ssawitsch.)

secretin injection, differs from it in the important fact that it contains
not trypsinogen but active trypsin. Since the normal pancreatic juice
contains trypsinogen, this last mentioned fact would appear to indicate
that vagus control of the normal secretion can not be an important affair.
The vagus secretion of pancreatic juice is, moreover, paralyzed by atro-
pine, which has no action on the secretin mechanism (cf. Bayliss).

464 DIGESTION

The copious secretion of pancreatic juice produced by secretin, -on the
one hand, and the scanty, thick secretion produced by vagus stimula-
tion, on the other, calls to mind similar differences observed in the secre-
tion of saliva as the result of chorda-tympani or sympathetic stimulation.
It will be remembered that from these latter results it was concluded
that there must be secretory and trophic fibers concerned in the control
of the activities of gland cells. Interesting corroboration of this conclusion
has recently been obtained \>y Jiistological examination of the pancreas fol-
lowing secretin or vagus activity. After the repeated injection of secre-
tin, it is difficult to observe any signs of fatigue in the cells ; the zymogen
granules remain practically as numerous as in a resting gland, but in the
clear protoplasm of the outer third of the cell, it is said that fine channels
of fluid can be seen. Through these channels water is believed to pass
from the blood towards the lumen and in its course to carry with it some
of the zymogen granules, without, however, changing them. Thus, when
the gland cells are stained with eosin and orange, after secretin activity
some of the zymogen granules can occasionally be seen! in the lumen of
the acini stained with eosin like those in the cell itself. After vagus
stimulation the appearances are different ; not only are the granules more
freely extruded from the cells, but they undergo a preliminary change;
they lose the property of staining with eosin and become stained with
orange, at the same time increasing in size so as to form vacuoles.
These vacuoles may wander into the ductules, and when they are present
here they are stained by orange (Figs. 146 and 147) (Babkin, etc.10).

Why there should be both a nervous and a hormone control of the pan-
creatic secretion is not clear. This gland, unlike the gastric and salivary
glands, is not called upon to become active all of a sudden, and it is dif-
ficult to see what could serve as the normal stimulus operating through
the nervous pathway. Taking it all in all, it is probably safe to con-
clude that the nervous mechanism is relatively unimportant, and that
under normal conditions it seldom if ever is called into operation. Cor-
roboration for this view is afforded by the fact, above mentioned, that
the pancreatic juice produced by vagus stimulation contains active tryp-
sin, which is not the case with normal pancreatic juice.

CHAPTER LTI

PHYSIOLOGY OF THE DIGESTIVE GLANDS (Cont'd)

Up to the present we have been concerned with the physiological activi-
ties of digestive glands in general, but now we must study each of them
separately in order to find out the conditions under which they become
stimulated to activity in the normal process of digestion. The secretion
of each gland has a definite role assigned to it in the complex and lengthy
process of digestion. It takes up its work where the preceding secre-
tion left off; e.g., the pepsin of gastric juice digests protein so far as
proteoses and peptone; the trypsin of pancreatic juice then attacks the
proteoses and peptone, and the resulting lower degradation products
are finally attacked by the erepsin of the intestinal juice. The secre-
tions of the various glands are, therefore, required in a certain definite
order — they are correlated; and we must now give some attention to the
precise conditions upon which the activity and correlation depend.

THE NORMAL CONDITIONS UNDER WHICH THE GLANDS
BECOME STIMULATED TO INCREASED ACTIVITY

To make possible such observations on the normal activities of the
glands, a preliminary operation has to be performed so as to bring the
duct of the gland to the surface of the body and permit of the observa-
tion of its secretory activity after the animal has recovered from the
immediate effects of the operation. We owe to Pavlov1 the surgical
technic by which these conditions can be fulfilled. The general principle
of the operation, in the case of glands provided with ducts, consists in
making a circular cut through the mucous membrane surrounding the
opening of the duct and then, after dissecting the duct free, stitching
the edges of the cut to the skin wound. Healing then takes place without
the formation in the duct of any stricture due to cicatricial tissue. After
the wound has healed, the secretion can readily be collected in a receiver
attached over the duct fistula, the animal being in every other way in a
perfectly normal condition. In the case of glands not provided with a
duct, other methods must be adopted to collect the . secretions. These
will be described elsewhere.

465

466 DIGESTION

THE NORMAL SECRETION OF SALIVA

The duct fistula can in this case be made either for the submaxillary
gland, representing a mucous gland, or for the parotid, representing a
serous gland. Under ordinary conditions there is very little secretion
from either duct. When secretion occurs, it is, of course, caused by
influences acting on a nerve center or centers in the medulla oblongata,
the exact location of which for the different glands has been worked out
in recent years by Miller.11 The impulses acting on these centers may be
transmitted along afferent nerves coming from the mucous membrane of
the mouth, nares, etc., or by impulses which we may call psychic, trans-
mitted from the higher nerve centers. The reflex secretions caused by
impulses traveling by the afferent nerve from the mouth, etc., have been
called unconditioned, and those from the higher nerve centers, condi-
tioned. With regard to the former, there is considerable discrimination
in the type of stimulus that will be effective. Thus, if the dog — for most
of the experiments have been performed on this animal — is given meat,
a secretion of thick, mucous saliva will be observed to occur (submaxil-
lary gland). On the other hand, if the meat is dried and pulverized,
the secretion which it calls forth will be very copious and watery (par-
otid gland). There is, then, an obvious association between the nature
of the secretion and the function it will be called upon to perform when
it becomes mixed with the food. The mucous secretion called forth by
meat will serve to lubricate the bolus of food and thus facilitate its
swallowing, whereas the thin watery secretion produced by the dry
powder will have the effect of washing the powder from the mouth.

It is evident that the mechanical condition of the food partly deter-
mines its exciting quality. Mechanical stimulation of the mucosa in it-
self is, however, not an adequate stimulus, for if pebbles are placed in
the mouth, . little secretion occurs, whereas with sand, secretion immedi-
ately becomes copious. The nerve endings also respond to chemical stimuli.
Thus, weak acid causes a copious secretion, while alkali has no effect;
disagreeable, nauseous substances also excite secretion. The above dif-
ferences in the response of the glands according to the mechanical condi-
tion of the food has been observed in the case of the parotid gland,
increase in the submaxillary secretion being obtained only when actual
foodstuffs are placed in the mouth.

The investigations that have been made on the conditions of psychic
secretion of saliva are still more interesting and important. Their im-
portance depends not so much on the information they give us concern-
ing the secretion of saliva as such, as on the methods they afford us for
investigating the various conditions that affect the psychic processes

PHYSIOLOGY OF THE DIGESTIVE GLANDS 467

associated with the taking of food. It is from the psychic rather than
from the physiologic standpoint, therefore, that these observations are
of importance, for they permit us, by objective methods, to study on
dumb animals problems that would otherwise be beyond our powers of
investigation. Many of the results, with their bearing on the functions
of the higher nerve centers, have been discussed elsewhere (Chapt. CII).
Meanwhile, however, even at the risk of repetition it may not be out of
place to cite a few of the most interesting experiments.

If we tease a hungry animal with food for which he has a great appe-
tite, a copious secretion of saliva immediately occurs. If we go on teas-
ing him without giving him food, and repeat this procedure on several
succeeding days, it will be found that gradually he no longer responds
to the teasing by increased salivation. Evidently, therefore, the reflex
is conditioned upon the animal's afterward receiving the food.

The experiment may be performed in another way. If, for example,
we offer the animal some food for wrhich he has no appetite, no secre-
tion of saliva will occur; but, if at the end of the process we give him
appetizing food, it will be found after repeating this procedure on
several successive days that the presentation of the unappetizing food
calls forth a secretion. He has learned to associate the presentation of
unappetizing food with the subsequent gratification of his appetite. The
experiment can even be performed so that a definite interval of time
elapses between the application of the stimulus and the salivation: if
the animal is teased on successive days with food for which he has an
appetite but is not given the food until after ten or twenty minutes,
presentation of this food will come to be followed by salivation — not
immediately, but after the exact interval of time that had been allowed
to intervene in the training process. During this interval there must be
an inhibition of psychic stimulation of the salivary centers by other nerve
centers. It is of great interest that this inhibition may itself be inhib-
ited by various forms of stimulation of the nervous system (see page 957).

THE SECRETION OF GASTRIC JUICE

Methods of Investigation

There being no common duct, the secretion of the gastric glands is a much more
difficult problem to investigate than is that of glands which, like the salivary, are
supplied with ducts. One of the most interesting chapters in the history of physiology
concerns the methods which from time to time have been evolved for the collection of
this juice and for studying the digestive processes in the stomach. Prominent among
the problems confronting the earlier investigators was the question whether the main
function of the stomach is to crush or triturate the food or to act on it chemically.
The great French scientist Reaumur and a little later the Italian Abbe Spallanzani

468 DIGESTION

(1729-1799) attacked this problem by methods that anticipated those of Eehfuss and
Einhorn. Spallanzani ultimately devised the method of swallowing small perforated
wooden tubes containing foodstuffs and covered by small linen bags. After the bags
were passed per rectum, he found that considerable erosion or digestion of the food
had occurred, but that the wooden tubes, however thin-walled they might be, were
not crushed. In order to secure samples of the gastric juice free from food, the
only method available to the older investigators consisted in swallowing sponges at-
tached to threads, which, after being for some time in the stomach were withdrawn
and squeezed dry of juice.

The next great contribution came from this country, where, in 1833, Dr. Beaumontf,
while a surgeon in the service of the American troops located at Mackinaw, made ob-
servations on a Canadian voyageur by the name of Alexis St. Martin, who by the
premature discharge of his gun had wounded himself in the stomach, the wound never
healing but leaving a permanent gastric fistula. Beaumont arranged to keep Alexis St.
Martin in his service for several years, during which time he made numerous observa-

Fig. 148. — Diagram of stomach showing miniature stomach (5) separated from the main stomach
(V) by a double layer of mucous membrane. A. A., is the opening of the pouch on the abdominal
wall. (Pavlov.)

tions on the process of digestion in the stomach — observations many of which are of
great value even at the present day.

By none of these methods, however, could a sample of pure gastric juice be secured
while the digestive process was actually in progress. To make the collection of such a
sample possible, Heidenhain devised a method of isolating portions of the stomach wall
as pouches opening through fistulse on the abdominal wall. The results of Heidenhain 's
experiments are, however, open to the objection that the secretion in the isolated
pouches may not really correspond to that occurring in the main stomach, since the
connections of the pouches with the central nervous system must have been severed.
In order that these connections might remain as nearly intact as possible, the Russian
physiologist, Pavlov,i devised an ingenious operation in which the pouch, or "minia-
ture stomach, ' ' remains connected with the main stomach through a considerable width
of mucous and submucous tissue and in which the nervous connections are not severed.
The essential nature of this operation will be evident from the accompanying diagram.
(Fig. 148.)

PHYSIOLOGY OF THE DIGESTIVE GLANDS 469

The most recent investigations have been made by Cannons and by Carlson.* The
former fed animals food impregnated with bismuth subnitrate, and then exposed the
animal to the x-rays. A shadow is produced by the food mass in the stomach, and
from the changes in the outline of this shadow facts have been collected, not only
concerning the movements of the viscus, but also concerning the rate of discharge of
food into the intestine and therefore the duration of the gastric digestive process.
Carlson's contribution has been rendered possible by his good fortune in having in
his service a second Alexis St. Martin, a man with complete closure of the esophagus
and a gastric fistula large enough to permit of direct inspection of the interior of
the stomach. Seizing the opportunity thus presented, Carlson during the last four
or five years has devoted his attention exclusively to a thorough investigation, not
only of the movements of the stomach, but also of the rate of secretion of the gastric
juice under different conditions. He has also, with praiseworthy enthusiasm and .keen
scientific spirit, extended his observations both on laboratory animals and on himself
and his coworkers, so as not to incur the error, which is all to frequently made of
confining the observations to one species of animal.

The Nervous Element in Gastric Secretion

The first stimulus, to the secretion of gastric juice is nervous in origin,
and is dependent on the gratification of the appetite and the pleasure of
taking food. This fact, after having been suggested by observations
made in the clinic, was first thoroughly investigated by Pavlov, who for
this purpose observed the gastric secretion flowing either from a fistula
of the stomach itself, or from a i{ miniature stomach," in dogs in which
also an esophageal fistula had been established. When food was given
by mouth to these animals, it was chewed and swallowed in the usual
manner, but before reaching the stomach, it escaped through the esopha-
geal fistula. This experiment is known as that of "sham feeding."
Within a few minutes after giving food the gastric juice 'was found to
be secreted actively, and if the feeding process was kept up, which could
be done almost indefinitely since the animal never became satisfied, the
secretion continued to flow. Thus, in one instance Pavlov succeeded in
collecting about 700 c.c. of gastric juice after sham feeding an animal
for five or six hours in the manner above described.

After the stomach has emptied itself of the food taken with the pre-
vious meal, it is said by Pavlov to contain only a little alkaline mucus.
The more recent work of Carlson, however, shows that this is not strictly
the case, there being more or less of a continuous secretion of gastric juice
in the entire absence of food. The amount varies from a few c.c. up to
60 c.c. per hour, more secretion being produced when it is collected every
five or ten minutes than if it is collected every thirty or sixty, thus
indicating that, ordinarily, some escapes through the pylorus into the
duodenum. The secretion contains both pepsin and hydrochloric acid.
As to the cause of this continuous secretion, little is known. It may be
an example of the periodic activities of the digestive glands described by

470 DIGESTION

Boldyreff, or it may in part be due to a psychic stimulation dependent
upon the thought of food. That the latter is probably not the cause, is
indicated by the fact that, at least in Carlson's patient, the psychic juice
could not be made to flow short of giving food.

The sham feeding causes stimulation of the gastric secretion through
impulses transmitted to the stomach along the vagus nerves; for it has
been found, in animals in which the vagus nerve has been cut, that the
sham feeding no longer induces a secretion of gastric juice. The ques-
tion therefore arises as to how the nerve center is stimulated. Three
possible causes may be considered: (1) mechanical stimulation of the
sensory nerves of the mouth; (2) chemical stimulation of these nerves;
(3) the agreeable stimulation of the taste buds and olfactory endings
concerned in the tasting of food. In investigating these possibilities,
mechanical stimulation was readily ruled out by showing that mere
taking of solid matter in the mouth did not excite any secretion, although
it might cause a flow of saliva. Mere chemical stimulation could not be
the cause, for no secretion was induced by placing substances such as
acetic acid or mustard oil in the mouth. By exclusion, then, it would
appear that the adequate stimulus must consist in the agreeable stimula-
tion of the taste buds, etc. — that is to say, in the gratification of appetite.

Further justification for this conclusion was readily secured by noting
that foodstuffs for which the animal had no particular desire or appe-
tite failed to excite the secretion. Most dogs, for example, although
they may take it, are not particularly fond of bread, and when fed with
it, these animals did not produce any appetite juice. In one animal that
showed considerable liking for bread, active secretion occurred when he
was fed with this foodstuff.

Pavlov further noted that usually it was not necessary actually to
allow the animal to take the food into his mouth, but that mere teasing
with savory food was sufficient to cause the secretion, and that in
highly sensitive animals even the noises and other events usually asso-
ciated with feeding time were sufficient to excite the secretion. In the
case of a hungry animal, the mere approach of the attendant with food,
or some other noise or action definitely associated with feeding time,
was a sufficient excitant. The appetite juice when started was found
to persist for some time after the stimulus causing it had been removed.

Carlson has succeeded in confirming in man most of these observa-
tions. He noted, however, that the secretion produced by seeing or
smelling or thinking of food is much less than would be expected from
Pavlov's observations on dogs. Even when his subject was hungry,
Carlson did not observe that the bringing of a tray of savory food into
t'he room caused any secretion of gastric juice. It is, of course, to be

PHYSIOLOGY OF THE DIGESTIVE GLANDS

471

expected that the quantity of the psychic secretion will not be the same
in different individuals. It has been observed by Pavlov, for example,
to vary considerably in the case of dogs, and it is very likely that it will
vary still more in man, with his more highly complicated nervous system.
In no case could Carlson observe any secretion of gastric juice to be pro-
duced by having his patient chew on indifferent substances, or by stim-
ulating the nerve endings in the mouth by substances other than those
directly related to food.

In man the rate of secretion is proportional to the palatability of the
food, the smallest amount, during twenty minutes' mastication of pal-
atable food, being 30 c.c. and the largest 150 c.c., in a series of 156 obser-
vations. A typical curve showing the amount of the secretion is given
in Fig. 149. To construct this curve the gastric juice was collected dur-

10 15 20' 25' 30' 35 40' 45 50* 55

Chewing food

Fig. 149. — Typical curve of secretion of gastric juice collected at 5-minute intervals on mas-
tication of palatable food for 20 minutes. The rise in secretion during the last 5 minutes of
mastication is due to chewing the dessert (fruit) for which the person had great relish. (From
Carlson.)

ing five-minute intervals while the man was chewing a meal of average
composition and of his own choice. An interesting feature depicted on
this curve is that the secretion rate was highest in the last five-minute
period, this being the time during which the dessert was being taken,
for which this man had a great relish. Quite clearly there was a direct
relation between the rate of the secretion of the appetite juice and the
palatability of the food. It will further be observed that it took only
from fifteen to twenty minutes after discontinuing the chewing before
the juice returned to its original level.

The practical application of these facts in connection with the hygiene
of diet and the feeding of patients during convalescence, is obviously
very great. However perfect in other regards a diet may be, it will
probably fail to be digested at the proper rate unless it is taken with
relish. Frequent feeding with favorite morsels is more likely to be fol-

472 DIGESTION

lowed by thorough digestion and assimilation than occasional stuffing
with larger amounts. We see too in these experiments an explanation
of the well-established practice of starting a meal with something
savory. A hors d'oeuvre is nothing more than a physiological stimulant
to appetite. It is also interesting from a practical standpoint to observe
that with those who have a keen relish for sweetmeats the taking of des-
sert has a real physiological significance, for, as in Carlson's patient, it
stimulates toward the end of a meal a further secretion of the gastric
juice, and thus insures a more rapid digestion of the food. Good cooking,
it should be remembered, is really the first stage in digestion, and it is
the only stage over which we can exercise voluntary control.

The Hormone Element in Gastric Secretion

Although gastric digestion is initiated by the appetite juice, it is
clear that this alone can not account for all the secretion that occurs
during the time the food is in the stomach. After an ordinary meal this
occupies usually about four hours, whereas we have seen, particularly
from Carlson's observations, that the appetite juice lasts only for some
fifteen or twenty minutes after the exciting stimulus has been removed.
The appetite juice, in other words, serves only to initiate the process of
secretion, and the question arises, What keeps up the secretion during
the rest of gastric digestion? The answer was furnished by Pavlov, who
observed animals in which not only a miniature stomach had been made,
but a fistula into the main stomach as well. The behavior of the secre-
tion of gastric juice as a whole could be followed by collecting that
which was secreted in the miniature stomach, for it was shown, in con-
trol experiments, that this secretion runs strictly parallel with that in
the main stomach, being quantitatively a definite fraction of it — accord-
ing to the relative size of the miniature stomach — and qualitatively
identical. The miniature stomach, in other words, mirrors the events
of secretion in the main stomach.

It was observed that when the animal was allowed to take the food
into the main stomach by the mouth and esophagus, the secretion from
the miniature stomach continued to flow until the process of gastric
digestion had been completed, a result which was quite different from
that obtained after sham feeding. The only possible explanation for this
result is that the food in the stomach sets up secretion as a result of
local stimulation. To investigate the nature of this local stimulation,
whether mechanical or chemical, food and other substances were placed
in the main stomach through the gastric fistula without the animal's
knowledge so as to avoid possible psychic stimulation, and the secretion
observed from the miniature stomach. When the mucous membrane of

PHYSIOLOGY OF THE DIGESTIVE GLANDS 473

the main stomach was stimulated mechanically, as by placing inert
objects such as a piece of sponge or sand in the stomach, no secretion
occurred. Evidently, therefore, the stimulus is dependent upon some
chemical quality of the food.

By introducing various foods it was found that there is considerable
difference in the degree to which they can excite the secretion. Water,
egg white, bread and starch, were all found to have very little if any
effect. On the other hand, when protein that had been partly digested
by means of pepsin and hydrochloric acid was introduced into the
stomach, it immediately called forth a secretion. The conclusion is that
the partly digested products, even of insipid food, are capable of directly
exciting the secretion. These include proteoses and peptones, and it
was, therefore, of great interest to find that a solution of commercial
peptone is also an effective stimulus. This is a result of deep significance,
for it indicates that the food which has been partially digested by the
appetite juice will serve as a stimulus to continued secretion.

The psychic juice has been aptly called the "ignition juice, " because
by producing partial digestion it serves to ignite the process of gastric
secretion. Experimental evidence of its great importance in gastric
digestion was secured by Pavlov in experiments in which he placed
weighed quantities of meat attached to threads in the stomach through
a gastric fistula, and after some time removed them and determined by
the difference in weights the extent to which they had become digested.
It was found that when the appetite juice was excited by sham feeding
at the same time that food was placed directly in the stomach, its diges-
tion was much more rapid than in cases in which it was placed in the
stomach without the animal's knowledge, as when he was asleep.

Other foods having a direct stimulating effect on the gastric secre-
tion are meat extracts and, to a certain extent, milk. This effect of meat
extract is interesting in connection with the practice of taking soup as
a first or early stage in dining. It not only excites the appetite juice,
but also serves as a direct stimulus to the gastric secretion.

As to the nature of the mechanism by which this direct secretion takes
place, it was shown by Popielski12 that the secretion still occurs after all
the nerves proceeding to the stomach are cut. Evidently, therefore, it
is independent of the extrinsic nerve supply of the viscus. As a result
of his experiments Popielski concluded that the secretion must depend
on a local reflex mediated through the nerve structures present in the
walls of the stomach itself. Another explanation of the result has,
however, in recent years been given more credence by the experiments of
Bayliss and Starling on the influence of hormones on the secretion of
pancreatic juice (cf. page 460). Eclkins1" suggested that a similar

474 DIGESTION

process in the stomach might account for the continued secretion of
gastric juice. To test such a possibility this investigator, after ligating the
cardiac sphincter in anesthetized animals, inserted a tube into the
pyloric end of the stomach, through which he placed in the stomach
about 50 c.c. of physiological saline. After this had been in the stomach
for an hour, he found that no water was absorbed, and that it contained
neither hydrochloric acid nor pepsin. On the other hand, if during the
time the saline was in the stomach a decoction of the mucous membrane of
the pyloric end, made either with peptone solution or with a solution of
dextrine, was injected intravenously. in small quantities every few min-
utes, the saline contained distinct quantities of hydrochloric acid and pep-
sin. Furthermore, it was found that, if the peptone solution or the dextrine
solution alone was injected intravenously, there was no such evidence
of gastric secretion. The conclusion which Edkins drew from his experi-
ments is to the effect that the half-digested products of the earlier stages
of gastric digestion act on the mucous membrane of the stomach so as to
produce a hormone, which is then carried by the blood to the cells of
the gastric glands, upon which, like secretin, it directly develops an
exciting effect. This hormone has been called gastrin. These observa-
tions of Edkins have been confirmed, and they explain very simply how
gastric secretion is maintained after the cessation of the secretion of the
appetite juice. By such a mechanism gastric juice would continue to be
secreted so long as any half-digested food remains in the stomach.

The action of gastrin is the first instance of a hormone control of the
digestive glands. In the earlier stages of digestion, the secretion of saliva
and appetite juice is mediated through the nervous system, because these
juices must be produced promptly. In the later stages of gastric diges-
tion, such promptitude in response on the part of the gland is no longer
necessary, so that the slower, more continuous process of hormone con-
trol is sufficient.

Quantity of Gastric Juice Secreted

According to Carlson, the total amount of gastric juice secreted in
man on an average meal composed of meat, bread, vegetables, coffee or
milk, and dessert, amounts to about 700 c.c., being divided into 200 c.c.
in the first hour, 150 in the second, and 350 c.c. during the third, fourth
and fifth hours. These figures were estimated partly on the basis of
observations made on the man with the gastric fistula, and partly from
the data supplied by Pavlov's observations on dogs. Carlson believes
that Pavlov overestimated the relative/ importance of the appetite juice
in gastric digestion. He found, for example, that after division of both
vagus nerves in dogs normal gastric digestion might be regained a few

PHYSIOLOGY OF THE DIGESTIVE GLANDS

475

days after the operation, although, of course, under such circumstances no
appetite juice could have been secreted. Moreover, he observed that cats
when forcibly fed with unpalatable food may digest that food as rapidly
as when they eat voluntarily. In support of his contention, Carlson
states that he has frequently removed, all of the appetite juice from his
patient's stomach before the masticated meal was put into it without
any evident interference with the digestive process.

Fat has a distinct inhibiting influence on the direct secretion of gas-
tric juice; cream takes considerably longer to be be digested than milk,

14 < * ~ .9 1 ?* 1 4 S 6 7 S fi 101 23456

Flesh, 200 gin. Bread, 200 gm. Milk, 600 c.c.

Fig. 150. — Cubic centimeters of gastric juice secreted after diets of meat, bread, and milk. (From

Pavlov.)

Hours 12345

10.0

78234 56789234-56

8,0

QC

II

o o

r

-05

0

-10

O

Flesh, 200 gm.

Bread, 200 gm.

Milk, 600 c.c.

Fig. 151. — Digestive power of the juice,' as measured by the length of the protein column digested
in Mett's tubes, with diets of flesh, bread, and milk. (From Pavlov.)

and the presence of oil in the stomach delays the secretion of juice poured
out on a subsequent meal of otherwise readily digestible food. By col-
lecting all of the gastric juice from the miniature stomach after feeding
by mouth with quantities of different protein-rich foods containing the
same quantities of nitrogen, interesting observations have been recorded
concerning the amount of juice secreted and its proteolytic power. The
results of some of the experiments are shown in the accompanying
curves (Figs. 150 and 151).

476 DIGESTION

It will be seen that the most abundant secretion occurs with meat, that
of milk being not only smaller but also slower in starting. The digestive
power is greatest in the case of bread.

THE INTESTINAL SECRETIONS

Pancreatic Juice

Regarding the natural secretion of pancreatic juice, little need be added
to what has already been said (see page 460) . The secretion begins when the
chyme enters the duodenum, and attains its maximum when the outflow
of this is greatest. By collecting the juice from a permanent fistula of the
pancreatic duct, it has been found that the amount varies with different
foods. When quantities of food containing equivalent amounts of nitro-
gen are fed, the greatest secretion is said to occur with bread and the least
with milk. Such differences are probably dependent upon the amount of
acid secreted in the stomach and passed on into the duodenum. It was
thought at one time that, besides variation in quantity, the nature of the
enzymes in the pancreatic juice might vary according to the kind of
food. This, however, has been shown not to be the case.

Bile

The secretion of bile runs practically parallel with that of pancreatic
juice. The liver is producing bile more or less continuously, since besides
being a digestive fluid it is also an excretory product. The bile produced
between the periods of digestion is mainly stored in the gall bladder.
When the acid chyme comes in contact with the duodenal mucous mem-
brane, it excites afferent nerve endings that cause a reflex contraction of
the gall bladder, and this expresses some of the bile into the duodenum.
The secretin, which the acid at the same time produces, besides affecting
the pancreas, acts on the liver cells, stimulating them to the increased
secretion of bile. Thus, by a nervous reflex operating on the gall bladder
and later by a hormone mechanism operating on the liver cell, the increased
secretion of bile is insured throughout digestion. Of the bile discharged
into the intestine, a certain proportion of the bile salts is reabsorbed into
the portal blood. When these arrive at the liver they also excite secre-
tion of bile, thus assisting secretin in maintaining the secretion through-
out the process of intestinal digestion.

Intestinal Juice

The secretion of intestinal juice, or succus entericus, can obviously be
studied only after isolating portions of the intestine and connecting them

PHYSIOLOGY OF THE DIGESTIVE GLANDS 477

with fistulas of the abdominal walls. It appears here again that both a
nervous and a hormone mechanism exist. Mechanical stimulation of the
intestinal mucous membrane causes an immediate outfloAV of intestinal
juice, the purpose of which under normal conditions is evidently to assist
in moving forward the bowel contents. This mechanically excited juice
does not contain any enterokinase and only small amounts of the other
enzymes. Further evidence for nervous control of the secretion of intes-
tinal juice has been obtained by isolating three pouches of intestine be-
tween ligatures, and then denervating the central pouch by carefully
cutting all the nerves without wounding the blood vessels. On returning
the pouches to the abdomen and leaving them several hours, it has been

Fig. 152. — Loop of intestine after tying off the portions, cutting the nerves running to the middle
portion, and returning the loop to the abdomen for some time. (From Jackson.)

found that the middle pouch becomes distended with secretion, whereas
the two end pouches remain empty (Fig. 152). If the pouches are left for
several days in the abdomen, however, the secretion from the denervated
portion disappears again. The explanation of the result is possibly that
the nerves under ordinary conditions convey impulses to the intestinal
glands, which tonically inhibit their activity.

The existence of hormone control is evidenced by the fact that no
enterokinase is present in the intestinal juice unless pancreatic juice is
placed in contact with the mucous membrane. Injection of pancreatic
juice into the blood, however, does not cause any secretion of intestinal
juice ; whereas the injection of secretin has such an effect.

CHAPTER LIII

THE MECHANISMS OF DIGESTION
MASTICATION, DEGLUTITION, VOMITING

Mastication

By the movements of the lower jaw on the upper, the two rows of
teeth come together so as to serve for biting or crushing the food. The
resulting comminution of the food, forms the first step in digestion. The
up and down motion of the lowrer jaw results in biting by the incisors,
and after the mouthful has been taken, the side to side movements enable
the grinding teeth to crush and break it up into fragments of the proper
size for swallowing. The most suitable size of the mouthful is about
5 c.c., but this varies greatly with habit. After mastication, the mass
weighs from 3.2 to 6.5 gm., about one-fourth of this weight being due to
saliva. The food is now a semifluid mush containing particles which
are usually less than 2 mm. in diameter. Some, however, may measure
7 or even 12 mm.

Determination of the proper degree of fineness of the food is a func-
tion of the tongue, gums, and cheeks, for which purpose the mucous
membrane covering them is supplied with very sensitive touch nerve
endings. The sensitiveness of the tongue, etc., in this regard explains
why an object which can scarcely be felt by the fingers seems to be
quite large in the mouth. If some particles of food that are too large
for swallowing happen to be carried backward in the mouth, the tongue
returns them for further mastication.

The saliva assists in mastication in several ways: (1) by dissolving
some of the food constituents; (2) by partly digesting some of the
starch; (3) by softening the mass of food so that it is more readily
crushed; (4) by covering the bolus with mucus so as to make it more
readily transferable from place to place. The secretion of saliva is
therefore stimulated by the chewing movements, and its composition
varies according to the nature of the food (page 466). In some animals,
such as the cat and dog, mastication is unimportant, coating of the food with
saliva being practically the only change which it undergoes in the mouth.
In man the ability thus to bolt the food can readily be acquired, not, how-
ever, without some detriment to the efficiency of digestion as a whole. Soft

478

THE MECHANISMS OF DIGESTION 479

starchy food is little chewed, the length of time required for the mastica-
t'ion of other foods depending mainly on their nature, but also to a
certain degree on the appetite and on the size of the mouthful.

It can not be too strongly insisted upon that the act of mastication is
of far more importance than merely to break up and prepare the food
for swallowing. It causes the food to be moved about in the mouth so as
to develop its full effect on the taste buds; the crushing also releases
odors which stimulate the olfactory epithelium. On these stimuli depend
the satisfaction and pleasure of eating, which in turn initiate the process
of gastric digestion (see page 470).

The benefit to digestion as a whole of a large secretion of saliva, brought
about by persistent chewing, has been assumed by some to be much
greater than it really is, and there has existed, and indeed may still
exist, a school of faddists who, by deliberately chewing far beyond
the necessary time, imagine themselves to thrive better on less food than
those who occupy their time with more profitable pursuits.

Deglutition or Swallowing

After being masticated the food is rolled up into a bolus by the action
of the tongue against the palate, and after being lubricated by saliva is
moved, by elevation of the front of the tongue, towards the back of the
mouth. This constitutes the first stage of swallowing, and is, so far, a
voluntary act. About this time a slight inspiratory contraction of the
diaphragm occurs — the so-called respiration! of swallowing — and the
mylohyoid quickly contracts, with the consequence that the bolus passes
between the pillars of the fauces. This marks the" beginning of the
second stage, the first event of which is that the bolus, by stimulating
sensory nerve endings, acts on nerve centers situated in the medulla
oblongata so as to cause a coordinated series of movements of the
muscles of the pharynx and larynx and an inhibition for a moment of
the respiratory center (page 351).

The movements alter the shape of the pharynx and of the various
openings into it in such a manner as to compel the bolus of food to pass
into the esophagus (see Fig. 153): thus, (1) the soft palate becomes
elevated and the posterior wall of the pharynx bulges forward so as to
shut off the posterior nares, (2) the posterior pillars of the fauces ap-
proximate so as to shut off the mouth cavity, and (3) in about a tenth of
a second after the mylohyoid has contracted, the larynx is pulled up-
wards and forwards under the root of the tongue, which by being
drawn backwards becomes banked up over the laryngeal opening. This
pulling- up of the larynx brings its upper opening near to the lower half
of the dorsal side of the epiglottis, but the upper half of this struc-

480

DIGESTION

ture projects beyond and serves as a ledge to guide the bolus safely past
this critical part of its course. (4) As a further safeguard against any
entry of food into the air passages, the laryngeal opening is narrowed by
approximation of the true and the false vocal cords.

So far the force which propels the bolus is mainly the contraction of
the mylohyoid, assisted by the movements of the root of the tongue.
When it has reached the lower end of the pharynx, however, the bolus
readily falls into the esophagus, which has become dilated on account
of a reflex inhibition of the constrictor muscles of its upper end. This so-
called second stage of swallowing is, therefore, a complex coordinated
movement initiated by afferent stimuli and involving reciprocal action

Fig. 153.— The changes which take ' place in the position of the root of the tongue, the soft
palate, the epiglottis and the larynx during the second stage of swallowing. The thick dotted line
indicates the position during swallowing.

of various groups of muscles: inhibition of the respiratory muscles and
of those that constrict the esophagus, and stimulation of those that
elevate the palate, the root of the tongue, and the larynx. It is purely
an involuntary process.

The third stage of deglutition consists in the passage of the swallowed
food along the esophagus. The mechanism by which this is done de-
pends very much on the physical consistence of the food. A solid bolus
that more or less fills the esophagus excites a typical peristaltic wave,
which is characterized. by a dilatation of the esophagus immediately in
front of and a constriction over and behind the bolus. This wave travels
down the esophagus in man at such a rate that it reaches the cardiac
sphincter in about five or six seconds. On arriving here the cardiac

THE MECHANISMS OF DIGESTION 481

sphincter, ordinarily contracted, relaxes for a moment so that the bolus
passes into the stomach. In many animals, including man and the cat,
the peristaltic wave travels much more rapidly in the upper part of the
esophagus than lower down because of differences in the nature of the
muscular coat, this being of the striated variety above, and of the non-
striated below. The purpose of more rapid movement in the upper part
is no doubt that the bolus may be hurried past the regions where, by
distending the esophagus, it might interfere with the function of neigh-
boring structures, such as the heart. In other animals, as the dog, the
muscular fiber is striated all along the esophagus, and the bolus of food
correspondingly travels at a uniform, quick rate all the way. It takes
only about four seconds for the bolus to reach the stomach in the dog.

The peristaltic wave of the upper part of the esophagus in the cat and
presumably in man, unlike that of the intestines (see page 501), is trans-
mitted by the esophageal branches of the vagus nerves. If these are
severed, but the muscular coats left intact, the esophagus becomes dilated
above the level of the section and contracted below, and no peristaltic
wave can pass along it; on the other hand, the muscular coat may be
severed (by crushing, etc.) but the peristaltic wave will continue to
travel, provided no damage has been done to the nerves.

In the lower part of the esophagus, however, the wave of peristalsis,
like that of the intestines, travels independently of extrinsic nerves.
This has been observed in animals in which all of the extrinsic nerves
have been cut some time previously. This difference between the upper
and the lower portions is associated with the difference in the nature of
the muscular fibers above noted (Meltzer).14

The propagation of the wave by the nerves in the upper part of the
esophagus indicates that the second stage and the first part of the third
stage of deglutition must be rehearsed, as it were, in the medullary
centers from which arise the nerve fibers to the pharynx and the upper
levels of the esophagus. It is thought that the discharges from these
local centers are controlled by a higher swallowing center situated in the
medulla just above that of respiration, the afferent stimuli to which
proceed from the pharynx by the fifth, superior laryngeal, and vagus
nerves. The exact location of the sensory areas whose stimulation is
most effective in initiating the swallowing reflex varies considerably
in different animals. In man it is probably at the entrance to the
pharynx; in the dog it is on the posterior wall. A foreign body placed
directly in the upper portion of the esophagus of man has been observed
to remain stationary until the individual made a swallowing movement.
The afferent fibers in the glossopharyngeal nerve exercise a powerful
inhibitory influence on the deglutition center as well as on that of respira-

482 DIGESTION

tion. Thus, if swallowing movements are excited by stimulating the cen-
tral end of the superior laryngeal nerve, they can be instantly inhibited
by simultaneously stimulating the glossopharyngeal, and the respiratory
movements stop in whatever position they may have been at the time.
When the glossopharyngeal nerves are cut, the esophagus enters into a
condition of tonic contraction, which may last a day or so. This shows
that the inhibiting impulses are acting continuously.

This inhibition of the esophagus is indeed a most important part of
the process when liquid or semiliquid food is swallowed. By contraction
of the mylohyoid muscle fluids are quickly shot down the dilated esopha-
gus, at the lower end of which, on account of the closure of the cardiac
sphincter, they accumulate until the arrival of the peristaltic wave which
has meanwhile been set up by stimulation of the pharynx. As the per-
istaltic wave approaches the cardia the sphincter becomes inhibited al-
lowing the fluids to be passed into the stomach. If the swallowing is
immediately repeated the esophagus remains dilated because peristalsis
is inhibited and the fluid collects above the closed cardiac sphincter
until the last mouthful is taken when the peristaltic wave passes over
the esophagus and sweeps the contents through the sphincter which is
at the same time relaxed. When a series of swallows in rapid succes-
sion, as in drinking, is made the cardiac sphincter may remain inhibited
throughout, so that the fluid passes directly into the stomach unassisted by
the peristaltic wave.

The Cardiac Sphincter

The passage between the esophagus and the stomach is guarded by
the cardiac sphincter or cardia. This exists in a permanently con-
tracted state, or tonus, superimposed on which from time to time are
rhythmic alternations of contraction and relaxation. This tonus is never
very pronounced. In man it is said that a water pressure of from 2 to 7
cm. applied to the esophageal side of the sphincter will drive air or
water into the stomach, this pressure being less than that of a column
of fluid filling the thoracic esophagus in the erect position. During
repeated deglutition the tonus becomes less and less marked, and after
a number of swallows the sphincter may become completely relaxed.
When this relaxation disappears, however, the sphincter becomes more
contracted than usual and remains so for a longer time.

The tonic condition of the sphincter is controlled by the vagus nerve,
stimulation of which causes relaxation with an after-effect of strong
contraction. Mechanical or chemical stimulation of the lower end of the
esophagus increases the tonus of the sphincter. Forcing of the sphincter
from the stomach side requires a higher pressure than from the esopha-
geal. Eructation of gas, for example, does not take place until intra-

THE MECHANISMS OF DIGESTION 483

gastric pressure has risen to about 25 cm. of water. In deep anesthesia,
however, intragastric pressure may rise considerably higher without
forcing the sphincter.

In animals fed with starch paste impregnated with subnitrate of bis-
muth and then examined by means of the x-rays, the variation in degree
of tone of the sphincter has been observed to be responsible for occasional
regurgitation of some of the gastric contents into the esophagus up to the
level of the heart or even to the base of the neck. The presence of the
gastric contents in the esophagus starts a peristaltic wave, which pushes
the material back again into the stomach. This peristaltic wave starts
in the absence of any other phases of the deglutition process, indicating
that it has been excited by the presence of the material in the esophagus
itself, and belongs, therefore, to the lower order of peristaltic wave, as
seen in the intestines but not in the upper half of the esophagus. Kegur-
gitation of food into the esophagus occurs only when the intragastric
pressure is fairly high. It may last for a period of from twenty to thirty
minutes after the meal is taken, and disappears when the tonus of the
sphincter becomes increased as a result of the presence in the gastric
contents of free hydrochloric acid.

Much information has been secured by listening with a stethoscope to
the sounds caused ~by swallowing and by observing with the x-ray the
shadows produced along the course of the esophagus when food impreg-
nated with bismuth subnitrate is taken. When a solid bolus is swal-
lowed only one sound is usually heard, but with liquid food there are
two, one at the upper end, due to the rush of the fluid and air, and
the other at the lower end (heard over the epigastrium), four or six
seconds later, due to the arrival here of the peristaltic wave with the
accompanying opening of the cardiac sphincter and the escape of the
fluid and air into the stomach. Sometimes, when the person is in the
horizontal position, this second sound may be broken up into several,
indicating that, unassisted by gravity, the fluid does not so readily pass
through the sphincter. The x-ray shadows yield results in conformity
with the above. After swallowing milk and bismuth, for example, the
shadow falls quickly to the lower end of the esophagus and then passes
slowly into the stomach. When the passage of a solid bolus is watched
by the x-ray method, its rate of descent will be found to depend on
whether or not it is well lubricated with saliva; if not so, it may take as
long as fifteen minutes to reach the stomach; if moist, but from eight
to eighteen seconds.

Vomiting*

Vomiting is usually preceded by a feeling of sickness or nausea, and
is initiated by a very active secretion of saliva. The saliva, mixed with

484 DIGESTION

air, accumulates to a considerable extent at the lower end of the esopha-
gus, which it distends. A forced inspiration is now made, during the
first stage of which the glottis is open so that the air enters the lungs,
but later the glottis closes so that the inspired air is sucked into the
esophagus, which, already somewhat distended by saliva, now becomes
markedly so. The abdominal muscles then contract so as to compress
the stomach against the diaphragm and, simultaneously, the cardiac
sphincter relaxes, the head is held forward and the contents of the
stomach are ejected through the previously distended esophagus. The
compression of the stomach by the contracting abdominal muscles is
assisted by an actual contraction of the stomach itself, as has been clearly
demonstrated by the x-ray method. After the contents of the stomach
itself have been evacuated, the pyloric sphincter may also relax and
permit the contents (bile, etc.) of the duodenum to be vomited.

The act of vomiting is controlled by a center located in the medulla,
and the afferent fibers to this center may come from many different
regions of the body. Perhaps the most potent of them come from the
sensory nerve endings of the fauces and pharynx. This explains the
tendency to vomit when the mucosa of this region is mechanically stimu-
lated. Other afferent impulses come from the mucosa of the stomach
itself, and these are stimulated by emetics, important among which are
strong salt solution, mustard water and zinc sulphate. Certain other
emetics, particularly tartar emetic and apomorphine, act on the vomit-
ing center itself, and can therefore operate when given subcutaneously.
Afferent vomiting impulses also arise from the abdominal viscera, thus
explaining the vomiting which occurs in strangulated hernia, and in
other irritative lesions involving this region. X-ray observations have
been made on the movements of the stomach of cats after the admin-
istration of apomorphine (Cannon). The first change observed is an
inhibition of the cardiac end of the stomach, which becomes a perfectly
flaccid bag. About the midregion of the organ, deeper contractions then
start up, which sweep towards the pylorus, each contraction stopping as a
deep ring at the beginning of the vestibule, while a slighter wave con-
tinues. A very strong contraction at the incisura angularis finally
develops and completely divides the gastric cavity into two parts. On
the left of this constriction the stomach remains completely relaxed, but
at the right of it waves continue running over the vestibule. It is while
the stomach is in this condition that the sudden contraction of the dia-
phragm and abdominal muscles shoots the cardiac contents into the
relaxed esophagus. As these jerky contractions are continued, the gastric
walls seem to reacquire their tone. Afferent impulses from the duodenal
mucosa are even more potent for the initiation of the vomiting reflex than
are impulses arising in the stomach itself.

CHAPTER LIV

THE MECHANISMS OF DIGESTION (Cont'd)
THE MOVEMENTS OF THE STOMACH

The Character of the Movements

Even from the earliest days it has been recognized that the stomach
performs two important functions: (1) receiving the swallowed food
and then discharging it slowly into the intestine, and (2) initiating the
chemical processes of digestion. In order to understand the mechanism
by which the stomach collects and then discharges the food, it is neces-
sary first of all to recall certain anatomical facts concerning the organ,
and for this purpose it is most convenient to accept the description
given by Cannon, which is illustrated in the accompanying figure. The
organ is divided into a cardiac and a pyloric portion by a deep notch in
the lesser curvature, called the incisura angularis. The cardiac portion
is further subdivided into two by the cardiac orifice. The part which
lies, in man, above a line drawn horizontally through the cardia is the
fundus. The part lying between the fundus and the incisura angularis
is known as the body of the stomach, which, when full, has a tapering
shape. The pyloric portion lying on the right of the incisura angularis
is further divided into two parts: the pyloric vestibule and the pyloric
canal, the latter of which lies next the pyloric sphincter and in man
measures about 3 cm. in length (see Fig. 154).

The filled stomach of a person standing erect is so disposed that the
greatest curvature forms its lowest point, which may be considerably
below the umbilicus. As digestion proceeds and the stomach empties,
the greater curvature becomes gradually raised, so that ultimately the
pylorus comes to be the most dependent part of the stomach. From
these and many other observations it is certain that the emptying of the
stomach does not at all depend on the operation of the force of gravity.
Indeed, that this can not be the case is perfectly clear when we con-
sider the disposition of the stomach in quadrupeds.

Exact observation on the movements which the stomach performs from
the time it is filled with food till it empties, have been made by the
x-ray method, first introduced by Cannon.10 The method consists in feed-
ing the animal with food that has been impregnated with bismuth sub-

485

486

DIGESTION

nitrate, then exposing him to the x-ray and either taking instantaneous
photographs of the shadows or observing them by means of a fluorescent
screen. The descriptions of the original observations made by Cannon
on the- stomach of the cat have been so little modified by observations

Fig. 154. — Schematic outline of the stomach. At C is the cardia; F, fundus; IA, incisura an-
gularis; B, body; PC, pyloric canal; P, pylorus. (From Cannon.)

on man that we may take them as a convenient type. In the accompany-
ing figure (Fig. 156) the outline of the shadow cast by the stomach is
shown at intervals of an hour each during digestion. Soon after the
stomach has become filled, peristaltic waves are seen to take their

Fig. 155. — Diagrams of outline and position of stomach as indicated by skiagrams taken on
man in the erect position at intervals after swallowing food impregnated with bismuth subnitrate.
A, moderately full; B, practically empty. The clear space at the upper end of the stomach is due
to gas, and it will be noticed that this "stomach bladder" lies close to the heart. (From T. Win-
gate Todd.)

THE MECHANISMS OF DIGESTION

487

origin about the middle of the body of the stomach, and to course
towards the pylorus. Above the region at which these waves originate —
that is, the cardiac half of the body of the stomach and all of the
fundus — there are no waves, but as digestion proceeds the walls slowly
and steadily contract on the mass of food. This so-called cardiac pouch
does not, however, dimmish in size so rapidly as the part of the body of
the stomach over which the peristaltic waves are passing. The circular
fibers of the walls of this part of the stomach — sometimes called the
gastric tube — contract tonically, so that it becomes tubular in form,
with the full cardiac pouch at the left and above and the pyloric por-
tion at the right. The latter portion meanwhile does not dimmish much
in size, although the peristaltic waves traveling over it are very pro-

Fig. 156. — Outlines of the shadows cast by the stomach at intervals of an hour each after feeding
a cat with food impregnated with bismuth subnitrate. (From Cannon.)

nounced. As will be clear from the figure, these changes in outline go
on until the cardiac pouch has become practically empty and the food
has been all moved along the -now tubular portion of the body into the
pyloric vestibule.

From this description it is evident that the function of the cardiac
end is to serve as a reservoir for the food, which, by a slow contraction
of the walls, is gradually delivered into the gastric tube, where by
peristalsis it is carried towards the pyloric vestibule.

The time required for the peristaltic waves to travel from their place of
origin to the pyloric sphincter is considerably longer than the interval be-
tween the waves, so that several of these are always seen on the stomach at

488 DIGESTION

the same time. They sometimes become so pronounced in the pyloric
region, especially in a half-empty stomach, that they appear almost to
obliterate the cavity. They always stop at the pylorus, never going on
to the duodenum. The rate of recurrence of the waves varies somewhat
in different animals, being about six per minute in the cat and about
three in man. Their initiation does not seem to depend on the presence
of acid in the gastric contents, for, when food is introduced into the
stomach, they do not wait for the gastric contents to become acid in
reaction (see page 516). Nevertheless, acid does seem somewhat to stim-
ulate the depth and frequency of the waves, and they recur oftener with
carbohydrate than with fatty food.

The adaptation of the capacity of the normal stomach to the volume of
its contents is remarkable. When the stomach of a living animal is dis-
tended by fluid the intragastric pressure shows very little change even
up to the point of rupture of the viscus (Grey16). After excision, the
stomach loses in great part this adaptive power which seems to be con-
trolled not through the extrinsic nerves, but by the nervous elements
residing in the gastric wall itself.

The Effect of the Stomach Movements on the Food

This has been studied: (1) by dividing the food into portions that
are differently colored and, after some time, killing the animal, freezing
the stomach and making sections of it (see Fig. 157) ; (2) by mak-
ing little pellets of bismuth subnitrate with starch and observing their
behavior under the x-rays; or (3) by removing samples of the stomach
contents by means of a stomach tube (Rehfuss tube) inserted so that
its free end lies in either the cardiac or the pyloric region. By the
first of the above methods it has been found that the first mouthfuls
of food lie along the greater curvature, where they form a layer over
which that subsequently swallowed accumulates, with the last por-
tions next the cardia. The pepsin and hydrochloric acid of the car-
diac end, therefore, act soonest on the first swallowed portion of a
meal, and the more recently swallowed central masses are not affected
by the secretions for some time, so that .opportunity is given for the
saliva mixed with the food to develop its digestive action.

As has been shown by removing the stomach contents with a tube at
various periods after feeding with starchy food, considerable amylolysis
may occur for some time. When separate samples are removed in this
way from the cardiac and pyloric parts, it has been found that after
half an hour the contents of both have about the same percentage of
sugar, but that for some time after this interval the cardiac contents
contain considerably more sugar than the pyloric. Later the percentages

THE MECHANISMS OF DIGESTION 489

of sugar again become about equal, no doubt on account of diffusion.
The diastatic action in the fundus is finally brought to an end when
the contents become completely permeated by the hydrochloric acid.
In this connection it is worthy of note that the addition of hydrochloric
acid up to the point of neutrality greatly accelerates the rate of diastatic
digestion.

As the outer layers of food in the stomach become partly digested on
account of the action of the pepsin and hydrochloric acid, the food is
slowly pressed into the active right half of the stomach, where by the
action of the peristaltic waves it is moved on to the pyloric vestibule.
By observing the x-ray shadows cast by two pellets of bismuth subni-
trate it has been noted by Cannon that, as the peristaltic wave approaches
a pellet, it causes it to move forward more rapidly for a short distance,
but soon overtakes it and in doing so causes the pellet to move back a
little towards the fundus. This backward movement is less than the

Fig. 157. — Section of the frozen stomach (rat) some time after feeding with food given in three
differently colored portions. (From Howell's Physiology.)

forward movement, so that after the wave has passed, the position of
the pellet is a little forward of that which it would have occupied had
there been no wave. The behavior of the pellet, and, therefore, of the
stomach contents, is very like that of a cork floating at the edge of the
sea; as each wave approaches, it hurries the cork on a little, but after
its passage the cork recedes again until the second wave carries it still
a little farther forward. As the peristaltic wave approaches the pyloric
vestibule and becomes more powerful its effect on the pellets becomes
more marked. They are carried rapidly along this part of the stomach,
until the pylorus is reached. If this remains closed, they are shot back
into the vestibule. From nine to twelve minutes may elapse before they
are transferred to the pylorus from the place where they are first affected
by the peristaltic wave.

These observations made on cats and other laboratory animals no
doubt also apply in the case of man. Removal of the contents of the
cardiac and pyloric regions separately with a stomach tube after feeding

490 DIGESTION

with a test meal part of which was colored with carmine or charcoal,
has shown that none of the coloring material was present in the contents
of the pyloric end up to twenty minutes or so after the food had been
taken. It then appeared but at first only in traces. Another important
distinction between the food in the two portions of the stomach relates
to its consistency. In the pyloric end it is semifluid and homogeneous
in character; in the cardiac end, on the other hand, it is a lumpy, rather
incoherent mass.

The gastric movements must greatly facilitate the digestive processes
in the stomach. In the cardiac part the undisturbed condition of the
food will, as we have seen, facilitate the digestive action of ptyalin,
whereas in the body of the stomach the peristaltic, waves, besides mov-
ing the food onward, will tend to bring fresh portions of mucous mem-
brane and food in contact, so that the latter becomes more thoroughly
mixed with the pepsin and hydrochloric acid. In the pyloric part, where
no hydrochloric acid is secreted, the contents, already sufficiently acid
in reaction, become more thoroughly churned up with the local pepsin
secretion, so that proteolytic action progresses very rapidly.

The peristaltic waves also facilitate absorption from the stomach of such
substances as glucose in concentrated solution and, probably, of hydro-
lyzed protein; water, however, is not absorbed. One effect of such
absorption is the production of gastrin, which we have seen is the hor-
mone concerned in maintaining the gastric secretion after the psychic
flow. The fact that the mucosa of the vestibule has, relatively to the
cardiac end, few secreting glands is in harmony with the view that
absorption is an important function of this part of the stomach.

The observations of Carlson,17 Ginsburg18 and others indicate that the
usually accepted explanation of the pains of gastric and duodenal ulcers,
namely, corrosion and irritation of exposed nerve endings in the gastric
and duodenal mucosae by highly acid stomach contents, is not correct.
The pains of ulcer may be present when the contents of the stomach are
alkaline and they may be absent when marked hyperacidity exists. Ac-
cording to these authors the pains are analogous in origin to those of
hunger, and are the result of contractions of the stomach and duodenum,
the nerves of which are in a hyperexcitable state. Hyperacidity then,
will affect the pain of ulcer in so far only as it increases the motility
of the stomach.

THE EMPTYING OF THE STOMACH

The Control of the Pyloric Sphincter

When digestion has proceeded far enough in the stomach to bring the
food into a homogeneous, soup] ike fluid (chyme), portions of this, as they

THE MECHANISMS OF DIGESTION 491

are driven against the pyloric sphincter by the peristaltic waves, instead of
being returned as an axial stream into the stomach, are ejected into the
duodenum.

We must now consider the mechanism by which the pyloric sphincter
opens to permit the passage of the chyme. Bombardment by the peri-
staltic waves is evidently not the cause of its opening, for, as we have
seen, many such waves may arrive at it without this result. Since it is
evidently in order that the intestine may not suddenly become over-
whelmed with large masses of food that the pylorus only occasionally
opens, it might be thought that its opening depends upon the degree of dis-
tention of the upper part of the intestine. It is true that excessive disten-
tion of the upper part of the intestine does hold the pyloric sphincter
closed, but this can not be the physiological stimulus, because considerable
quantities of chyme are never found here.

The first clue to the real nature of the mechanism was afforded by
observing the behavior of the sphincter when solutions are introduced
into the duodenum through a fistula. Acid solutions were found to
cause a complete inhibition of gastric evacuation, whereas alkaline solu-
tions had no effect. This difference indicates that acids in contact with
the duodenal mucous membrane reflexly excite contraction of the sphinc-
ter, and that it relaxes only after the acid has become neutralized
by mixing with the pancreatic juice and bile.

On account of the great importance of the pyloric mechanism in insur-
ing that the chyme shall enter the intestine only in such quantities that
it can be properly acted upon by the intestinal digesting juices, it will
be of interest to consider briefly some of the experimental observations
by which this mechanism has been studied. We may consider first the
evidence that acid on the stomach side of the pylorus causes a relaxation
of the sphincter: (1) When carbohydrate food is fed, it ordinarily leaves
the stomach fairly rapidly, but if its acid-absorbing power is increased
by mixing it with sodium bicarbonate, exit from the stomach is greatly
delayed. (2) Proteins ordinarily leave the stomach more slowly than
carbohydrates, but if acid proteins are fed, their exit is much more
rapid. (3) If a fistula is made into the pyloric vestibule through which
some of the contents can be removed, it will be found that just prior' to
the opening of the pyloric sphincter, a distinctly acid reaction develops
in the food ; and furthermore if acid solutions are injected through this
fistula, they cause the pyloric sphincter to open, whereas alkalies retard
its opening. (4) A similar effect of acid in opening the sphincter can
be demonstrated by applying it to the pyloric mucosa of an excised
stomach kept alive in oxygenated Ringer's solution.

The. evidence that acid on the duodenal side causes closure of the

492 DIGESTION

sphincter is as follows: When acid is placed in the duodenum through
a fistula, the sphincter will not open ; when the alkaline secretions of
the liver and pancreas are excluded from the duodenum by the ligation
of the bile and pancreatic ducts the evacuation of the stomach is delayed ;
if acid is excluded by suturing the pylorus to the intestine below the
duodenum, the evacuation of the stomach is hastened. Water and egg
white may leave the stomach independently of any acid reflex control of
the pylorus. By observations made through a duodenal fistula, it has
been found that, after a quantity of water has been swallowed, most if
not all of it very soon enters the duodenum in a more or less continuous
stream. It is no doubt on this account that drinking contaminated water
is especially dangerous on an empty stomach.

The nervous pathway through which these acid reflexes take place has
been shown to be the myenteric plexus. Indeed, the whole mechanism
is quite analogous with that which we shall see occurs in the intestine
during peristalsis: the stimulus, that is, the acid, causes a contraction
of the gastric tube behind.it and a dilatation in front.

Fig. 158. — Outlines of shadows in abdomen obtained by exposure to x-rays 2 hours after
feeding with food containing bismuth subnitrate. The food in A was lean beef, and in B boiled
rice. The smaller size of the stomach shadow and the much greater total area of the intestinal
shadows in B than in A show that carbohydrate leaves the stomach earlier than protein. (From
Cannon.)

Rate of Emptying- of Stomach

The relationship of these facts to the rate at which different foodstuffs
leave the stomach is very readily explained. The method for investigat-
ing this problem, which again we owe to Cannon, consists in feeding ani-
mals with a strictly uniform amount of different foods made up, as
nearly as possible, of equal consistency and containing bismuth subni-
trate in the proportion of 5 gin. to each 25 c.c. By feeding such mix-
tures to cats previously starved for twenty-four hours, and examining
the abdomen by the x-ray at regular intervals, the shadows cast by the food
after passage into the intestine can be outlined on tracing paper, and

THE MECHANISMS OF DIGESTION

493

the total length* measured (Fig. 158). In taking this as an estimate of
the amount of food in the intestine, several errors are no doubt incurred
on account of the crossing and foreshortening of the loops, etc., but, as
their constancy testifies, there is no doubt that the results are sufficiently
close for the purpose of finding out how quickly food gains access to the
small intestine; and the method has a great advantage over all others
in that digestion is allowed to proceed practically without interruption.
The points we have to determine are: (1) when the food first leaves the
stomach; (2) the rate at which different foods are discharged; (3) the
time required for their passage through the small intestine.

Let us consider first of all the results obtained ~by feeding with prac-
tically pure fat or carbohydrate or protein. By plotting the length of
the shadows in centimeters along the ordinates, with hours along the
abscissas, curves such as those shown in Fig. 159 have been secured.
When fats were fed (dash line in chart), the discharge began rather

40

tim

S

0 >2 1234 567

Hours

Fig. 159. — Curves to show the average aggregate length of the food masses in the small
intestine at the designated intervals after feeding. The curve for various fat foods is in the
dash line, for protein foods in the heavy line, and for carbohydrate foods in the light line.
(From Cannon.)

slowly, and continued at a slow rate. Even after seven hours some fat
still remained in the stomach, and at no time was any large quantity
present in the intestine, indicating that almost as quickly as it is dis-
charged into this part of the gastrointestinal tract fat becomes digested
and absorbed. The discharge of carbohydrates was quite different (light
line in chart) ; it began often in ten minutes, and soon became abundant,
reaching a maximum, as a rule, at the end of two hours, after which it
fell off, the stomach being empty in about three hours. Protein left at a
rate intermediate between that for fats and that for carbohydrates
(heavy line). Little left before the first half hour; the curve then
slowly rose, attaining a maximum in about four hours, and then gradu-
ally declined at about the same rate as it rose. It "is interesting to note
that at the end of half an hour about eight times as much carbohydrate

*This is permissible since the shadows are practically all of the same width.

494 DIGESTION

had left the stomach as protein; at the end of an hour, five times as much.

These results are clearly dependent upon the rates at which the dif-
ferent foodstuffs assume an acid reaction in the stomach. Carbohydrate
has no combining power for acids, so that the acid secreted with the
psychic juice remains uncombined and on gaining the pyloric vestibule
excites the opening of the sphincter. Protein, on the other hand, as is
well known, absorbs considerable quantities of free hydrochloric acid,
so that for some considerable time after it is taken, none of the acid exists
in a free state. Fats owe their slow discharge partly to inhibition of
gastric secretion, and partly to the longer time it takes for them to become
neutralized in the duodenum, because of the fatty acid split off by the
action of lipase.

Interesting observations have also been made on the rate of discharge
when various combinations of foodstuffs were fed; This has been done
by feeding one foodstuff before the other, or by mixing the foodstuffs.
When carbohydrates were fed first and then protein, the discharge be-
gan much earlier than with protein alone, because the carbohydrate food
first reached the pyloric vestibule (see page 488). However, at the end
of two hours, when the carbohydrate curve should begin to come down,
it remained high, indicating that the protein had by this time reached
the pylorus and was being discharged at its own rate. When the meat
was fed before the carbohydrate, the curve to start with was exactly
like that for protein, becoming, however, considerably heightened later
when the carbohydrate reached the pyloric vestibule. The presence of
protein near the pylorus, therefore, distinctly retards the evacuation of
carbohydrate from the stomach. These facts, it will be remarked, all
fit in admirably with the observations which we have already detailed
concerning the disposition of food in the stomach.

When mixtures of equal parts of different foods were fed, the results
indicated that the emptying of the stomach occurred at a rate which
was intermediate between those of the foods taken separately. Mixing
protein with carbohydrate, for example, accelerated the rate at which
protein left, and mixing fats with protein caused the protein to leave
the stomach considerably more slowly than if protein alone had
been fed.

Influence of Pathological Conditions on the Emptying

An important surgical application of these facts concerns the behavior
of food after gastroenterostomy. It has been thought that this operation
would cause the food to be drained from the stomach into the intestine
and thus leave the region of the stomach between the fistula and the
pylorus inactive. This assumption is based on the idea, which we have

THE MECHANISMS OF DIGESTION 495

seen to be erroneous, that gravity assists in the emptying of the stomach.
As a matter of fact, it has been found that, if the gastroenterostomy is
made when there is no obstruction at the pylorus, the chyme takes its
normal passage through the sphincter and, almost without exception,
none leaves by the fistula. When the pylorus is partly occluded, the
food sometimes passes in the usual way, and sometimes by the fistula.
The cause for this predilection for the pyloric pathway depends on the
pressure conditions in the gastric contents. Gastroenterostomy, there-
fore, is efficient only when gross mechanical obstruction exists at the
pylorus. The operation should never be performed in the absence of
demonstrable organic pyloric disease.

Another objection to gastroenterostomy in the presence of a patulous
pyloric sphincter rests on the fact that the food, after passing the sphinc-
ter and moving along the intestine, may again enter the stomach through
the fistula. This is most likely to occur when the stomach is full of
food, for under these conditions the stretching of its walls separates the
edges of the opening, the intestine being drawn taut between the edges,
so that the opening between the stomach and the intestine assumes the
form of two narrow slits, which act like valves permitting the food to
enter but preventing its escape from the stomach. Only seldom under
these circumstances can any food pass into the intestine beyond the
stomach opening. Repeated vomiting after gastroenterostomy has been
observed in experimental animals only when obstructive kinks or other
demonstrable obstacles were present in the gut, the obstruction being lo-
cated in that part of the intestine beyond its attachment to the stomach.

When the pyloric obstruction is complete, food must, of course, leave
by the fistula, digestion by the pancreatic juice and bile being still car-
ried on because of the fact that for a considerable distance down the
intestine, secretin, which we have seen is essential for the secretion
of these fluids, is still produced by the contact of the acid chyme with
the intestinal mucosa. Further provision for adequate digestion of
food in such cases is secured, as some of the food after leaving the
fistula passes back for a certain distance into the duodenum, where, however,
it soon excites peristaltic waves, which again carry it forward. This
insures thorough mixing with the digestive juices. Prom their experi-
mental experience Cannon and Blake19 recommend that, when the
fistula has to be made, it should be as large as possible and near the
pylorus, and that the stomach afterwards should not be allowed to
become filled with food. To avoid kinking of the gut, they also recom-
mend that several centimeters of the intestine should be attached to the
stomach distal to the anastomosis.

The effect of hyperacidity of the contents on the emptying of the

496 DIGESTION

stomach has been studied by feeding animals with potatoes containing
varying percentages of hydrochloric acid. With an acidity of 0.25 per
cent, the rate of discharge was increased, but it became slower when the
acidity rose to 1 per cent. With an acidity of 0.5 per cent, the rate of
discharge was about the normal. Hyperacidity, therefore, causes a retar-
dation of the emptying of the stomach.

The consistency of the food appears to have little influence on its rate of
discharge from the stomach — at least in the case of potatoes. Dilution
of protein food, however, increases the rate. Distinctly hard particles
in the food retard the stomach evacuation.

There is usually a considerable amount of gas in the part of the stomach
above the entrance of the cardia, on account of which this part of the
stomach has sometimes been called the stomach bladder. In the upright
position this gas forms a bright area in the x-ray plate (Fig. 155), but
when the person reclines it spreads to a new location. Its presence may
influence gastric digestion by preventing the contact of the food with
the mucous membrane, and by interfering with the efficiency of the peri-
staltic waves in moving the food. Considerable gas therefore retards the
emptying of the stomach, as has been shown experimentally by x-ray
observations on animals fed with the standard amount of food followed
by the introduction of air. It was noted that the air did not diminish
the frequency or strength of the peristaltic waves, but that these could
not efficiently act on the food. When along with gas there is also atony
of the stomach walls, the retardation in the discharge will, of course, be
still more pronounced. The temperature of the swallowed food does
not appear to have much influence on the stomach movements or on the
the rate of discharge from the organ.

CHAPTER LV
THE MECHANISMS OF DIGESTION (Cont'd)

THE MOVEMENTS OF THE INTESTINES

The length of the small intestine and the size of the cecum of the
large intestine vary considerably in different animals. In the carnivora,
such as the cat, the small intestine is relatively short; in the herbivora,
relatively long. Thus, it is three times the length of the body in the cat,
and four to six times in the dog ; whereas in the goat and sheep, it may
be nearly thirty times the length of the body. In the carnivora the
cecum is either absent or rudimentary, whereas in those herbivora which
do not have a divided stomach the cecum is very large and sacculated,
as is also the colon. The reason for the great size in herbivora is that
practically the whole of the digestion of cellulose takes place in this
part of the gut. This digestion, as we shall see later, does not depend
on any secretion poured forth by the animal itself, but upon the action
of bacteria and of certain enzymes (cytases) that are taken with the
vegetable food.

Movements of the Small Intestine

The movements of the small intestine have been studied (1) by the
bismuth subnitrate and x-ray method, (2) by observing them after open-
ing the abdomen of an animal submerged in a bath of physiologic saline
at body temperature, (3) by observing the changes in pressure produced
in a thin-walled rubber balloon inserted in the lumen of the gut and
connected with a recording tambour (Fig. 160), and (4) by excising
portions of the intestine and keeping them alive in a bath of saline solu-
tion at body temperature, through which oxygen is made to pass.

THE SEGMENTING MOVEMENTS

When a suitably fed animal is placed on the holder for examination
by the x-ray method, no movement in the intestinal shadows is generally
observed for some time. The first movement to appear is the breaking of
one of the columns of food into small segments of nearly equal size.
Each of these segments again quickly divides, and the neighboring
halves suddenly unite to form new segments, and so on, in a manner

497

498

DIGESTION

which will be made clear by consulting Fig. 161. This rhythmic seg-
mentation, as Cannon has called it, continues without cessation for more
than half an hour, and the food shadow does not meanwhile seem to change
its position in the abdomen to any extent. The splitting up of the seg-
ment and the rushing together of the neighboring halves proceed as a
rule with great rapidity; thus, if we count the number of different seg-

Fig. 160. — Apparatus for recording contractions of the intestine. (From Jackson.)

ments during a definite period, we may find the rate of division in the
cat to be as high as 28 or 30 a minute. In man the divisions occur at a
frequency of approximately 10 per minute, which corresponds to the fre-
quency with which sounds can be heard when the abdomen is auscultated.
Although half an hour is the period which this process usually oc-
cupies, it may last considerably longer. In certain animals, such as the
rabbit, segmenting movements have not been observed, but instead

THE MECHANISMS OF DIGESTION 499

of them a rhythmic to-and-fro shifting of the masses of food along the
lumen of the gut, rapidly repeated for many minutes.

When the intestines are floated out in a warm bath of saline solution,
it is seen that the rhythmic segmentation is caused by narrow rings of
contraction. Under such conditions also it is often noted that the
loops of intestine sway from side to side. The balloon method also re-
veals the presence of slight waves of contraction that pass rapidly along
the gut, and follow each other at the rate of twelve to thirteen per minute.
Both of the muscular coats of the intestine are involved, and it is believed
that the contractions are responsible not only for the pendular move-
ments but for the rhythmic segmentation observed by the x-ray method.
According to this view these movements are constantly passing along
the intestine, and become exaggerated by the mechanical stimulus which
is offered by the masses of food to such an extent that they divide the
masses into portions. The evidence for this belief rests on the fact that

Fig. 161. — Diagrammatic representation of the process of segmentation in the intestine. An
unbroken shadow is shown in / and its segmentation in 2. The dotted lines across each mass
show the position of division and in j is shown how new masses are formed by the split portions
coming together. (.From Cannon.)

when the contraction is studied by the balloon method, it becomes marked
over the middle of the balloon, where the greatest tension exists.

Several functions can be assigned to these movements. They cause
intimate mixture of the food with the digestive juices, and by bringing
ever new portions of food in contact with the mucosa, they encourage
absorption. They also have an important massaging influence on the
blood and lymph in the vessels of the intestinal walls. Indeed, the pas-
sage of lymph from the lacteals into the mesenteric lymphatics seems to
depend very largely upon these movements.

The investigations of Alvarez20 and his coworkers show that the rhyth-
mic intestinal contractions are not of uniform rate throughout the entire
length of the small bowel, but vary in frequency inversely with the dis-
tance from the pylorus. For example, the contractions of a segment
of the duodenum proceed at a more rapid rate (17-21 per minute) than
do the contractions of an ileal segment (10-12 per minute) under the

500 DIGESTION

same experimental conditions. Associated with the variations in fre-
quency are also differences in the amplitude of the contractions of the in-
testinal muscle. As the contractions become less frequent their ampli-
tude increases to the extent that the ratio between the amplitude of the
contractions of duodenal and ileal segments is as 3 to 20. Tone and irrita-
bility diminish progressively from duodenum to ileum. According to
Alvarez the underlying cause of the decline in contraction rate is to be
found in a study of the metabolism of the intestinal muscle in the differ-
ent regions. The determination of the metabolic changes in different
parts of the intestinal muscle from pylorus to the lower end of the ileum
showed a gradual descent in the curve of energy output (metabolic gra-
dient) which ran a course parallel to that of the intestinal contractions,
a slow or a rapid metabolism being associated with a slow or a rapid
contraction rate, respectively. This direct relationship between the fre-
quency of rhythm and the metabolism rate of intestinal muscle is in favor
of the view that the intestinal contractions are myogenic, moreover,
the graded activity of the muscle with regard to rhythm, tonus and ir-
ritability is probably an important factor in the production of peristalsis
and in the determination of the direction which this movement shall take.

THE PERISTALTIC MOVEMENTS

The other movement observed in the small intestine is that known as the
peristaltic wave. It occurs in two forms: (1) as a slowly advancing con-

Fig. 162. — Intestinal contractions (balloon method) after excision of the abdominal ganglia and
section of both vagi. Mechanical stimulation above (/) and below (2) the balloon causes relaxa-
tion and contraction respectively. (From Starling.)

traction (1 to 2 cm. per minute), preceded by an inhibition of the walls,
and proceeding only through a short distance in a coil (4 to 5 cm.); and
(2) as a swift movement called the peristaltic rush, which sweeps with-
out pause for much longer distances along the canal.

Further analysis of the peristaltic wave can readily be made by the

THE MECHANISMS OF DIGESTION 501

balloon method (Fig. 162). If the gut is pinched above the balloon, a
marked relaxation occurs over the latter, and this relation extends for about
two feet down the intestine. If, on the other hand, the gut is pinched
a little below the situation of the balloon, a long-continued contraction
occurs over the latter. The conclusion that we may draw from this result
is that the stimulation of the gut causes contraction above the point of
the stimulus and relaxation below, this being known as "the law of the
intestine" — (Bayliss and Starling). We have seen that it applies also in
the case of the cardiac and pyloric sphincters.

THE PHYSIOLOGICAL NATURE OF THE RHYTHMIC AND PERISTALTIC MOVE-
MENTS

Interesting information in this connection has been gained by obser-
vation of the behavior of the movements after the application of drugs
to the gut or after cutting the nerve supply. The rhythmic movements
are not affected by the application of nicotine or cocaine. Since these
drugs paralyze nervous structures it has been concluded that the rhythmic
movements are myogenic in origin. The question is not a settled one,
however, for it has been found by Magnus that, although strips of the
longitudinal muscle, isolated in oxygenated saline solution, will continue
to beat, they do not do so if the adherent Auerbach's plexus of nerves
is stripped off from them. The nature of the peristaltic contractions is
more definite; they must clearly depend upon a local nervous struc-
ture, since they are paralyzed by the application to the gut of cocaine or
nicotine. This local nervous system no doubt also resides in Auerbach's
plexus, which must therefore be considered as complex enough to be (see
page 830) endowed with the power of directing nervous impulses so as to
bring about relaxation of the gut in front of the stimulus and contrac-
tion over it.

NERVOUS CONTROL OF MOVEMENTS

The influence of the central nervous system on the intestinal movements
has been studied by the usual methods of cutting and stimulating the
extrinsic nerve supply. Through the splanchnic nerves tonic inhibitory
impulses are conveyed to the intestine (except the ileocolic sphincter),
for after these nerves are severed the movements become more distinct.
Indeed, in many animals after opening the abdomen no intestinal move-
ment can be observed until these nerves have been cut. Stimulation of the
peripheral end of the nerve also inhibits any movement which may mean-
while be in progress. The impulses through the vagus nerve are of an
opposite character. Section of these nerves has little effect, but stimula-
tion causes contraction. (Figs. 163 and 164.)

502 DIGESTION

By observing the rhythmic contractions of an isolated strip of the small
intestine suspended in a bath of oxygenated saline solution at body tem-
perature, it can readily be shown that the presence of even a minute trace
of epinephrine is sufficient to produce complete inhibition of the movement.
The parallelism between the effects of splanchnic stimulation and those of

Fig. 163. — The effect of excitation of both splanchnic nerves on the intestinal contractions. (From

Starling.)

Fig. 164. — The effect of stimulation of right vagus nerve on the intestinal contractions. (From

Starling.)

epinephrine injection is very significant, for in this way the marked inhi-
bition of intestinal movement which occurs during fright may possibly
be explained (see page 787).

The circular muscular coat of the last two or three centimeters of
the ileum before it joins the cecum is definitely thicker than the rest of
this coat, indicating that it has a sphincter-like action. This ileocolic

THE MECHANISMS OF DIGESTION 503

sphincter, as it is called, opens when food is pressed against it from the
ileum, but remains closed when food is pressed against it from the cecum.
It therefore obeys the law of the intestine. That it is physiologically
distinct from the musculature of the rest of the ileum is indicated by the
fact that the splanchnic and vagus nerves do not affect it in the same
way; thus, stimulation of the splanchnic causes a strong contraction of
the sphincter, whereas it is unaffected by stimulation of the vagus.

Peristalsis is much more rapid in the duodenum than in other parts of
the small intestine. During the first stages of digestion, the food ordi-
narily lies mainly in the right half of the abdomen, and later in the left
half. There is considerable variation in the time that elapses before it
enters the colon. In the cat, carbohydrates reach this part of the gut in
about four hours.

Movements of the Large Intestine

On account of the great differences which we have already seen to
exist in the size and relative importance of the colon as a digestive organ
in different classes of animals, it is not surprising that the movements
observed are very different according to the dietetic habits of the animal.
Apparently the movements are much the same in the cat as in man. As
the food passes through the ileocolic sphincter into the cecum and
accumulates there, it gradually sets up, by its pressure, a contraction of
the muscular walls of the gut somewhere about the junction between
the ascending and transverse colon. This wave of contraction then
begins to travel slowly toward the cecum, without, however, being pre-
ceded by any relaxation of the wall of the gut, as is the case with a true
peristaltic wave. This first wave is soon followed by others, with the
result that the food is forced up into the cecum, against the blind end
of which it is crowded, being meanwhile prevented from passing into
the ileum by the operation of the ileocolic sphincter and by the oblique
manner in which the ileum opens into the cecum.

As the result of the distention of the cecum set up by these so-called
antiperistaltic waves, a true coordinated peristaltic wave is occasionally
initiated, and passes along the ascending colon preceded by the usual
wave of inhibition. These waves, however, disappear before they reach
the end of the colon, so that the food is again driven back by the so-
called antiperistaltic wraves. The effect of the movements is to knead
and mix the intestinal contents, and thus encourage the absorption of
water from them. The resulting more solid portions then collect toward
the splenic flexure, and become separated from the remaining more fluid
portion by transverse waves of constriction, which develop into peri-
staltic waves carrying the harder masses into the distal portions of the

504

DIGESTION

colon, where they collect chiefly in the sigmoid flexure. The descending
colon itself is never distended with contents and merely serves as a tube
for transferring the masses from the transverse colon to the sigmoid
flexure. The time taken for a capsule of bismuth to reach the various
parts of the large intestine is shown in Fig. 165.

After a certain mass has collected in the sigmoid flexure and rectum,
the increasing distention causes a reflex evacuation of this portion of the
gut through centers located in the spinal cord. The impulses from these
centers, besides contracting the rectum, etc., also coordinate the contrac-
tion of the abdominal muscles and the relaxation of the sphincter ani
so as to bring about the act of defecation. By the skiagraphic method it

Fig. 165. — Diagram of time it takes for a capsule containing bismuth to reach the various parts

of the large intestine. •

has been found that the pelvic colon gradually becomes filled with feces
from below upward, and-that the rectum remains empty until just before
defecation.

EFFECT OF CLINICAL CONDITIONS ON THE MOVEMENTS

Observations of practical value have been made on the behavior of the
peristaltic wave after various intestinal operations. After an end-to-end
anastomosis of the gut, no evidence can be obtained by the x-ray method
that any hesitation occurs in the movement of the shadows at the anas-
tomosis. On the other hand, when a lateral anastomosis is established,
stagnation of the food in the region of the junction may occur, this
having been found, on opening the gut, to be caused by the accumu-

THE MECHANISMS OF DIGESTION 505

lation of hair and undigested detritus at the opening between the op-
posed loops. Another objection to lateral anastomosis is the fact that
in performing the operation a considerable amount of the circular muscle
is cut, which interferes with peristaltic activity. Moreover, the end of
the proximal loop beyond the opening is in danger of becoming filled up
with hardened material, and the end of the distal loop may become
invaginated and induce obstruction in the region of the anastomosis.

Observations have also been made by the x-ray method on the be-
havior of the intestinal contents following intestinal obstruction. It has
been observed that, as the material collects in the gut just above the
obstruction, strong peristaltic waves are set up, which move the food
toward the obstruction so powerfully as to cause the walls of the canal
in front to become bulged, until at last the pressure causes the con-
tents to be squirted back through the advancing ring of peristaltic con-
traction. These waves were observed to succeed one another rapidly.
When a portion of gut is reversed in position, the peristaltic waves con-
tinue to travel in their old direction toward the duodenum. The effect of
this is to produce a partial obstruction at the upper end of the re-
versed gut.

The type of peristalsis known as the peristaltic rush can be induced
experimentally in animals by intravenous injection of ergot. It prob-
ably also occurs in conditions of abnormal irritation of the gut in man,
and is believed to be the characteristic activity of the gut after a
strong purge.

CHAPTER LVI

HUNGER, APPETITE AND THIRST

The sensations of hunger and appetite are due to different causes, the
former being definitely correlated with contraction of the empty stomach,
and the latter being a complex of sensations operating in the nervous
system along with memory impressions of the sight, taste, and smell of
palatable food. Appetite is therefore a highly complex nervous integra-
tion, whereas hunger is a much simpler process. It is particularly with
hunger that we shall concern ourselves at present.

Hunger

When a thin-walled rubber balloon of proper size is placed in the
stomach and connected by a rubber tube with a water, bromoform or
chloroform manometer (made of wide glass tubing 1.5 cm. in diameter
and provided with a suitable float on the free limb) a tracing may be
taken of the movements of the stomach (Fig. 166). For use on man the
capacity of the balloon should be from 75 to 150 cubic centimeters. The
record thus obtained when the balloon is placed in the empty stomach of a
normal person shows four types of wave. Two of these may be discounted,
being due to the arterial pulse and the respiratory movements. The
third is known as the tonus rhythm, and is caused by tonic contractions
of the fundus of the stomach of varying amplitude. The periods of tonus in-
crease during the powerful rhythmic contractions to be immediately
described. While these changes in tone. are occurring, no subjective sen-
sation of hunger is experienced. (See Fig. 167.)

The fourth and most significant type consists of powerful rhythmic
contractions, alternating with periods of quiescence. These contrac-
tions occupy a period of about twenty seconds, and are superimposed
upon the tonus rhythm. They gradually increase in amplitude and fre-
quency; and, in the case of young and vigorous persons, may pass into
a condition of incomplete tetanus, after which they suddenly subside,
leaving only a faint tonus rhythm. The rhythmic contractions are defi-
nitely associated with the sensation of hunger, and are more marked
the more intense the sensation is. When tetanus occurs the hunger sen-
sation is continuous, but it instantly disappears when the tetarlus gives
place to relaxation.

50G

HUNGER AND APPETITE

507

When the contractions are comparatively feeble, the length of the period during
which they occur is about twelve minutes. When the contractions are powerful, the
periods are always initiated by weaker contractions with long intervening pauses;
finally the pauses disappear and the contractions become more and more pronounced
until, as above mentioned, a virtual tetanus lasting from two to five minutes, may
supervene. The duration of the entire hunger period varies from one-half to one
and a half hours, with an average of from thirty to forty-five minutes, and the num-
ber of individual contractions in a period varies from twenty to seventy. Between the
hunger periods, intervals of from one-half to two and one-half hours of quiescence
may supervene. (See Fig. 168.)

Similar contractions, often passing into incomplete tetanus, have been
observed in the stomach of healthy infants, some of the observations hav-
ing been made before the first nursing. The intervals of motor quies-
cence between the hunger periods are shorter than in adults. In obser-

Fig. 166.— -Diagram of method for recording stomach movements. B. rubber balloon in stomach.
D, kymograph. F, cork float with recording flag. M, manometer. L, manometer fluid (bromo-
form, chloroform, or water). R, rubber tube connecting balloon with manometer. S, stomach.
T, side tube for inflation of stomach balloon. (From Carlson.)

vations made during sleep, it was observed that, when the contractions
were very vigorous, the infant would show signs of restlessness and
might awake and cry. As in the adult, the contractions are evidently
associated with subjective sensations of hunger. Contractions of the
empty stomach have also been recorded on a large variety of animals,
including the dog, rabbit, cat, guinea pig, bird, frog and turtle. They
vary somewhat in type in different animals.

With regard to the time of onset of the tonus and hunger contractions,
it has been observed that the only period during which the fundus is
free of them is immediately after a large meal. After a moderate meal
the tonus rhythm begins to appear in about thirty minutes. It gradually
increases in intensity, until by the time the stomach has nearly emptied

508 DIGESTION

itself the tonus has become conspicuous, and the stronger hunger con-
tractions usually begin to appear. Superimposed upon those of the
tonus rhythm, hunger pangs may appear in man when the stomach still
contains traces of food.

By studying the shadow of the outline of the stomach produced by

Fig. 167. — Tracing of the tonus rhythm of the stomach (man) three hours after a meal. (From

Carlson.)

having a person or animal swallow two balloons, one inside the other
and with a paste of bismuth subnitrate between them, it has been ob-
served that the weaker type of hunger contraction begins as a con-
striction involving the cardiac end of the stomach, and moving toward
the pyloric end as a rapid peristaltic wave. When the contractions are

Fig. 168. — Tracings from the stomach during the culmination of a period of vigorous gastric hunger
contractions. One-half original size. (From Carlson.)

very vigorous, this wave spreads so rapidly over the stomach that it is
difficult to determine whether it really occurs as a very rapid peristalsis
or as a contraction involving the fundus as a whole. These contractions
resemble very closely the movements that have sometimes been observed

HUNGER AND APPETITE

509

after a bismuth meal, and which have been thought by clinical observers
to indicate a hyperperistalsis of the stomach. The fundus is therefore
not entirely passive during digestion; for, although early in this act
there may be no evidence of contraction, yet the contractions of the tonus
rhythm may appear and become pronounced before the stomach is en-
tirely empty. In other words, the digestion contractions of the filled
stomach (see page 485) pass gradually over into the hunger contractions
of the empty organ.

Remote Effects of Hunger Contractions. — It is well known that during
hunger certain general subjective symptoms are likely to be experienced,
such as a feeling of weakness and a sense of emptiness, with a tendency to
headache and sometimes even nausea in persons who are prone to headache
as a result of toxemic conditions. Headache is likely to be more pronounced
or perhaps present only in the morning before there is any food in the stom-
ach. These symptoms indicate that hunger contractions are associated with

M i

\ , \ L

j

- 1

i

!

. L_

Fig. 169. — Showing augmentation of the knee-jerk (upper tracing) during the marked hunger con-
tractions (lower tracing). (From Carlson.)

hyperexcitability of the central nervous system, and it is of considerable
interest that objective signs of this association can be elicited. If the
knee-jerk be recorded along with a record of the gastric contractions, it
will be found that it is markedly exaggerated simultaneously with the
strong hunger contractions of the empty stomach, this augmentation
being greatest at the height of the stomach contractions, when the hun-
ger pangs are most intense, and falling off again to normal when these
disappear (Fig. 169). Further changes occurring during the hunger
period include an increase in the pulse rate and vasodilatation. By
comparing plethysmographic tracings of the arm volume (see page 209)
and stomach contractions, it has been found that the increase in volume
occurs pari passu with the increasing tonus of the stomach, but that it
begins to shrink before the stomach contraction has reached its maximum.
Occasionally, however, as in acute hunger, a somewhat different rela-

510 DIGESTION

tionship obtains, vasoconstriction being more prominent. During each
hunger contraction there is also increased salivation, the degree of
which varies with different individuals. This salivation is independent
of the more copious "watering of the mouth" that accompanies the
thought or sight of appetizing food.

Hunger During Starvation. — During enforced starvation for long periods
of time, it is known that healthy individuals at first experience intense sen-
sations of hunger and appetite, which last however only for a few days, then
become less pronounced and finally almost disappear. It is of interest to
know the relationship between these sensations and the hunger contractions
in the stomach. This has been investigated by Carlson and Luckhardt, who
voluntarily subjected themselves to complete starvation, except for the
taking of water, for four days. During a great part of this time records
of the stomach contractions were taken by the balloon method, and it
was found that the tonus of the stomach and also the frequency and
intensity of the hunger contractions became progressively more pronounced
as starvation proceeded. Towards the end of the period it was also noted
that incomplete hunger tetanus made its appearance where ordinarily,
as in Carlson's case, this type of hunger contraction was infrequent.
Sensations of hunger were present more or less throughout the period,
being therefore probably due to the persistently increased tonus. The
onset of a period of hunger contraction could usually be foretold by an
increase in the hunger sensation, and as these contractions became more
marked, the hunger sensations became more intense. On the last day of
starvation a burning sensation referred to the epigastrium was added to
that of hunger. The appetite ran practically parallel with the sensa-
tion of hunger, and both of these sensations became perceptibly dimin-
ished on the fourth or last day of starvation, this diminution being,
however, most marked in the sensation of appetite. Indeed, instead of an
eagerness for food, there developed on the last day a distinct repugnance
or indifference towards it. Accompanying these sensations of hunger
and appetite a distinct mental depression and a feeling of weakness were
experienced during the latter part of the starvation period.

On partaking of food again the hunger and appetite sensations very
rapidly disappeared, and also practically all of the mental depression
and a great part of the feeling of weakness. Complete recovery from
the latter, however, did not take place until the second or third day
after breaking the fast. From this time on both men felt unusually
well; indeed they state that their sense of well-being and clearness of
mind and their sense of good health and vigor were as greatly improved
as they would have been by a month's vacation in the mountains. They
further point out that, since others who have starved for longer periods

HUNGER AND APPETITE , 511

of time unanimously attest to the fact that, after the first few days, the
sensations of hunger become less pronounced and finally almost dis-
appear, they must have experienced the most distressing period during
their four days of starvation. Although the hunger sensation was
strong enough to cause some discomfort, it could by no means be called
marked pain or suffering, and was at no time of sufficient intensity to
interfere seriously with work. Mere starvation can not therefore be
designated as acute suffering. It is of further interest to note that dur-
ing the starvation period a continuous flow of secretion of acid gastric
juice was found to be occurring in the stomach, to the presence of which
acid or burning sensation experienced in the epigastrium on the last days
is probably to be attributed.

Control of the Hunger Mechanism. — The control of the hunger mecha-
nism, like that of any other mechanism in the animal body, may be ef-
fected through the nervous system or it may depend on the presence of
chemical substances or hormones in the blood. As a matter of fact, it
can readily be shown that both those methods of control are employed,
and we will now consider briefly some of the facts upon which this con-
clusion depends.

Although many facts are now known with regard to the nervous control of the
hunger mechanism, it is difficult to piece these together in such a way as to formulate
a simple theory which fits in with all the observed facts. We know that the stomach
possesses in itself a local nervous mechanism by which, like the heart or intestine, it
can automatically perform many of the movements which are exhibited in the intact
animal. These local movements may, however, be considerably influenced by impulses
transmitted to the stomach along the vagus and splanchnic nerves. We have therefore
to seek for evidence indicating the relative importance of the local nervous mechanism
in the stomach itself and of the impulses transmitted to this organ by the extrinsic
nerves. We must then seek the position of the center which perceives the sensation
of hunger.

It will be simplest to consider first the effect of- section of the extrinsic nerves in
observations made on lower, animals. Section of the splanchnic nerves increases gas-
tric tonus and augments the gastric hunger contractions. Section of both vagus nerves,
performed of course below the level of the heart, leaves the -stomach in a more or less
hypotonic condition. The tonus is not entirely abolished; it varies somewhat from
day to day, and may become quite pronounced even though the vagi are cut. In this
hypotonic state the hunger contractions are diminished in rate and regularity. Sec-
tion of both the splanchnic and vagus nerves throws the stomach into a permanent
hypotonus, except in prolonged starvation, when hunger contractions develop that are
usually of great amplitude and with particularly long intervals between the contrac-
tions. The general conclusion to be drawn from these experiments is that, although
completely isolated from the central nervous system, the stomach still exhibits typical
hunger contractions, which must therefore be essentially dependent upon an automatic
mechanism in the stomach wall itself. Over this mechanism, extrinsic nerve impulses
have merely a regulatory control.

Variations and Inhibitions of the Hunger Contractions. — The afferent

512 DIGESTION

stimuli that may set up impulses traveling by the extrinsic nerves
to the stomach are convoyed by the nerves of sense or are of psy-
chic origin. Stimulation of the gustatory end organs in the mouth, as
by chewing palatable food, always causes an inhibition of the tonus
and a diminution or disappearance of the hunger contractions. Even the
chewing of indifferent substances, such as paraffin, suffices to produce
distinct inhibition, unless in a case in which the contraction has passed
into a tetanus. It is of interest that swallowing movements, in the ab-
sence of any food substance in the mouth, are sufficient to produce a
transitory inhibition of the gastric tonus — a receptive relaxation of the
stomach, as it has been aptly called. The diminution in tonus and
hunger contractions in these various ways is accompanied by a diminu-
tion in the hunger pains.

Afferent nerve stimulation affecting the hunger contractions may also originate in
the stomach mucosa itself, as has been shown by Carlson on his patient by introducing
the various substances to be tested through a tube into the stomach. A glassful of
cold water introduced in this way inhibits the tonus and the hunger contractions for
from three to five minutes unless these are severe, this inhibition being followed by no
augmentation either of the tonus or of contractions. Ice-cold water has a greater
effect than water at body temperature. This result is somewhat different from that
which most men experience as the result of drinking a glass of cold water.

Weak acids of strengths varying up to that found present in the gastric juice itself
— 0.5 per cent — cause a marked inhibition of the hunger movements, but this inhibition
does not persist until all the acid has escaped from the stomach or been neutralized,
which explains why hunger contractions should still occur when an acid secretion is
present in the stomach, as in starvation. Normal gastric juice itself produces an in-
hibition, which is no doubt dependent upon the acid which it contains, and it is prob-
able that, at the same time that it leads to inhibition of the hunger contractions, the
acid initiates peristalsis of the pyloric region (see page 487). Weak alkaline solu-
tions have no greater effect on the hunger contractions than an equal volume of water.
Weak solutions of local anesthetics, such as phenol or chloretone, are without effect.

With regard to alcoholic beverages interesting results were obtained. Wine, beer,
brandy, and diluted pure alcohol inhibit both the tonus and the contractions. The
duration of this inhibition varies directly with the quantity of the beverage intro-
duced into the stomach and with its alcohol percentage. These observations are ap-
parently not in harmony with the experience of most men that the taking of alcoholic
beverages serves to awaken or increase the appetite, the difference being no doubt due
to the fact that appetite and hunger contractions of the stomach are not dependent on
each other, appetite being, as we have seen, a complex psychic affair, whereas the
hunger contractions depend upon a local mechanism in the stomach wall itself.

As the inhibition produced in one or other of these ways passes off,
the hunger contractions are resumed at their previous intensity and not
in an augmented form. From the promptness of the inhibition, it would
appear that the stomach contractions are affected, not reflexly through
the central nervous system or by changes in the chemical composition
of the blood, but by a direct action on the neuromuscular mechanism

llUNGEfe AND APPETITE

in the stomach walls, and it is important to bear in mind that the
inhibitory effects on the stomach contractions of the fundus may proceed
quite independently of the changes in the pyloric region that are con-
cerned with the mechanical processes of digestion. After one or both
of the extrinsic nerves of the stomach were severed in dogs, a certain
degree of inhibition could still be induced by the above methods, indicat-
ing that, although section of the extrinsic nerves depresses the inhibitory
reflex, it does not abolish it.

Various mitigations of the hunger contractions have been discovered.
Smoking has this effect, and compression of the abdomen by tightening
the belt also inhibits the contractions provided they are not of marked
intensity. Considerable muscular exercise, such 'as brisk walking or
running, causes inhibition, which usually persists until after the exer-
cise is discontinued. When the tonus and contractions return, in this
case, they seem to be somewhat more pronounced. Application of cold
to the surface of the body — as by placing an ice pack on the abdomen
or taking a cold douche, procedures which are well-known to induce
increased neuromuscular tonus, in general — causes an inhibition of the
gastric tonus and hunger contractions, the degree of which is roughly
proportional to the intensity of the stimulation. There is certainly never
an increase in the gastric tonus or hunger contractions. If such stimula-
tion is maintained, the inhibitory effects on the stomach gradually
diminish, even though the individual be shivering intensely.

With regard to the nerve centers concerned in these phenomena, little that is definite
is known. The sensory nuclei of the vagus nerve in the medulla must be considered
as the primary hunger center, and through this center, not only influences affecting the
stomach contractions, but also those associated with the hunger sensations, must be
mediated. It would appear from observations on the hunger behavior of decerebrate
animals that there can be no hunger center located on the cerebral cortex itself, for
such animals exhibit practically the same hunger effects as normal animals. It is in-
teresting to note that, at least in the case of deeerebrate pigeons, this hunger behavior
entirely disappears on removal of the optic thalami, where important nerve centers hav-
ing to do with the bodily responses of the animal to hunger impulses would therefore
appear to be located. These observations support the suggestion that has been made
by several neurologists that the sense of pain is located somewhere in the thalamic
region.

Concerning the influence of psychic states, Carlson says that in his
own case the hunger contractions became weaker and the intervals
between them greater when he was suddenly awakened during his
fast and saw two of his friends partaking at his bedside of a "feast of
porterhouse steak with onions, potatoes, and a tomato salad." These
results are no doubt due to local inhibition dependent upon the psychic
secretion of appetite gastric juice. When no such juice is produced,
the sight and smell of good food does not appear to affect materially

514 DIGESTION

the hunger contractions of the stomach. No doubt it stimulates the
appetite, but that, as we have seen, is a psychic affair.

Thirst

The Sensation of Thirst has been believed by some observers to be a
general one either dependent primarily upon dehydration of the tissues
of the body, including those of the central nervous system, or resulting
secondarily from a rise in the osmotic pressure of the blood the hyper-
tonicity producing disturbances in the nerve cells. It is probable, how-
ever, that the thirst sensation is a purely local one, namely, drying of the
mucous membranes of the mouth and pharynx. This view is supported
by the fact, that if the pharynx of a person suffering from thirst be
painted with a solution of cocaine all craving is relieved and it does not
return until the effect of the anesthetic has passed off. That thirst
•may be produced through the drying of the interior of the mouth as by
prolonged speaking, or mouth breathing, is common experience. Admin-
istration of atropine acts similarly by inhibiting the oral secretions.
According to Cannon21 the salivary glands play the chief role in the
mechanism for the production of the thirst sensations. He finds that the
secretion of these glands, which normally moistens the interior of the
mouth and pharynx, is reduced markedly (60 to 75 per cent) after a
few hours of abstinence from fluids. Since the composition of the sali-
vary secretion is from 97 to 99 per cent water it is readily seen how
a fall in the general water content of the body would bring about a re-
duction of salivary flow with consequent drying of the oral and pharyn-
geal mucous membranes. This view ascribes to the salivary glands the
important duty of keeping sentinel over the water content of the body,
the sensation of thirst being the signal which warns the organism that
the tissue fluids require to be replenished.

CHAPTER LVII

THE BIOCHEMICAL PROCESSES OF DIGESTION

In a book designed primarily for clinical workers, it would be out of
place to enter into details concerning the biochemical processes taking
place during the digestive process. There is, however, a certain amount
of fundamental knowledge which it is essential that we should consider.
In the first place it should be borne in mind thait in the digestion of
carbohydrates and proteins, various intermediate stages are passed
through before the final absorption products are formed. The highly
complex molecule of which protein, for example, is composed, is first
of all broken down into several smaller but still highly complex mole-
cules, each of which then undergoes further disruption, until ultimately
the amino acids are set free. Certain enzymes, such as trypsin, can
carry this process from the beginning through the greater part of its
course without the assistance of other enzymes, but in the natural proc-
ess of digestion, as it occurs in the gastrointestinal tract, the different
stages of the disruption are controlled by different enzymes. One enzyme
prepares the food for action by the next. This interdependence of their
actions demands that some provision should be made whereby each en-
zyme is secreted at the proper time; that is, when the foodstuff has al-
ready been prepared for its action by that of its predecessor. Thus, it
would be useless after food is taken for the gastric and pancreatic
juices to be secreted at the same time. Instead, the gastric juice is
secreted first, and the pancreatic only after the food has been prepared
for its action. This correlation in function we have already seen to be
dependent largely on the action of hormones.

DIGESTION IN THE STOMACH

The gastric juice contains two important digestive agencies: (1) the
enzyme, pepsin, and (2) hydrochloric acid. It is particularly in juices
secreted in the cardiac end of the stomach that these two substances are
found present; towards the pyloric end the hydrochloric acid entirely
disappears, and the pepsin content becomes distinctly less.

515

516 DIGESTION

The Functions of Hydrochloric Acid

The functions of hydrochloric acid may be conveniently divided into
physiological and biochemical. The former functions have to do with
the control of the movements of the stomach, including the opening
of the pyloric sphincter, and, after the chyme has entered the duodenum,
with the secretion of pancreatic juice and bile. The biochemical functions
are concerned: (1) in assisting the pepsin in the digestion of proteins,
(2) in bringing about a certain amount of inversion of disaccharides,
and (3) in having an antiseptic action on the stomach contents. Re-
garding the last mentioned of these functions, it may be said that the
chyme, as it is ejected from the stomach, is usually sterile, although it
may contain spores and certain bacteria that are protected against the
digestive agencies of the stomach. This protection is afforded by an
outer covering of a chitinous nature (spores), or, as in the case of the
tubercle bacillus, by a covering of waxlike material. It is believed that
persons with strictly normal digestion are much less liable to infection
by such bacteria, as those of typhoid and cholera, than persons with less
active gastric secretion. When the acid of the gastric juice falls below
the level at which it develops an antiseptic action, various bacteria and
yeasts grow in the stomach contents, producing by the resulting fermen-
tation irritating organic acids and gases. It is under these conditions
that yeasts, sarcinae, and lactic and butyric acid bacilli find in the gastric
contents a suitable nidus on which to grow.

THE AMOUNT OF ACID

It has long been known that considerable variations in the amount of
hydrochloric acid in the gastric juice are associated with symptoms of
indigestion. On this account a more or less elaborate technic has been
developed for the purpose of determining the amount of hydrochloric
acid in the gastric contents.*

There are three things in connection with this activity that we may measure: (1)
the total titrable hydrochloric acid; (2) the free hydrochloric acid; and (3) the actual
hydrogen-ion concentration. The determination of the total available acids is made by
titrating a measured quantity of gastric juice against a standard alkali, using phenol-
phthalein as an indicator. By this method about 75 c.c. of decinormal alkali solution
are required to neutralize 100 c.c. of normal gastric juice. The determination of the
free hydrochloric acid is made by using special indicators, such as those of Giinzberg
and Tb'pfer, which change color at a hydrogen-ion concentration of about 10-s (see
page 27). To produce this hydrogen-ion concentration, a considerable quantity —
0.05 per cent or more — of an organic acid is necessary, whereas it requires only a
trace of hydrochloric acid. Normal human gastric juice, when titrated with one of

*The methods can be found in any volume on clinical diagnosis.

THE BIOCHEMICAL PROCESSES OF DIGESTION 517

these indicators, gives a figure which corresponds to about 0.03 N. hydrochloric acid
(see page 22). For the accurate determination of the hydrogen-ion concentration, it
is necessary to use the gas-chain method (see page 29).

, When gastric juice is collected through a fistula from an empty
stomach, very little difference will be found between the free hydro-
chloric acid and the total acid; that is, between the results obtained by
the second and the first of the methods described above. This is because
in such juice there is no organic matter capable of combining with the
hydrochloric acid, and there are no other acids, such as lactic or butyric,
which might be produced by fermentative processes. The difference
between the two titrations, however, becomes marked when protein
food is undergoing digestion in the stomach, because at its different
stages of digestion protein combines with increasing quantities of the
hydrochloric acid. The pathological condition in which there is most
definitely a diminution of the hydrochloric acid is cancer, either of the
stomach itself or occasionally of some other part of the body. An in-
crease is particularly marked in ulcer of the stomach. A considerable
variation in hydrochloric acid may however be the result merely of func-
tional (neurotic) conditions.

THE SOURCE OF THE ACID

A question that has puzzled physiologists for many years concerns the
mechanism by which hydrochloric acid is secreted. The percentage of
hydrochloric acid in the gastric juice is considerably above that at which
any animal cells can live, and yet this acid is secreted by the lining
membrane of the stomach, its source being, of course, the sodium
chloride of the blood plasma. How then do the cells of the gastric
glands bring about the separation of this powerful acid from the per-
fectly neutral blood plasma ? In the first place, it is significant that the
mucous membrane of the stomach contains a higher percentage of
chlorine than the average of other organs and tissues, indicating that it
has the power of abstracting chlorine from the blood. The excess of
chlorine in the mucosa must, moreover, be but a very small fraction of
that actually secreted into the the gastric juice. The chlorine content
of the mucosa of the cardiac end is considerably greater than that of the
pyloric. These facts indicate that chlorine is attracted by the gastric
cells, but they throw no light on the question as to where the hydro-
chloric acid is really formed. Is it in the cells, or only in the lumen of
the gland tubes? That is to say, is it formed before or after the gastric
juice has been secreted from the cells? After intravenous injection of
solutions of potassium ferrocyanide and some inert salt of iron, such as
one of the scale preparations, examination of the gastric glands has

518 DIGESTION

shown that the prussian blue reaction, which requires the presence of
free mineral acid, is most pronounced in certain of the parietal cells. A
considerable amount of the precipitate is, however, also visible in the
lumen of the glands and in the stomach itself. Certain observers affirm
that, although some of the parietal cells may take the stain, the vast
majority of them do not do so; and, moreover, that cells incapable of
forming hydrochloric acid (e. g., of the liver) may also become stained,
and that the precipitation may occur in the blood and lymph.

The confusion in the results by these methods prompted A. B. Macal-
lum22 and Miss M. P. Fitzgerald to investigate the distribution of the
chlorine in the cells by a microchemical method, in which the chlorides
were precipitated with silver nitrate and the silver chloride then reduced
by exposing the section to light. It was found that both kinds of gas-
tric-gland cell, chief and parietal, but particularly the parietal, gave the
chloride reaction. Using as a stain a substance (cyaninine) which reacts
blue with acid and red with alkali, Harvey and Bensley,23 however, aver
that the secretion of the glands is practically neutral until the foveola is
reached, where the stain becomes blue, indicating an acid reaction.
This seems to show that the acid is not really secreted by the cells of
the gastric gland, but is formed after secretion.

According to the latter investigators, the chlorine is secreted by the
cells into the fovea as some weak chloride, such as ammonium chloride,
or it may be as an ester. Shortly after its secretion this weak chloride
undergoes a hydrolytic or other dissociation, during which free hydro-
chloric acid is liberated and ammonia or some other weak base set free.
Of these two products of the reaction the weak base is reabsorbed by
the gland cells, but the hydrochloric acid is left behind because the
cells are impervious to it. Indirect evidence in support of this view is
afforded by certain other instances in which hydrochloric acid is pro-
duced by the action of cells ; thus, the mould Penicillium giaucum when it
is grown in a medium containing ammonium chloride absorbs the am-
monia but leaves the hydrochloric acid. The high penetrating power
of the ammonia ion in practically all cells, and the fact that the mucosa
of the stomach contains a higher percentage of ammonia than any other
tissue in the body, must also be considered as circumstantial evidence
in favor of this view.

Whatever be the mechanism by which hydrochloric acid is produced,
there is no doubt that the epithelium is impenetrable by it. When the
vitality of the epithelium becomes lowered, as in anemia or after partial
occlusion of the arteries, the acid may penetrate the cells and cause
digestion of the stomach walls. Hyperacidity may on this account
become dangerous, as it lowers the resistance of the cell.

THE BIOCHEMICAL PROCESSES OF DIGESTION 519

The digestive action of hydrochloric acid is closely linked with that of
pepsin, with which it will, therefore, be considered.

The Action of Pepsin

It is commonly believed that before its secretion pepsin exists in the
cells of the gastric glands as zymogen granules. The chief evidence for
this belief appears to be that after considerable activity the amount of
zymogen granules in the gland cells is found to be decidedly dimin-
ished. By such an hypothesis it is easy to explain certain interesting
results concerning the effect of weak alkali on the activities of extracts
of the mucous membrane of the stomach. When the mucous membrane
is extracted with weak acids, the extract is very active proteolytically.
If this so-called pepsin solution be made faintly alkaline, or even only
neutralized, and again made acid, it will be found to have lost much,
if not all, of its activity. On the other hand, an aqueous extract may be
rendered slightly alkaline for a short time and still display its digestive
activity on subsequent acidification. The extract made with water is
therefore much more resistant toward alkali than that made with weak
acid, and the difference is explained on the supposition that the watery
extract contains pepsinogen, whereas the acid extract contains pepsin.

It is believed that there are several varieties of pepsin, because the optimum con-
centration of acid in which pepsin, derived from the stomachs of different animals, acts
is not always the same. Pepsin of the dog, for example, acts best in a hydrogen-ion
concentration corresponding to that of a 0.05 N. hydrochloric acid solution, whereas
that of the human stomach works best at a concentration of 0.03 N. Different pepsin
solutions also show a difference with regard to the optimum temperature at which they
act, and with regard to the nature of the protein which they most readily attack. Thus,
the pepsin of a calf's stomach digests casein very rapidly, but coagulated egg white
only slowly, whereas the pepsin of the pig's stomach acts on both these proteins at
about the same rate.

It is well known that the activity of pepsin can proceed only in the presence of
acids, but this action of acids does not appear to depend on the hydrogen-ion concen-
tration alone, for when equal quantities of the same pepsin are mixed with quantities
of different acids so that the hydrogen-ion concentration of the mixtures is uniform,
it is found that digestion proceeds most rapidly with hydrochloric acid and least
rapidly with sulphuric acid. The SO4 ion seems, therefore, to be unfavorable for
peptic activities. The acid seems to combine with the protein before the pepsin attacks
the latter; for, if we first combine the protein with acid and then wash away all
traces of free acid, the protein can be digested in a neutral pepsin solution without the
liberation of any free acid.

There is evidence to show that pepsin itself also becomes combined with the pro-
tein during the digestive process. If a piece of protein such as fibrin be immersed
in a solution of pepsin and then taken out and washed thoroughly to get rid of all
adherent pepsin, it will be found, 011 placing it in a hydrochloric acid solution of the
proper strength, that peptic digestion proceeds. Advantage may be taken of this fact
to separate pepsin from a solution, but the best protein to use for this purpose is

520 DIGESTION

not fibrin but elastin. By such a method it has, for example, been shown that there
is some pepsin in the intestinal .contents, which indicates that when the chyme passes
into the intestine, the pepsin is not, as used to be thought, immediately killed by the
proteolytic enzyme.

PRODUCTS OF PEPTIC DIGESTION

With regard to the products of peptic digestion, little can be said
here. The first product is a metaprotein known as acid albumin or
syntonin. It is precipitated from the digestion mixture by neutraliza-
tion. The next product is known as primary proteose, being precipi-
tated by half saturation with ammonium sulphate. The third product
is secondary proteose, produced by complete saturation with the above
reagent; and after all these bodies have been separated out, there re-
mains in solution the fourth product — peptone — which among other
things is characterized by the fact that with the biuret test it gives not
a violet but a rose-pink color.

It has often been claimed that along with these products a certain
amount of free amino acids may also appear in a peptic digestive mix-
ture. This, however, may be due to the action of erepsin, which is
usually present in pepsin preparations. It is important to note that the
term proteose is a general one, and that there are probably many varieties
of this substance, differing from one another according to the protein
from which they are derived.

The change produced by pepsin and hydrochloric acid is of the nature
of an hydrolysis, for it has been found that the amount of hydrogen and
oxygen in the digestive products is greater than that in the original
protein. It is by a similar process of hydrolysis that the other proteolytic
enzymes, such as pancreatin and erepsin, operate, but this does not
imply that the exact grouping that is split apart by the hydrolytic proc-
ess is the same for each of these enzymes. Indeed, there is considerable
evidence that pepsin does not, like the other enzymes, break up the long
chain of amino acids that are linked together to compose the polypep-
tides, but that it only splits the big molecule of albumin or globulin
into several large groups, each of which is composed of long amino-acid
chains. Its action appears to be analogous with that of amylase on
starch, by which, it will be remembered, the big polysaccharide mole-
cule is split into smaller polysaccharide molecules, which then become
attacked by the dextrinase and split into disaccharide molecules (see
p<)<i'e 689). The evidence in support of this view is: (1) that pepsin is
unable to digest polypeptides, and (2) that it is able to digest certain
proteins upon which erepsin (see page 524) has no action.

The hydrolytic splitting of large into smaller protein molecules, like
that by which the chains of ammo acids in the polypeptides are subso-

THE BIOCHEMICAL PROCESSES OF DIGESTION 521

quently broken up, consists in a breaking of amino-carboxyl linkings
(NHCO) (see page 634), with the consequent liberation of a large num-
ber of unattached amino groups. The number of these free ammo groups
can be determined quantitatively by the formaldehyde titration method
of Sorensen.* By this method it can be shown that from the very start
of peptic digestion the number of free amino groups increases, and pari
passu the power of the digestive products to combine with free hydro-
chloric acid. Indeed, when the experiments are done quantitatively and
the digestion allowed to proceed for a considerable time, the increase in
the formol titration is practically equal to the decrease in the free acids
as determined by the Giinsberg reagent.

The rate of peptic digestion is usually estimated by the law of Schiitz
and Borissow, according to which the amount of coagulated albumin
that is digested in a Mett's tube is proportional to the square root of the
amount of pepsin, f

The pepsin which leaves the stomach in the chyme is not all destroyed
in the intestine, as was at one time believed to be the case, for, as we
have seen above, some pepsin can be detected in the gastrointestinal con-
tents. A part of the pepsin may be absorbed into the blood and carried
back to the gastric glands to be used again. This would account for the
presence of antipepsin in the blood, and' also for the presence of pepsin
in the urine. It is probable, however, that most of the pepsin is de-
stroyed after it enters the intestine.

Clotting of Milk in the Stomach

Besides its power of digesting protein, the gastric juice is also endowed
with the property of clotting milk. This action is commonly attributed
to the presence of another enzyme besides pepsin, namely, rennin; but
in recent years considerable controversy has raged around the question
as to whether pepsin and rennin are not the same thing. One strong
argument in favor of this view is that all digestive juices that are capable
of digesting protein can also clot milk. In any case, when gastric juice
acts 011 milk, it splits the casein! of the milk into two portions, one of
which, called paracasein, immediately combines with calcium to form an
insoluble colloidal compound, which is precipitated and, by entangling
the fat of the milk, forms the clot; the other protein remains in solution

*In this method the basic character of the amino acids is destroyed by the formaldehyde, so
that a higher decree of acidity develops in the mixture. By determining the increased acidity bv
titration with alkali, an estimate is obtained of the number of amino groups. (See page 635.)

fThe amount of coagulated egg albumin digested is ascertained by measuring the length digested
away from the end of a column of coagulated egg white contained in a glass tube (Mett's method).
(See Cobb, P. W. : Am. Jour. Physiol., 1905, xiii, 448.)

Jin Hie above nomenclature casein is the same as easeinogen, and paracasein tin- same as casein,
of the Knglish physiologists.

522 DIGESTION

and is known as whey albumose. From studies on molecular weight it
is believed that the paracasein is produced from casein by the splitting
of the molecule of the latter into two, from which it would appear that
the action of this enzyme is nothing more than the first stage in the
hydrolysis of the casein molecule. The whey albumose, according to this
view, is a by-product.

There are many investigators, however, who believe that rennin and pepsin are not
identical, since an infusion of the stomach of a calf has a powerful clotting action
on milk but a very weak digestive one on egg white, whereas a similar infusion from
the stomach of a pig shows exactly the reverse properties. This question is one of so
controversial a nature that it would be out of place to go into it further here. It
should be pointed out, however, that, when the gastric contents are acid in reaction,
milk will become clotted by the action of the acid itself quite independently of any
pepsin or rennin the juice may contain. This acid clotting of milk is probably of a
different chemical nature from that produced by the enzymes.

On other foodstuffs than proteins the action of the gastric juice is
relatively unimportant, although polysaccharides may be considerably
broken down in the cardiac end of the stomach on account of the action
of swallowed saliva (see page 489), and disaccharides, as we have seen,
may become split by the hydrolyzing effect of the hydrogen ion. Fat
digestion also takes place in the stomach when the fat is taken in an
emulsified condition, as in milk "and egg yolk, but not when in masses,
as in meat or butter. This action is due to the presence of a fat-splitting
enzyme, or lipase, in the gastric juice.

CHAPTER LVIII
THE BIOCHEMICAL PROCESSES OF DIGESTION (Coiit'd)

DIGESTION IN THE INTESTINES

The further changes which the half-digested foodstuffs in the chyme
undergo in the intestinal canal depend on the enzymes present in the
secretion of the various glands and on the presence of bacteria. The
most important of the digestive juices are the pancreatic juice and bile.
The latter, however, does not contain any enzyme, its influence on diges-
tion being entirely adjuvant.

Pancreatic Digestion

When we were considering the mechanism of secretion of the pan-
creatic juice, we saw that the juice produced by the action of secretin on
the gland cells does not contain any active proteolytic enzyme, although
it contains one capable of acting on polysaccharides and another, on fat.

THE ACTION OF TRYPSIN

When pancreatic juice is mixed with the secretion of the duodenum or of
the upper part of the small intestine, it immediately develops powerful
proteolytic power. The same result may also be obtained by mixing it
with an extract of the mucous membrane of the duodenum made with
dilute bicarbonate solution. A very small amount of the extract is
capable of increasing the digestive activity of a very considerable quan-
tity of pancreatic juice, showing that the action depends on the presence
of an enzyme which has been called enterokinase. This influence of the
intestinal secretion is readily destroyed by heating.

Large quantities of alkali are contained in the pancreatic juice and
bile, so that in the upper reaches of the intestine the acidity of the
chyme is practically neutralized. A little lower down, however, an acid
reaction may again develop (see page 539). On account of these facts it
has been concluded that the activity of trypsin is most rapid in the pres-
ence of a slight excess of hydroxyl ions; i. e., in a weakly alkaline solu-
tion. It is interesting to note that, as a result of the great secretion of
alkali by the pancreas, extracts of this organ after death show a very
high degree of acidity in comparison with extracts from other organs

523

524 DIGESTION

and tissues. It has also recently been shown that the activity of trypsin
does not depend on the presence of free hydroxyl ions, but that it may
proceed in the presence of a decided amount of free acid. If pepsin
is present together with trypsin in a distinctly acid solution, the pep-
sin seems to destroy the trypsin, unless the mixture contains a con-
siderable ' quantity of protein, when the tryptic activity may persist
even for several hours. A practical conclusion that we may draw from
these results is to the effect that preparations of trypsin — the so-called
pancreatin, for example — if given with the food, may pass in an active
condition into the duodenum, where, in the more favorable environment
created by the neutralization of the excess of acid, it will develop its
proteolytic power. The therapeutic administration of pancreatin is,
therefore, justified (Long24).

The activated trypsin acts on proteins in very much the same way as
pepsin, except that the decomposition of the peptone and proteoses into
polypeptides is the chief feature of the process. Thus, after tryptic
digestion has proceeded for some time, only a trace of primary proteoses
but considerable quantities of leucine, tyrosine and other amino acids
will be found present. Some investigators believe that the thorough
nature of the digestive action of activated pancreatic juice may depend
on its also containing erepsin, an enzyme which we shall see to be pres-
ent in considerable amount in the mucous membrane of the intestine and
other tissues, and whose particular function is to split polypeptides into
the amino acids. From the autolytic digestion which takes place in
organs kept in a sterile condition after death, tryptic digestion differs
in that it produces only small quantities of ammonia. The large quanti-
ties of ammonia produced in autolytic digestion no doubt have a rela-
tionship to the acids simultaneously set free during this process.

• In the products of tryptic digestion it is usually found that, although
there has been considerable splitting of the protein into amino acids,
there are still a good many amino-carboxyl (NHCO) linkages left un-
broken, indicating that certain polypeptides are still intact in the mix-
ture. To split the polypeptides requires the aid of the erepsin, which is
present in the mucous, membrane of the intestine. Interesting inves-
tigations have been made on the exact degree to which trypsin-entero-
kinase can split up the various known polypeptides. This seems to
depend on the structure of the polypeptide molecule and on the number
of amino acids present in the chain. For example, alanylglycine, but
not glycylalanine is hydrolyzed, although both contain the same amino
acids but linked together in a different way; and tetraglycylglycine,
which contains five glycine radicles, is hydrolyzed, whereas diglycylgly-
cine, which contains only three, is not.

THE BIOCHEMICAL PROCESSES OF DIGESTION 525

The importance of the presence of erepsin in the mucous membrane
of the intestine is that it serves as a barrier to the passage of any unsplit
ammo acids from the intestinal contents into the blood. It insures the
breaking up of the protein molecule into its ultimate units before absorp-
tion. The further fate of the absorbed amino acids will b'e considered
under the subject of protein metabolism.

THE ACTION OF LIPASE

Neutral fat is decomposed into fatty acids and glycerine by the lipase
present in the pancreatic juice. This enzyme may also be extracted from
the glands by means of 60 per cent alcohol. Its action is remarkably
accelerated by the presence of bile, and considerably depressed .by inor-
ganic salts. It is also very dependent on the degree of alkalinity, the
optimum being a hydrogen-ion concentration of H x 10'8. The favoring
action of bile is undoubtedly owing to the bile salts (see page 528), and
it is probable that this action is dependent upon the influence which
these have in lowering surface tension and therefore bringing about a
more intimate contact between fat and water.

THE ACTION OF AMYLOPSIN

The action of pancreatic juice on carbohydrates depends on the
amylolytic enzyme Called amylopsin. In animals having no active ptyalin
in the saliva, amylopsin serves as the only diastatic enzyme concerned
in the digestive process. In any case, at least for the first stages of the
disruption of the starch molecule — that is, its conversion into dextrines —
amylopsin is a more powerful enzyme than ptyalin. It does not appear
to be so efficient as ptyalin in the final stages of the hydrolysis, for it
does not produce so much reducing sugar as ptyalin does. Indeed ex-
tracts of pancreas will sometimes convert starch into soluble starch and
dextrine with- great speed, but • produce scarcely any reducing sugar.
On this account it is believed by many investigators that there are at least
two distinct and separate enzymes in amylopsin and also perhaps in
ptyalin, one a true amylase, which converts starch into dextrine, and
the other a dextrinase, which converts dextrine into maltose. In the
case of both ptyalin and amylopsin digestion proceeds best in a very
weak acid reaction. Amylopsin, as it is secreted in the pancreatic juice,
is fully activated; bile, apart from the alkali which it contains, having
no influence on its digestive power.

Besides amylopsin the pancreatic juice also contains maltase, and in
the case of young animals or of those that take milk with their food
throughout their lives, lactase also. After the suckling animal has dis-

526 DIGESTION

continued taking milk, the lactase disappears from the pancreatic juice.
Attempts have been made to bring it back by feeding the adult upon
milk, but without success. Occasionally the pancreatic juice also con-
tains invertase.

The Bile

Associated with the pancreatic juice in all its functions is the bile.
When this fluid is prevented from entering the intestine, the digestive
process becomes very imperfect, the absorption of fat being particularly
interfered with (see page 722). Bile is also an excretory product, and
its composition therefore is much more complex than that of the other
digestive fluids. This varies very much, however, according to the
method of collection. Bile from the gall bladder after death contains
much more solid material, particularly bile salts and mucin, than that
collected from a fistula of the bile duct or gall bladder during life.
These differences will be evident from the accompanying table.

Bile from

Gall bladder Fistula

100 parts contain —

Water 86 97

Solids 14 3

Organic salts (bile salts) 9 0.9-1-8

Mucin and bile pigment 3 0.5

Cholesterol 0.2 0.06-0.16

Lecithin and fat 0.5-1.0 0.02-0.09

Inorganic salts , 0.8 0.7-0.8

In general it may be said that bile obtained from a fistula in man
contains only about 3 per cent of total solids, of which from one-fourth
to one-half are inorganic, whereas bile from the gall bladder contains
10 to 20 per cent of total solids, of which only about one-twentieth are
inorganic. The chief cause for this difference appears to be that when
the bile goes to the intestine, a considerable proportion of its bile salts
is reabsorbed into the portal blood and reexcreted by the liver. Some
of the difference may also be caused by the fact that absorption of
water takes place from the gall bladder, and that mucin and possibly
cholesterol are secreted by this organ. These striking differences be-
tween fistula and gall-bladder bile are observed only when the com-
mon bile duct is occluded. If the bladder fistula is made with the com-
mon duct left open, some of the bile gains entry to the duodenum and
therefore becomes reexcreted. It is well known that a fistula of the gall
bladder in man after a time closes up and the bile again takes its usual
course along the bile duct into the duodenum.

THE BIOCHEMICAL PROCESSES OF DIGESTION

Interesting observations have been collected on the amount of the secre-
tion from a fistula both in man and in the lower animals. In man it is
commonly stated that about 500 c.c. of bile are secreted daily, the
amount varying considerably during the different hours of the day. The
secretion of bile is greatly reduced by hemorrhage. It is greater on a
meat diet than on one of carbohydrates. It is reduced during starva-
tion, but continues to be secreted up to the moment of death.

FUNCTIONS OF BILE

X. One of the main functions of the bile salts is that they greatly assist,
not only in the digestion, but also in the absorption of fats.y When bile
is excluded from the intestine, the feces are loaded with fatty acids
which have been split off partly by the now less effective lipase and
partly by the action of bacteria. The fatty acid thus liberated in the
absence of bile salts is not absorbed, because the bile salts serve as the
carriers of fatty acids into the epithelial cells and lacteals. They com-
bine with the fatty acids, probably by forming some chemical compounds
in which they carry them into the endothelial cells where the compounds
become disrupted, the fatty acid combining with glycerine to again form
neutral fat and the bile salts being carried to the liver and reexcreted.
The influence of bile salts in assisting the action of lipase is probably
due to a lowering of the surface tension, thus bringing water and fat
into closer union. This accelerating influence has also been demonstrated
when synthetic bile salts have been used, showing clearly that it is really
these and not any other constituent of the bile that are responsible for
its accelerating influence.

Bile also functionates as a regulator of intestinal putrefaction. This
it does apparently because of its slight laxative properties, by which
the intestinal contents are expelled before the bacteria have grown to
any great extent in them. Bile itself is a favorable culture medium for
certain bacteria, so that it can have no antiseptic action. Its assistance
in the action of trypsin and amylopsin depends very largely upon the
alkali which it contains.

As an excretory vehicle bile is important, because it possesses the
power of dissolving cholesterol. Toxins and metallic poisons of various
kinds are also excreted in it.

Although not directly concerned with the digestive function, it will be
convenient to say something here concerning the chemical nature and
derivation of the various biliary constituents.

528 DIGESTION

THE CHEMISTRY OF BILE

The Bile Salts

In most animals the bile salts consist of the sodium salts of glycocholic
and taurocholie acids. Each of these acids is composed of a part called
cholic acid which is more or less related to cholesterol, and of glycine
(CH2NH2COOH ammo-acetic acid) or taurine (C2H7NS03), a derivative
of cysteine, which is a-amino-/?-thiopropionic acid (CH2HS.CHNH2.
COOH). The exact form of cholic acid varies in different animals, that
of the pig, for example, being different from that of man. Bile salts are
an exclusive product of liver metabolism ; i. e., they are not formed in
any other part of the animal body. They give a very sensitive color
reaction known as Pettenkof er 's, which however is not specific of bile acids,
since it is also given by oleic acid and by many aromatic substances and
alcohols. It must be remembered that the part of the bile salts that is
characteristic of the liver is the cholic acid, the taurine and glycine
being present in other tissues and organs.

When cholic acid is given to animals mixed with the food, the amount
of taurocholie acid excreted with the bile is increased, indicating that
there must be a store of taurine available in the organism. This store
can not, however, be large, for if the feeding with cholic acid is repeated
several times, it will be found that the taurocholie acid diminishes and
glycocholic acid takes its place; and this increased excretion of glyco-
cholic acid goes on just as long as cholic acid is fed. The reserve of
taurine in the animal body appears therefore to be limited, although it is
used in preference to glycine when there is an excess of cholic acid to be
neutralized. On the other hand, the store of glycine seems to be inexhaust-
ible. That there is no reserve of cholic acid itself in the body is indicated by
the fact that no increase in taurocholie acid excretion by the bile results
when cystine, the mother substance of taurine, is given with the food.
If both taurine and cholic acid be fed, however, the excretion of tauro-
cholie acid increases.

The relative amounts of taurocholie and glycocholic acids in the bile of
different animals differ considerably. Human bile contains relatively
a small amount of taurocholie acid; on the other hand, the bile of the dog
contains a large excess of it.

Cholesterol

In human bile the percentage of this important substance is not high
(1.6 parts per 1000), but it is of great clinical importance because of the
fact that it may separate out as a precipitate forming gallstones. The

THE BIOCHEMICAL PROCESSES OF DIGESTION 529

percentage of cholesterol in these varies from 20 to 90; the remainder
being organic material such as epithelial cells, inorganic salts, pigment,
etc. The origin of cholesterol is partly endogenous and partly exoge-
nous. In the former case it comes from the envelope of red blood cor-
puscles and from the nervous tissues, where it is present in considerable
amount. The latter source is, of course, the food. The increase in
cholesterol esters in the blood after feeding with food rich in this sub-
stance has been shown, particularly in rabbits. .

That the bile should be the pathway through which cholesterol is
excreted depends no doubt on the fact that it contains bile salts, which
along with their other properties have a remarkable solvent action on
cholesterol. This solvent property depends on the cholic acid part of
the bile salts, which, as already remarked, is chemically very closely
related to cholesterol; indeed, the relationship is so close that some have
suggested that cholic acid is derived from cholesterol. This would mean
that the cholesterol of blood is excreted in two ways, as cholesterol and
as cholic acid. Other observers, however maintain that the cholesterol
is excreted mainly by the lining membrane of the gall bladder, and
that this explains why gall-bladder bile contains more of it than fis-
tula bile. This evidence is, however, not very strong, for the greater
excretion of cholesterol under conditions where the circulation of bile
is going on may be explained as due to the presence of bile salts, which
serve to carry the cholesterol out of the blood.

Many problems remain to be elucidated in connection with the metabolic
history of cholesterol. That some of it is absorbed when cholesterol is
contained in the food might seem to indicate that its source is entirely
exogenous. Against this view, however, stand two facts: (1) that the
cholesterol in the feces of herbivorous animals is of the same variety as
that present in those of carnivorous animals and not the phytosterol
which is present in plants; and (2) that the universal presence of
cholesterol in cells indicates that it must be manufactured there.

The Bile Pigments

The pigments of bile are 'bilirubin and biliverdin. The latter is pro-
duced from the former by oxidation. If the oxidation be carried a
stage further, a blue pigment called bilicyanin is formed. This process
of oxidation can be observed in the ring test for bile pigment with
fuming nitric acid. When bilirubin is reduced, urobilin, one of the
pigments in urine, is formed. Bilirubin must therefore be considered
as the mother substance of all these pigments, and it is of interest in
connection with its derivation to know that it has the same formula

530 DIGESTION

as iron-free hematin or hematoporphyrin, which is produced by treating
hemoglobin with concentrated sulphuric acid.

Chemical investigation has shown that bilirubin is built up from sub-
stituted pyrrols, probably four such being contained in the molecule.
The pyrrol group is also present in indole and tryptophane, and con-
sists of four carbon atoms and an NH group linked together as a ring
(see page 639). Similar pyrrol derivatives can be produced by decom-
posing chlorophyl, the green coloring matter of plants. It is important
to remember that bilirubin is acid in nature, and, therefore, can com-
bine with alkalies to form salts. The relative amounts of bilirubin and
biliverdin vary in the bile of different animals.

When these pigments enter the intestine they are reduced to urobilin,
part of which passes out with the feces, another part being absorbed into
the blood and excreted in the urine. Part of that excreted in the urine
exists, however, as a so-called chromogen named urobilinogen. The
urobilinogen is converted into urobilin by the action of oxygen.

The method by which bile pigments are produced from blood pigment has
been studied by histological examination of the liver particularly of birds
and amphibia, in which destruction of blood pigment goes on rapidly.
Increased destruction of blood pigment can be induced by poisoning
with certain substances such as arseniureted hydrogen. From such
studies it is usually believed that the bile pigments are a peculiar product
of hepatic activity, being produced from blood pigments that are de-
rived from erythrocytes which have been broken down either in the liver
itself or in some other viscus (e. g., the spleen). Whipple and Hooper25
have brought forward seemingly incontrovertible evidence against such
a view. They have found, for example, that the bile pigments are
formed just as readily in animals in which the circulation of the liver
was greatly curtailed by anastomosing the portal vein with the vena
cava (Eck fistula) as in normal animals. Even when the circulation
was limited to the anterior end of the animal (head and thorax) bile
pigment appeared in the blood when hemolyzed erythrocytes were in-
jected, and it was also formed when hemoglobin was placed in the pleural
and peritoneal cavities. The endothelial cells of the blood vessels and
elsewhere can evidently form the pigments, at least when the liver is
absent. When such a process occurs under normal conditions, it is quite
probable that the liver acts merely as an excretory organ for the pig-
ments in the same way as the kidney does for urea. Possessed of endo-
thelial cells, the liver might itself also produce some of the pigments,
but no more than other organs with a similar number of those cells.

Even the derivation of bile pigments from hemoglobin is called in
question, for the same workers have observed that, whereas the excre-

THE BIOCHEMICAL PROCESSES OF DIGESTION 531

tion of pigment from a biliary fistula is remarkably constant in a dog
fed on a fixed mixed diet, it becajne increased, sometimes by 100 per
cent, when the diet was changed to one of carbohydrates, and depressed
on a diet of meat. The question arises as to whether, after all, the bile
pigments are really derived from broken-down hemoglobin. May they
not be manufactured de novo out of other materials?

Whipple and Hooper have also shown that bile is a most important
secretion, for dogs rarely survive on an ordinary diet if bile is perma-
nently prevented from entering the intestine. Intestinal symptoms
soon supervene, and become progressively more severe until the death
of the animal. Feeding with bile does not relieve the condition, but
feeding with cooked liver seems to have a beneficial effect.

After extravasation of blood in the subcutaneous tissues, as in a bruise,
for example, a decomposition of hemoglobin proceeds quite like that
occurring in the liver, and leads to the production of blue and brown
and green pigments like those of the bile. When hemolysis is produced,
as by inhalation of arseniureted hydrogen or the injection of inorganic
or biological hemolysins, there is an immediate increase in the amount
of bile pigment in the bile. Even the injection of hemoglobin solutions
has this effect. Under these conditions of hemolysis, besides an increase
in urobilin, there may be considerable quantities of hemoglobin secreted
in the urine.

Bile salts and pigments usually accompany each other when any-
thing occurs to interfere with the free secretion of bile. For example,
after ligation of the bile duct both bile pigments and bile salts accumu-
late in the blood, in the serum of which they may be recognized by the
ordinary chemical tests in from four to six hours after the operation.
If the accumulation be allowed to proceed further, the bile pigments
become deposited in the tissues, giving them the peculiar yellowish ap-
pearance known as jaundice. Under these conditions the bile salts and
pigments also appear in the urine. ' The accumulation of bile salts in
the body affects certain physiological processes; for one thing, it causes
a great lengthening in the clotting time of the blood.

If the blood supply to the liver is interrupted by ligation of the portal
vein and hepatic artery at the same time that the bile ducts are occluded,
not a trace either of bile salts or of bile pigment appears in the blood
during the six to eighteen hours that the animals survive the operation.

The amount of obstruction of the bile duct necessary to produce these
symptoms is very slight, since bile is secreted at a very low pressure.
Even a clot of mucus or a swollen condition of the mucous membrane
of the duct is sufficient to produce obstruction. In the discharge of bile
from the gall bladder into the duodenum it is claimed by Meltzer20 that a

532 DIGESTION

reciprocal relationship exists between the contraction of the bladder
musculature and the relaxation of the muscular fibers surrounding the
duct in the duodenum. If this reciprocal innervation fails to operate
properly, discharge of bile into the duodenum may become obstructed
so that a certain amount passes back into the blood, as in cases of bile-
duct obstruction.

Bile also contains a certain amount of lecithin and other phospholipins.
The amount varies considerably in the bile of different animals, even in
animals of the same species. It is probably derived, as already men-
tioned, like the cholesterol, from the breaking-down of red blood cor-
puscles that goes on in the liver. It is no doubt digested by the ferments
of the intestinal tract, the liberated cholin, since it is toxic if absorbed,
being further attacked by bacteria so as to become converted into cer-
tain substances of a nontoxic nature.

CHAPTER LIX

BACTERIAL DIGESTION IN THE INTESTINE

On an average diet, in twenty-four hours the feces of man weigh
about 100 grams, or after drying, about 20 grams. About one-fourth of
the dry matter consists of the bodies of bacteria. If plated out by the
ordinary bacteriologic methods, however, it will be found that only a
small proportion of these bacteria are living. The greater number have
been destroyed, probably by the action of the mucin in the large intes-
tine. The nitrogen content of the feces amounts to about 1.5 grams a
day, of which about one-half is bacterial nitrogen. If the diet contains
large quantities of cellulose material, as in green vegetable food and
fruit, the mass of feces as well as the bacterial content may be consid-
erably greater.

The foregoing facts indicate that very extensive bacteriologic proc-
esses must be going on all the time in the intestinal contents, and the
question arises as to whether such action is beneficial or otherwise to the
animal economy. To answer this question interesting observations have
been made on the growth and well-being of animals excised from the
uterus under strictly sterile conditions and maintained thereafter on
sterile food. Such observations made on guinea pigs have shown that
the animals thrive and grow perfectly for a considerable time. Experi-
ments carried out on chicks have not, however, yielded similar results.
Chicks hatched out from the egg under strictly sterile conditions and
then fed on sterile grain, do not thrive, but do so if with the grain is
mixed a certain amount of fowl excrement. These experiments, appar-
ently contradictory in their results, show that for certain groups of
animals bacteria are required, but not for others.

The difference is probably dependent on the nature of the foods. It
will be remembered that the size of the large intestine varies consider-
ably according to the nature of the diet (see page 497). Animals taking
great quantities of cellulose foodstuffs have very large ceca and very
long large intestines; whereas those which, like the cat, live practically
entirely on cellulose-free food, have a rudimentary large intestine. The
size of the lower intestine is obviously dependent on the presence or
absence of cellulose in the food. It will be remembered also that the
forward movement of the contents of the large intestine is very slow ;
indeed, special provision is made, by the presence of the so-called anti-
peristaltic wave, to delay its movement. This suggests that an important

533

534 DIGESTION

digestive process must be proceeding in this part of the gut. In these
ways conditions become established in the.cecum for the active opera-
tion of bacteria. They attack the cellulose, and liberate the more diges-
tible foodstuffs contained in the vegetable cells, also producing out of
the cellulose itself materials of nutritive value. The acids that are also
produced by this process are neutralized by the carbonates secreted
by the mucosa.

In certain herbivorous animals — the ruminants — this process in the
cecum is not relatively of such importance, because it takes place in the
paunch. The animals swallow the food and it mixes in this part of the
stomach writh the saliva, so that bacteria and ferments contained in it,
called cytases, attack the cellulose, liberating the more easily digested
foodstuffs inclosed within the cell walls. As this process goes on acids
accumulate in the digestive mixture. The food is then returned to the
mouth, chewed over again, and swallowed again into the main stomach,
where it is digested. The aid which bacteria render to digestion depends
therefore on the nature of the diet. Man, being omnivorous, stands mid-
way between the two groups of animals discussed above. Although the
cellulose contained in his food is not itself sufficiently digested to furnish
nutriment, yet it is so far acted upon as to permit the rupture of the
cell, the contents of which are then digested. The cellulose is, however,
of value in furnishing bulk to the intestinal contents — " intestinal bal-
last," it is sometimes called.

In tHe small intestine in man there are bacteria capable of acting on
carbohydrates and producing from them organic acids, such as lactic,
acetic, etc. So long as a sufficiency of carbohydrate exists to encourage
the action of these bacteria, others having an action on protein do not
seem to thrive. It may be that this is to be accounted for partly by the
production of acid substances by the carbohydrate fermentation, and
partly by the fact that, as soon as the protein molecule is broken
down by the digestive enzymes, its building-stone ammo acids are ab-
sorbed. There are probably also bacteria in the small intestine capable
of splitting fat into fatty acid and glycerine, but practically nothing is
known of their action. In the large intestine of man, along with the
cellulose-digesting bacteria already mentioned, protein-digesting bac-
teria are also present. These bacteria belong to the class, Bacillus coli
communis, the various members of which are known as facultative anae-
robes because they can -grow in the presence or absence of oxygen.

If bacterial growth is excessive or there is an insufficiency of carbohy-
drates in the small intestine, the bacteria attack the amino acids pro-
duced by the digestive enzymes and decompose them into products
that may be toxic if absorbed into the blood.

BACTERIAL DIGESTION IN THE INTESTINE 535

Bacterial Digestion of Protein

From a pathological standpoint, the most important action of bacteria
is that which takes place on protein. Under anaerobic conditions the
intestinal bacteria have in general the power of splitting off the amino
group whereas under aerobic conditions they split off the carboxyl
group. This splitting off of the carboxyl group as carbon dioxide is per-
formed by the so-called carboxylase bacteria, and it may take place either
before or after deamidization (see page 649). If it happens after this
process, the products are not highly toxic and include phenol, cresol,
indole and skatole, which are partly absorbed into the blood and partly
excreted with the feces.

The fractions of those substances that are absorbed into the blood
have their toxicity removed by conjugation mainly with sulphuric acid
to form the so-called ethereal sulphates. A part is also combined with
glycuronic acid (see page 665). In the case of phenol and cresol this
conjugation occurs immediately after absorption, but in the case of
indole and skatole it is preceded by an oxidative process, converting
these substances into indoxyl and skatoxyl respectively. The detoxica-
tion process occurs in the liver, as has been shown by experiments in
which this organ was artificially perfused outside the body. They are
then removed from the blood by the kidneys and excreted in the urine.
The proportion of ethereal sulphates in this fluid therefore gives an esti-
mate of the extent of intestinal putrefaction of protein (see page 665).
The indican, being readily detectable by the well-known color reaction
of Jaffe, serves as an indicator of excessive intestinal putrefaction.
The indole and skatole which are not thus absorbed and detoxicated are
excreted with the feces, to which they give the characteristic odor.

The source of the phenol is tyrosine and that of the indole is trypto-
phane. The chemical processes involved are shown in the following
equations, in which the by-products of the reactions are in brackets.

C.OH

COH

COH

COH

COH

//\

//\

//\

//\

//\

HC CH

HC CH

HC CH

HC CH

HC CH

1 II

1 II

1 II

1 II

! II

HC CH

HC CH

HC CH

HC CH

HC CH

\X

\x

\x

\/

\/

C

C

c

CH

CH2

CH2

CH2

CH3(C02 + I

I20)

1

(NH.) | (C02+H20) |

(00,)

CHNH2

CH2

1

COOH

COOH

COOH

(tyrosine)

(p-oxyphenyl-

(p-oxyphenyl-

(paracresol)

(phenol)

propionic acid)

acetic acid)

536 DIGESTION

Putrefaction of tryptophane is probably preceded by deamidization :

OH CH

HC C C— CH2.CHNH2.COOH HO C C— CH0CH2.COOH

I II II — > I II I! — >

HC C CH (NH,) HC C CH (CO2+H2O)

V X V KH

(tryptophane) (indolc-propionic acid)

CH CH CH

/\ /\ /\

HC C C— CH...COOH HC C CH HC

I il II » I II II I II

HC C CH (CO2 + H,O) HC C CH HC C

\/\/ \X\X \/\/

CH NH CH NH (+CH3) CH NH

(indole-acetic acid) (indole) (skatole)

If, however, the carboxylase bacteria remove the carboxyl group be-
fore the amino group has been removed, highly toxic substances called
amines are produced. They ar<e the so-called ptomaines. From alanine,
ethylamine is formed; from tyrosine, phenolethylamme; from histidine,
which it will be remembered is an important protein building-stone,
histamine, (imidazylethylamine) and so on. The process of formation is
illustrated in the accompanying formulae:

1. CH3.CH(NH2).COOH — CO2 -f CH3.CH2(NH,)

Alanine Ethylamine

2. O.HXOHJ.OHyOHCNH,) .COOH = CO2 -f C6H4(OH) .CH^CH^NH,

Tyrosine Phenylethylamine

3. C3N2H3.CH2.CH(NH2).COOH=:CO2 + C3H3N2. CH,.CH2.NH2

Histidine. Histamine.

Similar substances are very common in the metabolic products of
plants; for example, they constitute the active principle of ergot. They
are also no doubt produced in the tissues of mammals, imidazylethyla-
mine, commonly called histamine, being thus produced, as well as the
closely related epinephrine, which is the active principle of the supra-
renal gland (see page 773), and may be described as a methylated ethyla-
mine derivative of tyrosine.

Phenylacetic acid produced by a similar process from tyrosine may
be excreted in the urine, where it forms the mother substance of homo-
gentisic acid, to which the dark brown color of the urine in alkaptonuria
is due.

The great importance attached to these decomposition products of proteins
depends on the fact that they have powerful pharmacological actions. These
actions are developed very largely upon the vascular system; histamine,
(pages 253 and 307) for example, produces marked vasodilatation and
lowers the coagulability of the blood, whereas other substances of the
same class, like epinephrine, have the property of raising the blood pres-
sure. In larger doses, serious nervous symptoms and a condition of pro-

BACTERIAL DIGESTION IN THE INTESTINE 537

found collapse are produced. These observations have led several inves-
tigators to believe that the persistent occurrence of bacterial fermen-
tation and the absorption of the resulting decomposition products of
protein into the blood ultimately cause arteriosclerosis and the other symp-
toms that accompany senescence. It is difficult at the present time to
know how much of this one ought to believe, although it can not be
doubted that putrefaction has an unfavorable action on the arteries,
and that an excessive degree of it causes the symptoms of ptomaine
poisoning.

If the ptomaines have formed in the food before it is eaten, the symp-
toms develop in from one to five hours after the meal, but if the decomposi-
tion occurs in the intestine on account of bacteria that are taken at the same
time as the food, the ptomaines may not have developed sufficiently to
cause symptoms until from twelve to forty-eight hours; sometimes, how-
ever, they develop in an hour or so. Prominent among the symptoms is
usually diarrhea, which develops for the purpose of getting rid of the
offending bacteria and ptomaines.

Actual infection of food with bacteria of the paratyphoid-enteritidis
type is much more common than poisoning by substances (ptomaines) that
have been generated in food before it is taken (Jordan27). Meat, milk
and other protein foods are usually the carriers of the bacilli, and in most
of the accurately recorded cases the meat or milk was found to be
derived from animals suffering from enteritis or some other infection.
Sometimes, however, perfectly good food may become infected by
handling. Although the symptoms are usually acute, they may closely
simulate those of typhoid fever, and the effects of the attack may linger
for weeks or months.

BOTULISM

The commonest type of poisoning by substances actually present in the
food is that known as botulism. In this the gastrointestinal symptoms, as a
rule are not pronounced, — indeed, paralysis of the intestinal tract with con-
stipation is the rule, — but those affecting the nervous system, dizziness,
diplopia and other visual disturbances, with difficulty in swallowing,
are very prominent. The temperature and pulse are usually normal.
In practically all of the reported cases of botulism, the source of infection
has been food which after having been subjected to some preliminary treat-
ment, such as smoking, pickling, or canning, had been allowed to stand
for some time and then eaten without cooking. The Bacillus botulinus,
which is responsible for the production of the poisons or toxins, is a
strict anaerobe and is readily destroyed by cooking, as are also the
poisons. Antitoxins are formed by sublethal injections. Another but

538 DIGESTION

now very rare example of poisoning by products formed in food is
that caused by "ergotoxin."

The treatment in such cases is to encourage diarrhea by giving pur-
gatives. If the intoxication is of a more chronic character, the symptoms
are vague, consisting of drowsiness, lassitude, headache, and general de-
pression. The treatment here also is to clear out the intestines by a
good purge. There can be little doubt that many of the unhealthy condi-
tions of the skin leading to the formation of pimples, acne, arid boils,
are also caused by chronic intoxication with protein decomposition prod-
ucts. Again, purgation is the proper treatment.

It is unnecessary in a work of this character to go further into these
highly important questions. It is probable, however, that the importance
of the relationship of excessive protein putrefaction in the intestine to
many of the so-called minor diseases can not be overemphasized. On the
other hand, we must be careful not to attribute every sort of chronic
condition to this putrefaction. Toxemia is often a shibboleth of the
profession. When a chronic disease can not be diagnosed, it is put down
as a toxemia. This, however, is not medical science — it is medical shirk-
ing. It is certainly unsafe at the present time to conclude that the
ordinary symptoms of senescence, such as hard arteries or increased blood
pressure, are invariably to be attributed to this cause. It will be re-
membered that Metchnikoff is largely responsible for such a view, and
also that he suggested, as the surest way to ward off the chance of such
intoxication, the taking of buttermilk, which would supply bacteria
through whose growth in the intestine the protein-destroying bacteria
would not be able to thrive. It is probable that the same result could be
attained in patients showing undoubted signs of suffering from intestinal
putrefaction by a change in diet in the direction of giving more carbo-
hydrate, for, as we have seen, if there is a plentiful supply of this food-
stuff in the small intestine, the bacteria do not tend to attack the protein.

Before leaving this subject it is interesting to consider for a moment
the cause of the severe symptoms that follow intestinal obstruction.
This question has recently been diligently investigated by Whipple,28 who
found that the nonprotein nitrogen of blood (page 641) becomes greatly
increased in intestinal obstruction. The cause for this increase in non-
protein nitrogen is found to be an excessive breakdown of tissue protein
caused by the absorption into the blood of a proteose. When this pro-
teose isolated from obstructed loops of intestine was injected into fast-
ing dogs, profound symptoms of depression were produced, followed, in
cases in which the dose was sublethal, by recovery in from twenty-four
to forty-eight hours. Along with these symptoms the nitrogen elimina-
tion by the urine increased by 100 per cent. A very interesting fact is

BACTERIAL DIGESTION IN THE INTESTINE 539

that animals can be rendered immune to this proteose by progressively
increasing periodic administration. When they are thus immunized,
the toxic symptoms do not follow upon its injection, nor are the symp-
toms produced by artificially creating an intestinal obstruction. Con-
versely, when a chronic toxic condition is kept up by a partial obstruc-
tion, such as that produced by making a gastrojejunal fistula and occlud-
ing the duodenum, the animals are less susceptible than normal ones to
proteose injection.

We have here and there incidentally referred to the reaction of various
parts of the gastrointestinal contents, but we would call attention once
again to this important subject, especially since many points of uncer-
tainty have recently been cleared up by the accurate observations of
Long and Fenger,29 who used the electrometric method for measuring
the hydrogen-ion concentration. The contents of the duodenum removed
by means of the Rehfuss tube in man showed a reaction varying from dis-
tinctly acid to slightly acid, depending upon the proximity of the tube
to the pylorus or papilla, this position being determined by x-ray exam-
ination. The slight degree of alkalinity is surprising. Lower down in
the duodenum the reaction was as frequently acid as alkaline, the de-
gree of acidity, however, being so slight as to favor rather than retard
the digestive powers of the pancreatic juice.

To determine the reaction lower down, the observations were made on
recently slaughtered animals (pigs, calves, and lambs), the small intes-
tine being tied off in loops of the upper, middle, and lower thirds. The
contents of the last loop were often alkaline, but might be more acid even
than those of the first, which were usually faintly of this reaction. Con-
siderable variations were, however, the rule. The mixed intestinal con-
tents of a recently fed dog, removed immediately after death, gave
PH = 6.79 ; i. e., very faintly acid.

DIGESTION REFERENCES

(Monographs)

iPavlov, J. P.: The Work of the Digestive Glands. Trans, by Sir W. H. Thomp-
son, London, Griffin, ed. 2, 1910.

^Starling, E. H. : Recent Advances in the Physiology of Digestion, W. T. Keene &
Co., Chicago, 1907.

3Cannon, W. B.: The Mechanical Factors of Digestion, Internat. Med. Monographs,
London, Ed. Arnold, 1911.

•^Carlson, A. J.: The Control of Hunger in Health and Disease, Univ. of Chicago
Press, 1917.

sTodd, T. Wingate: The Clinical Anatomy of the Gastrointestinal Tract, Manches-
ter, Univ. Press, 1915.

6Macallum, A. B.: Ergeb. der Physiol., xi, 598-657.

^Cannon, W. B., and Cattoll, McKeen: Am. Jour. Physiol., 1916, xli, 39.

sGesell, E. : Proc. Am. Physiol. Soc., Am. Jour. Physiol., 1918, xlv, 559.

540 DIGESTION

, H. H., and Laidlaw, P. P.: Proc. Phys. Soc., Jour. Physiol., 1912, xliv, 12 and

13.
lofiabkin, B. P., Eubaschkin, W. J., and Ssawitsch, W. W. : Arch, f . mikr. Anat., 1909,

Ixxiv, 68.

"Miller, F. E. : Quart. Jour. Exper. Physiol., 1913, vi, 57.
i2Keeton, E. W., and Koch, F. C. : Am. Jour. Physiol., 1915, xxxvii, 481; also Popiel-

ski, L. : Arch. f.d. ges, Physiol., 1901, Ixxxvi, 215.
"Eclkins, J. S. : Jour. Physiol., 1906, xxxiv, 133-144.
"Meltzer, S. J. : Am. Jour. Physiol., 1899, ii, 266.
isCannon, W. B. : Am. Jour. Physiol., 1898, i, 359.
isGrey, E. G. : Am. Jour. Physiol., 1917, xlv, 272.
"Carlson, A. J. : Am. Jour. Physiol., 1917, xlv, 81.

18Ginsburg, Tumpowsky, and Hamburger: Jour. Am. Mod. Assn., 1916, Ixviii, 990.
^Cannon, W. B., Blake, J. B. : Ann. Surg., 1905, xli, 686, Of. No. 3.
soAlvarez, W. C. : Am. Jour. Physiol., 1918, xlvi, 238.
siCannon, W. B.: Proc. Eoy. Soc., 1918, xc, B, 283.

22Macallum, A. B. : See Fitzgerald M. P.: Proc. Eoy. Soc., Ixxxiii, B, 56.
ssHarvey, B." C. H., Bensley, E. E. : Biol. Bull. Woods Hole, 1912, xxiii, 225.
24Long, J. H., et al. : Jour. Am. Chem. Soc., 1917, xxxix, 162 and 1493; also ibid.,

1916, xxxviii, 38.

25Whipple, C. H., Hooper, C. W. : Am. Jour. Physiol., 1916, xl, 332 and 349; ibid.,

1917, xlii, 257 and 264; Hoope; ibid, p. 280.
2GMeltzer, S. J. : Am. Jour. Med. Sc,, 1917, cliii, 469.

27 Jordan, E. V. : Food Poisoning, Univ. Chicago Press, 1917.

2«Whipple, G. H., Cooke,. J. V., and Stearns, T. : Jour. Exper. Med., 1917, xxv, 479.

Also Whipple, G. H., Stone, and Bernheim: Ibid., 1913, xvii, 286 and 307.
2oLong, J. H., and Fenger, F. : Jour. Am. Chem. Soc., 1917, xxxix, 1278.

PART VI
THE EXCRETION OF URINE

CHAPTER LX

THE EXCRETION OF URINE

(Partly contributed by R. G. PEARCE)

It will be advisable to introduce the subject by a brief review of the
essential structural features of the kidney, in so far as they apply to
che excretory function of the organ.

STRUCTURE OF THE KIDNEY

The kidney is mainly derived from the surface of the celom, and is a
mesodermal structure. In this respect it differs from ordinary secreting
glands, which are endodermal in origin. Just as it is more or less
unique in its development as a gland, it is also unique in its method
of functioning. The physiological theories of the mechanism of urinary
secretion are closely related to the highly characteristic structure of the
kidney. For this reason a brief survey of the structure of the different
parts of the uriniferous tubules and the epithelial cells with which these
are lined, is advisable.

The uriniferous tubule, which is the secreting unit of the kidney,
takes its origin in the capsule of Bowman, which may be likened to a
hollow sphere of very delicate epithelium, one side of which is
invaginated by a very much convoluted capillary mass, the glomerulus.
The capsule opens up by a narrow twisted neck into a tubule, which is
rather tortuous in the cortex (the proximal convoluted tubule), but soon
takes a sharp descending course in the medulla towards the pelvis of the
kidney, and doubles back (loop of Henle) in a straight course again to
the cortex, where it again makes a twisted course (the distal convoluted
tubule), and terminates in a collecting tubule, which, uniting with other
tubules, collects the urine and conducts it to the pelvis of the kidney (Fig.
170). The capsule is lined with very thin epithelial cells, especially over
the capillaries comprising the glomerulus. The proximal and distal tubules

541

542

THE EXCRETION OF URINE

contain epithelium showing a prominent striation. These striations are
rows of granules, which run towards the lumen of the cell, becoming
less distinct as they approach it and apparently standing in close rela-
tionship to the rather prominent internal (lumen) striated border of
the cell. Some histologists believe that the striations at the border are

Fig. 170.— Diagram of the uriniferous tubules (C) the arteries (A), and the veins (B) of the

kidney.

really cilia, which are described as being immobile. The cilia are shown
in Fig. 171. The descending limb of Henle's loop is lined with a thin
pavement epithelium with large bulging nuclei. The distal convoluted
tubule is lined with cells not unlike those found in the proximal tubules,
except that the inner border is not striated. The diameter of the lumen

THE EXCRETION OF URINE

543

of the capsule varies with the activity of the kidney, as is shown in
the following figures given by Brodie and Mackenzie.1

RESTING
KIDNEY
MM.

KIDNEY DURING
DIURESIS
MM.

Mean diameter of capsule
1 ' li (l glomerulus
1 ' " " space of capsule
Lumen of proximal convoluted tubule
11 distal " "

93.4
90.4
3.0
0.0

7.2

123.8
100.0

23.8
17.6
20.6

The urinary tubule has a remarkable Mood supply. The renal arteries
arise directly from the abdominal aorta and are very short. They run
through the medulla to the cortex, and join with neighboring arteries to

Fig. 171. — Cross sections of convoluted tubules from kidney of rat. A, during slight secretion; B,
during maximal secretion. (From Sauer.)

form arches from which proceed branches, that radiate into the cortex
and give off smaller branches each of which very shortly breaks up into a
small capillary tuft, — the glomerulus, — which lies in the invaginated sphere
of Bowman's capsule. The capillaries collect into an efferent vessel, which
appears to be smaller than the afferent artery, and this vessel in emerging
from the capsule again breaks up to form a capillary network about the con-
voluted tubules, forming their sole blood supply. These capillaries
coalesce to form the renal vein. The blood of the kidney must, accord-
ingly, pass through two sets of capillaries.

The kidney is richly supplied with nerves, which are for the most part
derived from the celiac ganglion and are in connection with the splanch-

544 THE EXCRETION OF TTRTNE

nic and the vagus. Other branches from plexuses in the region of the
suprarenal body and the aorta join with those coming from the celiac
ganglion to form what is known as the renal plexus, which is arranged
in a network along the blood vessels and on the walls of the pelvis of
the kidney. These fibers are distributed to the very smallest blood ves-
sels, and nerve fibers have been observed among the cells of the tubules.

THE MECHANISM OF THE EXCRETION OF THE URINE

The great number as well as the variety of substances which are pres-
ent in both the blood and the urine makes it appear improbable that
urine excretion is dependent upon chemical combinations within the
renal cells, and leads us to seek a physicochemical mechanism to explain
the phenomenon. Can we discover the processes by which the kidney
manufactures a highly concentrated solution of salts from a very dilute
solution of the same salts in the blood plasma ? The problem is compli-
cated by the fact that the ratios existing between the concentration of
each urinary salt in the urine and the concentration of the same salt
in the blood are different. In other words, the urine is not merely
concentrated blood plasma freed from protein.

The passage of water and salts through the capillary wall and through
the basement membrane surrounding the renal cell probably takes place
by simple diffusion. If it were otherwise, an expenditure of energy
would be required, and it is difficult to understand how a basement
membrane could bring about energy changes. Any substance to which
the cell membrane is permeable wrill diffuse into the cell until an equi-
librium is established between its concentration within the cell and
that of the lymph or blood plasma. A nondiffusible substance will not
enter the cell because it can not pass through the cell membrane, and
if it exerts an osmotic pressure, it will also tend to keep the water in
which it is dissolved from entering. If water does pass into the cell
under these conditions, it is due to the expenditure of energy opposed
to and greater than that which is offered by the osmotic pressure of the
nondiffusible substances. Possible sources for such energy are the pres-
sure of the blood in the renal capillaries, which would exert a force op-
posite to that of its osmotic pressure, and the presence within the cell of
a concentration of salts greater than is present in the blood, and able to
exercise a sufficient osmotic force to draw fluid into the cell against the
osmotic force of the nondiffusible salts. The passage of the urinary
constituents through the cell might also be due to simple diffusion, the
substances passing through the cell to be extruded on the other side in
the same concentration as in the blood. In this case, the renal cells

TfiE EXCRETION OF URINE 545

would act merely as a* filter, the urine having the same concentration
of each urinary salt as is present in the blood.

A comparison of the concentrations of the urinary salts in the urine
and the blood shows, however, that the urine is not merely a deprotein-
ized blood plasma, so that other factors must be sought to explain the
excretion. Since the concentration of the urine requires the expenditure
of much more energy than is provided by the known physical factors,
it is generally accepted that the renal cell in some manner supplies this
energy by its metabolic activity. It is impossible at present even to
surmise the nature of the process. Two possibilities may be considered.
One is that the urine is a filtrate of the blood which has passed through
a portion of the renal epithelium into the tubules as a very dilute fluid,
resembling the blood plasma minus its colloidal substances, and that
this dilute fluid is concentrated by the reabsorption of fluid and of salts
by other cells of the kidney, and again replaced in the blood stream. The
other is that the salts and fluid are each actively and individually ex-
creted by the kidney. Whichever condition is the true one, the fact
remains that the change in the concentration entails the expenditure
of a great amount of energy on the part of the renal cells.

The energy which the kidney must use in the actual work of concen-
trating the urine from the fluid of the blood plasma can not be com-
puted from a comparison of the concentration of the urinary salts as a
whole in both the blood and the urine. Each constituent must be con-
sidered apart. We can not, for example, determine the molecular con-
centration of the blood plasma and the urine (by measuring A) (page
10) and estimate the work which is expended in producing the con-
centration from the observed difference. On the basis of such comparisons,
however, it is said that the excretion of 100 c.c. of urine requires at the
minimum 500 kilogrammeters of work (Cushny2). Even this conserva-
tive estimate may be wrong, for it does not take into consideration the
possibility that the excretion of water by the kidney requires energy
expenditure on the part of the renal cells.

Theories of Renal Function

For many years two rival hypotheses have dominated the teaching of
the mechanism of renal function. Bowman and Heidenhain postulated
that the constituents of the urine are secreted by the vital activity of
the epithelium of the capsule and the tubules. The glomerular capsule
secretes the water and the easily diffusible salts in a dilute solution, and
the uriniferous tubules add to this fluid the various organic and inor-
ganic salts to bring the urine to the necessary concentration. This
theory has been termed the vital theory. Ludwig, on the other hand,

546 THE EXCRETION OF URINE

advanced what is termed the physical theory,* which holds that the
glomerulus and capsule act simply as a filter, which allows the fluid
of the blood plasma to pass through in a very dilute solution and in
large amounts. This fluid is concentrated by physicochemical processes
on its passage along the urinary tubules to the pelvis of the kidney.

Both of these theories are inadequate and fail to explain the phenom-
ena which research has shown to occur in the kidney, but they have
served to develop what Cushny terms a modern theory of urinary
excretion.

The Modern Theory of Urine Formation. — This theory accepts the
general scheme of filtration and reabsorption of Ludwig, but pays due
respect to the fact that the known physical forces are not adequate
to explain the reabsorption which must occur in the tubules. It therefore
supplements Ludwig 's theory by assuming a vital activity on the part
of the epithelium of the tubules in reabsorbing fluids and salts from
the dilute filtrate coming from the glomerulus and capsule. A large
amount of plasma fluid is filtered through the walls of the glomerular
vessels. This fluid has the same concentration of the salts to which the
capsule is permeable as does the blood plasma, but it is free of the col-
loidal substances normally present in the plasma. The blood leaving the
glomerulus is therefore a somewhat concentrated solution of plasma col-
loids, and must have returned to it the proper amount of water and
salts to make it an optimum fluid for the body cells. This is accomplished
by active absorption from the glomerular filtrate.^The salts that are of
no use to the body are not reabsorbed and therefore appear in highly
concentrated form in the urine.\These salts are termed nonthreshold sub-
stances, and since their presence in the plasma is unnecessary, they con-
tinue to be excreted as long as they are present in any concentration in
the blood. The salts that are necessary for the plasma are termed
threshold substances, and are reabsorbed until they are again present in
the plasma in optimal strength. For example, urea continues to be ex-
creted as long as any is present in the blood, while glucose is almost com-
pletely reabsorbed so long as its concentration remains under a more or less
fixed level.

The volume of deproteinized blood plasma which the capsule would require to filter
off from the blood in order to furnish the amount of the various salts excreted each
day, and the volume of water which would have to be absorbed by the epithelium of
the tubules to account for the concentration in which the salts are found in the urine,
has been calculated as follows: in order to produce 20 grams of urea in 1000 c.c. of
urine, 62 liters of the water of the blood-plasma, containing 0.033 per cent of urea,
'would, have to be filtered through the capsule, and 61 liters of water returned to the
blood from the uriniferous tubules. This amount of water would be derived from 67
liters of plasma (see table on page 551). Since the bloodflow through the kidneys is

THE EXCRETION OF URINE 547

very great, at least 500 liters per day, only about 13 per cent of the fluid contained in
the blood passing through the glomerulus would pass by filtration through the capsule of
Bowman. The fact that such a large amount of fluid would have to be reabsorbed from
the uriniferous tubules is a possible a priori criticism of the theory, but Cushney points
out that the amount each tubule would have to absorb per hour would be very small
(in his experiment on a cat amounting to less than 0.014 c.c. per hour).

According to the modern view, there are therefore two fundamentally
different processes occurring' in the kidney; filtration in the capsule and
selective reabsorption in the tubules. It is important to consider some
of the evidence which is considered to indicate that each of these pro-
cesses occurs.

The Filtration Process. — The filtration of the protein-free blood fluid
through the renal capsule, like that through any other membrane, depends
on several factors. (1) There must be a difference in the pressure between
the blood and the urinary filtrate. In the laboratory the pressure used in
filtering is usually supplied by gravity, but in the case of the filtration of
the urine through the capsule the force is furnished by the pressure of blood
in the glomerular vessels. (2) The character of the filter determines what
substances shall pass. The renal capsule is a membrane normally im-
pervious to the proteins of the blood, but pervious to the other constitu-
ents. Under certain conditions it loses this character. (3) The char-
acter of the fluid determines how readily it will filter through the mem-
brane. If the fluid contains a substance which can not pass through the
filter and which exerts an osmotic pressure in opposition to the filtering
force, the rate of filtration as well as the amount filtered, will be reduced.

If the capsule acts as a filter it should be possible to alter the rate of
urine excretion by varying any of the above mentioned factors, and
experimentally this is true. The factors can be varied in several ways. If
the blood pressure is raised by tying off several of the branches of the aorta,
the urine is appreciably increased, or if the blood pressure is lowered, as can
be done by cutting the spinal cord the amount of urine is decreased. In the
artificially perfused kidney, the fluid exuding from the ureter increases
as the pressure of the perfusion fluid is raised, and decreases as
the pressure is decreased. Whether changes in the pressure in the blood
are directly responsible for variations in the rate of urine excretion, or
whether they act indirectly by varying the rate of the bloodflow in the
kidneys, has been the subject of much debate. Probably both factors are
involved. Apparently, excretion can continue only as long as the col-
loids of the plasma are not notably increased, for, as the osmotic pressure
due to the indiffusible colloids rises, the pressure in the capillaries is no
longer able to oppose it. The same point has been shown by Star-
ling and his pupils, who found that the excretion of urine ceases when
the capillary pressure in the glomerulus fell below that exerted by

548 THE EXCRETION OF URINE

the osmotic pressure of the blood proteins, the critical pressure being
from 30 to 40 mm. Hg. They also found that dilution of the blood with
saline solution by reducing the osmotic pressure of the proteins in the
plasma, was accompanied by an increase in the rate of excretion; excre-
tion in such cases being maintained at a blood pressure below the normal
critical pressure. If the dilution of the blood was made with saline con-
taining gelatin or gum arabic, on the other hand, the diuretic effect was
greatly diminished, and any fall in the blood pressure was followed by a
suppression of the urine (Knowlton9). These experiments evidently
indicate that saline causes diuresis by diluting the plasma proteins and
lowering their osmotic pressure, since no diuresis occurs when the os-
motic pressure of the blood is maintained by the addition of colloids
having an osmotic pressure. The significance of these facts, in connec-
tion with the raising of lowered blood pressure after hemorrhage, has
already been alluded to (page 140).

The view that saline diuresis is • caused by physical changes alone
is confirmed by the, experiments of Barcroft and Straub,10 who showed
that the oxygen consumption is often not appreciably raised during the
diuresis which occurs after the injection of saline. If the diuresis were
due to an actual increase in the work of the kidney, the oxygen con-
sumption would have been increased.

In the frog, the glomerulus and the tubules are supplied with blood
by the renal artery, as is the case in the mammal, but the tubules
are also supplied with some of the blood coming from the lower ex-
tremities and the trunk through a vessel which has no counterpart
in the mammal — the renal portal vein. The blood, therefore, which
is supplied to the tubule is a mixture from the glomerulus and the renal
portal system. By ligating the renal vessels it is possible to cut off the
blood supply of the glomerulus while leaving the tubules supplied by the
renal portal vein. Normally the pressure in the renal portal system is
not sufficient to force blood back through the glomerular vessels. Liga-
tion of the renal vessels at once results in a suppression of the urine.

If the glomerular vessels are perfused with Ringer's solution at a
pressure equal to that found in the aorta, a considerable flow of fluid
may be secured from the ureters, but no fluid is obtained when the renal
portal vein is perfused at a pressure equal to that normally present in
this vein. Rowntree and Geraghty11 found that phenolsulphonephthalein
added to the fluid perfused through the renal portal vein, did not
cause secretion, but when urea was added, fluid containing the dye was
obtained from the ureter. Unfortunately the pressure employed in these
experiments may have allowed some fluid to be forced backward into the

THE EXCRETION OF URINE

549

glomerulus, so that the results may be due to filtration through the
capsule.

The Reabsorption Process. — It is generally accepted that the proof that
the capsule acts as a filter is fairly complete. Unfortunately such decisive
experimental facts can not be offered to prove the assumption that the epi-
thelium of the tubules reabsorbs the excess of water and salts which are fil-
tered off through the capsule. If the modern theory of urine excretion is cor-
rect, the cells of the tubules must not only absorb large amounts of water,

Renal
artery

Malpighian
corpuscle

Renal-portal vein

Fig. 172. — Diagram of blood supply of Malpighian corpuscle and of convoluted tubules in amphibian

kidney. (Redrawn from Cushny.)

but they must also allow for the reentrance into the blood, either completely
or partially, of certain salts, while they must reject others entirely.

We have called attention above to the fact that the glomerular filtrate is
very different from the urine that is finally passed. The urine contains a
very high percentage of small molecules, and the proportion in which they
are present is entirely different from that in the blood plasma or in the
glomerular filtrate. This is shown in the following table, in which the
figures in the first two columns represent the average number of grams of
urea, uric acid, chlorine, and glucose in 100 c.c. of protein-free blood
plasma and in 100 e.c. of urine. In the third column is given the change
in concentration which must occur in the kidney.

550 THE EXCRETION OF URINE

100 C.C. PROTEIN-

100 C.C. URINE

CHANGE IN

FREE BLOOD

CONTAINS

CONCENTRATION

PLASMA CONTAINS

IN THE KIDNEY

Urea

.033

2.

60

Uric Acid

.0022

.05

22.7

Chlorine

.41

.6

1.5

Glucose

.1

—

—

Among the experiments that have been offered in support of the absorption of fluid
and salts by the tubules, are those in which the pressure of the urine in the tubules is
slightly increased by partial closure of the ureter (Cuslmy). In these experiments the
ureter of one kidney is partly closed with a clamp and the excretion obtained from
this kidney is compared with that of the opposite normal kidney. Considerable ob-
struction of the ureter results in a decrease in the amounts of water, chloride and
urea excreted, but the urea content is decreased relatively less than is the chloride
and water 'content. These results can be explained on the basis that a pressure that
is sufficient to oppose the head of pressure producing filtration in the glomerulus will
reduce the amount of the glomerular filtration, and accordingly the time allowed for
the passage of this nitrate along the tubules is increased and absorption becomes more
complete. Since urea is probably not absorbed at all and chloride is, the discrepancy
in the effects on the excretion of urea and chlorine in the partially obstructed kidney
can be explained. When the obstruction of the ureter is only slight, however, opposite
results to that just mentioned are obtained (Brodie and Cullis). This observation is
difficult to harmonize with the reabsorption hypothesis.

When very large amounts of water are taken by mouth, it often hap-
pens that the urine excreted has a concentration of salts less than that
present in the fluid of the blood. Some investigators believe that such a
condition is possible only on the assumption that water is actively ex-
creted, but a more plausible explanation based on the modern theory
is that the water that is absorbed from the alimentary tract reaches the
kidney as a dilute saline solution, and is rapidly filtered off in a form
somewhat more dilute than the optimal solution which blood plasma must
have for the well-being of the tissues. The tubules reabsorb the amounts
of water and of substances, such as chlorides, and sugar that are nec-
essary to restore the plasma to the optimal concentration, but they do not
reabsorb the nonthreshold substances, such as sulphates and urea.

Many attempts have been made, by destroying the capsules or the
tubules by means of poisons or by operation, to determine directly or
indirectly the question of the function of the tubules. In such experi-
ments, however, the number of factors involved confuses the issue and
makes the results practically valueless so far as determining the normal
function of the tubules.

Other experimenters have attempted to show absorption in the tubules by injecting
diffusible substances, such as chemicals and dyes, into the ureter under what they
deemed sufficient pressure to force the solution into the tubules, and by an examination
of the blood or the tissues to determine whether or not the injected substances had been
absorbed. The results obtained by this method are not convincing, probably chiefly

THE EXCRETION OF URINE

551

because of the difficulty in reaching the tubules. Indeed, it is very questionable
whether it is possible to inject a substance into the tubules from the ureter.

Years ago Heidenhain, the exponent of the vital theory of excretion, believed that
he had demonstrated the ability of the renal cells to excrete dye substances injected in-
travenously. Since he failed to find evidence of dye excretion in the capsule, but
found masses of dye in the tubules and stained granules in the cells of the tubules,
he concluded that the cells of the tubules had the power to excrete the dye, and from
analogy he believed that the tubules must likewise excrete the water and the various
urinary salts. Subsequent work, however, has failed to confirm his belief that the
capsule is not concerned in the excretion of the dye, and it is as reasonable to explain
the results of the experiments with the dyes by assuming that the masses of dye sub-
stances found in the tubules and in the cells are due to the reabsorption of water and
perhaps of some of the dye from the dilute glomerular filtrate, as to accept Heiden-
hain 's hypothesis.

In the following table taken from Cushny the movements of the con-
stituents of the plasma may be followed through the kidney. The ulti-
mate destination of each is indicated in the enclosures.

67 LITERS PLASMA
CONTAIN

62 LITERS
FILTRATE

61 LITERS
REABSORBED FLUID
CONTAIN

1 LITER URINE
CONTAINS

PER
CENT TOTAL

IN ALL

PER
CENT TOTAL

PER

CENT TOTAL

Water

92 62 1.

62 1.

61 1.

95 950 c.c.

Colloids

| 8 5360 gm.|

Dextrose

0.1 67 gm.

67 gm.

0.11 67 gm.

Uric acid
Sodium
Potassium
Chloride

0.002 1.3 "
0.3 200 "
0.02 13.3 "
0.37 248 "

1.3 "

200 "
13.3 "
248 "

0.0013 0.8 "
0.32 196 "
0.019 11.8 "
0.40 242 "

0.05 0.05 gm.
0.35 3.5 "
0.15 1.5 "
0.6 6.0 "

Urea

Sulphate

0.03 20 "
0.003 1.8 "

20 "
1.8 "

2.0 2.0 "
0.18 1.8 "

(From Cushny.2)

It will be noted that the dextrose alone is completely absorbed, and
that the urea and the sulphate are not absorbed at all from the glom-
erular nitrate. The other salts are partly absorbed.

Although at present it is probably most useful for practical purposes
to accept Cushny 's hypothesis, it should be remembered that we are far
from being in a position to explain all the known facts of the renal
function by means of it. There can be no doubt that a process that is
closely analogous, if not identical Avith nitration plays an essential part
in the formation of urine, and that it is assisted by a more obscure
process depending on a selective action of the renal cells. But whether
this latter process is essentially one of reabsorption of certain molecules
from tubule to blood, or one of secretion from blood to tubule is problem-
atical. As G. N. Stewart points out, the reabsorption hypothesis is no
simpler to comprehend than the older hypothesis of Bowman and Heiden-

552 THE EXCRETION OF URINE

hain, for according to both views the renal cells are assumed to exercise
discriminative powers.

DIURETICS

As already mentioned, Barcroft and Straub10 have shown that the
diuresis which results from the injection of saline into the blood is not
accompanied by any increase in the oxygen consumption of the kidney.
This observation, coupled with the fact that the total amount of chloride,
urea, and sulphate which is excreted during saline diuresis is greater than
under normal conditions, indicates that the excretion of these salts is
not due to any active secretory process in the kidney, but rather to a
greater filtration because of increased heart action.

The diuresis Avhich is caused by adding urea or sodium sulphate to the
blood, on the other hand, is accompanied by an increase in the oxygen
consumption of the kidney. Since there is no increase in oxygen con-
sumption accompanying the increased excretion of practically the same
salts during saline diuresis, the increased oxygen consumption must be
due to more work being done in separating the water from the sulphate
etc., to return it to the blood.

The action of the xanthine compounds — caffeine, theobromine and
theophylline — in the production of diuresis is unexplained. It may be
due in part to vascular changes and in part to reduction in the resis-
tance to filtration brought about by alteration in the permeability of
the capsule.

According to the modern theory the polyuria in diabetes is caused
by the excessive amount of water taken and by the inability of the
kidney to concentrate the urine (by reabsorption) against the osmotic pres-
sure offered by the concentrated sugar solution in the tubules. The diuresis
following the injection of sugar is therefore of the same type as that pro-
duced by sulphate and urea. The diuretic action of the digitalis group is
dependent upon its influence on the circulatory system. If the circulation
is already sufficient, digitalis does not cause diuresis. The cause of the
diuresis produced by pituitary extract is not known. It may be owing in
part to its action on the circulation and in part to a direct action 011 the
kidney (see page 811).

ALBUMINURIA

The plasma proteins ordinarily do not obtain entrance into the tubules
of the kidney. In disease such as acute nephritis and cardiac fail-
ure, the plasma colloids are filtered off through the capsule, proba-
bly because of some change that has occurred in the permeability
of its membrane due to inflammation or asphyxia. In these cases the
urine is usually reduced in amount. Probably there is 110 purely glom-

THE EXCRETION OF URINE

553

crular or tubular type of nephritis, both structures sharing in the dis-
ability. When foreign proteins such as egg albumin gain entry to the
blood, they appear in the urine. This is also the case when hemoglobin
is liberated from the blood corpuscles. In both cases masses of the ex-
creted protein in the capsule may be detected by microscopical examina-
tion when the kidney is excised and hardened during the excretion.
There is also some evidence that the capsule is damaged during the fil-
tration of the foreign protein, for it has been found after injecting egg
albumin, that more protein may appear in the urine in 24 hours than the
amount injected.

Albuminuria is also readily induced experimentally by clamping the
blood vessels of the kidney. After occlusion of the renal artery for

Si

Fig. 173. — Nerve supply of the kidney. K, kidney; Si, S2, major and minor splanchnic nerves; V,
vagus; C.G., Celiac ganglion; A, aorta. (From Cushny.)

30 seconds, the urine for some time ceases entirely to flow, and when
it returns (in about an hour) it is loaded with protein which gradually
disappears. In all cases of albuminuria the albuminous filtrate in its
passage along the tubules is concentrated by the reabsorption process,
and this may occur to such an extent that the protein is precipitated
so as to form a cast to which detritus from the tubular epithelium may
become added, the exact type of cell composing this detritus depending
on the point at which the protein solidifies.

The Influence of the Nervous System on the Excretion of Urine. — In
spite of numerous and repeated attempts to demonstrate that a nervous
mechanism governs the excretion of urine, no proofs which are above

554 THE EXCRETION OF URINE

criticism have been forthcoming. Stimulation of the splanchnic nerves
results in a diminution in the excretion of urine, probably because of a
diminution in the blood supply of the renal vessels owing to the vasocon-
striction. Stimulation of the vagus nerves below the level of the cardiac
branches has been said to result in the augmentation of the rate of urine
excretion ( Asher and Pearce12) . The results are doubtful, however, since
there is no increase in the oxygen absorption under the above conditions
(Pearce and Carter13).

There is no doubt that the renal nerves profoundly affect the excretion
of urine, but that they do so directly is very improbable, since perfectly
adequate renal function can be maintained in animals that have had the
kidneys entirely removed and then replaced. There are numerous re-
flexes that affect the rate of urine excretion by constriction of the renal
vessels. Injury to the bladder or ureter, abdominal injuries to the kid-
ney, or even cold applied to the skin, may result in incomplete suppres-
sion of the urine.

CHAPTER LXI

THE AMOUNT AND COMPOSITION OF THE URINE IN HEALTH

AND DISEASE

(Partly contributed by R. G. PEARCE)

In the chapters on digestion and metabolism, we have followed the
course which food takes with especial reference to the nutrition of the
body. The excretion of these elements of nutrition is taken up under a
number of the subdivisions of physiology, viz., respiration, digestion,
kidney function and the skin. In the chapters on digestion attention was
called to the fact that the feces, besides containing the indigestible resi-
due of the aliment, contain several excretory products which at one
time or another have actually been within the body proper. These in-
clude normally the pigments of the body and many of the heavier mineral
salts, such as iron, magnesium, lime and phosphates; and under abnormal
conditions, as when the metals are given as medicine, bismuth and mer-
cury. The respiratory system excretes most of the oxygen and carbon.
In this chapter we shall take up the manner in which the body rids itself
of the nitrogenous, and some of the mineral waste materials. Even at
the risk of repetition, it will be advantageous to recapitulate certain facts
concerning the essential chemical structure of the urinary constituents,
so that we may be in a position to appreciate the kidney function in
health and disease.

We now know that the kidney does not form any of the specific con-
stituents of its secretion (except hippuric acid). These substances are
formed in the various tissues of the body, and are brought to the kidneys
by the blood, where they are eliminated. But while the constituents in the
urine are unchanged in chemical composition from that in which they
are found in the blood, they do occur in greatly changed proportions.
It is this variation in the concentration of the urinary constituents in
the blood and the urine which presents the most important and at the
same time the most difficult question in the physiology of the kidney.
In the following table the percentage composition of the blood plasma is
compared with that of an average sample of human urine. The third

555

556

THE EXCRETION OF URINE

column gives the change in concentration which each constituent under-
goes in passing through the renal filter.

BLOOD PLASMA
PER CENT

URINE CHANGE IN
PER CENT CONCENTRATION

Water

90-93

95

—

Proteins, fats and other colloids
Dextrose

7-9
0.1

—

—

Urea

0.03

2

60

Uric acid

0.002

0.05

25

Creatinine

Ammonia

0.001

0.04

40

Sodium

0.32

0.35

1

Potassium

0.02

0.115

7

Calcium

0.008

0.015

2

Magnesium
Chlorine

0.0025
0.009

0.006
0.27

2
30

Phosphates (PO4)
Sulphates (SO4)
Amino acids

0.003

0.18

60

The Amount of Urine

The amount of urine passed in twenty-four hours varies with the
amount of fluid ingested and the proportion of fluid retained by the body
or excreted by other channels. Under ordinary conditions a twenty-four-
hour sample amounts to from 1000 to 1800 c.c. of urine. On a constant
water intake the volume of urine is extremely variable for any single
day or part of the day (Addis and Watanabe3). The average volume of
urine excreted by twenty individuals on the third, fourth and fifth days
of a constant diet in which the fluid intake was 2,070 c.c., varied from
1,013 to 1,712 c.c. for a twenty-four-hour period, from 684 to 1,195 c.c.
for the first twelve hours of the day, and from 501 to 788 c.c. for the
first eight hours of the day. In normal subjects the amount of urine
excreted during the night is usually less than that during the day. This
is such a constant finding that in cases where more than 50 per cent of
the urine is excreted in the twelve hours of the night, suspicions of renal
disease should be aroused.

With a constant intake of food and water, the specific gravity of samples
of urine collected at frequent intervals throughout the twenty-four
hours exhibits considerable variations. The night urine is usually of
higher specific gravity than that of samples passed every two hours
during the day, the variation often amounting to as much as ten points.
If the variation does not occur, but the different specimens show a fixed
specific gravity, either at a high or a low level, it is usually indicative
of renal trouble. This is illustrated in the following table:

AMOUNT AND COMPOSITION OF THE URINE

557

DAY

NIGHT

8-10

A.M.

10.12

A.M.

12-2

P.M.

2-4

P.M.

4-6

P.M.

6-8

P.M.

8-8

P.M. -A.M.

Normal person
In Hypertensive Nephritis
In Myocardial Decompensation

1.016
1.010
1.018

1.019
1.009
1.020

1.012
1.010
1.019

1.014
1.009
1.018

1.020
1.019
0.020

1.010
1.010
1.021

1.020

1.009
1.022

(Compiled from MosenthaPs figures.)

The proportion of water to total solids is often very similar in plasma
and urine, but when water is taken in large quantities the urine shows
much greater changes than does the blood, and the solids may sink to a
very low concentration. On the other hand, when little fluid is taken or
when the skin and bowel eliminate a large amount of fluid, the urine
may become very concentrated without any change in the blood plasma.
The total solids in urine can be determined with approximate accuracy
by multiplying the last two figures of the specific gravity by the con-
stant coefficient 0.233 (Haeser).

The Depression of Freezing Point, — While the solids of the blood con-
sist, for the most part, of proteins and colloids, those of the urine are
made up of inorganic salts and small organic molecules. The mole-
cular concentration — that is, the total number of molecules in a given
quantity of fluid — is under ordinary conditions much greater in the
urine than in the blood. The molecular concentration may be deter-
mined by the depression of the freezing point of a fluid below that of dis-
tilled water (see page 10). Blood freezes almost constantly at -0.56° C.,
while urine may freeze at temperatures which vary between -1° C. and
-2.5° C.; if very concentrated it may freeze at a temperature as low as
-5° C., or if dilute the freezing point may be as high as -0.075° C.

The variability of the freezing point and the specific gravity of the
urine lead us to a consideration of the relationship of the urinary volume
to its concentration. In the first place, the volume of water ingested is
more frequently than otherwise in excess of the minimum absolutely re-
quired by the body, and is subject to greater variation than the sub-
stances excreted in the urine. The kidney is able to eliminate one con-
stituent of the plasma which may be present in excess without involving
any changes in others. For example, when salt is added to the food and
excreted in the urine, the total chlorides are increased, but the amount
of urine and the other constituents may remain unchanged; or, again, as
may happen, excess of salt leads to an increase in the volume of the
urine, but the salt concentration remains constant while that of the
other urinary bodies is decreased. Similarly, although the rate of urea
excretion is not demonstrably augmented by an increase in the volume
of the urine, an increase in the rate of urea excretion induced by the

558 THE EXCRETION OF URINE

ingestion of urea is accompanied by a larger volume of urine. That these
two factors may not stand in a causal relationship to each other is sug-
gested by recent work of Addis and Watanabe,3 who find no quantitative
relationship between the rate of increase in urea excretion and the increase
in urine volume, and who believe that the apparent relationship is due to a
common cause, such as alteration in the rate of circulation or change in the
activity of the kidney cells. Nevertheless, there appears to be a limit set to
the power of the kidney to take the urinarj^ salts or water from the plasma
and to place them in the urine in quite different proportions. The definite
amount of water required to hold the urinary salts has been termed the
"volume obligative" (Ambard5). These limits of concentration may be
fixed by the energy which the kidney can bring to act against the osmotic
resistance.

The inconstancy in the behavior of the kidney toward ingested salts is
probably due to the fact that the salts reach the kidney in the concen-
tration in which they are held by the blood plasma, and not as they were
ingested. If salt is absorbed rapidly enough to disturb the salt equilib-
rium of the tissues and plasma, then water will be abstracted from the
tissues, and the plasma on reaching the kidney will eliminate the salt
and water together. The difference in the reaction arises from the
varied activity in the tissues in general rather than in the kidney itself.

THE REACTION OF THE URINE

In man and the carnivora the reaction of the urine is generally acid
to litmus or phenolphthalein, but alkaline to methyl orange. The acid
responsible for the reaction is phosphoric, not in a free state, but as a
mixture of the salts Na2, HP04 and NaH2P04, in which there is an excess
of the latter. If alkali be added to a solution of H4PO3, containing a
little methyl orange, the tint changes from red to yellowish when the
H,P04 has all been changed into NaH2P04; if more alkali be added, and
the indicator be now changed to phenolphthalein the tint turns red, when
the H3P04 has been changed to Na2HP04. The reaction of urine lies be-
tween these two points.^ In the herbivorous animals the alkaline re-
action is due to the fact that vegetables and fruits contain salts
of dibasic or polybasic acids, such as acid potassium malate, citrate,
acetate, and tartrate. Oxidation of these in the body gives rise to
carbonates.^ Some of the carbonic acid is excreted through the lungs,
and hence the associated base, generally sodium or potassium, is com-
bined so as to form a weak basic salt.

The measurement of the acidity of the urine in terms of the H-ion con-
centration like the same measurement in blood, requires the use of the

AMOUNT AND COMPOSITION OF THE URINE 559

rather difficult electrical or indicator method, the principle of which has
been described in Chapter V. Expressed in terms of CH, the acidity
varies between 4.7 x 10-7 and 100 x 10~7. The total potential acidity —
that is, the number of H ions which will be formed in the face of a con-
tinual neutralization of those in solution — may be obtained fairly accu-
rately by titrating the urine with Vio normal alkali in the presence of
neutral potassium oxalate, using phenolphthalein as an indicator (Folin).
The results may be expressed in acidity per cent in terms of c.c. N/10
NaOH required to neutralize 100 c.c. of urine. If the ammonia excretion
is added to the titration results, the total potential acidity is very closely
measured. In normal subjects the acidity is high in the relatively scanty
urine that is excreted during the night. In the forenoon more urine is
excreted and the acidity is much less, i. e., alkalinity much greater. This
alkaline tide in the forenoon is not dependent upon the accompanying
diuresis, and it is the only alkaline tide during the 24 hours. The old idea
of an alkaline tide following the ingestion of food is not correct. These
facts are taken advantage of in a test of renal efficiency in which the
conditions are standardized by having the patient, after awaking in the
morning, drink a definite volume of water, but take no food. The night
urine (from 11 p. M to 7 A. M.) and hourly specimens between 7 A. M. and
12 noon are collected and their volume and alkalinity (c.c. N/10 NaOH per
100 c.c.) measured. Typical results after drinking 500 c.c. water are
exhibited in the following table:

No. OF CASES

FROM WHICH

DIURESIS

ALKALINITY PER CENT

THE MEAN

c.c.

PER HOUR

MAXIMUM

FIGURES ARE

MAXIMUM

AT

AT 10 OR

CALCULATED

BEFORE

AFTER

NIGHT

11 A. M.

I

49

55

336

27

84

II

51

61

182

23

74

III

56

63

221

22

42

(Adapted from Leathcs.)

In this table, I represents the response of normal subjects in whom
diuresis and alkalinity both increased; II, that of nephritic patients in
whom the diuresis reaction was subnormal, but the alkalinity normal,
and III, more severe cases in whom both the diuresis and the alkalinity
were subnormal.

Leathes has been able to show that this morning alkaline tide is de-
pendent upon a greater excitability of the respiratory center on waking
compared with that during the night. This causes pulmonary ventila-
tion to become more thorough during the morning hours than during
the night, so that more C02 is washed out of the blood, thus lowering its
acidity and causing alkali to be excreted by the kidney. The CO2 content

560 THE EXCRETION OF URINE

of the alveolar air at night in a typical case was 7.4 per cent and after
rising 6.63. Leathes also showed that forced breathing causes a marked
increase in the alkalinity of the urine, a result which confirms those of
Haldane, Meakin, etc., referred to elsewhere in this volume (page 381).

THE SOLID CONSTITUENTS

In a person living on an ordinary diet the most important organic
and inorganic constituents of the urine are as follows :

TOTAL SOLIDS (40 TO 60 GRAMS) IN ONE LITER OF NORMAL URINE
ORGANIC CONSTITUENTS, 25-40 GM. INORGANIC CONSTITUENTS, 15-25 GM.

Urea, 20-35 gm. Sodium chloride (NaCl), 8-15 gm.

Creatinine, 1.0-1.5 gm. Phosphoric acid (P2O5), 2.5-3.5 gm.

Uric acid, 0.5-1.25 gm. Sulphuric acid, (SO,), 2-2.5 gm.

Hippuric acid, 0.1-1.7 gm. Potassium (K,O), 2-3 gm.

Other constituents (ethereal sulphates, Sodium (Na,O), 4-6 gm.

oxalic acid, urinary pigments, etc.), Calcium (Cab), 0.1-0.3 gm.

1.5-2.3 gm.' Magnesium (MgO), 0.2-0.5.

Ammonia (NH8), 0.3-1.2 gm.
Iron (in pigment), 0.001-0.010.

(Compiled from MosenthaPs4 figures.)

These urinary salts are present in the blood, and are only excreted by
the kidney. An investigation of the mechanism of renal excretion must
therefore include a study of the relationship existing between the con-
centration of the urinary salts in the blood and in the urine. We shall
briefly review the chief biochemical relationships of the most important of
these constituents and then give tables showing the quantitative changes
which they undergo in various diseases.

The Organic Salts of Normal Urine

Nitrogenous Constituents.— The greater number of the organic salts of
the urine are made up of bodies which contain nitrogen, and which are
derived from the protein element of nutrition. The proteins, which form
the chief building material of the body, are broken up into their con-
stituent amino acids in the intestinal tract and absorbed as such by the
blood. Portions of these acids are taken up by the tissues to repair and
to replace those proteins which have been discarded, and the remaining
protein, in excess of the body need for amino acids, is deamidized, the
major portion of the carbon, oxygen and hydrogen being oxidized to
form C02 and water, and the lesser portion of these elements being com-
bined with the nitrogen to form urea, ammonia, uric acid, etc. A similar
fate later awaits the nitrogen moiety which found a place in the tissues,
and which is replaced in turn by new nitrogenous bodies.*

*For further details see page 645.

AMOUNT AND COMPOSITION OF THE URINE 561

Since all the ingested nitrogen, except a small and rather constant
amount which is lost by the feces and the sweat, is excreted in the urine,
the total nitrogen of the urine has been taken as a measure of the nitro-
gen or protein metabolism of the body. In normal conditions the protein
metabolism is adjusted in such a manner that the nitrogen intake- is
equal to the nitrogen output, a condition known as nitrogenous equilib-
rium. If the nitrogen intake is reduced below the actual body needs,
the excretion of nitrogen is greater than the intake which indicates that
the body protein is replacing the protein usually furnished by the food.
The minimum amount of protein that the body must have to maintain
equilibrium varies in individuals, and with the nature of the protein
(page 605). With the ordinary mixed diet it is usually between 12 and
20 grams a day, corresponding to from 75 to 125 grams of protein. Ordi-
narily, nitrogen is not retained and an increase in the protein ingested is
followed by an increase of nitrogen in the urine. In periods of growth and
after undernutrition, however, protein is stored in the body. For this
reason, unless the amount of nitrogen ingested is known, the study of the
total nitrogen of the urine gives no information concerning the nature of
the nitrogen metabolism of the body. The total output of nitrogen per day
usually amounts to 10 to 15 grams — from 1 to 2 per cent of the urine by
weight.

Urea. — The chief of the nitrogenous bodies of the urine is urea, the
origin of which has been fully described in the chapters on metabolism.
No constituent of the urine is subject to greater variation both in abso-
lute and in relative amounts. On an average diet containing 120 grams
of protein per day, the absolute urea excretion may amount to about 30
grams ; on a low protein diet it may be only a few grams. When the pro-
tein intake is high, the nitrogen eliminated as urea may be 90 per cent
of the total nitrogen; but when the protein intake is low, this proportion
may fall to 60 per cent. The difference is because on a low protein diet
the greater percentage of nitrogen eliminated is endogenous in origin,
and urea, which is the chief constituent of the exogenous nitrogen moiety
of the urine, is accordingly decreased on low diets.

In recent years the importance of the relationship between the con-
centration of the urinary constituents in the blood and the urine has
been much insisted upon, and since the estimation of the amount of
urea in the blood and the urine is relatively simple, most of the work
has been done by using these values. Ambard and Weil5 believe that a
quantitative relationship exists between the rate of urine excretion and
the concentration of urea in the blood and the urine, since the urea in
the blood acts as a stimulus to the renal cells. By comparing the rate
of urea excretion and the concentration of urea in the blood and urine

562 THE EXCRETION OF URINE

in a mathematical formula, they have obtained a value which they be-
lieve is more or less fixed for the normal kidney. This expression is
known as Ambard's coefficient and formula* and has been used as a
means of evaluating the functional capacity of the kidney.

Whatever may be the value of the formula in expressing the relation-
ship existing between the rate of urea excretion and the concentration of
this substance in the blood, it is certain that, in diseased conditions where
there is impairment of the kidney the concentration of urea in the
blood remains permanently at an abnormally high average level, al-
though the amount of urea excreted during twenty-four hours may be
exactly the same as under normal conditions. Probably the increased con-
centration of urea in the blood under these conditions is a compensatory
measure to provide sufficient pressure to cause its excretion through a
damaged outlet. It is this increase in urea of the blood which is indicated
by the term urea retention in nephritis.

The upper limit of blood urea-nitrogen is about 20 mg. per 100 c.c.,
which would correspond to about 0.45 gm. of urea per liter of blood.
The average figure is half of this amount. The maximum concentration
of urea in the urine is seldom over 8 per cent. On this basis the kidney
can raise the concentration of the urea in the urine, at a conservative
estimate, from 100 to 200 times. Normally the daily output of urea
nitrogen may range from 8 to 12 gm., and the nitrogen which it contains
is roughly 80 per cent of the total excretion for the day.

Ammonia. — The chief source of ammonia in the body is the ni-
trogenous portion of the deamidized amino acids. The ammonia found
in excess in the portal blood is derived from ingested ammonium salts
and from ammonia resulting from bacterial action on proteins in the
intestinal tract. The ammonia of the body is present chiefly in the form
of ammonium carbonate, and it is this salt that is the precursor of urea.
Because ammonium carbonate is so readily converted into urea by the
tissues of the body, little ammonia is normally present in the systemic
blood. The greater portion of the ammonia that finds its way into the
urine serves as a base to transfer acid radicles either ingested or formed

*Ambard and Weil's formula is:

Ur

K = , in which:

70 V~C~

D x — x

P v'25

K •= coefficient of urea excretion (Constant of Ambard).
Ur =: grams of urea per liter of blood.
D — output of urea in grams per 24 hours.
P = weight of the patient.
C = grams of urea per liter of urine.
70 = standard weight.
25 r= standard concentration of the urine.

The average value for this constant in normal individuals is said to lie between .06 and .09.
Critical reviews of the work have been published recently by Maclean6 and by Addis and
Watanabe.8

AMOUNT AND COMPOSITION OF THE URINE 563

within the body. The amount of ammonia in the urine, therefore, is an
indirect measure of the extent of urea formation and of the acid bodies
of the blood. For the latter reason the determination of the ammonia
excretion in urine is of some clinical importance. The ingestion of
mineral acids increases the ammonia excretion, while alkalies tend to
reduce it. During fasting and in diseases such as diabetes, where there
is an abnormal metabolism, the amount of ammonia in the urine is in-
creased. Ordinarily the daily output of ammonia nitrogen does not
exceed 0.5-0.6 gm., constituting 3-5 per cent of the total amount of
nitrogen.

Creatinine. — On a meat-free diet the daily excretion of creatinine is
remarkably constant, amounting to from 7 to- 11 mg. per kilogram of
body weight. For this reason its determination is accepted as an in-
dispensable feature in metabolism investigations involving urine anal}^-
sis. Any gross variation from the normal amount indicates the certain
failure of the attendants to collect all of the twenty-four-hour specimen
of urine.

The creatinine is one of the last of the urinary constituents to accumu-
late in the blood during renal insufficiency, and for this reason affords
a reliable prognostic indication concerning the patients' condition. A
rise in the creatinine concentration of the blood is evidence of serious
renal disease, patients with concentrations of 5 mg. never recovering
(Chase and Myers).7 The concentration of creatinine in the urine is
about 100 times greater than in the blood, in which there is 1-2 mg. per
100 c.c.

In adult man creatine does not appear in the urine save during starva-
tion or wasting diseases. In woman it is absent save after postpartum
resolution of the uterus. Children commonly excrete creatine along
with creatinine until the middle years of childhood.

The Purine Bodies and Uric Acid. — The most important purine in
human urine is uric acid. Xanthine is the next in importance, and small
amounts of hypoxanthine, guanine, and adenine are found. Among the
most interesting of the salts of the urine to the clinician are the urates,
because an accumulation of uric acid in the body was believed to be
responsible for many obscure clinical conditions. It is quite true that
the salts of uric acid are found in higher than normal amount in some
diseases, especially gout, leukemia, and chronic nephritis, but the many
vague theories associated with uric acid and disease have long ago been
exploded.

The human body has the almost unique distinction among mammals
of not being able to destroy any of the uric acid it produces, and hence
all the uric acid formed during metabolism must be excreted in the urine.

564 THE EXCRETION OF URINE

Unfortunately the kidney appears to be less competent to rid the body
of this waste than it is of the other urinary metabolites, and one of the
earliest signs of renal insufficiency is now held to be a failure of the
kidney to prevent the uric acid of the blood from increasing. Perhaps
the reason for the inability of the kidney to excrete uric acid readily
lies in the fact that its salts are among the least soluble of those in the
urine. It is on this account that when the urine cools, a red sediment of
urates containing certain pigments often separates out.

The uric acid of the urine is possibly derived entirely from the purine
metabolism of the body, in which the nucleins either of the body cells or
of the exogenous food take part. It is decreased during starvation and
increased by eating food rich in nucleins, such as liver and sweet-
breads.

Under ordinary conditions the excretion of uric acid amounts to from
0.3 to 1.2 gm. per day (0.02 to 0.10 per cent), the variation being de-
pendent upon the state of health, diet, or personal idiosyncrasy. The
blood of a normal individual contains on the average 1.8 mg. of uric
acid per 100 c.c. The kidneys are therefore able to concentrate the
uric acid in the urine from 30 to 60 times over its concentration in the
blood plasma.

The purines found in coffee and tea (caffeine, etc.) are excreted in
the urine as salts not of uric acid but of methylated xanthines.

Hippuric Acid, — This is a constant constituent of the urine of her-
bivorous animals, and is usually present in small amounts in human
urine. The amount rarely exceeds 0.7 gm. a day, but on a diet rich in
fruits and vegetables it may exceed 2 gm. It is interesting, since it is
the only urinary constituent that is synthesized by the renal cells.'

Ammo acids are always present in small amounts in the urine, con-
stituting, according to D. D. Van Slyke, about 1.5 per cent of the total
nitrogen. The estimation of the amino-acid nitrogen of the urine has
not been found to be of any clinical significance.8

The aromatic oxyacids are normally present in the urine in varying
amounts. These include phenol, indoxyl, skatoxyl, and phenylacetic,
paraoxyphenyl, propionic, oxymandelic and homogentisic acids. These
bodies are derived from phenylamino acids, such as tyrosine, tryptophane,
and phenylalanine. It is believed that the putrefactive decomposition
of proteins in the large intestine results in the production of these toxic
bodies. The body protects itself by oxidizing them and uniting them
to sulphuric acid to form the ethereal or conjugated sulphates, which
are found in the urine in the form of sodium or potassium salts. The
determination of the amounts of these bodies in the urine has therefore
been taken as an index of the putrefaction going on within the bowel.

AMOUNT AND COMPOSITION OF THE URINE 565

The chief of these bodies is urinary indican, which is found usually as
a potassium salt. The test for indican in the urine consists in oxidiz-
ing the indoxyl in an acid solution by means of ferric chloride to indigo
blue, and shaking out the indigo blue with chloroform. The depth of
the color of the chloroform affords a rough means of determining
the amount of indican present. The fact that the indican test is nega-
tive must not be taken to mean that the intestinal processes are normal,
for if the intestine fails to contain phenylated ammo acids, or the proper
bacteria are not present, no indican will be found. On the other hand,
the putrefactive process of the large bowel may not be very extensive,
yet the amount of indican in the urine be increased, because of greater
absorption due to constipation.

Skatole, a fecal-smelling substance, is formed by certain kinds of bac-
teria. The greater proportion of this substance is excreted by the bowel,
but if the person is constipated, some of it may find its way into the
blood to impart a fecal odor to the breath and urine. Its presence
therefore has some diagnostic importance.

A very interesting body which is sometimes found in the urine is
homogentisic acid. It is thought to be an intermediate step in the metab-
olism of tyrosine, and 'is found in the urine of people suffering from
alkaptonuria. The disease is remarkable in that it appears to run in
families and produces no ill effects. Homogentisic acid is a strong
reducing agent, and for this reason may be confused with sugar in
Fehling's test.

The inorganic constituents of the urine include the acids: chlorides,
sulphates and phosphates; and the bases: sodium, potassium, magnesium,
and calcium.

The Salts of the Normal Urine

The Chlorides.— The chlorides compose the bulk of the acid rad-
icles in the urine. Although they appear to be necessary constituents
of the living cell, they do not, so far as known, enter into combinations
with the organic constituents. The tissues appear to require a rather
definite concentration of sodium chloride in order to carry on their
work, for reduction in the sodium-chloride intake of the body results
in a reduction in the chloride excretion by the urine. In salt starvation
the chlorides may disappear entirely from the urine, the amount of
chloride excreted appearing to be closely related to the amount of salt
ingested. When the intake is constant, the rate of excretion is likewise
more or less constant, but a sudden reduction in the salt of the diet may
be accompanied by a slight decrease in the salt content of the blood,
with an attendant loss of water. On the other hand, when the salt is

566 THE EXCRETION OF URINE

again taken, there is a retention of salt and of water, with a consequent
increase in body weight, until equilibrium is re-established on the old
level. While the above is the usual reaction, a considerable retention of
salt without an increase in the water content of the body may occur in
some apparently normal cases. This is due probably to the deposition
of salt in the tissues.

Careful studies fail to confirm the idea that there is a fixed relation-
ship between the salt and the water of the body. As with the nitroge-
nous constituents, however, there appears to be a relationship between
the rate of excretion of chlorides and the amount of chloride in the blood.
Ambard believes that this relationship, like that of the excretion of urea
to the blood urea, is capable of being expressed mathematically (see
page 562), if allowance is made for the fact that NaCl is not excreted
after it falls below a certain concentration in the blood equal to about
5.62 gm. per 1000 c.c. This level is more or less constant for normal
individuals, but is considerably increased in disease of the kidney. This
is known as the threshold of chloride excretion.

The amount of sodium chloride excreted in the urine in twenty-four
hours varies between 8 and 20 gm. a day, according to the intake. It
is therefore apparent that the kidney is able to concentrate the salts
of the plasma from ten to twenty times.

The Sulphates. — Since the inorganic sulphates do not form an im-
portant constituent of the food, the greater portion of the sulphates of
the urine are derived from the sulphur found in the protein molecule.
For this reason the sulphates of the urine, like the nitrogen, are a meas-
ure of protein metabolism. An increase in the nitrogen excretion is
accompanied by an increase in the sulphur excretion, the ratio being
about 5 to 1. The daily output of sulphur is between 1 and 3 gm. The
greatest output is in the form of the alkaline sulphates, about 10 per-
cent in combination with aromatic bodies, and a small amount in com-
bination with amino acids and neutral organic salts.

The phosphates of the urine are derived from the food and from the
oxidation of phosphorus-containing bodies in the tissues such as
nuclein, lecithin, etc. The daily excretion varies between 1 and 5 gm.,
calculated as P205. When calcium or magnesium is present in the
food, they are excreted by the bowel as phosphate, a,nd proportionately
less is found in the urine. The amount usually excreted in the feces
equals about 30 per cent of the total.

Since phosphates in the urine exist as a mixture of the mono- and di-
sodium hydrogen phosphates, they have an important bearing on the

AMOUNT AND COMPOSITION OF THE URINE 567

reaction of the urine, the amount of each varying with the degree of
the acidity of the urine (see page 558).

On a heavy protein diet the urine is acid on account of the sulphuric
and other acids formed from the meat, and in this case there is a greater
amount of phosphoric acid and the mono-sodium hydrogen phosphate.
When the urine is alkaline or less acid, as it is on a vegetable diet, there
is a large amount of the disodium hydrogen phosphate. Since calcium
and magnesium phosphates are more soluble than the diphosphates of
the same metals, deposits of the earthy phosphates are often found in
neutral or alkaline urines. When the urine is heated, the diphosphate
of calcium breaks up into the mono-calcium and a tri-calcium phos-
phate, which accounts for the fine turbidity often taken for albumin in
the flame test. Addition of acid will cause this to disappear. The crys-
tals of triple phosphates which occur in alkaline urine are ammonium
magnesium phosphate, NH4MgP04.

Quantitative Changes in the Blood and Urine in Disease

The precise diagnosis of many diseases is being greatly assisted by
quantitative determinations of the various nitrogenous metabolites, of
sugar and of inorganic salts, not only in the urine but also in the blood.
Although the details of this work must be sought for in the texts deal-
ing with clinical diagnosis, it may be of value, as indicating the practical
nature of the work if we give one of the tables (page 568) recently pub-
lished by Myers16 which illustrates the nature of the results that have
been obtained.

COMPARATIVE NITROGEN PARTITION OF URINE AND BLOOD.
(In per cent of total nonprotein nitrogen)

URICNACID

UREA CREATININE

N N

AMMONIA

N

REST

N

Normal Urine 1.5
Normal Blood 2
Blood in Gout and Early Nephritis 6
Blood in Parenehymatous
Nephritis (Nephrosis) 2
Blood in Terminal Interstitial
Nephritis 2 to 3

85
50
50

55

75

5
2

2

2
2.5

4
0.3
0.3

0.3
0.5

4.5
46
42

40
20 '

In the foregoing table is given a comparison of the partition of the non-
protein nitrogenous constituents of the blood and urine as well as that of
the blood in nephritic conditions. A useful description of the most prac-
tical and simple of the methods employed for making the necessary an-
alyses will be found in the papers of Myers.

568

THE EXCRETION OF URINE

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AMOUNT AND COMPOSITION OF THE URINE 569

KIDNEY KEFERENCES

(Monographs)

Beddard, A. P.: Eecent Advances in Physiology, Longmans. Green & Co., London.

1906.
Cushny, A. E.: Secretion of Urine, Longmans, Green & Co., London, 1917.

(Original Papers)

iBrodie, T. G., and Mackenzie, J. J.: Proc. Eoy. Soc., 1914, Ixxxvii, B, 593.

sCushny, A. E.: Secretion of Urine, 1917, p. 48.

sAddis and Watanabe: Jour. Biol. Chem., 1916, xxiv, 203.

^Mosenthal, H. O.: Arch. Int. Med., 1915, xvi, 733.

sAmbard and Weil: Physiologic normale et pathologique des reins, Paris, 1914
J. B. Bailliere et fils.

eMaclean, F. C.: Jour. Exper. Med., 1915, xxii, 212.

7Chase and Meyers: Jour. Am. Med. Assn., 1916, Ixvii, 931.

s Van Slyke, D. D., and Meyer, G. M.: Jour. Biol. Chem., 1912, xii, 399; and 1913,
xvi, 197, 213 and 231.

sKnowlton, F. P.: Jour. Physiol., 1911, xliii,,219.
loBarcrof t, J., and Straub, H. : Jour. Physiol., 1910, xli, 145.
nBowntree and Geraghty: Jour. Pharm. and Exper. Therap., 1910, i, 579.
isAsher and Pearce, E, G.: Zeitschr. f. Biol., 1913, Ixiii, 83.
isPearce, E. G., and Carter, E. P.: Am. Jour. Physiol., 1915, xxxviii, 350.
"Stewart, G. N.: Text Book of Physiology, 1918.
isLeathes, J. B.: Brit. Med. Jour., Aug. 9, 1918, p. 165.
leMyers, V. C.: Jour. Lab. and din. Med., 1920, v, 343, 418, 490.

PART VII

METABOLISM

CHAPTER LXII

METABOLISM

Introductory. — The object of digestion, as we have seen, is to render
the food capable of absorption into the circulatory fluids — the blood and
lymph. The absorbed food products are then transported to the various
organs and tissues of the body, where they may be either used at once
or stored away against future requirements. After being used, certain
substances are produced from the foods as waste products, and these pass
back into the blood to be carried to the organs of excretion, by which they
are expelled from the body. By comparison of the amount of these ex-
cretory products with that of the constituents of food, we can tell how
much of the latter has been retained in the body, or lost from it. This
constitutes the subject of general metabolism. On the other hand, we may
direct our attention, not to the balance between intake and output, but to
the chemical changes through which each of the foodstuffs, must pass be-
tween absorption and excretion. This is the subject of special metabolism.
In the one case we content ourselves with a comparison of the raw ma-
terial acquired and the finished product produced by the animal factory;
in the other we seek to learn something of the particular changes to which
each crude product is subjected before it 'can be used for the purpose of
driving the machinery of life or of repairing the worn-out parts of the
body.

In drawing up a balance sheet of general metabolism, we must select
for comparison substances that are common to both intake and output. In
general the intake comprises, besides oxygen, the proteins, fats and car-
bohydrates; and the output, carbon dioxide, water and the various nitrog-
enous constituents of urine. This dissimilarity in chemical structure be-
tween the substances ingested and those excreted limits us, in balancing the
one against the other, to a comparison of the smallest fragments into which
each can be broken by chemical agencies. These are the elements, and of
them carbon and nitrogen are the only ones which it is possible to measure

570

METABOLISM 571

with accuracy in both intake and output. From balance sheets of intake
and output of carbon and nitrogen and from information obtained by ob-
serving the ratio between the amounts of oxygen consumed by the animal
and of carbonic acid excreted, we can draw far-reaching conclusions re-
garding the relative amounts of protein, fat and carbohydrate that have
been involved in the metabolism.

As has already been stated, the essential nature of the metabolic proc-
ess in animals is one of oxidation — that is, one by which large unstable
molecules are broken down to those that are simple and stable. Dur-
ing this process of catcibolism, as it is called, the potential energy locked
away in the large molecules becomes liberated as actual or kinetic energy —
that is, as movement and heat. It therefore becomes of importance to
compare the actual energy which an animal expends in a given time with
the energy which has meanwhile been rendered available by metabolism.
We shall first of all consider this so-called energy balance and then pro-
ceed to examine somewhat more in detail the material balance of the body.

ENERGY BALANCE

The unit of energy is the large calorie (written C.), which is the amount
of heat required to raise the temperature of one kilogram of water through
one degree (Centigrade) of temperature.* We can determine the calorie
value by allowing a measured quantity of a substance to burn in com-
pressed oxygen in a steel bomb placed in a known volume of water at a
certain temperature. Whenever combustion is completed, we find out
through how many degrees the temperature of the water has become
raised and multiply this by the volume of water in liters. Measured
in such a calorimeter, as this apparatus is called, it has been found that
the number of calories liberated by burning one gram of each of the proxi-
mate principles of food is as follows :

Carbohydrates I ^tarch
| Sugar

4.1

4.0

Protein ." 5.0

Fat . . 9.3

The same number of calories will be liberated at whatever rate the com-
bustion proceeds, provided it results in the same end products. When
a substance, such as sugar or fat, is burned in the presence of oxygen, it
yields carbon dioxide and water, which are also the end products of the
metabolism of these foodstuffs in the animal body ; therefore, when a gram
of sugar or fat is quickly burned in a calorimeter, it releases the same

*The distinction between a calorie and a degree of temperature must be clearly understood. The
former expresses quantity of actual heat energy; the latter merely tells us the intensity at which the,
heat energy is being given out.

572

METABOLISM

amount of energy as when it is slowly oxidized in the animal body. But
the case is different for proteins, because these yield less completely oxi-
dized end products in the animal body than they yield when burned in
oxygen ; so that, to ascertain the physiological energy value of protein, we
must deduct from its physical heat value the physical heat value of the
incompletely oxidized end products of its metabolism. It is obvious that
we can compute the total available energy of our diet by multiplying the
quantity of each foodstuff by its calorie value.

Methods. — In order to measure the energy that is actually liberated in the animal
body, we must also use a calorimeter, but of somewhat different construction from

Fig. 174. — Respiration calorimeter of the Russell Sage Institute of Pathology, Bellevue Hospital,
New York. At the right is seen the table with the absorption tubes; and in the middle, at the
back, the electric control table for regulating the temperature of the double walls of the calorimeter.
At the extreme left is the oxygen cylinder. (L/usk's Science of Nutrition.)

that used by the chemist, for we have to provide for long-continued observations and
for an uninterrupted supply of oxygen to the animal. Animal calorimeters are also
usually provided with means for the measurement of the amounts of carbon dioxide
(and water) discharged and of oxygen absorbed by the animal during the observation.
Such respiration calorimeters have been made for all sorts of animals, the most perfect
for use on man having been constructed in America (see Fig. 174). As illustrating the
extreme accuracy of even the largest of these, it is interesting to note that the actual
heat given out when a definite amount of alcohol or ether is burned in one of them
exactly corresponds to the amount as measured by the smaller bomb-calorimeter. All

METABOLISM 573

of the energy liberated in the body does not, however, take the form of heat. A
variable amount appears as mechanical work, so that to measure in calories all of the
energy that an animal expends, one must add to the actual calories given out, the
calorie equivalent of the muscular work which has been performed by the animal dur-
ing the period of observation. This can be measured by means of an ergometer,
a calorie corresponding to 425 kilogram* meters of work. That it has been possible to
strike an accurate balance between the intake and the output of energy of the animal
body, is one of the achievements of modern experimental biology. It can be done in
the case of the human animal; thus, a man doing work on a bicycle ergometer in the
Benedict calorimeter gave out as actual heat 4,833 C., and did work equalling 602 C.,
giving a total of 5,435 C. By drawing up. a balance sheet of his intake and output
of food material during this period, it was found that the man had consumed an amount
capable of yielding 5,459 C., which may be considered as exactly balancing the actual
output.

It would be out of place to give a full description of the respiration calorimeter here.
The general construction will be seen from the accompanying figure of the form of
apparatus in use for patients in the Russell Sage Institute, New York. One of the most
interesting details of its construction concerns the means taken to prevent any loss of
heat from the calorimeter to the surrounding air. This is accomplished in the follow-
ing way: The innermost layer of the wall is of copper; then, separated from this by
an air space, is another wall of copper, outside of which are two wooden walls separated
from each other and from the outer copper walls by air spaces. The two copper walls
are connected through thermoelectric couples, so that an electric current is set up when-
ever there is any difference in their temperatures. The current is observed by means of
a galvanometer placed outside the calorimeter, and from its movements the observer
either heats up or cools down the outer copper walls so as to correct the difference of
temperature causing the current. This is done by an electric heating device or by cold
water tubes placed between the outermost copper and the innermost wooden walls.
Since the temperature of the two copper walls is the same, there can be no exchange of
heat between them, and consequently none of the heat that is absorbed by the inner cop-
per walls is allowed to be carried away. All the heat given out by the animal is ab-
sorbed by the stream of cold water flowing through the coils of pipe in the chamber.
The heat used to vaporize the moisture from skin and lungs must of course also be
measured. This is done by collecting the water vapor in a sulphuric-acid bottle placed
ip the ventilating current. By multiplying the grams of water by the factor for the
latent heat of vaporization, we obtain the calories of heat so eliminated.

"The calorimeter contains a comfortable bed and is provided with two windows, a
shelf, a telephone, a fan, a light and a Bowles stethoscope for counting the pulse.
The ordinary experiment takes about as long as a trip from New York to New London.
Patients, as a rule, doze from time to time or else try to work out some scheme by
which they can amuse themselves without moving. After three or four hours they are
rather bored by the quiet, and the observations are not prolonged beyond this time.
They are allowed to turn over in bed once or twice an hour, but reading and telephon-
ing are discouraged, since these increase the metabolism. The air in the box is fresh
and pure, the patient suffers no discomfort, and objections to the procedure are very
infrequent. Most of the patients are only too glad of the extra attention, and they
insist that the calorimeter has a marked therapeutic value." (Du Bois.)

Normal Values. — Having thus satisfied ourselves as to the extreme

*A kilogram meter is the product of the load in kilograms multiplied by the distance in meters
through which it is lifted.

574 METABOLISM

accuracy of the method for measuring energy output, we shall now con-
sider some of the conditions that control it. To study these we must first
of all determine the basal heat production — that is, the smallest energy
output that is compatible with health. This is ascertained by allowing a
man to sleep in the calorimeter and then measuring his calorie output
while he is still resting in bed in the morning, fifteen hours after the last
meal. When the results thus obtained on a number of individuals are
calculated so as to represent the calorie output per kilogram of body weight
in each case, it will be found that 1 C. per kilo per hour is discharged
—that is to say, the total energy expenditure in 24 hours in a man of 70
kilos, which is a good average weight, will be 70 X 24 = 1,680 C.

When food is taken the heat production rises, the increase over the
basal heat production amounting for an ordinary diet to about 10 per
cent. Besides being the ultimate source of all the body heat, food is there-
fore a direct stimulant of heat production. This specific dynamic action,
as it is called, is not, however, the same for all groups of foodstuffs, being
greatest for proteins and least for carbohydrates. Thus, if a starving
animal kept at 33° C. is given protein with a calorie value which is equal
to the calorie output during starvation, the calorie output will increase by
30 per cent, whereas with carbohydrates it will increase by only 6 per
cent. Evidently, then, protein liberates much free heat during its as-
similation in the animal body; it burns with a hotter flame than fats or
carbohydrates, although before it is completely burned it may not yield
so much energy as is the case, for example, when fats are burned. This
peculiar property of proteins accounts for their well-known heating qual-
ities. It explains why protein composes so large a proportion of the diet of
peoples living in cold regions, and why it is cut down in the diet of those
who dwell near the tropics. Individuals maintained on a low protein diet
may suffer intensely from cold.

If we add to the basal heat production of 1,680 C. another 168 C. (or
10 per cent) on account of food, the total 1,848 C. nevertheless falls far
short of that which we know must be liberated when we calculate the
available energy of the diet, which 'we may take as 2,500 C. What be-
comes of the extra fuel? The answer is that it is used for muscular work.
Thus it has been found that if the observed person, instead of lying down
in the calorimeter, is made to sit in a chair, the heat production is raised
by 8 per cent, or if he performs such movements as would be necessary for
ordinary work (writing at a desk) it may rise 29 per cent — that is to say,
to 90 C. per hour. There is, however, practically no difference in the en-
ergy output of a person lying flat or lying in a semi-reclining posi-
tion, as in a steamer chair. Allowing eight hours for sleep and sixteen
hours for work, we can account for about 2,168 C., the remaining 300 odd

METABOLISM 575

C. that are required to bring the total to that which we know, from statis-
tical tables of the diets of such workers, to be the actual daily expenditure,
being due to the exercise of walking. If the exercise is more strenuous,
still more calories will be expended ; thus, to ascend a hill of 1,650 feet at
the rate of 2.7 miles an hour requires 407 extra calories. Field workers
may expend, in 24 hours, almost twice as many calories as those engaged
in sedentary occupations.

Standard for Comparison

"When the energy output per kilo body weight is determined in animals
of varying size, the values are greater the lighter the animal. This is
evident from the following results obtained on dogs:

Weight of dog Heat production in calories

per kilo per day

(1) 31.2 35.68

(2) 18.2 46.2

(3) 9.6 65.16

(4) 0.5 66.07

(5) 3.19 88.07

(Rubner)

When, on the other hand, instead of body weight, the area of the sur-
face of the body is taken as the basis of calculation, results that are almost
constant are obtained. Following are the results in the above animals on
this basis :

Heat production in calories

Surface in square cm. per square meter of sur-

face per day

(1) 10,750 1036

(2) 7,662 1097

(3) 5,286 1183

(4) 3,724 1153

(5) 2,423 1212

(Rubner)

Such results have prompted observers to conclude that the determining
factor in the calorie output of warm-blooded animals is the relative sur-
face of the animal. This is greater the smaller the animal, with the con-
sequence that heat is more rapidly lost to the surrounding air from the
surface, thus requiring more active combustion. Until quite recently it has
been generally believed that such a relationship between body surface and
heat production did actually exist, but, thanks to the work of F. G. Bene-
dict7 and E. F. and D. Du Bois6, it is now known that the calculations were
based upon incorrect computations of the body surface. In the older re-
searches the calculation was made by using a formula known as Meeh's, in
which weight was multiplied by a certain factor (viz., 12.312 x ^weight).
Du Bois, however, has shown that an average error of 16 per cent is in-
curred in using this formula. For more accurate measurement of the

576

METABOLISM

surface area in man this worker covered the body with thin underwear,
which was then impregnated with melted paraffin and reinforced with
paper strips to prevent it from changing in area when removed. This
model of the surface was afterwards cut up into flat pieces and photo-
graphed on paper of uniform thickness, the patterns being then cut out,
and weighed. Prom the results it wras easy to calculate the actual sur-
face area.

Where the height and weight are known, a fairly accurate computation
of the surface can be secured by using the following formulas : A=W°-425
XH°-720X71.84; A being the surface area in square centimeters; // the
height in centimeters; and W, the weight in kilograms. Based on this
formula, a chart has been plotted from which the surface area may be de-

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WEIGHT-KILOGRAMS

Fig. 175. — Chart for determining surface area of man in square meters from weight in kilo-
grams (Wt.) and height in centimeters (Ht.) according to the formula: Area (Sq. Cm.) — Wt.
0.425 XHt. 0.725 X71.84. (From Dubois and Dubois, Arch. Int. Med., 1917, vol. 17.)

termined at a glance (Fig. 175). Another method recently employed by
Benedict is based on measurements made from photographs of the subject
in various poses.

By the use of these more accurate measurements of body surface, it is
now known that, although the surface-area law gives us constant results
for the energy output of different individuals of similar build, and offers
us a much more accurate basis for comparing those of different laboratory
animals than body weight, yet it breaks down when applied to men in widely
differing states of body nutrition. Thus, in the case of a man who starved
for a month, the calorie output per square meter of surface decreased to-
wards the end of the fast by 28 per cent. Obviously, therefore, it would be
incorrect to draw conclusions regarding possible changes in energy output

METABOLISM 577

of a series of emaciated or corpulent individuals by comparison of their
calorie output per square meter of surface with that of normal individuals.

The determining factor of energy output is undoubtedly the general
condition of bodily nutrition — the active mass of protoplasm of the body
(Benedict). That there is a relationship between the body surface and
metabolism is undoubted, but the relationship is not >a causal one. At
present, therefore, the only safe method to employ in comparing the
metabolism of normal and diseased individuals is that called by Benedict
"the group method, " in which the metabolism of groups of persons of
like height and weight is compared, it being assumed that such individuals
have the same general growth relations.

Benedict, in collaboration with Harris, has carried this idea into effect
by the preparation of standard tables which give the values for basal
metabolism for both men and women for the commoner ranges of weight,
stature and age. The values in the tables are based on the statistical
constants of a sufficient number of accurate normal data so that they
can be used as the standards for comparison with results obtained under
various physiological and pathological conditions.

Two sets of tables are employed, one for body weight and the other
for stature and age, the values of the two tables being added together,
and, since women have a lower metabolism than men, sets of tables for
both sexes are necessary. To determine whether there is a significant
modification of metabolism in clinical cases, it is necessary to compare
the actually measured calories with those calculated from the tables on
the assumption that the patient is in normal health. It has been found
by this method that athletes have a somewhat higher metabolism than
untrained persons, and that living on a vegetarian diet does not funda-
mentally alter it.

Influence of Age and Sex

The energy output is low in the newly born ; it increases rapidly during
the first year, reaching a maximum at about three to six years of age, and
then rapidly declining to about twenty, after which it declines much more
slowly. The decline in the earlier years does not proceed steadily, how-
ever, for at the period just preceding the onset of puberty a decided in-
crease becomes evident, indicating that at this period the metabolism of
the growing organism is being stimulated. Females have a lower energy
output than males, and the stimulating influence of puberty is less marked
in them.

In round numbers, 40 C. per square meter of surface per hour is the
energy output of normal men, a 15 per cent deviation being considered
as decidedly abnormal. The average metabolism of fat and thin subjects is

578 METABOLISM

the same, but that of women is 6.8 per cent lower than that of men. The
basal metabolism of a group of men and women between the ages of forty
and fifty was 4.3 per cent below the average for the larger group between
the ages of twenty and fifty ; and that of a group between fifty and sixty
years was 11.3 per cent lower.

Influence of Diseases

The measurements have been made by the direct method which has just
been described, but since the much simpler indirect method (page 589)
yields comparable results, it is being adopted for clinical purposes. These
results were obtained by making parallel determinations of energy out-
put by both methods, in disease as well as in health. Some of the ob-
servations that have been made on the energy output in various diseases
are as follows : In very severe cases of exophthalmic goiter, heat produc-
tion may be increased from 50 to 75 per cent over the normal. The
warmth of the skin and the sweating, which are prominent symptoms
of this disease, are therefore accounted for by the increased elimina-
tion of heat, and it is considered possible that the other symptoms
would be caused in any normal individual were his metabolism
maintained for months or years at the high level which it occupies in
goiter. In the opposite condition of myxedema, the energy output is
markedly reduced, but rises slowly during treatment with thyroid extract,
or much more rapidly with the very active thyroid hormone recently iso-
lated by Kendall (page 798). In diabetes it has often been thought that
the rapid emaciation and loss of strength were dependent upon an excited
state of metabolism, or a useless burning up of the energy material. Al-
though an increase could not be shown when the surface area was used as a
basis for calculation (Du Bois) the group method shows an increased
energy metabolism in many cases of diabetes amounting sometimes to
12 per cent (Benedict). In uncompensated cases of cardiorenal dis-
ease, there is increased energy output. In pernicious anemia metabolism
is normal, although in severe cases there may be an increased demand for
oxygen.

Even at the risk of repetition, it is important to point out that in all
these diseases the energy output is the same whether measured directly or
by the indirect method about to be described.

The value of following the basal metabolism in the therapy of exoph-
thalmic goiter has been demonstrated in recent work by Means and
Aub, who have followed the metabolism and clinical condition of a series
of cases over a period of several years. They found in the majority of
cases that the results with the x-ray treatment are as good as those se-
cured by surgical methods. The basal metabolism shows a rapid pre-

METABOLISM 579

liminary fall after surgical removal, but a secondary rise occurs, whereas
with x-rays the metabolism gradually declines throughout the treatment.
There is practically no mortality with the x-ray treatment, and the
risks of surgical interference in very acute cases is decidedly amelio-
rated by a preliminary treatment with the rays. They conclude that "in
the management of exophthalmic goiter periodic determination of the
basal metabolism should be quite as much a routine as the examination
of the urine for sugar in diabetes mellitus."

THE MATERIAL BALANCE OF THE BODY

We must distinguish between the balances of the organic and the in-
organic foodstuffs. From a study of the former we shall gain information
regarding the sources of the energy production whose behavior under
various conditions we have just studied. From a study of the inorganic
balance, although we shall learn nothing regarding energy exchange—
for such substances can yield no energy — we shall become acquainted
with several facts of extreme importance in the maintenance of nutrition
and growth.

To draw up a balance sheet of organic intake and output requires an
accurate chemical analysis of the food and of the excreta (urine and ex-
pired air).

Methods for Measuring Output

The principle by which the output is measured will be understood by referring to
Fig. 176, from which it will be seen that the calorimeter is connected with a closed
system of tubes provided with an air-tight rotary blower or pump to maintain a con-
stant current of air, as indicated by the arrows. Following the air stream as it leaves
the chamber, we note a side tube connecting with a meter to indicate changes in vol-
ume of the air in the system. Beyond this and the pump is a specially constructed
bottle containing concentrated H.,SO4, then one containing soda lime, and lastly another
H2SO4 bottle. The first H2S.O4 bottle absorbs all the water vapor contained in the
sir coming from the chamber; the soda lime bottle absorbs the CO2, and the second
HJ8O4 bottle absorbs water that is produced in the chemical reaction involved in the
absorption of the CO9 by the soda lime ( 2NaOH + CO2 = H2O + Na2COg ) . By weigh-
ing these absorption bottles before and after an animal has been for some time in
the chamber, the weight of HoO and of CO given out can be determined. Another
side tube leads to an oxygen cylinder, the valve of which is manipulated so as to cause
oxygen to be discharged into the system at such a rate as to compensate exactly for
that used up by the animal, as indicated by the behavior of the meter. The amount of
oxygen required is determined either by weighing the oxygen cylinder before and after
the observation or by measuring the volume of oxygen used by passing it through a
carefully calibrated and very sensitive water meter inserted on the side tube that con-
nects the O2 cylinder with the main tubing of the system. Since muscular activity
causes pronounced changes in the rate of metabolism, means are usually taken to
secure graphic records of any movements made during the observation.

580

METABOLISM

The growing importance in clinical investigations of measurements of
the respiratory exchange and the necessity for having methods that are as
simple as is consistent with accuracy, have led to the introduction of
several other forms of apparatus, of which those of F. G. Benedict and of
Tissot are the most important. In these methods no calorimeter is em-
ployed but the energy exchange is calculated from the amount of 02
inspired in a given time. In Benedict's method a tightly fitting mask is
applied over the nose and mouth and connected, by a short T-piece, with
the same tubing as that used in the respiration calorimeter. The patient

Fig. 176. — Diagram of Atwater-Benedict respiration calorimeter. As the animal uses up the Qz,
the total volume of air shrinks. This shrinkage is indicated by the meter, and a corresponding
amount of O2 is delivered from the weighed O2-cylinder. The increase in weight of bottles
II and III gives the CO2; that of I, the water vapor.

thus breathes in and out of the air stream that is passing along the tubing
without any of the obstruction experienced when the breathing has to be
performed through valves, as in the older (Zuntz) forms of portable
respiratory apparatus. It is particularly for studies on man that this
apparatus has been devised. The Tissot and Douglas methods are de-
scribed in Chapter LXIV, where the method used for calculating the re-
sults is also outlined.

This is called the method of indirect calorimetry, and it has been clearly
established by numerous observations that the results agree exactly with
those secured by the method of direct calorimetry described above. For

METABOLISM 581

most purposes the indirect method is quite satisfactory, and it is espe-
cially valuable in cases in which there are considerable and sudden
changes in body temperature. That the results by the two methods should
agree shows clearly that the law of the conservation of energy must apply
in the animal body, for it is evident that if any energy were derived from
outside the body other than that taken with the food, the results by the
direct method would be higher than those by the indirect.

CHAPTER LXIII

THE CARBON BALANCE

Before proceeding to discuss the special metabolism of proteins, fats
and carbohydrates, it will be advantageous to consider briefly some gen-
eral facts concerning the excretion of carbon dioxide and the intake of
oxygen. In the first place, it is important to note that the extent of the
combustion process in the animal body is proportional to the amount of
oxygen absorbed and of carbon dioxide produced, whereas the nature of
the combustion is indicated by the ratio existing between the amounts of
carbon dioxide expired and of oxygen retained in the body. An investi-
gation of the carbon balance, in other words, is partly quantitative and
partly qualitative — quantitative in the sense that it indicates how in-
tensely the body furnaces are burning, and qualitative in the sense that
it tells us what sort of material is being burned at the time.

THE RESPIRATORY QUOTIENT

Influence of Diet. — The respiratory quotient is determined by com-
parison of the volume of carbon dioxide expired with the volume of oxy-
gen meanwhile retained in the body or, as a formula,

Vol. C02 expired
Vol. 02 retained

For the sake of brevity the respiratory quotient is often written R. Q. That
it serves as an indicator of the kind of combustion occurring will be evi-
dent from the following equations:

1. Carbohydrate: CrH12O6 + 6O, = 6CO2 + 6H2O
(Dextrose.)

2. Fat: CJI.(C18H33O2)3 + SOO2 = 57CO2 4- 52H.O

(Olein.)

3. Protein : C72H112N18O22S + 77O2 = 63CO2 + 38H2O + 9CO (NH2) 3 + SO3

[Empirical formula for
albumin (Lieberkuhn).] ,

.-. R.Q.— ^-— — =082
Oa 77

582

THE CARBON BALANCE 583

4. Conversion of fat into carbohydrate:

2C3H5(C18H3302)3 + 6402 = 16C6H12O6 + 18CO2 + 8H2O
(Olein.)

5. Conversion of carbohydrate into a tniaced fat:

13C6H1206 = C55H1M06 + 23C02 + 26H2O.
( Oleostear opalmitin. )

Taking carbohydrates first, the general formula may be written CH20,
from which it is plain that, to oxidize the molecule, oxygen will be re-
quired to combine with the carbon alone, according to the equation,
CH20 + 02 = C02 + H20. In other words, the volume of carbon dioxide pro-
duced by the combustion will be exactly equal to the volume of oxygen
used in this process, in obedience to the well-known gas law that equi-
molecular quantities of different gases occupy the same volume. The
respiratory quotient is therefore unity (Equation 1)! With fats and pro-
teins, however, the general formula must be written CH2+0, indicating
therefore that for its complete oxidation the molecule must be supplied
with oxygen in sufficient amount to combine not only with all of the car-
bon, but also with some of the hydrogen, forming water; so that the vol-
ume of C02 produced will be less than the volume of oxygen retained,
and the respiratory quotient will be less than unity. As a matter of fact,
as the above equations show (2 and 3), the respiratory quotient for fats
and proteins lies somewhere between 0.7 and 0.8, being usually nearer
0.7 in the case of fats, and nearer to 0.8 in the case of proteins.

That the conditions hypothecated in the equations exist in the animal
body during the combustion of the foodstuffs can easily be shown by ob-
serving the respiratory quotient of animals on different diets. An her-
bivorous animal, such as a rabbit, when it is well fed gives invariably a
respiratory quotient of about 1, whereas a strictly carnivorous animal,
such as the cat, gives a respiratory quotient of about 0.7. Even more
striking perhaps is the comparison of the respiratory quotients in an
herbivorous animal while it is well fed and after it has been starved for a
day or two. In the latter case the respiratory quotient will fall to a low
level because, by starvation, the animal has been compelled to change its
combustion material from the carbohydrate of its food to the protein and
fat of its own tissues.

As already explained (page 582), it is from the respiratory quotient
that we are enabled to tell what proportions of fat and carbohydrate,
respectively, are undergoing metabolism. A useful table showing the
percentage of calories produced by each of these foodstuffs, after allow-
ing for protein, is given by Graham Lusk (see page 598).

584 METABOLISM

Influence of Metabolism. — Apart from diet, the respiratory quotient
may often be altered by changes in the metabolic habits of the animal.
These are most conspicuously exhibited in the case of hibernating
animals. In the autumn months, when the animal is eating voraciously
of all kinds of carbohydrate food and depositing large quantities of
adipose tissue in his body, the respiratory quotient may be considerably
greater than unity, indicating therefore either that relatively more
carbon dioxide is being discharged or less oxygen retained. As a matter
of fact, it can easily be shown that it is the former of the causes that
is responsible for the higher quotient, the explanation for the increased
production of C02 being that, as the carbohydrate changes into fat, the
relative excess of carbon in the former is got rid of in the form of C02,
as indicated in Equation 5. On the other hand, if the animal is examined
while in his winter sleep, it will be found that the respiratory quotient is
extremely low, often not more than 0.3 to 0.4, which may be interpreted
as indicating either an excessive absorption of oxygen or a markedly
decreased excretion of. carbon dioxide. As a matter of fact, there is a
great diminution in both the excretion of carbon dioxide and the intake
of 02, because the whole metabolic activity of the animal is extremely
depressed, but this diminution affects the oxygen to a much less degree,
indicating therefore a relative increase in the oxygen retention. The
explanation is that the oxygen is being used in the chemical process in-
volved in the conversion of the fat back into carbohydrate.

Whatever may be the relationship between fat and carbohydrate in
the nonhibernating animal, there is no doubt that during hiberna-
tion, before the fat stores are burned, fat is converted into something
closely related to carbohydrates, the equation for the process being rep-
resented as given above (No. 4).

In man and the higher mammalia, the only condition apart from diet
which can affect the nature of the combustion process is disease; thus
in total diabetes (page 709) the organism loses the power of burning
carbohydrate, so that whatever the diet may be, the respiratory quotient
is very low, never higher than that representing combustion of fat and
protein. It has been claimed by certain investigators that in diabetes
the respiratory quotient may fall considerably below 0.7, indicating, as
in hibernating animals, that fat is being converted into carbohydrate.
The most recent and carefully controlled observations, however, deny
this claim, and for the present we must assume that in the body of man
fat is not converted into carbohydrate (see page 696). In numerous other
diseases investigated by Du Bois and others6 no qualitative change in
the combustion processes in man has been brought to light.

THE CARBON BALANCE

585

THE MAGNITUDE OF THE RESPIRATORY EXCHANGE

It is evident that the amount of carbon dioxide expired and of oxy-
gen retained will be proportional to the energy liberation in the animal
body. Even at the risk of repetition it should be noted that the
energy exchange can be very accurately calculated from the result of
the material balance sheet — indirect calorimetry, as it is called (page
580). On account of the comparative simplicity of measuring the carbon
dioxide output and oxygen intake, it is natural that many of the obser-
vations that have been made on energy production in the animal body
depend on the use of this method, justification for which is found in the
complete agreement between the results of direct and indirect calorim-
etry in a great variety of diseases and conditions in man (Du Bois6).*

In the first place, it is interesting to compare the respiratory ex-
changes of different animals computed per kilo body weight. This is
shown in the following table.

ANIMAL

WEIGHT
GM.

OXYGEN AB-
SORBED PER KILO
AND HOUR
GM.

CARBON DIOXIDE
DISCHARGED
PER KILO
AND HOUR
GM.

VOL. CO2
VOL. 02

TEMPERA-
TURE OF
AIR

Insecta

Field cricket

0.25

2.305

—

—

Amphibia

Edible frog

0.063

0.060

0.69

15°-19°

(44.2 c.c.)

(30.76 c.c.)

0.105

0.1134

0.78

—

(73.4 c.c.)

(57.7 c.c.)

Aves

Common hen

1280

1.058

1.327

0.91

19°

(740 c.c.)

(675 c.c.)

Pigeon

232-380

3.236

—

—

Sparrow

22

9.595

10.492

0.79

18°

(6710 c.c.)

(5334.5 c.c.)

Mammalia

Ox

638,000

0.389-0.485

—

—

660,000

Sheep

66,000

0.490

0.671

0.99

16°

(343 c.c.)

(341 c.c.)

Dog

6213

1.303

1.325

0.74

15°

(911 c.c.)

(674 c.c.)

Cat

2464

1.356

1.397

0.75

-3.2°

3047

(947 c.c.)

(710 c.c.)

)>

0.645

0.766

0.86

29.6°

(450 c.c.) '

(389 c.c.)

.

Rabbit

1433

1.012

1.354

0.97

18°-20°

Guinea pig

444.9

1.478

1.758

0.86

22°

Rat (white)

80.5

3.518

—

7°

(1789 c.c.)

Mouse ' '

25

8.4

__

17°

Man

66,70

0.292

0.327

—

(Modified from Pembrey.)17

*For the convenience of those who may desire to know more about the methods of analysis
thai arc suitable iu (he clinic, a chapter on the subject will be found beginning on page 589.

586 METABOLISM

Several factors operate to explain these differences, and of these the
following are of importance:

1. The Body Temperature. — Increase in body temperature entails in-
creased combustion. This explains why the metabolism of a bird is
greater than that of a mammal of the same size, for, as is well known, the
temperature of a bird is two or three degrees centigrade above that of
other animals. Eise in body temperature also explains, in part at least,
the increased metabolism observed in fever.

2. The Temperature of the Environment. — In considering this we must
distinguish between the effect produced on warm-blooded and on cold-
blooded animals. Since the body temperature of a cold-blooded animal
is only one or two degrees Centigrade above that of its environment, it
follows that the metabolic activity will be directly proportional to the
temperature of the latter. In a warm-blooded animal, on the other hand,
the body temperature remains constant whatever changes may occur
in that of the environment, this constancy of body temperature being
dependent on the fact that the intensity of the combustion processes is
inversely proportional to the cooling effect of the atmosphere. Thus,
suppose the external temperature should fall, then the loss of heat from
the body will tend to become greater, and to maintain the body tempera-
ture at a constant level, the body furnaces must burn more briskly, with
the result that an increased excretion of carbon dioxide and intake of
oxygen will occur.

This influence of the surrounding atmosphere on the metabolic activ-
ity of warm-blooded animals has, as already pointed out, been used by
several investigators to explain the greater combustion per kilo body
weight of small as compared with large animals. The argument is that,
since the surface of small animals relatively to their mass is much greater
than in large animals, the cooling of the small animals will be proportion-
ately greater. The relationship between surface and mass is shown by tak-
ing two cubes and putting them together; the mass of the two cubes is
equal to double that of either cube, whereas the surface is less than
double, since two aspects of the cubes have been brought together. To
prove the contention, the respiratory exchange has been computed per
square meter of surface instead of per kilo body weight, with the result
that a very close correspondence in the metabolism of different animals
has been observed ; but this question has already been discussed, and we
now know that the law of cooling can not be the only one that determines
the extent of the respiratory exchange (see page 577).

3. Muscular Exercise. — This has a most important influence on the ex-
change and it is particularly in connection with it that studies in carbon-
dioxide output and oxygen intake have been of great practical value, par-

THE CARBON BALANCE 587

ticularly when the investigations are undertaken on men doing ordinary
types of muscular exercise, such as walking or climbing. It is true
that the influence of muscular exercise on the energy metabolism may
also be studied by having a person in the calorimeter do exercises on an
ergometer, but the results thus obtained are in many ways not nearly so
valuable as those which can be secured by observing the respiratory
exchange of persons doing ordinary types of muscular exercise in the
open. The following table of observations on horses is of interest in this
connection.

CONDITION

AIR EXPIRED

CARBON DIOXIDE

OXYGEN ABSORBED

C02

IN LITERS

DISCHARGED IN

IN LITERS PER

02

PER MINUTE

LITERS PER

MINUTE

MINUTE

Best

44

1.478

1.601

0.92

Walk

177

4.342

4.766

0.90

Trot

333

7.516

8.093

0.93

It will be observed that the metabolism increases extraordinarily for
even a moderate degree of work, but that at the same time the respiratory
quotient remains constant. From observations on the respiratory ex-
change of working men and animals, extremely important facts concern-
ing the efficiency of muscular work have been secured. The form of
respiratory apparatus (Zuntz or Douglas) employed for this purpose
must be capable of being strapped on the man's back without causing
any embarrassment to his bodily movements. By a comparison of the
respiratory exchange with the amount of work done, the efficiency of the
work can readily be determined. It has been found, for example, that
the efficiency is much greater after the man or animal has got into the
swing of the work, his energy expenditure per unit of work being much
greater during the first half hour's work in the morning than it is
later on. This indicates that after a little practice the muscles can ex-
ecute a given movement and perform a given amount of work much
more smoothly than when they are not in training. Another interesting
outcome of the investigations has been to show that work done under ab-
normal conditions that tend to produce any kind of muscular strain is
done inefficiently. It has been found in marching soldiers, for example,
that the slightest abrasion of the foot greatly increases the energy
expenditure, for the man, in trying to avoid the pain produced by the
abrasion, brings into operation muscular groups that are really not
required for the efficient performance of the movement, but are used in
the attempt to avoid pressure on the sore. Fatigue also causes inefficient
performance of work ; that is to say, the fatigued person, on attempting

588 METABOLISM

the same amount of work as he performed before becoming fatigued,
will do so at a much greater expenditure of energy.

There is a diurnal variation in the respiratory exchange, which is in
general parallel with the body temperature ; it rises during the day, the
time of activity and work, and falls during the night, the time of rest
and sleep. Food also affects respiratory exchange, but it will be unnec-
essary to go into this further after what has been said on page 582.

CHAPTER LXIV

A CLINICAL METHOD FOR DETERMINING THE RESPIRATORY

EXCHANGE IN MAN*

(Contributed by R. G. PEARCE)

Principle, — Since the determination of the respiratory exchange in
man is of some importance in the study of certain diseases of the respira-
tion, circulation and metabolism, and also because directions for carry-
ing out the necessary procedures are not generally available, we have
thought it might be of assistance to include here brief directions for the
Tissot and the Douglas methods. These methods have been found to
compare favorably in accuracy with others in use at present,! and be-
cause of their adaptability and simplicity they are specially suited for
clinical work.

By these methods the energy metabolism of the body is calculated from
oxygen consumption or carbon dioxide excretion per minute (indirect
calorimetry) (page 580), the figures for which are determined from the
volume and percentile gaseous composition of the expired air.

The subject breathes through valves which automatically partition the
inspired and expired air. The expirations from a number of respirations
are collected in a spirometer or bag, and the volume of the respirations
per minute is determined. The gaseous composition of the expired air
is determined by gas analysis, and the oxygen consumption and energy
output of the body are calculated from the data obtained.

Description and Use of Parts of the Apparatus: 1. THE MOUTHPIECE AND VALVES.
—The mouthpiece is made of soft pure gum rubber, and consists of an elliptical rub-
ber flange having a hole in the center 2 em. in diameter. The flange is attached on
one side to a short rubber tube. On the other side at right angles to the rubber flange,
are attached two rubber lugs. The rubber flange is placed between the lips, and the
lugs are held by the teeth. The rubber tube of the mouthpiece is connected to the
tube carrying the valves. The nose must be tightly closed if mouth breathing is used.
This is accomplished by a nose clip, which consists of a V-shaped metal spring, the
ends of which are provided with felt pads. A toothed rachet is attached to the ends of
the spring, and serves to hold the spring tightly clamped on the nostrils in the proper

)sition (see Fig. 177).
Some individuals experience great distress when made to breathe through the mouth.

*This chapter is added for the convenience of workers in this subject.
tCarpenter: Carnegie Institution of Washington Reports, No. 216, 1915.

5S9

590

METABOLISM

For these it is best to use a face mask. Unfortunately at the present time no mask is
entirely satisfactory. Perhaps the best is one sold by Siebe, Gorman & Co.,* which is
pictured in the cut. After being placed^ in position the face mask should be tested for
leaks, which can be done by putting soap around the edges.

Fig. 177. — A, Nose clip; B, Face mask; C, Mouth piece.

Fig. 178. — Diagram of respiratory valves.

2. THE VALVES. — The valves of Tissot are probably the best for the purpose, but
they are expensive and difficult to obtain. We have made perfectly satisfactory valves
from the prepared casings used in the manufacture of bologna sausage. These can

*This mask has been used extensively by Carpenter. The agent on this continent is TT. N. Elmer,
1140 Monadnock Bldg., Chicago.

METHOD FOR DETERMINING RESPIRATORY EXCHANGE IN MAN

591

be obtained preserved in salt, and they will keep indefinitely on ice. When needed a
short piece is taken, washed free from salt by allowing water from the tap to run
through it, and softened in a weak glycerine solution. The gut becomes very soft
and pliable, and does not dry quickly. A piece of the casing about 10 cm. long is
threaded through a glass tube of about 15 mm. bore and 4 to 6 cm. long. One end

Fig. 179. — The Tissot spirometer. In actual experiment, subject is reclining or lying down and
the valves and mouthpiece are held with a clamp.

of the casing is brought around the outside of the tubing and secured by means of a
thread. The lower end of the membrane is pinched off and the casing is then cut a
little more than half way across its middle, so that the opening will lie just within
the free end of the tube when the casing is drawn back through it. The loose end of
the casing is slightly twisted — an essential procedure — and is then secured by a thread
on the outer side of the tube. If properly made, the valve will work freely without

592

METABOLISM

vibration, and the opening be sufficiently large to allow a good current of air to pass.
It should collapse instantly and be air-tight when the current of air is reversed. The
back lash, or lag of closure, of these valves is extremely small, and they will open or
close with a pressure of air not exceeding the pressure changes in normal respiration.
When not in use, the valves should be kept in glycrine water on ice. Valves prepared
in this way have been in use a month without loss of efficiency. They are, however,
made with so great ease that new valves are provided for each subject, and they are
therefore especially adapted to ward work (Fig. 178).

The valves are inserted in reverse order into a supporting metal T-piece, and the
joints made air-tight by tape. The stem of the T is connected with the mouthpiece.

Fig. 180. — The Douglas bag method for determining the respiratory exchange. The arrange-
ment of mouthpiece, valves, and connecting tubes shown here has been found to be more con-
venient than that recommended by Douglas.

Through a rubber tube of about % inch bore, the expired air is collected in the spirom-
cter, or Douglas Bag.

3. THE TISSOT SPIROMETER is pictured in Fig. 179. We have found the 100-liter
s'ze to be very serviceable in the clinic. This instrument is mounted on a platform
having rubber wheels, and can be moved about the wards with ease. The bell of the
spirometer is made of aluminum and is suspended in a water-bath between the double
Avails of a hollow cylinder made of galvanized iron. The height of the bell is 72 cm. and
the diameter 42 cm. An opening at the bottom of the cylinder connects through a
three-way stopcock with the rubber tube leading from the expiratory valve of the
mouthpiece (see Fig. 177). The bell is counterpoised by means of a weight. In the
original Tissot spirometer an automatic adjustment permitted water in amount equal

METHOD FOB DETERMINING RESPIRATORY EXCHANGE IN MAN

593

to the water displaced by the bell to flow from the spirometer cylinder into a counter-
poise cylinder as the bell ascended out of the water. The bell, being heavier out of
water than when it is immersed, is accordingly counterpoised in any position, although
Carpenter has shown that this refinement is unnecessary. An opening in the top of
the spirometer permits the insertion of a rubber stopper, through which are passed a
thermometer, a water manometer, and a stopcock with tube for drawing the sample
of air. A scale on the side of the instrument gives the volume of the air.

During an observation the subject sits in a reclining position or lies upon a couch.
When the bell of the spirometer is placed at zero, the mouthpiece adjusted in the

A. B.

Fig. 181. — Haldane gas apparatus (A) and Pearce sampling tube (B).

mouth, and the nose clamped, respiration is started, the expirations being passed
through the stopcock, which is so turned as to allow them to pass to the outside air.
After a few minutes the stopcock is turned so that the expirations are passed into
the spirometer for a definite length of time. At the end of the period the cock is
again turned, and after the barometric pressure, temperature, and volume of air have
been noted, the composition of the air is determined in the Haldane gas analysis ap-
paratus.

4. THE DOUGLAS BAG.— The Douglas bag is made of rubber-lined cloth, and is
capable of holding from 50 to 100 liters. It is especially useful for investigations
during exercise, since it is fitted with straps so that the bag can be fastened to the

594 METABOLISM

shoulders (Fig. 180). It is then connected with the valves, the mouthpiece of which
is placed between the lips. Respirations are commenced with the three-way valve
turned so as to allow the expirations to pass directly outside. After respiratory equi-
librium is established, the three-Avay valve is turned during an inspiratory period so
that the succeeding expirations may pass into the bag. The time required to fill the
bag comfortably is determined with a stop-watch. The air which has been collected
in the bag during the period is thoroughly mixed and passed through a meter, the
temperature and barometric pressure are noted, and a sample analyzed in the Haldane
gas-apparatus. The bag should be emptied completely by rolling it up when nearly
empty.

5. THE HALDANE GAS-ANALYSIS APPARATUS. PRINCIPLE. — The Haldane method of
analysis of expired air is simple and easily learned. The apparatus (Fig. 181) consists
of a gas burette, a control burette of the same size (both surrounded with a water
jacket), and bulbs containing dilute caustic potash or soda solution for the absorp-
tion of the carbon dioxide and an alkaline pyrogallate solution for the absorption of
the oxygen. The gas burette is connected with the bulbs by a two-way stopcock, which
allows a sample of gas to pass into either bulb. A control tube (10) is put into con-
nection with the burette through a manometer tube, which is connected with the alkali
bulb, and can be made to compensate for any changes in temperature that may occur
during the course of the analysis. For an analysis the gas is transferred to the burette
from the sampling tube, saturated with water vapor over mercury, and then measured,
after which it is transferred into the caustic solution to free it from C02, and returned
to the burette to determine the loss of volume due to CO absorption. It is then trans-
ferred into the alkaline pyrogallate solution, which frees it from oxygen, after which
it is again brought back to the burette to determine the loss in volume due to the
absorption of the oxygen.

THE APPARATUS. — The detail of the Haldane apparatus is shown in the accompany-
ing cut. The measuring burette (1) holds 21 c.c. The bulb is of 15 c.c. capacity,
and the graduated stem, which is about 4 mm. in bore and 60 cm. in length, is grad-
uated to 0.01 c.c. from 15 c.c. to 21 c.c. The stopcock at the top of the burette is
double-bored, so that in one position air- can be drawn in from a gas sampler (2) and
in another sent into the absorption bulbs (3). The lower part of the burette extends
through the rubber cork at the bottom of the water jacket (4). A piece of rubber
tubing is attached to the bottom of the burette and is passed through 9, metal tube
furnished on its inside with a metal disc which presses against the rubber tubing, the
pressure being controlled by means of a fine adjusting screw (6). Below this a glass
stopcock (7) connects with rubber tubing to the mercury leveling bulb (5). The
absorption bulb for COo, containing 20 per cent NaOH or KOH (9), is put in con-
nection with the burette by suitably turning stopcocks (3 and 8).* The control burette
(10) is also in connection with this bulb through the manometer tube (11). ^ Any
variation in temperature which may occur during the analysis will cause the level of the
alkaline solution in the manometer to change.

When final readings of the shrinkage of volume are made, the level of the caustic
solution is returned to the level of that in the manometer. By so doing any error due
to temperature changes is avoided, since change in temperature must be equal in the two
burettes.

The absorption bulb for oxygen (12) is filled with a solution made by dissolving
1.0 grams of pyrogallic acid in 100 c.c, of a nearly saturated KOH solution. The

*The stopcock (5) is double-bored, so that the tube leading1 from the burette can be brought into
connection with either 9 or 12.

fThis tube also has a three-way stopcock (79), so that it may be opened to the outside.

METHOD FOR DETERMINING RESPIRATORY EXCHANGE IN MAN 595

specific gravity of the KOH should be 1.55, which is obtained approximately by dis-
solving the sticks (pure by alcohol) in an equal weight of water. The mark (13) on
.the stem of the bulb indicates the level at which the solutions should stand. Enough
pyrogallate solution is introduced through tube 15 to fill bulbs 12 and 14 two-thirds
full. Then pyrogallate solution is poured into tube 16 until the difference in level
of fluids is sufficient to produce enough pressure to raise the level of the pyrogallate
solution in IS to the level 13 on the stem. Stopcock 8 must be open during this pro-
cedure. It may be necessary to add or take away a little pyrogallate solution through
''15 to attain the above level.

Care must be taken to allow for complete absorption of oxygen from the air that
is entrapped between 14 and 16 before an analysis is made; otherwise changes will
"be produced in the level of the pyrogallate solution. The air in the capillary tubing
connecting the burettes with the absorption bulbs must also be freed of CO2 and O2.
This can be accomplished by making a dummy analysis of atmospheric air before the real
analysis. Great care must be taken to have atmospheric pressure in all the tubes at
the start of the analysis. This is accomplished by opening the stopcock in the burette
first to atmospheric air and then to the absorption bulbs, until no further change
in the level of the fluids in the stems of the absorption bulbs occurs. This level is
then marked and used as the standard. A small amount of water in the burette over
the mercury assures saturation of the air with water vapor. Time for drainage must
be allowed before making readings.

A very serviceable sampling tube for the transfer of air can be made from a 30
c.c. ground-glass syringe, to which is attached a two-way stopcock. A cut of this is
shown in Fig. 181. The dead space in these syringes is washed out by working the
piston back and forth several times. A thin coating of vaseline prevents leakage of
the gas. We have found that these sampling tubes will retain a sample of expired
air without change up to eight hours.

MANIPULATION OF APPARATUS. — 'The sampling syringe (20) is attached to opening 2
of the burette, and its stopcock (17) opened to atmospheric air. The level of the
mercury is raised to the level of the stopcock of the syringe and is then turned so that
syringe and burette are in communication. The bulb of mercury is lowered so that
the mercury falls in the burette. This draws the piston of the syringe with it, and fills
the burette with air from the syringe. It is advisable to put a little positive pressure
on the piston of the syringe in the maneuver to prevent possible leakage. When all
of the air is in the burette a slight positive pressure is produced in the burette by
gently pressing on the piston, and immediately thereafter the stopcock on the syringe
(17) is again turned to the original position. This allows the pressure of air in the
burette to come to that of the atmosphere. The height of the mercury is now adjusted
to a convenient height in the burette by closing cock 7 and turning the milled screw
6. The cock 18 is now made to communicate with the absorption bulbs. If the air in the
burette is at atmospheric pressure, no change will occur in the level of the fluids.
The reading is then taken on the burette.

The next step in the analysis consists in turning stopcock 8 to communicate with
the caustic soda solution in bulb 9, and the leveling tube (5) is raised, forcing mercury
into the burette and the air into bulb 9. The gas is passed back and forth several
times until absorption is complete, as can be determined by the fact that the level
of the mercury in the burette remains constant when the fluid in the bulb is returned
to its original level (13) on the stem. In this adjustment it is convenient to make
the gross leveling by the mercury bulb and the fine leveling by closing 7 and turning 6
until the fluid in 9 is at the original height. The reading on the burette indicates
the loss in volume due to the CO2 absorbed.

596 METABOLISM

The oxygen is removed by a similar procedure, the gas being passed into the alkaline
pyrogallate solution by turning cock 8 to communicate with bulb 12. The absorption
of oxygen is slower than for CO2, and more care must be taken to get complete
absorption. The air in the tubing between the fluid in 9 and stopcock 8 must be
washed out several times in order to get the oxygen which is left in it after the
absorption of the CO2. When this is complete, the final reading on the burette is
made and the loss in volume from the second reading represents the oxygen.

THE CALCULATIONS

The calculation of the peroentile composition of the air and of the respiratory
quotient is represented in the following example of an actual analysis:

(The temperature and barometric pressure as taken at the time of the experiment
were 20° C. and 747 mm. Hg.)

CO 2 analysis —

1st reading of burette 20.00

2nd reading of burette after absorption of CO2 19.20

CO2 absorbed 0.80

0.80 -:- 20 = 4.0 per cent CO2 in expired air.

02 analysis —

2nd reading of burette 19.20

3rd reading of burette after absorption of O2 15.90

O2 absorbed 3.30

3.30 -f- 20 = 16.50 per cent of 02 in expired air.

Determination of E.Q. —

O2 in atmospheric air = 20.94%

O2 + CO2 in expired air (16.50 -f 4) = 20.50%

100 - 20.94* = 79.06%, N in atmospheric air.
100 - 20.50 = 79.50%, N in .expired air.

Since the nitrogen is not changed in volume, the last figure shows that more oxygen
must have been taken in during inspiration than O2+ CO2 has been given back in expira-
tion. This obviously must be taken into account in the calculations. The amount of
O2 actually inspired for each 100 c.c. of air expired is found as follows:

20.94 (% O2 in atmospheric air)

79.06 (% N2 in atmospheric air) X 79'50 (% N2 in expired air) ; or 0.265 (con-
stant factor x 79.5 (% N found for this observation) =21.07, the volume of 02 which
would have been present in expired air to account for N present, t

21.07-16.50 = 4.57% O2 actually absorbed.
4.00 - 0.03 (CO2 in inspired air) = 3.97% CO2 excreted.
3.97
:. A =0.87, the respiratory quotient, or ratio of CO2 excreted to O2 absorbed.

4.0 /

Total Gas Exchange. — The volume of air expired in 15 minutes into the Tissot
fipirometer was found to be 100 liters measured at 20° C. and 747 mm. Hg (brass-scale
barometer). This volume of gas must be corrected so as to give the volume of dry
air at 0° and 760 mm. Hg. To do this two things must be taken into account. (1)
Since the expired air is saturated with water, the pressure due to water vapor must

*This is the constant O2 percentage in air.

fThis calculation can be simplified by using an abbreviated table (page 597) giving the Og figure
corresponding to the various percentages of N in the expired air.

METHOD FOR DETERMINING RESPIRATORY EXCHANGE IN MAN 597

be subtracted from the observed barometric pressure to obtain the true pressure. The
vapor tension of water for various temperatures is given in Table II on page 598.
(2) The barometer tube lengthens or contracts with heat or cold, and therefore the
barometric readings must be corrected. The corrections for ordinary barometric read-
ings are found in Table III, page 598. The figure corresponding to the temperatures
is subtracted from the barometric reading in order to obtain correct baromjetie pres-
sure.

In the above experiment, the correction for the barometer is 2.41 mm. (see Table III,
page 598), and that for vapor tension at 20° C. is 17.4 (see Table II, page 598).
Actual Barometric Pressure— 747— (17.5 + 2.39) =727.21 mm.

The coefficient of expansion of gases is taken as 0.003665) or 1/273; therefore the
volume of 0° equals the volume at 1° divided by 1-0. 003665 t; and hence

Vo = Vx273 = - , when Vo = Volume at 0° and V = Volume at t°.

273 + t 1 + 0.003665 t

VT*
The volume of gas being inversely as the pressure, Vo = , where V = volume at

P pressure ; or working both corrections together,

VPx273 VP

760 x (273 + t)~~760 (1 + 0.003665 t)
This formula applied to the present problem reads:

Vo = 100x727.2 = 89.2 liters.

760 (1 + 0.003665x20)

The latter calculation can be considerably simplified by using standard tables
which give constants for corrections of gas volumes. These are easily obtainable and
are given in part in Table IV.

According to these tables for 20° C. and 727.21 mm. Hg. B.F., the factor is
0.89124; therefore:

0.89124 x 100 = 89.124 liters, 0°C. and 760 mm. Hg.

0.89124 x 4.57 = 40.7 liters of O2 in 15 min., or 16.28 L. per hour.

The Caloric Value Calculated from the Gas Exchange. — By reference to Table V
giving the Eeat value of 1 liter of O, at various respiratory quotients, it is found
that at a E.Q. of 0.87, 4.888 calories are expended; 16.28 liters of O3 is therefore
equivalent to 18.4 x 4.888 = 79 calories.

The results must be calculated for surface area as well as body weight. Suppose
the subject weighed 85 kg. and was 170 cm. in height; by reference to the chart for
determining the surface area of man (page 576), this would be found to be 1.96
square meters. The caloric expenditure per square meter in the above case is therefore

79

= 40.3 calories.

1.96

TABLE I

THE PERCENTAGE OF OXYGEN WHICH is EQUIVALENT TO THE NITROGEN FOUND IN THE

EXPIRED AIR

To obtain the nitrogen in the expired air, add the percentage of CO2 and O2 found
and subtract the sum from 100. The table gives the percentage for O2 corresponding to
this figure :

%N2 78.7 78^8 78^9 79X) TJU 79^2 79J3 79A 79^5 79^6 79/7 79.8

%O, 20.86 20.88 20.90 20.93 20.96 20.98 21.01 21.04 21.07 21.10 21.12 21.14

79.9 80.0 80.1 80.2 80.3 80.4 80.5 80.6

21.16 21.19 21.22 21.25 21.28 21.31 21.35 21.38

598 METABOLISM

TABLE II

TENSION OF AQUEOUS VAPOR IN MILLIMETERS OF MERCURY

To obtain .the dry barometer pressure, subtract the mm. Hg corresponding to the
temperature of the air from the barometer pressure at the time of the experiment:

Temp.
Mm.

15°
12.7

16°
13.5

17°
14.4

18°
15.4

19°
16.3

20°
17.4

21°
18.5

22° .
19.7

23°
20.9

24°
22.2

25°
23.5

TABLE III

TEMPERATURE CORRECTIONS TO REDUCE READINGS OF A MERCURIAL BAROMETER WITH A

BRASS SCALE TO 0°C.

Subtract the appropriate quantity as found in table from the height of the barometer.
The table is for a barometer with a brass scale, and the values are a little lower (about
.2 mm.) than for the glass scale. The corrections for intermediate temperatures can be
approximated.

Temp.

700
mm.

710
mm.

720
mm.

730
mm.

740
mm.

750
mm.

760
mm.

770
mm.

15°
20°
25°

1.69
2.26

2.83

1.72

2.22
2.87

1.74
2.32
. 2.91

1.77
2.36
2.95

1.79
2.39
2.99

1.81

2.42
3.03

1.84
2.45
3.07

1.86
2.48
3.11

TABLE IV

TABLE FOR REDUCING GASEOUS VOLUMES TO NORMAL TEMPERATURE AND PRESSURE
The observed volume, when multiplied by the factor corresponding to the temperature
and pressure, will give the volume of the expired air reduced to 0° and 760 mm.

Mm.

15°

16°

17°

18°

19°

20°

21°

22°

23°

24°

25°

720
730
740
750
760
770

.898
.910
.922
.935
.947
.960

.894
.907
.919
.932
.944
.957

.891
.904
.916
.928
.941
.953

.888
.901
.913
.925
.938
.950

.885
.897
.910
.922
.934
.948

.882
.894
.907
.919
.931
.945

.880
.891
.904
.916
.928
.940

.877
.888
.901
.913
.925
.936

.873
.885
.897
.910
.922
.933

.870
.882
.894
.907
.919
.930

.867
.879
.891
.904
.916
.927

TABLE V

R. Q. CALORIES FOR 1 LITER O2 RELATIVE CALORIES CONSUMED AS

Number Carbohydrate Fat

per cent per cent

0.707

4.686

0

100

0.71

4.690

1.4

98.6

0.72

4.702

4.8

95.2

0.73

4.714

8.2

91.8

0.74

4.727

11.6

88.4

0.75

4.739

15.0

85.0

0.76

4.752

18.4

81.6

0.77

4.764

21.8

78.2

0.78

4.776

25.2

74.8

0.79

4.789

28.6

71.4

0.80

4.801

32.0

68.0

0.81

4.813

35.4

64.6

0.82

4.825

38.8

61.2

0.83

4.838

42.2

57.8

METHOD FOB DETERMINING RESPIRATORY EXCHANGE IN MAN

599

ABLE V (CONT'D)

R. Q.

CALORIES FOR 1 LITER O2

Number

RELATIVE CALORIES CONSUMED AS

Carbohydrate Fat

per cent per cent

0.84

4.850

45.6

54.4

0.85

4.863

49.0

51.0

0.86

4.875

52.4 .

47.6

0.87

4.887

55.8

44.2

0.88

4.900

59.2

40.8

0.89

4.912

62.6

37.4

0.90

4.924

66.0

34.0

0.91

4.936

69.4

30.6

0.92

4.948

72.8

27.2

0.93

4.960

76.2

23.8

0.94

4.973

79.6

20.4

0.95

4.985

83.0

17.0

0.96

4.997

86.4

13.6

0.97

5.010

89.8

10.2

0.98

5.022

93.2

6.8

0.99

5.034

96.6

3.4

1.00

5.047

100.0

0.0

(From Lusk.)

CHAPTER LXV
STARVATION

In order to provide a standard with which we may compare other
conditions, we shall first of all study the metabolism during starva-
tion. A valuable chart compiled from observations made in the Carne-
gie Institution of Washington on a man who fasted for thirty-one clays
is produced in Fig. 182.

The Excretion of Nitrogen. — When an animal is starved, it must
live on its own tissues, but in doing so it saves its protein, so that the
excretion of nitrogen falls after a few days to a low level, the energy
requirements being meanwhile supplied, so far as possible, from stored
carbohydrate and fat. Although always small in comparison with fat,
the stores of carbohydrate vary considerably in different animals. They
are much larger in man and the herbivora than in the carnivora. Dur-
ing the first few days of starvation it is common, in the herbivora, to find
that the excretion of nitrogen is actually greater than it was before
starvation, because the custom has become established in the metabolism
of these animals of using carbohydrates as the main fuel material, so
that when carbohydrates are withheld, as in starvation, proteins aye
used more than before and the nitrogen excretion becomes greater. We
may say that the herbivorous animal has become carnivorous. The same
thing may occur in man when the previous diet was largely carbohy-
drate; thus, almost invariably in man the nitrogen output is larger on
the third and fourth days of starvation than on the first and second.

Another factor influencing the nitrogen excretion during the early
days of the fast is the amount of previous intake of nitrogen; the greater
this has been, the greater the excretion. By the seventh day, however, a
uniform output of nitrogen will usually be reached irrespective of the
individual's protein intake. During the greater part of starvation, most
of the energy required to maintain life is derived from fat, as little as
possible being derived from protein. This type of metabolism lasts until
all the available resources of fat have become exhausted, when a more
extensive metabolism of protein sets in, with the consequence that the
nitrogen excretion rises. This is really the harbinger of death — it is often
called the premortal rise in nitrogen excretion. It indicates that all the
ordinary fuel of the animal economy has been used up, and that it has

600

STARVATION

601

[NUTRITION LABORATORY OF THE CARNEGJE INSTITUTION OF WASHINGTON. BOSTON. MASSACHUSETTS]
METABOLISM CHART OF A MAN FASTING 31 DAYS

APRIL 14 -MAY 15.1912

OXYGEN AND CARBON
OIOXIDC. c.c.

45 7 8 9 10 II 12 1314 15 16 17 18 192021 32 23 24 25 26 27 28 2930 3f

4 3 6 7 8 9 1,0 I.I 12 13 14 15 16 17 18 19 20 21 22 23 24 2.5 26 27 28 29 30 3

Fig. 182. — Curve constructed from data obtained from a man who fasted for thirty-one days.
The days of the fast are given along the abscissae, and the various measurements along the or-
dmates. (From F. G. Benedict.)

602 METABOLISM

become necessary to burn the very tissues themselves in order to obtain
sufficient energy to maintain life. Working capital being all exhausted,
an attempt is made to keep things going for a little longer time by liq-
uidation of permanent assets. But these assets, being represented largely
by protein, are of little real value in yielding the desired energy because,
as we have seen, only 4.1 calories are available against 9.3, obtainable
from fats.

These facts explain why during starvation a fat man excretes daily
less nitrogen than a lean man, and why the fat man can stand the starva-
tion for a longer time. The premortal rise is, however, not prevented by
feeding oil, which would seem to indicate that death may be due not so
much to the absence of fuel as to serious nutritional disturbance of es-
sential organs; e. g., there may be no available material to supply the
glands of internal secretion with the building stones they must have
(see page 614).

Not only is there this general saving of protein during starvation,
but there is also a discriminate utilization of what has to be used by the
different organs, according to their relative activities. This is very
clearly shown by comparison of the loss of weight which each organ un-
dergoes during starvation. The heart and brain, which must be active if
life is to be maintained, lose only about 3 per cent of their original
weight, whereas the voluntary muscles, the liver and the spleen lose
31, 54 and 67 per cent, respectively. No doubt some of this loss is to
be accounted for as due to the disappearance of fat, but a sufficient
remainder represents protein to make it plain that there must have been
a mobilization of this substance from tissues where it was not absolutely
necessary, such as the liver and voluntary muscles, to organs, such as the
heart, in which energy transformation is sine qua non of life. The vital
organs live at the expense of those whose functions are accessory.

The energy output per square meter of body surface steadily declines.
In the man examined -by Benedict, it was 958 C. per square meter of
surface at the end of the first twenty-four hours, but only 737 on the
thirty-first day of the starvation period. The oxygen intake and carbon-
dioxide output correspondingly dimmish.

The behavior of the nitrogenous metabolites in the urine is of par-
ticular interest, the following facts being of significance: Urea nitrogen
relatively falls and NHa nitrogen rises. For example, on the last day of f eed-
iijg the percentage output of NH3 nitrogen in relation to total nitrogen was
3.16 ; on the eighth day of the fast it was 14.88 (Cathcart).2 Acidosis is the
cause. The total amount of creatmme and creatine shows only a slight
fall, but creatinine relatively decreases and creatine increases (Cathcart).
Since creatine is a substance peculiar to muscle tissue, it is possible by

STARVATION 603

comparing the creatine and creatinine output with, that of nitrogen to
determine whether all of the nitrogen liberated by the breakdown of
muscle has been excreted, or whether some has been retained either for
resynthesis in the muscle itself or for use elsewhere. As a matter of fact
the muscle breakdown as calculated from the creatine-creatinine output
is greater than that calculated from the nitrogen, indicating that synthesis
of the noncreatine remainder must be occurring.

That transference of nitrogenous substances from place to place in the
body in starvation is proved (1) by the constant presence of amino ni-
trogen in the blood and tissues (Van Slyke) ; and (2) by the effect of
copious water drinking. The latter causes a decided increase in the out-
put of nitrogen, because of the excretion of some of the nitrogenous
substances. It is probable, however, that in such cases there is also a
subsequent increase in endogenous protein metabolism, since the wrashed-
out free nitrogen would have to be replaced.

Excretion of Purines.— Although at first they fall somewhat, the total
amount increases as the fast progresses. Perhaps the first decline is
due to general using up of hypoxanthine of muscle and the later rise
to the breakdown of nuclei (page 671).

Excretion of Sulphur. — It is important to compare the excretion of
sulphur and nitrogen. In the early days of starvation a ratio of 17 N : 1 S
has been found, but later one of 14.5:1, which is practically the same
as that in muscle (i.e., 14; 1), indicating that late in fasting the main
source of protein supply is muscle.

Several of the changes observed during starvation can be attributed
to the condition of acidosis which supervenes. The acids are derived
from incomplete combustion of fat (see page 715), and are represented
by /?-oxybutyric, the amount being sometimes considerable (10-15 grams
a day), especially in obese individuals. The large ammonia excretion
(sometimes 2 grams a day) is evidently for the purpose of neutralizing
the excess of acid. Another consequence of the acidosis is the decline
in the alveolar tension of CO., (page 379), and it is possible that some of
the circulatory changes shown in the chart may also be dependent on
it. For reducing obesity the method of repeated fasting is quite safe
provided the acidosis is carefully watched and the diet which is given
contains accessory food factors (page 618).

Many secondary changes also occur in the starving organism. Thus,
the mobilization of fat is often responsible for a pronounced increase in
the fat content of the blood (see page 698).

The amino nitrogen of the blood is riot perceptibly reduced by starva-
tion (page 613) but early in the condition the blood sugar becomes much
lower than normal, after which it remains steady. This is significant

60-i METABOLISM

when we remember that after two or three days of starvation all of the
available glycogen has been used up. It indicates that carbohydrate must
be essential for life, and that it is produced in starvation from proteins
(see page 699). The glycogen content of the skeletal muscles becomes
reduced but not that of the heart.

Starvation ends in death in an adult man in somewhat over four
weeks but much sooner in children, because of their more active metab-
olism. At the time of death the body weight may be reduced by 50 per
cent. The body temperature does not change until within a few days
of death, when it begins to fall, and it is undoubtedly true that if means
are taken to prevent cooling of the animal at this stage, life will be
prolonged.

Death from starvation must be due either to a general failure of all
the cells or to injury of certain organs that are essential for life. Since
the loss of protein from the body as a whole only amounts to between 20
and 50 per cent at the time of death by starvation, it is unlikely that gen-
eral failure can be the cause. If it were so, death would always occur
when some fixed loss of protein had occurred. Certain organs evidently
cease to perform their function, either because they are deprived of raw
material for the elaboration of some substance (hormone) necessary for
life, or because they themselves wear out from want of nourishment.

NORMAL METABOLISM

Apart from the practical importance of knowing something about the
behavior of an animal during starvation, such knowledge is of great
value in furnishing a standard with which to compare the metabolism
of animals under normal conditions. Taking again the nitrogen balance
as indicating the extent of protein wear and tear in the body, let us
consider first of all the conditions under which equilibrium may be re-
gained. It would be quite natural to suppose that, if an amount of pro-
tein containing the same amount of nitrogen as is excreted during
starvation were given to a starving animal, the intake and output of
nitrogen would balance. We are led to make this assumption because we
know that the balance sheet of a business concern showing an excess of
expenditure over income could be adjusted in this way. But it is a very
different matter with the nitroycn balance sheet of the body; for, if we
give the starving animal just enough protein but no other foodstuffs to
eover the nitrogen loss, we shall cause the excretion to rise to a total
which is practically equal to the starvation amount phis all that we have
given as food ; and although by daily giving this amount of protein there
may be a slight decline in the excretion, it will never become the same as

STARVATION 605

that of the intake. The only effect of such feeding will be to prolong
life for a few days.

Nitrogenous Equilibrium. — To attain equilibrium we must give an
amount of protein the nitrogen of which is at least two and one-half
times that excreted during the starvation level. For a few days follow-
ing the establishment of this pure protein diet, the nitrogen excretion
will be far in excess of the intake, but it will gradually decline until the
two practically correspond. Having once gained an equilibrium, we may
raise the level at which it stands by gradually increasing the protein in-
take. During this progressive raising of the ingested protein, it will be
found, at least in the carnivora (cat and dog), that a certain amount of
nitrogen is retained by the body for a day or so immediately following
each increase in protein intake. The excretion of nitrogen, in other
words, does not immediate^ follow the dietetic increase. The amount of
nitrogen thus retained is too great to be accounted as a retention of dis-
integration products of protein; it must therefore be due to an actual
building up of new protein tissue — that is, growth of muscles.

Nitrogenous equilibrium on a protein diet alone is readily attainable
in the cat, and less readily in the dog. But in man and the herbivorous
animals, it is impossible to give a sufficiency of protein alone to maintain
equilibrium; there will always be an excess of excretion over intake.
Indeed it scarcely requires any experiment to prove this, for it is self-
evident when we consider that there are less than 1000 C. in a pound of
uncooked lean meat, and that there are few who could eat over three
pounds a day, an amount, however, which would scarcely furnish all of
the required calories. A person fed exclusively on flesh is therefore
being partly starved, even though he may think that he is eating abundantly
and is quite comfortable and active. This fact has a practical application
in the so-called Banting cure for obesity.

Protein Sparers. — Very different results are obtained when carbohy-
drates or fats are freely given with the protein to the starving animal.
Nitrogen equilibrium can then be regained on very much less protein,
so that we speak of fats and carbohydrates as being "protein sparers."
Carbohydrates are much better protein sparers than fats; indeed they
are so efficient in this regard that it is now commonly believed that car-
bohydrates are essential for life, and that when the food contains no
trace of carbohydrates, a part of the carbon of protein has to be con-
verted into carbohydrate. This important truth is supported by evi-
dence derived from other types of investigation (e. g., the behavior of
diabetic patients, in whom the power to use carbohydrates is greatly
depressed). The marked protein-sparing action of carbohydrates is il-
lustrated in another way — namely, by the fact that we can greatly

606 METABOLISM

diminish the protein breakdown during starvation by giving carbo-
hydrates. By using protein sparers we can indeed reduce the daily nitro-
gen excretion to about one-third its amount in complete starvation. Re-
moval of carbohydrate from the diet is said to entail a failure of the
muscles to use again in their metabolism certain of the products (e. g.,
creatine) which result from their disintegration. At any rate it has
been found that creatine is excreted in the urine under these conditions.

As to the nature of the processes occurring in the body during protein
sparing, two possibilities have to be borne in mind: either the body pro-
tein is catabolized less rapidly or the protein sparer unites with certain
of the breakdown products of protein to form new protein. Recent work
by Davis, Hall and Whipple08 affords strong support to the latter view.
These workers investigated the rate of repair of the liver and the curve
of urinary nitrogen excretion in dogs after causing destruction of a large
part of the liver tissue by chloroform administration. In animals in
which about one half of each lobule had been destroyed, only about 50
per cent was found to be repaired in nine days, and the urinary nitrogen
was higher than the normal starvation level although no food was given ;
to other animals to which sugar was given the repair of the liver was
complete in nine days and the curve of nitrogen decidedly below that
of starvation. These observations open up a new field for the investiga-
tion of problems of the growth of new tissue in the adult animal and their
prosecution should afford aid in determining the influence of various
dietetic conditions on such growth. Davis and Whipple09 have already
published some important observations in this direction and among other
things have found that a diet of bread and milk, or one of cooked liver
or kidney, causes more rapid repair than one of cooked skeletal muscle.
Fats do not accelerate the repair process.

The Irreducible Protein Minimum. — In the case of a man living on an
average diet, although the daily nitrogen excretion is about 15 grams,
it can be lowered to about 6 grams provided that in place of the protein
that has been removed from the diet enough carbohydrate is given to
bring the total calories up to the normal daily requirement. If an excess
of carbohydrate over the energy requirements is given, the protein may
be still further reduced without disturbing the equilibrium. It has been
found that it is not the amount of carbohydrate alone that determines
the ease with which the irreducible protein minimum can be reached ; the
kind of protein itself makes a very great difference. This has been very
clearly shown by one investigator, who first of all determined his nitro-
gen excretion while living exclusively on starch and sugar, and who then
proceeded to see how little of different kinds of protein he had to take
in order to bring himself into nitrogenous equilibrium. He found that

STARVATION 607

he had to take the following amounts : 30 gm. meat protein, 31 gm. milk
protein, 34 gm. rice protein, 38 gm. potato protein, 54 gm. bean protein,
76 gm. bread protein, and 102 gm. Indian-corn protein. The organism
is evidently able to satisfy its protein demands much more readily with
meat than with vegetable proteins.

This variability in the food value of different proteins depends on their
ultimate structure — that is, on the proportion and manner of linkage
of the various amino acids that go to build up the molecule. In no two
proteins are these building stones, as they are called, present in exactly
the same proportions, some proteins having a preponderance of one or
more and an absence of others, just as in a row of houses there may be
no two that are exactly alike, although for all of them the same build-
ing materials were available. Albumin and globulin are the most im-
portant proteins of blood and, tissues, so that the food must contain the
necessary units for their construction. If it fails in this regard, even to
the extent of lacking only one of the units, the organism will either be
unable to construct that protein, and will therefore suffer from partial
starvation, or it will have to construct for itself this missing unit. It
is therefore apparent that the most valuable proteins will be those that
contain an array of units that can be reunited to form all the varieties
of protein entering into the structure of the body proteins. Naturally,
the protein which most nearly meets the requirements is meat protein,
so that we are not surprised to find that less of this than of any other
protein has to be taken to gain nitrogenous equilibrium.

The most exact information regarding the "food value" of different
proteins has been secured by observations on the rate of growth of young
animals. This method yields more reliable information than can be
secured by studies on the nitrogenous balance, because it is not usually
possible to keep up the latter observations for a sufficient period of
time, or to secure an adequate number of data. During growth the
building-up processes are in excess of the breaking-down, so that the
effect is an increase in bulk of the tissues, thus permitting us, by the sim-
ple expedient of observing the body weight, to draw conclusions as to
the influence of various foodstuffs on tissue construction.

CHAPTER LXVI
NUTRITION AND GROWTH

In the growth of animal tissues two factors are concerned, one being
the property of the cell to grow, the growth factor; and the other, the
availability of suitable material to grow upon, the food factor. Concern-
ing the growth factor little is known; its variability in different species
of animal, its irregularity despite proper adjustment of the food factors,
its abnormality leading to tumor formation, etc., are all well-known but
apparently inexplicable facts (Mendel8). The growth factor is very sen-
sitive towards the activity of certain of the ductless glands such as the
anterior lobe of the pituitary (page 808), and towards substances of
unknown chemical nature contained in various foods. These are called
accessory food factors or vitamines (page 618).

THE FOOD FACTOR OF GROWTH

Our knowledge is constantly increasing concerning the food factor of
growth, and many facts of extreme practical importance have been ac-
cumulated in recent years. In seeking for the relationship of food to
growth, we must first of all. consider whether this process entails a
greater expenditure of energy than is necessary for mere maintenance
in adult life. Important results bearing on this question have been se-
cured by observations on the basal metabolism of young children. In
computing the energy supply of fasting adult animals of different sizes,
it will be remembered that the smaller the animal, the greater is the
energy exchange in relationship to the body weight, although when
computed in relationship to body surface tolerably constant values are
obtained. When the calorie output per square meter is determined in
growing children, there is, as we have already seen, clear evidence of
greater energy expenditure (see page 577), particularly marked in boys
just before puberty. An increased energy metabolism has also been de-
scribed in the case of infants, but the uncontrollable muscular activity,
the psychic disturbances, etc., may explain the result. Even after dis-
counting these factors, however, it is possible that there may be a cer-
tain influence, depending probably on the active mass of growing proto-
plasmic tissue, which stimulates the energy expenditure. The question
is not yet finally settled.

608

NUTRITION AND GROWTH

609

The Relationship of Proteins to Growth and Maintenance of Life. —

Since protein constitutes the fundamental chemical basis of the cell, it
is natural to devote attention in the first place to this food principle.
In the pioneer investigations, studies on the nitrogen balance in young
animals yielded results from which it was concluded that the conditions
for the disintegration of protein are less developed in young animals
than in adults, so that the growing organs rapidly withdraw circulating
protein and build it into tissue protein.

In consideration of the accumulation of data extending over several
decades, Rubner denied these conclusions, and showed that the diet of
the growing infant is by no means relatively rich in protein. He con-
cluded that "growth is not proportional to the quantity of protein in the
diet." Important though this pioneer work may have been in the de-
velopment of our present-day conception, the viewpoint of the men who
carried it out was very much narrowed on account of the paucity of
knowledge concerning the structure of the protein molecule. No allow-
ance was made for the fact, which has recently been firmly established,
that the protein molecule may vary extremely in regard to the units
of which it is composed, and that the growing tissues may demand, not
so much an abundance of protein as such, but rather a proper supply of
all the .building stones which are required for growth (Mendel).

QUANTITATIVE COMPARISON OF AMINO ACIDS OBTAINED BY HYDROLYSIS OF PROTEINS*
(Compiled by T. B. Osborne, 1914) t

CASEIN

OVAL-

BUMIN

GLIADIN

ZEIN

EDESTIN

LEGUMIN

OX

MUSCLE

Glycocoll

0.00

0.00

0.00

0.00

3.80

0.38

4.0

Alanine

1.50

2.22

2.00

13.39

3.60

2.08

8.1

Valine

7.20

2.50

3.34

1.88

6.20

?

2.0

Leucine

9.35

10.71

6.62

19.55

14.50

8.00

14.3

Proline

6.70

3.56

13.22

9.04

4.10

3.22

8.0

Phenylalanine

3.20

5.07

2.35

6.55

3.09

3.75

4.5

Glutaminic acid

15.55

9.10

43.66

26.17

18.74

13.80

10.6

Aspartic acid

1.39

2.20

0.58

1.71

4.50

5.30

22.3

Serine

0.50

?

0.13

1.02

0.33

0.53

?

Tyrosine

4.50

1.77

1.61

3.55

2.13

].55

4.4

Cystine

?

?

0.45

?

1.00

?

?

Histidine

2.50

1.71

1.84

0.82

2.19

2.42

4.5

Arginine

3.81

4.91

2.84

1.55

14.17

10.12

11.5

Lysine

5.95

3.76

0.93

0.00

1.65

4.29

7.6

Tryptophane, about

1.50

present

1.00

0.00

present

present

present

Ammonia

1.61

1.34

5.22

3.64

3.28

1.99

1.07

65.49

48.85

85.68

88.87

82.28

57.43

102.87

*These analyses are combinations of what appear to be the best determinations of various
chemists.

fThe figures for the more recent analyses of gliadin are inserted.

From the accompanying table giving the percentage of the various
amino acids, etc., present in certain proteins, it will be evident that there

610

METABOLISM

are very marked variations in the units of which different proteins are
composed. If any one of these units should be essential for growth and
the organism be unable to manufacture the missing unit for itself, it
is clear that growth could not proceed however much protein not contain-
ing the necessary unit we might feed to the animal. It is an application
of the law of the minimum, and is analogous with the failure of growth
which has long been known to ensue when certain inorganic substances
are withheld from the growing animal. A diet might be perfectly bal-
anced as judged by comparison of the nitrogen intake and output, and
yet if it should fail to contain even one of the essential units and the
organism should be incapable of supplying this unit, then would the
diet be inadequate for growth.

These important facts are the outcome of modern wrork, and they

Days

Each division = 20 days.

Fig. 183. — Curves of growth of rats on basal rations plus the various proteins indicated. The
normal curve may be taken as that with casein (I). (Adapted from Lafayette B. Mendel and
T. B. Osborne.)

have been established by observations on the growth of young animals
fed with a ''basal ration" to which were added mixtures of amino acids
or various proteins which differ considerably from one another in the
nature of the units entering into their make-up. In such experiments
the periods during which growth is observed must be prolonged, since
a transient increase in weight might depend merely on repair processes
occurring in tissues which had previously for some reason been brought
below par.

Among the most important observations have been those of F. Gow-
land Hopkins, Lafayette B. Mendel and T. B. Osborne8 and of McCollum9
and his collaborators. The animals chosen for Mendel and Osborne 's
experiments were young white rats. Large batches of these animals

NUTRITION AND GROWTH

611

were fed on a basal ration consisting of protein-free milk (containing
the inorganic salts, the sugars, traces of protein, and unknown substances
having an important influence on growth — vitamines), to which were
added more carbohydrate, purified fat, and the protein whose influence
on growth it was desired to study. The same diet wras fed at regular in-
tervals to a given batch of rats, and the weight of each rat was period-
ically taken, the observation being prolonged until the animals grew to
maturity and produced young, and these again grew to maturity, repro-
duced, and so on. By plotting the results in curves, with the time peri-
ods along the abscissae and the average weight of the rats of each batch
along the ordinates, the extent of the influence of a given diet on the
curve of growth was obtained. A normal curve of growth is shown in

100
MO

Ho

f*0
110

100
w

lt.0
IVO

lie

(00

So
fcc

Days

Each division -20 days

Days

Each division -20 days

Fig. 184. — Curves of growth of rats on basal rations plus the proteins indicated. In curve

III the effect of the addition of zein to an inadequate allowance of the! perfect protein, lactalbumin,

is shown; and in IV the effect of the addition of cystine to a deficient casein allowance. (From
Lafayette B. Mendel and T. B. Osborne.)

No. 1 of Fig. 183. It was obtained from results secured by adding liberal
amounts of casein to the basal diet. Similar curves were obtained with
lactalbumin of milk and ovalbumin and ovovitellin of egg. Perhaps the
most interesting substances capable of producing the normal curve of
growth are certain of the proteins that T. B. Osborne has succeeded in
separating in crystalline form from vegetable foodstuffs. These are
edestin (hempseed), globulin (squash seed), excelsin (Brazil nut), glu-
telin (maize), globulin (cottonseed), glutein (wheat), glycinin (soy bean),
cannabin (hempseed).

That growth proceeds normally with any one of these proteins when it
is fed abundantly does not, however, necessarily indicate that each con-

612 METABOLISM

tains in adequate proportion all of the necessary units to meet the pro-
tein demands of growing tissues. In the case of casein, for example,
one of the units, namely, glycocoll, which is the simplest of all the
amino acids, is entirely missing, and another, cystine, which is a sul-
phur-containing amino acid, is present only in small amount. The ab-
sence of glycocoll, however, is not of importance, because the organism
can manufacture it for itself (see page 663). In the case of cystine,
which the tissues can not manufacture themselves, the deficiency has to
be made up for by feeding an excess of casein so as to cover the needs
of the tissues for this amino acid. By so doing a superabundance of
most of the other units will be ingested, and this superabundance will
entail the destruction and excretion of the useless amino acids, a process,
however, which is conducted in such a way as to permit of the utilization,
by the organism, of a part of the energy which the cast-off amino acids
contain (see page 699). It is, therefore, not entirely a wasteful process.

When the supply of casein is limited, on the other hand, the curve
of growth becomes subnormal, because an insufficient supply of cystine
is thereby offered (Fig. 184). Similar results have been obtained in the
case of edestin, a protein from hempseed. This contains an insufficiency
of the diamino acid, lysine. Fed in abundance, edestin gave a normal
curve of growth, but when fed in insufficient amount the curve failed to
ascend properly (which, however, it could be made to do by adding some
lysine to the edestin).

There is a large group of proteins which fail to permit of any growth
no matter in what amounts they may be added to the basal ration. These
include: legumelin (soy bean), vignin (vetch), gliadin (wheat or rye),
legumin (pea), legumin (vetch), hordein (barley), conglutin (lupine),
gelatine (horn), zein (maize), phaseolin (kidney bean). The adequacy
to maintain growth of any of these pure proteins varies according to
the deficiency in their amino acids. In the case of gliadin of wheat or
rye, glycocoll is lacking, and lysine is present only in small amount (see
table). The absence of glycocoll can not, however, as we have already
seen in the case of casein, explain the inadequacy of gliadin as a foodstuff
for growth ( Curve II in Fig. 183 ) . It must be the lysine that is at fault. A
still more deficient protein is the zein of maize. With this as the only
protein added to the basal diet, the curve of growth actually descends
(Curve III of Fig. 183), thus indicating that the animal is starving and
must soon succumb. The missing units in this protein are glycocoll,
lysine and tryptophane (see table on page 609), and it is very signifi-
cant that if the latter two amino acids are supplied along with zein, an
almost normal curve of growth will result. Some improvement can
even be brought about by giving tryptophane alone; that is to say, the

NUTRITION AND GROWTH 613

curve assumes a horizontal line instead of descending, indicating that,
although inadequate for growth, the diet is now sufficient for the main-
tenance of life.

An important fact demonstrated by these experiments, is that cer-

Fig. 185. — Photographs of rats of same brood on perfect diet (uppermost picture); on a main-
tenance diet but inadequate for growth (middle picture) ; and on a diet that was inadequate both
for maintenance and growth. (From Mendel and Osborne.)

tain diets are adequate for the maintenance of life although they are
inadequate for growth. In conformity with this conclusion, it was found
when young white rats were fed with gliadin alone for periods of time ex-
ceeding those in which they should have become full grown, that
they remained in an ungrowii stunted condition. The capacity to grow

614 METABOLISM

had not, however, been lost, for when the gliadin was replaced by milk,
the animals resumed growth at a very great rate. The capacity to grow
had only been inhibited by the inadequate diet, and there was nothing
really abnormal about the stunted animals. For example, the reproduc-
tive function developed normally, as was shown in the case of a young
female rat which, after being fed with gliadin as the sole protein sup-
ply for 154 days, was mated and produced four young. Although the
mother was still maintained on the gliadin diet, the young rats pre-
sented normal growth, for they were living on the milk supplied by the
mother, and this milk, because it contained either casein or some other
necessary accessory factor (vide infra), was an adequate food.

After removal from the mother, three of these rats were fed on an arti-
ficial diet of casein, edestin and the basal ration, and continued the nor-
mal course of growth, but when one of them was placed on the gliadin
food mixture it immediately failed to grow properly. It would appear
from these experiments that, of the two amino acids that are missing or
deficient in gliadin — namely, glycocoll and lysine — it must be the lysine
that is essential for growth. This very important conclusion was fully
corroborated by finding that, in young rats stunted by previous gliadin
feeding, growth immediately started when lysine was added to the diet
and ceased again when the lysine was removed, and so on, the experi-
ments being often repeated in various modifications. Mendel and Os-
borne call attention to the relatively high percentage of lysine in all
those proteins that are concerned in nature with the growth of young
animals; thus, it is present in large amounts in casein, lactalbumin and
egg vitellin.

It is particularly in protein of vegetable origin that indispensable units
are likely to be missing, the best known of these units being the aromatic
amino acids, tyrosine and tryptophane ; the diamino acid, lysine ; and
the sulphur-containing acid, cystine. Some animal proteins, such as
gelatine, also fail to contain aromatic groups, and are therefore utterly
inadequate as foods.

That the absence of one or two units should render a protein in-
capable of maintaining life suggests that a specific role may be taken
by certain amino acids in the maintenance of nutritional rhythm; thus,
they may be necessary for the elaboration of some hormone or other in-
ternal secretion essential to life, such as epinephrine, the active principle
of the suprarenal gland. This is an aromatic substance not far removed
in its chemical structure from tyrosine (see page 773). It is therefore
natural to suppose that the absence of the tryptophane unit in zcin is the
reason that this protein is incapable of maintaining the initial body weight.

NUTRITION AND GROWTH 615

In attacking the problem from this viewpoint, Hopkins and Willcock10
made observations on the survival period of young mice; -that is, the
period during which the animals survived when fed on a basal diet
mixed either with zein alone or with zein plus small quantities of tryp-
tophane. It was found that, with zein alone, the mice were unable to
maintain growth; they lost in weight and died in from about a week to
about a month. Other mice fed on the same amount of basal diet and
zein, but to which was also added some tryptophane, although they did
not grow, were capable of maintaining their body weight and lived in
some instances for nearly a month and a half. There were other indica-
tions of the difference in the efficiency of the two diets. The mice fed
on the zein alone were very inactive, and remained for a considerable
period of the time in a condition of torpor. The hair was ruffled, the
eyes were half closed, and the ears, feet and tail were cold. The ani-
mals, however, gave evidence of having a good appetite. On the other
hand, the mice to which tryptophane was also given manifested a strik-
ingly different behavior, being active and more or less normal until
just before death. That both groups of animals failed to live more than
forty-four or forty-eight days is probably to be accounted for by the
absence in the zein of the other unit, lysine. Had this been added along
with the tryptophane it is probable, in the light of Mendel and Osborne's
observations, that the animals would have survived much longer.

To supply the missing unit, besides using the pure amino acid, we
may employ other proteins which contain the required amino acid (Curve
III of Fig. 184) . That mixtures of protein foodstuffs are desirable has long
been apparent to those who have studied practical dietetics. We must com-
bine the unsuitable protein with others which, although in themselves
perhaps also unsuitable, yet furnish us with a mixture which contains all
the essential units both for maintenance and growth. As Mendel points
out, these considerations suggest that we may be able to utilize certain
of the low priced protein by-products of the cereal, meat and milk in-
dustries. The test of the adequacy of the corrected diet must, however,
be determined by experiments of the type which we have just described.
It is probably in stock-raising rather than in connection with human nu-
trition that these facts will prove of practical value ; for, not only is the diet
of man more varied, but it contains animal proteins in which the deficien-
cies are not so common.

Most important work of this character is being conducted by McCol-
lum and his collaborators.12 It would take us beyond the confines of
this book to discuss the results in detail, but it may be mentioned that
they have shown that, since the adequacy of the diet depends on a
multiplicity of factors besides the ammo-acid make-up of proteins, —
some of which we shall discuss immediately, — very extensive observa-

616 METABOLISM

tions with various food mixtures must be conducted over long periods
of time. The nutritive values of the common cereals added to a stand-
ard diet that had brought the animals (rats) to the threshold of death,
were found to be as follows: With cornmeal there was immediate recov-
ery and rapid growth, both of which were also secured in considerable
degree by wheat embryo and entire wheat kernel; with rye and oats, on
the other hand, there was little if any improvement.

Much work is, of course, yet to be done before we can determine the
exact role which each unit plays in the physiological development of
young animals. To sum up what we already know, it may be said that
glycocoll is not essential, since it can be manufactured by the animal
itself; that tryptophane is essential for maintenance, probably because
it is required for the production of certain essential hormones, for the
make-up of which in its absence other tissues must become disintegrated,
leading therefore to a diminution in body weight; and that lysine ap-
pears to be essential for growth. Tissues can be maintained without
lysine, but they can not grow. That the young rats in the experiments
of Mendel grew normally while living on milk supplied by the stunted
mother indicates that the requisite lysine must have been produced in
the mother's body.

In the application of the foregoing principles to human dietetics, it
is undoubtedly safe to follow Bayliss's advice to take care of the calo-
ries and allow the proteins to take care of themselves.11 For example,
in the case of milk the deficiency of cystine in its chief protein, casein,
is corrected by the presence of lactalbumin, which, though present in
only small amounts, contains sufficient quantities of this amino acid to
meet the demands of the growing tissue.

These observations on maintenance and growth suggest very interest-
ing applications in connection with the growth of tumors. Is it possible
that we might retard the growth of tumors by a diet that was insufficient
for growth while sufficient for maintenance. In an experiment devised
to test this proposition mice were fed on a diet of starch, lard, lactose
and gluten on which they could merely maintain existence but failed
to grow. Some of these rats were inoculated with a rapidly growing
tumor at the same time as another batch of mice kept on normal diet, and
it was found that the tumor grew much more slowly in the stunted mice
than in the others. One mouse, for example, on the restricted diet had
a scarcely visible tumor 52 days after the inoculation. When this mouse,
however, was placed on a normal diet of bread, milk, etc., the tumor
immediately began to grow at a very great rate.13 Too much importance
should not be placed on this experiment.

We shall now pass on to consider some of the factors besides the pro-
tein content which have an important bearing on dietetic efficiency.

CHAPTER LXVII .
NUTRITION AND GROWTH (Cont'd)

THE RELATIONSHIP OF OTHER FACTORS THAN PROTEINS

The Relationship of Carbohydrates. — As we have seen elsewhere, car-
bohydrates are almost certainly essential for normal metabolism. If they
are not given with the food, they must be manufactured out of protein by
the organism itself. It is not surprising, therefore, that their absence
from the diet of growing animals should lead to abnormality in the
rate of growth. Pediatrists have not infrequently insisted that one
form of carbohydrate is more advantageous for growth than another.
This no doubt in the main is true, but the whole question of adequacy
probably depends on the digestibility of the carbohydrate and not upon
its essential chemical nature. It is likely that the only carbohydrate
required by the tissues is glucose. The readiness with which the car-
bohydrate of the food becomes converted into this monosaccharide is
probably the only determinant of its efficiency as food material.

The Relationship of Fats, — Although fats are an invariable constit-
uent of practically every diet, it is yet a debatable question as to
whether they are essential to the maintenance of a healthy normal
organism. Difficulties standing in the way of a solution of this problem
are that it is not only technically very difficult to remove fat entirely
from the common foodstuffs, but also that the simple fats are usually
associated with substances having similar solubilities and physical
properties: namely, the lipoids, phosphatides, cholesterol, pigments, etc.
Since these substances are present in practically every cell, it is almost
certain that they can be manufactured by living protoplasm. Indeed,
experimental evidence is not wanting to show that this is actually the
case. Although the cell can manufacture lipoids, a young animal can
apparently not grow when these substances, as well as simple fat, are
entirely absent from the diet. This has been shown by feeding young
mice on a diet from which all traces of fat and lipoids had been removed
by extraction with alcohol and ether (Stepp)14. On such a diet the mice
lived only a few weeks. They could be kept alive much longer when
some of the alcohol-ether extract was mixed with the diet, but not so
when neutral fat instead of the alcohol-ether extract was added. The

G17

618 METABOLISM

addition of the ash of the lipoid extract failed to maintain the mice, so
that the lacking substance could not be inorganic in nature.

As we shall see immediately, these results are dependent upon the
presence in fats of so-called accessory food factors or vitamines.

The Relationship of Inorganic Salts. — Inorganic salts are also an es-
sential ingredient of the diet. McCollum found that young animals soon
ceased to grow when fed on a diet of corn and purified casein, but that
rapid growth returned when a suitable salt mixture was added. Oats,
wheat, and beans have also been shown to require some adjustment of their
ash content to make them adequate for growth. Most of the animal foods
contain in themselves sufficient inorganic material, as is evidenced
among other things by the adequacy of milk alone as diet for growing
animals and the abhorrence of salt that is shown by strictly carnivorous
animals. In the usual mixed diet of man there is almost always enough
inorganic material, the salt which he adds being largely for seasoning
purposes. When a preponderance of vegetable food is taken, however,
the salt comes to have a real dietetic value.

ACCESSORY FOOD FACTORS, VITAMINES

Even when the requirements of the animal body for calories and
protein building stones are fully met, the diet will fail to maintain
health unless it also contains substances of an unknown chemical nature
called " accessory food factors" or "vitamines." These are entirely of
plant origin, and require to be taken only in very small quantities to
display their beneficial action. They do not become rapidly destroyed
in metabolism, but may remain attached to the tissues sufficiently long
so that carnivorous animals obtain them indirectly. Great advancement
in our knowledge of vitamines had been made in recent years, particu-
larly through the work of F. Gowland Hopkins and Harriette Chick,70
Osborne and Mendel,71 Funk15 and McCollum.12

Serious and prolonged absence of certain vitamines from the dietary
may hinder the growth of young animals or may be the cause of various
serious diseases in adults.

The human diseases which are known definitely to be due to the absence
of one or other of the vitamines are beriberi, scurvy and rickets, and
accordingly three vitamines are distinguished :

1. Antiberiberi or aiitineuritic vitamine (also called water soluble "B"
growth factor.)

2. Antirachitic vitamine (also called fat-soluble A growth factor)

3. Antiscorbutic vitamine.

It will be observed that the vitamines also differ from one another in
their solubilities.

NUTRITION AND GROWTH 619

Investigation of the distribution of the vitamines among the various
foodstuffs, and their degree of stability towards heating, etc., has been
very materially facilitated by the fact that certain of the lower animals
suffer diseases like those seen in man when vitamines are absent from
the diet. This renders it possible to prosecute the investigations in-
tensively and under scientifically controlled conditions, thus affording
knowledge which enables us to alleviate human suffering.

The Antiberiberi or Antineuritic Vitamine, — Beriberi is a disease char-
acterized by wasting, anesthesia and paralysis, and sometimes by ex-
cessive edema. Pathologically, it is a form of severe neuritis. It is
common in rice-eating communities, and the first clue to its precise cause
was afforded by the observation that it does not occur among people
who take unmilled rice, and that it disappears in those who take "pol-
ished" rice when the millings or a watery extract of them (pericarp and
germ) are added to the diet. It was observed by Eijkman that the poul-
try of a prison where beriberi was prevalent exhibited symptoms very
like those of the human disease, and further investigation showed ex-
tensive nerve degeneration to exist in the affected animals. Pigeons
fed on polished rice develop exactly the same symptoms so that experi-
mental investigation soon rendered it possible to determine with accu-
racy which foodstuffs prevent beriberi, and the further properties of
the active substance.

Meanwhile McCollum and Davis discovered that the absence of the
same water-soluble vitamine interfered seriously with the growth of
young animals. This is shown in Curve II of Fig. 186, from the observa-
tions of Hopkins and Chick, which is constructed on the same principles
as those of Fig. 184. It will be observed that the withdrawal of the
vitamine caused an immediate cessation of growth followed by the pe-
riod during which the body weight remained more or less constant, but
ultimately declined. During this stage muscular incoordination is a
prominent symptom, and death ultimately occurs. The curves show
that this vitamine must disappear from the organism when it is with-
drawn from the food and that the animal cannot synthetize it.

The table on page 623 shows the distribution of the water-soluble
vitamine in the commoner foodstuffs. It will be noted particularly that
it is present in abundance in the seeds of plants and the eggs of animals.
It is very plentiful in yeast and in yeast extracts, which may there-
fore be added to the diet when there is risk of its deficiency. It is
absent from bread made with white wheat flour, but beriberi is rare in
people living on this food, since other foodstuffs containing the vitamine
are usually also taken. Beriberi is unknown where rye bread is the
staple food.

The Antirachitic Vitamine (Fat-soluble A Factor). — The first inkling

620

METABOLISM

of the existence of this factor we owe to Stepp who found that mice
could not live for long on animal foods from which all fatty substances
had been thoroughly extracted by alcohol and ether. If the extract was
restored to the extracted food, this again became adequate. Hopkins
then showed in carefully controlled work that animals (rats) not only
failed to grow, but declined and died when they were fed on artificial
diet composed of the purified constituents of milk, although they might
eat voraciously. The addition of a few drops of milk, insufficient to
raise the energy or protein value appreciably, invariably caused normal

liRAMS
25-0 ,

150

IS

I?

VCKJN& FED BV MOTHEK

m

•REMOVING

\

AFTER

Fig.^ 186. — Curves of growth of rats as influenced by the accessory food factors. I. The effect
of the "A" (fat-soluble) factor. Note that the curve does not immediately descend after removal of
this factor from the diet. II. The effect of the "B" (water-soluble) factor. Note that growth ceases
immediately after it is withdrawn. III. The time during which animals survive after removal of the
"A" factor at different ages, the uppermost curve being that obtained for cats that were nearly
mature before the factor was removed from the diet and the lower ones for less mature animals.
IV. The continuous curve is for young fed by mothers receiving "A" factor in| their diets;
the broken-line curve is for young fed by mothers receiving none of this factor. (From Hopkins
and Chick.)

growth to return. Osborne- and Mendel also found that although the
rats in their experiments already referred to on page 609 grew for about
two months upon a diet containing protein, protein-free milk, starch and
lard, they ultimately declined, but that this could be avoided by substi-
tuting butter for the lard, and that the active substance was concen-
trated in the butter-fat portion of the butter. Later work by various
investigators showed that most animal fats, but not those of plants,
contain this essential, and it was hence called fat-soluble A factor or

NUTRITION AND GROWTH 621

vitamine. Lard does not contain it, so that young animals fed with this
as the only fat of an otherwise perfect diet fail to grow as shown in
Curve I, Fig. 186. An important difference will be observed in this
curve from that of II in which the factor B (antiberiberi vitamine) is
alone deficient, namely, that a small amount of growth continues for a
time after the removal of the proper diet. This indicates that there must
be some reserve of the fat-soluble vitamine in the body, and it is only
after this is exhausted that growth entirely ceases and decline then sets
in. Further evidence of tissue storage of this vitamine is afforded in
Curve IV in which the upper curve represents the normal growth of
young rats, the lower, of those nursed by a mother receiving a diet that
was deficient in the vitamine.

When the reserves of the fat-soluble vitamine are exhausted, not only
do the young animals fail to grow, but they become highly susceptible to
bacterial disease, one symptom of which is a very characteristic eye in-
fection (xerophthalmia) which begins with a swelling of the lids, and
later develops into a purulent conjunctivitis, often leading to blindness.
Administration of some fat-soluble vitamine in the diet dispels the eye
symptoms usually within a few days. When the dietary of adult ani-
mals contains none of this vitamine, the eye symptoms also develop,
the general condition greatly deteriorates and the animals become ex-
tremely susceptible to bacterial infections, particularly those affecting
the lungs, and from which they readily succumb. Adults are, however,
much less susceptible to the absence of the fat-soluble vitamine than
growing animals. This may be because of great storage capacity for it
and is shown in Curve III of Fig. 186.

At the same time it is worthy of note that there is reason to believe
that the condition known as war edema is due to a deficiency of this
vitamine. It may be stated here that when both the A and B factors
are absent from the diet young animals immediately cease to grow and
develop the nervous symptoms due to the absence of the B factor, from
which they usually succumb before the symptoms due to the absence of
the A factor have had time to develop.

It is believed that it is with the metabolism within the cells rather
than with that of fat itself that the fat-soluble vitamine is concerned.

A most important relationship probably exists between this vitamine
and the occurrence of rickets. Thus when the puppies of large dogs are
fed with separated milk, bread, linseed oil, yeast and orange juice, they
grow at a normal rate, but in about six weeks develop undoubted symp-
toms of rickets (bones defectively calcified so that the long bones bend,
swelling at the epiphyses, a rosary at the costochondral junctions, the
ligaments loose, general lethargy and loss of muscular tone). In this
diet both the water-soluble and the antiscorbutic factors are present in

622 METABOLISM

abundance (the yeast and the orange juice), but the fat-soluble factor
is very low. Judged by its effect upon the growth curve of rats this factor
would appear to be absent from linseed oil. The latter, however, does con-
tain a trace which is sufficient to allow of an abnormal form of growth
in puppies. When animal fats, such as cod-liver oil or butter, are sub-
stituted for the linseed oil in the above, or a similar diet, rickets does
not occur.

It will be seen in reference to the table on page 623 that there are
two main sources for the fat-soluble vitamine, (1) certain animal fats,
and (2) green leaves. It is particularly abundant in cream, butter, beef
fat, fish oils (particularly cod-liver oil and whale oil) and egg yolk. It
is absent or present only in traces in most vegetable oils, such as lin-
seed, olive, cotton-seed, but in some of them such as peanut oil it is
present in larger amounts.

Its presence in green leaves stands out in contrast to its absence from
root vegetables. It is also present in certain cereals and pulses.

The Antiscorbutic Vitamine. — That scurvy is definitely due to the
absence from the dietary of some vitamine has been known in a general
way for a long time. It used to be very common among the crews in
the days of sailing ships, and nautical history records many interesting
observations, by captains and ship's surgeons, showing that it could be
prevented by adding certain fruits or the juices of fruits or vegetables
to the daily ration. Indeed lime juice became a regular part of the
mariner's ration. Great progress was made in the investigation of
the precise distribution and behavior of the antiscorbutic vitamine by
the discovery that guinea pigs develop the disease when all green stuff
is removed from the diet and the animals are fed on grains and water
or autoclaved milk. The symptoms appear in about 20 days, up to which
time if young animals are used, the growth curve continues. The symp-
toms and the postmortem findings are similar to those seen in man, (ten-
derness and swelling in the joints, swelling of the gums, loosening of
the teeth, tendency to hemorrhages and fractures of the bones). The
curve of growth declines, and the animal dies usually between the 30th
and 40th days. Important work is being done in the Lister Institute in
London to determine the minimal amounts of various foodstuffs that
are required in the scurvy diet to prevent the occurrence of the disease.

Regarding distribution it may be said that this vitamine is found in
nature in all tissues which are actively undergoing metabolic change.
It is abundant in growing green leaves, in fruits and in germinating
seeds. But it is absent, or present only in traces, in dormant seeds, or
in plant tissues that have been dried. It is also present, though less
abundant in fresh animal tissues and in milk. Although potatoes do
not contain much of this vitamine, a diet composed mainly of them is

NUTRITION AND GROWTH G23

seldom scorbutic because of the large quantities that are usually con-
sumed. Canned vegetables and meats only contain traces of it because
it is destroyed in the heating process. Canned fruits, however, contain
more of it because it is preserved by the acid.

The practical application of the results of these observations to the
nutrition of man, and particularly to the dietetic treatment of disease,
is undoubtedly very great. This is especially so in infants and growing
children, in whom the correction of some slight inadequacy in the diet
may have the most pronounced results, not only on growth and nourish-
ment, but also on the power of resistance against disease and infection.
The beneficial influence of cod-liver oil, for example, may depend on some
fat-soluble accessory food factors, while the miraculous benefit which
scorbutic children derive from the addition of the juice of limes, lemons,
etc., to the food is undoubtedly due to such influences. The accumu-
lating mass of evidence as to the faulty nutrition in animals fed on
single kinds of food that fail to contain food factors emphasizes the
necessity in the dietetic treatment of such diseases as diabetes, nephritis,
etc., of seeing to it that the diet is sound, not only in calories, protein
content, and palatability, but also with regard to the presence of these
factors.

In the accompanying table the relative amounts of the various vita-
mines in different foodstuffs is indicated by the use of plus signs.

THE DISTRIBUTION OF THE THREE ACCESSORY FACTORS IN THE COMMONER FOODSTUFFS

WATER-SOLUBLE B

CLASSES OF FOODSTUFFS FAT-SOLUBLE A OR OR ANTINEURITIC ANTISCORBUTIC

ANTIRACHITIC (ANTIBERIBERl) FACTOR

FACTOR FACTOR

Fats and oils.

Butter + + + 0

Cream + + 0

Cod-liver oil -f + 4- 0

Mutton or beef fat or suet + +
P'ea-nut or arachis oil +

Lard 0

Olive or cottonseed oil 0

Linseed oil 0

Fish oil, whale oil, herring

oil, etc. + +
Hardened fats, animal or

vegetable origin 0

Margarine from vegetable

fats or lard 0

Nut butters +

Meat, fish, etc.

Lean meat (beef, mutton,

etc.) + + +

' Liver ++ ++ +

Kidney and Heart ++ +

Brain and sweetbreads + + +

Fish, white 0 very slight, if any

624 METABOLISM

THE DISTRIBUTION OF THE THREE ACCESSORY FACTORS IN THE COMMONER FOODSTUFFS

( CONT'D.)

-FAT-SOLUBLE A WATER-SOLUBLE B

CLASSES OF FOODSTUFFS OR OR ANTINEURITIC ANTISCORBUTIC

ANTTRACHITIC (ANTIBERIBERl) FACTOR

FACTOR FACTOR

Fish, fat (salmon, herring,

etc.) +-f very slight, if any

Fish, roe + + +

Tinned meats ? very slight 0

Milk, cheese, etc.

Milk, cow's whole, raw ++ + +

Milk, skim, raw 0 +

Milk, dried whole less than + + + less than +

Milk boiled whole undetermined + less than +

Milk condensed, sweetened + + less than +

Cheese, whole milk +

Cheese, skim

Eggs

Fresh or dried ++ + + +

Cereals, pulses, etc.

Wheat, maize, rice, whole

grain + f ' 0

Wheat, germ ++ + + + 0

Wheat, maise, bran 0 ++ 0

White wheaten flour, pure
corn-flour, polished rice,

etc. 000

Custard powders, egg sub-
stitutes prepared from

cereal products 0 0

Dried peas, lentils, etc. + +

Soy beans, haricot beans + + + 0

Germinated pulses or cereals + ++ + +

Vegetables and fruits

Cabbage, fresh + + +

Cabbage, fresh cooked

Swede, raw expressed juice

Lettuce, Spinach (dried) + +

Carrots, fresh raw + + +

Potatoes, cooked +

Beans, fresh, scarlet runners,

raw + +

. Onions, cooked + (at least)

Lemon juice, fresh + + +

Lemon juice, preserved + +

Lime juice, fresh . + +

Lime juice, preserved very slight

Orange juice, fresh + + +

Kaspberries + +

Apples +

Bananas + + very slight

Tomatoes (canned) +-r

Nuts + + +

Miscellaneous.

Yeast, dried + + +

Yeast, extract and autolysed ? + + + 0

Meat extract 000

Malt extract + in some

specimens
Beer 0 0

CHAPTER LXVIII

DIETETICS
THE CALORIE REQUIREMENT

In the application of the important facts that have been reviewed in
the preceding chapters to the science of dietetics, the question arises as
to how we may determine with scientific accuracy just exactly how much
food should l)e taken under varying conditions of bodily activity. In a
general way, we know that the amount of food that we require to take
is proportional to the nature and amount of bodily exercise that is
being performed at the time ; and that, if the food supply is inadequate,
the work before long will fall off not only in quantity but in quality as
well. "Horses (also men) work best when they are well fed, and feed
best when they are well worked," is an old adage and one the truth of
which can not be overestimated in the consideration of all questions of
dietary requirements. An ill-fed beggar will rather suffer from the
pain and misery of starvation than attempt to perform a piece of work
that the well-meaning housewife bargains should be done before she
gives him a meal. The spirit may be willing but the flesh is weak. If he
could be trusted, he should be fed first and worked afterwards. Besides
the amount of work, two other factors are well known to influence the
demand for food — namely, growth and climate. A young, growing boy
will often demand as much if not more food than would appear' to be
his proper share, from a comparison of his body weight with that of
his seniors ; and, other things being equal, it Js well known that we are
inclined to eat much more heartily of food during the cold days of
winter than during the sultry days of July and August.

That we know these facts in a general way, indicates that the first
step to take in the exact determination of dietetic requirements is to
find out how much energy the body expends under varying conditions
of activity. This, as we have seen, may be done by having the person
live for some time in a respiration calorimeter, so that we may measure
the calorie output. To the conclusions drawn from results of observa-
tions made under such artificial and unusual conditions of living, the,
objection might, however, quite justly be raised that they need not
apply to persons going about their ordinary routine of life. To meet

623

626 METABOLISM

this objection another method, which we may call the statistical, is avail-
able. It consists in taking the average diet of a large number of indi-
viduals and comparing the calorie value with the average amount and
type of work that they are meanwhile called upon to perform, and can
best be used where the diet is accurately known, as in public institu-
tions, the army, the navy, etc. The total food supplied is then divided
by the number of individuals, this giving the per capita consumption.
Obviously some get more than others, but when a sufficient number of
individuals is included, such errors become eliminated by the law of
averages.

The reliability of this method is testified to by the remarkable corre-
spondence in the calorie value of the food consumed by farmers in widely
different communities:

Calories

Farmers in Connecticut 3,410

11 " Vermont 3,635

" " New York 3,785

" " Italy 3,565

" " Finland 3,474

Average 3,551*

*I,usk: The Fundamental Basis of Nutrition.

The average inhabitant of various cities:

London 2,665

Paris 2,903

Munich 3,014

Konigsberg 2,394**

**Rubner.

Individuals in different callings:

Farmers' families (U.S.A.) 3.560

Mechanics' families (U.S.A.) 3,605

Professional men's families (U.S.A.) 3,530

Army (U.S.A.) 3,851

Navy (U.S.A.) 4,998t

fAtwater.

In general, it is usually computed that a man
weighing 70 kg. requires in calories:
2,500 for a sedentary life,
3,000 for light muscular work,
3,500 for medium muscular work,
4,000 and upwards for very hard toil.J
tMcKillop.

These figures apply to the average man, but in calculating the calorie
requirements of a family or a community we must make allowance for
the lesser requirements of women and children. Several dietitians have
compiled tables showing how many calories are expended according to
age and sex, and from the figures have calculated a generalized mean,
which shows in comparison with men the percentage that should be al-
lowed for women and children. The mean values are as follows :

DIETETICS . 627

Man 100

Woman 83

Boy over 16 92

Boy 14-16 81

Girl 14-10 74

Child 10-13 64

Child 6-9 49

Child 2-5 36

Child under 2 23

In calculating the calorie requirement of the population as a whole,
the necessity of making allowance for the varying needs of men, women,
and children would obviously make the calculations far too complicated
for practical purposes. It is necessary to have a factor by which we
may multiply the total population in order to determine its "man value."
This factor is based on the relative proportion of men to women and
children, and it amounts very nearly to 0.75, i. e., three-quarters of the
total population gives "the man value.'* Knowing the total population,
say, of a city, we must therefore multiply this by 0.75 in order to ascer-
tain for how many men doing moderate muscular work (3000 C.) food
has to be provided.

THE PROTEIN REQUIREMENT

The facts considered in the previous two chapters lead to the question:
To what extent may the proportion of protein in the diet be reduced
with safety? It is evident that there must be a minimum below which
every one of the necessary building materials of protein could not be
supplied in adequate amount to reconstruct the worn-out tissue protein.

The extent to which the protein content of the diet of man can be
lowered with safety depends on several factors, of which the most im-
portant are: first, the nature of the protein; second, the number of non-
protein calories ; and third, the extent of tissue activity. Where so many
factors must be taken into consideration, the only method by which the
actual minimum can be determined consists in what may be called "cut
and try experiments." Of the many investigations of such a nature,
probably the best one for us to consider, is that recently published from
the Nutrition Laboratory of Copenhagen. The subject, an intelligent
laboratory servant, lived a perfectly normal and active life for a period
of five months on a diet of potatoes cooked with margarine and a little
onion, and containing 4000 C., with a total protein content of 29 grams.
During another period he did outdoor work as a mason and laborer, and
took 5000 C. daily, and 35 grams of protein.

It is important to contrast these results with the following based on
municipal statistics of gross consumption.

628 METABOLISM

MUNICIPAL FOOD STATISTICS

PROTEIN

FAT

CARBOHYDRATES

CALORIES

Konigsberg
Munich
Paris
London

gm.
84
96
98
98

gm.
31
65
64
60

gm.
414
492
465
416

2394
3014
2903
2665

It is certain that man can lead a normal existence and remain in good
health, on very much less protein than the 100 grams which statistical
studies show to be the amount he actually takes. This discrepancy be-
tween the amount which experiment demonstrates to be adequate and
that which habit and custom demand, raises the question as to whether,
after all, our instincts may not have erred and so made us unnecessarily
extravagant in our protein intake. It has been suggested that such pro-
tein extravagance will in various ways have a deleterious effect on the
organism; thus, that the excretory organs, such as the kidneys, will be
overtaxed in eliminating the unused amino acids, that the constant pres-
ence of these bodies in excess in the blood will cause degeneration and
sluggish metabolism, and that the excess protein in the intestine will
lead to the production of poisonous decomposition products, the subse-
quent absorption of which into the blood will cause toxemic symptoms.

Important support to such views appeared to be supplied some dozen
years ago by Chittenden, who was able to show that he himself and many
other persons doing different kinds of work could be supported on daily
amounts of protein that were not more than from one-third to one-half
of the amount usually taken. Not only so, but it was averred that dis-
tinct improvement was experienced in the general sense of well-being
and of mental efficiency as a result of the lesser protein consumption.

Taking these results as a whole, it is quite clear that man can get
along under ordinary conditions with much less protein than he usually
takes; but that really proves nothing, for the question is not can he, but
should he, so deprive himself? Are instinct and custom wrong and is
Chittenden right ? That is the question. To answer it many studies have
been made of the condition of peoples who for economic or other rea-
sons are compelled to live on less protein than the average. Are these
people healthier, less prone to infections and degenerative diseases, and
more efficient mentally than others? In such studies great care must be
exercised to see that conditions other than diet, such as climate, exercise,
etc., are properly allowed for. It would not be fair, for example, to
compare the mental and bodily condition of peoples living in the tropics
and who take comparatively little protein, with those living in temperate
zones, who consume much more. After discounting' all of these other

DIETETICS 629

factors, it has been quite clearly shown that, when the protein allowance
is materially reduced, the people as a whole are less robust, mentally in-
ferior, and, instead of being less prone to the very diseases which are
usually supposed to be due to overloading of the organism with useless
excretory products, are more liable to suffer from them.

That a decided reduction in protein weakens the defense of the organ-
ism against infection is probably due to the fact that the fluids of the
body normally contain a great variety of so-called antibodies — that is,
of highly complex substances that are largely protein in nature. When
bacteria, or the poisons produced by them, enter the body, they are met
by one or more of these defense substances and destroyed or neutralized.
Now it is clear that there should always be a surplus of protein-building
materials from which the antibodies may be constructed. Such an excess
will constitute a " factor of safety" against disease. And there are fac-
tors of safety of another nature to be provided for. For example there
must always be an adequate supply of tryptophane, of lysine, and of
cystine, not only to meet the bare necessities of the protein constructive
processes that go on under normal conditions, but also to make good the
larger amount of protein wear and tear that greater degrees of tissue
activity will entail. Although moderate muscular exercise does not ap-
pear to cause any immediate consumption of protein (carbohydrate and,
later, fat being the fuel material that is used), yet it does throw a greater
strain on the tissues thus causing a greater wear and tear of the ma-
chinery, and hence a demand for more protein-building material. There
are also certain of the internal secretions of the body, such as epineph-
rine (adrenaline), that are essential for life, and as crude materials
for the manufacture of which certain amino acids are essential. Tyro-
sine is one of these, and since proteins, as we have seen, differ from one
another quite considerably in the amount of this amino acid which they
contain, it is advisable to provide an excess, so that an adequate supply
of tyrosine may always be available.

The answer to one of the most important practical questions in die-
tetics— namely, "What proportion of protein should the diet contain?"
depends on these scientific principles. The source of the protein is the
important thing. With animal protein there is no doubt that we could
get along with perfect safety by taking daily not more than 50 or 60
grams, which is about half of what we actually consume. If the protein
is of vegetable origin and part of it of the first quality, as wheat and
Indian corn preparations, more should be taken so as to allow for the
deficiency of certain amino acids. When vegetable proteins of the sec-
ond quality, such as those of peas, beans, lentils, etc., are alone available,
much larger amounts are necessary. Such proteins are inadequate in the

630 METABOLISM

case of growing children at least, and even in adults it is undoubtedly
advisable that other proteins should supplement them.

To insure safety, therefore, it is almost imperative that the diet should
contain proteins of various sources. If for economic reasons the main
source must be proteins of vegetable origin, then some animal protein, such
as is contained in milk or meat or eggs, should be added to at least one of
the daily meals. When peas and beans are mainly depended on for the
protein supply, they should be taken either with milk or one of its prep-
arations, or with a thick gravy or sauce made from meat and containing
the finely minced meat. This must not be strained off, for if it is, the
sauce will contain only the meat extractives but not any of the protein,
which is coagulated by the boiling water. Meat extract, in other words,
contains no proteins; it is not a food but merely a condiment of no greater
dietetic value than tea or coffee.

ACCESSORY FOOD FACTORS

The practical point to be remembered is that three accessory fac-
tors or vitamines are known. There is little danger of the diet being
inadequate with regard to food factors if it contains some fruits or
green vegetables or unheated fresh milk. Certain of the food factors
are destroyed by prolonged cooking. It is during times of food scarcity
that the restricted diet may require to be scrutinized to see that it con-
tains the essential vitamines. The reader is referred to page 618, where
this subject is more fully dealt with.

DIGESTIBILITY AND PALATABILITY

We have seen that practical dietetics depends on several factors, the
exact relative importance of which can not perhaps be gauged in every
case, but preparation of the food so as to make it appetizing must un-
doubtedly rank high. The importance of good cooking will now be ap-
parent. It is the act of making food appetizing and therefore digestible.
It is really the first stage in digestion, the stage that we can control, and one
therefore to which much attention must be given, especially when it becomes
necessary to make attractive, articles of diet that are ordinarily considered
common and cheap. Most people can cook a lamb chop so as to make it
reasonably appetizing, but few can take the cheaper cuts of meat and con-
vert them into cooked dishes that are as popular and attractive. And there
are still fewer who can take the left-overs and trimmings and convert them
in the same way. This is the real art of cooking, and too much encourage-
ment can not be given to the effort which our cooking experts are making

DIETETICS 631

to show people how these things can be done. The waste of good food in
a large city is truly appalling.

Cooking has other advantages than making the food appetizing. The
heat loosens the muscle fibers of the meat so that it is more readily
masticated; it destroys microorganisms and parasites in the meat; it de-
stroys antibodies which might interfere with the action of the digestive
ferments. Thus, untreated raw white of egg is not digested in the stom-
ach because it contains one of the antibodies which prevent the pepsin
from acting on it; but boiled egg white, if properly chewed, can be di-
gested, and whipping the egg white into a foam partly destroys the in-
hibiting substance.

Before concluding, something should be said about the laxative quali-
ties of food, for it is often in this particular alone that one food is more
satisfactory than another. A diet of meat, milk, eggs, and white bread is
apt to be'unphysiological because there is nothing in it to act as what has
been called intestinal ballast; that is, a material which will keep the
intestines sufficiently filled to stimulate their muscular movements. This
ballast is best furnished in the shape of cellulose, the most important
constituent of green food. Peas, beans, cabbage, salad, and many fruits,
especially apples, should always occupy a place in the daily menu. An-
other food which is valuable because it yields this ballast is the outer
grain of wheat, oats, etc. So much must not be taken as to produce a
constant intestinal irritation, and each person must determine for him-
self where this limit lies. The difference among various breads depends
partly on the degree to which they supply ballast. It must not be lost
sight of that many of these foods of plant origin are most important be-
cause of the valuable vitamines they contain.

The all-important subject of food economies can receive no attention
here, except to point out that it is one which must be most carefully con-
sidered in the solution of all problems of dietetics. An admirable ac-
count of the subject will be found in Graham Lusk's "Science of Nutri-
tion" (third edition) and in McKillop's "Food Values."16

CHAPTER LXIX
THE METABOLISM OF PROTEIN

Introductory. — The older physiologists believed that the protein taken
with the food was brought into a soluble condition by the digestive en-
zymes, and that it was then absorbed into the blood and directly incor-
porated with the tissues. The discovery of the enzymes trypsin and
erepsin and of free amino acids in the gastrointestinal contents clearly
showed that this simple theory of Liebig could not be correct. It was,
furthermore, found that when an excess of proteins such as egg albumin
gains entry to the blood, part of the protein appears in an unchanged
condition in the urine ; and that enzymes capable of digesting this pro-
tein, but not other varieties, make their appearance in the blood.

After the injection of foreign proteins into the blood, symptoms of
varying severity often develop, from the almost instantaneous death
produced by snake venom to the slowly developing anaphylactic reac-
tions which follow the injection into the blood of many proteins chemi-
cally indistinguishable from those of the blood serum itself. When pro-
tein is taken in the usual amounts by mouth, these poisonous reactions
do not supervene, — even snake venom is harmless when swallowed, — nor
is it possible during digestion of a protein meal to detect food protein in
the blood by means of the precipitin reaction. Finally it was 'discovered
that the very slow intravenous injection of completely digested flesh did
not produce on the part of the body any of the reactions that injected
protein itself produces, indicating that perfect assimilation had occurred.
From these and similar observations it soon became clear that protein,
can not be absorbed as such from the alimentary canal, but must first of
all ~be completely broken down into the amino acids, which are then rebuilt
into the protein of the organism. The direct evidence for this important
change in belief concerning protein metabolism has been gained by the
discoveries that: (1) nitrogen equilibrium can be maintained in animals
fed with completely digested protein mixtures; and (2) amino acids can
be isolated from the blood.

The experiments of the first group consist, in principle, in breaking down protein
until there is no longer the characteristic biuret test and then feeding this digestion
mixture to animals and observing them from day to day, using as criteria of their
nutritional condition the body weight and the nitrogen equilibrium. (Page 605.) It
has been shown that success in maintaining nutritional efficiency depends partly on the

632

THE METABOLISM OF PROTEIN 633

nature of the process used for digesting the protein, and partly on the presence or ab-
sence of carbohydrate in the digestion mixture. It was found that the products of
hydrolysis by acid failed to maintain equilibrium, and it was believed that this was
owing to the fact that the acid had more completely disrupted the protein molecule, and
had left no polypeptides, which, it was imagined, remained intact during enzyme action
and were essential for proper protein metabolism. This view has now been consider-
ably altered, since it has been shown that the acid actually destroys certain amino
acids which the enzyme leaves! intact. The amino acid particularly concerned is
tryptophane. Thus, when different groups of animals were fed with diets, consisting of
(1) fully digested casein, (2) fully digested casein from which the tryptophane
had been removed, it was found that nitrogen equilibrium could not be maintained on
the second diet, whereas it was maintained on the first. When the protein was only
partly digested by acid — that is, not digested enough so as to break up all the trypto-
phane— or when tryptophane was added to the second diet, nitrogen equilibrium could
be satisfactorily maintained.

These results obtained in different classes of animals have also been confirmed for
the human subject. For example, nitrogen retention has been observed in a case of
a boy suffering from a stricture of the esophagus, when he was fed by rectum for
fifteen days with digestion products resulting from the action of trypsin and erepsin
on flesh.

Concerning the second type of evidence, many investigators attempted to separate
the amino acids themselves from the blood, particularly during the digestion of a large
amount of protein, but the results were at first entirely negative because of the lack
of methods that were sufficiently delicate to make it possible to detect the slight increase
that could be expected even when a maximum absorption of nitrogen had occurred.
The very large flow of blood through the portal vein causes such extensive dilution of
any substances added to it that the concentration of the substance in an isolated
sample of the blood can be only trivial.

This brief historical survey of the subject brings us to a position where
we may proceed to discuss the present-day teaching regarding protein
metabolism. Briefly stated, this teaching is to the effect that the protein
molecule is broken down into its ultimate building stones, the amino acids,
by the digestive enzymes of the gastrointestinal tract. These amino
acids are absorbed into the blood, by which they are carried tot the various
organs and tissues, which sift out the amino acids and use 'those of themi
which they require for the reconstruction of their broken-down protein.
The amino acids not required for the process, along with those which may
be liberated in the tissues themselves by disintegration of tissue proteins,
are then split into two portions, one represented by ammonia and the other
by the remainder of the amino acid, molecule. The former is excreted as
urea and the latter is oxidized to produce energy.

CHEMISTRY OF PROTEIN

Before proceeding to discuss the evidence upon which the above con-
clusions depend, it will be necessary to consider some of the most important
facts concerning the chemistry of the protein molecule. We shall require
this information not only to understand the history of protein in the

634 METABOLISM

animal body, but also to follow intelligently the important work that
has already been discussed concerning the relative value of different
proteins as food. A knowledge of protein chemistry has come to be
essential in practically all branches of medical science.

Proteins, like starches, are composed of numerous smaller molecules.
In the case of starch these molecules are the various monosaccharides —
glucose (dextrose), levulose and galactose; in the case of proteins they
are the amino acids. The breaking apart of the links that hold the mole-
cules together is effected in both cases by the process of hydrolysis, so
called because of the fact that the reaction consists in the taking up of a
molecule of water at each of the places where the chain falls apart. This
hydrolysis may be effected either by the action of mineral acids or alka-
lies, or by enzymes, the only difference in the action of these reagents
being that in the former case the breaking apart takes place more or
less indiscriminately, whereas in the latter it proceeds according to a
definite plan, which varies somewhat with the type of enzyme employed.
Just as a chemical knowledge of the structure of sugar or monosac-
charides is the basis of carbohydrate chemistry, so is that of the amino
acids the basis of protein chemistry.

Amino Acids. — There are, so far as known, eighteen different amino
acids concerned in the constitution of protein, but they are all alike in
their characteristic structure. The most striking characteristic depends
on the presence in the molecule of: (1) an amino group with a basicity
comparable to that of ammonia, and (2) an acid group with an acidity
comparable to that of acetic acid. Let us take in illustration one of the
simplest fatty acids — namely, acetic. It has the formula CH3COOH.
The COOH group is called carboxyl, and on it depend the acid properties
of the compound. The CH3 group is known as methyl, and the amino
group (NH2) is attached to it in place of one of the hydrogen atoms, thus
giving the formula CH2NH2COOH, which is aminoacetic acid or gly-
cocoll. If we take the next higher acid of the fatty acid series, having
the name propionic and the formula CH3CH2COOH, its amino acid, called
alanine, has the formula CH3CHNH2COOH. Now let us place the formu-
las of these two acids side by side in the following manner:

H CH3

NEL - C - COOH NH2 - C - COOH

| 1

(amino group) H (acid group) (amino group) H (acid group)
Aminoacetic acid Aminopropionic acid

(glycocoll) (alanine)

It will be observed that the only difference between the two acids is
dependent upon a change in the group that is attached to the upper verti-

THE METABOLISM OF PROTEIN 635

cal valency bond of the central carbon atom, which therefore must be
considered as the center of the entire molecule. The various amino acids
entering into the structure of protein differ from one another solely with
regard to the chemical nature of the group that is attached to this ver-
tical valency bond. Evidently, then, the reactions that amino acids pos-
sess in common must depend on the end groups containing the carboxyl
and amino radicles, whereas the characteristic reaction of each of the eight-
een amino acids must depend upon the differences in the radicles attached
to the upper vertical bond. This may be represented thus :

Any radicle
NH2-C-COOH

(Any amino acid)

The end groups endow the amino acids with the power to combine with both acids
and bases. With acids they behave like substituted ammonias to form salts, which can
here ionize into the amino acid, as the cation, and the acid group, as the anion. With
bases the carboxyl group reacts to form salts, which yield amino acid as the anion. A
most important reaction consists in the condensation of aldehydes with the amino group.
This occurs particularly readily with formaldehyde, water being eliminated in the re-
action, and the basic nature of the ammo acid thus destroyed. Upon this reaction de-
pends the method of Sb'rensen for determining the amount of amino acid in a mixture
(see page 641). The titration is performed by rendering the solution of amino acids
neutral, then adding formaldehyde and titrating with standardized acid, using phe-
nolphthalein as the indicator. This tells us to what degree the acidity of the mixture
has become increased as a result of adding the formaldehyde, and since this increase
in acidity must depend upon the number of amino groups, we are furnished with an
indirect estimate of the concentration of the amino acids. The reaction is illustrated
by the equation:

radicle H radicle

I I I

NH.-C-COOH + H-C^O = CH2 — N - C - COOH + H2O

(amino acid) (formaldehyde)

Another reaction of amino acid of physiological interest is that known as the car-
bamino reaction, consisting in a union of the amino acid with calcium and carbonic acid.

Finally, it is important to note that the amino group is very firmly attached ; it
remains intact in acids and alkalies and is removable only by a process of oxidation.
This can be accomplished by treating the amino acid with such reagents as hydrogen
peroxide or with potassium permanganate, when the amino group is displaced and a
so-called ketonic acid formed. The reaction will be evident from the accompanying
equation :

CH3 CH3

I I

O + NH,-C-COOH *± O — C-COOH+ NH3

( alanine ) , ( py ruvic acid )

G36 METABOLISM

To illustrate this reaction we have chosen aminopropionic acid or alanine, because
the substance formed by its oxidation and known as pyruvic acid is of very great im-
portance in intermediary metabolism. It serves as the common substance from which
proteins, carbohydrates or fats may be formed, and therefore as the intermediary sub-
stance through which one of them may pass on being transformed into another (page
698). The use of two arrows pointing in opposite directions in the above equation in-
dicates that the reaction may proceed readily in either direction.

The ammonia set free from amino acids may be oxidized to free nitrogen by using
nitrous acid according to the general equation: NH3 + HONO:=2H2O + N2. Upon this
reaction depends another extremely important quantitative method for measuring the
number of amino groups prese'nt in protein (Van Slyke). To make the estimation,
nitrous acid is allowed to act on the amino acids, and the volume of nitrogen gas set
free by the reaction is measured, the principle being similar to that used for the de-
termination of urea by the hypobromite method.

The apparatus employed for decomposing the substance and collecting and measuring
the evolved nitrogen consists essentially of a mixing bulb, connected below through stop-
cocks with two small burettes, one containing a solution of sodium nitrite and glacial
acetic acid, and the other a solution of the substance to be investigated. The upper end
of the mixing bulb is connected through a three-way cock with a graduated gas burette
and with another bulb containing potassium permanganate solution. By allowing some
nitrite and acid solution to run into it and shaking, the mixing bulb is first of all filled
to a certain mark with nitrous oxide gas. A measured quantity of the amino solution
is then allowed to mix with the nitrite; the apparatus is shaken for five minutes at 15
to 20° C., and the evolved nitrogen and nitric oxide are driven over into the permanganate,
which absorbs the nitric oxide, leaving the nitrogen, which is then measured in the burette.

The apparatus has now been so perfected that numerous analyses may be made with
it in a very short time and with a degree of accuracy that is scarcely surpassed in any
other biochemical estimation.

Protein Synthesis. — From the point of view of protein chemistry, the
most significant reaction of the amino acids is their ability to link to-
gether to form compounds called peptides. This linking occurs between
the amino group of one amino acid and the carboxyl group of the next.
When alanine and glycocoll, with which we are familiar, are thus linked
together, the reaction takes place according to the equation:

H CH3 H

CH. __ | j |

/!H + HO: OC - C - NH2 = HOOG -C-NH-CO-C- NH2 + H2O
HOOC-C-N | ! ! I

^ \H H H H

(alanine) (glycocoll) (alanyl - glycocoll)

In this manner, then, a so-called dipeptide is formed, in which it will
be observed there still remain free carboxyl and amino groups, thus per-
mitting the linking on of other amino-acid groups to form tripeptides or
tetrapeptides or other polypeptides. Indeed, this process of condensa-
tion may go on practically indefinitely, a polypeptide containing eighteen
amino-acid groups — namely, three leucine and fifteen glycocoll groups — hav-

THE METABOLISM OF PROTEIN

637

V

2 ?

s— — a

Two or m
The three

.
e basic groups
COOH group
hexone bases.

Si

638 METABOLISM

ing actually been synthesized. The resulting polypeptides have the proper-
ties of derived proteins like the proteoses; thus, they give the biuret
and other reactions characteristic of proteins and are precipitated by
such reagents as mercuric chloride and phosphotungstic acid. Some are
also digested by trypsin and erepsin. They have the same optical activities
as proteins. One of them has been prepared which produces a typical
anaphylactic reaction. So far a polypeptide that can be coagulated by
heat or is in other ways identical with the naturally occurring proteins,
has not been synthetized; but there is no doubt that it is only a matter
of time before this will be accomplished.

Eighteen distinctly different amino acids have been isolated from pro-
tein, and it may assist in the conception of our problem if we place these
amino acids side by side and link them together in the manner described
above. This is done in the accompanying chart compiled by D. D. Van
Slyke, in which also various other important facts concerning the chem-
istry of the amino acids are incidentally added.

At the lower part of each formula will be seen the characteristic car-
boxyl and amino groups of neighboring acids linking together the ter-
minal carbon atoms. The upper vertical bond of this carbon atom is con-
nected with the characteristic group of the amino acid, which may be very
simple and represented only by hydrogen, as in glycocoll, or highly com-
plex and including a ring formation, as in tryptophane. It will further
be observed that there may ~be other amino groups connected in various
positions in this radicle. This is particularly the case in the first three of
the amino acids in the table — namely, the basic amino acids. In lysine
the extra amino group reacts with nitrous acid, liberating free nitrogen
by the Van Slyke method; but in other cases, as in arginine, it fails to
give this and the other characteristic reactions of the amino group.

It will further be observed that the amino acids are arranged in three
main groups: one basic, another neutral, and the third acid. The basic
amino acids are three in number and have an alkalinity similar to
that of ammonia. They have been called the hexone 'bases, because each
contains six carbon atoms. They are alone present in certain forms of pro-
tein called prot amines. The neutral amino acids contain one amino group
and one carboxyl group, which exactly neutralize each other. This is
the largest group of amino acids, and is further subdivided into three:
one containing aromatic or benzene rings and including the very im-
portant amino acids, tyrosine and tryptophane; another containing the
so-called pyrrolidine ring; and the third, the largest of all, containing
the so-called aliphatic chains; that is, the chains characteristic of the
fatty acids and which may be either straight or branched. When the chains
are branched, the substance is called an isosubstance, as in isoleucine.
The acid amino acids, including glutamic acid and aspartic acid, are

THE METABOLISM OF PROTEIN 639

characterized by containing two carboxyl groups and only one amino
group. They therefore resemble acetic acid in acidity.

It may be of assistance to some if we restate these chemical facts
from a slightly different standpoint as follows:

Glycine, or glycocoll, is aminoacetic acid, CH2NH2COOH.

NH2

Alanine is glycine plus a methyl group, CH8CH ; it is therefore amino-

COOH

OH

propionic acid and is closely related to lactic acid, which is CH3CH . Many of

COOH

the other amino acids may be considered as derivatives of alani/ne^ thus:

1. Serine is alanine with an "OH'-' (hydroxyl) group in place of one of the "H"

NH2

atoms of the methyl group, CH2OH-CH

COOH

2. Cysteine is alanine with an "SH" (thio) group in this position,

NH2

CH2SH~CH

COOH

Two cysteine molecules united at the "S" groups give cystine.
NH2 1

CH2S-CH

COOH

NH2

3. Phenylalanine has a C6H3 (phenyl) group, CH2C6H5-CH

COOH
NH2

4. Tyrosine has a C6H4OH (phenol) group, CH2C6H4OH - CH

COOH
C

5. Tryptophane has a C6H4 CH (indole) group:

NH
C — CH2 - CH - NH2 - COOH.

C6H4 CH

NH

CH

N NH

6. Histidine has a CH = C - (imidazole) group:

640

METABOLISM

CH

NH
CH = C.CH2 . CH. NH2-COOH.

The last two are also called heterocyclic compounds, of which there
is another, viz.;

Proline (and oxyproline), which is a-pyrrolidine carboxylic acid:

CH2 — CH2

CH2

CH.COOH

\

NH

Other amino acids are:

[ GIL CH3

CH, CH8

CH3 C2I

\ /

\ /

\ /

CH

CH

CH

(1) Valine
Leucine

CH.NH2

CH, •

CH.NH2

Isoleucine

I

1

I

thus:

COOH

CH.NIT2

COOH

I

(valine)

COOH

(isoleucine)

(leucine)

(2) The amino dibasic acids:

Aspartic, which is aminosuccinic acid,

CH2COOH

I
CHNH2COOH; and

Glutaminic, which is aminoglutaric acid,
CH,

CH2-COOH

CHNH2 COOH.

Lastly there are the diamino acids, in which two groups exist :

Lysine a e-diaminocaproic acid.

NII2

NH2CH2 - CH2 - CH2 - CH2 - CH2 - CH

\

COOH.

Arginine a-amino — 5-guanidine-valerianic acid,

NH2

HN — C NH2

NH.CH2 - CH2 - CH2 - CH

COOH

The guanidine group in this acid is of interest because of its close relationship to
NH2

/

urea, which is O = C

CHAPTER LXX

THE METABOLISM OF PROTEIN (Cont'd)
AMINO ACIDS IN THE BLOOD AND TISSUES

In the Blood. — Furnished with the general facts concerning the chem-
istry of proteins, we may now proceed to consider the more precise
knowledge recently acquired concerning the history of this substance
in the animal economy. Although no one has succeeded in separating
ammo acids in pure condition from drawn blood even during the height
of digestion, it has nevertheless been possible to do so from circulating
blood by a method of dialysis, known as vividiffusion, elaborated by
Abel33 and his pupils. The method consists in connecting a long tube
of collodion with the two ends of a cut artery in an anesthetized animal.
(Fig. 187.) The tube, coiled many times, is then immersed in a solution
containing approximately the same salt content as the blood plasma of the
animal. The diffusible constituents of the blood plasma dialyze into the
saline solution ; or any one of them may be prevented from dialyzing by add-
ing that particular substance to the saline in such amounts as will make its
concentration in plasma and saline alike. It has been possible in this
way to isolate several of the ammo acids and other ammonia-yielding
substances from blood. Thus, alanine and valine have been obtained as
crystalline salts, and histidine and creatine have been (see page 656)
shown to be present by their reactions. All of the amino substances,
however, do not dialyze, and these exceptions are further characterized
by the fact that they do not readily give up their ammonia on the ad-
dition of sodium carbonate, as do the diffusible substances (Rohde).

Although amino acids can thus be separated in a pure state from cir-
culating blood, their concentration in a drawn specimen is too low to
make direct quantitative estimation possible. By the methods of Van
Slyke and Sorensen, already described, however, it has been shown
among other things that the blood always contains a certain concentra-
tion of- amino acids; thus, in that of fasting animals from 3 to 5 mg. per
100 c.c. of blood are usually found present. During the absorption of a
protein meal, the amino content of the blood undergoes a marked in-
crease, becoming doubled or more; and a similar result has been ob-
tained by placing pure amino acids in the small intestine. After 10
grams of alanine, for example, the amino nitrogen of the mesenteric
blood rose from 3.7 to 6.3 mg. per cent.*

"This is a convenient way of stating per 100 c.c. of blood.

641

642

METABOLISM

In the Tissues. — After entering the circulation, the amino acids very
quickly disappear from it again. This has been demonstrated by ob-
serving the amount of amino acids in the blood after intravenously
injecting a solution of amino acid into an anesthetized animal. After
injecting 12 gm. of alanine into the vein of a dog, 90 per cent was found
to have disappeared from the circulation within five minutes. The ques-
tion is, What becomes of the amino acids that rapidly disappear? Are
they decomposed in the blood, or do they become absorbed by the tis-
sues? This problem has been attacked by analyzing portions of various
organs and tissues removed before and some time after the injection

Fig. 187. — Vividiffusion apparatus of J. J. Abel.

into an animal of solutions of amino acids. In the case of the muscles it
has been found that the amino-acid content increases until from 60 to
80 mg. per cent of amino acid has accumulated. Beyond this point,
however, the muscles do not seem to be able to take up any more amino
acid (Fig. 188). The capacity of the abdominal organs, however, is more
elastic; for example, the amino nitrogen of the liver has been observed to
become increased to 125 or 150 mg. per cent of the original amount. Al-
though this absorption of amino acids by the tissues is extremely rapid, it
never proceeds to such a point that the blood becomes entirely free of them,
for even after many days' starvation the blood contains its normal quota
of from 3 to 10 mg. per cent (Fig. 189). This indicates that under these

THE METABOLISM OF PROTEIN

643

conditions a certain equilibrium must become established between the
amino-acid content of the blood and that of the tissues, the concentration
in the tissues being approximately from five to ten times greater than in
the blood.

The absorbed aniino acids are very loosely combined with the tissues,
for they can be extracted by such feeble reagents as water or dilute al-
cohol. Their presence can not, however, be merely due to diffusion;
for if it were, the concentration could not become greater in the tis-
sues than in the blood. The further fate of the amino acids is difficult

150

100

§>

8

£
8,

as

g
3

50

Injectio

,^.

Muscle

NH

1

Hours

Fig. 188. — Curves showing the amount of amino nitrogen taken up by different tissues after
the cutaneous injection of amino acids. The lowermost curve shows the urea concentration of the
blood. (From D. D. Van Slyke.)

to follow. We know that they do not remain in the body for a long time,
because most of the protein nitrogen in the food is excreted as urea
within twenty-four hours after ingestion; and when single amino acids
are fed, they quickly reappear in the urine as urea.

The tissues can therefore be only a stopping-place for the amino
acids. When the latter are determined in blood collected from different
parts while absorption of protein from the intestine is in progress, it
has been found, as shown in Fig. 189, that during the passage of the
blood through the liver there is a greater fall in the concentration of

644

METABOLISM

amino acids than during its passage through the entire remainder of
the body.

It will be seen that the above conclusions are drawn from estimations
made on blood taken from the vena cava, the portal vein, and the hepatic
artery, the upper curve in the chart being from animals during digestion
and the lower, from fasting animals. The results show that the liver must
be particularly greedy of amino acids, which, however, must rapidly be-
come transformed into other substances, since no conspicuous varia-
tion has been found to occur in the ammo-acid content of the tissues

(Q

Fig. 189. — Curves showing the concentration of ammo-acid nitrogen in the blood during fasting
and protein digestion. (From D. D. Van Slyke.)

according to whether the animal is fasting or is digesting protein food.
This result, it is to be noted, is quite different from that which is ob-
tained after the intravenous injection of amino acids, and the results of
the two experiments taken together, indicate that the amino acids after
their absorption can not remain in the tissues in a free condition for a
long time. It means that the amino acids during natural digestion must
~be, disposed of at a rate which is practically the same as that at which ab-
sorption is proceeding.

THE METABOLISM OF PROTEIN 645

THE FATE OP THE AMINO ACIDS

To follow the metabolism of the amino acids further we must deter-
mine the end product into which they tare converted. This is urea,
the estimation of which can nowadays be made with considerable accuracy
on account of the discovery, by Marshall, of the action of urease in con-
verting its nitrogen into ammonia, which can then be estimated by com-
paratively simple methods (Folin).

When the viscera are compared before and at various periods after
the intravenous injection of amino acids, the immediate increase in
amino nitrogen remains undiminished in all of them except the liver, in
which a very rapid reduction is observed to occur. At the same time
the percentage of urea in the blood steadily rises. These facts are illus-
trated in Fig. 188.

The simplest interpretation of these results is that the liver converts
the amino acids into urea and discharges this urea into the blood. This
conclusion, however, it must be observed, is not inevitable; for it is pos-
sible that the amino acids may be condensed into polypeptides in the
liver, just as sugar is condensed by this organ into glycogen, and that
the increase in urea is merely coincident (Fiske).

It must not be imagined that the conversion of the amino acids into
urea is exclusively a function of the liver. On the contrary, it is well
known that this process may occur in animals from which the liver has
been entirely removed. It is probably safe to conclude, however, that
the liver is the most active center for amino-acid transformation and
urea formation.

When urea is estimated in samples of blood removed at short inter-
vals of time after the ingestion of a large amount of protein, it is found
that the increase becomes very early established. In one experiment,
before the food was taken the concentration of urea nitrogen in the blood
was a little over 10 mg. per cent; one hour after taking 500 grams of
meat, it had risen to about 18, and in two hours to nearly 25. Evidently
the increase had occurred about the same time as the passage of food
from the stomach into the duodenum. These facts indicate that urea
formation in the liver becomes stimulated long before the other tissues,
such as the muscles, have had time to take up their full quota of amino
acids. During digestion of protein the liver does not appear to wait
until the other tissues have become saturated with amino acids before it
begins to destroy the unnecessary excess by conversion into urea; on
the contrary, this process sets in with the very first installment of amino
acid that reaches the liver by the portal blood. This conclusion is in
harmony with the well-established fact that, when protein is given to a

646 METABOLISM

starving animal, the greater part of its nitrogen is soon excreted as
urea, leaving only a small fraction to be used for rebuilding the wasted
tissues.

The amino acids that are absorbed by the extrahepatic tissues become
very quickly converted into formed protein, as is evident from the fact
that the concentration of free amino acids in the tissues of an animal
during absorption of protein is not perceptibly greater than in those of
a fasting animal, and the question remains to be considered, What 'be-
comes of the protein thus formed? The answer is, that it is gradually
used up in the metabolic processes, so as to liberate again the amino
acids, which add themselves to those absorbed from the intestine and be-
come used again or excreted, according to the demands of the tissues at
the time for amino acid. •

This process of liberation of amino acid from the breakdown of body
protein goes on of course irrespective of absorption of amino acid from
the intestine. It goes on, for example, during starvation; indeed, in
this condition the percentage of free amino acids in the muscles is, if
anything, somewhat higher than that observed in an ordinarily fed an-
imal. In starvation also the migration of amino acid is going on among
the various organs, of which those whose activity is essential to the
maintenance of life, such as the heart and the respiratory muscles, are
supplied with amino acids from tissues that are less vital, such as the
skeletal muscles (see page 602). These experiments further show that
free amino acids can not serve to any significant extent as food reserves
in the same way as glycogen and fat. If amino acids were of value as
food reserves, we should expect the store of them to be depleted
by starvation. As to how long a period of time elapses between the
incorporation of the absorbed amino acids into tissue protein and their
subsequent liberation again by autolysis, we are entirely ignorant.

The researches which we have just been considering do not throw any
light on the relative value of different proteins in tissue metabolism.
They do not inform us as to which of the amino acids must be absorbed
ready-made from the digested food, and which of them may be dispensed
with since the organism can manufacture them for itself. We know that
the higher animals can synthetize some amino acids, such as glycocoll,
but not others, such as tryptophane; but which amino acids belong to
the glycocoll and which to the tryptophane groups, can not as yet
be definitely stated. The investigation of this problem has to be under-
taken by experiments of an entirely different type — namely, by observing
the welfare and growth of animals fed on proteins of varying amino-
acid composition. A full discussion of these experiments is given in
the chapters on Nutrition and Growth.

CHAPTER LXXI
THE METABOLISM OF PROTEIN (Cont'd)

THE END PRODUCTS OF PROTEIN METABOLISM

Introductory. — So far we have approached the problem of protein
metabolism by studying the behavior of the absorbed products of pro-
tein breakdown, and we have seen that these become gradually assimilated
by the tissues and used by them in their metabolic processes. We have
been unable, however, to offer any facts regarding the exact chemical
changes which each amino acid undergoes during this process of tissue
metabolism. At first sight it might appear an easy matter to collect
such information by direct examination of the tissues themselves, either
by searching in them for amino derivatives which might be derived from
absorbed amino acids, or by studying the changes which occur when
the amiuo acids are subjected to the action of the isolated tissue en-
zymes that must be responsible for the change. Such methods of in-
vestigation are, however, fraught with technical difficulties so great that
very little can be learned from them, and for the present at least we
must be content to piece our information together from facts derived
by less direct methods. Such a method is offered by investigating
the behavior of the end products of protein metabolism.

The main end product is urea along with traces of its precursor am-
monia, but these are not the only ones, for some amino acids after being
incorporated with the tissue proteins break down into products that
are no longer members of the amino-acid series, although they may be
closely related to certain amino acids. Such substances are creatine and
its anhydrid creatinine. A part of the amino acids during their pres-
ence in a free state in the blood may also be excreted unchanged by
the kidney. Our list so far therefore includes urea, ammonia, creatine,
creatinine, and amino nitrogen, of which the last is usually included in
metabolism investigations in the fraction designated undetermined
nitrogen.

Another group of closely related substances coming, not from the
general protein metabolism of the tissues, but from the metabolism
which is peculiar to the nuclei, consists of the so-called purine bodies.
Furthermore, so as to serve as a check on results obtained by examining
these nitrogenous metabolites, it is important to observe the manner of

647

648 METABOLISM

excretion of the sulphur moiety of the protein molecule, for it will be
remembered that it is in protein alone that sulphur is usually taken into
the animal body. The excretion of sulphur therefore runs more or less
parallel with the intensity of protein metabolism.

After selecting the end products that are most likely to be of .signif-
icance, the first question concerns the amount of each of them excreted
during twenty-four hours on diets that are either rich or poor in pro-
tein. The possibility of conducting such investigations obviously de-
pends on the use of quick and yet reliable methods for the estimation
of the nitrogenous metabolites. Such methods have been furnished by
the painstaking and careful work of Folin, an example of whose results
is given in the accompanying table.

NITROGEN-RICH DIET NITROGEN-POOR DIET

Volume of urine 1170 c.c. 385 c.c.

Total nitrogen 16.8 grams 3.60 grams

Urea nitrogen 14.7 grams = 87.5% 2.20 grams = 61.7%

Ammonia nitrogen 0.49 gram — 3.0% 0.42 gram = 11.3%

Uric-acid nitrogen 0.18 gram — 1.1% 0.09 gram — 2.5%

Creatinine nitrogen 0.58 gram — 3.6% 0.60 gram —17.2%

Undetermined nitrogen 0.85 gram = 4.9% 0.27 gram — 7.3%

Total SO3 3.64 grams 0.76 gram

Inorganic SO3 3.27 grams =90.0% 0.46 gram =60.5%

Ethereal SO3 0.19 gram = 5.2% 0.10 gram =13.2%

Neutral SO3 0.18 gram = 4.8% 0.20 gram =26.3%

(Folin.)

The general conclusions which may be drawn from these results are
as follows:

1. With a protein-rich diet much more urine is excreted in twenty-
four hours than with one that is protein-poor. Evidently the nitrogenous
metabolites act as diuretics.

2. The total or absolute amounts of nitrogen and of all the other
nitrogenous metabolites, save creatinine, become diminished during the
starvation period. The same is true of the sulphur derivatives, except
in the case of the neutral sulphur, which behaves like creatinine.

3. The decrease in nitrogen is not borne proportionately by all of
the metabolites. This is seen by examination of the percentage figures
which are obtained by calculating the nitrogen of each substance as a
percentage of the total nitrogen. The urea decreases relatively much
more than the total nitrogen. The inorganic sulphate behaves in a
manner similar to the urea — that is, the percentage of total sulphate
excreted in the inorganic form becomes much less during starvation.

4. The relative amount of all the other nitrogenous metabolites, as
well as that of the ethereal and neutral sulphates, becomes increased
during starvation.

The most striking results of the above investigation are that creatinine
remains unchanged during starvation^ but that urea becomes relatively

THE METABOLISM OF PROTEIN 649

increased. The former must be derived from metabolic processes going
on in the tissues independently of the supply of foodstuff carried to
them, whereas the latter must depend, if not entirely, yet very 'largely,
on the protein content of the food. Creatinine may therefore be called
an end product of endogenous metabolism, and urea an end product of
exogenous metabolism.

Other metabolites — namely, ammonia, uric acid and the undetermined
nitrogen, as well as the ethereal sulphates — must represent processes
of metabolism that are partly exogenous and partly endogenous.

Having made ourselves acquainted with the general nature of the
changes that occur in the nitrogenous metabolites when protein metab-
olism is stimulated by the taking of food or is depressed by starvation,
we may now proceed to a study of the source and origin in the animal
body of each of the metabolites.

UREA AND AMMONIA

For various reasons it is important to consider these two metabolites
together. During the intermediary metabolism of the majority of the
amino acids, the amino group becomes broken off as ammonia, which
immediately combines with the available acids to form neutral ammonium
salts. The most available acid for this purpose is carbonic acid; there-
fore ammonium carbonate is formed in large amounts. A small propor-
tion of the ammonia may combine with other acid radicles, such as
chlorine, to form ammonium chloride. The fate of these two types of
salt is very different, The ammonium carbonate becomes quickly trans-
formed into urea, whereas the ammonium chloride is excreted in the
urine. The process of urea formation may therefore be considered as
having the function of preventing the accumulation of ammonium car-
bonate in the animal body. It is the means by which a harmful substance
is converted into an innocuous substance — a detoxication process, in
other words.

Regarding the nature of the chemical process involved in this trans-
formation of ammonium carbonate into urea, reference to the following
formulae will show that the ammonium carbonate that is formed by the
union of carbonic acid with ammonia, by losing one molecule of water
becomes ammonium carbamate, which by repetition of the process be-
comes transformed into urea :

. OH

ONH4

ONH4

NII2

CO +

2NH3 <=± C

0 - H20

^±CO

11,0 = CO

\

\

\

\

OH

ONII4

NH,

NH2

(carbonic

(ammo-

(ammonium

(ammonium

(urea)

acid)

nia)

carbonate)

carbamate)

650 METABOLISM

Some of the urea may come from metabolic processes of an entirely
different type. One of these at least is known ; namely, the splitting-off
of urea from arginine, which it will be remembered is guanidine-amino-
valerianic acid (see page 640). An enzyme called arginase, having this
action, has been isolated from various organs and tissues. The diamino-
valerianic acid, or ornithine, wrhich remains after the urea is split off,
may be further used in protein metabolism. The reaction is shown in
the following equation:

NH2 - C - NH - CH2 - CH2 - CH2 - CHNH2 - COOH + H,O

!l

NH (arginine)

— NH2-CO

| + NH2 - CH2 - CH2 - CH2 - CHNH2 - COOH
NH2
(urea) (ornithine)

On an ordinary diet, as we have seen, a man excretes somewhat more
than 90 per cent of his total nitrogen as urea and about 3 per cent as
ammonia, the remainder of the nitrogen appearing in the other nitrog-
enous metabolites.

Influence of Acidosis on Ammonia-Urea Ratio, — It sometimes happens
that a large proportion of the ammonia is not converted into urea, but
is used for the purpose of neutralizing abnormal acids present in the
organism. "When mineral acids are given to an animal, or when acids
are produced in the organism itself by some faulty type of metabolism,
the ammonia excretion by the urine immediately rises. In diabetes, for
example, where considerable quantities of /?-oxybutyric acid are pro-
duced (see page 715), a decided increase in the ammonia excretion by
the urine is observed. A milder type of acidosis may also be induced
in normal persons by withholding carbohydrates from the diet, and
here again the ammonia excretion is relatively increased.

In such cases it is quite evident that ammonia is used as an alkaline
reserve of the body ; that is, as a substance which is capable of prevent-
ing acidosis by neutralizing the acids. It does not appear, however,
that all types of acidosis entail the utilization of ammonia as reserve
alkali, and an increase -in the relative amount of ammonia in the urine
does not necessarily indicate a condition of acidosis. In the pernicious
vomiting of pregnancy, for example, a relatively high excretion of am-
monia has been found associated with no greater a degree of acidosis
than in normal cases of pregnancy, as determined by the power of the
plasma to absorb carbonic acid. When there is a relative excess of al-
kali in the blood (alkalosis) the ammonia excretion becomes depressed,
as is the case after taking alkali with the food, or in the alkalosis pro-
duced by forced breathing (page 382).

THE METABOLISM OF PROTEIN 651

Influence of Liver on Ammonia-Urea Ratio. — Experimental Observa-
tions: (1) BEMOVAL OF LIVER. — There are several facts which indicate that
other causes than acid-production may interfere with the conversion of am-
monia into urea. What are these causes? Since, as we have seen,
the liver is the organ which most actively converts amino acids
into urea, it would be natural to expect that, when the functions of
this organ were interfered with, relatively more of the nitrogen excre-
tion would occur as ammonia and relatively less as urea. In order to
determine the exact significance of the liver as a urea-forming organ,
two types of investigation have been used; namely, (1) observation of
the changes produced in the ammonia-urea ratio in the urine by partial
or total removal of the liver; and (2) observation of the urea-forming
power of a liver perfused outside the body.

To remove the liver from the circulation the portal vein is brought
in apposition with the vena cava, the two are sewed together, and a
passage opened between them, after which the portal vein is ligated above
the anastomosis (forming the so-called Eck fistula). The. portal blood
then passes directly into the vena cava, and the liver is now supplied
only by the hepatic artery. The animals live for a considerable time
after the operation, and the urine frequently contains relatively less
urea and more ammonia than normal. The results are, however, not
nearly so striking as would be expected if the liver were the main seat
of urea formation. The experiments have nevertheless brought to light
a fact of considerable clinical interest — namely, although the animals
may thrive if kept on a diet not containing an excess of flesh, they im-
mediately begin to develop peculiar symptoms, not unlike those of ec-
lampsia or uremia, when they are fed with large amounts of flesh food.
Most of the symptoms can be referred to abnormal stimulation of the
central nervous system, and examination of the urine has shown a large
increase in the excretion of ammonia and a change from the normal
acid reaction to an alkaline one.

At one time it was assumed that the toxic symptoms were caused by
the presence in the blood of ammonium carbamate, since large quantities
of the calcium salt of this substance could be separated from the urine.
It is now known, however, that the ammonium carbamate is present only
because of the excess of ammonium carbonate, the two salts existing to-
gether in solution according to the laws of mass action. That the intox-
ication is not due to ammonium carbamate does not exclude the pos-
sibility that it may be due to ammonia itself, although it is more likely
that other nitrogenous metabolites, produced when excess of flesh food
is taken, are the responsible agents.

If the liver is entirely removed by ligating the hepatic arteries in an

652 METABOLISM

animal with an Eck fistula, a more pronounced decrease in urea and
increase in ammonia occur during the short period of time that the
animal survives the operation.

The results observed after the removal or diminution of liver function
fail to occur when other viscera are removed from the animal, which
would at least tend to indicate that the liver is very important in the
manufacture of urea out of ammonia. This does not, however, warrant
the conclusion that the liver is the only place in the animal body in which
such a process occurs.

In corroboration of these observations on mammals, it may be of in-
terest to note that when the liver is removed from birds, which is a com-
paratively simple operation on account of a natural anastomosis between
the portal and renal veins, there is a marked decrease in the excretion
of uric acid and a corresponding increase in the excretion of ammonia
during the twelve hours or so that the birds survive. In birds and
reptiles urea is excreted as uric acid, being produced by a synthetic
process in the liver (see page 677). The changes in this experiment are
of considerable magnitude; thus, before the operation the amount of
ammonia nitrogen relative to total nitrogen has been found to vary be-
tween 10 and 18 per cent; after the operation it may be increased to
between 45 and 60 per cent. The uric-acid nitrogen normally varies be-
tween 60 and 70 per cent of the total nitrogen ; after the operation it may
fall to between 3 and 6 per cent.

In animals with an Eck fistula and with the hepatic artery ligated,
an increase in the urea output occurs when amino acids are injected under
the skin. This result corroborates the conclusion that the liver can not
alone be responsible for the conversion of ammonia into urea.

(2) PERFUSION OF ORGANS. — This method consists in removing the or-
gan into a warm chamber or bath and perfusing it, through cannulac
inserted in its main artery and vein, with a solution of defibrinated blood
or of defibrinated blood mixed with saline solution. The perfusion
liquid is kept at body temperature and is saturated with oxygen. By
means of a pump it is made to circulate in a pulsatile flow, and the total
amount of urea or other metabolite in the circulating fluid is determined
before and after the fluid has been circulated several times through the
organ. When the liver is perfused, urea gradually accumulates in the
fluid, particularly after the addition of one of its known precursors —
for example, ammonium carbonate. When other organs or viscera are
perfused, no urea is formed. The evidence shows that the liver is an
important seat of urea formation, but not necessarily that other organs
are unable to form it in the intact animal, for there are many sources
of inaccuracy in perfusion experiments. Even though wre exercise the

THE METABOLISM OF PROTEIN 653

greatest care, we can not hope to maintain the organ in other than a
slowly dying condition. It is certainly far removed from the normal
state, as is revealed not only by histological examination, but by the fact
that edema almost invariably sets in and the blood vessels become ex-
tremely constricted, thus necessitating a gradual increase in the per-
fusion pressure as the perfusion goes on. Furthermore, the organ being
isolated from the nervous system, there can be no control of the rela-
tive blood supply of different parts. In the intact animal the circula-
tion is more or less distributed according to the particular needs of the
different viscera, and such conditions obviously can not be simulated in
a perfusion experiment. Another objection depends on the fact that
the well-being of the organs in the intact animal is largely dependent on '
hormones conveyed to them from other organs. Such hormones are
frequently quite labile in nature, and soon disappear from the perfusion
fluid.

Notwithstanding these objections, there can be no doubt that many
of the functions of an organ are retained much longer than they would
be if the organ were not perfused ; for example, the contractility of the
muscle or the power of forming urea in the liver. Perfusion experiments
are of value therefore when they yield positive results. Negative re-
sults may indicate either that the organ does not perform the particular
function that is being investigated or that it has lost this function as a
result of partial death. That a perfused muscle retains its power of
contraction does not necessarily indicate that it maintains all of its
metabolic functions; neither does the fact that the liver forms urea
prove that it is capable of performing its other functions. It is easy to
show that the liver dies piecemeal; some functions, such as glycogen-
formation, die early, while others, such as urea-formation, remain for a
long time intact. The use of perfusion experiments in the investigation
of problems of metabolism should always ~be very carefully controlled and
the results should never constitute the only evidence upon which impor-
tant conclusions are based.

(3) Before leaving this subject it may be well to point out that the
method which at first sight might appear to be the simplest for throwing
light on such problems as that under consideration — namely, the examina-
tion of the inflowing and outflowing blood of different parts or organs — is
not applicable in most cases. This is because of the extremely small
changes in concentration which may occur even although large amounts
of the particular substance in question are being absorbed or produced.
As we shall see later, this criticism is particularly applicable in the case
of sugar. Even during the injection of considerable quantities of sugar
into the portal vein, no difference in percentage can be demonstrated

654 METABOLISM

between the blood of the two sides of the liver, although we know that
sugar is being retained to form glycogen. For the same reasons, differ-
ences in the percentage amounts of amino acids or of urea are often dif-
ficult to demonstrate in the blood entering and leaving the liver even
when we know that large quantities of them are being added to or re-
moved from it.

Clinical. — Since the liver is an important seat of urea formation, the
question arises as to whether the relative percentage of urea and am-
monia in the urine will become altered by disease of the liver. Many
observations with this point in view have been undertaken, but it can
not be said that the results are very striking. In extreme destruction,
such as that produced by phosphorus poisoning, there may indeed be
a great increase in the relative amount of ammonia and a decrease in
that of urea. The same is true in acute yellow atrophy of the liver, in
which disease the nitrogen excreted as ammonia may amount to as much
as 70 per cent of that excreted as urea. In milder forms of liver dis-
turbance, however, such as cirrhosis, the figures are much less striking.
When an increased ammonia excretion is observed in such cases, we
must be cautious in drawing the conclusion that it is due primarily to
abolition of the hepatic function. It may just as well be caused by the
development of acids in the organism that require the ammonia for
their neutralization. It is significant, for example, that considerable
quantities of acids are produced in phosphorus poisoning.

Although the urea and ammonia excretions become altered by exten-
sive destruction of liver tissue, it is a remarkable fact that very little if
any change occurs in the amino nitrogen, either of the urine or of the
blood. In experimental necrosis of the liver caused by chloroform
or by phosphorus, it is only in the latest stages of the condition and
when it is of the very severest type that the amino acids have been
found to increase in the blood and urine. The conditions seem to be some-
what different in man, abnormally high amounts of amino nitrogen hav-
ing been observed in the blood in a considerable proportion of patients
with impaired liver function. In very severe cases of diabetes, for ex-
ample, figures that are distinctly higher than normal have been observed
(Van Slyke, etc.). In eclampsia the marked pathological changes in the
liver might be expected to be associated with an upset in the metabo-
lism of amino acids. Losee and Van Slyke35 have, however, recently
shown by the most accurate methods that neither in the blood nor in the
urine is any excess of amino acids to be found in this condition, although
in cases of pernicious vomiting of pregnancy, there was a relative in-
crease in the ammonia excretion. We have already seen that this

THE METABOLISM OF PROTEIN 655

increase did not bear any relationship to the acid-absorbing power of
the blood plasma (see page 650).

The importance of the kidneys in removing the urea from the Hood
is readily seen from the change in the percentage of urea in this fluid
after the partial or complete removal of the kidneys. Animals sur-
vive nephrectomy for about three days, and during this time urea rapidly
accumulates in the blood and begins to make its appearance in the
saliva and the intestinal secretions. In man also where the kidneys
are extensively diseased, a similar accumulation of urea occurs in the
blood, some of the excess being got rid of through the sweat and to a
certain extent through the intestine. The importance of encouraging
perspiration and a free movement of the bowels in cases of nephritis is
thus indicated. It must not be concluded that the accumulation of
urea in the organism is the direct cause of the symptoms. Urea itself
is comparatively inert, and it is generally believed that other metabolic
products with which the urea runs parallel in amount are the toxic
agents. Hewlett has found, however, that very large injections of urea
cause certain symptoms.34

CHAPTER LXXII
THE METABOLISM OF PROTEIN (Cont'd)

CREATINE AND CREATININE

Creatine and creatinine are very largely products of endogenous metab-
olism; they are mainly derived from chemical processes occurring in
the tissues although some of the creatine and creatinine present in the
food may appear as creatine in the urine.

Essential Chemical Facts

Before we proceed to discuss the metabolism of these important substances, it will
be necessary to refer briefly to some points in their chemistry. The simpler of the
two bodies is creatine, which is methyl-guanidine-acetic acid ; creatinine is its anhydrid,
being formed from creatine by the removal of a molecule of water, so that the NH,
groups become joined together in the same way as they do in the formation of pep-
tides from amino acids (page 636). The relationships are illustrated in the following
formulas :

CH, - N - CH - CO

(methyl) " , ,

CH-N

/ \

/ CH2COOH NH = C

NH = C - H..O = \

\ (acetic acid) - \

\ \

(guanidine) NH2 NH

(creatine) (creatinine)

It should be noted that guanidine is closely related to urea, O=C(NHa)2, and that
when creatinine is formed from creatine a ring formation occurs, giving what may be
regarded as an imidazole derivative (see page 639). Creatine is also related to one
of the important diamino acids, arginine, since both contain guanidine radicles, NH—
C(NH2),, and to histidine and the purines (see page 669), both of which contain the
imidazole ring. The close relationship which creatine bears to urea is illustrated by
the fact that urea is formed when creatine is subjected to the action of boiling barium
hydrate. When it is oxidized by means of potassium permanganate, urea is also

formed, the remainder of the molecule, more or less intact, being split off as methyl-
"[STTT r\TT

amino-acetic acid (CH < U3), also known as sarcosine.

The conversion of creatine to creatinine goes on slowly in aqueous solutions, but is
much accelerated by heating with acid. Heated in an autoclave at a temperature of
117° C. for thirty minutes, with half normal hydrochloric acid, the creatine goes over
almost quantitatively into creatinine. It will be noted that the creatinine ring is
partly oxidized. This renders it unstable, so that creatinine in the presence of alkalies

656

THE METABOLISM OF PftOTElN 657

has the power of reducing metallic oxides. Like glucose it can reduce alkaline solu-
tions of copper, silver and mercuric salts; it also reduces picric acid in weakly alkaline
solution to picramic acid, which, being red, furnishes us with a solution the strength
of which can be estimated colorimetrically.

Quantitative Estimation. — Although the presence of creatinine in the urine has been
known for many years, there being from 1 to 2 grams of it in the twenty-four-hour
urine, little progress was made in the study of its metabolism because of the absence
of a reliable method for its estimation. The elaboration by Folin of a colorimetrie
quantitative method for creatinine, depending on the reduction of picric acid, has
furnished the starting point for the modern work which has been done. To estimate
the creatine by this method, it is usual to proceed as follows: The creatinine content
is first of all determined, another portion of urine being then heated with acid in the
autoclave until all of its creatine has been converted into creatinine. A second de-
termination of creatinine is then made, and the difference between the two is calculated
as creatine.

It should be pointed out that, since the creatine is estimated by an indirect method,
there are considerable chances for inaccuracy. Indeed, it has been shown that errors
may have been incurred in some of the recent work on account of the fact that when
acetoacetic is present in the urine it prevents the creatinine from developing its
full reducing power on picric acid in the cold, so that when subsequently the urine is
heated with acid for the purpose of converting the creatine into creatinine, the
destruction of acetoacetic acid allows the reducing power of the creatinine to develop
to full intensity. It is obvious that this would make it appear as if creatine had been
converted into creatinine. It is particularly in the urine of diabetic patients, in which
aeetoacetic acid is present that mistakes are likely to be made.

Metabolism

When we come to consider the metabolism of creatine and creatinine,
we find that there are remarkably few facts definitely known concerning
it. The average amount excreted daily, expressed as the number of milli-
grams of creatinine in twenty-four hours per kilogram body weight,
is known as the creatinine coefficient (Shaffer).36 For a lean person this
is about 25 mg. ; for a corpulent person, about 20 mg., the difference in-
dicating that muscle mass, and not body weight, is the important factor
determining the coefficient. Further evidence that this relationship ex-
ists is furnished by the fact that in the muscular atrophies creatine ex-
cretion is distinctly below normal. It must be the mass of the muscles
rather than their activities that is the determining factor, for the creatine
excretion does not become increased by muscular exercise.

Influence of Food, Age, and Sex. — Although creatine and creatinine are
endogenous metabolites, it must be remembered that, under ordinary
dietetic conditions, a part of each is derived from these substances pres-
ent in the food. It is important therefore to consider the conditions
under which the creatine and creatinine in the food appear in the urine.
Regarding creatinine, it is pretty well established that practically all
that is taken with the food reappears as creatinine in the -urine. Shaffer

658 METABOLISM

has, for example, succeeded in recovering 76 per cent of ingested creat-
inine in the urine excreted during twenty-one hours following the in-
gestion of 0.7 gin. creatinine.

The conditions for the excretion of creatine are more complex. It is
present in the urine of children in considerable amount, but in that of
adults, only as traces. In the first years of life the creatine in boys'
urine may amount to one-half of the total creatine and creatinine, but
it becomes gradually less and practically disappears at about seven
years of age. Girls, on the other hand, continue to excrete creatine until
about puberty, after which, although ordinarily absent, it reappears in
the urine at each monthly sexual cycle, and is present during pregnancy
and for some days after delivery. Feeding creatine to children causes
it to appear in the urine, accompanied usually by a slight increase in
the creatinine. The same results can be observed in women during the
monthly periods, when as much as 0.1 gm. may be present, and during
pregnancy. Creatine is also present in the urine of most if not all of
the other mammalia. Some of these facts are shown in the following
table:

AGE

CREATININE-N

CREATINE-N EXCRETED
IN 24-HR. URINE

f 2

0.025

0.023

3

0.057

0.022

Boys

5

8

0.112
0.163

0.025
0.0

11

0.157

0.0

15

0.378

0.0

5

0.069

0.005

6

0.032

0.003

Girls]

7

0.157

0.066

10

0.147

0.020

12

0.201

0.011

(From Mathews.)

When creatine is given to an animal that has been kept in a starved
condition, most of it seems to disappear. It can not be recovered in the
urine either as creatine or as any other nitrogenous metabolite. It seems
to functionate more as a food than as a useless substance. The possi-
bility that some of it can be destroyed by the intestinal bacteria being
admitted, there is nevertheless some justification for the view that the
creatine finds a useful function in the anabolic process of the muscles.

Influence of Complete and Partial Starvation. — Although, as we have
seen, the creatinine excretion remains constant when the amount of pro-
tein in the diet is greatly reduced, yet it does not remain constant during
complete fasting or when carbohydrates are entirely withheld from the
diet. In fasting it has been found that creatine appears in place of the
creatinine which has disappeared, so that if both creatine and creatinine

THE METABOLISM OF PROTEIN 659

are determined, very little if any diminution will be found to have oc-
curred. Fasting, therefore, causes the creatine and creatinine metabol-
ism of the adult to become like that of the juvenile metabolism. As
pointed out by Mathews, it would be interesting in the light of this ob-
servation to see whether other substances, passed in the urine of young
animals but absent in that of the adult, would reappear in the urine when
the animals were made to fast.

A similar replacement of some of the creatinine by creatine appears
when carbohydrate is entirely withheld from the diet, or in diabetic
animals, either in the disease diabetes mellitus in man or in the experi-
mental condition induced in animals by giving phlorhizin. Unfortu-
nately, in a considerable part of the work that has been done on this
phase of the subject a method of estimation was employed which did not
take sufficiently into account the influence of acetoacetic acid on the
creatine estimation; but even after allowing for this possible source of
error, there can be no doubt that creatine appears in the urine when-
carbohydrates are improperly metabolized. If carbohydrates are given
to a starving animal, for example, the creatine is replaced in its urine by
creatinine, although this will not occur when either protein or fat is fed.
The general conclusion which may be drawn from these observations is
that carbohydrates in some way are required for the proper conversion
of creatine into creatinine in the animal body (Cathcart)37.

Origin of Creatine and Creatinine

Notwithstanding the large amount of excellent work that has recently
been done on the metabolism of creatine and creatinine, we know very little
indeed regarding the origin of these bodies in the animal organism. It
would be profitless to discuss this problem to any great extent, but a
few of the most important facts so far established may be of interest and
of value. The first step in attacking such a problem is to compare the
amounts present in the various organs and tissues, in the blood, and in
the excreta. Of the approximately 120 grams of creatine and creatinine
in the body of an average adult, a very large proportion is in the muscles,
the voluntary muscles containing the largest percentage, the heart con-
taining a medium percentage, and the involuntary (intestinal) muscles
containing relatively a small amount (Myers and Fine)38. Next to the
skeletal muscles, but containing more than the involuntary muscles,
come the testes and brain. The liver, pancreas, thyroid, kidneys, spleen,
etc., contain traces. The blood (human) contains about 1 mg. creatinine
per 100 c.c. and about 3 mg. creatine, the former being equally distrib-
uted between plasma and corpuscles, whereas the latter is contained
mainly in the corpuscles. (Hunter and Campbell.58)

660 METABOLISM

In all these places by far the greatest proportion of the total creatine-
creatinine exists as creatine, which is exactly the reverse of the condi-
tion obtaining in the urine of adults, where practically all is excreted as
creatinine. The close chemical relationship between creatine and creat-
inine, considered along with the above facts regarding their quantitative
distribution in the body, indicates that the creatinine of the urine is de-
rived from the creatine of the tissues. The question is, How does the
creatine come to be converted into creatinine f Such a transformation is
probably effected by many of the tissues of the body and certainly by
the blood, the active agency in all cases being no doubt an enzyme. That
the blood contains such an enzyme is indicated by the fact that creatine
is transformed to creatinine by blood serum more quickly than it is
when merely dissolved in water. Even heated blood serum possesses
some of this power. The liver also probably brings about the transfor-
mation, as has been shown by perfusion experiments, and by the fact
that in cases of phosphorus or hydrazine poisoning creatine displaces
creatinine in the urine.

The problem therefore narrows itself down to the question of the
origin of creatine. In the light of chemical knowledge there are several
precursors from which creatine might be formed. One, for example, is
arginine, which it will be remembered is guanidine-amino-valerianic acid
(see page 640). By oxidation this might become changed into guani-
dine-amino-acetic acid, which by methylation would then be changed into
creatine. That such a process of methylation may actually occur in the
animal body is definitely known, for it happens when such substances as
pyridine or naphthalene are given with the food. They appear in the
urine as methyl derivatives. The possibility of the derivation of creatine
by methylation of arginine is suggested by the result of the injection
into ducks of arginine, combined with such substances as paraformalde-
hyde (Thompson59). Even in this case however the results are not very
convincing. The closely related substance, guanidine-acetic acid, when
fed to animals (rabbits) also causes a slight increase in the excretion of
creatine (Jaffe), and, it is said, an increase in the creatine content of the
muscle. Even in this case, however, by far the largest proportion of the
administered guanidine-acetic acid is excreted in the urine unchanged.

The large percentage of creatine in muscle tissue leads one to expect
that some relationship must exist between muscular metabolism and the
amount of ereatine present either as such in the muscles or as creatinine
in the urine. Regarding the latter point it is definitely established that
muscular exercise leads to no increase in the creatinine excretion, al-
though it is said that such an increase occurs following a state of tonic
muscular contraction. In the light of the fact already stated that there

THE METABOLISM OF PROTEIN 661

is creatine in other organs than the muscles, it seems probable that the
substance has really little to do with muscular contraction as such, but
rather is concerned in some way in the formative metabolism of the cell,
with its general growth or maintenance. Indeed, it is a question whether
creatine is an actual constituent of the living tissue. It may rather, as
has been suggested by Folin, be a postmortem product, represented dur-
ing life by creatinine.

Creatine appears in the urine in phosphorus poisoning, in carcinoma of
the liver and during postpartum involution of the uterus. It is not de-
rived from the disappearing uterine muscle, however, for creatinuria also
occurs after cesarean section with removal of the uterus. Creatine
elimination is not an index of cellular destruction. Muscular fatigue also
leaves the creatine content of muscle unchanged. In late stages of
nephritis, creatinine accumulates in the blood and serves as an index of
the gravity of the condition (page 683).

CHAPTER LXXIII
THE METABOLISM OF PROTEIN (Cont'd)

UNDETERMINED NITROGEN AND DETOXICATION
COMPOUNDS

In the present chapter we shall refer briefly to the groups of urinary
substances styled undetermined nitrogenous compounds and to the com-
pounds that are excreted in the urine as the result of the combination in
the body of certain toxic bodies with chemical substances that render
them harmless (detoxication compounds).

Undetermined Nitrogen

Included under undetermined nitrogen are amino acids, peptides and
basic substances. The amount of amino acids and peptides in normal
urine is very small but may become considerable in -disease, especially
of the liver, when leucine and tyrosine may appear. The presence of
traces of amino acid and peptone in normal urine is to be expected,
for although the actual concentration of amino acids in the blood is
never very great, a certain leakage of ?mino acids must occur into the
urine.

The peptide is sometimes known as oxyproteic acid. It becomes dis-
tinctly increased in phosphorus poisoning and in such conditions as are
accompanied by excessive protein metabolism. The basic constituents
include such substances as trimethylamine, ethylamine, putrescine and
cadaverine (page 536), and there are probably many more of a similar
nature. Many of these substances are similar to the so-called ptomaines
found in meat, etc., and they have been called the ptomaines of urine,
from which they can be isolated by rendering the urine alkaline and
shaking out with ether. It is probably to the presence of these sub-
stances that urine mainly owes its toxic action.

The Detoxication Compounds

Certain nocuous substances are produced in the intestine during the
digestive process (see page 535), and others may result from the meta-
bolic processes in the tissues. To guard against the harmful action of
these substances on the organism, they become detoxicated in various

662

THE METABOLISM OF PROTEIN 663

ways, mainly by forming inert compounds with, other substances, par-
ticularly with glycocoll, sulphuric acid or glycuronic acid. The com-
pound thus formed is then excreted in the urine.

Hippuric Acid. — Glycocoll is used mainly to detoxicate the benzoic
acid which results from the oxidation of the aromatic substances pres-
ent in large quantities in vegetable food and fruit (particularly in cran-
berries). Some benzoic acid may also be produced by the breakdown
of the aromatic group of the protein molecule; phenylalanine, for ex-
ample, gives rise to benzoic acid by bacterial decomposition. The com-
pound formed is hippuric acid, this name indicating that it is present in
large quantities in the urine of the horse, as it is also in the urine of
all herbivorous animals.

Hippuric acid is benzoyl-glycine (C6H5.CO.NH.CHaCOOH), and it
can readily be produced in the laboratory by bringing together benzoyl
chloride with glycocoll, thus:

C6H5.CO :C1 + HJ HN.CH2COOH = C6H5CO.NH.CH2COOH

(benzoyl chloride") (glycocoll) (hippuric acid)

Under ordinary dietetic conditions only a trace of hippuric acid is
present in the urine of man, but much larger quantities, 2 grams a day
for example, may appear when the diet contains a large proportion of
fruit or vegetables. It is not known to undergo any characteristic varia-
tions in disease. The benzoic acid which is contained in certain canned
foods as preservative also combines in the body with glycocoll, so that
any toxic effect which it might produce is practically negligible. There
is certainly no very evident reason why canned foods containing benzoic
acid should be tabooed, for in so far as the benzoic acid is concerned, they
can be no more toxic than a diet composed largely of vegetables and
fruit.

This detoxication of benzoic acid requires the presence in the organ-
ism of a constant supply of glycocoll, which, it will be recalled,
is the lowest in the series of amino acids, being aminoacetic acid
(CH2NH2COOH). It is present in greatest amount in the protein of the
connective tissues. It is said, however, that not more than from 2 to
3.5 per cent of glycocoll is available in the proteins of the body. Al-
though this amount of glycocoll would amply suffice to detoxicate the
benzoic acid produced by the metabolism of the food in carnivora, it
is quite inadequate for this purpose in the case of herbivora, and the
question naturally presents itself as to where the glycocoll in these
animals comes from. It is said, for example, that of the total nitrogen
excretion in herbivora 50 per cent may appear as glycocoll under cer-
tain conditions. These facts along with those gained by observations on

664 METABOLISM

the growth curves (see page 610) indicate that the organism is capable of
producing new glycocoll for itself, and it is interesting to consider how
this glycocoll may be derived. A very probable source is by synthesis
between ammonia and glyoxylic acid (CHO. COOH). That glyoxylic acid
or its aldehyde, glyoxal, is readily produced during metabolism from car-
bohydrates and that ammonia is always available would seem to lend
some support to this view (see page 698). The synthesis of glycocoll
from glyoxal and ammonia occurs thus:

H.COCHO + NH3 = CHaNH2COOH.
(glyoxal) (glycocoll)

The linking up of glycocoll with benzoic acid occurs in various organs,
particularly the kidneys and the liver. An isolated perfused preparation
of the kidney produces hippuric acid provided benzoic acid is added to
the perfusion fluid, and the latter also contains an abundance of oxy-
gen, which is best secured by using defibrinated arterialized blood in-
stead of artificial serum (Locke's solution). The necessity of a plentiful
supply of oxygen is further shown by the fact that, if the hemoglobin of
the blood is rendered incapable of carrying 02 by bubbling carbon mon-
oxide gas through it, no synthesis of hippuric acid will result from per-
fusing the blood through the kidney. The kidneys are not the only site
of this synthesis, since hippuric acid is still formed after nephrectomy,
in both carnivorous and herbivorous animals. It has been isolated from
the liver of nephrectomised dogs after injection of glycocoll and benzoic
acid (Kingsbury and Bell60) ; and after damaging the liver cells by poi-
soning with hydrazin, in dogs, it has been found that the excretion of
hippuric acid falls decidedly. Hydrazin does not act on the kidney
cells.61

The actual chemical process by which the synthesis occurs (de-
hydration) is similar to that by which polypeptides are formed by the
union of amino acids, or creatinine from creatine.

(C6H5CO JOH + HJ HNCH2COOH).

Glycocoll may be used for detoxicating other substances than benzoic
acid, particularly cholic acid, forming the glycocholic acid of the bile
(see page 528) and phenylacetic acid. In birds the benzoic acid be-
comes combined with diamino-valerianic acid or ornithine (NH2-CH2-
CH2 - CH2 - CH - NH2 - COOH) in place of glycocoll, so that in the urine
of these animals in place of hippuric acid a compound called ornithuric
acid occurs.

It is of importance to point out here that this pairing of aromatic toxic
substances with certain of the metabolic products of the organism has

THE METABOLISM OF PROTEIN 665

frequently been found an excellent experimental method for demon-
strating the presence of intermediary metabolic substances that other-
wise would not have appeared in the excreta. These substances are
thus diverted from their normal course in metabolism so as to form
neutralization or detoxication compounds. Glycuronic acid is an example.

Ethereal Sulphates and Glycuronates. — The other substances used for
detoxication purposes are sulphuric and glycuronic acids. Phenol, and
its derivative cresol, after being absorbed from the intestine, in the
contents of which they are produced by the bacterial decomposition of
protein (see page 535) become combined in the body, probably in the
liver, with sulphuric acid or with glycuronic acid to form the sulphate
or glycuronate. The aromatic sulphate further combines with potassium
to form the so-called ethereal sulphates, as which the substance is excreted
in the urine. A small amount of phenol may however appear in the
urine unchanged. As we have already seen, the sources of the phenol
in the intestine are tyrosine and phenylalanine (see page 564), and
since these amino acids are also present in the tissues, it might be sup-
posed that some of the phenol sulphate of potassium present in the
urine could come from the tissues. It is usually assumed, however, that
derivation from the tissues does not occur.

Another ethereal sulphate is indoxyl sulphate of potassium, which re-
sults from the absorption into the blood of the indole and skatole pro-
duced by intestinal putrefaction from tryptophane (see page 536).
Immediately after absorption indole is oxidized to indoxyl, which then
combines with sulphuric acid and with potassium to form indoxyl sul-
phate of potassium, which is the well-known indican of the urine. As
in the case of phenol sulphate of potassium, none of the urinary indican
seems to come from the normal metabolism (of the tryptophane) of the
tissue proteins. It is a much more reliable indicator of the extent of intes-
tinal putrefaction than is phenol sulphate of potassium, but it also becomes
increased in amount during putrefaction in the body itself, as for example
in abscess formation.

The amount of indican in the urine may be roughly gauged by oxi-
dizing the urine by means of hypochlorite and then shaking out with
chloroform. If the resulting extract is more than light blue in color,
it indicates excessive putrefaction. A negative test does not neces-
sarily mean that intestinal putrefaction is absent, but a markedly positive
test always indicates that it is occurring. Skatole, the methyl deriva-
tive of indole, may undergo similar processes and appear in the urine
during excessive intestinal putrefaction. Its presence in the blood some-
times confers on the breath a distinctly fecal odor, for this body, as its
name indicates, is that to which the odor of the feces is due.

666 METABOLISM

Glycuronic acid, the other substance used for detoxication processes,
is of the nature of a dextrose molecule with the one end-group oxidized
to carboxj^l (CHO - (CHOH)4- COOH). It is probably produced under
normal processes of metabolism in the animal body, but is destroyed
except when such poisonous substances as camphor, chloral hydrate or
certain aromatic alcohols are given, when it is used for the purpose of
detoxicating them. The resulting glycuronates have reducing powers
and may be confused with glucose when present in large amount. Gly-
curonates may be distinguished from glucose in the urine (1) because
they are levorotatory, and (2) because they do not ferment. The free
acid itself, however, is dextrorotatory.

CHAPTER LXXIV

URIC ACID AND THE PURINE BODIES

Introductory. — The participation by highly trained organic chemists
in the investigation of biochemical problems has brought our knowledge
of the history of the purine substances in the animal body from a state
of chaos and guesswork to one of system and scientific accuracy. The
peculiar solubility reactions of uric acid and its salts and the discovery
of urates in gouty deposits served to make uric acid metabolism one of
the earliest research problems in both the medical clinic and the bio-
chemical laboratory, but the earlier results were practically valueless,
partly because they were inaccurate and partly because their interpretation
was impossible in the absence of even the most elementary facts concerning
the chemistry of uric iacid.

Before any real progress was possible, a clean sweep had to be made
of all the old speculations and hypotheses, such as that dignified by the
high-sounding name of "uric-acid diathesis," and a foundation of ac-
curate chemical knowledge established. This foundation is now wonder-
fully complete, and a superstructure of biochemical fact is already
beginning to grow upon it. In the present chapter we shall examine
some of the most important contributions that have made this progress
possible,

As in the study of any other problem of metabolism, we must, however,
make ourselves familiar with the main facts concerning the chemistry
of the purine bodies and of the tissue constituents into the composition
of which they enter, before proceeding to the more strictly biological
aspect of the subject.

The Chemical Nature of the Purines

By an examination of the empirical formulas of the purines of biochemical interest,
it will be observed that they are all derivatives of a substance purine, which although
in itself of no importance is interesting, since it serves as the basic substance from
which the others are derived. The list is as follows:

Purine . C5H4N4

Hypoxanthine C5H4N4O Monoxypurine c

Adenine . C5H3N4.NH, Ammo-purine I Purine

Xanthine . C5H4N4O2 Dioxypurine j bases.

Guanine . C5H3lSr4O"NH0 Amino-oxypurine [

Uric acid . C5H4N4O3 Trioxypurine

The first oxidation product of purine is hypoxanthine, which has long been known
as a constituent of meat extract. Adenine, the amino derivative of hypoxanthine,

667

668 METABOLISM

occurs in combination with other substances in the nuclear material. The second oxi-
dation product is xantliine and its amino derivative, guanine. They occur in the same
places as hypoxanthine and adenine. The highest oxidation product of all is the well-
known urinary constituent, uric acid, which may therefore be chemically designated as
trioxypurine. In addition to the purines of animal origin, there are also certain ones of
vegetable origin — the methyl purines, which exist as the alkaloids of tea and coffee —
namely, caffeine, theobromine, and theine.

To understand the chemical structure of this group of substances, it is perhaps
simplest to start with that of uric acid. This consists essentially of two urea molecules
linked together by a central chain of three carbon atoms, as will be evident from the
accompanying structural formula:

HN-CO
OC C - NH

CO

I II /

HN - C - NH

(urea) (urea)
(central chain)

This structure can be shown by methods both of decomposition and of synthesis.
When uric acid is decomposed by oxidizing it with nitric acid, it yields urea and a
residue called alloxan; or it can be synthetized from urea and trichlorlactamide, a
derivative of lactic acid, which it will be remembered contains three carbon atoms.
The changes involved in this synthesis will be made clear by examination of the ac-
companying structural formula, in which the manner of production of the by-products
of the reaction (NH , H^O and HC1) are shown by dotted lines:

\ — \ /

\ C- ! Cl H NH (urea)

\ / '-

(urea) NH. ! H Cl !

(trichlorlactamide)

By milder oxidation by means of potassium permanganate in the cold, uric acid be-
comes quantitatively converted to allantoine:

C.H4N4O3 f H2O + O — C4H6N4O3 + CO2
(uric acid) (allantoine)

The importance of this transformation lies in the fact that in most animals, man and
the higher apes being exceptions, uric acid is thus decomposed in the animal body.
The structural formulas for the other purine bodies in relationship with those of
purine and uric acid are given below.

URIC ACID AND THE PURINE BODIES

669

Purinc itself has the following structural formula :

IN CG H

H2-C

C5 -

NH7

C8-H

-C4-N9

(For convenience of description the atoms in purine are numbered as shown.)

HN-C=O

H- C

I

C-

NH

I.

\

HN - C = O
O = C C-NH

C-H

-C-

(hypoxanthine)

II.

\

C-H

N--C- N

(6-oxypurine)
= C-NH2

(xan thine) (2-6-oxypurine)

H- C C-NH

HN-C=0

I I
H2N = C C-NH

•-C- N

/

C-H

\

C-H

N-C- N

(adenine) (6-amino-purine) (guanine) (2-amino-6-oxypurine)
HN-CO
OC C-NH

\

CO

[N- C -NH

Uric acid (2-6-8-trioxypurine)

The substances with which the purine bases are most closely related are the pyri-
midine bases. Three of these are known:

thymine (NH-CO

I !

CO C.CH3

cytosine ( N = C-NH2

I
CO CH

NH-CH) ;

and uracil (NH-CO

I !
CO CH

NH-CH).

From an examination of the structural formulas, it will be seen that they are more
or less related to purine (having one of the urea radicles omitted), although it can
scarcely be doubted that they exist as separate constituents of the nucleic acid group
in the animal body, and are not derived from purine. They are primary products.

The Chemical Nature of the Substances in Which Purine and
Pyrimidine Bases Exist in the Animal Body. — In general it may be said
that the amino purines — adenine and guanine — together with the
pyrimldine bases — thymine and cytosine — occur combined with phos-
phoric acid and a carbohydrate in the various nucleic acids, each of which

670 METABOLISM

is again combined with some simple protein to form miclein, the essen-
tial constituent of the chromatin of the nucleus. One of the oxypurines,
hypoxanthine, may also exist combined with phosphoric acid and carbo-
hydrate to form a substance present in muscle and known as inosinic
acid.

The simplest form of nucleic acid is that known as guanylic, which is
found in certain organs (liver, pancreas, etc.) side by side with the more
complex variety. It consists of phosphoric acid, a pentose (5 C- atom
sugar) and the amino purine, guanine. The pentose which can be
detected in these organs is apparently derived solely from guanylic
acid. The more complex form of nucleic acid, and probably that present
in all nuclei, is composed of phosphoric acid, a hexose (in animal cells)
or a pentose (in vegetable cells), the two amino purines, adenine and
guanine, and the two pyrimidine bases, cytosine and thymine.

Nucleic acid may therefore ~be considered as a compound of polyphos-
phoric acid, containing carbohydrate groups, which serve to link the phos-
phoric acid molecules to those of purine and pyrimidine.

It has been found necessary to introduce certain terms to designate
the different parts of the nucleic acid molecule ; thus, the whole molecule
is called a tetranucleotide, composed of four mononucleotide molecules,
each of which consists of a phosphoric acid molecule plus a nucleoside,
which again is composed of a purine or pyrimidine nucleus attached to
pentose or hexose. The nucleoside is so named because it is similar in
structure to a glucoside.

Apart from differences in the carbohydrate group, it appears that
there is a close similarity in the structures of nucleic acids from dif-
ferent cells. This would indicate a common function for them all, which
may be either of a structural or of a physiological nature ; that is, nucleic
acid may have to do with the sustentacular material that builds the
nucleus, or it may have to do with some physiological function common
to all cells, such as irritability, or growth, or respiration. If nucleic
acid is merely a sustentacular material, then the study of the behavior
of chromosomes and chromatine in cells can not have the significance
that it would have were nucleic acid concerned in the more vital activ-
ities of the nucleus. All the so-called nuclear stains owe their specific
staining properties to the fact that they are of a basic nature and com-
bine with nucleic acid. Until we know more definitely what the exact
function of nucleic acid may be, it is unwise to place too much weight
on the behavior of the chromosomes in cytologic researches.

By studying the behavior of cells (ameba) from which the nucleus
was removed, it has been found that the process of reproduction and
growth alone are affected. The other functions proceed normally. In

URIC ACID AND THE PURINE BODIES 671

this connection it is interesting to note that much evidence is accumulat-
ing to show that the respiratory functions of cells are linked up with
the presence in the cytoplasm of bodies called mitochondria composed of
phospholipin and protein. (Lynch.61)

The History of Nucleic Acid in the Animal Body.— We shall first
of all study the manner in which nucleic acid may be broken down. As
is to be expected from its complex structure, various types of enzymes
are concerned in this process. The first to act are known as the nucle-
ases. They split the tetranucleotide molecule into two dinucleotides,
which immediately afterward split further into mononucleotides. Four
nucleotides, two of purine and two of pyrimidine, are thus formed from
each molecule of nucleic acid. Each nucleotide molecule may now un-
dergo decomposition in one of two ways: (1) either by the splitting off
of phosphoric acid, leaving a nucleoside (guanosine or adenosine), or
(2) by the splitting off of both phosphoric acid and carbohydrate, leaving
free purine bases. Nucleases have been found which specifically effect
either of these decompositions, and they have been called phospho-
nucleases* (1), and purine-nucleases (2), respectively. In the decompo-
sition of nucleic acid all of the four purine compounds — guanine, guano-
sine, adenosine and adenine — may be formed. This is illustrated in the
accompanying schema, in which the nucleic acid is represented as a
purine nucleotide:

Nucleic^Acid (without the pyrimidine group)
"""V

- -• V / \~x v — /

/ (Action of nucleates) \

Guanine f-(7) Guanosine Adenosine (8)-» Adenine

<*) (5) (6)

(Actioni of deaminizing enzymes)

v v

Xanthosiije Inosine

(9) (Action of hydrolyzing enzymes) (10)

UrfcAcidf-(ll) Xanthine < (11)- >Hypwanthine

(Action of xanthine oxidase)

(Jones.)

The next step in the disintegration process is that the amino group
is removed and the corresponding oxypurine is produced. To bring this
about, there exists a specific deaminizing enzyme for each of the above
amino compounds, and each enzyme is named according to the exact
amino purine upon which it acts; thus, guanase (3), guanosine-deaminase
(4), adenosine-deaminase (5), and adenase (6) have all been identified.

.

"The numbers refer to the enzymes indicated in the schema.

672 METABOLISM

The free base may then be split off from the nucleosides by specific
hydrolyzing enzymes (7) (8) (91) (10).

The joint action of these enzymes leads to the formation of oxypurines,
xanthine and hypoxanthine, which are oxidized to uric acid by xanthine-
oxidase (11).

In man and the anthropoid apes uric acid is the end product of the
above changes, but in other mammals most of the uric acid is further
oxidized into allantoine. It has also been found, except in man and the
chimpanzee, that extracts of organs such as the liver, are capable of
decomposing uric acid into allantoine. The identification of these specific
enzymes is sought by a determination of the free amino-purine bases
and the phosphoric acid produced by allowing an aqueous extract of
the tissue in question to act on nucleic acid (of yeast)* at body tempera-
ture. Another portion of the digested mixture is then hydrolyzed by
means of boiling sulphuric acid and the constituents again determined.
From the results it is often possible to draw conclusions as to the exact
nature of the enzymes present.

The most remarkable outcome of this work has been to show that
the distribution of the enzymes is not the same in the tissues and organs
of different animals. Very briefly, some of the most important results
that have so far been obtained are as follows: Gastric and pancreatic
juices do not contain a trace of any of the enzymes. Intestinal juice,
on the other hand, contains a nuclease capable of splitting the poly-
nucleotides into mononucleotides. The two pyrimidine nucleotides split
off do not undergo further change, but the purine nucleotides are con-
verted into nucleosides (the enzyme being designated "nucleotidase")-
Extract of the intestinal mucosa, besides having the same action as the
intestinal juice, can also decompose the purine, but not the pyrimidine
nucleosides, into carbohydrate and purine groups (specific action of
"nucleosidase"). A similar action is produced by extracts of kidney,
heart muscle, and liver. Blood serum, hemolyzed blood, and extract of
pancreas, on the other hand, are capable of carrying the decomposition
only as far as the mononucleotides.

Eegarding the other enzymes mentioned in the above list, it is im-
portant to note that they appear at different stages in embryonic develop-
ment, and that their distribution varies considerably in different species
of adult animal, the spleen, liver, thymus, and pancreas containing them
most abundantly. The distribution of enzymes in the organs of the
monkey resembles that in the lower animals considerably more than it
does that in man. Some remarkable facts have come to light regarding
guanase and adenase, particularly that guanase is deficient in the organs

*Yeast nucleic acid is used because it is less resistant to disintegration than thymic nucleic acid.

URIC ACID AND THE PURINE BODIES 673

of the pig, in the urine of which animal it has also been found that the
purine bases are in excess of the uric acid. This absence of guanase
no doubt accounts for the fact that deposits of guanine may occur in the
muscles, and that these may be so large as to constitute the condition
known as guanine gout found in this animal. Adenase, on the other
hand, is absent from the organs of the rat, which again corresponds with
the fact that, when adenine is injected subcutaneously into these ani-
mals, it undergoes oxidation without the removal of its amino group.
In the human organism, adenase appears to be absent from all of the
organs, whereas guanase is present in the kidney, lung and liver, but
not in the pancreas or spleen. Xanthine-oxidase exists only iri the liver.

The distribution of uricase is perhaps the most interesting. It is pres-
ent in most of the lower animals. On account of its presence extracts
of the liver, spleen, etc., in all breeds of dogs, with the exception of
Dalmatians, rapidly destroy uric acid; and practically no uric acid
when injected subcutaneously can be recovered unchanged in the urine,
but appears as allantoine. Uricase, however, is absent in man. This has
been demonstrated by finding (1) that when uric acid is injected sub-
cutaneously, nearly all of it reappears in the urine, and (2) that uric acid
is not destroyed when extracts of the organs are incubated with uric
acid or its precursors at body temperature. It must of course be kept
in mind that, although the uric acid is thus shown not to be destroyed
in vitro, it may nevertheless be destroyed in the living animal.

The importance of the above described results rests in the fact that
from them we may hope to be able, ultimately, to state exactly in what
organs and tissues the intermediary metabolic processes concerned in
nucleic acid metabolism occur. The work at the present time is of spe-
cial significance, since it represents one type of evidence which we must
have before we can trace exactly every step in the metabolism of any
other biochemical substance.

The absence of uricase from the tissues of man places him in a unique
position with regard to the metabolism of nucleic acid, and renders the
investigation of the problem particularly difficult, since investigations
on the usual laboratory animals are useless. Recently, however, S. R.
Benedict has, discovered that the Dalmatian breed of dog — also known
as the carriage dog, and having a spotted or mottled skin — has a purine
metabolism like that of man.4 When fed on food containing no purine
substances, a dog of this breed excretes large quantities of uric acid, and
when the latter substance is injected subcutaneously, it is eliminated
quantitatively as such in the urine. We shall see later how experiments
on this animal have been made use of in the investigations of problems
of purine metabolism as applied to man. In all other animals most of the

674 METABOLISM

uric acid is oxidized to allantoine before being excreted. The degree to
which this occurs varies between 79 and 98 per cent of the uric acid in
different species. This has been called the uricolytic index (Hunter and
Givens42).

The Balance between Intake and Output of Purine Substances under
Various Physiological and Pathological Conditions. — The main purine ex-
cretory product in man is uric acid, but there is also a certain amount
of purine bases. The presence of uric acid in urine has attracted at-
tention for decades in medical investigation, because of the relative
ease with which it can approximately be determined quantitatively, and
because of the well-known fact that it may be responsible for certain
diseases, such as gout, when it accumulates in the tissues in an insoluble
form. On a diet containing meat, or more particularly on one con-
taining glandular substances, the total daily excretion of uric acid is
very considerably greater than when the diet contains no such food
stuffs. The conclusion which Burian and Schur43 drew from this ob-
servation is that purine must be partly of exogenous and partly of
endogenous origin. In other words, some of it is derived more or less
directly from preformed purine substances in the food, and the remain-
der from the purine constituents of the animal's own tissues,

Endogenous Purines. — It was thought that a definite proportion of
each of the administered purines could be invariably recovered from
the urine. Although this has not been found to be exactly true, there
is nevertheless a certain constancy in the proportion of administered
purine that is excreted. Thus, Mendel and Lyman have found recently
that about 60 per cent of injected hypoxanthine, 50 per cent of xan-
thine, 19-30 per cent of guanosine, and 30-37 per cent of adenine are
eliminated in the urine as uric acid. When combined purines — i. e., nu-
clear material — are given, only a small proportion of the purine thus
reappears. There is, therefore, a general parallelism between the purine
content of the food and that of the urine, which indicates that purine-
rich food ought to be eliminated from the diet of patients who are
suffering from deposition of insoluble urate in the tissues, as in gout.
The fate of the purine that disappears in the body is unknown; some of
it may be decomposed in the intestine, but why so much of the remainder
should disappear, after absorption by the blood, is a mystery, since no
uricase can be discovered in any of the organs or tissues. The destroyed
purines can not be shown to influence any of the other well-known
nitrogenous metabolites of the urine.

The following table of experiments by Taylor and Rose45 may serve
to illustrate these points. The subject was placed on a purine-free diet
consisting of milk, eggs, starch and sugar, for three days. After this

URIC ACID AND THE PURINE BODIES G75

period a part of the total nitrogen (3 grams) was supplied as sweet-
breads— thymus gland, etc. — containing a high percentage (0.482) of
purine nitrogen; for another period of four days still more of the nitro-
gen (6 grams) was replaced by sweetbread nitrogen; and this was fol-
lowed by a final period in which the original diet of milk, etc., without
purine substances, was restored. The following table gives the results:

1ST PERIOD

4TH PERIOD

, PURINE-FREE

2ND PERIOD

3RD PERIOD

PURINE-FREE

DIET

DIET

Total urinary N

8.9

8.7

9.1

8.8

Urea N and NH.,

7.3

7.1

7.1

7.05

Creatinine

0.58

0.55

0.56

0.47

Purine N (total)

0.11

0.17

0.26

0.10

Uric acid N

0.09

0.14

0.24

0.07

Remainder N

0.91

0.88

1.18

1.18

The increase of uric acid accounted for less than half of the purine
nitrogen ingested. This appeared as uric acid, the excretion of purine
bases being practically unchanged.

CHAPTER LXXV
URIC ACID AND THE PURINE BODIES (Cont'd)

SOURCE OF ENDOGENOUS PUKINES

Even after the entire elimination of all purine substances from the
food in the case of man, purine continues to be excreted in the urine
as uric acid. This, as above remarked, is called endogenous excretion.
At first it was thought by Burian and Schur that the total nitrogen of
the purine-free diet could be considerably varied without causing any
alteration in the amount of the endogenous purine excretion, but a rep-
etition of the work has shown that, when these changes are of consider-
able magnitude, the endogenous moiety does not remain constant. This
has already been demonstrated in the table on Folin's results (see page
648), and is still better illustrated in the accompanying table, which
shows the excretion of uric acid and coincidently of urea from hour to
hour in the urine after taking food which is free from nuclein or purine
substances. After a fast of six hours, a diet consisting of bread and
potatoes was taken at 1:30, and the urea and uric acid measured in the
urine each hour thereafter.

TIME

UREA
GM.

URIC ACID
MG.

AMOUNT OF URINE
C.C.

10-11

1.07

26

175

11-12

1.13

27

118

12-1 P.M.

1.07

24

164

1-2 (meal)

0.64

21

60

2-3

1.12

22

43

3-4

1.16

38

41

4-5

0.84

40

53

5-6

146

56

59

6-7

1.20

39

56

7-8

1.37

30

95

8-9

1.47

33

183

9-10

1.33

24

155

10-11

1.33

23

180

(Hopkins and Hope.)46

A postprandial increase of endogenous purine excretion is very dis-
tinct, and it indicates that during the process of assimilation something
must be occurring in the organism which entails the production of purine
from the organism itself. As to what this may be, it is impossible to
say. It may be associated with the work of the gastric and intestinal
glands, which recalls the interesting suggestion, originally made by

676

URIC ACID AND THE PURINE BODIES 677

Horbaczewski, that ingested substances increase the excretion of uric
acid by causing a leucocytosis, the purine being derived from the nucleic
acid set free when the leucocytes become broken down. That this is
not the correct explanation, however, is indicated by the fact that in-
gested substances that give rise to an increased number of leucocytes
affect the excretion of uric acid during the period the leucocytes are
present in the blood, and not after they have disappeared, which would be
expected to be the case were the uric acid a product of purine substances
liberated by their breakdown. This would indicate that the purine sub-
stance is a metabolic product of the living leucocytes and not a break-
down product of those that are dead. It should be noted that the increase
in the postprandial uric-acid excretion occurs earlier than that of urea.

The most pressing question concerns the origin of the endogenous
purines. Uric acid is the purine with which we are most concerned in
the case of man, and chemistry shows us that it may be produced either
by a synthesis of two urea molecules with a carbon residue containing
three carbon atoms, or by the oxidation of the lower purines — namely,
of those which are the constituent parts of the nucleic-acid molecule.
There are consequently two sources from which the endogenous purine
excretion in man may be derived : (1) synthesis of two urea molecules,
and (2) oxidation of the lower purines.

We will consider first the possibility of synthesis. In birds and
reptiles practically all the nitrogen is excreted in the form of uric acid,
and it is easy to show that this has been produced in the organism
mainly in the liver by the synthesis of urea with carbon-rich resi-
dues. Minkowski found that by removing the liver from geese, which
is a comparatively simple operation on account of an anastomotic vein
between the portal and the renal veins, the uric acid in the urine became
very markedly decreased and ammonium lactate took its place (page
651). Since we know that ammonium in the animal body is ordinarily
converted into urea, we may conclude from this observation that some-
thing has occurred to prevent the synthesis of urea into uric acid. In
confirmation of this conclusion it was subsequently found that, if am-
monium lactate was added to the blood perfused through the isolated
liver of the goose, uric acid accumulated in the perfusion fluid. Fur-
thermore, when birds and reptiles are fed with ammonium salts or
with the degradation products of protein, there is an increase in the ex-
cretion of uric acid instead of urea. Everything which in a mammal
tends to cause an increase in urea excretion causes in birds and reptiles
a similar increase in the excretion of uric acid.*

. *The reason for the formation of this relatively insoluble metabolite in place of the soluble urea
is connected in some way with the fact that birds and reptiles do not take such large quantities
of water with their food as other animals.

678 METABOLISM

In the early days of research in the uric-acid problem, not inconsid-
erable mistakes were made on account of failure to recognize the essen-
tial difference in the metabolism of uric acid in birds and mammals,
and the tendency for some time after the exact state of affairs was
discovered was to consider that in mammals none of this synthetic proc-
ess occurs. The latter view, however, is surely incorrect, for a cer-
tain amount not only of uric acid itself but of tJie lower purine bodies
can be produced by synthesis -in the mammalian body. Thus, Ascoli and
Izar47 discovered that uric acid could be made either to disappear or
to be formed when a minced preparation of liver was incubated, the ex-
act result depending upon whether the incubation was conducted in the
presence of oxygen or of carbon dioxide. With oxygen uric acid disap-
peared, whereas with carbon dioxide uric acid accumulated, indicating
that in the presence of this gas the destroyed uric acid became reformed
from the disintegration products of the oxygenation process. As similar
results were obtained from the livers of birds, it is clear that no essential
difference exists between the purine metabolic processes occurring in
the livers of birds and of mammals. The difference is a quantitative not'
a qualitative one.

Regarding the chemical nature of the product into which uric acid is
broken clown and from which it may be resynthetized, it has been pos-
sible so far to identify but one substance — namely, dialuric acid. This
is a perplexing result, for from all other investigations it would appear
that in mammals, with the exception of man and the anthropoid apes,
uricase splits uric acid into allantoine (see page 673), which substance,
however, when added to liver extract does not cause any uric acid to be
formed; nor do any of the other known decomposition products of uric
acid have such a result. The chemical reaction involved in the produc-
tion of uric acid from dialuric acid and urea is indicated as follows:

NH — C = O

/ \

\

\

Nil — ' C j = O IT

NH

NH

c = o
X

(dialuric acid) (urea)

The synthesis of uric acid is brought about by the combined action
of a thermolabile enzyme in the blood and a thermostable body in the
tissues. An aqueous extract of blood-free liver of the dog can destroy
uric acid only in the presence of oxygen; it can not reform it even in

URIC ACID AND THE PURINE BODIES 679

the presence of carbon dioxide. On the other hand, blood serum can
not reform uric acid, whereas a mixture of the bloodless liver extract
and blood serum produces uric acid readily under suitable conditions.
Boiling of the liver extract does not affect the result, but boiling of the
blood serum renders it incapable of exerting its joint action with the
bloodless liver extract.

These experiments with dog's liver serve only as circumstantial evi-
dence that uric-acid synthesis occurs in mammals as well as in birds.
More direct proof that purine synthesis occurs in mammals is as follows:
(1) It was discovered long ago by Miescher that salmon, after leaving
the sea to ascend the rivers in order to spawn, have a well-developed muscu-
lar system, but that in the upper reaches of the stream the muscular system
becomes considerably atrophied and the testes enormously developed. As
the fish takes no food during the migration, there must be conversion of
the protein of the muscles into the cellular tissue of the sexual glands,
and nucleic acid must be produced. (2) A hen's egg before its incuba-
tion contains practically no nucleic acid, whereas after development has
well started nucleic acid increases by leaps and bounds. Similarly the
eggs of insects increase in purine content very markedly as development
proceeds. (3) Milk contains practically no purine derivative, and yet
when it is fed to young growing animals, the organs lay on purine sub-
stances abundantly. In general, indeed, it may be said that the combined
purine increase is in proportion to the increase in body weight on the
milk diet. (4) In Osborne and Mendel's experiments already alluded
to, it has been shown that adequate growth depends primarily on the
nature of the protein building stones, and not upon the purine content
of the food. (5) An objection might be raised to these results on the
score that they do not apply to the adult mammal. Investigation of
the problem has hitherto been seriously impeded by the fact that no or-
dinary laboratory animals were known in which uric acid is excreted in
the urine. The discovery that this occurs in the Dalmatian dog has,
however, made it possible for S. R. Benedict'41 to show, not only that
after increasing the amount of nonpurine food there was a very distinct
increase in the uric-acid excretion, but also that when the animal was
kept for a year on such foods there was excreted a total amount of uric
acid which was at least ten times greater than could have come from the
traces unavoidably included in the food.

Eegarding the chemical nature of the substance from which the purine is synthe-
tized, \ve know at present practically nothing. No doubt some of the protein build-
ing stones functionate in this capacity, pyrimidine being probably the product that is
first formed. Thus, pyrimidine may be produced as a result of the combination of
amino-malonic acid with* urea, the amino-malonic acid being produced by condensa-
tion of hydrocyanic-acid molecules:

680 METABOLISM

I
CO CNHa

NH

-CNH2

(hydrocyanic (amino-malonic (urea) (oxy-diamino-pyrimidine)
acid) nitrile)

Another possible source of pyrimidine is the oxidation of arginine to guanidine-pro-
pionic acid, which then condenses to form amino pyrimidine.

Purine synthesis undoubtedly occurs in the mammalian body, but it
is not easy to recognize for its occurrence is difficult to detect in metab-
olism investigations; it is a slow, continuous process. The probabil-
ity of its occurrence, however, is indicated by such results as those
described on page 648, in which increase in purine excretion is observed
after varying the intake of food, even when this is itself entirely free
from purine substances. Whether or not changes in the activity of
purine synthesis occur in conditions of disease is a question which awaits
investigation.

The Influence of Various Physiological Conditions, of Drugs, and of
Disease on the Endogenous Uric-acid Excretion. — Muscular exercise was
thought by Burian to cause an increased excretion of uric acid, from
which he drew the conclusion that the hypoxanthine present in compara-
tively large amount in muscular extract, or its precursor, inosinic acid,
must be an important source of endogenous uric acid. Other observers
(Leathes,62 etc.) have found that strenuous exercise causes a distinct in-
crease in uric-acid excretion, which, however, is much less marked on
repetition of the same kind of exercise on the next day. If some new
kind of muscular work is performed, another increase in uric acid will
result. There are still other investigators who deny that muscular work
has any influence on uric-acid excretion.

It has been observed by several investigators that the endogenous
purine excretion is distinctly higher during the waking hours than during
sleep. This can not be shown to depend on variations in the urinary
function, and since it is decidedly doubtful whether ordinary muscular
activity has any influence, the diurnal variation is most difficult to
account for. The endogenous excretion in man is not the same for
different individuals, even when calculated for the same body weight; it
varies between 0.12 and 0.20 per cent purine nitrogen in an adult man.
It remains remarkably constant for a given individual from time to
time, being unaffected by moderate degrees of variation in the amount
of food taken, provided this be purine-free; when, however, the amounts
are extremely variable, changes are produced (see page 648).

In disease, fever causes an increased excretion. This has been most
clearly shown by Leathes,62 who took a large enough dose of antityphoid

URIC ACID AND THE PURINE BODIES 681

serum to produce a distinct degree of fever (103° F.), and found that
an increase in uric-acid excretion occurred. That increased combustion
processes occurring in the tissues were responsible for the uric acid,
was shown by the same author, who caused a similar increase by sub-
jecting himself to cold baths for a considerable period of time. The in-
creased loss of heat thus induced stimulated the combustion processes in
the body so as to maintain the body temperature, and as a result there
was an increase in uric-acid excretion. It has long been known that an
excessive amount of uric acid is excreted in leuce^nia. The nuclein
of disintegrated leucocytes is commonly held responsible for the increase.
Naturally, much work has been done on the endogenous and exogenous
purine excretion in gout. No very striking anomalies of excretion have,
however, been brought to light, except perhaps that after the ingestion
of purine-rich foodstuffs it takes longer for the resulting exogenous ex-
cretion to develop and pass away.

Certain drugs affect the excretion of uric acid. Salicylic acid is said
to cause an increased excretion, and citrates certainly have this effect.63
In both cases the increase is followed by a compensatory fall, which
indicates that these drugs act by ' facilitating the excretion rather than
by influencing the metabolic processes that are the source of the uric
acid. The effect of caffeine has been very carefully investigated. Given
to the Dalmatian dog, referred to above, S. R. Benedict found that a
small dose caused a slight decrease, but that a larger dose had practically
no effect, although there was a notable retention of nitrogen. On man,
however, different results were secured, for it was found that when 1
gram of caffeine was given daily for several days, a slight but definite
progressive increase in the endogenous uric-acid excretion occurred, and
it lasted for 10 days after the caffeine administration was discontinued.
Liberal allowance of this alkaloid may, therefore, not be quite so innocu-
ous as it is assumed to be.

Uric Acid of Blood. — In all of the investigations considered above,
the behavior of uric acid is judged from the amount of it excreted in
the urine. Valuable though such results must be, their interpretation is
always difficult, since two factors that are quite independent of each
other have to be kept in mind — namely, the production of the uric acid
in the organs and tissues and its excretion by the kidneys. In connection
with the latter factor, we must also consider the method of transporta-
tion of uric acid by the blood fuom its place of production (or absorp-
tion) to the kidneys. These problems have recently been very consider-
ably simplified by the elaboration of an accurate method for the estima-
tion of the uric-acid content of blood.

By observing changes in the amount of uric acid in the blood rather

682 MPJTABOLISM

than in the urine, the excretory factor is partly controlled, and it can
be completely so if urine and blood are both investigated. Thanks to
the work of Folin, it is now possible to determine with an extreme de-
gree of accuracy the uric acid in as little as 10 c.c. of blood. The impor-
tance of this achievement will be appreciated when we state that prior
to Folin 's work no method existed by which uric acid could be approx-
imately measured even when large quantities of blood were available.
Much of the work that has been done by the use of this new method
has so far applied to the amount of uric acid in the blood of man in
various diseases. We shall refer to these results immediately, but
meanwhile it is important to call attention to some very suggestive
observations concerning the condition of uric acid in the blood. For
many years there have been investigators who have thought that uric
acid can not be simply dissolved in the blood plasma, like sugar or some
inorganic salt. It is believed by many that at least a portion of the uric
acid circulates in combination with nucleic (thymic) acid (see page 669),
which would account for the fact that some purines are catabolized in
the body when they are given in a combined state, as thymic acid, but
are excreted unchanged when ingested in a free state. When given freely,
certain purines — adenine, for example — may moreover cause inflamma-
tion and calculus formation in the kidneys of dogs, a result not obtained
when thymic acid is fed.

Other observers have concluded that uric acid exists as two isomeric varieties, lac-
tam and lactim, the monosodium salts of which are of unequal stability. The
less stable1 a-salt is mucn more soluble in the blood serum than the stable
/3-salt. It is the a-salt that becomes increased in the blood in gout, the deposition
of urates in the tissues, which is the most characteristic symptom of this disease,
being caused by conversion of the a-salts into /3-salts. The structural formulas of the
two isomers are as follows:

H.N - C : O N - C.OH

II II II

O : C C - NH HO.C C - NH

I

I !!
! II

H.N-C-

CO

C.OH

/ NU-N

[lactam modification forming [lactim modification forming

unstable a-urates] stable /3-urates]

(relatively soluble) (relatively insoluble)

The most recent work of S. R. Benedict has shown that uric acid ex-
ists, chiefly in combination in the blood of most mammals but not in
that of the bird. It was found, for example, that fresh ox-blood exam-
ined by the Folin method contains only 0.0005 gm. free uric acid per 100
gm. of blood; after boiling the protein-free blood filtrate with hydro-
chloric acid, hoAvever, the uric acid increased by about ten times. This

URIC ACID AND THE PURINE BODIES

683

larger amount was also found present in whole blood that had been
allowed to stand for some time, indicating that the uric-acid compound
can be split by means of an enzyme. The compound exists in the cor-
puscles and not in the plasma. It is of some significance that after thus
setting free the uric acid, there should be about 50 per cent more of it
present in the blood of the ox than in that of the bird, where most exists
in a free state in the serum, although the urine of the ox contains only
the smallest trace of uric acid, and that of the bird is loaded with it.
Investigation of the condition of uric acid in human blood is at present
in progress.

Uricemia in Gout and Nephritis

The practical application of these observations is particularly impor-
tant in connection with the etiology of gout. In typical cases of this dis-
ease, the uric acid of the blood increases from its normal value of 1 to
3 mg. per cent to nearly 10 mg., indicating a considerable degree of

URIC ACID, UREA N AND CREATININE OF BLOOD IN GOUT AND EARLY AND LATE NEPHRITIS

DIAGNOSIS

UREA N CREATININE
ACID

SYSTOLIC
BLOOD

PRESSURE

MG. TO 100 C.C.
BLOOD

Typical Cases of Gout

9.5

8.4
7.2
6.8

13
12
17
14

1.1
2.2
2.4
1.7

230
164
200

Typical Early Interstitial Nephritis

9.5
8.0
5.0
7.1
6.6
6.3
8.7
7.0
6.3
6.3

25

37
37
16
24
18
20*
33
31
23

2.5

2.7
3.9
2.0
3.3
2.1
3.6
2.6
2.1
2.4

185
150
130

185

100
117

150
240
170
238
145
210
120

165

200

Chronic Diffuse and Chronic Inter-
stitial Nephritis

8.0
4.9
8.3
5.3
9.5
2.5
7.7
6.7
8.3
6.5

80
17
72
21
44
19
67
17
39
24

4.8
2.9
3.2
1.9
3.5
1.9
3.1
1.6
2.9
3.0

Typical Fatal Chronic Interstitial
Nephritis

22.4
15.0
14.3
13.0

8.7

236
240
263
90
144

16.7
20.5
22.2
11.1
11.0

210
225
220
265
225

(Myers and Fine: Arch. Int. Mod., 1916.)

684 METABOLISM

renal insufficiency. This uricemia can not in itself, however, be the cause
of the deposition of urates in the joints, because it also occurs in other
diseases with renal retention, such as nephritis. Moreover, the blood
serum is capable of dissolving much larger quantities of uric acid than
are ever found present in it in gout. The real cause for the gouty deposits
must depend on some change affecting the blood so as to alter the form
in which uric acid exists therein, with the result that it passes into the
joints and is deposited there.

Other diseases showing uricemia are lead poisoning and nephritis. In
the latter disease the damaged excretory function of the kidney is
manifested first of all by an increase in the uric-acid content of the
blood, accompanied later by a retention of urea and later still by one
of creatinine. The severity of the renal involvement may therefore be
gauged by determining the percentage of these three metabolites. On
account of the importance of these facts from a clinical standpoint, we
append a table containing results secured by Myers and Fine, in which
the behavior of the metabolites in the blood is shown in relationship
to the severity of the case as gauged by the blood pressure.

Lastly, regarding the influence of drugs on the blood uric acid in dis-
ease, it has been found by Fine that both atophan and salicylates cause
a pronounced decrease in the amount, but that it gradually rises to the
old level even while administration of the drugs is being continued.

Important contributions to the behavior of uric acid in blood are
constantly appearing at present, mainly from the laboratories of Folin
in Boston, of S. E. Benedict, and of Myers and Fine in New York>

CHAPTER LXXVI
THE METABOLISM OF THE CARBOHYDRATES

The healthy animal organism is capable of rapidly oxidizing large
quantities of carbohydrate, as is evident from the following facts: If
carbohydrate is given to a starving animal, (1) the energy output very
shortly afterward increases; (2) the respiratory quotient also increases,
indicating that, relatively to oxygen intake, more carbon dioxide is being
excreted (see page 582) ; and (3) none of the ingested carbohydrate
makes its appearance in the excreta. Indeed, of the three proximate
principles of food, carbohydrate is the most available for combustion
in the animal body. It may therefore be considered as the quickly
available fuel for the body furnaces.

CAPACITY OF THE BODY TO ASSIMILATE CARBOHYDRATES

Assimilation Limits. — When the limit to the amount of carbohydrate
that the organism can metabolize is overstepped, some of it appears in
the urine. The amount that can be tolerated without causing glycosuria
is commonly called the assimilation or saturation limit. The use of the
term " limit" is, however, very unfortunate, for it implies that beyond
this point the organism is capable of dealing with no more carbohy-
drate, which is far from being the case, for if a larger amount is taken,
only a small trace of the excess will appear in the urine. When the
urine is allowed to collect for twenty-four hours, the mixed specimen
shows no trace of glucose in the majority of healthy individuals after
the ingestion of 200 gm. ; after 300 gm. a somewhat higher percentage
of cases develop a mild glycosuria, but frequently none is evident even
after 500 gm. Beyond the last mentioned amounts the limit of ingestion
is reached, on account of nausea, etc., and it is improbable even if
larger amounts could be tolerated, that any more of the glucose would
be absorbed than with 300 or 400 gm. The testing of the so-called as-
similation limit has been considered an important aid in the diagnosis
of early cases of diabetes.

It has been found that to make the results of any value, certain
conditions must be fulfilled in applying the assimilation test. The most
important of these concerns the activities of the gastrointestinal appa-
ratus at the time the sugar is given, for it has been found that if other

685

686 METABOLISM

foodstuffs are being absorbed at the same time as the sugar, more of
the latter can be tolerated than when the sugar alone is being absorbed.
It has therefore been customary to give the sugar dissolved in water,
or in weak coffee, the first thing in the morning after the patient awakes ;
i. e., at least twelve to sixteen hours after the last meal was taken. In
making these tests the urine voided before the sugar is administered should
of course itself be thoroughly examined for reducing substances, and
specimens should be collected about every ninety minutes and examined
by a reliable test (Benedict's or Nylander's).*

Although a limit is set to the ability of the organism for retaining
sugar (mono- or di-saccharides), this is usually considered not to apply, in
healthy individuals at least, when starches (polysaccharides) are ingested.
Thus, it is a well-known fact that people can eat enormous quantities of po-
tatoes or of bread without the appearance of any trace of reducing sub-
stances in the twenty-four-hour urine. It should be pointed out, however,
that urine collected and examined at short intervals (every half hour)
after taking large quantities of polysaccharide-rich food has frequently
been found to contain traces of reducing substances in apparently
healthy persons.

For practical purposes it has been considered that an individual who developes glyeos-
uria after taking 100 gm. of glucose must be. considered as at least a potential diabetic.
In the light of the above results and for many other reasons, there is, however, con-
siderable doubt as to the value of the assimilation test. Thus, when a solution of
glucose is given orally, its rate of absorption will depend very largely on the motility
of the stomach. If this is normal, the solution will very quickly find its way past the
pyloric sphincter into the jntostine, where it will be rapidly absorbed. If, on the other
hand, the pyloric sphincter does not open freely, the passage of the glucose into the
intestine may be so delayed that no more is present in this place at one time than
would be the case after an ordinary diet of polysaccharide. And even after the sugar
solution enters the small intestine, differences in the amount of the intestinal contents
with which it becomes mixed, in the extent of bacterial growth, and in the absorption
process, may very materially affect the rate at which the glucose gains entry to the
blood.

Although often of doubtful diagnostic value, determination of the
assimilation limit is of considerable aid in controlling the treatment of
diabetes. For this purpose the patient should first of all be instructed
to follow his usual diet, so that, by examination of the amount of sugar
excreted in the urine, an opinion may be formed of the severity of the
case. The diet should then be changed so as to consist of a part that
contains no carbohydrates and another composed entirely of starchy

•Examination of normal individuals has shown that the assimilation limit for different sugars
varies somewhat; for glucose it appears to be from about 150 to 250 gm. ; for leyulose, which, it
will be remembered, is the monosaccharide associated with glucose in the construction of the cane-
sugar molecule, the assimilation limit is from 100 to 150 gm. ; for cane sugar or saccharose itself
the figures seem to vary considerably, but are given as between 50 and 200 gm.; for lactose, another
disaccharide, and the sugar present in milk, the assimilation limit is distinctly lower — namely, 100 gm.

THE METABOLISM OF THE CARBOHYDRATES 687

food. The former is made up of eggs, fish, green vegetables, fat, etc.,
and the latter, to start with, should consist of 100 grams of bread, dis-
tributed between the two main meals of the day, one of which is break-
fast. This diet should be continued until the glycosuria either disappears
or attains a constant level. If it disappears, the case is classified as a
mild one of diabetes, and the daily allowance of bread may be increased,
by 50 grams a day, until the sugar again makes its appearance in the
urine, indicating that the assimilation limit has been reached. For
therapeutic purposes, the patient should now be instructed to take about
three fourths of this amount of carbohydrate in his daily ration, and
he should be supplied with explicit instructions in the shape of diet
tables as to what variety and quantities of the various carbohydrate
materials his food may contain. His urine should be examined at fre-
quent intervals — once a week — and he should be instructed as to the
nature of his disease and the importance of his remaining aglycosuric.
By further treatment such so-called latent cases of diabetes may be
kept in perfect health for many years.

When, on the other hand, the glycosuria persists with 100 grams of
bread in the daily ration, this must be reduced to 50 grams, and if after
some days the first reduction does not suffice to render the urine free
from sugar, carbohydrates must be withheld entirely from the diet.
If the glycosuria does not now disappear, the case is to be considered
severe, and it may be necessary to undertake the starvation treatment,
which has recently been developed in this country by Allen18 and Joslin19
with apparent success. By the reduction of carbohydrate, or by the
starvation treatment, it is usually possible to make even the severest
cases of diabetes aglycosuric. When this has been attained, the amount
of protein or carbohydrate food may be cautiously increased until just
short of the assimilation limit.

To avoid error caused by irregular absorption from the intestines, some investigators
have recommended the determination of the assimilation limit after intravenous or
subcutaneous injections of sugar. But even this refinement in technic has not, as a
rule, had the effect of rendering the results of any very evident value as a criterion
of the utilization of glucose in the animal body. The reason for the unreliability of
this method is mainly that the period of injection of the glucose solution usually oc-
cupies only a few minutes, so that it causes a sudden instead of a very gradual in-
crease in the sugar concentration of the blood, the conditions being therefore quite
unlike that which exists during the normal absorption of glucose from the intestine.
The mechanism by which the body ordinarily disposes of excessive amounts of glucose
absorbed into the portal blood, is not adjusted to operate when the systemic blood
is suddenly overcharged with this substance. In the one case the glucose is a food-
stuff; in the other, because of its excessive concentration in the blood, it is more or
less of a poison. Such results, in other words, merely show us how much glucose can
be added at one time to the organism without any overflow into the urine, but they

688 METABOLISM

furnish us with no information regarding the power of the organism to utilize a con-
stant though moderate excess of this substance. In the one case it is the ' ' satura-
tion limit, ' ' in the other the l ' utilization limit ' ' of the organism for glucose, that we
are really measuring.

The Tolerance of the Body for Glucose. — Consideration of these prin-
ciples has led Woodyatt, Sansum and Wilder20 to undertake a thorough
reinvestigation of the whole problem, of the utilization or, as they prefer
to call it,, the tolerance of the body for glucose. They emphasize the obvi-
ous fact that the ability of the organism to utilize glucose "must de-
pend on the rate at which the tissues are able to abstract it from the
blood by their combined powers, to burn it, to reduce it into fat or to
polymerize it into glycogen." To form any estimate of the combined
effect of these processes, we must take into account not only the amount
of glucose per unit of body weight (grams per kilogram), but also the
rate of injection, for "tolerance must be regarded as a velocity, not as
a weight. "

Briefly summarized, the conclusions which Woodyatt, etc., have so far
drawn from their investigations are as follows: In a normal rabbit, dog,
or man, 0.8-0.9 gm. of glucose per kilogram body weight and per hour can
be utilized by the organism for an indefinite time without causing gly-
cosuria. When between 0.8 and 2 gm. are injected, a part of the excess
appears in the urine, steadily increasing until a maximum is reached,
after which the excreted fraction remains constant (at about one-tenth).
If more than about 2 grams per kilogram an hour are injected, "a large
percentage of all glucose in excess of the 2 gm. per kilogram an hour
appears in the urine when constant conditions are once established/'

The fact that so much glucose injected intravenously can be used
without the appearance of any of it in the urine, indicates a method by
which foodstuffs may be supplied to the tissues in cases where, on account
of gastrointestinal disturbances, it is impossible to have food absorbed
by the usual pathways. The possible value of such a method of treat-
ment in cases of extreme weakness has been tested on laboratory animals
by Allen, who states that such injection seems to have a valuable nutri-
tive and strengthening effect. He found, for example, that in cats
starved to extreme weakness the injection of a fraction of a gram per
kilogram of glucose had an unmistakable strengthening effect, and
sometimes appeared to save life. Such results would seem to indicate that
in certain cases where blood transfusion is impracticable, glucose in-
fusions should be tried. Subcutaneous injection of sugar, either for the
purpose of determining the assimilation limit or with the object of sup-
plying foodstuffs parenterally, is impracticable because of the pain and
sometimes sloughing produced at the point of injection.

THE METABOLISM OF THE CARBOHYDRATES 689

We have devoted no inconsiderable space to a discussion of assimila-
tion limits because of the great interest in diabetic therapy which this
procedure has aroused during recent years. We may now turn our
attention to a closer analysis of the changes that take place in carbohy-
drates during their passage through the animal body.

DIGESTION AND ABSORPTION

Digestion. — All digestible carbohydrate taken with the food is con-
verted by the digestive agencies into the monosaccharides, glucose and
levulose, as which it is absorbed into the blood of the portal system.
To bring about this resolution of carbohydrate into monosaccharides,
several enzymes are employed. The first of these is the ptyalin of saliva.
It is not a very powerful enzyme, being capable of acting only on starches
that are in a free state, i.e., not surrounded by a cellulose envelope;
but even on free starch, ptyalin displays little of its activity during the
time the food is in the mouth. After the food is swallowed and becomes
deposited in the fundus of the stomach, there is an interval of time —
lasting until hydrochloric acid has been secreted to such an extent as to
permit some of the acid to exist in a free state — during which the ptyalin
acts on the starch of the swallowed food. During this time the activity
of the ptyalin is actually assisted on account of the fact that a slight
increase in hydrogen-ion concentration of the digestive mixture accel-
erates the action of ptyalin.

The product of ptyalin digestion is maltose, a disaccharide composed
of two molecules of glucose. On entering the intestine, the carbohydrates
therefore exist partly as undigested starch, partly as glucose, and partly
as maltose. In the favorable environment of the duodenum a much
stronger diastatic enzyme called amylopsin very quickly hydrolyzes the
starch through dextrine into maltose. The maltose derived from the
starch and the unchanged sugars, such as cane sugar, maltose and lac-
tose, which have been taken with the food, unless they are present in very
high concentration in the intestinal contents, are not immediately ab-
sorbed into the blood, but become subject to the action of other enzymes
contributed by the intestinal juice — namely, the inverting enzymes, one
of which exists for each of the disaccharides. By their action maltose
is converted into two molecules of glucose by the enzyme maltase; lac-
tose, into galactose and glucose by lactase; and cane sugar, into levu-
lose and glucose by invertase. It is interesting to note that in animals
whose food does not contain one or other of those disaccharides, the cor-
responding inverting enzyme is absent from the intestinal juice. The her-
bivorous animals, for example, do not take any lactose in their food, and the

690 METABOLISM

intestinal juice contains therefore no lactase, although it is present in
that of the young animals while still suckling.

A certain amount of carbohydrate becomes attacked by the intestinal
bacteria. These split the monosaccharides into lower fatty acids and
gases, such as methane and carbon dioxide. Besides this obviously de-
structive process, bacteria also perform a useful function in the digestion
of carbohydrates, in that certain strains of them are able to digest cellu-
lose, for which no special enzyme is provided. Bacterial digestion is con-
sequently essential in herbivorous animals; it takes place in the cecum,
which is enormously developed for this purpose (page 497).

Absorption. — The glucose and levulose produced by digestion are
absorbed into the blood of the portal system. When a very large quan-
tity of a disaccharide, such as cane sugar, is present in the food, a certain
amount of the sugar is absorbed unchanged — that is to say, as cane sugar
—and appears in the blood, from which, since it is an abnormal con-
stituent, it is excreted unchanged in the urine. This alimentary glyco-
suria is particularly evident when the sugar is taken without any other
food; thus, after taking cane sugar in an amount corresponding to 5
grams per kilogram body weight, it was found in one and a half hours
afterward that the urine of ten out of seventeen healthy individuals con-
tained cane sugar. The urine of three of these men, however, also con-
tained invert sugar — that is, dextrose and levulose. Cane sugar con-
tinued to be excreted for from six to seven hours. ,

The Sugar Level in the Blood. — While' no absorption of sugar is going
on, the percentage of this substance in the blood of the portal vein is the
same as that in the systemic circulation. During absorption the former
becomes perceptibly raised — to what extent we can not say — and in the
latter a less marked increase of sugar concentration is usually detectable.
Evidently, then, between the point at which the sugar is absorbed and
the blood of the systemic circulation, some barrier exists which holds
back some of the excess of absorbed sugar. We have very inaccurate
information as to how efficiently these barriers hold back the excess of
absorbed glucose because of the technical difficulty in collecting blood
from the portal vein without serious disturbance to the animal. Indeed,
the only way by which the problem can be studied is by comparing the
blood of the portal circulation with that of the systemic circulation dur-
ing the injection of a solution of glucose into one of the smaller branches
of the portal vein.21

In such experiments it has been found 'that .the percentage of sugar is a little less
in the blood of the abdominal vena cava than in that of the portal vein, and is still
less in the blood of the systemic veins, susch as the femoral — results which justify the
conclusion that the barriers responsible for taking out some of the absorbed sugar
from the blood exist in the liver and in the muscles. The curve in Fig. 190 will illus-
trate to what extent the mechanism operates.

THE METABOLISM OF THE CARBOHYDRATES

691

It will be observed that, so far as can be judged from changes in the concentration
of sugar in the blood, the sugar-retaining power of the liver is about equal to that of
the muscles. This result shows that the commonly held view is untenable that the liver
is capable of removing from the portal blood all of the sugar that is in excess of that
present in systemic blood. The muscles must assist extensively in this process.

One objection which may properly be raised to these observations is that the animals
on which they were made were under anesthesia, and that the anesthetic may have had
a paralyzing effect on. the sugar-retaining power of the liver. In view of this criticism
it is important to examine the results obtained on animals that are not under the in-
fluence of anesthesia. Such observations have been made on rabbits, and a few on
man himself. By collecting blood from the ear veins of rabbits, it has been found
that, after giving from two to ten grams of glucose by stomach, the glucose concentra-
tion of the systemic blood begins to rise in fifteen minutes, attaining a maximum in
about an hour and then returning to the normal level in about three hours.

Fig. 190. — Curves showing the percentage of glucose in blood after a constant injection of
an 18 per cent solution into a mesenteric vein. V.C., vena cava, continuous line; P.O., pan-
creaticoduodenal vein, broken line; I, iliac, dotted line.

Similar results have been obtained by examination of the venous blood
in man. After giving 100 grams of glucose by mouth, for example, there
is commonly an increase in blood sugar amounting to from 30 to 34 per
cent of the normal and lasting for from one to four hours. The existence
of this postprandial hyperglycemia, as we may call it, indicates that the
sugar-retaining powers of the liver and muscles are not sufficiently de-
veloped to prevent the accumulation of some of the absorbed sugar in the
systemic blood. Whenever this increase exceeds a certain limit, some of
the sugar begins to escape through the kidney into the urine, producing
glycosuria — postprandial glycosuria. The concentration to which blood
sugar must rise before glycosuria occurs in the case of man is, probably
about 0.10 to 0.11 gm. per cent. After damage to the kidney, as in nephritis,
or in long-standing cases of mild diabetes, the percentage may probably
rise considerably higher in the blood without evidence of glycosuria.

Value of Blood Examination in Diagnosis 6f Diabetes. — The determina-

692 METABOLISM

tion of the amount of ingested carbohydrate required to bring about post-
prandial glycosuria constitutes, as we have already seen, the so-called
assimilation limit for sugar, which is often taken as an index of the sugar-
metabolizing power of the organism. It is evident, however, that the time
of onset, and the extent and duration of postprandial hyperglycemia must
serve as a more certain index of the sugar-retaining power of the liver
and muscles; and now that several simple and rapid clinical methods
exist (Lewis-Benedict or Maclean methods) for the accurate determina-
tion of sugar in small quantities of blood, there is no reason why this
index should not be used for the detection of failing powers to metabolize
carbohydrate.

In no disease, probably not even in tuberculosis, is it more important
than in diabetes that an early diagnosis should be made. Thus, if we find
that the postprandial hyperglycemia after a certain amount of carbo-
hydrate develops to an unusually high degree and persists for an unusual
length of time, we are justified in curtailing the carbohydrate supply so as
to hold these values down to the level they attain in normal individuals.
It is almost certain that the earliest sign of diabetes is an unusual degree
and duration of postprandial hyperglycemia. At first the excess of sugar
leads to no damage and it is insufficient to cause any evident glycosuria, al-
though it is quite likely that if the urine in such individuals were collected
at very frequent intervals after eating carbohydrate-rich food, glucose would
be found present in at least some of the specimens. In incipient diabetes,
however, the condition progresses, until the postprandial hyperglycemia
after one meal has not become entirely replaced before the next is taken,
so that the increase in sugar produced by the second meal becomes super-
added on that following the first meal. The curve of blood sugar rises
ever higher and higher, until at last permanent hyperglycemia is estab-
lished, or rather the normal level from which the postprandial rise occurs
has become permanently raised, so that in blood collected at any time a
higher percentage of sugar is found.

The Relationship Between the Sugar Concentration of the Blood and
the Occurrence of Glycosuria. — Claude Bernard first pointed out that the
percentage of sugar in the blood may rise considerably above its normal
level without the appearance of any of the sugar in the urine, or at least
without a sufficient amount to give the usual tests for sugar. Even when
this limit is reached, as we have seen, the sugar which appears is not all of
the excess but only a small part of it. This overflow hypothesis, as it is
called, has not been universally accepted because of the many results
which are not in conformity with it. Many of these exceptional results
have been explained as due to alterations in the permeability of the kidney
for sugar, and in general it is probably safe to accept Claude Bernard's
hypothesis with certain reservations.

THE METABOLISM OF THE CARBOHYDRATES 693

Strong support has been lent to a modified form of the hypothesis by
the recent work of Woodyatt and his collaborators, who have shown by
continuous intravenous glucose injections that as much as 0.8 gm. of
glucose per kilo body weight can be injected during an hour into an
animal without any glycosuria, although under such conditions a very
distinct increase occurs in the percentage of sugar in the blood.

To explain the failure of glucose to pass into the urine under normal conditions,
it has been supposed by several investigators that the glucose exists in some form of
chemical combination in the blood. This compound is believed to behave like a
colloid. One of the recent supporters of this view is Allen, who has observed that,
when glucose is injected intravenously, it causes diuresis as well as glycosuria; whereas
glucose injected subcutaneously or taken by mouth causes neither of these conditions to
become developed; indeed it causes for some time after its administration a dimin-
ished urinary flow. To explain these differences in behavior between glucose ad-
ministered intravenously and that taken in other ways, it is supposed that the glucose
molecule in passing through the intervening wall of the capillaries combines with some
substance to form a compound which becomes available for incorporation into and
utilization by the tissues, glucose in a free state being incapable of utilization. This
compound is supposed to be of a colloidal nature, and the substance which combines
with glucose to form it is believed to be related to the internal secretion of the pan-
creas (see page 710).

The difficulty in explaining why the glucose of the blood does not constantly leak
into the kidney is, however, the only evidence upon which the hypothesis of a blood
sugar compound rests. No chemical evidence can be offered in support of such a view.
On the contrary, all experimental work indicates that the sugar exists in a free state;
but unfortunately even this evidence is not convincing. Thus, it has been found that,
when specimens of perfectly fresh blood are placed in a series of dialyzer sacs sus-
pended in isotonic saline solutions, each solution containing a slightly different per-
centage of glucose, diffusion of glucose, in one or other direction, occurs in all of them
save one — namely, that in which the percentage of glucose in the fluid outside the
dialyzer is exactly equal to the total sugar content of the blood. Such a result can
be explained only by assuming that all of the sugar in the blood exists in a freely
diffusible state. In its general nature this experiment is analogous to that by which
the tension or partial pressure of CO2 is determined in blood (see page 355).

It has been shown that glycosuria may sometimes become developed
because the kidney fails to hold back the blood sugar even when the
percentage is not above the normal — so-called renal diabetes. For the
diagnosis of this condition a comparison must be made between the
sugar concentration of the blood and that of the urine. In order to
do this at least two samples of blood must be taken, one of them at the
beginning and the other at the end of a period during which urine is being
collected. Merely to find that one sample of blood collected before or after
or during the period of urine collection contains a normal percentage of
sugar, does not necessarily indicate that at some other period while the
urine was being produced a temporary hyperglycemia may not have ex-
isted. Important contributions to this subject have recently been made
by Allen and others.74

CHAPTER LXXVII
THE METABOLISM OF THE CARBOHYDRATES (Cont'd)

FATE OF ABSORBED GLUCOSE, GLUCONEOGENESIS

We may now consider what becomes of the sugar that is retained by
the liver and muscles. Two things may happen to it: It may become
stored, or it may become oxidized or split up. Of these processes, storage
occurs in both the liver and muscles, whereas oxidation occurs mainly if
not entirely in the muscles, although a certain amount of splitting of the
glucose molecule may also occur in the liver.

Storage of Sugar. — For the present we shall consider the process of
storage of sugar and defer a consideration of its utilization until after we
have studied, not only the nature of the process by which the storage
occurs, but also the immediate destiny of the stored sugar. The storage
of sugar by the liver is brought about by its conversion into a polysac-
charide called glycogen. After an animal has been absorbing large quan-
tities of glucose, an acidified watery extract of a portion of liver made
immediately after death will be found to contain no more sugar than that
of a normal liver. On the other hand, it will be observed that the extract
is highly opalescent and yields on the addition of alcohol a copious precip-
itate, which on further purification can readily be shown to consist of a
polysaccharide — that is to say, of a starch-like substance which on hydrol-
ysis with mineral acid becomes entirely converted into sugar. If instead
of examining the liver immediately after death, it is allowed to stand for
some time, the yield of glycogen will greatly diminish, and in its place
will appear large quantities of glucose, indicating that some enzyme must
exist which attacks the glycogen after death and converts it into sugar,
This enzyme is called glycogenase. The existence of postmortem glyco-
genolysis, as it is called, would seem to indicate that during life a con-
stant tendency for the glycogen in the liver to be attacked by glycogenase
is held in check by conditions which depend on the vital integrity of
the liver cell. It is evident that if anything should happen during life
to interfere with this inhibiting influence, the glycogen will become con-
verted into glucose, which on escaping into the blood will produce hyper-
glycemia and glycosuria.

Sources of Glycogen. — In studying the sources of sugar in the animal
body it is of great importance that we should first of all know exactly the

694

THE METABOLISM OF THE CARBOHYDRATES 695

conditions under which glycogen may be formed in the liver; that is,
whether it is formed exclusively from absorbed sugar, or whether other
substances, such as protein and fat may also form it. The importance of
such knowledge rests in the fact that in severe diabetes, sugar continues
to be added to the blood, although no sugar is being taken with the food.
To check the hyperglycemia in such cases it becomes necessary, therefore,
to curtail the diet not only with regard to its carbohydrate content, but
also with regard to whatever other foodstuff may be capable of causing
glycogen formation. The practical question therefore is, What are these
foodstuffs? There are two methods by which the problem may be investi-
gated. The first, which we may call the direct method, consists in rendering
the liver free of glycogen and then some time afterward feeding the animal
with the foodstuff in question, afterward killing it and examining the liver
for glycogen. The other, which we may call the indirect method, con-
sists in first of all rendering the animal incapable of oxidizing glucose —
that is, making it diabetic — and then proceeding to see whether the in-
gestion of a given foodstuff causes an increase in the sugar excretion in
the urine. The methods for rendering an animal experimentally diabetic
will be considered later; for the present it is important to note that, if
a diabetic animal excretes more glucose while fed on a given foodstuff,
we may infer that the normal animal would convert it into glycogen.

The results of the direct method are much less reliable than those of
the indirect for the reason that it is extremely difficult to remove all
traces of glycogen from the liver. The methods employed for this pur-
pose have consisted in: (1) starvation of the animal; (2) muscular ex-
ercise; (3) exercise and starvation combined; and (4) the production of
certain forms of experimental diabetes — for example, that produced by
phlorhizin. Starvation alone is unsatisfactory, for it has been found
that, although at certain stages of this condition the liver may become al-
most entirely free from any trace of glycogen, at a later stage glycogen
may again make its appearance. It is therefore most difficult to decide
at what stage in starvation the animal should be considered as glycogen-
free.

If the starving animal is made to perform muscular exercise, complete
removal of glycogen from the liver can be depended upon. The exercise
may be produced by the administration of strychnine in such dosage as
just to produce convulsions of the voluntary muscles without permanent
contraction of those of respiration. The most useful method, however,
consists in starving the animal for a few days and then placing it in a
cold, damp room, after giving it a cold bath. The evaporation of mois-
ture from the surface so cools the body down that the stores of glycogen
all become used up in the attempt to supply fuel for the production of

696 - METABOLISM

sufficient heat to maintain the body temperature. This method can be
rendered still more certain in effecting a removal of all carbohydrate
from the body by giving the animal phlorhlzin every eight hours. Phlor-
hizin, as we shall see, renders the animal diabetic.

After removing the glycogen, further deposition in the liver can be
readily shown to occur when any of the ordinary sugars or starches are
given as food. It does not occur, however, when chemical substances
closely related to ordinary sugar, such as the wood sugars (pentoses)
or the alcohols and acids corresponding to dextrose, are contained in the
diet. Nor does it occur with cellulose or with inulin, a polysaccharide
built up from pentose sugar. When proteins are fed the results are not
so definite, although many observers have claimed that glycogen is
formed. With fat, on the other hand, no glycogen formation can be
shown to occur, although we know that a trace of carbohydrate must be
formed out of the glycerine of the fat molecule.

The results of the direct method, even when the conditions are per-
fectly controlled, are very unreliable, especially when they are of a nega-
tive character, because any new sugar that may be produced by the in-
gested substance instead of being stored as glycogen is likely to be used
by the tissues as it is formed. Where only a slight degree of gluconeo-
genesis, as the process of sugar formation is called, is occurring, it is not
probable that any of the glucose will be retained in the body as glycogen.

The methods employed for producing experimental diabetes in investi-
gation of these problems by the indirect method are (1) the entire removal
of the pancreas, and (2) the continuous administration of the drug
phlorhizin. The animal rendered diabetic by either of these methods is
first of all observed for several days to. determine the normal daily ex-
cretion of sugar. At the same time the nitrogen excretion for the day
is determined, the ratio between the total nitrogen and the glucose —
known as G to N ratio — being about 1 to 3.65 when complete diabetes
has become established. The foodstuff in question is then fed to the
animal, and the amount of extra glucose excreted thereby is taken to
represent that which has been derived from the ingested food. By this
method it has been possible to show that, not only the above mentioned
carbohydrates, but protein as well produce a very considerable quan-
tity of glucose in the animal body. Fats, however, yield only negative
results.

The indirect method has another great advantage over the direct in
that the results are much more quantitative in character; for example,
Lusk and his pupils have been able to determine the amount of glucose
which can be produced by feeding certain of the building stones of the
protein molecule. The great practical importance of such results in

THE METABOLISM OF THE CARBOHYDRATES 697

the therapy of diabetes makes it advisable for us to go into the subject
a little more in detail here.

After a cold bath and exposure in a cold room, dogs are rendered
diabetic by phlorhizin. When all of the original glycogen in the body
has been got rid of, as evidenced by the constancy of the G to N
ratio in the daily quantities of urine excreted, the substance under in-
vestigation is fed. If this substance contains no nitrogen and causes no
change in the nitrogen excretion, any increase in that of glucose must
obviously represent the extent to which the substance has become con-
verted into this sugar. On the other hand, if the substance itself con-
tains nitrogen, or if it causes a change in the excretion of nitrogen, it
becomes necessary to calculate how much of the excreted glucose may
have been derived from the body protein, assuming that this can form
glucose, and how much from the administered substance.*

From the results of this method it has been an easy matter to show
that the following substances are converted in the animal body into
glucose: (1) Glycol aldehyde (CH2OH-CHO). By placing three mol-
ecules of this substance together, a hexose molecule results, a synthesis
which can be accomplished in the chemical laboratory. The hexose formed
in the animal body is glucose. Glycol aldehyde may be formed in normal
metabolism out of glycocoll (CH2NH2CQOH).

(2) Glycerol (CH2OH- CHOH- CH2OH) may also readily be con-
verted into hexose in the laboratory, the possible intermediary products
being dioxyacetone (CH2OH- CO - CH2OH) and glyceric aldehyde
(CH2OH-CHOH-CHO). Two molecules of either of these may be
polymerized to form a hexose molecule, 'and when this process occurs
in the animal body, the hexose formed is glucose.

(3) Lactic acid (CH3CHOH - COOH) is completely converted to glu-
cose in the diabetic animal, and the process must involve both a re-
arrangement of the molecule and subsequent polymerization. The related
substance, propyl alcohol (CH3 - CH2 - CH2OH) is also converted into
glucose in the phlorhizinized dog. As to the exact nature of the chemical
changes which occur as intermediary stages in the conversion of these
substances into glucose, we are not as yet certain, but a clue has
been afforded by the discovery that a substance called methylglyoxal
(CHgCOCHO) can be obtained from lactic acid and also from glucose, and
that this substance is converted into glucose when it is administered to phlor-
hizinized dogs. We shall find later an important role for this substance
in fat metabolism. It can also readily be produced during the interme-

*This calculation is made as follows: The amount of nitrogen in the administered substance is
deducted from the nitrogen excretion, and the difference, which must represent the nitrogen of the
body protein, is multiplied by the G to N ratio which prevailed on the day previous to that on
which the substance was fed. We obtain in this way the glucose derived from the body. The
glucose coming from the administered substance can then be ascertained by deducting that derived
from the body protein from the total glucose excretion.

698 METABOLISM

diary breakdown of certain of the protein building-stones, such for
example as alanine (CH3CHNH2COOH).

These chemical possibilities regarding the nature of the substances
that serve as stepping stones between the above sugar-forming sub-
stances and sugar itself may be considered as probabilities on account
of the discovery that enzymes exist in various tissues which are capable
of converting methylglyoxal into lactic acid :

CH3 CH3

| !

CO + H2 -» HCOH

I 0<- |
CHO COOH

(methylglyoxal) (lactic acid)

These enzymes are called glyoxalases, and since the reactions which
they mediate, are undoubtedly reversible in character, it is probable that
the conversion into sugar of lactic acid and alanine — to take those two
as among the commonest of the sugar precursors of the animal body-
occurs according to the following equation:

CH3CHNH2COOH v.

( alanine ) CHXOCHO -» C6H12O6

CH,CHOHCOOH /*

(lactic acid) (methylglyoxal) (hexose)

The unique position of methylglyoxal, besides explaining the known
resolutions of protein and fat and carbohydrate in intermediary metab-
olism, is also of importance in explaining the synthetic production of
glucose from fructose (or levulose). Fructose will first of all become
converted into methylglyoxal radicles, and these will then become syn-
thetized into glucose.

The hypothesis of the conversion of glucose into lactic acid as a stepping
stone in the metabolism of carbohydrate is difficult to test by direct ex-
periment because the lactic acid does not accumulate in the organism,
except in cases where there is oxygen deficiency or excess of alkali in the
tissue fluids.

Coming now to the amino acids, which, it will be remembered repre-
sent the building stones of the protein molecule, it has been found that
glycocoll, alanine, and aspartic and glutamic acids increase the glucose
excretion when given to phlorhizinized dogs, whereas leucine and tyro-
sine have no such action. By the method described above, it is possible
to determine the exact proportion of the carbon of each of those amino
acids which becomes converted to glucose. This is shown in the accom-
panying table.

It is of further interest to point out that these four amino acids
constitute about 26 per cent of all the amino acids in flesh protein, and

THE METABOLISM OF THE CARBOHYDRATES

699

TWENTY GKAMS OF THE VARIOUS AMINO BODIES WERE GIVEN TO
PHLORHIZIN-DIABETIC DOGS

ACID AND FORMULA

AVERAGE AMOUNT
OF GLUCOSE PRO-
DUCED IN BODY

PROBABLE GLUCOSE THAT
CHANGE WOULD BE PRO-
DUCED BY CHANGE

Glycocoll
CH2NH2COOH

13.43 (five dogs,
one gave 15.77)

All C converted
to glucose

16.00

i. alanine
CH3CHNH2COOH

18.77 (two dogs)

< t

20.22

Aspartic acid
COOH— CH2—CHNH3— COOH

12.42 (four dogs)

Three of the four
C atoms converted

13.52

Glutamic acid
COOH

13.31

CH2

CHa— CHNH2
COOH

to glucose

Three of the five
C atoms converted
to glucose

12.24

that the total yield of glucose from them could be 26.3 grams; thus
accounting for nearly one half of the 66 grams which a diabetic animal
produces from 100 grams of flesh.

Gluconeogenesis in Normal Animals. — Although it has been clearly
shown by the indirect method that not only protein but its decomposi-
tion products as well, can be readily converted into glucose, yet this does
not necessarily indicate that a similar conversion occurs in the nondia-
betic animal. That such is the case, however, can be shown in various
ways. Thus, at the end of a period of long starvation considerable
quantities of glycogen are quite commonly found in the body, and the
blood sugar, although lower than normal, never entirely disappears.
Now, since no carbohydrate is being ingested, and the body stores of this
foodstuff become exhausted early during starvation (cf. page 695), it
is evident that the carbohydrate must be produced from the protein of
the animal's body. A still more convincing experiment can be con-
ducted by producing strychnine convulsions in a starving animal. If
the animal is killed after the convulsions have lasted for a certain time,
the tissues will be found almost if not entirely free of glycogen,
but if the convulsions are made to disappear by giving chloral and the
animal allowed to sleep for some time before killing it, glycogen again
accumulates in the body. This glycogen must have been manufactured
out of noncarbohydrate material.

Corroborative evidence of a somewhat different nature is furnished by
an examination of the respiratory quotient, which, it will be remem-
bered (page 582), varies according to the nature of the foodstuff or body

700 METABOLISM

constituent that is undergoing metabolism at the time, being about 1
with carbohydrate and about 0.7 with protein. If the quotient is
observed during starvation, it will often be found to fall below 0.7, a
figure which can be explained only by assuming that oxygen has been
retained in the body beyond the quantity which is necessary for imme-
diate purposes of oxidation (cf. equations on page 583).

Since it is known that this retained oxygen can not exist in the body
in a free state it must be concluded that it has become incorporated
into substances having a high oxygen content. Such would be the case
if protein or fat, which contains only from 12 to 20 per cent of oxygen,
were converted to carbohydrate, which contains about 53 per cent.
Utilization of inhaled oxygen for this purpose, as we have seen, becomes
very striking in the case of hibernating animals during the winter sleep.

CHAPTER LXXVIII

THE METABOLISM OF THE CARBOHYDRATES (Cont'd)
FATE OF GLYCOGEN

Having become familiar with the sources from which glycogen may
be derived, we may now proceed to study the fate of the glycogen found
in the liver cells and in the muscles. For the present we shall confine our
attention to the glycogen of the liver. If a portion of liver removed
from a well-fed animal is examined microscopically after staining either
with iodine or with carmine by Best's method, it will be found that the
cells of the lobules are filled with glycogen except for the nuclei, which
are free from this substance. If, on the other hand, the liver is from an
animal that has not been recently fed, the lobules will contain no glyco-
gen except in an area bordering on the central vein and perhaps a
narrow strip at the periphery of the lobule. "When it is present the rela-
tive amount of glycogen in different lobules, as determined chemically,
is the same over the entire liver — that is to say, no one lobe is richer in
this substance than another. Nothing definite is known as to how the
glycogen is held in the protoplasm of the cells, although some histolo-
gists suggest that it is combined with a sustentacular material especially
provided for this purpose.

The glycogen stored in the liver is gradually given up to the blood of
the hepatic vein at such a rate as to maintain in the blood of the sys-
temic circulation a more or less constant percentage of glucose. Under
ordinary conditions this process of glycogenolysis is relatively slow, but
when the requirements of the organism for fuel become increased, as
during muscular exercise, it becomes very rapid. The glycogenic func-
tion of the liver appears therefore to exist, in part at least, for the
purpose of preventing the flooding of the blood of the systemic circu-
lation with excess of sugar during absorption from the intestine and of
maintaining the normal percentage at other times. This function is
analogous to that occurring in plants, in which the sugar produced in
the leaves, if not immediately required, is transported to various parts
of the plant and there converted into starch, which, when the plant
requires it, as during new growth, may again become transformed into
glucose.

The agency converting the glycogen into glucose is the diastatic

701

702 METABOLISM

enzyme glycogenase, which is present, not only in the liver cell, but
also in the blood and lymph. It is a difficult matter to explain why
glycogen should be able to exist at all in the liver cells in the presence
of this powerful enzyme. The following possibilities may be considered:
(1) That glycogenase does not really exist in the living liver cells, but
.is a postmortem product; (2) that, although present, glycogenase is pre-
vented from acting on .the glycogen in the living liver cell on account of
the latter being protected from its influence by combination with a
sustentacular substance; or (3) that some chemical substance in the liver
cell prevents the glycogenase from acting on the glycogen — an anti-
glycogenase. Since the removal of any one of these inhibiting influ-
ences would cause glycogenolysis to become excessive, and so bring
about hyperglycemia, it is important, in searching for the possible
causes of this condition, to examine the evidence that has been brought
forward in support of each of these views.

Against the first of the above-mentioned possibilities, namely, that glycogenase is a
post-mortem product, may be cited the very rapid conversion into glucose that occurs
when glycogen is added to living blood, as by injecting some into a vein. On account of
the active; glycogenolytic action of blood, it has been suggested that during life glycogen
does not become transformed into glucose until after it has been discharged into the
blood from the liver cell. When increased sugar must be mobilized, glyeogen passes
unchanged, or perhaps as some dextrine, into the blood and lymph of the liver capillaries
and lymphatics, the glycogenase of which converts it into glucose, the conversion being
so rapid that, by the time the blood has traveled from the liver through the heart
and pulmonary vessels to the arteries, all the glycogen has already become transformed
into glucose. Postmortem glycogenolysis, according to this view, is due to the opposite
occurrence — the transference of glycogenase from the blood into the liver cell. Some
facts supporting this view are as follows: (1) It has been found that the amount of
free glucose in the blood of the vena cava is sometimes less than in that collected simul-
taneously from the carotid artery. (2) After giving certain substances, such as phos-
phorus or peptone, there is distinct diminution in the amount of glycogen in the liver,
accompanied, it is said, by no increase in the amount of glucose in the blood. And
(3) if the liver of an animal that has been rendered diabetic by stimulation of the
splanchnic nerve or by puncture of the floor of the fourth ventricle is examined micro-
scopically, after staining by the carmine method, masses of stained glycogen can be
found present in the capillaries (sinusoids) that lie between the liver cells.

According to the second view, the glycogen is removed from the influence of the in-
trahepatic glycogenase on account of its combination with a sustentacular material.
By disrupting this combination and thus exposing the glycogen to the action of glyco-
genase, glycogenolysis will occur. We may call this the mechanical hypothesis and
it deserves serious consideration, for it has been shown that very little postmortem
glycogenolysis occurs in the intact liver of frogs in winter, — even though at this time
the organ contains an excess of glycogen, — but becomes marked when the liver is broken
down by mechanical means.

The third view depends on the well-known fact that enzyme activities becomes most
markedly altered by slight changes in the chemical nature of the environment in which
they act. Diastatic enzymes are particularly susceptible to the reaction (CH) of their
environment, a very slight degree of acidity favoring and a trace of alkalinity mark-

THE METABOLISM OF THE CARBOHYDRATES 703

edly depressing their activities. That a tendency to increasing acidity in the liver
cells may accelerate the breakdown of glycogen is suggested by the depressing effect
produced on the assimilation limit of sugars by administering acids, and by the ob-
servation that postmortem glycogenolysis becomes marked in proportion as the dying
liver becomes acid in reaction. It might be thought then that glycogenolysis in the
liver cell could be set up by the local production of a certain amount of acid. Such
a liberation of free acid could be brought about by a curtailment in the arterial blood
supply of the hepatic cell, producing a local accumulation either of carbonic or of other
less completely oxidized acids (e. g., lactic). It may be that asphyxia causes hyperj
glyeemia by such a mechanism. Vasoconstriction and consequent curtailment of ar-
terial blood supply occurs in the liver when the hepatic nerves are stimulated, and
it is possible that the glycogenolysis which is also set up by such stimulation is due to
the appearance of acids. The accelerating effect of epinephrine on glycogenolysis might
also be explained as due to limitation of blood supply on account of vasoconstriction
and local asphyxia.

THE REGULATION OF THE BLOOD SUGAR LEVEL

The level at which the concentration of sugar in the systemic blood
is maintained represents the balance between two opposing factors: (1)
the consumption of glucose bv the tissues, and (2) the production of
glucose by the liver. Since this is the most readily oxidizable of all
the proximate principles of food (page 685), muscular activity causes
large quantities of it to be consumed, so that its concentration in the
blood tends to fall below the physiological level, a tendency which is
immediately met by an increased discharge of glucose from the liver.
The question therefore arises as to how the muscles or other tissues
transmit their requirements for glucose to the liver. There are two
possible ways by which this could be done: (1) by means of a nervous
reflex, or (2) by changes in the composition of the blood, either with
regard to the percentage of sugar itself or because of the appearance in
it of decomposition products of glucose or of some special exciting
agent or hormone.

In order to ascertain the relative importance of these .methods of
correlation between the places of supply and demand of glucose in the
normal animal, it is necessary to investigate the conditions under which
an excessive discharge of glucose occurs either, because of overstimulation
of the nervous control, or because of the presence of exciting substances
(hormones) in the blood. The glycogenic function can be excited through
the nervous system in a variety of ways so as to cause hyperglycemia
and glycosuria. This constitutes one form of experimental diabetes. In
laboratory animals mechanical irritation of the medulla oblongata and
stimulation of the great splanchnic nerves act in this way. Similar stimula-
tion may also occur under certain conditions in man. Excitation as a resuK
of changes in the composition of the blood can be produced experimen-
tally by certain drugs (phlorhizin), or by the removal of certain of the

704 METABOLISM

ductless glands or the injection of extracts prepared from them, such
as epinephrine.

Nerve Control and the Nervous Forms of Experimental Diabetes.—

The simplest experimental condition which illustrates the relationship
between the nervous system and the blood sugar is electrical stimulation
of the great splanchnic nerve in animals in which, by previous feeding
with carbohydrates, a large amount of glycogen has been deposited in
the liver. By examination of the blood as it is discharged into the vena
cava from the hepatic veins, the increase in blood sugar is very evident
in from five to ten minutes after the first application of the stimulus;
but it is not until later that a general hyperglycemia becomes estab-
lished. The conclusion which we may draw from these results is that
the splanchnic nerve contains efferent fibers controlling the s rate at
which glycogen becomes converted to glucose in the liver. The center
from which these fibers originate is situated somewhere in the medulla
oblongata, for the irritation that is set up by puncturing this portion of
the nervous system with a needle yields results similar to those which
follow splanchnic stimulation. This "glycogenic" or diabetic center, as
it has been called, must be provided with afferent impulses. Such im-
pulses have indeed been described in the vagus nerves, but their dem-
onstration is by no means an easy matter on account of the disturbance
in the respiratory movements coincidently produced by the stimulation.
The changes that such disturbances bring about in the aeration of the
blood may in themselves be responsible for the hyperglycemia (see page
348). It can at least be said that when the respiratory disturbances are
guarded against, as by intratracheal insufflation of oxygen, vagal hyper-
glycemia is much less marked, if not entirely absent. But this question
awaits more thorough investigation.

The increased glycogenolysis which results from stimulation of the
efferent fibers in the splanchnic nerves may depend either on^a direct
control exercised over the glycogenic functions of the hepatic cells, or
on the discharge into the blood of some hormone which excites the
glycogenolytic process. It must furthermore not be lost sight of that
the glycogenolysis may be secondary to local asphyxial conditions in
the liver cells resulting from vasoconstriction. From their anatomic
position, the adrenals are to be thought of as the source of the hormone,
and evidence that splanchnic hyperglycemia is due to hypersecretion
from these glands has seemed to be furnished by the fact that after they
are extirpated splanchnic stimulation no longer produces hyperglycemia,
neither, indeed, does puncture of the medulla. There is also no doubt
that the nervous system, acting by way of the splanchnic nerves, does
exercise a control over the discharge of the internal secretion of the

THE METABOLISM OF THE CARBOHYDRATES 705

adrenal glands and that extracts of the gland, which we must suppose
act in the same way as the internal secretion, cause hyperglycemia when
injected intravenously (epinephrine hyperglycemia and glycosuria) (page
776).

But on theoretical grounds alone, certain difficulties immediately pre-
sent themselves in accepting this as the mechanism by which the nervous
system controls the sugar output of the liver, for if increased sugar
formation in the liver is dependent on a discharge of epinephrine, the
question may be asked why this secretion should be caused to traverse
the entire circulation before reaching the liver.

There are, besides, certain experimental facts which do not conform
with such a view. Thus, after complete severance of the hepatic plexus
of nerves, stimulation of the splanchnic nerve does not cause the usual
degree of hyperglycemia, whereas electric stimulation of the peripheral
end of the cut plexus does cause it. On the one hand, therefore, there
is evidence that stimulation of the efferent nerve path above the level of
the adrenals has no effect on the sugar production of the liver in the
absence of these glands; and on the other, we see that when they are
present, stimulation of the nerve supply of the liver is effective, even
though the point of stimulation is beyond them. There is but one con-
clusion that we may draw — namely, that the functional integrity of the
efferent nerve-fibers that control the glycogenolytic process of the liver
depends on the presence of the adrenals, very probably because of the
hormone which the glands secrete into the blood. This conclusion is
corroborated by the fact that stimulation of the hepatic plexus, even
with a strong electric current, some time after complete removal of
both adrenals, is not followed by the usual degree of excitement of the
glycogenolytic process.

These experiments demonstrate an important relationship between
the nervous control, and at least one form of hormone control, of the
sugar output of the liver. They indicate that when a sudden increase
of blood sugar is required, the glycogenic center sends out impulses
which not only directly excite the breakdown of glycogen in the he-
patic cells, but also simultaneously influence the adrenals in such a man-
ner as to produce more epinephrine in the blood and so augment the ac-
tion of the nerve impulse.

We are as yet quite in the dark as to the mechanism by which the nerve impulses or
the hormone brings about increased glycogenolysis. It must consist of a removal of the
influence that prevents glycogenolysis from occurring in the normal liver, for it has
been shown by direct observation that there is no increase in the amount of glycogenase
present in extracts of the liver removed from diabetic animals over that present in
extracts of the liver of normal animals. The possible nature of this influence has
already been discussed (page 702). The change may consist either in a loosening of
the combination between the glycogen and the protoplasm of the liver cell, or in a
removal of the chemical influence that ordinarily prevents the glycogenase from at-

706 METABOLISM

tacking the glycogen. In the former case the glycogen liberated from its union with
the sustentacular substances would either become attacked by the glycogenase present
in the liver cell itself or it would first of all migrate, as glycogen, into the blood capil-
laries and there be attacked by the blood glycogenase. Evidence for the possibility of
the occurrence of such a process lias already been given (page 702). The chemical
'change referred to under the second possibility might consist in an alteration in the
hydrogen-ion concentration of the liver cell, a change, however, which for obvious reasons
it is impossible to investigate.

Nervous Diabetes in Man, — The main interest attaching to the inves-
tigation of these nervous forms of experimental diabetes depends on the
insight which they afford us into the nature of the mechanism by which
a prompt mobilization of glucose may be brought about in the normal
animal. There is also some evidence that a relationship may exist be-
tween certain of the clinical varieties of the disease in man and repeated
excitation of glycogenolysis brought about by nerve stimulation. In-
creased glucose output from the liver as a result of nerve excitation
may be a normal process, but there is reason to believe that frequent
repetition of this process tends to induce a permanent rise in the glucose
level of the blood and therefore a tendency to diabetes. There have
recently been collected several facts which lend some support to this
view. The frequent occurrence of diabetes in those predisposed by
inheritance to neurotic conditions, or in those whose daily habits entail
much nerve strain, and the aggravation of the symptoms which is likely
to follow when a diabetic patient experiences some nervous shock, all
point in this direction.

Diabetes is common in locomotive engineers and in the captains of
ocean liners — that is, in men who in the performance of their daily duties
are frequently put under a severe nerve strain. It is apparently in-
creasing in men engaged in occupations that demand mental concentra-
tion and strain, such as in professional and business work. Cannon23
found glycosuria in four out of nine students after a severe examination,
but only in one of them after an easier examination.* In the urines of
twenty-four members of a famous football squad, fsugar was found pres-
ent in twelve immediately after a keenly contested game. Anxiety and
excitement must have been responsible for its appearance, since five of
the twelve players were substitutes who did not get into the game.

Although these nervous conditions, by excitement of hepatic glyco-
genolysis, produce at first nothing more than an excessive discharge of
sugar into the blood — a condition which is exactly duplicated in our
laboratory experiments by stimulation of the nerve supply of the liver —
their repetition may gradually lead to the development of a permanent
form of hyperglycemia. To prevent the repetition of these transient

*We have been unable to confirm this observation even though the examinations were made
unusually "nerve-racking."

THE METABOLISM OF THE CARBOHYDRATES 707

hyperglycemias must be one of our aims in the treatment of early stages
of the disease.

It is possible that- the relationship of nerve strain to the incidence of
diabetes has been exaggerated, for it has been stated that there was a
marked decrease in the number of cases of this disease in Berlin during
the later years of the war. During this period the nerve strain was very
great, but the diet was greatly restricted and it may be in light of the
latter fact that the disease is related more to dietetic habits than to con-
ditions of nerve strain (Magnus Levy). In view of the observations, it
is significant that diabetes is said to be increasing in frequency in the
United States since prohibition came into effect. The excessive consump-
tion of sugar is possibly responsible for this condition.

Although there can be no doubt that the glycogenic function of the
liver is subject to nerve control, it is probable that its control by hor-
mones is of equal if not greater importance. This dual control of a
glandular mechanism is by no means unique for the glycogenic function,
for we have already seen it to exist in the case of the gastric glands
and the pancreas, and it is probable that it also exists in the case of
the thyroid. It may well be that the nerve control of the glycogenic
function has to do only with those transitory changes in sugar produc-
tion that would be demanded by sudden activities of muscle, and that
the hormone control has to do with the more permanent process of build-
ing up and breaking down of glycogen to meet the general metabolic
requirements of the tissues.

HORMONE CONTROL AND PERMANENT DIABETES

Nervous excitation can explain only transitory increases in blood sugar,
the more permanent hyperglycemias being dependent upon some dis-
turbance in the hormone control of carbohydrate utilization. This dis-
turbance is a much more serious affair than that produced by nervous
excitation. In the latter case the hyperglycemia ceases whenever all
of the glycogen stores of the liver have been exhausted; whereas a dis-
turbance in the hormone control, besides causing as its first step a
breakdown of all the available glycogen, goes on to cause a production
of sugar out of protein. A process of gluconeogenesis (new formation
of glucose) becomes superadded on one of glycogenolysis.

To ascertain the nature of this hormone and the mechanism of its
action has been the object of most of the researches on those forms of
diabetes that are produced by changes in certain of the ductless glands.
The following possibilities may be considered: (1) that the controlling
agency is the concentration of glucose in the blood; (2) that it is the

708 METABOLISM

presence in the blood of decomposition products of glucose; (3) that it
is due to a special hormone produced from some ductless gland. Con-
cerning the first of these possibilities, it is supposed that the mechanism
involved is dependent on the law of mass action ; namely, that glycogen be-
comes converted into glucose whenever the blood flowing to the liver con-
tains less than its normal concentration of glucose, and conversely, when this
blood contains an excess of glucose, as during absorption, that a glycogen-
building process occurs. Although there can be little doubt that the process
of glycogen formation or destruction will depend to a certain extent
upon the amount of glucose present in the blood flowing to the liver
cells, yet it is impossible that this can be an important means in the
control that exists between sugar production by the liver and sugar
consumption by the tissues, because the sugar that is added to the portal
blood during absorption would mask any depletion caused by sugar
consumption in the tissues.

The second possibility — that the hormone is some decomposition prod-
uct of glucose — would appear to have some support, if we consider this
hormone to be an acid product (carbon dioxide or lactic acid) produced by
sugar metabolism, for it is known that an increase in the hydrogeu-ion
concentration of the blood flowing to the liver cells excites a glycogen-
olysis. As we have already seen, however, it is difficult to secure ex-
perimental evidence, in anesthetized animals at least, that glycogen-
olytic activity is readily excited in this way.

The third possibility — that some specific hormone may exist in the
blood exciting the glycogenolytic process — is investigated by producing
disturbances involving various of the ductless glands, particularly the
pancreas, the adrenals, the parathyroids and the pituitary. The influ-
ence of certain of these glands may be closely bound up with that
exercised through the nervous control, as we have seen to be the case
with the adrenal gland. Whether it is by the production of hormones
directly necessary for proper carbohydrate metabolism, or by the re-
moval from the blood of such substances as interfere with this process,
that the ductless glands functionate, is one of the main problems we
have to consider.

Utilization of Glucose in Tissues. — Although the experimental diabetes
induced by disturbances in the function of the ductless glands is dependent
in the first instance on an upset of the glycogenic function and later on glu-
coneogenesis, the utilization of glucose in the tissues ultimately becomes
interfered with. It is therefore important that we should digress for a
moment to consider briefly what is known regarding the process by
which sugar becomes utilized in the organism. That glucose becomes
used up by active muscle there can be no doubt. Thus, if the muscles

THE METABOLISM OF THE CARBOHYDRATES 709

of one leg in the frog are tetanized, the glycogen content, compared with
that of the other leg, will be found to be diminished.

At first sight it might appear that the easiest way to study the utiliza-
tion of glycose in the muscles would be to compare its concentrations
in the blood flowing to and coming from them. The muscle that has been
most successfully employed in studies of this kind has been the heart-
Some years ago Starling and Knowlton24 sought to measure the consump-
tion of glucose by the excised mammalian heart, by comparing the per-
centage in the perfusion fluid at various periods during the observation.
Patterson and Starling25 showed later, however, that the results obtained
by such a method can furnish no criterion of the actual consumption of
glucose by the tissue on account of the fact that the heart itself may
store away large quantities of carbohydrate in an unused state, i.e., as
glycogen. After allowing for the glycogen as well as for the glucose
consumption by the lungs, Cruikshank and Patterson64 computed that
the heart (of the cat) uses 1.5 mg. glucose per gram per hour.

Other investigators have thought to study the utilization of glucose
by observing the rate at which it disappears from drawn blood kept in
a sterile condition at body temperature for some hours after death.
This process is called glycolysis, and it has been assumed that the process
is similar to that which occurs in the tissues themselves — an assumption,
however, for which there is no warranty. Indeed, it may readily be
shown that the glycolysis occurring in blood has very little if anything
to do with the utilization of glucose in the tissues, for it has been found
that glucose disappears from drawn blood very slowly indeed when
compared with the rate at which it disappears from the blood of animals
in which the addition of glucose from the liver has been prevented by

moval of this viscus (Macleod).26

A third method for studying the utilization of glucose consists in
observing the respiratory exchange of animals. In normal animals the
injection of glucose causes an increase in the carbon-dioxide excretion
and a rise in the respiratory quotient, which it will be remembered is
a ratio expressing the relationship between the amount of carbon dioxide
excreted and of the oxygen retained in the organism. When carbohy-
drate is undergoing combustion, the quotient is nearly 1, whereas with
that of protein it is about 0.7 (see page 582). By observing the quotient
under given conditions one can compute the proportions of carbohydrate
and of fat and protein that are undergoing metabolism. In the hands
of Murlin and others,27 this method has proved of some value in settling
certain questions concerning the utilization of glucose in normal and
diabetic animals ; but the results must be interpreted with great care on
account of the fact that temporary changes in the blood may cause a

710 METABOLISM

greater or a less expulsion of carbon dioxide from it. Thus, if acids
appear in the blood, they will dislodge carbon dioxide, and apparently
cause the respiratory quotient to rise. Alkalies, on the other hand, ap-
parently cause the quotient temporarily to fall, and unless the observa-
tions are done over a long period of time and with great care, faulty
conclusions are very apt to be drawn from the results. Starling and
Evans65 have measured the respiratory exchange in the heart lung prep-
aration (see page 163) and have found that the heart uses an average of
3.2 c.c. of oxygen per gram an hour when doing moderate work, the
E.Q. being 0.85. This corresponds to 1.6 mg. glucose consumption per
gram per hour, thus corroborating the results obtained by direct estima-
tion of glucose.

Diabetes and the Ductless Glands

We are now in a position to consider the forms of experimental dia-
betes produced by disturbances in the ductless glands.

Relationship of the Pancreas to Sugar Metabolism. — In no other of
the many causes of diabetes has greater interest been shown than in
that due to disturbance in the pancreatic function. Many of the earlier
clinicians who followed cases of diabetes mellitus into the postmortem
room, noted that definite morbid changes in the pancreas were a fre-
quent accompaniment of the disease. Prompted by these observations,
several investigators attempted experimental extirpation of the gland,
but did not succeed in producing glycosuria in the few animals that
survived the operation. Their failure, no doubt, was due to incom-
plete extirpation. To reduce the severity of the operation, Claude Ber-
nard injected oil into the pancreatic duct, and tied it; but he succeeded
in keeping only two dogs alive for any length of time, and these did
not exhibit glycosuria. Neither were other investigators that adopted
similar methods any more successful. It looked as if the pancreas had
no relationship to carbohydrate metabolism. In the year 1889 Minkowski
and von Mering in Germany, and de Dominicis in Italy, by thorough
extirpation of the gland, succeeded in producing in dogs a marked and
persistent glycosuria, accompanied by many of the other symptoms of
diabetes. The first two authors attributed the condition to removal of
an internal secretion.

The course of the diabetes produced by complete pancreatectomy is,
however, somewhat different from that usually observed in man. It is
extremely acute from the start, the G:N ratio being 1:3.6 (see page
696), and it is unaccompanied by any of the classical symptoms seen in
the clinical condition. Experimental pancreatic diabetes can, however,
be made to simulate very closely the disease in man. This was first of

THE METABOLISM OF THE CARBOHYDRATES 711

all demonstrated by Sandemeyer, who found that if the greater part of
the pancreas was removed, the animals for some months, if at all, were
only- occasionally glycosuric, but later became more and more frequently
so, until at last the condition typical of complete pancreatectomy super-
vened. Similar results have more recently been obtained by Thiroloix
and Jacob, in France, and by Allen in this country. These investigators
point out that different results are to be expected according to whether
the portion of pancreas which is left does, or does not, remain in con-
nection with the duodenal duct. When this duct is ligated, atrophy of
any remnant of pancreas that is left is bound to occur, and this is asso-
ciated with rapid emaciation of the animal, diabetes and death. When
the remnant surrounds a still patent duct, a condition much more closely
simulating diabetes in man is likely to become developed — one, namely,
in which there is, for some months following the operation, a more or
less mild diabetes, which, however, usually passes later into the fatal
type.

It is, of course, difficult to state accurately what proportion of the
pancreas must be left in order that the above described qondition may super-
vene. Leaving a remnant amounting to from one-fifth to one-eighth
of the entire gland -is commonly followed by a mild diabetes, whereas
if only one-ninth or less is left, a rapidly fatal type develops. As in
clinical experience, the distinguishing feature between the mild and the
severe types of experimental pancreatic diabetes is the tolerance toward
carbohydrates. In the mild form, no glycosuria develops unless carbo-
hydrate food is taken; in the severe form, it is present when the diet is
composed entirely of flesh. It is thus shown that "by removal of a
suitable proportion of the pancreas, it is possible to bring an animal
to the verge of diabetes, yet to know that the animal will never of itself
become diabetic. . . . Such animals, therefore, constitute valuable
test objects for judging the effects of various agencies with respect to
diabetes" — (Allen18). It therefore becomes theoretically possible to in-
vestigate, on the one hand, other conditions which will have an influence
similar to removal of more of the gland, or, on the other, conditions
which might prevent the incidence of diabetes, even though this extra
portion of pancreas is removed.

Allen has shown that the continued feeding of a partially depancreatized
dog with excess of carbohydrate food will surely convert a mild into a
severe case of diabetes, and in one experiment he succeeded in bringing
about the same transition by performing puncture of the medulla — that
is, by creating an irritative nervous lesion. By none of the other means
usually employed to produce experimental glycosuria could the mild
case be made severely diabetic, although this was accomplished in one

712 METABOLISM

animal after ligation of the portal vein. To the clinical worker the value
of these results lies in the fact that they furnish experimental proof that
a so-called latent case of diabetes — that is, one that has a low tolerance
value for carbohydrates — may be prevented from developing into a
severe case by proper control of the diet. Attempts to show whether or
not there are any conditions which might bring about improvements
in animals that were just diabetic have not as yet been sufficiently made
to warrant any conclusions that could help us in the treatment of human
cases. It has been suggested that stimulation of the internal pancreatic
secretion might occur when the secretion into the intestine is kept as
low as possible by selecting a diet that does not require the pancreatic
enzymes for its digestion and that the increased internal secretion might
be of value in delaying the onset of diabetes in susceptible cases.

The Pathogenesis of Pancreatic Diabetes

The certainty with which diabetes results from pancreatectomy in dogs,
as well as the frequent occurrence of demonstrable lesions of the pan-
creas in diabetes in man, leaves no doubt that this gland must be in some
way essential in the physiological breakdown of carbohydrates in the
normal animal, but how, we can not at present tell. All we know is
that the first change to occur after the gland is removed is a sweeping
out of all but a trace of the glycogen of the liver, although the muscles may
retain theirs; indeed, in the cardiac muscle there may be more than
the usual amount."8 Nor can any glycogen be stored in the liver when
excess of carbohydrates is fed. After the glycogen has disappeared,
gluconeogenesis sets in, so that the tissues come to melt away into sugar,
and all the symptoms of acute starvation, associated with certain others
that are possibly due to a toxic action of the excess of sugar or other
abnormal products in the blood, make their appearance.

So far it might be permissible to consider an overproduction of glu-
cose as the sole cause of the hyperglycemia of pancreatic diabetes, just as
we have seen it to be the cause of these forms of hyperglycemia that re-
sult from stimulation of the nervous system; but this can not be the case,
for another very definite abnormality in metabolism becomes evident —
namely, an inability of the tissues to burn sugar. This fact is ascer-
tained by observing the respiratory quotient. When glucose is added
to the blood in the case of a completely diabetic animal, no change oc-
curs in the quotient.

There are, therefore, two essential disturbances of carbohydrate
metabolism in pancreatic diabetes — overproduction of sugar and aboli-
tion of the ability of the tissues to use it. It becomes important for UP
to see whether the tissues exhibit this inability to use sugar when they

THE METABOLISM OF THE CARBOHYDRATES 713

are isolated from the animal; for if they should, a much more searching
investigation of the essential cause of their inability would be possible
than is the case when they are functioning along with the other organs
and tissues. The earlier experiments of Lepine and his pupils, which seemed
to show that diabetic blood did not possess the glycolytic power of
normal blood ; and those of Cohnheim, from which it was concluded that
mixtures of the expressed juices of muscle and pancreas, although ordinarily
destroying glucose, failed to do so when they were taken from a diabetic
animal, are now known to be erroneous.

The failure to show a depression of glycolytic power by these methods
prompted Knowlton and Starling24 to investigate the question whether
any difference is evident in the rate with which glucose disappears from
a mixture of blood and saline solution used to perfuse a heart outside
the body, according to whether the heart was from a normal or a dia-
betic dog. In the first series of observations which these workers made,
it was thought that the normal heart used glucose at the rate of about
4 mg. per gram of heart substance per hour; whereas that of a dia-
betic (depancreatized) animal used less than 1 mg. If such striking
differences in the rate of sugar consumption could make themselves
manifest for so relatively small a mass of muscular tissue as that of the
heart, it is permissible to assume that a much more striking difference
could be demonstrated when the perfusion fluid is made to traverse all
or practically all of the skeletal muscles, as well as the heart. For this
purpose an eviscerated animal may be employed — that is, one in which
the abdominal viscera are removed after ligation of the celiac axis and
mesenteric arteries, and the liver is eliminated by mass ligation of its
lobes. Using such preparations, R. G. Pearce and Macleod29 found that
the rate at which glucose disappears from the blood, although very
irregular, is in no way different in completely diabetic as compared
with normal dogs. They were thus unable to cojifirm any of Knowlton
and Starling's earlier conclusions. As has already been stated Patterson
and Starling subsequently pointed out that a serious error was involved
in the earlier perfusion experiments, partly on account of a remarkable
but irregular disappearance of glucose from the lungs, and partly be-
cause the diabetic heart may contain a considerable excess of glycogen,
from which its demands for sugar may be met without calling on that
of the perfusion fluid.

More recent work by Starling and Evans, in which the respiratory ex-
change of the heart in heart lung preparations from diabetic (pancreatic)
dogs was determined, has revealed a low R.Q. (0.71) although the oxygen
consumption was normal. These workers consider that their results indi-
cate "a depression or abolition of the power of the diabetic tissue to utilize

714 METABOLISM

carbohydrate." This conclusion, however, awaits confirmation by more
direct methods.

In spite of the failure to show that the isolated tissues of diabetic
animals have a lower glucose-consuming power than those of normal
animals, it is important from a practical standpoint that we should
know something regarding the possible nature of the disturbance which
a removal of the pancreas entails. Even if we could not tell exactly
how this disturbance operates, it would be of value to know whether
it depends on the removal from the organism of some hormone that is
essential to carbohydrate utilization, for, if this were proved to be the
case, encouragement would be offered to seek for the chemical nature
of this hormone so that we might administer it with the object of re-
moving the diabetic state. The hope of a fruitful outcome of such an
investigation is encouraged by the success of researches on diseases of
other ductless glands, particularly the thyroid.

The removal of some hormone necessary for proper sugar metab-
olism is, however, by no means the only way by which the results can
be explained, for we can assume that the pancreas owes its influence
over sugar metabolism to some change occurring in the composition of
the blood as this circulates through the gland — a change which is de-
pendent on the integrity of the gland and not on any one enzyme or
hormone which it produces. It is obvious that the results of removal
of the gland could be explained in terms of either view, and indeed
there is but one experiment which would permit us to decide which of
them is correct. This consists in seeing whether the symptoms which
follow pancreatectomy are removed, and a normal condition reestab-
lished, when means are taken to supply the supposed missing internal
secretion to the organism; if they should be, conclusive evidence would
be furnished that it is by "internal secretion" and not by "local in-
fluence" that the gland functionates.

The experiments have been of two types: in the one, variously pre-
pared extracts of the glands have been employed, and in the other,
blood which is presumably rich in the internal secretion. The most
recent work has shown that injection of pancreatic extracts into a de-
pancreatized animal produces no change in the respiratory quotient,
although injections of extracts of pancreas and duodenum may cause
a temporary fall in the excretion of glucose in the urine on account of the
alkalinity of the extract. Neither have experiments with blood transfusions
yielded results that are any more satisfactory. In undertaking these ex-
periments it is of course assumed that the internal secretion is present in
the blood, and that if this blood is supplied to an animal suffering from pan-
creatic diabetes carbohydrate metabolism will become normal. The general

THE METABOLISM OF THE CARBOHYDRATES 715

conclusion that may be drawn from the numerous researches of this nature,
is that there is no evidence that the blood of a normal animal, even
when it is from the pancreatic vein, contains an internal secretion that
can restore to a diabetic animal any of its lost power to utilize carbo-
hydrates. When the extent of glycosuria alone is used as the criterion
of the state of carbohydrate metabolism, serious errors in judgment are
liable to be drawn. The condition of the blood sugar and the extent
and character of the respiratory exchange are the most reliable indexes.

DIABETIC ACIDOSIS OR KETOSIS

Nature and Cause. — Much confusion has existed in medical literature
over the correct definition of acidosis, mainly because the term was first
used for the particular variety of the condition observed in the later
stages of diabetes mellitus. The acids which accumulate in the tissue
fluids in this disease are acetoacetic and /?-oxybutyric, which are re-
lated to acetone and are derived from fatty acids by a faulty metabolism
(see page 737). The essential cause of the acidosis is therefore en-
tirely different from that in nephritis ; in diabetes foreign acids are
added to the blood, whereas in nephritis the acids of a normal metab-
olism accumulate because of faulty excretion through the kidneys.
The usual signs of acidosis exist in both cases, because the surplus of
acid depletes the store of bicarbonate and causes changes in the alveolar
002, in the C02-absorbing power of the blood, in the reserve alkalinity,
and in the acid excretion by the kidney. It is important to recognize the
special nature of diabetic acidosis by a separate name — ketosis.

The chemical processes by which the ketone bodies are produced is
discussed elsewhere (page 737). It remains for us to consider the
general nature of the metabolic disturbance responsible for their ap-
pearance in diabetes.

For the thorough combustion of fat in the animal body a certain
amount of carbohydrate must be simultaneously burned. Fat evidently
is a less readily oxidized foodstuff than sugar; it needs the fire of the
burning sugar to consume it. If the carbohydrate fires do not burn
briskly enough, the fat is incompletely consumed; it smokes, as it were,
and the smoke is represented in metabolism by the ketones and derived
acids. Such a closing down of the carbohydrate furnaces may be
brought about either by curtailment of the intake of carbohydrates, as
in starvation (page 600), or by some fault in the mechanism of the
furnace itself, as in diabetes. Besides fat, protein may also contribute
to the production of ketones when carbohydrate combustion is de-
pressed. Fundamentally, therefore ketosis in diabetes is due to the

716 METABOLISM

same cause as in starvation — namely, an improper adjustment between
the metabolisms of fat and carbohydrate.

Bearing these principles in mind, it is easy to see how the intensity
of acidosis which develops during starvation will depend upon the re-
lative metabolism of carbohydrate, on the one hand, and of fat and
protein, on the other; it will therefore depend on the amounts of these
foodstuffs which have been stored in the organism, and this again will
depend on the nature of the diet previous to the starvation period. For
the first few days following entire abstinence from food in a healthy,
well-nourished individual, very few if any ketones will be excreted in
the urine, because the carbohydrate stored in the body as glycogen has
sufficed during this time to maintain the proper proportion between fat
and carbohydrate. Afterwards, however, their appearance is to be ex-
pected, because the glycogen stores become exhausted long before those
of fat. If starvation is still further prolonged, a stage will come when
the fat, as well as the carbohydrate, is used up so that the organism has
now to subsist on protein alone. When this stage arrives, the ketones
will diminish, for, although they might be derived from certain of the
amino acids, yet this does not actually occur, because a large part of the
protein molecule (nearly half) also becomes changed into glucose, which
by burning, as above explained, prevents the formation of ketones from
the other part of the molecule. For the same reasons, marked acidosis
will not be expected to occur during any stage of starvation in lean
persons, who from the start must utilize mainly their stored protein to
supply the fuel upon which to live.

In diabetes exactly the same principles apply, but to an organism in
which the ability to metabolize carbohydrate has been depressed, so that
"the maximum rate at which dextrose can be oxidized is fixed at some
level which is absolutely lower than in health. ' >3° Therefore, since a cer-
tain proportionality must exist between the rates of combustion of fat
and carbohydrate, the diabetic can thoroughly oxidize less fat; in other
words, an amount of fat which could readily be burned in a healthy body
is improperly burned by the diabetic, and ketones and their acids ac-
cumulate.

Starvation Treatment. — "In order to check a diabetic acidosis, it is
necessary to restore the proper ratio of fatty acid to glucose oxidation,"
which can best be done by starvation, rest in bed and warmth. But this
treatment may not at first suffice, because we have to deal not only with
the acidosis bodies derived from fat, but with those which can be derived
from protein on account of the diabetic organism having lost the power
even of burning the glucose which is derived from this foodstuff. By
persistence in the starvation, however, the ability of the organism to

THE METABOLISM OF THE CARBOHYDRATES 71?

utilize carbohydrate usually becomes so far restored that enough burns to
prevent acidosis. Every case of diabetes can not, therefore, be expected
to react in the same way to starvation, the determining condition being
the relation between the quantities of glycogen and fat stored in the body
at the outset of the fasting period. This relationship depends on the
nature of the previous diet.

To sum up, " fasting will lower acidosis either in health or in diabetes,
if it has the effect of stopping a one-sided metabolism and throwing the
tissues on a more nearly balanced ratio of fatty acids and glucose" —
(Woodyatt). A practical point may be noted here — namely, that there
is likely to be more danger of serious acidosis developing during starva-
tion in fat than in lean diabetics. The importance of our appreciation of
these facts in the starvation treatment of diabetes will be self-evident.

CHAPTER LXXIX

FAT METABOLISM

Before considering the physiology of fats, a few of the most essential
points regarding their chemistry may be of assistance.

THE CHEMISTRY OF FATTY SUBSTANCES

It is usual to classify all substances that are soluble in ether as lipoids. They in-
clude fatty acids, neutral fats, cholesterols, cholesterol esters, and phospholipins.

The fatty acids belong to two main homologous series, which differ from each other
with regard to whether they are saturated or unsaturated. A saturated fatty acid
is typified by palmitic, whose formula is CH3-CH2-CH2-CH2-CH2-CH -CHo- CH^-CH. -CHo
CH2-CH2-CH2-CH2-CH2-COOH, or CH-(CH2)i4-COOHj that is to' say2 it is" a higher
member of the series to which acetic acid (CH -COOH) belongs, differing from the
latter in having fourteen extra methyl radicles, each joined to its neighbor by one
bond or saturated linking on either side. Another member of this series is stearic, in
which there are sixteen extra CH2 groups (CH3(CH2)i6-COOH). An unsaturated
fatty acid is oleic (CH3(CH2)7— CH = CH-(aE2)7-COOH). Its unsaturation is rep-
resented in the formula by the double bond or unsaturated linking, which it will be
seen occupies a position in the middle of the molecule, the other methyl radicles being
linked together by single bonds.

The fatty acids readily combine with alkali to form soaps; thus,

CH3(CH2)i4-COOH + KOH = CH3(CH2)14-COOK + H2O,
(palmitic acid) • (soap)

the reaction being analogous to that by which acetic acid forms an acetate with
alkalies. In place of being combined with alkali, the COOH (carboxyl) group of fatty
acids may combine with alcohols to form substances called esters. Thus, acetic acid and
ethyl alcohol from ethyl acetate,

CH coo ,'H + OH,' c H — CH coo-c H +H o.

3 \ _ | 2 5 3 252

(acetic (ethyl (ethyl acetate)

acid) alcohol)

When the alcohol thus united with fatty acid is glycerol (glycerine), in which there
are three OH (hydroxyl) groups, the resulting ester — called triglyccride — is neutral fat.
Tripalmitin has the formula:

CH,-OOC-CI5H31

CH -OOC-C]5H31

CH2-OOOC1BH31.

By boiling neutral fats with alkali the fatty acid radicles are split off as soaps,
leaving the glycerol. This process is called saponification, and it may be effected in

718

FAT METABOLISM 719

many other ways, as for example by heating with steam or by the action of special
enzymes called Upases, which are widely distributed in plants and animals.

The natural fats are usually a mixture of triglycerides, and their differences in
properties are dependent upon the relative amounts of fatty acids present. The three
most important in animal fats are tripalmitin, tristearin and triolein. It is essential in
the study of fat metabolism that we should know the most important methods ~by which
the proportion of fatty adds present in a mixed fat is determined. These methods
are as follows:

1. The melting point. Olein is liquid at 0° C.; palmitic acid melts at 62.6° C.; and
stearic at 69.3° C. The solidity of animal fats depends on the proportion of olein,
palmitin and stearin present. Mutton fat, for example, is much stiffer than pig fat
because it contains less olein and more stearin. The melting points of fats from
different parts of the body may also vary.

2. The acid number indicates the amount of free fatty acid mixed with the fat,
and is determined by titrating a solution of a weighed quantity of the fat in alcohol with
a N/10 alcoholic solution of KOH, phenolphthalein being used as indicator.

3. The saponification value indicates the total amount of fatty acid present, both
that which is free and that combined with glycerol. It is determined by heating a
weighed amount of fat with an exactly known amount of alcoholic KOH (determined
by titration with standard acid). After saponification is complete, titration of the
mixture shows how much alkali has been used to combine with the fatty acid. This
is the saponification value.

4. The ester value indicates the amount of fatty acid combined with glycerol, and
is obtained by subtracting the acid value from the saponification value.

Besides these there are two values, known as the iodine and the Beichert-Meissl val-
ues, that are of importance because they depend on certain -characteristics of the fatty-
acid radicles.

5. The iodine value indicates the amount of unsaturated fatty acids present, or
the number of double bonds. It depends on the fact that iodine, like many other
substances, is capable of directly attaching itself to the fatty-acid chain wherever
double bonds exist.

6. The Eeichert-Meissl value indicates the amount of volatile soluble acid present
in the fat. It is determined by first of all saponifying the fat, then decomposing1 the
soap by mixing it with mineral acid and distilling the liberated fatty acid, the distil-
late being collected in a known amount of standard alkali and titrated. It is a value
that is not of very great use in physiological investigations, but it is so in connection
with food chemistry. Since volatile acids are present in butter, the Reichert-Meissl
value helps us to distinguish between butter and margarine.

Fat is insoluble in water but soap is soluble, forming a colloidal solution which
presents phenomenon "of surface aggregation of molecules. This consists in the con-
centration of the soap both at the free surface of the liquid, where a skin may form,
and at the interfaces between the soap solution and any undissolved particles present in
it. This pellicle-formation around the particles prevents them from running together
so that they remain suspended, thus forming an emulsion. An emulsion may there-
fore be formed either of neutral fat of any other physically similar substance. When
fat itself is used, -there is usually enough free fatty acid admixed with it to make it
unnecessary in forming the emulsion to do more than shake the fat with weak sodium-
carbonate solution. With other substances not containing any free fatty acid, some
soap should be added. To preserve the emulsion it is often useful to add some mucilage.
In the emulsified state, neutral fats are much more readily attacked by Upases than
when they are present in an unemulsified state. Thus, emulsified fats are "digested"

720 METABOLISM

by the relatively small amounts of lipase present in the stomach, whereas neutral fats
themselves are not so.

Fatty acids also exist in nature in combination not only with the triatomic alcohol,
glycerol, but also with monatomic alcohols such as cholesterol. These cholesterol fats
differ from the glycerol fats in being very resistant towards enzymes and microorgan-
isms. They are therefore used for protective purposes in the animal economy; for
example, they occur in the sebum, the secretion of the sebaceous glands, where they
serve to moisten the hairs and skin. They are also present in cells, in which it is prob-
able they take an important part in forming the skeleton of the cell. Cholesterol is
absorbed from the intestine ; it is always present in the blood both in plasma and in
corpuscles; and it is an important constituent of bile, from which it may separate out
in the bile passages and form calculi (gallstones).

In the cells themselves the lipoids are represented mainly by compounds of a some-
what more complex structure — namely, the phospliolipins. As their name indicates,
these consist chemically of phosphoric acid combined with neutral fat and with a nitro-
genous base, cholin. The best known of the phospholipins is lecithin, which is widely
distributed in the animal body (present in blood and bile as well as in all cells).
Other phospholipins present in nervous tissue are cephalin, cuorin and sphyngomyelin.
There are various lecithins distinguished from one another by the fatty-acid radicles
which they contain. Distearyl-lecithin, for example, has the formula:

CH2-0-OC(CH2)14-CH3

CH -0-OC(CH2)14-CH3

(stearic acid)
CH2-0 O

(glycerol) P

OH OCH2 - CH2 - N(CH3)2

(phosphoric j

acid) OH

(choline)

This complex molecule can readily be split up by hydrolysis (warming with baryta
water) into:

glycero-phosphoric acid, CH2 - OH
CH -OH

CH2-0

O

P ; choline, N

OH

C2H4OH

(CII.,)3 (oxy-ethyl-ammonium

OH

hydroxide) ; and fatty acids.

With hydrochloric acid, choline forms a salt which readily forms a double salt
with plantinic chloride. Since this double salt forms characteristic crystals, it is
used to identify and separate lecithins. For quantitative purposes, however, it il
more suitable to determine lecithin indirectly by the amount of phosphoric acid
present in an ethereal extract of the organ or tissue.

Evidence is constantly accumulating to show that lecithin is an extremely impor-
tant constituent of cells; indeed, it seems to be the intermediate stage in the utiliza-
tion of neutral fats by protoplasm. Its phosphorus also probably serves as the source
of this element for the construction of nucleie acid (see page 669). In nervous tissues

FAT METABOLISM 721

it is often associated with carbohydrate molecules (galactose), forming the substance
known as cerebrin. It may therefore have some role to play in carbohydrate metabo-
lism. Some workers also attribute to lecithin an important function in the transference
of substances through cell membranes. When mixed with water it swells up by imbibi-
tion, and if crystalloids or other substances are dissolved in the water, a means is
offered for bringing water-soluble and fat-soluble substances into intimate contact.

DIGESTION OF FATS

A certain amount of fat, especially when it is in an emulsified condi-
tion, can be digested in the stomach by the lipase contained in the gas-
tric juice. Most of it, however, is digested in the small intestine, into
which as we have seen, it is gradually discharged suspended in the chyme.
For this intestinal digestion of fat both pancreatic juice and bile are nec-
essary. This is easily shown in the rabbit, in which the pancreatic duct
enters the intestine at a considerable distance below the bile duct. If the
mesentery is inspected during the absorption of fatty foodj no fat in-
jection of the lymphatics will be noted between the bile and the pan-
creatic ducts but only below the latter. In the dog, in which both the bile
and the main pancreatic ducts enter the intestine at about the same level,
fat injection of the lymphatics starts at this point, but if the bile duct
(or rather the gall bladder) is transplanted at some distance down the
intestine, it will be found that the injection of the lymphatics with fat
occurs only below the new point of insertion of the bile duct.

Eemoval of the pancreas interferes very materially with the absorption
of fat. In man, for example, absence of the pancreatic juice alone di-
minishes the absorption of fat by 50 or 60 per cent. If the bile is also
absent, the diminution amounts to 80 or 90 per cent, and in such cases,
as is well known, the administration of bile or pancreas powder greatly
improves fat absorption. In the dog, although ligation of the pancreatic
duct apparently only slightly influences fat absorption, removal of the
pancreas itself greatly interferes with the process; from which fact some
observers have concluded that the pancreas, in addition to its external
secretion into the intestine, must produce an internal secretion into the
blood which has something to do with the efficient absorption of the
fat (Pratt, McClure and Vincent48). It is, however, improbable that such an
hypothesis is necessary, for it is very likely that the moribund condi-
tion into which an animal is brought by extirpation of the pancreas,
adequately accounts for the suppression of the fat-absorbing function.

As to the relative roles of pancreatic juice and bile in the digestion of
fat, we know of course that in the pancreatic juice there exists a lipolytic
enzyme, lipase, which, under suitable conditions has the power of split-
ting neutral fat into fatty acids and glycerol. If bile is examined, no
lipolytic enzyme will be found in it. It is entirely inactive on fat, but

722 METABOLISM

if we mix .bile with fresh pancreatic juice, which by itself only slowly
digests fat, we shall find that the bile very materially increases the lipo-
lytic activity of the pancreatic juice. It has been found that the salts
of cholalic acid, the so-called bile salts, are the constituents of bile
that are responsible for this activation of lipase, this fact having been
demonstrated with bile salts prepared in such a way that there was no
possible chance of any other biliary constituent being present as an
impurity. It is important to remember, however, that lipase itself be-
comes slowly activated on standing, which explains why it should be
that bile added to pancreatic juice that has stood for some time, has a
less evident activating influence than bile added to fresh juice. It is
probable that the activating influence of bile salts is due to some physico-
chemical change induced in the digestion mixture.

One may ask how it happens that, when bile and pancreatic juice are
both absent from thfe intestine, the fat which appears in the feces is not
neutral fat but fatty acid. The reason is that the neutral fat that has
escaped digestion in the small intestine becomes acted on by the intestinal
bacteria, particularly in the large intestine. Under these conditions,
however, the fatty acid that is split off is not absorbed, because the
epithelium of the lower parts on the intestinal tract can not perform this
function.

Besides assisting the action of lipase, bile facilitates fat digestion in
other ways. Thus, by its containing alkali and mucin-like substances
it assists in the emulsification of fat. Although emulsification is no es-
sential part of fat absorption, yet it greatly facilitates the process by
breaking up the fat into small globules on which the lipase can act
much more efficiently. The alkali also combines with the fatty acids,
as they are liberated by the digestive process, to form water-soluble
soaps, which are readily absorbed by the epithelial cells. The bile salts
further assist in the solution of the fatty acids, and they lower the sur-
face tension of fluids in which they are contained and so bring the fat
and lipase into closer contact.

ABSORPTION OF FATS

After its digestion fat lies in contact with the intestinal border of the
epithelial cells as fatty acid and glycerol. The fatty acid is combined
either with alkali to form a water-soluble soap, or with bile salts to
form a compound, which is also soluble. The glycerol and the dissolved
fatty acids are separately absorbed into the epithelial cells of the in-
testine, in the protoplasm of which — after the fatty acid has been set
free from the alkali or bile salt — they become united or resynthetized

FAT METABOLISM 723

to form neutral fat, which gradually finds its way by the central lac-
teals into the villi, and then by way of the lymphatics to the thoracic
duct.

The chemical explanation of the absorption of fat is very different from
that formerly held by histologists who maintained that the fine particles of
emulsified fat in the intestine penetrate by a mechanical process through
the striated border of the epithelial cell into its protoplasm. The histolog-
ical evidence for this view seemed very convincing, for fine fat globules can
readily be seen in the epithelial cells of the intestine after fatty food
has been taken, while they are absent during starvation. These par-
ticles seemed to have passed directly from the intestinal canal into the
epithelial cells because, when the fat was stained with characteristic fat
stains before feeding it to the animal, the globules in the epithelial cells
were found to be similarly stained. The supporters of this mechanistic
view of fat absorption maintained that the appearance of the stained fat
globules in the epithelial cells could not be explained in any other way
than by supposing that the fat globules had wandered unbroken into
the epithelial cells. Such a conclusion is, however, unwarranted, for the
stains that are soluble in fat are also soluble in soap, so that when the
fat splits up, the stain will remain attached to the soap and be carried
along with it into the intestinal epithelium.

Proof that the chemical theory is the correct one has been supplied by a large
number of experiments. The following may be cited: (1) When the lymph flowing
from the thoracic duct is examined after feeding with fatty acids instead of neutral
fat, it is found to contain only neutral fat, indicating that a synthesis must have
occurred between glyeerol and fatty acid during the absorption. The glyeerol for
this synthesis is furnished from sources which will be described later. (2) When an
emulsion made partly of neutral fats and partly of some hydrocarbon, such as albo-
lene, is fed and the feces are examined for these substances, it has been found that
all the fat but none of the hydrocarbon is absorbed; the feces contain all of the albo-
lene but none of the fat. This experiment supplies very strong evidence against the
mechanistic theory, for microscopic examination of the above described emulsion shows
the particles of neutral fat and hydrocarbon to be of exactly the same size. (3) By
examining the properties of the fatty substances in the thoracic lymph collected during
the absorption of such an emulsion as that described above, nothing but neutral fat
has been found present. (4) Similar results are obtained when wool fat, which is an
ester of cholesterol and fatty acid, is fed.

We may conclude that fatty substances which are insoluble in water or
can not be changed by digestion into substances (soap) that are soluble
in water, are not absorbed, however like fat they may be in other particulars.

The chemical theory of fat absorption further explains why there should
be such large quantities of soapy substances in the intestinal contents,
also why the globules of fat present in the epithelial cells of the

724 METABOLISM

intestine are so very much smaller than those which lie on the surface of
the epithelium.

It might be objected to the conclusions just stated that, although undetectable,
there is really some essential physical difference between emulsified fat and emulsified
hydrocarbon. In order entirely to prove the case for the chemical theory, it is neces-
sary to feed a neutral fat possessing some characteristic that depends on the manner of
union existing between fatty acid and glycerol, and then to see whether it appears in
an unchanged condition in the thoracic duct. If it does so, the fat must have been
absorbed through the intestinal epithelium in an unbroken, unsaponified condition, for
it is unlikely that, in the resynthesis which occurs in the intestinal epithelium, the fatty-
acid molecules would recombine with the glycerol molecules in exactly the same manner
as before.

There are, however, but very few qualities of neutral fats, apart from those of the
fatty acids which compose them, by which they can be characterized. The most likely
one is that of optical activity. None of the ordinary fats is optically active, although
from chemical considerations it is quite conceivable that some ought to be so. In
order to obtain such a fat Bloor49 conducted numerous experiments with the esters of
stearic acid.* In a series of experiments Bloor fed isomannid-dilauratc, a synthetic fat
of dextrorotatory power and as readily absorbed as natural fats, and by examination
of the neutral fat present in the chyle flowing from the thoracic duct, found no evi->
dence of the dextrorotatory fat. This result confirms previous work by Frank, who
found that the ethyl esters of fatty acids are not absorbed unchanged. The results of
both workers emphasize the probability that readily saponifiable fatty-acid esters do
not escape saponification under the favorable conditions of the normal intestine. In
other words, had the fats been absorbed unchanged, as would be required by the
mechanistic theory of fat absorption, they would have appeared in the chyle in optic-
ally active conditions.

These most important conclusions lead us to inquire as to the reason
for the change in fat during its absorption. It can not be for the purpose
of preventing the absorption of undesirable fatty substances, such as the
petroleum hydrocarbons or the wool fats, because such substances are
so rarely present in our food. It is most probable that the breakdown
and resynthesis of neutral fat occurs for the same reason that similar
processes occur during the absorption and assimilation of protein. It
will be remembered that protein is entirely disintegrated in the intestine
into its so-called building stones. These are absorbed separately into
the blood, which carries them to the tissues, in which they become re-
synthesized to form the body protein. And so it appears to be in the
case of fats. The process, in other words, permits of the rearrangement
of fatty-acid molecules, as a result of which the newly formed fat is more
adaptable for use in the organism. It comes to be more like the char-
acteristic fat of the animal. There may be another reason for the proc-

*Eloor prepared an optically active mannitan distearate, but found it to have a very high melt-
ing point and to be only half as digestible as the ordinary fats. Its absorption was too slow and
unsatisfactory to make it suitable for the above purposes. He, therefore, proceeded to prepare the
di-ester of isomannitan with lauric acid, and he found the resulting compounds to be as well-ab-
sorbvd as ordinary fat, and yet to possess very marked dextrorotatory power, which, of course,
they lose on saponification. This fat seemed suitable, therefore, for testing the above question.

FAT METABOLISM 725

ess. It will be remembered that lecithins, which constitute the most
important of the fatty substances of the cell itself, are mixed glycerides —
that is to say, are compounds containing a variety of fatty acids. The
rearrangement of the molecules of neutral fat which occurs during ab-
sorption may be the first step in the transformation of fat into lecithin.

In order to throw further light on the question, Bloor has performed
a number of interesting experiments in which the chemical properties
of fats before and after absorption were compared. The criteria which
he took were melting point, iodine value, and mean molecular weight;
the melting point representing the solidity of the fat, and the iodine
value, its degree of unsaturation — that is, the number of double links in
the fatty-acid chain. It was found that during absorption very con-
siderable changes occur in these two characteristics; for example, when
fat with high melting point and low iodine value was fed, the fat in the
thoracic lymph was of distinctly lower melting point and higher iodine
value. When fat with a low melting point and a high iodine value was
fed, the reverse change occurred, for the melting point of the thoracic
lymph fat was higher and the iodine value lower. These results could
be explained as due in the first case to the addition of oleic acid to the
fat during its synthesis in the intestinal epithelium, and in the second
case to the addition of some saturated fatty acid.

When a fat consisting mainly of glyceride and saturated fatty acid,
but with a low melting point, was fed, the addition of oleic acid was still
found to occur, as judged from the iodine value. This indicates that the
change is, not merely in order that the melting point of the absorbed fat
may be lowered, but also for some chemical reason. In a fourth series
of experiments, a lowering of iodine value occurred after feeding with
cod-liver oil, which contains a high percentage of glycerides of highly
unsaturated fatty acid.

Evidently, then, the intestine possesses the power of modifying the com-
position of fat during its absorption, and this modification is apparently
of such a nature that it causes a change toward the production of a
uniform chyle fat, presumably characteristic of the animal body. The
changes are probably greater than could be produced by admixture of
the absorbed fat present in the normal fasting chyle, but the source of
the oleic acid or of the saturated acid required for this synthesis is at
present unknown.

CHAPTER LXXX

FAT METABOLISM (Cont'd)

THE FAT OF BLOOD

Methods of Determination. — Normally the blood contains only a small percentage
of fat, but after a fatty meal it may contain so large an amount that the fat actually
rises to the surface of the blood like a cream. By means of the ultramicroscope, ex-
amination of the blood in the dark field after a fat-rich meal reveals the presence of
glancing particles, the so-called ' ' fat dust. ' ' These particles are most abundant about
six hours after the meal has been taken, and they gradually disappear by the twelfth
hour. They do not appear after a meal when the thoracic duct is ligated. They dis-
appear when oxygen is bubbled through the blood.

Fat dust has also been found abundantly present in the blood of embryo guinea pigs
at full time, but not in the mother 's blood. This would indicate that the placenta must
have the power of taking the constituents of fat from the mother's blood and building
them into fat, which then passes into the blood of the fetus. The placenta under these
conditions acts like the mammary gland. In this connection it is of interest that there is
also much fat present in the blood of pregnant women. The fat content of the placenta
is, however, greater in the early stages of pregnancy than later.

Although these facts have been known for some time, it has been impossible, either on
account of the large quantities of blood required for a chemical examination or because
of the difficulty in estimating the amount of fat from the density of the "fat dust,"
to follow with any great degree of accuracy the exact chemical changes that take place
in the fat of the blood. Recently, however, Bloor has succeeded in elaborating methods
by which the fat content of the blood can be determined with satisfactory accuracy in
small quantities of blood, so that a continuous series of observations can be made over a
considerable period.

The fat is extracted from the blood by an alcohol-ether mixture with moderate heat.
An aliquot portion of the filtrate is evaporated in the presence of sodium ethylate, which
saponifies the fat. The residue, consisting of soap, is well washed and then treated
with hydrochloric acid so as to precipitate the fatty acid. The density of the precipitate
thus produced is compared in an optical apparatus, called a nephelometer, with a
standard solution of two milligrams of oleic acid treated in the same way. The fatty
acids in human blood are mainly oleic and palmitic.

The lecithin and cholesterol may also be estimated in the same blood extract. For
lecithin the above extract of blood, after the removal of the alcohol and ether, is digested
by heating with concentrated HNO3 and H2SO4. This decomposes the lecithin, liberating
the phosphorus, a solution of the resulting ash being rendered faintly alkaline to phenol-
phthalein and then slowly added to a silver nitrate solution. The density of the pre-
cipitate thus produced is compared in the nephelometer with that of a precipitate pro-
duced in the same amount of silver nitrate by adding to it a standard phosphoric acid
solution.

For cholesterol an aliquot portion of the above extract is saponified with sodium
ethylate and then saturated with chloroform ; the chloroform extract is mixed with acetic

726

FAT METABOLISM 727

anhydrid and H2SO4 (eon.) until the bluish color is fully developed (Liebermann reac-
tion), the intensity of which is then compared in a, colorimeter with that obtained by
similar treatment from a standard cholesterol solution.

Variations in Blood Fat. — In the dog the percentage of fat in the
blood is remarkably constant under normal conditions. After a fatty
meal the increase in fat begins in about an hour, and reaches its maxi-
mum in about six. The increase is not found in animals in which the
thoracic duct has been ligated. Although this result would seem to
contradict the view held by some that part of the fat which can not be
accounted for in the thoracic-duct lymph is absorbed by way of the
portal vein, it does not by itself disprove the hypothesis, for it has been
found that the fat content of the portal blood is always higher than that
of the jugular.

Very interesting results have been obtained following the intravenous
injection of emulsions of oil, either the so-called casein emulsion or col-
loidal suspensions. Up to a dose of 0.4 gram per kilogram of body
weight — which by calculation would suffice to raise the fat content of
the blood by 100 per cent — there was no increase in fat content. In or-
der to explain this disappearance of fat, it might be imagined that the
injected fat particles formed emboli in the smaller capillaries. Against
such a view, however, is the fact that the particles of fat in these emul-
sions are one-half to one-seventh the size of a red corpuscle. Although
this argument is no doubt of some weight, it should be remembered
that the physical condition of these fine fat globules is not the same as
that of the red blood corpuscle. Their surface condition may be such
that they readily agglutinate so as to form small masses, which may
stick at the branching of the smaller arterioles and capillaries. Bloor
himself suggests that the injected fat may be Stored, possibly in the liver,
since the fat in this organ, as we shall see later, increases under similar
conditions. When twice the above quantity was fed in the form of egg-
yolk fat, some of it persisted in the blood for several hours. This in-
crease may have been owing to the flooding of the temporary storehouse
with fat, or, more probably, to a retarding influence that lecithin may
have on fat assimilation, for lecithin itself persists in the blood for a
long time after intravenous injection.

During fasting, no increase in blood fat was found unless the animal,
by special feeding, had been stuffed with excess of fat prior to the fast-
ing period. The lipemia in this case indicates that fat is being trans-
ported from one place to another to serve as fuel for the starving tissues.
Narcotics were found to produce an increase in blood fat. Ether pro-
duced this increase during the narcosis, whereas morphine and chloro-
form did not do so until after recovery. The explanation given for the

728

METABOLISM

ether effect is that a mixture of blood and ether has a higher solvent power
for fat than blood alone. The explanation for the chloroform and mor-
phine effects is that a certain amount of breakdown of the tissue cells,
in which lipins are set free, supervenes upon the action of these narcotics.

The blood fat also becomes enormously increased in about forty hours
after the administration of phlorhizin, and on the second or third day
after the administration of phosphorus. The special significance of
these facts we shall consider later in connection with the relationship of
the liver to fat metabolism.

By comparison of the fatty acid, lecithin, and cholesterol contents of
blood during fat absorption, it has been found that there is a steady but
very variable increase in fatty acid, accompanied by no change in
cholesterol, but with an increase in lecithin, which varies from 10 to 35
per cent, but does not run strictly parallel with the fatty-acid increase.
It is probable that this increase in lecithin represents that part of the
absorbed fat which is intended for immediate use in the tissues (page
734). The more or less independent increase in lecithin is of significance
in connection with the fact that in many pathological conditions of so-
called lipemia the increase does not affect the fats of the blood but rather
the lipoids (i.e., lecithin and cholesterol). Separate analyses of blood
plasma and whole blood show the increase of lecithin to be much more
marked in the corpuscles than in the plasma, whereas the fatty-acid
increase is confined to the plasma.

To illustrate some of these points the following table will be of value.
In it is shown the average distribution of fatty acid, lecithin and choles-
terol in normal individuals and in cases of diabetes, in which disease,

BLOOD LIPOIDS IN NORMAL AND IN DIABETIC PERSONS

NORMAL
PER CENT

MILD
DIABETES
PER CENT

MODERATE
DIABETES
PER CENT

SEVERE
DIABETES
PER CENT

Fat by Bloor's j
Method 1

Whole Blood
Plasma

0.59

0.62

0.83

0.90

0.91
1.06

1.41
1.80

Total Fatty Acidsj

Whole Blood
Plasma
Corpuscles

0.37
0.39
0.34

0.59
0.64
0.45

0.65
0.75
0.48

1.01

1.28
0.62

Lecithin -I

Whole Blood
Plasma
Corpuscles

0.30
0.21
0.42

0.32
0.24
0.42

0.33

0.28
0.40

0.40
0.40
0.40

Cholesterol I

Whole Blood
Plasma
Corpuscles

0.22
0.23
0.20

0.24
0.26
0.21

0.26
0.30
0.20

0.41
0.51
0.24

Glycerides J

Plasma
Corpuscles

0.10
0

0.38
0.18

0.46
0.23

0.84
0.38

Total Lipoids

Plasma

0.68

0.98

1.16

1.98

FAT METABOLISM 729

as has been known for long, there is marked disturbance of fat metab-
olism.

It will be observed that there is about 0.7 per cent of total fatty sub-
stances in normal blood. The fatty acids (palmitic and oleic) amount to
about 0.4 per cent, and are equally distributed between plasma and
corpuscles; the lecithin, about 0.3 per cent, being twice as abundant in
corpuscles as in plasma, and the cholesterol, 0.2 per cent, about equally
distributed. In diabetes all of these substances are seen to be increased
in proportion to the severity of the disease, the increase being mostly
in the plasma. The increase in cholesterol (confined mainly to the
plasma) is particularly interesting, since the substance is unaffected in
amount by excessive feeding with fat.

The Destination of the Fat of the Blood. — In general, it may be said
that the blood fat is transported to three places: (1) the depots for fat; (2)
the liver; and (3) the tissues. The fat present in each of these places
differs from that in the others, as is revealed by chemical examination
by the methods described on page 719. The depot fat usually yields about
95 per cent of its total weight as fatty acid. The tissue fat, on the other
hand, yields only about 60 per cent of its total weight as fatty acid.
This difference indicates that the fatty acid must be combined in the
tissues with a much larger molecule than is the case in the fat of the
depots. This large molecule is probably that of lecithin or other phos-
pholipin, and the smaller molecule in the depots, that of neutral fat.
The liver fat takes an intermediate position between depot fat and tissue
fat in its yield of fatty acid. When no active metabolism of fat is go-
ing on, the liver fat is like that of the tissues ; but when fat metabolism
is active, the liver fat occupies an intermediate position between liver
fat and depot fat.

Another difference among the fats in these three places is with regard
to the degree of saturation of the fatty-acid radicles. This, it will be
remembered, is indicated by the iodine value; the higher the iodine
value, the greater the desaturation of fatty acid. In depot fat this value
is relatively low — for example, about 30 in the goat and about 65 in man ;
depending somewhat on the fat taken in the food, compared with which
it is usually a little higher. The fat in the tissues, on the other hand,
has a high iodine value, possibly 110 to 130. The iodine value of the
fat of the liver is remarkably inconstant, being about the same as that
of the tissues when fatty-acid metabolism is not particularly active, but
approximating that of the depots when fat mobilization is proceeding.
The significance of this fact we shall consider later.

730 METABOLISM

The Depot Fat

The places in the animal body Avhere depot fat is deposited in great-
est amount are the subcutaneous and retroperitoneal tissues. These
fat depots may sometimes become of enormous size, as in the case of
the famous dog of Pfliiger, of whose total body weight 40 per cent was
due to fat. Bloor suggests that there may really be two different types
of fat storage : one of a purely temporary character, which readily
takes up and liberates the fat, but which is of limited capacity and
possibly under the control of some quickly acting regulating mech-
anism, like that of the glycogenic function of the liver; and another
of a more permanent nature, into which the fat is slowly taken up, but
the capacity of which is very much greater.

Two questions present themselves concerning the depot fat: (1) where
does it come from, and (2) what becomes of it? Regarding the source
of the depot fat, there is no doubt that it comes partly from the fat and
partly from the carbohydrate of the food; in other words, it is either
taken ready-made with the food or manufactured in the organism. That
some of it comes from the fat of food is now a well-established fact, the
evidence for which need not detain us long. The best-known experiment
consists in first of all starving an animal until his stores of fat are
nearly exhausted and then feeding him with some "ear-marked" fat —
that is, with some fat having a characteristic property which it will
not lose during absorption. It will be found that the depot fat thereby
deposited presents many of the qualities of the fed fat. The "ear-
marking" of the fat may be secured by using fats of different melting
points, such as mutton fat, which has a high M.P., or olive oil, which has
a low M.P. On feeding a previously starved dog with mutton fat, the
M.P. of the depot fat approaches that of mutton fat — he becomes a
dog in sheep's clothing; whereas when olive oil is fed, the subcutaneous
fat becomes oily. Or again we may "ear-mark" the fat by combining it
with bromine, when the deposited fat will likewise be brominized fat.

It must not be imagined, however, that no change takes place in the
fat during its absorption and before it becomes deposited in the tissues.
On the contrary, the stamp of individuality is put upon the fat, for, as
we have already seen, its iodine value may become altered and its melt-
ing point changed during the process of absorption. In other words,
although the absorbed fat does not become entirely adapted to conform
with the ordinary qualities of the depot fat, yet it tends to change in
this direction.

That some of the depot fat comes from carbohydrate is well known to
stock raisers. When, for example, an animal is fed on large quantities
of carbohydrate and kept without doing muscular exercise, its tissues

FAT METABOLISM 731

become loaded with fat. Strict scientific proof of its production from car-
bohydrate is given in the old experiments of Lawes and Gilbert, who,
it will be remembered, showed that the fat deposited in the tissues
of a growing pig is greatly in excess of the fat that could have been
derived from the fat or protein which was meanwhile metabolized.
The experiment was performed on two young pigs from the same litter
and of approximately equal weight ; one was killed and the exact amounts
of fat and nitrogen in the body determined; the other was fed for several
months on a diet the fat and protein contents of which were accurately
ascertained. When after four months this pig was killed and the fat
determined, it was found that much more had become deposited than
could be accounted for by the fat and protein of the food, even suppos-
ing that all the available carbon of the protein had become converted
into fat. The only conclusion is that the carbohydrate must have been
an important source of the extra fat.

The Destination of the Depot Fat. — The depot fat becomes mobilized
and transported by the blood to the active tissues whenever the energy
requirements of the body demand it. During starvation, as we ' have
seen, the depot fat is used to supply 90 per cent of the energy on which
the animal maintains its existence. Before the fat is transported, it is
probably broken dowrn into fatty acid and glycerol, as which it passes
through the cell walls to be again reconstructed into neutral fat in the
blood. What agency effects this constant breakdown and resynthesis
of fat it is difficult to say. Two ester-splitting enzymes are present in
blood, one acting mainly on simple esters, the other on glycerides; but
it has been impossible to demonstrate any evident relationship between
either of them and the extent of fat mobilization.

The Fat in the Liver

The physiology of the liver fat has been very diligently studied,
particularly by Leathes and his pupils.50 The outcome of this work
has been to show that the liver occupies an extremely important posi-
tion in the metabolism of fat, being, as it were, the half way house
in the preparation of the fatty-acid molecule for consumption in the
tissues. Fat is a material containing large quantities of potential en-
ergy. While in the depots this potential energy is so locked away as
to be unavailable for tissue use. To make it available the depot fat
is carried to the liver, where the energy becomes unlocked but not actu-
ally liberated. The fat is then transported to the tissues, and the libera-
tion of the energy occurs. Neutral fat is like wet gunpowder: it con-
tains much potential energy, but not in a suitable condition for explo-

732 METABOLISM

sion. The liver, as it were, dries this gunpowder, whence it is sent to
the tissues to be exploded.

The great importance of the liver in fat metabolism is indicated by
comparison of the percentages of fat — or better of fatty acid — contained
in it under different conditions of nutrition. In the ordinary run of
slaughter-house animals the liver contains from 2 to 4 per cent of higher
fatty acid, but in about one in every eight animals a much higher per-
centage will be found to occur. The same is true in .laboratory animals.
In the case of the human liver as obtained from autopsies in certain
classes of patients, from 60 to 70 per cent of the dry weight of the
organ, or 23 per cent of the moist weight, may be fatty acid. There is
no other organ in the animal body that is ever loaded with fat to this
extent. As in the depots, this liver fat might be derived either from fat
carried to the organ from elsewhere in the body, or it might represent
a surplus of manufactured fat.

Transportation of Fat to the Liver. — About forty hours after giving
phlorhizin to a dog, it has been found that enormous quantities of
fat appear in the liver; a few hours later, however, this excess of fat
may have entirely disappeared. Fatty infiltration of the liver is also
observed in phosphorus poisoning, although in this case the fat usu-
ally persists till the death of the animal. In man, in delayed chlo-
roform poisoning and in cyclical vomiting, enormous quantities of fat
may be present in the liver within a very short period of time after the
onset of the condition. There can therefore be no doubt that fat is
transported to the liver under abnormal conditions, but this can not
be taken as evidence that the liver has anything to do with fat metab-
olism in the normal animal. Such evidence has been supplied by Coope
and Mottram,51 who have been able to show that, at least in rabbits, a
similar invasion of the liver with fat occurs in late pregnancy and early
lactation. They also found that the fatty acid deposited in the liver
in late pregnancy gives an iodine value which lies nearer to that of the
mesenteric fatty acid than is the case in normal animals. Mottram con-
cludes that "wherever . . . there is abundant fat metabolism, the
liver is found to be infiltrated with fats, presumably to be handed on
elsewhere when worked up." It is interesting that the fetus is greedy
of unsaturated fatty acids.

The most likely source of the fat transported to the liver is the fat pres-
ent in the depots, unless when digestion is in progress, when it may be
the fat from the intestine. That much of it comes from the depots is
easily demonstrated. Thus, the more extensive the infiltration of the
liver with fat, the more closely will this fat be found to agree with the
depot fat in its chemical characteristics. This has been very clearly

FAT METABOLISM

733

shown by, first of all, starving an animal so as to clear the depots of fat
as much as possible; then feeding- it on some " ear-marked " fat (unusual
melting-point or a brominized fat) ; and after another day or so of
starvation, so as to clear the liver itself of fat, poisoning the animal
with phosphorus or phlorhizin. The liver will be found shortly after-
wards to be invaded with fat which has all the ear-marks of that on
which the animal had been fed.

Evidence of the same character has been furnished in a series of clin-
ical cases by observations on the amount of fat and the iodine value of
the fatty acid of the liver. This is shown in the accompanying table.

FATTY ACIDS OF LIVER

CAUSE OF DEATH

HIGHER FATTY
ACIDS PER CENT
OF DRY WEIGHT

IODINE VALUE
OF FATTY ACIDS

1. Pernicious anemia

12.1

116.8

N"orim.l

2. Lobar pneumonia

13.7

116.8

3. Pernicious anemia

14.25

116.0

figures

4. Diabetes

14.4

119.6

5. Toxemic jaundice

15.6

109.5

Commencing

6. Accident

17.2

103.5

fatty

7. Empyema

21.5

96.0

change

8. Phthisis

25.4

96.4

9. Broncho-pneumonia

38.4

84.9

10. Appendicitis

44.0

91.1

Marked

11. Carcinoma of bladder

47.2

77.8

fatty

12. Broncho-pneumonia -

54.6

71.8

change

13. Ulcerative colitis

60.9

80.3

14. Accident

66.3

63.0

15. Dysentery

73.5

69.1

This table clearly shows that the more fat there is in the liver, the
nearer this fat approaches in character that stored in the depots.

That some of the fat in the liver may come directly from the fat re-
cently absorbed from the intestine is also very readily demonstrable.
Thus, when cocoanut oil was placed in the intestine of anesthetized an-
imals, along with bile salts and glycerine, it was found by Raper52 that
30 per cent of the absorbed oil appeared in the liver.

The characteristic feature of cocoanut oil is that its fatty acids are volatile in steam
and are saturated. Some of the fatty acids of the liver are volatile in steam, but they
are unsaturated. By distillation in steam of the fatty acids obtained by saponification
of the liver, it is possible to determine how much of the cocoanut oil has passed to the
liver.

Similar results have been obtained when unsaturated fatty acids, such
as those contained in cod-liver oil, are fed. In all these cases the rela-
tionship of the liver fat to that of the food is even more evident than
that between food fat and depot fat, because in the liver the newly absorbed

734 METABOLISM

fat is not diluted by that deposited, it may be months, previously, as is
the case in the connective tissues.

Changes in the Fat Deposited in the Liver.— An indication of the nature
of the change is furnished by observing the iodine value of the fat. This, it
will be remembered, indicates the degree to which the fatty acid is unsatu-
rated. It does not necessarily indicate the number of unsaturated bonds
present in the fatty-acid molecule, for the difference in iodine-absorbing
power may depend not on the number of such bonds but on the position in
the chain at which a given double bond is inserted. Even with this reserva-
tion, however, it is evident that the increase observed in the iodine values
shows that the liver has the power of desaturating fat. The advantage of
this change depends on the fact that the desaturated fatty acid will
be more liable to break up than the saturated fatty -acid. In other words,
the double linkage will weaken the chain with the consequence that it is
liable to fall apart at this place; such at least is the natural interpreta-
tion which the chemist would put on the result. It may not, however,
be the correct interpretation, for it has been shown that, although un-
saturated fatty acids are more susceptible to chemical change in the
laboratory than saturated, yet when fed to animals they appear to be
more stable than many saturated acids. It may then be wrong to con-
clude that the introduction of a double linkage in fat necessarily means
the liability of the fatty-acid chain to break at that point. However
this may be, it seems likely that one function of the liver consists in
introducing double linkages at places in the fatty-acid chain, as a result
of which the chain breaks at these places, and the fragments then undergo
further oxidation.

Double linkages may be introduced not only in one place in a fatty-acid chain, but
in several. For example, it has been found in the liver of the pig, after oxidizing the
fatty acids with permanganate, that oxidation products are obtained indicating the ex-
istence of unsaturated acid with four double links. Permanganate (in alkaline solution)
is used for detecting the position of these double bonds, because, when it is allowed
to act on unsaturated fatty acids in the cold, it causes hydroxyl groups to be introduced
in the position of the double bonds. When the oxidation is performed at a moderate
temperature, the fatty acid falls apart at the hydroxyl groups. A fatty acid with eight
hydroxyl groups has been obtained in this way from the liver of the pig. The presence
of the hydroxyl groups has been confirmed by finding that an octobromide is obtained
by treatment with bromine. An acid of the same formula is said to be present in cod-
liver oil. To sum up, we may conclude that there are certain positions, in the chains of
carbon atoms which constitute the fatty-acid radicle, where the liver introduces double
bonds, and that the weakened radicles then circulate to the tissues, where they break up
at those positions.

Desaturation is probably not the only process by which the liver assists in
the metabolism of fat. It may also take part in the 'building of fatty-
acid radicles into the complex molecule of lecithin. The process of de-

FAT METABOLISM 735

saturation is probably a preliminary step to this incorporation of the fatty-
acid molecule into lecithin, for it is well known that lecithin contains highly
unsaturated fatty-acid radicles. In support of such a view it is interesting
to note that in alcohol-ether extracts from normal and pathological livers,
the lecithins, which are precipitated by acetone, have higher iodine values
(i.e., are more unsaturated) than the neutral fats extracted from the same
liver, which also have higher iodine values than the depot fat of the same
animal. The desaturation process -must, therefore, involve the fatty acids
before these become built into the lecithin molecule.

Desaturation of fatty acids occurs in other places besides the liver. The
relative activity of the different tissues in this regard has been studied by
feeding cats with fatty fish and then determining the iodine value of fat
from various places in the body. The absorbed fat was more obvious in the
liver than in the subcutaneous tissues, because it had not become diluted
with fat deposited, it may have been months, previously, which would be the
case in the fat of the fat depots; and it was found that, although the
iodine value of the subcutaneous fat was slightly raised, that of the
liver was much more so, indicating that the desaturation process had
been more active in this organ, but had also occurred to a certain extent
in the depots.

Before leaving this subject of fat in the liver, it is important to re-
call the old observation of Rosenthal, that a more or less reciprocal
relationship exists between glycogen and fat in the liver. When much
glycogen is present there is little or no fat, and vice versa. It is impor-
tant to note that the exact locations of fat and carbohydrate in the he-
patic lobule are somewhat different in the two cases.

A practical clinical application of the above work is found in the fact
that fats will be more readily utilized by the body when they contain a
high percentage of unsaturated fatty acids. It is possibly for this
reason that Norwegian cod-liver oil is of such undoubted nutritive value.
It is much more so than 'Newfoundland cod-liver oil, because in the prep-
aration of this variety oxidation occurs, which makes it no longer unsat-
urated. Fish oils in general are more unsaturated than other animal
oils, and are for this reason more nutritious. The presence of vitamines
rather than their assimilative properties may, however, be the factor
which determines the nutritive value of different brands of cod-liver oil.

The fat in the tissues differs very materially from that of the liver or
the depots. Only 60 per cent of this fat consists of fatty acid, which is
present very largely as part of the lecithin molecule, thus accounting for
the high iodine value. Some is probably also present as simple glyceride,
in a highly unsaturated and therefore very fragile condition.

CHAPTER LXXXI

FAT METABOLISM (Cont'd)

Two very important questions of fatty-acid metabolism may now be
considered: namely, (1) how is fatty acid formed from carbohydrate?
and (2) what becomes of the fragments into which the fatty -acid molecule
is split as the result of the desatiiration process? Although these prob-
lems involve chemical details of a somewhat complex nature, we must
not on this account fail to consider them; for, as we shall see, much of
what is known has an important practical application depending on the
fact that certain of the intermediary substances may accumulate in the
organism and develop a toxic action.

The Production of Fatty Acid out of Carbohydrate. — If we place the
formulas for glucose and palmitic acid side by side, thus:

CH2OH-(CIIOH)<-CHO (glucose), and
CH3-(CH2)14-COOH (palmitic acid);

we shall see that this transformation must involve: (1) a considerable
alteration in the structure of the molecule, (2) the removal of oxygen,
and (3) the fusion of several glucose molecules into one molecule of fatty
acid.

The conversion of carbohydrate to fat therefore involves a process of
reduction, and the resulting molecule must be capable of yielding more
energy when it is oxidized than the original one of carbohydrate, for
obviously the system 02 - CH2 (which corresponds to fat) will develop
more energy than that of 02 - CHO (which corresponds to carbohydrate) ;
just as a piece of wood when it is burned will develop more heat than a
piece of charcoal. This explains why one gram of fat yields 9.3 calories
of heat, and one gram of carbohydrate, only 4.1 (page 571). Fatty
acid therefore contains more potential energy than sugar, and in explain-
ing its synthesis from sugar in the animal body we must indicate the
source of the extra energy. This is dependent on oxidation of some sugar
molecules — which do not themselves become changed to fatty acid —
proceeding side by side with the reduction which affects the others and
is represented in the outcome of the reaction by the combustion products
C02 and H20, thus:

6CGH1206 + 13 02 - 20 C02 + C10H3202 + 20 H20.
(glucose) (fatty acid)

736

FAT METABOLISM 737

What evidence have we that such a process actually occurs in the body?
If we compare the intake of oxygen with the output of carbon dioxide
in the respired air, we shall find that usually there is less of the latter;
that is to say, the respiratory quotient, as this ratio is called, is usually
less than unity. During the extensive conversion of carbohydrate into
fat, however, which occurs during the fall months in hibernating animals,
the R.Q. has been found to rise as high as 1.4. The great excess of
C02 - output over 02 - intake which such a quotient indicates conforms
with the above equation.

The entire dissimilarity in chemical structure between the molecules
of fat and carbohydrate suggests that the primary step in the conversion
must be a thorough breakdown of the carbohydrate chain into compara-
tively simple molecules, from which the fat molecules are then recon-
structed and the unnecessary oxygen set free. The problem is to ascer-
tain the chemical structure of these simpler molecules and the manner
of their union into fatty acid.

The Method by Which the Fatty Acid is Broken Down. — In the chemi-
cal laboratory, ordinary oxidizing agents attack the fatty-acid chain at the
C-atom next the carboxyl (COOH) group (the alpha C-atom). But
this can not occur in the animal body, because it would leave behind a
smaller chain containing an uneven number of C-atoms, and such chains
are never found present in the animal fats. On the contrary, the com-
moner fats all contain an even number of C-atoms, thus : Butyric, C4H802 ;
palmitic, C10H3202; stearic, C18H3fi02; oleic, C18H3402.

The intermediary substances which are produced during the gradual
breakdown of the fatty-acid molecule in the normal animal are of a very
transitory character so much so indeed that it is impossible for any one
of them to accumulate in sufficient amount to permit of isolation, or even
detection, by chemical means. How then are we to identify the inter-
mediary product sf This has been rendered possible by the discovery that,
when anything occurs to disturb the normal "course of fat metabolism, as,
for example, when the tissues are deprived of carbohydrates (as in star-
vation or in severe diabetes), the oxidation of the fatty-acid chain stops
short when a chain of four C-atoms still remains unbroken. These last
four C-atoms seem to form a residue that is more resistant to oxidation
than the remainder of the fatty-acid molecule. It is a residue, therefore,
which is quite readily further oxidized to C02 and H20 under normal con-
ditions, but which, undergoes only a partial oxidation when the metab-
bolism is upset, resulting in the production of various intermediary prod-
ucts. These accumulate in the body in sufficient amount to overflow into
the urine, from which they can be isolated and identified.

The fatty acid with 4 C-atoms is butyric, CH3CH2CH2COOH, and the

738 METABOLISM

first oxidation product formed from it in the body seems to be ft-oxybuty-
ric acid, CH3CHOHCH2COOH. This then becomes oxidized to form a
body having the formula CH3COCH2COOH, acetoacetic acid, which, on
further oxidation, readily yields CH3COCH3, or acetone. These sub-
stances (/?-oxybutyric acid, acetoacetic acid and acetone) appear in the
urine during carbohydrate starvation, as in diabetes.

It might be objected, however, that a chemical process occurring under
abnormal conditions need not also occur in the normal animal. That it
probably does, however, is indicated by the results of the experiments
of Knoop and of Embden and his coworkers. Knoop conceived the idea
of introducing into the fatty-acid molecule some group which is resistant
to oxidation in the body. The phenyl group (C6H5) was found to have
this effect. By feeding an animal with the phenyl derivatives of acetic,
propionic, butyric, and valeric acids, it was found that the urine con-
tained either hippuric (see page 663) or phenaceturic acid. Both of
these are compounds of aromatic acids with glycocoll or aminoacetic
acid (CH2NH2COOH), one of the protein building-stones and always
available in the organism to form such compounds, thus :

( 1 ) C^COOH + CH2NH2COOH = CCH5CONHCH2COOH.

(benzole (glycocoll) (hippuric acid)

acid)

( 2 ) C6H5CH2COOH + CHJJH^COOH — CCH5CH2CONHCH2COOH.
(phenylacetic (glycocoll) (phenaceturic acid)

acid)

When either benzoic acid (CGH5COOH) or phenylacetic acid (CGH5CH2-
COOH) is formed in the body as a result of the oxidation of phenyl
derivatives of th'e higher fatty acids, the acid combines with glycocoll
according to the above equations. From this it follows that if oxidation
occurs so that two C-atoms are thrown off at a time (^-oxidation), fatty
acids with an even C-atom chain should yield hippuric acid, and those
with an uneven chain, phenaceturic. This was found to be the case, as
the accompanying table showrs.

ACID FED

OXIDATION
PRODUCT

EXCRETED AS

Benzoic acid, CCH5.COOH
Phenylacetic acid, C6H5 . CH2 . COOH

Not oxidized
Not oxidized

Hippuric acid
Phenaceturic

acid

Phenylpropionic acid, C6Hr, . CH, . CH2 . COOH CJL.COOH Hippuric acid

Phenylbutyric acid, CCH0 . CH2 . CH2 . CH2 . COOH CCH5 . CH2 . COOH Phenaceturic

acid
Phenylvaleric acid, C6H5 . CH2 . CH2 . CH . CH2 . COOH CCH,.COOH Hippuric acid

(From Dakin.)

FAT METABOLISM 739

Embden's experiments are equally convincing. He studied the forma-
tion of acetone in defibrinated blood perfused through the freshly excised
liver. Normally only a trace of this substance is formed, but when fatty
acids with an even number of carbon atoms were added to the blood,
they gave rise to a marked increase in acetone, whereas those with an
uneven chain failed to cause any change. The acetone was found to be
derived immediately from acetoacetic acid. The following table shows
the results.

NORMAL FATTY ACID FORMATION OF

ACETOACETIC ACID

Acetic acid CH3.COOH

Propionic acid CH3.CH2.COOH

Butyric acid CH3 . CH2 . CH2 . COOH +

Valeric acid CH3 . CH2 . CH2 . CH2 . COOH

Caproic acid CH3 . CH2 . CH2 . CH2 . CH, . COOH +

Heptylic acid CH3 . CH, . CH2 . CH2 . CH2 . CH, . COOH

Octoic acid CH3 . CH"2 . CH2 . CH, . CH, . CH', . CH2 . COOH +

Nonoic acid CH3 . CH2 . CH2 . CH, . CH2 . CH2 . CH2 . CH2 . COOH

Decoie acid GH3 . GH2 . CH2 . CH2'. CH2 . CH2". CH2 . CH2 . CH2 . CH2 . COOH +

(From Dakin.)

For a long time it was difficult for chemists to understand how such
a process of oxidation at the /3-C-atom could occur, since they were
unable to bring it about in the laboratory by the use of the ordinary
oxidizing agents, but recently Dakin has removed the difficulty by show-
ing that hydrogen peroxide (H202) oxidizes fatty acids just exactly in
this way.

We may sum up the results of these experiments and observations by
stating that normal saturated fatty acids and their phenyl derivatives can
undergo oxidation, not only in the animal body, but also in vitroy in such
a manner that the two (or some multiple thereof) terminal C-atom\s are
removed at each successive step in their decomposition.

But we must not be too hasty in concluding from these experiments that the steps
in the process are necessarily in the order of first, the production of a /3-hydroxy acid,
and second the oxidation of this to a Ketone group. The mere presence, side by side,
of j3-hydroxy butyric acid and of acetone in the above experiments does not indicate
which is the antecedent of the other, and indeed there are several experimental facts
that seem to show that the hydroxy acid may be derived from the ketone. For example
when acetoacetic acid is added to minced liver and the mixture incubated, 0-hydroxy-
butyric acid is formed (a reduction process), although less usually the reverse action
(oxidation) may occur when /3-hydrqxy acid is added. A reversible reaction must there-
fore be capable of occurring between these two substances, thus:

reduction

CH3.CHOH.CH2.COOH < - CH3.CO.CH,.COOH.

oxidation
(/3-oxybutyric acid) > (acetoacetic acid)

740 METABOLISM

We know practically nothing as to the conditions determining whether oxidation or
reduction shall predominate, but there are two significant facts that one should bear in
mind: (1) that a plentiful supply of oxygen is necessary for the oxidative process, and
(2) that the presence of readily oxidizable material in the liver (e.g., carbohydrates)
may determine the direction which the reaction shall take. It is commonly said that
fats burn in the fire of carbohydrates, and it may be that the undoubted diminution in
acidosis which occurs in diabetes when carbohydrate food is given is dependent upon the
directive influence which its combustion in the liver has on the above processes. But
we must be cautious not to transfer results obtained by experiments with minced liver
in. judging of the reactions which occur during life. Provisionally, then, we must assume
either that j8-hydroxybutyric acid is a necessary stage in the oxidation of butyric acid
or that it is formed by reduction of acetoacetic acid, which is really the first step in
that process.

Of course there is no evidence in the above experiments that the higher fatty acids
are also broken down by the removal of two C-atoms at a time, nor has it been possible
to detect any ketonic or j3-hydroxy derivatives of them in the animal body. We can only
reason from analogy that a similar process may occur, although some support is fur-
nished for such a view by the fact that ketonic fatty acids have been found in vegetable
organisms.

What, then, it may be asked, is the relation of the desaturation of fatty acids which
we have seen occurs in the liver (and probably elsewhere) to the j3 oxidation? There
can be no doubt that both processes can occur in the animal body, indeed in the same
organ, e.g., the liver; and it is important to ascertain their relationship to each other.
The conclusion which would seem to conform best with the known facts is that the de-
saturation process occurs (in the liver) so as to break up the long fatty-acid chain into
smaller chains, which are then capable of /3 oxidation (in the tissues) ; desaturation may
be the process by which the molecule is rough hewn, and )3 oxidation that by which the
resulting pieces are finally split to their smallest pieces — that is, to molecules of the size
of acetic acid, which are finally completely burnt to carbonic acid and water.

The increase of iodine value observed by Leathes and his coworkers need not, as has
already been pointed out, necessarily indicate that new double linkages have been intro-
duced in the fatty-acid chain; it may merely indicate that structurally isomeric deriva-
tives which absorb iodine more readily have been formed. Direct evidence of desatura-
tion has, however, been offered by Hartley, who isolated the unsaturated fatty acids (by
dissolving the lead soaps in ether) from pig's liver and then proceeded to oxidize them
with alkaline permanganate. When the olein of the depot fat is thus treated at a low
temperature, two hydroxyl groups become attached where the double linkage existed
(forming dioxystearic acid), and when the mixture is now warmed, the molecule splits
into two at this place, forming two lower acids (pelargonic and azelaic) :

(1) CH3-(CH2)7CH:CH(CHn)TCOOH;
(oleic acid)

OH OH

/ /

(2) CH3-(CH2)7-CH- -CH -- (CH,)tCOOH;

(dioxystearic acid)

(3) CH3 (CH^^OOH + COOH-^CHO.COOH.
(pelargonic acid) (azelaic' acid)

We may conclude from this that the double linkage in the oleic acid of the depot fat
exists between the ninth and tenth C-atoms. But it is otherwise in the case of the un-
saturated acid from the liver (pig's), for under the above process of oxidation this
yielded caproic acid, which, since this acid has six C-atoms, would indicate that the

FAT METABOLISM 741

double linkage existed between the sixth and seventh C-atoms. Another interesting fact
brought to light by the experiments was that a tetraoxystearic acid was formed, which
fell apart in such a way as to indicate that the hydroxyl groups occurred between the sixth
and seventh and between the ninth and tenth C-atoms. The occurrence of this substance
would be satisfactorily explained by the introduction into the molecule of oleic acid of a
second double bond — i. e., between the sixth and seventh C-atoms. ' ' The acids found in
the pig's liver may be accounted for, in other words, by supposing that desaturation
of stearic acid and of the ordinary (depot) oleic acid occurs by the introduction of a
double link between the sixth and seventh carbon atoms in each case" — (Leathes). Still
other double links may, however, be introduced into the fatty-acid chain, for acids of the
linolic acid series are present in cod-liver oil. Finally, it is of interest to note that caproic
acid is a product of the above oxidation process, for it has an even number of C-atoms
and therefore will form /3-oxybutyric acid.

To go into these chemical problems any further here would be out of
place. One other fact, should, however, be borne in mind — namely, that
the unsaturated acids may be formed from saturated acids through the
intermediate formation of /Miydroxy and /8-ketonic acids. Their mere
presence, in other words, should not be taken as evidence, that the oxida-
tion of fatty acids is initiated by the introduction of an hydroxyl group
at the (3 position in the chain.

CHAPTER LXXXII

CONTROL OF BODY TEMPERATURE AND FEVER

The classification of animals into two groups — warm-blooded and cold-
blooded— according to their ability to maintain the body temperature at
a constant level, is more or less arbitrary. Between the two groups an-
other exists, represented mainly by hibernating animals, in which at
certain times of the year the animal is warm-blooded and at other times
cold-blooded. The ability of the higher mammals to maintain a constant
body temperature may or may not be present at the time of birth. The
heat-regulating mechanism of the human infant for example remains ill
developed for so'me time, so that exposure to cold is liable to lower the
body temperature to a dangerous degree.

VARIATIONS IN BODY TEMPERATURE

In animals in which the heat-regulating mechanism is fully developed,
there is not, even during perfect health, entire constancy in temperature
in the different parts of the body or in the same part at differ ent. periods
of the day. The average rectal temperature of man is usually stated as
being 37° C. (98.6° F.), but the diurnal variation may amount to 1° C.,
being highest in the late afternoon and lowest during the night. There
are probably several causes for this variation, and they are in part at
least dependent upon the greater metabolic activities of the waking
hours and upon the taking of food. Apart from these influences, how-
ever, others which are less evident appear to operate; for it has been
found that, when the daily program is reversed by night work, the usual
diurnal variation, although much less pronounced, still remains evident
even although this reversal in habit may have been kept up for years.
It is of interest to note in this connection that nocturnal birds have their
maximum temperature at night and their minimum during the day.

Regarding the temperature in different parts of the body, that of the
rectum is usually about 1° C. higher than that of the mouth, and this
again higher than that of the axilla. Of these three the mouth tempera-
ture is the most variable, for many conditions, such as mouth breathing,
talking, drinking cool liquids and even exposure to cold air, are sufficient
to lower markedly the temperature of this region. When the mouth
temperature is carefully taken by leaving the bulb of the thermometer

742

CONTROL OF BODY TEMPERATURE AND FEVER 743

under the tongue for a minute or more, it is practically the same as the
temperature of the arterial blood of the hand when this is exposed to the
ordinary conditions of outside temperature. Greater differences than
1° C. in the temperature of different regions of the body are often ob-
served in feeble individuals and in those with some circulatory disturb-
ance.

FACTORS IN MAINTAINING THE BODY TEMPERATURE

The body temperature represents the balance between heat production
and heat loss. The production is effected mainly in the muscles by the
oxidative processes which are constantly ensuing there. When the
activity of the muscles is abolished by paralyzing the terminations of
the motor nerves with curare, the temperature of warm-blooded animals
immediately falls or rises according to the temperature of the environ-
ment. A curarized warm-blooded animal is thus made to behave like a
cold-blooded one. Increased muscular activity, on the other hand,
promptly raises the body temperature by 1° or 2° C,, above which, how-
ever, a further rise does not occur, provided nothing has been done to
interfere with the mechanism by which the excess of heat is got rid of
from the body. The temperature in such cases adjusts itself at a higher
level, at which it remains fairly constant however strenuous the exer-
cise. It is possible that a certain amount of heat may also be generated
by the chemical processes occurring in the liver and other viscera, but
when compared with the muscles this source of heat is undoubtedly in-
significant. Many of these chemical processes, as in the liver, instead
of producing actually absorb heat, so that the balance between heat-
producing and heat-evolving mechanisms may or may not come out in
favor of the liberation of heat.

The production of heat goes on all the time in muscles on account of
the condition of tonic contraction in which they are held (see page 905),
and which is also necessary for keeping the joints in the proper degree
of flexion or extension. When more heat is required by the animal body,
the tone of the muscles increases independently of the function which
they may be performing in controlling the position of the joints. This
increased tone may become so pronounced that it causes visible contrac-
tions, which we recognize as shivering. Whenever the insensible hyper-
tonicity and the shivering are inadequate to produce a sufficient amount
of heat, the animal instinctively moves about in order that the greater
contractions may liberate more heat.

The heat is produced in the muscles by oxidation of the foodstuffs that
have been assimilated from the blood. Even during the process of as-
similation itself a certain amount of heat is generated; this is known

744 . METABOLISM

as the specific dynamic action of the foodstuff, and is most pronounced
with protein and least so with carbohydrate (page 574). Advantage
may be taken of this heating power of protein to produce more heat
when the cooling conditions are excessive ; in winter, for example, there
is an inclination to take more protein food than during summer, and the
per capita consumption of such food is much greater in peoples living in
temperate zones than in those living in the tropics. The ultimate amount
of heat produced by oxidation is greatest with fat and least with carbo-
hydrate.

Heat loss in man is effected partly through the lungs, but mainly
through the skin. Through the latter pathway heat is lost by the physical
processes of heat conduction and radiation and by the evaporation of the
sweat. Through the lungs it is lost mainly in the vaporization of the
water contained in the expired air (latent heat of vapor). The amount
of heat lost from the skin by conduction and radiation depends on the
temperature of the skin, which again depends on the rate at which the
blood is circulating through the cutaneous vessels. Under ordinary con-
ditions of external temperature two or three times as much heat is lost
by these methods as by evaporation. The losses by evaporation, under
conditions of rest and average external temperature, are about equally
divided between the lungs and the skin.

Under average conditions in man the main regulation of heat loss is ef-
fected ~by variations in the skin temperature brought about by peripheral
vaso-constriction and dilatation. The marked sensitivity of the cutaneous
blood supply to changes in the temperature of the environment has been
very clearly shown by observations made with the hand calorimeter of
Stewart described elsewhere (page 296).. When the bloodflow through
the hand is examined in a person who has been exposed to the outside
air, it may be little more than half that which it attains after he has
been in a warm room for some time. In the outside air the vessels con-
strict to prevent heat loss by conduction and radiation; in the warm room
they dilate to facilitate this loss. The afferent impulses which reflexly
control the change in the cutaneous blood circulation may be set up by
local applications of heat or cold, as can be shoAvn in the hand-calorim-
eter experiments by applying a cold pad to the skin of the correspond-
ing forearm, or allowing an electric fan to blow on the arm when
an immediate curtailment of bloodflow takes place. Or the reflex may be
excited from distant skin areas, as illustrated in the curtailment in blood-
flow observed when the opposite hand to that on which the observation
is being made is placed in cold water. The magnitude of the change
in cutaneous circulation is nevertheless dependent upon the extent
of the area of the body that is opposed to the change in temperature,

CONTROL OF BODY TEMPERATURE AND FEVER 745

as seen in the dilatation of the skin vessels prior to a rise in body tem-
perature when a person is immersed in a warm bath.

Although afferent impulses from the skin are therefore of great im-
portance in adjusting the cutaneous blood supply according to the
amount of surface cooling that has to occur, a further effect is also pro-
duced 011 them by the action on the nerve centers of temperature dif-
ferences in the blood itself. Thus, when the temperature of blood going
to the brain is raised by placing the carotid arteries on some heating de-
vice or when the region of the corpora striata is directly warmed, the
skin vessels become dilated as if the animal had been exposed to general
warmth.

When the loss of heat by radiation and conduction is no longer ade-
quate to prevent a rise in body temperature, or when the processes can
not operate on account of a high temperature in the environment, the
loss of heat from the skin is mainly dependent upon the evaporation of
sweat. Under ordinary conditions this evaporation takes place at such
a rate that there is no visible perspiration on the surface of the body —
the so-called insensible perspiration. When the heat loss by this channel
must become greater, the perspiration is produced in larger amount, so
that it collects on the surface of the body; and, provided the conditions of
the environment are such that evaporation can readily take place (low
relative humidity), the amount of cooling of the body that can be effected
becomes very great. A man may exist without any marked rise in body
temperature in a very hot environment even when he is exposed to an out-
side temperature that is the same as that of his body, or even greater. To
encourage evaporation, however, he should be naked or very lightly clad,
and the air should be kept in constant motion so that the layers of air
next to the skin, which ordinarily very quickly become saturated with
vapor, are transferred and replaced by dryer air. Movement of the air
also increases the heat loss by conduction, provided the temperature of
the air is not too near that of the body.

The importance of the movement of air in the regulation of heat loss
has been clearly demonstrated by Leonard Hill,54 R S. Lee, and others,
and will be fully discussed in the chapter on ventilation (page 754).

The stimulus to increased sweating seems to be dependent mainly on
changes in the temperature of the blood; for sweating does not im-
mediately set in when the body is subjected to heat, as by a warm bath or a
hot pack. It usually takes from ten to twenty minutes after the person
has been placed in the bath or surrounded by the warm blankets of the
pack before sweating becomes pronounced. It can usually be shown that
before it sets in the body temperature has been raised from 0.1 to 0.8
degrees C. (0.2 to 1.4 degrees F.). In this regard, therefore, the response

746 METABOLISM

of the sweat glands does not occur so promptly as does the dilatation of
the cutaneous vessels.

Loss of heat by evaporation of sweat occurs only in certain animals.
It is practically absent, for example, in the dog. The degree to which
it may occur also varies in different individuals of the same species. The
power of withstanding high temperatures is proportional in man to the
facility with which he perspires. Where sweating is interfered with by
skin diseases, — by ichthyosis, for example, — exposure to heat or in-
creased heat production, as by muscular activity, may raise the body
temperature to a dangerous degree.

Another factor upon which the efficiency of evaporation of sweat in
cooling the body depends is the relative humidity of the air. When this
is high, evaporation of water into it . can not occur, and it is on this
account that an increase in body temperature is much more likely to
occur in warm, humid atmospheres than in those that are dry. At the
same temperature people can live in perfect comfort in the dry air of the
open plains, but suffer immediately from rise of temperature when they
go into the humid air of the river valleys. Similarly, work in hot fac-
tories or in mines is quite possible at very high temperatures if the air
is kept dry and in motion, but becomes impossible when the air is moist.
In judging of the adequacy of air from this point of view, it is there-
fore important to take not the ordinary dry-bulb thermometer reading
but that of the wet-bulb.*

In animals, like the dog, that do not perspire over the surface of the
body, vaporization of the water in the expired air is the most important
method of regulation of heat loss. When such an animal is exposed to
warmth or when the region of the corpora striata is artificially warmed,
the breathing immediately becomes much quicker and deeper, so that
pulmonic ventilation, is greatly increased and much more water is carried
out as vapor with the expired air. To vaporize the water large quanti-
ties of heat are required (seen in the latent heat of steam). In man this
method is, ordinarily, not of great importance, but it may become so
when sweating is interfered with, as in ichthyosis. The more rapid
breathing also facilitates cooling by increasing the conduction of heat
from the mucous membranes of the tongue, mouth, throat, etc. The im-
portance of this method of cooling has been shown by finding that after
the introduction of a tracheal cannula a dog can not withstand an in-
crease of external temperature nearly so well as a normal animal.

*The wet-bulb thermometer registers a temperature that is lower than that of the dry -bulb in
inverse proportion to the relative humidity of the air. When the air is completely saturated with
moisture, the temperature recorded by the two instruments will be the same; when it is perfectly
dry, the difference will be maximal.

CONTROL OF BODY TEMPERATURE AND FEVER 747

THE CONTROL OF TEMPERATURE

In the case of man the body temperature is very largely under volun-
tary control, as by the choice of clothing and the artificial heating of the
room. Desirable as this voluntary control of heat loss may be, there can
be little doubt that it is often managed to the detriment of good health.
Living in overheated rooms during the cooler months of the year so
diminishes the loss of heat from the body that the tone and heat-produc-
ing powers of the muscular system are lowered. Not only does this
diminish the resistance to cold, but it causes the food to be incompletely
metabolized so that it is stored away as fat. The superficial capillaries
also become constricted and the skin bloodless and "pasty." It is not
looks alone that suffer, however, but health as well, for by having so
little to do the heat-regulating mechanism gets, as it were, out of gear,
so that when it is required to act, as when the person goes outside to
the cold air, it may not do so as promptly as it should, with the result
that the body temperature falls somewhat and catarrh, etc., are the
result, There can be little doubt that much of the benefit of open-air
sleeping is owing to the constant stimulation of the metabolic processes
which it causes.

As will be inferred from what has been said above, the control between
heat production and heat loss is effected through a nerve center located
in or near the corpora striata. In most animals, when the spinal cord
is cut in the cervical region, the body temperature quickly falls unless
artifically maintained. In the case of man, on the other hand, it has
usually been observed, after accidental section of the spinal cord in the
cervical region, that a rise in temperature occurs. In twenty-four un-
complicated cases of spinal-cord injury in man, collected from the rec-
ords of Guy's Hospital by Gardiner and Pembrey, it was found that
nineteen showed hyperthermia (sometimes amounting to 43.9° C.), and
only five, hypothermia (sometimes 27.6° C.). If the patient lived, the
ultimate effect of the section, as in the lower animals, would no doubt
be the loss of the power of maintaining a constant temperature.

The extent to which the animal comes to behave as if cold-blooded, after
section of the spinal cord, varies considerably according to the level of
the lesion; if the cord is cut in the upper thoracic region, for example,
the regulation against cold, although distinctly less efficient than normal,
is far better than when the section is made through the cervical cord.
This difference is dependent on the fact that after the lower lesion much
larger muscular groups and skin areas are left intact, so as to make
regulation possible. Section of the dorsal cord in mice has been found
by Pembrey to abolish entirely the increased metabolism which occurs
in normal mice when they are exposed to cold.

748 METABOLISM

In the light of these experiments it is probable that the difference in
the effects produced on body temperature by section of the cervical
spinal cord in man and the lower animals depends on the relative im-
portance of the heat-producing and heat-dissipating mechanisms. When
the control of heat loss is paralyzed in the smaller animals, the cooling
of the body becomes excessive in relation to the amount of heat produced
in the paralyzed muscles, because the body surface is extensive in com-
parison with the body weight (see page 586). In the larger animals such
as man, on 'the other hand, the cooling effect is much less marked, espe-
cially .when, as is common after such an accident, the patient is kept
unusually warm.

FEVER

The clinical application of a knowledge of the mechanism of heat regu-
lation in the animal body concerns the causes of fever. In the most
familiar form fever is produced by infectious processes, but it may also
be owing to various other causes, among which may be mentioned the
parenteral injection of foreign protein, excessive destruction of protein
substances in the body itself, the action of certain drugs, and lastly,
injury to the base of the brain or lesions of the upper levels of the spinal
cord. Various types of fever are recognized: when the temperature re-
mains constantly above the normal, it is known as continuous fever;
when oscillations occur but the temperature never falls to the normal
level, it is known as remittent; when it attains the normal level at cer-
tain periods during the day, it is known as intermittent.

Causes of Fever

During a sudden rise in temperature there is, on the one hand, in-
creased heat production in the muscles, and on the other, dimin-
ished heat loss from the surface of the body. The fever is therefore
due to an exaggeration of the processes ~by which the body normally re-
acts to conditions which tend to lower the ~body temperature. The increased
muscular activity thus induced often causes visible contractions, familiar
as shivering; and the constriction of the cutaneous blood vessels pro-
duces the subjective sensation of chills, and causes the skin to become
pale and cold to the touch. The skin muscles also contract, producing
" goose skin." During this stage, objective demonstration of the cur-
tailment of the skin circulation can be secured by observation of the
bloodflow through the hands and feet (page 296). When the temperature
suddenly falls again, (the crisis, as it is called) the muscles become flaccid
and produce less heat, and the cutaneous blood vessels dilate, as has
been shown by measurements of the bloodflow of the hands and feet.

CONTROL OF BODY TEMPERATURE AND FEVER 749

At the same time also, the sweat glands are stimulated and marked per-
spiration occurs.

Concerning the cause of continuous fever, it must be assumed that the
balance between heat production and heat loss has been adjusted at a
higher plane than normal. We can not explain the fever on the basis
either that heat production is permanently increased or that heat loss
is permanently diminished, for in neither of these cases would the tem-
perature stand at a permanent level but would steadily rise or fall, ac-
cording to which mechanism was disturbed. While set at this higher
plane of fever, the thermogenic nerve centers are still capable of re-
sponding in the usual way to the influences which cause the body tem-
perature to change in a normal person. For example, when a fever pa-
tient is subjected to a hot bath so that his body temperature rises about
0.2 to 0.5 degrees C., sweating occurs just as in a normal individual; or
if exercise is taken the increased amount of heat thereby produced in
the muscles is dissipated in the usual way. When, on the other hand,
the patient is exposed to cold, the vessels of the skin contract and he
shivers.

Although fever is not caused by an actual disturbance of balance be-
tween heat production and heat loss, neither of these processes is pro-
ceeding at its normal level. That there is a distinct increase in the total
heat production of the body in acute fevers in well-developed persons
has been shown by means of the respiration calorimeter. This increased
heat production is not observed in patients who have been brought into
a weakened condition and in whom the muscular tissues have become
atrophied by long-continued fever. The increased heat production in
continuous fever is mainly dependent upon the increase in body tem-
perature and is not one of its causes, as is evident from the fact that far
larger quantities of heat are frequently produced in normal individuals
as a result of muscular exercise or the taking of large quantities of
protein-rich food. The heat thus produced is, however, very quickly
dissipated, so that only a temporary rise in temperature occurs, (cf.
Hewlett.57)

Similarly, it can be shown that in continuous fever there is a relative
inefficiency in the mechanism of heat dissipation. When the temperature
of a normal person is artificially raised through about 1° C., a marked
increase in cutaneous bloodflow and profuse perspiration are invariably
noted. In a patient with fever of the same degree, on the other hand,
there is practically no change in the skin circulation; indeed, it is usually
diminished, and there is no unusual perspiration. The heat-regulating
mechanism is now fixed on a plane that is higher than the normal, so
that although further increase in body temperature, as we have seen,

750 METABOLISM

calls forth responses like those in a normal individual, yet at the fever
temperature itself there are none of the reactions which a normal individ-
ual would exhibit if his temperature were artificially raised to that level.57
The adjustment of the temperature at the higher level is by no means
so perfect as it is at the normal level of health, so that a normal subject
is more resistant to the effects of cold than is a patient with fever. The
degree of response of the fever patient, however, varies considerably
from time to time ; a cold bath in typhoid fever, for example, lowers the
body temperature much less effectively at an early stage in the disease,
when the fever is more or less continuous, than later when it is becoming
of the intermittent type. In the third week of the disease the cold bath
more readily brings down the temperature and keeps it down for a longer
time than during the first or second week. The mechanism for heat loss
is also deranged in fever, which explains the rise in temperature that is
likely to follow the performance of even moderate muscular exercise or
the taking of too hearty a meal in tuberculous and convalescent typhoid
patients.

Changes in the Body During Fever

In seeking for the cause of fever which is evidently of an obscure
nature, it is necessary to collect all the information we can regarding
the metabolic changes that are then occurring in the animal body. A
few of the most significant facts that have so far been collected may
be mentioned here. Some of the most important concern the dis-
turbance in nitrogenous equilibrium caused by the considerable loss of
nitrogen which takes place in fever patients when they are fed on
the usual hospital diet prescribed for such cases. This loss of nitro-
gen is no doubt the result of the partial starvation in which the pa-
tient is kept; for it has been shown by Shaffer and Coleman55 that
patients with typhoid fever may be maintained in nitrogenous equi-
librium by feeding them with relatively large amounts of carbohy-
drate, which acts by protecting the protein of the body from disintegra-
tion (see page 605). Even with a diet excessively rich in carbohydrates
that no more than covers the calorie requirements of the patient, nitrog-
enous equilibrium has also been attained. The protein minimum to
which fever patients can be reduced is nevertheless considerably higher
than the minimum in normal individuals.

From the above results as a whole, it is probably safe to conclude that
there is a specific destruction of protein going on in the body during fever.
Further evidence of such a destruction is furnished by the presence in
the urine of excessive amounts of creatinin, of purine bases, and, it is
said, of incompletely hydrolyzed proteins, such as the albumoses (pro-

CONTROL OF BODY TEMPERATURE AND FEVER 751

teoses.) Moreover, when the fever suddenly terminates in crisis, there
is a marked increase in the excretion of urea (the epicritical urea in-
crease), which indicates that an extensive deamination of protein build-
ing stones (amino acids) is occurring. The so-called "diazo reaction"
obtained in the urine during the fever is also believed to depend on the
presence of abnormal protein-disintegration products.

As to the specific cause of the increased protein disintegration, little
is known. Several factors may operate: (1) the partial starvation of the
patient, entailing an increased breakdown of protein to meet the calorie
requirements; (2) the high temperature, which in itself may stimulate
increased protein metabolism, for it has been shown that, when normal
animals are artificially warmed, protein metabolism becomes increased;
and (3) toxic protein-decomposition products specifically causing an ex-
cessive breakdown of protein.

Although there is increased protein breakdown during fever, it must
not be forgotten that only about '20 per cent of the total expenditure
of the body is derived from this foodstuff, 80 per cent coming from non-
nitrogenous material, which must be fat, because the available carbo-
hydrates are used up at an early stage.

Since the general metabolism is increased, the excessive breakdown of
the fatty substances, occurring as it does in the presence of a diminished
combustion of carbohydrates, interferes with the proper oxidation of the
fatty-acid molecules and leads to the appearance of so-called acidosis
products in the urine, and consequently to a relative increase in the
urinary ammonia (page 650). A tendency to acidosis therefore exists.
The acidosis may reach a considerable degree of severity and cause the
tension of carbon dioxide in the alveolar air to become diminished. Since
a similar degree of acidosis may be produced in partially starved ani-
mals by overheating them with moist air, but not so if the animals are
liberally fed with carbohydrates, it is probably safe to conclude that
abundance of carbohydrate is advisable in the food that is furnished to
fever patients.

Another interesting metabolic change in fever concerns the salt 'bal-
ance. This is studied by observing the amount of sodium chloride excreted
by the urine. As is well known, this becomes markedly diminished until
the crisis of the fever, when it suddenly increases. Salt retention is more
marked in certain types of fever than in others, and it is essentially dif-
ferent in nature from the salt retention that has been observed to occur
in nephritis. This difference has been brought to light by examination
of the chloride content of the blood. In nephritis, the concentration of
chlorides in the blood is considerably increased, whereas in fever it is
markedly diminished. The deficiency in salt elimination can not be at-

752 METABOLISM

tributed to a deficiency of salt in the food, for it sets in before the diet
has been curtailed and, when salt is given to a febrile patient, it is re-
tained in the body to a greater degree than is the case in the normal
individual. For some reason the tissues in fever have acquired the
property of retaining large quantities of salt.

Attempts to study the water balance during fever have frequently been
made, but the technical difficulties of such investigations make the re-
sults uncertain and of little value. That some retention of water occurs
during fever is, however, evidenced by the dilution of the blood. At the
crisis this hydremia quickly disappears at the same time as the increased
elimination of chlorides is going on. Chlorides and water would there-
fore seem to behave in a similar fashion during fever.

The Heat-regulating Center

In all discussions on the regulation of body temperature and the
causes of fever, it is assumed that a heat-regulating or thermogenic
center exists somewhere in the brain. It is believed to be located
about the optic thalami or corpora striata, for it has been found in
rabbits that destruction of the brain anterior to this region does not
cause any change in body temperature, whereas destruction behind it
is followed by an entire upset in the heat-regulating mechanism. Fur-
thermore, artificial puncture of this part of the brain causes marked
elevation in body temperature in rabbits (heat puncture). Most in-
teresting experiments have been recorded by Barbour,56 who succeeded
in applying heat or cold locally in the region of the centers. By the
application of cold, increased muscular metabolism, on the one hand,
and diminished heat loss, on the other, were excited; and conversely,
when warmth was applied, an increased heat loss and a diminished heat
production were observed. Irritation of this region of the brain in man,
as after cerebral hemorrhage, is also accompanied by remarkable dis-
turbances in heat regulation. It is believed by many that the essential
cause of fever in infective conditions, is an action on these centers by toxic
substances which develop in the blood.

The centers may also be acted on by various drugs, some of wrhich
excite them to increase the body temperature, others, to lower the tem-
perature when this has already been elevated. When solutions of sodium
chloride are injected intravenously or subcutaneously or even sometimes,
particularly in children, when administered by mouth, more or less fever
may result. This must be a specific action of the Na ion, for, if instead
of pure solutions of NaCl. solutions containing calcium and potassium
salts as well as those of sodium are injected, no fever is induced. This
fact, taken along- with the close similarity between puncture diabetes

CONTROL OF BODY TEMPERATURE AND FEVER 753

and heat puncture, lends support to the view that in its initial stages
experimental fever of this type is the result of an excessive breakdown
of glycogen in the liver. It must not be imagined, however, that persist-
ent fever can be attributed to such a cause, since the fever remains after
the glycogen has all been removed. Other chemical substances produc-
ing fever are caffeine, certain other purines, and particularly tetra-hydro-
naphthylamin.

Belonging to this group of fevers must also be considered the im-
portant ones produced by the intravenous injection of certain forms of
protein, as those of egg white or those derived from the bodies of bac-
teria or from the laked corpuscles of a foreign blood. The fever in
these cases is no doubt caused by a mechanism, closely related to that
responsible for anaphylaxis (see page 90). Such injections do not pro-
duce fever in animals after division of the cervical spinal cord or ex-
cision of the midbrain. It is believed that many cases of so-called asep-
tic fever, occurring after severe contusions or other wounds, may be
the result of destruction of proteins within the body. Similarly the rise
in temperature during infections may be owing to the breakdown of pro-
tein by microorganisms within the cells.

Significance of Fever in the Organism

It is impossible at present to state definitely whether fever is a re-
action of the organism against some infection and therefore of benefit
in assisting the organism to combat it, or whether it is in itself an un-
favorable condition. . The question can certainly not be answered by
observing the behavior of bacteria growing at different temperatures
in various media outside the body. That certain bacteria should be
found not to thrive at incubator temperatures equal to those found in
the body during fever, does not at all prove that this fever is of sig-
nificance as a means of combating the growth of the bacteria in the
body. It is undoubted that, where the body temperature becomes ex-
cessively high, the correct treatment is to keep it down as much as
possible. On the other hand, the reduced mortality that has followed
the introduction of the cold-bath treatment in typhoid fever may not
be due so much to the reduction in body temperature itself as to
the favorable effect produced on the nervous system and circulation.
We certainly know that in normal animals moderate degrees of hyper-
pyrexia produced by exposure to moist heat are well borne for consider-
able periods of time, thus indicating that it is the infection and not the
hyperthermia that causes the serious damage to the body in infectious
fevers.

CHAPTER LXXXIII

THE PHYSIOLOGICAL PRINCIPLES OF VENTILATION

The well-being of a conscious animal in relationship to its environment
constitutes the main problem of the study of ventilation. In the case of
animals leading an outdoor life, it is a problem of relatively little im-
portance, but for those like man which spend much of their time in
confined spaces, it is a problem of great importance, because it becomes
necessary to determine the limits within which the outside influences may
be altered without detriment to health or comfort. This problem is con-
sidered here because it is closely related to that of the body temperature.

The Relationship Between the Chemical Composition of the Air and
the Well Being of the Body. — When our knowledge of the function of
breathing became developed to the extent of showing that an animal
requires the oxygen of the air for the living processes of its body, and
as a result of these processes that it produces carbonic acid, which is
then added to the air, it was natural to suppose that the unfavorable ef-
fect of overcrowded confined spaces was due either to the using up of
the available oxygen or to a poisonous action of- the carbonic acid.

It needs only a few words to point out how utterly erroneous were
these earlier explanations. That deficiency of oxygen is no factor is in-
dicated by the facts, first, that this gas is seldom reduced by more than
one per cent, even in the most crowded places; and secondly, that people
live a normal existence at altitudes at which the oxygen percentage, meas-
ured at sea level, is reduced to less than two-thirds the normal.

It is not altogether easy to understand why excess of C02 was thought
to be responsible for the evil effects of vitiated atmospheres. No doubt
the chief reason was that the percentage ' of this gas is often raised in
such atmospheres, but this is nothing more than coincidence, for on the
one hand most unsuitable conditions may exist when the percentage of
C02 is normal, and on the other, air loaded with almost a hundred times
the percentage found even in the most polluted atmosphere can be breathed
for indefinite periods of time without any unfavorable symptoms.

As a matter of fact, even in the open, we arc constantly taking into the pulmonary
alveoli large percentages of C02,' for obviously with each inspiration the first air to be
drawn in is that which remains over in the air passage from the preceding expiration.
This air contains somewhere about 5 per cent of CO2, and in quiet breathing it amounts
in volume to about one-third of all the air that is drawn in from the outside. This in
'itself indicates that CO2 per se can not be poisonous, and when we consider further the

754

THE PHYSIOLOGICAL PRINCIPLES OP VENTILATION 755

now well-known fact that a certain amount of this gas in the alveoli is absolutely es-
sential to the well-being of the animal, the whole hypothesis of its toxic action becomes,
to say the least of it, absurd. Indeed so important is the presence of this constant
amount of CO2 in the alveolar air that whenever there comes to be a marked increase in
the amount of CO2 in the atmosphere, the breathing becomes greater, so as to ventilate
the air sacs more thoroughly, and thus keep the relative amount of CO2 in them at the
normal level. The extent of this increase in respiration is usually so small as to be
unnoticed by the individual, and certainly increased breathing is not one of the symp-
toms of which persons complain who are living in polluted atmospheres.

In the face of such evidence, even the most ardent supporters of the
theory that the vitiated air owes its evil influence to C02, were compelled
to abandon their position, but they did not do so without a final attempt to
retain for determinations of C02 a certain significance in the appraisement
of the healthfulness of air. Their new interpretation was to the effect that
the C02 percentage is proportional to the amount of deleterious organic
matter, and for many years this view prevailed. It is still believed by some
that an increase from the normal of 3 to 10 parts of C02 per 10,000 parts
of air indicates a degree of organic pollution which is dangerous to health.
More recent work definitely shows, however, that this view also must be
abandoned, and there remains for C02-analysis only the secondary value
that it indicates, in a readily measurable way, to what extent the inside air
is being mixed by ventilation with pure air from the outside. However
free this dilution may be, the atmosphere may still be deleterious to health
and comfort unless certain other properties of it are incidentally altered.

This interpretation of the value of CO, analysis naturally leads to a con-
sideration of the next possibility, namely, that the air in confined spaces
is contaminated by the accumulation of organic poisons derived from the
exhaled air of the persons living in it.

It is many years ago now since experiments apparently proving this hypothesis were
published. These have been shown to be entirely fallacious, and we need refer to only
one group of them here, namely, those that were devised to show that inhalation by one
animal of volatile proteins contained in the exhaled air of others caused anaphylactic
reactions (page 90). As proof for this hypothesis, experiments were performed in
which a man breathed through a filter of glass wool (to catch any saliva) into a cooled
vessel, and the condensed vapor was then inoculated in appropriate dosage into guinea
pigs, so as to sensitize them, and a month or so later the animals were inoculated with a
minute trace of human blood serum. The injected animal showed decided symptoms of
anaphylactic shock, whereas other animals not previously sensitized were unaffected by
the injection of the same amount of serum. Such results taken by themselves did seem
to afford substantial support for the new hypothesis, but it is almost certain that they
depended on contamination of the condensed vapor by traces of saliva which it is im-
possible to keep out by any kind of filter. This saliva contains traces of soluble protein
(mucin) wh'ch had been responsible for the anaphylactic reaction. The symptoms are,
however, entirely dissimilar from those of a vitiated atmosphere. Hay fever, some forms

756

METABOLISM

of asthma, and the reaction which some persons show when near to horses may be due
to anaphylaxis, but the symptoms are not at all like those of persons breathing polluted
air.

Once and for all, the toxic theory, as we may call it, both in its new
and its old form, is disproved by a very simple series of experiments per-
formed a few years ago by Leonard Hill, Flack and others.72 These ob-
servers kept rats and guinea pigs in deep boxes so that they were huddled
together in a very poorly ventilated place, the atmosphere of which indeed
often contained 1 per cent of C02 — ten times more than the legal' limit.
The animals lived and thrived for months, although they must have been
breathing air which was highly contaminated by the supposed volatile
proteins. Not only did the animals show no symptoms while in the box,
but they failed to exhibit any anaphylactic reaction when, after some
time, they were inoculated subcutaneously with the serum of animals of
the other species with whom they had been in cohabitation. This was
really a most excellent test of the anaphylactic theory because there are
probably no two animals in which anaphylaxis is more pronounced than
in the rat and guinea pig. The only things that were found to be of im-
portance in maintaining the animals in a thriving condition were cleanliness
and plenty of food.

By an eliminative process we are gradually approaching the correct
solution of our problem, but before we proceed to consider this, it may
be well to remark that the odor of polluted air has nothing whatever to do
with its unhealthy influence, except in so far as it excites disgust and puts
one off his appetite. Indeed one very soon becomes so accustomed to these
odors that they fail entirely to be sensed after a short period in contact
with them. Their influence is entirely psychological. In many trades
and occupations people are constantly exposed to odors that are almost un-
bearable to one who is unused to them, and these people are perfectly heal-
thy, and indeed do not complain at all of the smells.
• We have so far considered in what is approximately their chronological
order the various hypotheses that have been brought forward to account
for the harmful influence of vitiated atmospheres. We have done this
mainly in order to correct any false conclusions that may still exist in
connection with the subject.

And if further evidence be demanded to justify this position, there is
one crucial experiment which once and for all shows that changes in the
chemical composition of the atmosphere has no relationship whatsoever to
the unhealthful influence of vitiated air. This experiment is all the more
convincing because it was performed on healthy young men. In its simplest
form it consists in crowding as many persons as possible into an airtight
cabinet, provided with an electric fan, and with the necessary apparatus
for measurements of the physical and chemical conditions of the air.

The following is a description of the results of such an experiment:

THE PHYSIOLOGICAL PRINCIPLES OP VENTILATION 757

"After 44 minutes the dry-bulb thermometer stood at 87° F., the wet bulb at 83° F.
The carbon dioxide had risen to 5.26 per cent. The oxygen had fallen to 15.1 per cent.
The discomfort felt was great; all were wet with sweat and the skin of all was flushed.
The talking and laughing of the occupants had gradually become less and then ceased.
On putting on the electric fans and whirling the air in the chamber the relief was im-
mediate and very great, and this in spite of the temperature of the chamber continuing
to rise. On putting off the fans the discomfort returned. The occupants cried out for
the fans. No headache or after effects have followed this type of experiment which
has been repeated five times." (Leonard Hill) Long before the discomfort had become
extreme 'the oxygen percentage became so low that matches would not light. The disin-
clination to smoke cigarettes was not noticed until some time after it was impossible
to light them.

In other experiments of similar type the person in the cabinet was allowed
to breathe outside air through a tube, but with no amelioration of the un-
comfortable feeling, or a person outside the chamber breathed for hours
the air inside it through a tube without suffering any discomfort. Clearly
therefore neither the chemical nature of the air, nor the presence of toxic
substances in it, has any relationship to its evil influence. But the experi-
ment is not merely destructive of previously held hypotheses ; it also points
the way to the true solution of the problem, for it indicates that stagna-
tion of air loaded with moisture has some very close relationship to the
discomfort. It shows that a change in the physical rather than the chemical
properties of the air is the real cause of its deleterious action.

THE RELATIONSHIP BETWEEN THE PHYSICAL CONDITION OF THE AIR AND
THE WELL-BEING OF THE BODY

The changes observed in the preceding experiment can affect but one
function of the body, namely, that of heat dissipation, and by so doing
cause disturbances in the mechanism of heat control. This does not nec-
essarily imply that this disturbance is so great as actually to cause an in-
crease in the body temperature, although this is very commonly observed
in persons who have been for some time in crowded places, but it interferes
with a mechanism which is responsible not alone for proper heat regulation
but also for the maintenance of a correct relationship of blood supply
to different parts of the body, and for tonic stimulation of the nervous
system.

It is in connection with this phase of the subject, more than any other,
that many people find it difficult to understand the true significance of
relative humidity to the well-being of the body. The difficulty depends
on the fact that the relative humidity has an opposite influence at low
and high temperatures. In the former case it increases the conductivity
of the atmosphere for heat and has a cooling influence, and in the latter
it interferes with the evaporation of sweat, andvhas a heating influence.
Below about 65° F. the cooling effect of moist air is prominent because
there is little sweating, therefore a cold wet atmosphere is chilling — it

758 METABOLISM

conducts heat aAvay. At about 70° F. the cooling effect of air disappears
and sweating occurs. The evaporation of the sweat now causes cooling,
the degree of which varies inversely with the relative humidity. Be-
tween these two temperatures, i.e., 65° and 70° there is a range in which
humidity has little influence — a neutral region. The influence of high
relative humidity on bodily comfort at temperatures above the neutral
temperature becomes very marked indeed at 85° F. and a relative hu-
midity of 90 per cent, for example, very serious symptoms appear in a
few minutes, when there is no movement of the air.

Relative humidity and temperature alone are not, however, the only
physical conditions to be considered. Another is the movement of the
air, for even under the unfavorable conditions just cited, immediate
relief is afforded if an electric fan be started, as it will be recalled was
the result in Hill's experiment. The movement of the air enables it,
though nearly loaded to its full capacity with moisture, to carry away
considerable quantities in small loads.

The wearing of clothes greatly affects the rate with which these changes occur. The
clothes act as barriers, preventing the movement and exchange of air around the body.
The garment next the skin entraps a layer of air which is more or less at the same
temperature as the skin, and which soon becomes saturated with moisture at that tem-
perature. Between the inner garments and those over them other layers of air arc en-
trapped, each one being at a somewhat lower temperature and containing less moisture
than the one inside. These layers of air, therefore, form stepping stones, as it were, 'be-
tween the extreme conditions next the surface of the skin, and the environment of the
clothed body. Obviously if the layers of air next the skin are to be renewed at such
a rate that they remain cooler than the skin and unsaturated with moisture the clothing
must be adjusted to suit the outside conditions.

There is every reason for believing that it is because of interference
with the processes of heat loss that improperly ventilated and over-
crowded places are uncomfortable. The moisture exhaled and evapo-
rated from the bodies soon raises the relative humidity so that heat loss
is retarded from the skin, and the heat that is actually given off raises
the temperature so that loss from the body by radiation and convection
becomes suppressed. As the temperature steadily rises, the air takes up
more and more moisture, with the result that less and less heat comes to
be lost from the lungs in saturating the expired air with vapor. The
physical conditions of the environment become unsuitable for the physi-
ological mechanism of heat loss, although meanwhile heat production
goes steadily on. The body furnaces are not damped down in propor-
tion as the loss of heat diminishes, and the consequence is a rise in the
temperature of the blood — a mild fever. Now it is well-known that the
cellular activities, which, taken together, make up the life process of
the body are extraordinarily sensitive to change of temperature; their
chemical activities become interfered with, they demand more oxygen,

THE PHYSIOLOGICAL PRINCIPLES OF VENTILATION 759

they fail to get rid of effete products properly, substances which have
no action on them under the ordinary conditions of temperature become
toxic and so forth. A highly abnormal internal environment therefore
becomes created around the living tissues of the body.

The Relationship between the Conditions of Ventilation and Suscepti-
bility to Infections. — But short of a measurable rise in the temperature,
improperly ventilated places cause reactions in the human body that are
responsible not only for the discomfort which is experienced, but also for
a lowering of resistance to infections. These reactions are due in the
first instance to alteration in the temperature differences between the
skin and the underlying tissues. Normally, as has been remarked before,
this difference maintains at the skin a constant stimulation of the ther-
mic nerves, and this stimulation is important in maintaining the tone of
the nerve centers. The nerve cells that control the functions of the
body do not originate impulses; they only act when other afferent im-
pulses arrive at them. There are many varieties of stimuli which may
excite these afferent impulses, but none more important than those which
excite the heat nerves of the skin. This stimulation depends on the rate
at which heat is passing through the sense organs (or receptors), in
which these nerves terminate. It is necessary to emphasize that 'it is
the rate of change that acts as the stimulus, and this depends on the dif-
ference between the deep and superficial temperatures. When the skin
vessels become dilated, so large a .volume of blood reaches the surface
that this difference becomes slight, and the thermic receptors are not
stimulated. There are many practical applications of these principles;
thus it is because of stimulation of the thermic skin nerves that cold
baths have a bracing effect, that the open-air treatment, as in tuberculo-
sis, tones up the body and enables it the better to hold its own against
the tubercle bacillus, and that sleeping out of doors is the best tonic for
maintaining good health. In the open-air treatment it is true that the
body is closely wrapped up — that is essential — but this does not elim-
inate the cooling influence, for not only does the cool air play on the
exposed face and hands, in the skin of both of which the thermic nerves
are very sensitive, but it acts also on these nerves in the skin, under the
clothes, for the clothing merely serves to regulate the rate of cooling.
This still goes on very much more than it would with much less clothing
in an atmosphere that is stagnant, hot, and humid. Open windows in
bedrooms are never so healthy as open-air porches, because there is no
draft. It is the draft that is important. Naturally it must be regulated
so that it is not restricted to one part of the body only — that obviously
would introduce conditions to which the body is unaccustomed — it
must blow equally all over. There is probably no greater fallacy in pop-
ular hygiene than that drafts are dangerous. Like all good and desirable

760 METABOLISM

things they become so only when they are improperly used — when a per-
son overheated by being in a hot atmosphere is suddenly subjected to a
restricted draft, of course there is danger that the sudden change of
conditions, affecting one part of the body only, will cause vascular dis-
turbances that may be undesirable, but if the conditions be properly con-
trolled, drafts are the healthiest things and the best tonics.

It is a common experience not only that ordinary colds, but more
serious infections as well, can be directly traced to some unsuitable
condition of ventilation ; such as sudden exposure to a draft while over-
heated, or going out into a cold, damp atmosphere from an overheated
room. What is the reason for the infection under these conditions? At
the outset we must recognize that all these conditions, colds, catarrhs,
bronchitis, just like the more acute infectious diseases, as diphtheria,
pneumonia, cerebrospinal fever, etc., are due to microorganisms, and the
question therefore is why should unfavorable ventilating conditions so
frequently be the immediate cause of the attack.

There are two methods by which the infection might occur. First, by
a great increase in the number of organisms in the air, and secondly by
a lowering of the resistance of the body towards the organisms, which
would not then require to become increased in numbers. The former
method is usually known as mass infection, and there can be no doubt
that it is very common, perhaps, indeed, is the commonest cause for
infection. The organisms, of course, come from infected individuals,
who add them to the atmosphere in the exhaled air, particularly when
this is forcibly discharged as in coughing or sneezing, or even in speaking.

Evidence of the importance of this factor is as follows. If the mouth be rinsed with
a culture of some readily recognizable organism not commonly present in detectable
amounts in the atmosphere, and the person, standing in front of a row of P'etri dishes
each cotaining some culture medium upon which the organism will grow, then speaks at
ordinary pitch, the plates after proper incubation develop colonies of the organism, those
nearest the speaker having most, but even those at a distance of several feet also show-
ing them.

A serious problem in zoological gardens has been to keep animals that are highly
susceptible to tuberculosis free from this disease. The higher apes, for example, inevi-
tably succumb to this disease, being infected by the bacilli exhaled by persons standing
in front of their cages, many of whom harbor these bacilli, though they may not show
any of the symptoms of tuberculosis. Now it has been found that if glass screens are
erected in front of the cages, the animals remain almost free from the disease.

But mass infection does not suffice to explain the cause for the onset
of attacks of many conditions that are, nevertheless, fundamentally due
to bacteria, such as ordinary colds. These can frequently be traced to
some chill, or wet feet, or exposure to sudden change in temperature. In
such cases it is believed that the bacteria are present on the mucous mem-
branes of the upper respiratory passages, but that they remain inactive

THE PHYSIOLOGICAL PRINCIPLES OF VENTILATION 761

because of the normal protective influences which exist on these surfaces.
So long as the blood supply is normal, these protective influences are
adequate to protect the body from invasion, but if this should become cur-
tailed, then the bacteria become active and set up pathological processes.
Evidence favoring this view has been obtained by several recent investi-
gators by finding that the blood supply of the upper respiratory passages
becomes decidedly curtailed when the surface of the body is cooled. For
example Leonard Hill and Muecke some years ago examined with a spec-
ulum the mucous membranes of the nose under various conditions, par-
ticularly out of doors, and in rooms which were ventilated and heated to
an average degree. Out of doors the mucosa was pale and taut, and when
touched by a probe did not show any pitting. This is the normal con^
dition. Indoors it was common to find the membrane decidedly swollen,
flushed with blood and covered with thick secretion, and when a probe
was pressed 011 it a depression resulted lasting for some time. In one
case that was frequently examined during these observations there was
a deflected septum which only partly blocked the nasal passage on one
side when the person was outside, but which did so completely under un-
favorable conditions of ventilation. It is this swelling of the nasal
mucosa and probably of that of the cavities which extend upward from it
on to the forehead that causes the sense of stuffiness and probably also
the headaches which are common in crowded, overheated places.

The conditions found to bring about these changes with greatest cer-
tainty were when the feet were cold and the air round the head was
warm, conditions which are just exactly the opposite of those obtaining
out of doors. Here the head is usually more quickly cooled than the feet
because convection currents of cool air play around it freely, whereas
next the ground the air is more stagnant. Besides if the sun is shining
the earth becomes heated by absorbing the heat. The temperature as
registered by a thermometer, either wet or dry bulb, may be the same
at the feet as at the head. It is not this that counts, however, it is the
rate of cooling which is dependent, mainly, on the movement of the air.
Now in a poorly ventilated room, such for example as one heated by a
stove, or even by radiators, and in which there is no movement of air,
the feet become colder than the head, and it is under these conditions
that the nasal membranes become swollen. It ought to be emphasized
that the cause for these changes is not cold feet alone. It is the com-
bination of cold feet and hot head. Out of doors, it is well known, that
any one may stand with cold feet for hours without any risk of catching
cold, but then the head is really cooling as fast as the feet, because of
convection currents.

The ideal system of warming a room is to supply radiant heat near

762 METABOLISM

the floor level; open fires, properly flued modern gas fires, and electric
heaters at floor level are the best methods to attain this.

Suppose the person subjected to conditions which cause the mucous
membrane to become swollen and congested should go outside, then the
membrane at once becomes pale because the blood vessels constrict, but
for some time it remains swollen and boggy and continues to show pitting
with a probe. It is while in this state that it offers favorable conditions
for the growth of bacteria. The membrane is swollen and covered with
secretion, and the blood flow is cut down. The natural defensive agen-
cies that are normally carried by the blood do not succeed in combating
the multiplication of the bacteria in the swollen membrane. After some
time out of doors the blood supply returns because it is required to warm
up the cool air, but this reaction does not occur before the mucosa has
regained its normal condition.*

The protective influence of a rapid blood flow through the nasal mem-
brane is possibly the explanation of the relative immunity from infec-
tious colds of those who work in air containing irritating gases, such as
workers in various kinds of chemical factories. Even the irritation set up
by coal dust may, by similar methods, afford some protection against in-
fection by the tubercle bacillus — for phthisis is relatively infrequent
among coal miners. The supposedly antiseptic action of ozone is prob-
ably due to a similar irritating effect. Any benefit that may be derived
from its presence in the atmosphere can not otherwise be explained. It
is possible that a useful prophylactic practice to avoid infection, such as
that of influenza, would be to stimulate the nasal mucosa at intervals by
snuff, but this may be an unwise suggestion.

After becoming acclimatized to outdoor conditions, the nasal mucous
membrane is in a much more favorable condition to withstand infection
than indoors because of the very rapid blood flow that is necessary in or-
der to supply heat with which to warm up the inspired air. This more
rapid blood flow, and the freer flow of lymph which accompanies it, is
reinforced by increased secretion, which assists to wash away invading
bacteria. Mass infection being equal inside and outside, the animal body
can withstand it much less satisfactorily in the former case.

Many other observations bearing on the relationship between chilling
and immunity to infection have been recorded, but it would take us be-
yond our subject to discuss them here. Because of their accuracy and the
excellent control of possible fallacies, it is important, however, to say
something about the recent investigations of Mudd and Grant.73 These
observers measured the temperature of the mucous membranes of the
palate, tonsils and pharynx by means of thermo-couples before and dur-

*The congestion of the mucous membrane brought about by warm moist air does not probably
depend on dilatation of the small arteries — entailing increased flow of blood, but rather on dila-
tation of the capillaries and therefore a stagnation of blood.

THE PHYSIOLOGICAL PRINCIPLES OF VENTILATION 763

ing application to the skin of cold towels, or while cold air from a fan
was allowed to play on it. A rise in temperature would indicate that the
part had become more vascular, and a fall, the contrary. That this in-
terpretation was the correct one was confirmed by direct inspection of
the degree of flushing (redness). It was found that chilling the body
surface immediately caused a fall in the temperature of the mucous mem-
branes which could not be accounted for by any accompanying change
in blood pressure, or, entirely at least, by changes in respiration or by
lowering of the temperature of the blood. The conclusions are "that chill-
ing of the body surface causes reflex vasoconstriction and ischemia in
the mucous membranes of the palate, faucial tonsils, oropharynx and naso-
pharynx."

The Methods for Determining the Healthfullness of Air. — Although the
present review does not venture to discuss the methods that are employed
for the measurement of the various physical properties which have to
be considered in gauging its influence on health, or the engineering
problem of how ideal conditions may be maintained, it may not be out
of place to mention, in connection with the former of these, that the
physical property to which most attention should be devoted is the cool-
ing power. This can not be done by reading an ordinary thermometer,
for this instrument only registers the temperature of the piece of wood
and of the wall against which it is hung. It registers the same whether
the air is dry or moist, or whether it is stagnant or moving. Somewhat
more information regarding cooling power is afforded by readings of a
wet-bulb thermometer, an instrument in which the bulb is kept constantly
moist, so that evaporation occurs from it. This evaporation tends to cool
the thermometer, in proportion to its rate, and since this is dependent
mainly on the degree to which the air can take up more moisture, we can
tell by the use of a formula or tables the relative degree of humidity of
the air. Still this does not tell us the real degree of cooling which the
atmosphere can bring about. It does not adequately register the cooling
which is dependent upon the movement in the air, the so-called convec-
tion currents. To afford this information Leonard Hill has invented what
he calls the Kata thermometer, by which the rate of cooling is directly
measured. The instrument consists of an alcohol thermometer with a rel-
atively large bulb, and with the scale registering between 105° F and 90°
F. It is placed in warm water at about the former temperature, and is
then removed, and the time required for the temperature to fall from
100° F. to 95° F. is measured by means of a stop watch. This time di-
vided by a factor determined for each instrument, and written on the
stem, gives the actual amount of heat in millicalories per square centi-
meter per second which would be given off from, say the surface of the
human body, under similar environmental conditions. Hill and his as-

764 METABOLISM

sociates3 have shown that much important information concerning the
cooling power of the atmosphere can be gained in this way, which can
not be gained by any other.

METABOLISM REFERENCES

(Monographs and Original Papers)

iLusk, Graham: The Elements of the Science of Nutrition, W. B. Saunders Co., ed.

3, 1917.

^Cathcart, E. P.: The Physiology of Protein Metabolism, Monographs on Bio-
chemistry, Longmans, Green & Co., 1912.

sTaylor, A. E.: Digestion and Metabolism, Lea & Febiger, New York, 1912.
•*Underhill, F. P. : The Physiology of the Amino Acids, Yale Press, New Haven, 1915.
sMacleod, J. J. E.: Diabetes, Its Pathological Physiology, E. Arnold, 1913.
saFiirth, von: The Problems of Physiological and Pathological Chemistry, etc., J. B.

Lippincott Co., 1916.
sbJones, W.: Nucleic Acids, Monographs in Biochemistry, Longmans, Green & Co.,

1914.

scMendel, Lafayette B. : Ergebnisse der Physiologic, 1911.

saLeathes, J. B.: The Fats, Monographs in Biochemistry, Longmans, Green & Co.
seMathews, A. P.: Physiological Chemistry, Wm. Wood & Co., 1917.
sfDakin, H. K. : Oxidations and Reductions in the Animal Body, Monographs in Bio-
chemistry, Longmans, Green & Co., 1912.
5gLeathes, J. B.: Problems in Animal Metabolism, 1906.
6Du Bois, E. F., and collaborators: Clinical Chemistry, Papers 1 to 25, Arch. Int. Med.,

1915-17, xvi-xix.

7Benedict, F. G.: Am. Jour. Physiol., 1916, xli, 275 and 292.

sMendel, Lafayette B.: Harvey Lecture, J. B. Lippincott Co., 1914-1915, p. 101.
9McCollum, E. V., and collaborators: Numerous papers in Jour. Biol. Chem., be-
ginning 1913.

loHopkins, F. Gowland, and Willcock, E. G.: Jour. Physiol., 1906, xxxv, 88.
nBayliss, W. M.: The Physiology of F'ood and Economy in Diet, Longmans, Green

& Co., 1917.

isMcCollum, E. V.: Harvey Lecture, Jour. Am. Med. Assn., 1917.
isSweet, J. E., Carson-White, E. P., and Saxon, G. J.: Jour. Biol. Chem., 1913, xv,

181; ibid., 1915, xxi, 309.

i*Stepp, W.: Biochem. Ztschr., 1909, xxii, 452.
15Funk, Casimir: Ergebnisse der Physiologic, 1915.
isMcKillop, M.: Food Values: What They Are and How to Calculate Them,

Rutledge.

irtaMcCoy, D. Major: The Protein Element in Nutrition, E. Arnold, London, 1912.
i7Pembrey, M. S.: Chemistry of Respiration, in Schafer's Text Book of Physiology,

1898, i.

isAllen, F. P.: Glycosuria and Diabetes, Boston, 1913.
19Joslin: Diabetes.

2<>Woodyatt, R. T., Sansum, W. D., and Wilder, R. M.: Jour. Am. Med. Assn., 1915,
Ixv, 2067. Also Taylor, A. E., and Hulton, F.: Jour. Biol. Chem., 1916, xxv,
173.

2iMacleod, J. J. R., and Fulk, M. E.: Am. Jour. Physiol., 1917, xlii, 193.
22Hamman, L., and Hirschbaum: Arch. Int. Med., 1917, xx, 761-788.
23Cannon, W. B.: Bodily Changes in Pain, Hunger, Fear and Rage, D. Appleton &

Co., 1915.

2*Knowlton, F. P., and Starling, E. H.: Jour. Physiol., 1912, xlv, 146.
2spatterson, S. W., and Starling, E. H.: Jour. Physiol., 1913, xlvii, 135; also Cruick-

shank and Patterson: Ibid., p. 113.

26Macleod, J. J. R.: Glyeolysis, Jour. Biol. Chem., 1913, xv, 497.
27Murlin, J. R.: Jour. Biol. Chem., 1913, xvi, 79.
28Cruickshank: Jour. Physiol., 1913, xlvii, 1.

29Macleod, J. J. R., and Pearce, R. G.: Zentralbl. f. Physiol., 1913, xxvi, 1311.
soWoodyatt, R. T.: Jour. Am. Med. Assn., 1916, Ixvi, 1910.

THE PHYSIOLOGICAL PRINCIPLES OF VENTILATION 765

Slyke, D. D.: The Present Significance of the Amino Acids in Physiology and
Pathology, Harvey Lectures, J. B. Lippincott & Co., 1915-1916, p. 146. Also
papers in Jour. Biol. Chem., 1911, ix, 185; xii, 275; ibid.. 1912, xii, 301 and 399;
ibid., 1913, xiii, 121, 125 and 187.

32Folin, O., and Denis, W. : Jour. Biol. Chem., xi, 87 and 493 ; ibid., 1912. xii, 14 and
253.

ssAbel, J. J.: The Mellon Lecture, Science, 1915, xlii, 135.

34Hewlett, A. W., Gilbert, L. O., Wickett, A. D.: Arch. Int. Med.r 1916, xviii, 636.

ssLosee, J. R., and Van Slyke, D. D.: Jour. Am. Med. Assn., 1917, cliii, 94.

seShaffer, P. A.: Am. Jour. Physiol., 1908, xxviii, 1.

37Cathcart, E. P.: Jour. Physiol., 1907, xxxv, 500.

ssMyers and Fine: Jour. Biol. Chem., 1913, xiv, 9.

39Levene, P. A.: Cf. W. Jones.4o

40 Jones, W.: Nucleic Acids, Monographs on Biochemistry, Longmans. Green & Co..
1914.

4iBenedict, S. R.: Harvey Lecture, 1915-16.

42Hunter, A., and Givens, M. H.: Jour. Biol. Chem., 1914, xviii, 403.

43Burian, R., and Schur, H.: Cf. Macleod in Eecent Advances in Physiology and Bio-
chemistry, ed. by Leonard Hill, E. Arnold, London, 1905.

44Mendel, Lafayette B., and Lyman, J. F.: Jour. Biol. Chem., 1910, viii, 115.

45Taylor, A. E., and Rose, W. C. : Jour. Biol. Chem., 1913, xiv, 419.

•46Hopkins, F. G., and Hope, W. B.: Jour. Physiol., 1899, xxiii, 277.

47Ascoli, M., and Izar, G. : Ztschr. f . Physiol. Chem., 1909, Iviii, 529 ; ibid., 1911, Ixiii,
319.

48McClure, C. W., Vincent, B., and Pratt, J. H. : Am. Jour. Physiol., 1916, xlii, 596.

49Bloor, W. R.: Jour. Biol. Chem., 1912, xi, 429; ibid., 1913, xv, 105; ibid., 1914, xvi,
517; ibid., 1912, xi, 141; ibid., 1915, xxi, 421; ibid., 1914, xix, 1; ibid., 1915,
xxiii, 317; ibid., 1914, xvii, 317; ibid, 1915, xxii, 133. Also Bloor and Knudson:
Jour. Biol. Chem., 1916, xxvii, 107; ibid., 1916, xxiv, 447; Bloor, Joslin and
Homer: Ibid., 1916, xxvi, 417; ibid., 1916, xxv, 577.

soLeathes, J. B.: The Fats, Monographs on Biochemistry, Longmans, Green & Co.

siCoope, R., and Mottram, V. H.: Jour. Physiol., 1914, xlix, 23; ibid., 1915, xlix, 157.

52Raper, H. S.: Jour. Biol. Chem., 1913, xiv, 117.

ssSmedley, I. D.: Proc. Phys. Soc., Jour. Physiol., 1912, xiv, 25.

5*Hill, Leonard: Address to the Phys. Sec. Brit. Assn. for the Adv. of Sci., Section,
J, 1912.

ssShaffer, P. A., and Coleman, W.: Arch. Int. Med., 1909, iv, 538.

56Barbour, H. G. : Arch f. Exper. Path. u. Pharmac., 1912, Ixx, 1. Also Barbour and
Wing, S. S. : Jour. Pharmac. and Exper. Therap., 1913, v, 105.

57Hewlett, A. W.: Monographic Medicine, D. Appleton & Co., 1917, i.

csHunter, A., and Campbell, W. R. : Jour. Biol. Chem,., 1918, xxxiii, 169.

^Thompson, Sir W. H.: Biochem. Jour., 1917, xi, 307.

eoRiiigsbury, F. B., and Bell, E. T.: Jour. Biol. Chem., 1915, xxi, 297.

eiLynch, V.: Am. Jour. Physiol., 1919, xlviii, 258.

62Leathes, J. B., and Haskins, H. D. : Problems of Animal Metabolism, (London, 1906).

63Maeleod, J. J. R.: Jour. Biol. Chem., 1906, ii, 231.

64Cruikshank and Patterson: Jour. Physiol., 1913, xlvii, 381.

^Starling, E. H., and Evans, C. Lovatt: Ibid., 1914, xlix, 67.

66Harris, J. A., and Benedict, T. G. : Report Carnegie Institution of Washington, 1919.

"Means, J. H., and Aub, J. C.: Arch. Int. Med., 1919, xxiv, 645.

esDavis, N. C., and Hall, C. C., and Whipple, G. H. : Arch. Int. Med., 1919, xxiii, 689.

G9Davis, N. C., and Whipple, G. H.: Ibid., 709.

7oHopkins, F. Gowland, and Chick, Hariette: Medical Research Committee National
Health Insurance, Special Report No. 38, 1920, H. M. Stationary Office, Imperial
House, Kingsway, London, W.C. 2.

TiOsborne, T. B., and Mendel, J.: Jour. Biol. Chem., 1917, xxxi, 144.

72Hill, L.: Special Report No. 32. The Science of Ventilation and Open Air Treat-
ment, Medical Research Committee, H. M. Stationary Office, London, 1919.

73Mudd, S., and Grant, L. B. : Jour. Med. Research, 1919, xl, 53.

74Allen, F. M., Wishart, M. B., and Smith, L. M.: Arch. Int. Med., 1919, xxiv, 523.
Also Merlin, J. R., and Nites, W. L: Am. Jour. Med. Sc., 1917, cliii, 79.

PART VIII
THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

(Revised by N. B. Taylor)

CHAPTER LXXXIV

GENERAL CONSIDERATIONS, THE ADRENAL GLANDS

In order that the various activities of the animal organism may act
efficiently as a whole, it is necessary that those of one part be correlated
with those of another. This correlation of function is mediated either
through the nervous system or through the action on one part of the
body of substances produced in another part and carried between them by
the blood. Control through the nervous system is especially developed for
those functions which have to be brought promptly into play, such as
muscular movement and the other physiological processes concerned in the
adjustment of the organism to quickly changing conditions of its environ-
ment. Control through the blood is the mechanism by which the metabolic
activities of different organs are mainly correlated. The chemical sub-
stances involved are often called internal secretions.

Some of these internal secretions are merely by-products of metabolism,
and are only incidentally used for the purpose of bringing about control
between different parts of the body. To this group belong carbon dioxide,
which may act on the respiratory and other nerve centers, and urea, which
may stimulate increased activity of the kidneys. Indeed, the list of sub-
stances included under such a definition of internal secretions is almost
illimitable, and to designate by the special name of hormone every con-
stituent that can affect physiological functions, as some have done, can lead
only to confusion. The internal secretions with which we are more
directly concerned are those that are specially produced for the purpose
of controlling the metabolic functions. They are given the general name
of autacoids (E. A. Schafer).3 Autacoids may be either the sole product
of some special gland or a secondary product of glands which have other
functions. To the former class belong the autacoids produced by the para-
thyroid, thyroid, pituitary and adrenal glands, and to the latter, those
produced by the pancreas and generative glands.

766

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS 767

Autacoids have further been subdivided by Schafer into two classes
according to whether they excite metabolic processes or depress them.
Examples of excitatory autacoids, also designated as hormones, are the
epinephrine produced by the adrenal glands, which excites the termina-
tions of the sympathetic nervous system, and pituitrin produced by the
posterior lobe of the pituitary gland, which excites plain muscular fiber.
Inhibiting autacoids, also called chalones, are not so commonly known, but
are illustrated by the substance contained in extract of the placenta,
which tends to prevent the secretion of milk.

Autacoids may have either an immediate or a delayed action ; the effect
which- they produce may be like that with which we are familiar as the
result of stimulation of the nerve supply of a gland, being illustrated
again by the effect of epinephrine, or they may act so slowly that it is
only after a considerable period of time during which they have been
in the organism in excess, that any apparent effect is produced. The
slowly acting autacoids have been called morphogenetic, and they are
well illustrated in the internal secretions of the anterior lobe of the
pituitary and of the generative glands — secretions which affect growth.

• . Kegarding the chemical nature of autacoids, certain facts stand • out prominently.
Being very largely the products of glands, it might be imagined that they would be
enzymic in nature, for enzymes are now known to be the most important active agents in
bioplasm as well as the active agents in many of the external secretions, like those of
the salivary, gastric and intestinal glands. Autacoids, however, are not enzymes. They
are far simpler in chemical structure, and are not destroyed by heat in the presence of
water. They are represented by a comparatively small molecule, and are therefore
dialyzable. This latter fact justifies the hope that it may be possible to prepare them
or their simpler salts in crystalline form — a hope which has already been realized in
the case of at least one of them — epinephrine. Great progress has likewise been made
in isolating the active principles of the thyroid and of the anterior and posterior lobes
of the pituitary glands. To sum up, then, we may say that an autacoid is a specific
organic substance, formed by the cells of one organ and secreted into the circulating
fluid, which carries it to other organs, upon which it produces effects similar to those
of drugs.

Methods of Investigation

To investigate the function of an autacoid, careful studies are made of
the effects produced (1) by excision of the gland which furnishes the
autacoid and (2) by administering intravenously or subcutaneously or
orally extracts prepared from the gland. Frequently, also light is thrown
on the function of the autacoid by observing the effect which fol-
lows prolonged feeding with the endocrine organ that manufactures it
and by observing the pathological changes in the various endocrine organs
in diseased conditions. Embryological and histological studies are also of
the greatest importance. A difficulty in investigating the function of
an endocrine organ lies in the fact that the secretion of no one gland

768 THE ADRENAL GLANDS

acts independently of those from other glands. On the contrary, there is
undoubtedly a close association of function, so that we can not tell
whether a change of function observed after removal of some gland or
administration of some extract is a direct consequence of the experi-
mental procedure, or is induced by some secondary effect developed on
another endocrine organ. It will no doubt take many years before suf-
ficient data have been collected to enable us definitely to state what the
particular function of each endocrine organ may be. Since most progress
has been made in connection with the adrenal gland, it will be advan-
tageous to consider the functions of this gland first.

ADRENAL GLAND

In mammals the adrenal gland is composed of two parts, the cortex
and the medulla. The origins of these two are quite different, and though
in mammals they are intimately associated in anatomical position, in other
groups of animals they are more or less separate, being completely so
in fishes. This not infrequent separation of cortex and medulla, together
with their distinctive origins, suggests different functions for the two.
Experimental investigation supports this view.

The Cortex

The cortex on microscopic examination is seen to be composed of rows of epithelial
cells arranged more or less in columns except at the periphery, where they form glomeru-
lar masses, and next the medulla, where they assume a reticular formation. The cells
of the greater part of the cortex, unlike those of the medulla, contain no granules with
special staining qualities, but they do contain particles which are believed to be com-
posed of cholesterol esters and lecithin. In the cells of the reticular portion of the
cortex, however, pigment particles are not infrequently observed. The blood supply of
the cortex is not nearly so rich as that of the medulla, being represented by fine arterioles
which run inwards from the capsule towards the medulla in the connective tissue that
lies between the columns of cortical cells. Nerves similarly penetrate into the cortex,
some supplying its blood vessels and cell columns, but most of them proceeding to the
medulla. They are derived from a network of nerve fibers in the capsule of the organ,
and the nerve supply of this network comes partly from the suprarenal plexus, and partly
from the splanchnic nerve. Embryologically the cortex is developed from the cells of
the genital ridge, that is, from mesodermie cells.

Very little is known concerning the function of the adrenal cortex al-
though there is little doubt that it is closely related to the development
of the sexual organs. The evidence for this is as follows: (1) Its origin
from the mesoderm in common with the sexual organs. There is also
a remarkable similarity between the cortical cells and those of the corpus
luteum. (2) In cases of sexual precocity it is found that the adrenal
cortex is much hypertrophied. Also, certain tumors of the cortex occur-
ring in young children are associated with premature development of the

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

769

secondary sexual characters. The subjects of these growths (Fig. 191),
which are termed hypernephromata, present, in many cases, a most re-
markable appearance. A boy, for instance, of four or five years may
possess the sexual development of a mature male, the testicles are en-
larged, hair grows upon the chest and pubis, and a moustache or a beard
may develop. There may be also undue muscular development or ex-
treme obesity of an adult type, so that these prodigies have been likened
in appearance to '"an infant Hercules" (Weber) or "a burly brewer's

Fig. 191. — Child aged

years suffering from hypernephroma. (Guthrie.)

drayman" (Guthrie).4 In female children the breasts hypertrophy, hair
appears upon the mons veneris and labia majora, the uterus tends toward
the mature type, and menstruation may occur. In appearance these
patients resemble stout little women. (3) The cortex becomes hypertro-
phied during pregnancy. (4) It is ill-developed in sexual deficiency. (5)
Changes occur in it during the estrual cycle of many animals. In the
frog during the mating season it becomes greatly enlarged at the ex-
pense of the medullary tissue and develops peculiar pear-shaped ele-
ments, the "summer cells" of Stilling. (6) After castration the cortex is
said to be hyperphied. (7) The innermost portion of the cortex, sometimes

770 THE ADRENAL GLANDS

called the boundary zone, is much hypertrophied in the human fetus, but
this hypertrophy entirely disappears after the first year of extrauterine
life.

The other functions of the cortex are not as yet known, but there is very
strong evidence that they are of great importance to the welfare of the
animal. It has been suggested that the passage of blood through the
cortex before reaching the medulla indicates that some change, which
is preparatory to the main change occurring in the me.dulla, takes place
in the blood while it is in the cortex. This view is partly substantiated
by the observation that when an excised portion of cortex is incubated
at body temperature, a substance develops in it which has an action
like that of the hormone of the medulla — epinephrine. It is possible,
however, that this action is due to the fact that certain of the decomposition
products of protein develop an epinephrine-like action (see page 536).

A detoxicating function has been ascribed to the cortex. This possi-
bility has been suggested by the fact that cobra venom, to which had
been added an emulsion of this portion of the gland, was rendered innoc-
uous. (Meyers).5 The addition of other tissue extracts to the poison
was without effect.

The weight of evidence favors the view that it is the cortex and not
the medulla which is essential to life. Biedl2 claims to have removed the
cortex leaving the medulla intact; the operation resulted invariably in
the death of the animals. Conversely he found that, in cats and dogs,
the adrenals could be removed with impunity to the extent of seven
eighths of their bulk, provided that the portion remaining consisted of
cortex. Wheeler6 endeavored to remove the medulla, leaving the cortex
intact ; though this was not wholly successful, it is a noteworthy fact that
it was those animals only, in which the cortex was inadvertently injured,
that succumbed to the operation. Evidence for the indispensability of the
cortex is also offered from the clinical side. Cases of acute adrenal de-
ficiency, followed by rapid death, occur, in which the medulla, postmor-
tem, shows few or no lesions or disease of a longstanding nature, whereas
acute 'lesions are observable in the cortex.

The Medulla

Histologically the medulla is composed of masses of polygonal cells
with blood sinuses between them. The blood supply is derived from ves-
sels that have proceeded to the medulla through the capsule, and it is
extremely rich, being indeed the richest blood supply to any organ in the
body, greater even than that to the thyroid gland. The nerves form a
dense plexus, extending into and between the secretory cells. The most
characteristic feature of the cells composing the medulla is the presence
in them of granules which stain readily with chromic acid, and are hence

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS 771

often called chroma ffin cells. There are also some cells containing coarser
granules that are soluble in water and do not stain with chrome salts.

Embryologically, the medulla is developed from tissue common to it and the sym-
pathetic nervous system. From that part of the neuroblast in which are laid down the
primitive ganglia of the posterior roots, masses of cells are split off which become the
common ancestors of the sympathetic ganglia and the chromamne system. These cell
groups wander from their sites of origin and come to lie along the vertebral bodies,
ranging themselves, in the case of the abdomen, on either side of the aorta. One mass
seeks the adrenal cortex, which has been formed at a prior stage of development, and
passes into its interior. Differentiation of these cells then proceeds in two directions,
those lying along the aorta form, for the most part, sympathetic ganglia; those within
the adrenal cortex develop into chromaffin cells to constitute the medulla of the gland.
These embryological considerations will enable us to understand the close functional re-
lationship which, as we shall see, exists between the sympathetic nervous system and the
adrenal medulla.

The intimate anatomical association of the cortex and medulla renders
the removal of one part alone, if not an actual impossibility, a procedure
at least, of extreme difficulty. On this account, with the exception of the
investigations cited above, attention has been paid only to the effects pro-
duced by removal, or by the injection of extracts of the whole gland.

Adrenalectomy

Excision of the adrenal gland in most animals is very quickly fatal,
the only well-known exception being in the case of the white rat, in which
excision of both adrenals may not be incompatible with life. For some
time after recovery from the anesthetic the animal upon which double
adrenalectomy has been performed usually behaves in a perfectly normal
fashion, although it may be less lively and less inclined to feed than
usual. Very soon, however, generally within twenty-four or forty-
eight hours, definite symptoms of muscular weakness are apparent. This
weakness soon becomes extreme, and is accompanied by a feeble pulse,
a depression of body temperature, and, later, by dyspnea. After an
interval which is never longer than a few days, death supervenes, being
sometimes preceded by convulsions.

When only one adrenal is removed, very few animals succumb; and
if some time is allowed to elapse so that the immediate shock of the
operation has disappeared, it will usually be found that removal of the
remaining adrenal, although ultimately fatal, is not so quickly so as
when both glands are removed at one operation. The reason for this
result is that opportunity is given for a compensatory hypertrophy of
accessory adrenal bodies to occur. Such accessory adrenal bodies may
be composed of cortical or medullary tissue, and there is a growing belief
that the cortical tissue is the more important. Chromaffin tissue is found
in most animals along the front of the aorta, between the renal arteries,

772 THE ADRENAL GLANDS

where it can usually be recognized by staining the tissue with chromic acid.
Sometimes accessory chromaffin tissue is located in distant parts,
as in the epididymis of the rat, for example. It is said that life can
be maintained if one-eighth of the total amount of the adrenal substance
be present in the body. Attempts to prolong life after adrenalectomy
by adrenal transplantation have almost invariably met with negative
results, because the graft undergoes a rapid process of necrosis and dis-
appears; although it is said that transplantation may sometimes be suc-
cessfully accomplished if the grafting is done into the kidney. Adminis-
tration of suprarenal extract is also without definite benefit after
adrenalectomy.

Adrenal Disease in Man. — Besides the hypertrophy of the cortex, which
has already been alluded to, destructive disease (usually tuberculous)
of the adrenal gland occurs, which has been recognized to be the cause
of a characteristic clinical condition known as Addison's disease. This
condition, which runs a more or less protracted course and is almost in-
variably fatal, is characterized by muscular weakness, low blood pres-
sure, pigmentation of the skin and gastrointestinal disturbances. Injec-
tions of epinephrine have little or no influence over the symptoms or over
the course of the disease; administration of extracts of the whole gland
are, perhaps, of more benefit. Though it is almost universally accepted
that inadequacy of the adrenals is responsible for the disease, the imme-
diate cause of the symptoms is obscure, nor is it known whether cortex or
medulla is at fault. It might appear that the muscular weakness and ar-
terial hypotonus were due to incompetency of the medulla; yet the results
of epinephrine administration do not support such a conclusion. Further-
more, as we shall see, it has been demonstrated conclusively that epine-
phrine is not a factor in the maintenance of normal arterial tone (page
785).

The bronzing of the skin, a prominent symptom of Addison's disease, is
due to an increase of the normal pigment — melanin — in the Malpighian
layer. To account for the excessive deposition of pigment (chromatosis)
Halle7 has suggested that there is an increase of tyrosine, the precursor
of melanin, in the tissues. Part of the tyrosine of the body is believed
to be converted, under normal conditions, into epinephrine. This belief
is supported by a comparison of the formulae of the two substances
(epinephrine C9H13N03, tyrosine CgH^NOs) and by the following experi-
ment: An emulsion of the gland was divided into two halves, to one of
which tyrosine was added; the two portions were incubated for six days,
after which period analysis showed that the portion to which the amino
acid had been added contained from 15 to 33 per cent more epinephrine
than the control. That melanin may be produced by the action of the
enzymes upon tyrosine is well known, for example, an extract of the

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS 773

tissue forming the wall of the inksac in the cuttle fish will, upon the ad-
dition of tyrosine, produce a sepia pigment. Halle's hypothesis, then,
implies that the tyrosine which under normal circumstances would be
employed for the manufacture of epinephrine, is, in the case of adrenal
deficiency converted into pigment. Attractive though this hypothesis may
be, it should be pointed out that Ewins and Laidlaw8 have failed to con-
firm it.

In addition to this chronic form of adrenal disease cases of acute
adrenal insufficiency occur. Death, which very rapidly ensues, may be
preceded by symptoms of cerebral hemorrhage, or acute abdominal dis-
ease or may follow a short period of extreme myasthenia. In other in-
stances death is sudden and unheralded, and that the adrenals are re-
sponsible is revealed by finding that they are the seat of extensive disease.
This may be manifested by areas of necrosis, by hemorrhage or by ve-
nous thrombosis. In a case reported recently by Boyd,9 the subject,
prior to the rapidly fatal attack, was in apparently good health. An
autopsy showed the medullary tissue to be entirely consumed by a process
of long standing, whereas the cortex was the seat of an acute lesion which
apparently was the cause of the fulminating symptoms.

Suprarenal Extracts — Preparation

Injection, particularly intravenous, of extract of the adrenal gland
has furnished us with most of the evidence upon which our knowledge
regarding the function of this organ depends. Such an extract is best
made by grinding the entire gland with fine sand in a mortar and then
extracting with a weak (decinormal) solution of hydrochloric acid. The
extract may then be boiled, filtered through muslin and nearly neutral-
ized, preferably by means of sodium acetate. If kept in this acid reac-
tion, the active principle of the extract does not materially deteriorate
with time, but if it be neutralized or considerably diluted, destruction
due to oxidation occurs, as evidenced by a distinct browning of the
solution. The active principle of such extracts has been isolated in a
crystalline form (Takamine and Abel). It has been given various names
(adrenalin, suprarenin, adrenin, etc.), but the tendency is definitely
towards the use of epinephrine. Chemically, epinephrine has been found
to be orthodioxyphenylethylolmethylamine.

HO

N -*CH(OH) -CH2NHCH3.

It will be noted that it is closely related to tyrosine (see page 639). It
is also closely related to a group of substances (amines) occurring in
putrid meat and to which the active principles of ergot belong. It

774 THE ADRENAL GLANDS

contains an asymmetric carbon atom (asterisked in formula), which
indicates that there must be three varieties of epinephrine, differing
from one another in the effect which they produce on the plane of
polarized light (i.e.., a dextro- and a levo-rotatory and a racemic form).
Epinephrine can be prepared by synthetic means, the first product of
this synthesis being the racemic salt, which can then be split by appro-
priate methods into dextro- and levo- varieties. The levo- variety ap-
pears to be identical in its pharmacological action with the natural product.
The dextro- variety on the other hand has only poorly developed physio-
logical activities (about seven per cent that of the levo- variety), while
the racemic variety comes in between the two in its action. A valuable
assay of the amount of epinephrine in tissue extracts can be made by
the method of Cannon, Folin and Denis,10 in which an acid extract of
the gland is treated with phosphotungstic acid, and the blue color thereby
developed compared colorimetrically with a standard blue.

Physiological Action

The physiological effects of the intravenous injection of epinephrine are
markedly excitatory and slightly inhibitory in nature. We will consider
the excitatory action first. Immediately after the intravenous injection
of as small an amount as 0 '00008 milligrams per kilogram of body weight,
a distinct rise in arterial blood pressure may be observed. When the
rise is distinct, it is accompanied by a slowing of the pulse. This slow-
ing is caused by stimulation of the vagus center, as is evidenced by the
fact that if the vagus nerves are cut, or sufficient atropine administered
to paralyze them, the same dose of epinephrine produces not a slowing
but a quickening of the pulse, and consequently a much greater rise in
blood pressure. The vagus action is developed not because of an effect
of epinephrine on the vagus center, but secondarily because of the rise
in blood pressure.

These preliminary experiments indicate that the locus of action of
epinephrine, so far as the circulatory system is concerned, is mainly on
the small blood vessels, constricting them and thus raising the peripheral
resistance. This conclusion can readily be confirmed by applying the
epinephrine directly to the blood vessels of the exposed mesentery, or
by enclosing a vascular organ such as the kidney in a plethysmo graph
during the injection of epinephrine, when a great diminution in volume,
accompanying the rise of arterial blood pressure, will be observed. The
vasoconstricting effect of epinephrine does not become developed on the
large blood vessels near the heart on account of the deficiency in muscu-
lar tissue in their walls. Indeed, these vessels may become passively
dilated because of the increased blood pressure. The arterioles of dif-

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS 77o

f erent parts of the circulation are not equally sensitive to epinephrine ;
those of the splanchnic area are most sensitive, whereas those of the
heart — the coronary vessels — do not respond at all in most animals (see
page 268). The pulmonary and cerebral vessels have a variable reactivity
to epinephrine.

The effect on the vessels persists after complete destruction, not only
of the central nervous system, but also of the vasomotor nerves; epi-
nephrine still acts, for example, on vessels the nerve fibers of which
have been allowed to degenerate by cutting them several days before the
epinephrine is applied. This would seem to indicate that the epinephrine
acts directly on the muscular tissue in the walls of the blood vessels,
but this does not appear to be the case, for it has been found that epi-
nephrine is incapable of acting on tissues which are devoid of sympathetic
nerve fibers, and is also inactive on those tissues in the embryo which have
not yet received any nerve supply. In brief, then, although epinephrine
acts only on blood vessels that are supplied by the sympathetic nervous
system, it is not on the nerve fibers that the epinephrine unfolds its
action. We shall see immediately that this conclusion is in conformity
with the results of observations made on structures other than the blood
vessels.

Other muscular structures excited by epinephrine are as follows:
(1) the dilator muscle of the pupils, especially after the nerve supply has
been destroyed by extirpation of the superior cervical ganglion; (2) the
sphincters of the pylorus and of the ileocecal valve; (3) the muscle fibers
of the spleen, the vagina, the uterus, the vas deferens, and the retractor
penis. Regarding the action on the uterus, however, it should be noted
that a different response may be obtained according to whether the
uterus is pregnant or not. The plain muscles of the orbit and globe of
the eye are sometimes excited by suprarenal extract, causing the eyes to
protrude, the palpebral fissure to become large and the third eyelid to
be retracted, changes which are very like those which develop as a
result of fright.

Inhibitory effects of epinephrine on muscle are exhibited by the follow-
ing: (1) the muscle of the intestine; (2) the stomach; (3) the esophagus;
(4) the gall and urinary bladders.

The effect of epinephrine in inhibiting the rhythmic contractions of
an isolated portion of the intestine in oxygenated Ringer's solution is a
very striking phenomenon, and one which, as we shall see, may be very
successfully employed for detecting small quantities of epinephrine.

The effects of epinephrine on glandular structures are the same as those
which would be produced by stimulation of the sympathetic nerve supply
of the gland. Thus, the secretions of the lachrymal gland, the salivary

776 THE ADRENAL GLANDS

gland (in the cat), the mucous glands of the mouth and pharynx, the
gastric but not the pancreatic glands, can readily be shown to be
excited. In the case of the kidney the immediate effect is a diminution
of the urinary flow, due to constriction of the renal vessels. It has been
suggested by Cow11 that one role of the suprarenal is to act as a regula-
tor of the urinary excretion. This observer has demonstrated, by ana-
tomical methods, direct vascular communications between the adrenal
medulla a,nd the kidney. That epinephrine actually gains the kidney
by these channels was shown by collecting and testing the blood after
its circulation through them. Blood collected, while the gland was ex-
cited reflgxly by sciatic stimulation, exhibited marked pressor action.
The work of Addis12 and others shows that the excretion of urea is in-
creased under the influence of epinephrine in certain dilutions so that
though the urine may be diminished in quantity, its concentration is
raised.

From these results as a whole, it is evident that the effect of epineph-
rine on muscles and glands is exactly the same as that which would be
produced by stimulation of their sympathetic nerve supply. This paral-
lelism of action between epinephrine and the sympathetic nervous sys-
tem becomes still more evident when we consider certain of the changes
in metabolism that follow administration of epinephrine. Injection of
epinephrine excites glycogenolysis in the liver so that hyperglycemia
and glycosuria become established, results which are also obtained by
stimulating the great splanchnic nerve. Intravenous injection of epineph-
rine causes the clotting time of the blood discharged from the liver
tb be very materially shortened, an effect also produced by stimulating
the splanchnic nerve.13

As in the case of the blood vessels, the above results are obtained even
after the sympathetic nerves to the part have been allowed to undergo
degeneration, from which it is concluded that the tissues elaborate some
substance which reacts with epinephrine. This substance may be pro-
duced either at the junction between the nerve and muscle — the myo-
neural junction, — or perhaps throughout the protoplasm itself. It is
called the receptor substance of JLangley, and is believed to react not
only with epinephrine, but also with various drugs. The receptor sub-
stance seems to increase, if not in amount, at least in sensitivity after
the removal of the nerve control.

Ergotoxin, which is an amine obtained from ergot and also from cer-
tain of the products of histidine, has an action on the receptor substance
which is inhibitory and therefore antagonistic to that of epinephrine.

The antagonistic action of ergotoxin affects the excitatory but not
the inhibitory actions of epinephrine. By using this drug we are en-
abled to show that, although the main effect of epinephrine on the tissue is

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS 777

excitatory, a less marked inhibitory influence may be simultaneously
developed. The inhibitory effect may also sometimes be evoked by
doses of epinephrine very much smaller than those used to produce
excitatory effects. These facts are well illustrated in the case of the
muscle fiber of the blood vessels. With an ordinary dose of epinephrine
constriction occurs; after ergotoxin the same dose of epinephrine causes
dilatation. Or this latter result may also be obtained by administer-
ing to a normal animal quantities of epinephrine that are very much
smaller than the usual quantity. The coexistence of inhibitory and ex-
citatory influence is also well noted in the case of the uterus. In some
animals the effect of epinephrine on this organ is to augment its rhythmic
contractions, in others to inhibit them. In the former case, however, if
ergotoxin is first of all administered, epinephrine in its usual dosage will
invariably produce an inhibitory effect. The ergotoxin no doubt acts on
the receptor substance, and similar effects have also been produced with
apocodeine.

It was first noted by Moore and Purinton14 that the usual rise of blood
pressure which followed the injection of epinephrine was replaced by
a depressor effect when the dose was very small. Later it was shown that
this was not an isolated instance of a reversed action of epinephrine
when employed in high dilutions; the intestinal tone is augmented by
minute doses (1 part in 500 million or more according to Hoskins)15 and
the contractions of the pregnant uterus inhibited.

The nature of the vasomotor effects differs not only in accordance with
the dosage, but it is of dissimilar sign in different vascular areas, though
the dilution of the drug be kept constant. Hartman16 has shown that
epinephrine in high dilution causes dilatation of the peripheral vessels
simultaneously with vasoconstriction in the splanchnic area. These con-
clusions were drawn from blood pressure records taken in two series of
experiments in which the splanchnic and the peripheral vessels, respec-
tively, were excluded from the circulation. In the former series a fall
in pressure was effected, in the latter a pressor response was obtained.
Hoskins, Gunning and Berry17 went further and found, by means of
plethysmographic records, that all the vessels of the peripheral circula-
tion did not respond alike to a given dose, those of the muscles being
dilated, while those of the skin underwent simultaneous constriction.
The variations in limb volume and of blood pressure would then depend
upon which of these effects predominated at the time. Neither are all
parts of the splanchnic area affected similarly, for, though the spleen
and kidney both show vasoconstriction with all dilutions, the intestinal
vessels are constricted by small doses, but dilated by large. (Hartman).
The vasodilator responses to epinephrine are not, as is the case with the
constrictor effects, mediated by the myoneural junction. The vasodilator

778 THE ADRENAL GLANDS

mechanisms for the intestine are located in the sympathetic ganglia, those
for the limbs are contained in the sympathetic as well as the posterior
root ganglia. These mechanisms are of comparatively late development;
in newborn mammals (with the exception of rodents) administration of
epinephrine in all dilutions produces universal vasoconstriction, and it is
not until the animal is several weeks old that dilator effects can be ob-
tained, peripheral dilatation is the first to appear, somewhat later dila-
tation of the intestinal vessels may be elicited.

Although it is especially on plain muscular fiber having a sympathetic
nerve supply that epinephrine unfolds its action, yet, according to Can-
non, Gruber,18 and others, it increases the contracting power of volun-
tary muscle and diminishes the tendency to fatigue.

CHAPTER LXXXV
THE ADRENAL GLANDS (Cont'd)

Variations in Physiological Activity

Since it is clearly established that the adrenal glands are indispensable
to life and that extracts of them have a very pronounced physiological ac-
tion, it remains to consider whether the glands produce this internal secre-
tion within the body, and if so, whether it is essential for the well-being
of the animal or is required only under certain conditions. We must also
endeavor to find out upon which of the bodily functions of the intact
animal the internal secretion acts. These problems have been attacked
by three methods of investigation: (1) by comparing the epinephrine
content of similarly prepared extracts of the resting gland and of one
removed after a period of supposed increased activity; (2) by collecting
the blood as it flows into the vena cava from the adrenal vein and ex-
amining it for epinephrine by physiological tests. These consist in observ-
ing the behavior of some tissue that is sensitive to the action of epineph-
rine, such as the intestine or uterus, after applying the blood or serum
to it, or by injecting the blood or serum intravenously into another ani-
mal and looking for epinephrine effects; and (3) by allowing the blood
of the adrenal vein to be discharged under certain conditions through
the vena cava into the blood vessels of the same animal, and observing
the effect produced on certain physiological processes which in one way
or another have been sensitized toward the influence of epinephrine.
This autoinjection method has recently been used successfully by Stew-
art and Rogoff,19 their favorite structure upon which to observe the
epinephrine effect being the denervated pupil.

Assaying the Epinephrine Content of the Gland

With regard to the first mentioned of the methods, either chemical or
physiological means may be employed to assay the strength of the ex-
tracts. The best chemical method is that of Cannon, Folin and Denis,10
the principle of which has already been described. The physiological
method yielding most satisfactory results is that of Elliott,20 which con-
sists in injecting a portion of the extract intravenously into animals
from which the influence of the nerve centers on the heart and blood
vessels has been removed by decapitation. The rise in arterial blood

779

780 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

pressure produced by the injection is then a very fair measure of the
amount of epinephrine contained in it. It has been shown that the re-
sults obtained by the chemical method agree very closely with those obtained
by the physiological, but it should be remarked that it is difficult to see how
the physiological method could be accurate in all cases, since it has been
shown that with great dilution of epinephrine a reversed effect — a vaso-
dilatation — may be obtained. Attempts to assay the strength of an
epinephrine solution by investigating the effects which it produces on
other preparations, such as isolated loops of intestine or uterus, or the
enucleated eyeball of the frog, are not always successful, since the effects
are not alone dependent on the concentration of epinephrine in the
extract. When such preparations are used for quantitative purposes,
the strength of the extract may be judged by finding the extent to which
it can be diluted and still remain active.

Quite apart from the foregoing possible sources of error, it must be
remembered that the results merely give us an idea of how much epineph-
rine may have been contained in the gland at the time of its excision.
They can not tell us how much epinephrine the gland was secreting. Prior
to excision as much of this hormone might have been undergoing a process
of manufacture in the gland as was being discharged from it, so that the
assayed amount would represent merely the balance of production and loss
of hormone by the gland. We might quite well find that the amount of
epinephrine in the excised gland was normal under conditions where
there had been an excessive discharge of it into the blood; that is to say,
loss and production might have been equal. Where, however, a marked
deficiency was found to exist, it would probably indicate that exhaustion
of the power of producing epinephrine was taking place.

The Epinephrin© Content of the Blood. — The second method, in which
blood from one animal is tested for its epinephrine effect by intravenous
injection into another animal or by applying it to some isolated prepara-
tion on which epinephrine acts, has yielded important results. Since
serum contains all the epinephrine of blood, it can be conveniently used
for the tests (Stewart and Eogoff). The isolated physiological prepara-
tions that have been used in testing for epinephrine in the animal fluids
are as follows:

1. A segment of the small intestine of a rabbit, suspended in oxygen-
ated Locke's solution at body temperature.

2. A segment of the uterus of a nonpregnant rabbit similarly prepared.

The apparatus used for observing the contractions of either prepara-
tion consists of a small glass chamber furnished below with a hook to
which one end of the segment is attached, the other end being connected
to a muscle lever, so that the regular rhythmic contractions can be regis-
tered on a drum (Fig. 192).

THE ADRENAL GLANDS

781

Epinephrine inhibits the contractions of the intestine but stimulates
those of the uterus of most animals, the intestine preparation being the
more sensitive (Fig. 193). Indeed, it is said that the inhibition in this
case may be obtained with a solution containing 1 part of epinephrine in
20,000,000 of solution. In using this method, however, great care and
judgment must be exercised in drawing conclusions, because other sub-
stances present in the blood are liable to affect the contractions; thus,
certain substances in blood serum which have been produced by the act
of blood clotting may cause augmentation of the beat in both the intes-

Air vent

Metal waterbath

38'c.

Harvard muscle
warmer with
aduated jca/e

n. metal
heating rod
soldered in
wall of
water bath

Fig. 192. — Arrangement of apparatus for recording contractions of a uterine strip, intestinal
strip, or ring, etc. The metal water-bath is made of a cheap metal water-pail with a heating rod
soldered through the side at the bottom. A short metal tube is soldered into a 1-inch opening in
the bottom to receive a perforated cork for connecting with the Harvard muscle-warmer inside.
(From Jackson.)

tinal and the uterine preparations. A certain amount of epinephrine in
Locke's solution is consequently more likely to cause inhibition of the
intestine than a similar amount added to blood serum, because in the lat-
ter case the pressor substance will neutralize the depressor effect of the
epinephrine. On the uterine preparation, both the blood serum and the
epinephrine have pressor effects. As has been pointed out by G. N.
Stewart,21 if both preparations are employed for testing a solution sup-
posed to contain epinephrine, little chance of error is likely to be in-

782

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

eurred; that is, if the solution produces inhibition of the intestine along
with augmentation of the uterus, it must contain epinephrine.

3. The fresh carotid artery of the sheep. A ring cut from the artery
is suspended in oxygenated Locke's solution and attached below to a
small hook and above to a loaded muscle lever, by which the contraction

Fig. 193. — Tracing showing the effect of epinephrine on the intestinal contractions and on the
arterial blood pressure. (The preliminary addition of barium to the nutritive fluid may be disre-
garded.) (From Jackson.)

of the muscle fibers can be magnified. Epinephrine causes the muscle to
contract, but the test is not so sensitive as the foregoing, especially in
the presence of blood serum, because the pressor substances therein con-
tained also cause contraction. Blood plasma does not contain the pres-
sor substances, so that oxalated plasma should be used in place of serum

THE ADRENAL GLANDS

783

in applying the test. To increase the sensitiveness of the muscle, the
artery ring should be slightly stretched by loading the lever.
4. The blood vessels of a frog. This method depends on the same prin-

Funnel, or
small pressure
bofHe

Hook through
lower jaw

Cannula In
one aorta

Fig. 194. — Arrangement of apparatus for perfusion of the vessels of a brainless frog. (From

Jackson.)

ciple as in that just described. The fluid supposed to contain epinephrine
is added to Locke's solution, which is meanwhile being perfused under
constant pressure through the blood vessels and the rate of outflow

784 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

noted (Fig. 194). If the fluid added to the inflowing fluid contains epi-
nephrine, the outflow will become diminished. This is a very satisfactory
method, although it is somewhat limited in scope unless large frogs are
procurable, because of the difficulty of getting the necessary cannulae
into the vessels (aorta and abdominal vein).

5. Tlie pupil of the enucleated eye of the frog. Extremely small traces
of epinephrine are observed to cause a dilatation.

6. The denervated iris. The fluid to be tested is placed in the coirjunc-
tival sac of an animal from which the superior cervical ganglion of the
corresponding side has been removed some days previously. Under such
conditions, if epinephrine is present in the fluid, dilatation of the pupil
occurs. Both of the preceding methods we owe to Meltzer.22

It should be emphasized that, although each of these methods is in
itself very sensitive for the detection of epinephrine without being al-
ways specific, yet the result should not be considered conclusive unless
definite effects have been secured by at least two methods that are as
far as possible independent of each other.

As an outcome of investigations by these methods it has been found that
when blood was taken from the inferior vena cava at the level of the adrenal
veins, i. e., blood with a relatively high concentration of adrenal secretion,
the presence of epinephrine could be revealed after splanchnic stimulation
or massage of the glands. Such methods which depend upon the removal
from the animal of the blood to be tested, are open to the objection that the
blood so obtained may become altered in the process of shedding of defib-
rination. As a matter of fact it has been shown that shed blood, very rap-
idly develops vasoconstrictor substances. On this account conclusions re-
garding epinephrine content, based upon the behavior of such samples, are
not wholly reliable. The method about to be described is preferable.

The Autoinjection Method. — Such a method was first of all success-
fully used by Asher, who employed an animal from which all the abdom-
inal viscera had been removed. On stimulation of the great splanchnic
nerve a rise in arterial blood pressure occurred provided the adrenal
veins were open, but not so if the adrenal veins were clamped. By re-
moving the viscera, the effect of splanchnic stimulation on the abdom-
inal blood vessels themselves is eliminated, and any constriction which
occurs in the blood vessels of the rest of the body must obviously be due
to the action of epinephrine.

The most satisfactory modification of this method is that employed more
recently by Stewart, Rogoff and Gibson.23 Blood from the adrenals was col-
lected in a pocket of the inferior vena cava, which was made by applying
clamps to this vein above and below the level of the adrenal veins. An
animal in which the iris had been sensitized towards the action of epineph-
rine by prior removal of the superior cervical ganglion was employed

THE ADRENAL GLANDS 785

(page 784). It was found after the pocket has been allowed to fill with
blood that removal of the upper clamp caused the pupil to dilate. Fur-
thermore, the latent period of the response coincided with the time which
the wave of concentrated blood was calculated to take in traveling from
the pocket to the eye. This reaction time, consequently, varied inversely
with the rate of blood flow. Stimulation of the splanchnics or massage of
the gland was without effect upon the pupil so long as the upper clamp
remained in position, but the usual response ensued when the clamp was
removed.*

When the adrenals were not artificially excited in any way the con-
tents of the pocket, after removal of the upper clamp produced the char-
acteristic reaction upon the pupil, thus demonstrating the spontaneous
liberation of epinephrine from the glands. The capacity of the pocket,
together with its time of filling, having been determined, the rate of
flow through the adrenal veins was readily arrived at. The degree of
concentration of the pocketed blood was determined indirectly by noting
the precise extent of the pupillary response following the removal of
the upper clamp, and subsequently reproducing this reaction by the intra-
venous injection of an equal quantity of epinephrine solution of known
concentration. It is clear that the product of the rate of blood-flow
through the veins and the degree of concentration in epinephrine of the
pocketed blood will give the amount of epinephrine liberated from the
glands in a given time. This was found to vary between .0003 and .001
mg. per kilo of body weight per minute.

The splanchnic fibers concerned in the secretion of epinephrine seem
to come from a nerve center situated relatively low down in the spinal
cord. Section of the cord at the level of the last cervical segment does
not affect the spontaneous secretion, but this disappears when the sec-
tion is made below the third thoracic segment. (Stewart and Rogoff).

In connection with these observations it is of interest to note that
during stimulation of the splanchnic nerve in a normal animal, the conse-
quent rise in blood pressure shows two peaks (see Fig. 29, p. 137). The
first is no doubt due to direct stimulation of the splanchnic vasoconstric-
tors, and the second to the outpouring of epinephrine into the blood, the
justification for this conclusion being that the latter rise fails to appear
after removal of the adrenal glands. In many cases a well-marked
"dip" is seen between the two rises. This is explained as being due to
initial minute amounts of epinephrine passing into the blood streamf (see
page 777).

*It does not seem to be possible to exhaust the adrenal gland of its supply of active material
by stimulating the splanchnic — a fact which would seem to throw considerable doubt on the relia-
bility of the conclusions arrived at by the use of those methods in which extracts of the gland are
assayed (see page 779).

fA great part of the work done by clinical observers purporting to show that in such conditions
as nephritis and arteriosclerosis there is an increase of epinephrine in the blood, has been found
by Stewart and Rogoff to be unproved.

786 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

That epinephrine is being constantly liberated in certain minute
amounts is probably true, but whether this amount is a factor in the
maintenance of normal arterial tone, or is concerned in lowering the
resistance of the sympathetic endings, is another question. Experimental
investigation does not sustain the so-called "tonus" hypothesis. In the
first place, in the experiments already cited (page 785), the amount of
epinephrine secreted spontaneously would be, when diluted with the mass
of blood of the entire circulation, quite inadequate to have any effect
upon blood pressure; in the second place if any effect upon the vessels
did occur with these minute doses it would be one not of constriction
but of dilatation, on many vessels at least (page 777). No effects were
observed on the general health or the blood pressure of animals in
which the adrenal of one side was removed, and the nerve control of the
opposite gland severed, although under the conditions it is evident
that very little epinephrine could have been present in the blood (not
more than 1 part in 400 million parts of blood). Experiments performed
by Vincent and others gave similar results. Hoskins and McClure24 at-
tacked the problem in a different way, but arrived at a like conclusion.
They found that the amount of injected epinephrine necessary for the pro-
duction of a certain predetermined response was, after adrenalectomy,
but slightly in excess of that required to be injected into the same ani-
mal with intact glands. This excess, which represented the tonic secre-
tion of the glands, was far below the threshold for vasoconstrictor stim-
ulation. Finally, epinephrine is not present in the sera of patients suf-
fering from vascular hypertonus in sufficient concentration to be detected
by any of the biological tests at our disposal. (Stewart.)25

Since the "tonus" hypothesis of the adrenal function is untenable,
another, or emergency hypothesis has been brought forward. According
to this, epinephrine is considered to be secreted into the blood in super-
normal amounts when certain emergencies arise, such as asphyxia or con-
ditions of extreme emotion such as fright or fear. An experimental hy-
persecretion of an analogous character is also said to occur during stimu-
lation of the central end of large sensory nerves such as the sciatic.
The chief exponent of this hypothesis is Cannon,26 and he has supported
it by a seemingly incontrovertible mass of experimental evidence. In the
earlier researches which appeared in 1911 the blood was removed from the
vena cava opposite the openings of the adrenal veins, by pushing a cath-
eter up to this level through a slit in the femoral vein, and blood was
tested for the presence of epinephrine by observing its effect on the
beating of an isolated strip of intestine. It was found that whereas the
blood of a normal male cat did not give evidence of the presence of epine-
phrine, it did so in a cat that had previously been frightened by allowing a
dog to bark at it. Such results were not obtained after the removal of the

THE ADRENAL GLANDS 787

adrenal glands, or in a female cat, which is usually indifferent to such a
method of frightening. Cannon also thinks that many of the other adap-
tations which take place in an animal in this condition are associated with
the presence of an excess of epinephrine in the blood. The three most im-
portant of these are: (1) increased discharge of sugar from the liver
into the blood; (2) increased efficiency of muscular contraction; (3) di-
minished clotting time of the blood — -all of which are adaptations ena-
bling the animal either to conquer the source of the fear or to be in a
better position to recover from any bodily injury, which he might suffer,
involving a loss of blood.

It has been pointed out by Stewart and Rogoff,27 however, that there
are several serious sources of error in the methods adopted by Cannon
in the earlier investigations, particularly the uncertainty as to the ex-
act source of the blood collected through the catheter, the chances for
pressor substances developing in the shed blood, the unreliability of using
only one test object for the detection of epinephrine in blood, (page
784) and the unknown rate of blood flow through the adrenal glands
during the removal of the blood. These authors, as a matter of fact have
not been able to secure any results which would confirm Cannon's con-
clusions, either by repetition of the catheter method employed by this
worker, or in other observations in which blood was collected from a
pocket of vena'cava (page 784) or in which the pupillary reaction was
employed. Neither could Stewart28 and Rogoff obtain any evidence that
an increased secretion of epinephrine bears any relationship to the hyper-
glycemia that is induced by ether or by asphyxia. They did not find that
animals in which the adrenal had been excised on one side and the nerve
supply of the remaining gland cut, responded to emotional conditions in
any way differing from normal animals.

These criticisms have prompted Cannon29 to repeat his earlier observa-
tions by the use of a method which would not entail the removal of blood,
that is, by an autoinjection method. He chose as the test object for ex-
cess of epinephrine in the blood, a denervated heart which Levy,30 Gas-
ser31 and Meek had shown to respond by a quickened beat to extremely
small concentrations (for example 0.007 mgm. per kg. of "adrenalin" in-
jected intravenously per minute increases the heart rate by as much as 28
beats per minute). The denervation of the heart was effected by section
of the vagi and removal of the stellate ganglia, and in such animals it was
found that stimulation of the sciatic nerve, asphyxia and emotional states
caused decided acceleration. It would be rash to venture a final verdict
at the present stage of this most interesting controversy, but it appears
to the author that Cannon's evidence is very strong, provided it can
be proved that the heart is really thoroughly denervated and that sub-

788 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

stances in the blood other than epinephrine may not be responsible for
the cardiac changes.

Of interest with regard to the action of epinephrine as part of a pro-
tective mechanism, is the fact that the contractile pigment cells pos-
sessed by certain types of lizards and whereby the hue of these creatures
is varied in accordance with the shade of the surroundings, are stimu-
lated by epinephrine ; the latter contracts such cells, and nervous excite-
ment in these animals has a similar influence (Redfield32). It is scarcely
necessary to point out that, until it is definitely established by experi-
mental investigation that epinephrine may be discharged in excessive
amounts under certain conditions, it is irrational to assume that such may
occur in disease. The surgical removal of the adrenal gland is certainly not
warranted under any circumstances.

The Association of the Adrenal with Other Endocrine Organs

We have at present very little accurate and reliable information on the
association of the adrenal with other endocrine organs. That epinephrine
has* an influence on many diverse organs and glands is an undoubted
fact, but this is more probably to be attributed to an activating influence
on sympathetic nerve endings than 'to any specific relationship between
the adrenal glands and the particular gland in question. The most impor-
tant of the results that have been obtained are the following :

1. With the Thyroid and Parathyroid.— Cannon and Cattell, after con-
firming Bradford's discovery that an electric current of action is set up in
the salivary gland when it is excited to activity, proceeded to investigate
the occurrence of such a current in the thyroid gland.33 By placing one
nonpolarizable electrode on the gland itself and the other on the neigh-
boring subcutaneous tissues or on the trachea, a current was found to be
set up by stimulation of the sympathetic nerve supply of the thyroid, by
intravenous injection of epinephrine, or by stimulation of the great
splanchnic nerve before it reaches the adrenal gland. This last result,
which is the most important in the present connection, was, however, not
observed when the blood of the inferior vena cava was prevented by the
application of a clamp from getting to the heart, but immediately ap-
peared, after stimulation, when the clamp was removed. This experiment
taken alone does not, however, justify the conclusion that there is any
direct relationship between the adrenal glands and the thyroid, because
there are in the thyroid gland structures such as the muscle fibers in the
blood vessels, which a hypersecretion of epinephrine might affect. Before
any direct relationship between the two glands could be claimed to exist,
it would be necessary to show that the thyroid action current is obtained
with a concentration of epinephrine in the blood lower than that affecting
the blood vessels.

THE ADRENAL GLANDS 789

2. With the Sexual Glands. — As mentioned above (page 768), a very
direct relationship exists between the development of the sexual glands
and that of the suprarenals, particularly the cortex of the glands. In ad-
dition to the evidence already furnished, it may be mentioned that in hyper-
plasia of the adrenals -changes occur in the testicles, particularly in their
interstitial cells.

3. With the Liver. — Of the many functions of this gland that which is
most directly associated with epinephrine is the production of glucose
from glycogen — the glycogenolytic process (see page 701). The injection
of epinephrine causes an immediate discharge of such an excess of glucose
into the blood that hyperglycemia and glycosuria immediately follow.
This result is most striking when the injection is made in glyco gen-rich
animals. In animals from which all the glycogen of the liver has been
removed by starvation, the injection of large amounts of epinephrine
causes glycogen to accumulate in the liver cells — a result which it is
difficult to interpret.

In the light of the fact that stimulation of the great splanchnic nerve
causes a demonstrable increase of epinephrine in the blood, a natural con-
clusion is that the glycosuria and hyperglycemia which are known to re-
sult from stimulation of the splanchnic nerve or of its center in the
medulla, must be dependent upon a hypersecretion of epinephrine.
Evidence supporting this hypothesis seemed to be furnished by the obser-
vation that, after the removal of the adrenal glands, stimulation of the
splanchnic or of the so-called " diabetic" center in the fourth ventricle
no longer produced glycosuria even in a glycogen-rich animal. But it is
difficult to see how such an important physiological process as that of the
nerve control of the production of sugar by the liver should be dependent
on the hypersecretion of the adrenal gland, especially since the epineph-
rine would have to be carried by the blood around a considerable part of
the circulation before it arrived at the place on which it was to act. More-
over, it has been shown that stimulation of the previously cut hepatic
nerve plexus (around the hepatic pedicle) in a normal animal produces
hyperglycogenolysis, in which case there can be no question of a hyper-
secretion of epinephrine.

No doubt the adrenal glands have some important relationship to the
nerve control of the glycogenolytic process, for, in animals from which the
adrenal glands have been removed, stimulation of the hepatic plexus does
not produce hyperglycemia. From this result it would appear that the
presence of a certain amount of epinephrine in the blood is- necessary for
the proper transmission of the nerve impulse from the sympathetic nerve
fibers to the liver cell. When the nervous system is stimulated in such
a way as to excite the glycogenolytic process, two effects both operat-

790 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

ing in the same direction with regard to the glycogenic function are
developed: the one, a hypersecretion of epinephrine, which activates
the sympathetic nerve endings, the other, the transmission of the nerve
impulse to the liver cell (Macleod and R. G. Pearce).34

4. With the Pancreas. — The function of the pancreas here concerned
is that of its supposed internal secretion from the Isles of Langerhans.
Since epinephrine readily produces glycosuria, and since excision of
the pancreas has the same effect, it has been natural to inquire whether
any relationship exists between the two glands, and some observers
have obtained results which they interpret as indicating that it does.
Certain observers even state that glycosuria does not occur after the
injection if at the same time extract of pancreas is injected. It is al-
most certain, however, that these results are not trustworthy. Thus,
removal of the adrenal glands in an animal suffering from pancreatic
diabetes does not restore any of the lost power of utilizing glucose
during the few hours that the animal remains alive.34 That some rela-
tionship may, however, exist is indicated by the fact that epinephrine
causes dilatation of the pupil when it is dropped into the eye of a per-
son suffering from diabetes, whereas it has no such effect in the normal
individual.

CHAPTER LXXXVI

THE THYROID AND PARATHYROID GLANDS
Structural Relationships

The thyroid and parathyroid glands are intimately associated, anatomically, in most
animals. The thyroid is present in all the vertebrates, but the parathyroids do not
occur below the amphibia. The thyroid exists as two lateral lobes joined over the trachea
by the so-called isthmus. The parathyroids are very much smaller, being four in num-
ber and located in pairs on the posterior aspect of the thyroid lobes. The two upper
parathyroids are usually more or less embedded in the thyroid tissue, where as lower ones
are much more loosely attached to the thyroid ; indeed, in some animals, particularly the
herbivora, they are quite separate from it and may be located at a distance, as in the
mediastinum. Accessory thyroid and parathyroid glands are sometimes present in the
tissues of the neck, or in the anterior mediastinum, accessory parathyroids being common
ii! the rabbit and rat, and parathyroid tissue being present in the thymus in 5 per cent
of dogs (Marine35). Before these anatomical relationships were thoroughly worked
out, there was much confusion in the interpretation of the results following removal of
one or the other gland.

In their histologic structure and embryological derivation, the two glands are very
different. The parathyroids are developed as an outgrowth from the third and fourth
branchial pouches, and they are composed of masses of epithelial-like cells, sometimes
more or less divided up into lobules or trabeculse by bands of connective tissue. The
cells contain granules, some of which are of a fatty nature. Sometimes colloid-like ma-
terial is found betAveen the cells, or it may be enclosed in small vesicles not unlike those
of the thyroid, although usually considerably smaller. The blood vessels are extremely
numerous, and form sinus-like capillaries, which come into close relationship with the
epithelial cells of the glands. Nerves also are abundant and pass both to the vessels
and to the secreting cells. The blood vessels are derived from the inferior thyroid artery.

The thyroid is developed by immediate outgrowth from the entoderm lining the floor
of the pharynx, at a level between the first and second branchial pouches. Represented at
first by a solid column of cells, there very soon occurs a division at the lower end into
two lateral portions, and the original solid column becomes hollowed out. The two
lateral branches of the original column divide again and again so as to form a system of
hollow tubes lined with epithelium. These afterward become cut up so as to form the
closed vesicles characteristic of the gland. Each vesicle is more or less spheroidal in
shape, and has no basement membrane, but its walls are formed by a layer of epithelial
cells, which may be columnar, cubical, or flattened in shape. Each vesicle is filled with
the so-called colloid material, which is peculiar in containing iodine, and between the
vesicles is a layer of connective tissue often containing small cells, some of which are
not unlike those of the parathyroid. The connective tissue also contains the blood ves-
sels, which are very numerous — indeed, the thyroid, in proportion to its size, receives
more than five times as much blood as the kidneys, the only tissue that surpasses it in
this regard being the medulla of the adrenal gland (see page 211). The nerves arise
from both the vagus and the sympathetic systems and have been traced to the secreting
epithelial cells. The above description applies to a strictly normal gland.

791

792 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

THE THYROID GLAND

Condition of the Gland

In the crowded communities of the Great Lakes Basin of this conti-
nent, it has been found that in most animals the thyroid gland is more or
less abnormal. In Cleveland, for example, Marine has found this to be
the case in well over 90 per cent of the dogs brought to the laboratory.36
The condition usually goes under the name of simple goiter, which in-
cludes all thyroid enlargements except those of exophthalmic goiter.
In man the goiter originates usually about the age of adolescence and
more frequently in girls than in boys. It may sometimes pass over into
the exophthalmic type. The exact pathological changes in the goitrous
gland vary with the species of animal and with the duration of the dis-
ease. In man, besides the cystic or colloid goiter an adenomatous type
is very common although rare in other animals.

From the numerous observations that have been made on the glands of
domestic animals, it has been clearly established that the very earliest
sign of goiter is a diminution in the iodine content of the gland; fol-
lowed by an increase in the epithelial cells and in the blood supply and a
decrease in the colloid. Such hyperplasia may be induced in what re-
mains after removal of a large part of a normal gland (compensatory
hyperplasia), or if a similar operation be performed early in pregnancy,
the young when born will be found to have hyperplastic thyroids. A
certain degree of hyperplasia exists as an accompaniment of pregnancy,
and it can be produced in certain normal animals (particularly rats) by
placing them on an excessive meat diet. Important observations bearing on
this point have been made by Marine37 on brook trout, in which it has been
found that the so-called carcinoma that develops when the fish kept in
hatcheries are fed with unsuitable food and overcrowded, is really a
typical hyperplasia. In its second stage this develops into what is known
as colloid goiter which is produced by a deposition of colloid material
between the rows of cells so as to cause an opening out again of the
vesicles (Fig. 195), with a consequent tendency to a reversion to the
normal histological structure, so far as this is possible. The vesicles in
such a gland are of enormous size, and the lining epithelium, low cubical,
or almost flat in shape.

The outstanding characteristic feature of the colloid material is that
it contains iodine, which exists in combination with a nonprotein nitrog-
enous base, and is usually called iodothyrin. In the gland itself the
iodothyrin may be in combination with protein, forming iodothyro-
globulin. (E.G. Kendall38 has recently succeeded in isolating a pure crys-
talline substance of perfectly constant composition and containing over 60

THE THYROID AND PARATHYROID GLANDS

793

per cent of iodine. It is called thyroxin and has been identified as an indole
compound and has been made synthetically ./In extremely minute dosage it
greatly affects the energy metabolism, and is said to induct symptoms like
exophthalmic goiter. Its therapeutic value in cases of thyroid deficiency is
remarkable. Kendall believes this substance to be the active constituent of
the thyroid and to be associated with the metabolism of amino acids. For one

Fig. 195.— Microphotographs of thyroid gland of dog. A, normal gland; B, active hyperplasia; C,
colloid goiter. (From Marine and lyenhart.)

thing, when it is given alone no change occurs in pulse rate, whereas if
amino acids are given along with it, there is acceleration.

The importance of the relationship between the function of the thyroid
and the iodine-containing material is indicated by the changes which
occur in the percentage of iodine in the glands under varying condi-
tions of activity. Marine observed that the amount of iodine is inversely
proportional to the degree of hyperplasia of the gland, and when the

794 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

hyperplastic condition becomes fully developed, scarcely a trace of
iodine is contained in the gland. Later, when the hyperplasia gives
place to colloid goiter, the iodine increases again, both absolutely and
relatively. Moreover, it has been found that if iodide is administered
to an animal suffering from hyperplasia, the hyperplastic condition very
quickly disappears and the animal becomes normal, v^ Thus, in brook
trout, the poor nutritive condition of the fish when hyperplasia has
developed can be immediately remedied by placing them in larger quan-
tities of running water or by adding small traces of iodide to the water./
The administration of small amounts of iodine as in ordinary salt from
salt deposits also prevents goiter in farm stock, this having been first
noted in the State of Michigan, where prior to the discovery of salt
deposits sheep breeding was an entire failure. The importance of admin-
istering small doses of iodides to school children living in goitrous dis-
tricts has recently been emphasized by Marine and Kimball.39 As small
a dose as 0.001 gm. at weekly intervals prevents goi'ter in puppies sus-
ceptible to it.

Feeding experiments carried out by Gudernatsch40 and subsequently by
Kogoff and Marine,41 indicate that the thyroid hormonp has a powerful
influence upon the development of the body. Tadpoles fed upon thyroid
substance showed a striking acceleration of the normal metamorphosis.
Those fed with the glandular material grew less rapidly than the con-
trols fed upon ordinary diet, but the tails of the former showed more
rapid involution and the arm buds developed prematurely.

Experimental Thyroidectomy

A correct interpretation of the functional changes and symptoms which
follow upon partial or complete removal of the thyroid gland, or from
its disease, has proved a very difficult problem, partly because sufficient
care has not been taken to note how much parathyroid tissue was re-
moved along with the thyroid, and partly because the fact has been over-
looked that the effects produced by thyroidectomy and parathyroid-
ectomy are often very different in animals of the same kind at dif-
ferent ages. Speaking generally, it may be said that the influence of the
parathyroid is focused mainly on the nerve centers and only to a second-
ary degree on the metabolic functions, whereas the reverse is the case
with the thyroid, its main effect being on metabolism, although it prob-
ably also exercises a secondary effect on the nerve centers. More so
than in the case of any other endocrine organ, our knowledge concerning
the function of the thyroid has been gained by clinical experience, and
it is difficult to say whether the clinical or the experimental method has
contributed the greater amount of information.

THE THYROID AND PARATHYROID GLANDS 795

The results of experimental extirpation of the thyroid vary accord-
ing to the age of the animal, and frequently they are by no means
marked, provided sufficient parathyroid tissue has been undamaged.
The symptoms are in general thickening and drying of the skin, with a
tendency to adiposity and a loss of tone of the muscles. The body tem-
perature is low and the sexual functions become subnormal. Nervous
symptoms in the direction of mental dullness and lethargy are also
usually present. Surgical removal of the thyroid in man produces the
condition known as cachexia strumipriva. The symptoms may first of
all become apparent a few days after the operation, or they may remain
latent for years, and then develop so as to produce the condition known
as myxedema. When nervous symptoms are prominent in cachexia
strumipriva, it is usually taken as evidence that an excessive amount
of parathyroid tissue has been destroyed. Kocher states that after com-
plete loss of the thyroid, life is impossible for more than seven years,
and that to prevent ultimate ill effects, at least one-fourth of the organ
should be left intact.

Disease of the Thyroid

The symptoms of diseased conditions of the thyroid may be inter-
preted as the consequence of increased or diminished functioning of the
gland. Sometimes, however, the less active gland is really increased in
bulk, this increase being caused by the accumulation in it of very large
quantities of colloid material accompanied by an attenuated condition
of the vesicular cells (see page 793). When the gland is atrophied at
birth, the condition of cretinism soon becomes developed (Fig. 196). The
characteristic features of cretinism are: (1) An arrest of growth, espe-
cially of the skeleton, accompanied by incomplete ossification of the long
bones and a delay, often of several years, in the closure of the fontanelles.
The disturbance in growth of the long bones occurs along the epiphyseal
line, but the deposition of new bone beneath the periosteum proceeds,
more or less, normally. The consequence is that the bones increase in
thickness but fail to develop properly in length. (2) Poor development
of the muscular system. (3) An unhealthy, swollen condition of the skin,
so that it is yellowish in color, the face being pale and puffy. (4) An
abnormal development of the connective tissues causing a shapeless con-
dition of the surface; the abdomen is always swollen, the hands and
feet are shapeless, and the root of the nose depressed. (5) The nerv-
ous system also fail's to develop properly, so that at the age of puberty
or over, the child remains like an infant in his mental behavior, idiocy
being common. Indeed, the whole clinical picture is so character-
istic that once having seen a case no one can: fail afterward to

796

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

recognize the disease. Besides being due to congenital absence of the
thyroid (sporadic type), cretinism may also occur as a result of goitrous
degeneration of the gland. This forms the so-called endemic variety of
the disease, and is more commonly seen in goitrous districts, being not
infrequently associated with disease of the parathyroid, in which case
the nervous symptoms are very prominent.

The occurrence of thyroid deficiency in adults produces clinical mam-

Fig. 196. — Cretin, nineteen years old. The treatment with thyroid extract started too late to be of
benetit. (Patient of Dr. S. J. Webster.)

festations allied to those of cretinism, but necessarily modified by the fact
that the patient has attained full stature and sexual maturity. Though
the skeletal changes are absent, the metabolic disturbances are if anything
more pronounced. This adult form of the disease, which is known as myxe-
dema, may occur spontaneously from atrophy of the gland, or follow the sur-
gical removal of the latter, when the term cachexia strumipriva or operative
myxedema is applied to the condition. The symptoms are very character-
istic (Fig. 197). The skin is dry and thick, with a deposition of connective

THE THYROID AND PARATHYROID GLANDS

797

tissue often containing fat in its deeper layers ; the hands and feet become
unshapely; the lips thick and the tongue somewhat enlarged, so that
when the person attempts to speak, it appears as if the tongue were too
large for the mouth ; the hair falls out ; there is a low body temperature,
and it can be shown that the energy metabolism is greatly depressed, and
that there is a deficiency in oxygen consumption. It is said the person can
take a larger quantity of sugar than an ordinary individual without the
development of glycosuria, but the depression of the metabolic function
causes the patient to take sparingly of food, in spite of which, however,
the body weight may steadily increase. The sexual function becomes
depressed, and there is involvement of the nervous system as shown by
mental dullness and lethargy.
Although the thyroid gland is much atrophied in myxedema, symptoms

A. B.

Fig. 197. — A, Case of myxedema; B, Same after seven months' treatment. (From Tigerstedt.)

that are very similar may also occur when the gland is enormously en-
larged. As already explained, however, this enlargement is due merely
to an accumulation of colloidal material and is really an atrophic con-
dition. A patient suffering from endemic goiter may at first exhibit
symptoms which are usually attributed to a hypersecretion of thyroid
material into the blood (the symptoms will be described immediately),
but later these give place to symptoms not unlike those of myxedema.
It is concluded that the above conditions are due to deficiency of
thyroid function, or hypothyroidism, because: (1) the gland is atrophied,
and (2) similar symptoms to those exhibited by the clinical conditions

798 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

can be produced experimentally by the removal of the gland in animals.
By observations on the effect of administration of thyroid extract to
cretinous or myxedematous patients, prompt amelioration of the symp-
toms occurs, which certainly suggests that the real cause is the absence
of an internal secretion. There is probably nothing more striking in
the whole domain of therapeutics than this effect from the administration
of thyroid extract or, more so still, of thyroxin. If the treatment is
started early enough, the cretinous child from being an ill-developed
idiot quickly catches up with children of his own age and becomes in
every respect normal. Even if this treatment is not undertaken until
the child is several years of age, it is remarkable how quickly the benefit
may show itself. In myxedema and cachexia strumipriva also, the
symptoms very quickly disappear and the person becomes perfectly nor-
mal by the treatment. In all these conditions, however, the thyroid
extract must be administered continuously in order to prevent the reap-
pearance of symptoms.

Quite distinct from the above described conditions of hypothyroidism
are those produced by an excess of thyroid autacoid in the blood, namely,
hyperthyroidism. Such a condition can be produced experimentally in
normal animals by the administration of thyroid extract or of thyroxin
(Kendall). In man its continuous administration is soon followed by great
quickening of the pulse with some irregularity, flushing of the skin, in-
creased perspiration, tremor in the limbs, emaciation, and marked nervous
excitability. Along with these symptoms, metabolic investigations have
shown that the energy output per square meter of surface is greatly in-
creased, being sometimes nearly doubled ; that the nitrogen excretion is ex-
cessive; and that alimentary glycosuria is very commonly present. The
body temperature is not, however, as a rule increased, because although
metabolism is excited, yet heat loss is correspondingly increased. Ex-
ophthalmos is said to develop very occasionally after such administra-
tion, but this is doubtful. Lastly, there are usually digestive disturb-
ances, although the appetite is likely to be increased. The pulse is quick-
ened after administration of thyroxin only when protein food is also taken.
This is believed by Kendall to be due to the association between the thyroid
hormone and the metabolism of the amino acids.\It has been shown that
a single large dose of thyroxin has little demonstrable effect, whereas
minute doses administered over a prolonged period produce decided, toxic
manifestations, and, if the administration is persisted in, death results^-
These facts are explained on the hypothesis that thyroxin acts in the body
as a catalyst and hastens certain metabolic processes which are responsi-
ble for the symptoms, and that they are not due to the action of thyroxin
perse. (Kendall.)42

The symptoms following the injection of the extract are very similar

THE THYROID AND PARATHYROID GLANDS 799

to those of the disease known as exophthalmic goiter. Indeed, the symp-
toms are so much alike in the two conditions that it is scarcely neces-
sary to describe them specially for the disease except to mention that
in the latter exophthalmos is much more likely to be present.

Like simple goiter this variety is from three to four times more fre-
quent in women than in men, a fact of significance when we recall the
evidence of association between the thyroid gland and the generative
organs. It is said that the disease is usually coupled with persistence of
the thymus gland. The thyroid gland in exophthalmic goiter is enlarged,
sometimes in one lobe; it is hard and pulpy, and on auscultation a mur-
mur is heard. Histologically the gland presents a picture very like
that which has been described above as hyperplasia; that is to say, the
vesicles have a deficiency of colloid material ; their epithelium is colum-
nar and folded up into the vesicles; and the interstitial tissue between
the vesicles is very markedly increased.

Exophthalmic goiter is almost universally claimed to be due to hyper-
secretion of the thyroid, because: (1) the symptoms of the disease are not
unlike those produced by excessive administration of thyroid to a normal
individual; and (2) they are in general opposite in character to the symp-
toms found in cases where the thyroid gland is atrophied. The blood of
a person with exophthalmic goiter when injected into mice increases their
resistance to the toxic action of acetonitrile, which is also the case after
thyroid extract has been injected. In many cases of exophthalmic goiter
partial removal of the gland is said to ameliorate the symptoms. Other
clinicians, however, state that if the patient is given proper medical
treatment, rest, and diet, equally beneficial results can be obtained.

Certain investigators, however, deny that it has yet been conclusively
demonstrated that exophthalmic goiter is due to hypersecretion of the thy-
roid (Marine).43 It is pointed out that, if hypersecretion were the cause of
the disease, one would expect that the injection into animals of the blood
of patients suffering from it would produce symptoms similar to those
following the injection of thyroid extract. The results of such experi-
ments, however, have been extremely confusing and very indecisive, since
it is difficult to recognize in laboratory animals many of the characteristic
symptoms, especially those affecting the skin and eyes and the general
bodily nutrition. Another difficulty in accepting the hypersecretion hypoth-
esis is the fact that an extract of a gland removed from an exophthalmic
patient has no different physiological action on a normal animal from an
extract of a normal gland containing the same percentage of iodine.
The evidence is by no means conclusive one way or the other, and it may
well be that the observed changes in the thyroid gland are not the cause
of the symptoms of exophthalmic goiter, but merely, like the other symp-

800 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

toms of this disease, a result of some condition elsewhere. In this con-
nection it is of interest to note that degenerative and pigmentary changes
in the ganglion cells of the cervical sympathetic have been found by Wil-
son44 in cases of exophthalmic goiter and which are believed to be dis-
tinctive of this condition. On this account disease of the sympathetic
is suggested, by some, as the possible cause of the cardiac and ocular
symptoms, as well as of the thyroid hyperactivity, the latter producing
secondarily, it is supposed, the metabolic phenomena characteristic of
the disease.

The Relationship of the Thyroid with Other Endocrine Organs

1. With the Generative Organs. — Evidence of an association between
the female generative organs and the thyroid is very strong; thus, the
thyroid becomes enlarged at puberty, during the menses, and during
pregnancy, and in thyroidectomized young animals the sexual glands
fail to develop properly.

2. With the Adrenal Glands.— (See pag»e 788.)

3. With the Pituitary Body. — After removal of the thyroid, the pitu-
itary becomes greatly altered and enlarged, particularly the pars an-
terior, in which it is not uncommon to find that a certain amount of
vesicles containing colloid, not unlike those of the thyroid, become devel-
oped. This colloid material, however, does not contain iodine. It is said
that this increase of the pituitary after thyroidectomy does not occur if
thyroid extract be administered. Increased activity of the pars inter-
media of the pituitary is also quite plain. These facts would at first
sight seem to indicate that the pituitary and the thyroid can act vica-
riously, but this is very doubtful, for it has not been found that pitu-
itary extract has any beneficial effect in the treatment of goiter and myx-
edema. Nevertheless the association in function of the two glands must
be more or less close, not alone for the above reasons, but also because they
are both associated to much the same degree with the sexual organs,
and both act on the higher functions of the nervous system in much the
same manner.

4. With the Thymus Gland. — The persistence of the thymus in ex-
ophthalmic goiter, as well as the anatomical and embryological relationship
between thymus and thyroid, is taken to indicate some close relationship.

THE PARATHYROIDS

Experimental Parathyroidectomy

Experimental parathyroidectomy yields results which vary in dif-
ferent groups of animals, undoubtedly because of the fact that in some,
such as the rat and rabbit, accessory parathyroids may exist. In gen-

THE THYROID AND PARATHYROID GLANDS 801

eral, however, it has been found that if more than two of the four
parathyroids be removed, very definite and pronounced nervous symp-
toms soon supervene and if all four glands be removed, a quickly fatal
result is inevitable. The most acute symptoms are exhibited by the
carnivora. They may not be apparent for a day or two after the opera-
tion, although during the period the animal is in a depressed state, re-
fusing food and losing weight rapidly. The muscles are also more or less
stiff during this stage. When more definite symptoms appear, they con-
sist of a marked abnormality of muscular contraction, leading to the
occurrence of fibrillar contractions, or tremors and, later, to cramp-like
and clonic contractions. When spontaneous movements are made, a
peculiar shaking of the foot, like that made by a normal animal to shake
water off its pads, is a characteristic symptom. The slightest stimulation
of the peripheral nerves is sufficient to induce one of these attacks, which
recur with ever increasing frequency, becoming at the same time more
pronounced and accompanied by other disturbances, such as diarrhea,
profuse salivation and rapid pulse. In addition to the clonic seizures,
there appears a tonic contraction of the extensor muscles of the limbs and
in a certain percentage of dogs (but not of cats) spasm of the adductor
muscles of the larynx (laryngismus stridulus) occurs. In this latter con-
dition owing to the consequent narrowing of the rima glottidis the res-
pirations are noisy, difficult and high pitched in tone. In cases that are
not quickly fatal the hair tends to be shed and the teeth to be improperly
calcified (in young animals). Where a certain amount of parathyroid tis-
sue has been left — for example, one of the four lobes — the symptoms may
not appear except under conditions of special strain to the animal econ-
omy, such as pregnancy or improper diet. Thus, .in a bitch from which
three of the four glands had been removed, no symptoms of tetany oc-
curred until she became pregnant. Under the same conditions it has
been found that a diet of flesh is much more apt to bring about the con-
dition than one of vegetables or milk.

Injury or Disease of the Parathyroids in

Tetania parathyreopriva, as the condition described in the foregoing
paragraph is called, may become developed also in man as the result
of surgical removal of the parathyroids. This was a common enough
sequela to operations for goiter a few years ago, before the significance
of these bodies was recognized or, indeed, even their existence known.
It was the result of accident rather than of design, were the parathyroids
not removed along with the thyroid. A similar condition (idiopathic
tetany) occurs spontaneously, in children more particularly, but also in
adults when it may be associated with gastrointestinal disorders, infec-
tious diseases, or pregnancy. The clinical phenomena resemble closely

802 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

those described above as appearing in laboratory animals, with the dif-
ference that the clonic movements and the extensor spasm are more or less
replaced by a tonic spasm of the flexor muscles, which produces charac-
teristic attitudes of the hands and feet. Associated witn the carpopedal
spasm generalized convulsions or laryngismus stridulus may occur. Laryn-
geal spasm may, indeed, be the sole manifestation of parathyroid de-
ficiency and it is also believed that many cases of convulsions occurring
in young children really depend upon a deranged function of these glands.
In brief, tetany, infantile convulsions, and laryngismus stridulus are proba-
bly but different manifestations of the same condition.

It has been suggested that certain obscure nervous diseases of adults
such as paralysis agitans and Thomsen's disease are dependent upon
lesions of the parathyroids. Chorea, epilepsy, and eclampsia likewise have
been ascribed to disease of these bodies, but no cogent evidence has been
adduced to connect the parathyroids with any of these conditions. That,
on the other hand, the belief in the association of idiopathic tetany and
parathyroid disease is well founded is evMenced by the close resemblance
between the nervous symptoms of the two conditions. In the case of
monkeys especially, are the symptoms of the experimental condition often
strikingly similar to those of the idiopathic disease. In these animals
the muscular spasms following parathyroidectomy may imitate almost
unerringly those of infantile tetany, so that the tonic flexor spasms pro-
ducing the characteristic carpopedal attitudes of the idiopathic condi-
tion, appear,

With regard to the culture of the disturbances set up by parathyroid de-
ficiency. Noel Paton, Findlay and Watson45 have recently shown that the
clonic spasms are not primarily dependent upon the cerebrum or cere-
bellum, since they persist after ablation of these parts of the nervous
system ; in fact, removal of the hemispheres or suppression of their usual
functions by light anesthesia increases the severity of the clonus. This
does not imply that secondary involvement of the cerebrum may not
occur; on the contrary, the epileptiform convulsions, observed in the se-
verer types of tetany, indicate considerable cerebral mischief. Division
of the cord does not remove the spasms below the site of section, nor
has severance of the posterior roots any influence upon them ; but they
disappear after division of the anterior roots. These observations show
that the seat of origin of the spasms cannot lie in the peripheral nerves
or in the muscles. This leaves the efferent neuron of the spinal arc as the
affected structure.

The other nervous disturbance following parathyroidectomy, namely,
tonic spasm of the extensor muscles has been shown to depend upon the
cerebellar arc. The hypertonus is uninfluenced by decerebration, whereas
the removal of cerebellar impulses by severance of the spinal cord abol-

THE THYROID AND PARATHYROID GLANDS 803

ishes this symptom below the transection. In the severer cases other
more marked evidences of cerebellar involvement may appear, e. g., dis-
turbances of equilibrium and forced movements of a circling or rotatory
nature.

Though the foregoing ascribes a central origin to the eminent nervous
symptoms the peripheral nerves are not entirely unaffected as has been
shown by Noel, Paton and his co-workers. These investigators compared
the response of muscle and nerve to electrical stimulation in nor-
mal and in parathyroidectomized animals, and found that though there
were considerable variations in the responses of a normal animal, they
were very definitely exaggerated in experimental tetany when either
the motor nerve or the muscle itself was stimulated. This increased
electrical excitability is uninfluenced by the central nervous system,
since it persists after section of the nerves, and though it is manifested
by direct stimulation of the muscle it does not depend upon any change
in the myal structures, for degeneration of the nerves or the administra-
tion of curare in sufficient dosage to block nervous impulses, abolishes it ;
it is concluded that the nerve ending is the part of the neural structure
affected. Idiopathic tetany shows a similar exaggeration of electrical
excitability, the excitability to mechanical stimuli is increased to an even
greater degree in this condition, a fact most valuable in the diagnosis of
latent disease; tapping over the facial nerve is the common method em-
ployed for its elicitation. Though these changes in the excitability of the
peripheral nerves are useful in diagnosis, neither in the experimental
nor in the idiopathic condition can they be taken as a measure of the se-
verity of the process, for they may be no more marked in instances where
there is involvement of the cerebral hemispheres (causing epileptiform
convulsions) than in milder cases.

The parathyroid gland, besides influencing the nerve centers, has also
an influence on metabolism. The symptoms produced by parathyroidec-
tomy are; (1) rapid emaciation and failure to grow; (2) a tendency to
the production of glycosuria, often detected by finding that the assimi-
lation limit for carbohydrate is lowered (page 685) ; and (3) most defi-
nitely of all, an interference with calcium metabolism, as illustrated
by the failure of the teeth and bones to calcify properly.

When the tetany is the result of a complete extirpation of all parathyroid
tissue, the symptoms can be combated by a successful transplantation or
graft of pa'rathyroid tissue made from an animal of the same species. In-
deed, it has been found that the success of a graft of parathyroid is
assured only when the graft is derived from the same kind of animal as
that from which the parathyroid has been removed. Implantation into
the subcutaneous tissue of a tetany patient of parathyroid tissue ob-
tained fresh from the deadhouse has been performed with beneficial out-
come.

804 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

As to the cause of the symptoms, many possibilities have to be considered,
in the first place, no direct relationship exists between the thyroid and
parathyroid in this connection. One cause might be the absence of
some substance which checks the activity of the nervous system, some
chalone in Schafer's sense. It was previously thought by W. G. Macal-
lum46 that, since, nervous symptoms like those of tetany could be pro-
duced by deficiency of calcium in the body and the symptoms of parathy-
roidectomy were relieved by the administration of this cation, calcium
deficiency was the cause of the symptoms. The defective calcification of
the bones and teeth following parathyroid deprivation together with the
frequent association of rickets (a condition characterized by a modified
calcium metabolism) enhanced the plausibility of such an hypothesis.
On the other hand, that no view can be correct which takes as its basis
the absence or deficiency of some one or other substance which is sup-
posed, normally, to influence the activity of nervous tissues is indicated
by the fact that blood-letting or the transfusion of normal saline imme-
diately removes the symptoms, and keeps them in abeyance for some time.
Moreover, such a view does not adequately explain the metabolic dis-
turbances, which may continue when the nervous symptoms are slight as,
for example, after the administration of calcium. The most probable ex-
planation of the beneficial effect of calcium upon the nervous symptoms is
that it behaves merely as a sedative, reducing the excitability of the
nervous system, an action which it is known to possess.

While not denying that calcium ions may have some minor relation-
ship to the symptoms, Noel Paton ascribes them chiefly to intoxication
by guanidine (page 640). The evidence is as follows: (1) Guanidine
or methyl guanidine administered to normal animals produces symp-
toms that are identical with those following parathyroidectomy. (2)
No drug, other than guanidine, which can effect a decided increase in
the excitability of the motor nerve endings to the constant current, has
been found. (3) There is a marked increase in the amount of these sub-
stances in the blood and urine of parathyroidectomized dogs, and in
the urine of children suffering from idiopathic tetany. It is also true
that while creatine (which contains the guanidine nucleus and is a prob-
able source of this substance) is absent from the urine of healthy adults,
it is normally present in the urines of children between the ages of 12
and 15 years, a period during which the incidence of tetany is most
frequent. Under 6 months creatinuria does not usually occur, tetany
also is extremely rare at this age. These facts taken in conjunction with
the other evidence, seem to have more than a coincidental bearing upon
the genesis of tetany. (4) In certain cases, the serum of parathyroidecto-
mized dogs acts upon the muscles of the frog similarly to weak solutions
of guanidine. (5) There is a striking similarity in the relative amounts
of the nitrogenous metabolites in the urine of parathyroidectomized dogs

THE THYROID AND PARATHYROID GLANDS 805

and normal animals injected with guanidine, in either instance the total
nitrogen is increased and the proportion of urea diminished.

It is concluded that the parathyroids control the metabolism of guani-
dine "by preventing its development in undue amounts. In this way
they probably exercise a regulative action upon the tone of the skeletal
muscles."

Though the evidence of these observers is most formidable, it seems
that the question has not yet reached finality, for Howland and Mar-
riott47 still insist that a lowered calcium content of the blood is responsi-
ble for idiopathic tetany. This contention is supported by a mass of
analytical data from which the fact is brought out that the blood of chil-
dren suffering from tetany shows a reduction of calcium, to the extent
of 40 per cent in many instances. The question whether this deficiency
is merely an accompaniment of the condition or the causative factor
does not appear to have been fully investigated. It is possible that neither
of these factors — guanidine formation or calcium deficiency — is the pri-
mary cause of tetany, but that one or perhaps both may be secondary to
some condition as yet unrevealed.

CHAPTER LXXXVII

THE PITUITARY BODY

Structural Relationships

Situated at the base of the brain and lying in the sella turcica, the pituitary body
in man does not weigh much more than half a gram. It is connected with the brain by
a funnel-shaped stalk, the infundibulum. On account of a natural cleft, which runs
across the gland in an oblique plane, it is an easy matter to split it into two portions,
an anterior, or pars glandularis, and a posterior, or pars nervosa. This cleft in the
case of man is usually found to be more or less broken up into isolated cysts containing
a colloid-like material, and it represents the remains of the original tubular structure
from which the pars glandularis is developed; namely, a pouch growing out from the
buccal ectoderm.

On histologic examination it will be found that the pars glandularis consists of masses
of epithelial cells with large sinus-like blood capillaries lying between them. These
blood vessels are very numerous, so that in an injected gland this portion of the pituitary
stands out very prominently. The vessels are derived from about twenty small arterioles
that converge toward the pituitary from the circle of Willis, and enter the gland by the
infundibulum or stalk by which the gland is connected with the base of the brain. Three
types of cell can be differentiated: nonstaining (chromophobe) and granular (chroma-
phil), of which latter there are cells with acid-staining and others with base-staining
granules, the former being by far the more numerous (Schafer). In some animals such
as the cat, the cells of the pars anterior are arranged around the blood sinuses in rows
as in a columnar epithelium. The cells with acid-staining granules are said to become
much increased in number in pregnancy and also in the enlarged gland of acromegaly
(see page 816). After thyroidectomy it has been observed that colloid-like masses ac-
cumulate in the pars glandularis, the cells sometimes arranging themselves around these
masses as in the thyroid gland. The colloid, however, contains no iodine.

The posterior part of the gland, or pars nervosa, is composed almost entirely of
neuroglia, cells, and fibers, usually with some hyaline or granular material lying be-
tween them, particularly in the neighborhood of the infundibulum, into which it may be
traced. It is believed that the active principle of the gland is represented by this ma-
terial. The blood supply of the pars nervosa is relatively scanty.

Between the pars nervosa and the intraglandular cleft above referred to is a layer
of cells differing from those of either the anterior or the posterior lobe. This layer of
cells constitutes the so-called pars intermedia. The cells are somewhat like those of the
pars glandularis, except that they are distinctly granular, the granules being of the neu-
trophile variety, that is to say, they stain with neither basic nor acid dyes. Well-defined
vesicles, containing an oxyphile colloid material which is believed to furnish the
active principle of the posterior lobe, are- of ten found between them. Although well
separated by the cleft from the pars glandularis, the pars intermedia is not well separated
from the pars nervosa, because many of its cells extend for some distance into the latter
between the neuroglial fibers. Certain of the cells in the pars intermedia may be seen
in various stages of conversion into globular hyaline bodies, or a granular mass of ma-

806

THE PITUITARY BODY

807

terial may appear in them. In either case, the cells ultimately break down, setting free
the hyaline or granular material, which is believed to be the origin of the similar ma-
terial already described as existing between the neuroglial fibers of the pars nervosa
and therefore ultimately finding its way by the infundibulum into the third ventricle of
the brain. As evidence that the pituitary secretion takes this course are the facts, that
in the first place, the active principle of the gland may be detected in the cerebrospinal
fluid, and secondly, if in the living animal the infundibulum be severed close to its junc-
tion with the ventricular floor, a subsequent examination of the gland shows an unusual
accumulation of hyaline material in the stalk and adjacent portion of the posterior lobe.
It should be mentioned, finally, that at the margin of the intraglandular cleft the inter-
mediary and anterior portions of the pituitary come together, although the cells of each
can readily be distinguished on account of their staining properties. This pars glandu-

Fig. 198. — Drawing from a photograph of a mesial sagittal section through the pituitary gland
of a human fetus (5th month): a, optic chiasma; c, third ventricle; d, pars glandularis; e, intun-
dibulum surrounded by epithelial cells; /, pars intermedia; g, intraglandular cleft; h, pars nervosa.
(Herring, from Howell's Physiology.)

laris et intermedia also extends as a thin layer over part of the pars nervosa and around
the neck of the gland at the infundibulum. These relationships are well shown in the
accompanying diagram (Fig. 198).

Functions

Concerning the functions of the pituitary, it may be said in general that
the anterior lobe has an important relationship to the nutritive con-
dition of the body during growth, especially of the skeletal structures,
and that the posterior lobe produces a very active autacoid having to do
with the physiological activity of unstriped muscle fiber. The pars inter-
media seems to be associated with the posterior lobe in the production of

808 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

this autacoid. The function of these two parts will therefore be con-
sidered together.

Function of the Anterior Lobe, — The facts concerning the function
of the pars glandularis have been gleaned largely by observing the ef-
fects produced by partial or complete removal of the entire pituitary.
Justification for ascribing the results of this operation to removal of the
anterior lobe, rather than to removal of the posterior is furnished by
control experiments in which removal of the posterior lobe alone failed
to produce similar effects.

Complete removal of the pituitary is almost invariably fatal, the con-
dition being called apituitarism. Two operative procedures have been
employed for the removal of the gland. One of these, originated by
Paulesco and elaborated by 'Gushing and his pupils,48 consists in trephin-
ing the skull and elevating the temporal lobe of the cerebrum so as to
expose the gland. The other, elaborated by Horsley,49 consists in ap-
proaching the gland through the orbital cavity. Although there is some
danger of injury to nervous tissues by the intracranial method, its re-
sults are more dependable since the gland is actually exposed to view
before being removed.

Most hypophysectomized animals die within two or three days, unless
they are very young. This longer survival of young animals is ascribed
to the presence of accessory pituitary material situated in the dura mater
lining the sella turcica. The most extensive observations have been made
on dogs. On the day following the operation the animal appears about
normal, but it gradually becomes less active, refusing food and respond-
ing slowly to stimulation. It gradually gets weaker and weaker; muscu-
lar tremors may appear, the respiration and pulse become slow, the back
arched, the temperature subnormal; and, usually within about forty-
eight hours, coma develops and the animal dies in this condition. Symp-
toms of equal severity ensue if the anterior lobe alone is removed. When
the symptoms are less acute and death does not occur so early, it is be-
lieved by Gushing either that small portions of the gland have been left
behind or that some vicarious activity of other organs has developed
to replace that of the pituitary.

When only a part of the pituitary is removed either unintentionally
or intentionally, the symptoms are not nearly so acute, provided that
the portion remaining includes tissue of the anterior lobe. The condition
is known as hypopituitarism. It is by a study of this condition that
most facts concerning the function of the anterior lobe have been
learned. When the operation is performed on young animals, they
fail to grow properly ; the milk teeth and the lanugo are retained ;
the epiphyses do not ankylose; the thyroid and thymus glands are en-
larged; and the cortex of the suprarenal and the sexual organs fails to

THE PITUITARY BODY 809

develop. The animal, though small, becomes very fat and may therefore in-
crease in weight. There is distinct evidence of mental dullness. From these
results it is concluded that the anterior lobe of the pituitary produces
autacoids having to do with the development of the skeletal and other
structures of the growing animal. That this autacoid is not derived from
the posterior lobe is indicated by the fact that partial injury of this
lobe, or indeed its entire removal, is not followed by similar symptoms.

Closer examination of the metabolic function in hypophysectomized
animals has shown that there is a marked depression in the respiratory
exchange of oxygen and carbon dioxide, and that the ability to metabo-
lize carbohydrate becomes heightened ; that is to say, the animal can tolerate
a larger quantity of sugar than the normal animal without develop-
ing glycosuria. This effect on carbohydrate metabolism may how-
ever be associated not so much with the function of the anterior lobe as
with that of the posterior, for, as we shall see later, Gushing and his
pupils have found that extract of the posterior lobe has a marked influence
on the assimilation limit of carbohydrate.

Attempts have been made to graft the pituitary, especially the anterior
lobe, into various parts of the body. It has been found, however, that
within a few days the grafts atrophy and disappear unless there has
been complete removal of the pituitary itself, in which case the graft
may remain for a month or so and the otherwise fatal outcome of hypophy-
sectomy be warded off. Sometimes, where the graft has remained for a
longer time, it is said that a temporary increase in the growth of the
animal has been noticed.

Other observers have investigated the effects in normal animals of
continuous oral administration of pituitary substance or of subcutaneous
injection of extract. The earlier results were indefinite and confusing,
but recently Brailsford Robertson50 has succeeded in isolating from the
anterior lobe a substance called tethelin, which accelerates growth in
young animals and is thought to have a possible value in hastening the
healing process in wounds.

Tethelin is precipitated by dry ether from an alcoholic extract of the
carefully isolated anterior lobes. It contains 1.4 per cent of phosphorus,
and nitrogen in the proportion of four atoms for every atom of phos-
phorus, two of the nitrogen atoms being present as amino groups and
one in an imino group. The effects on growth of mice are in every par-
ticular like those of the administration of anterior lobes, and consist in
retardation of the first portion of the third growth cycle,* followed by

*Robertson has contributed valuable and very extensive data on the normal curve of growth of
white mice kept under carefully controlled conditions. Three growth cycles are present: the first
attains its maximum velocity between seven and fourteen days after birth; the second, between
twenty-one and twenty-eight days; and the third about six weeks, after which the velocity decreases
progressively, until further growth ceases between the fiftieth and sixtieth weeks succeeding birth.

810 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

acceleration of the latter portion of this cycle. When fully grown,
tethelin-fed mice also differ from normal animals in being smaller in
size but of greater weight, with a distinct difference in the condition of
the coat. Normal animals at fourteen months of age have " shaggy,
staring and discolored coats," whereas tethelin-fed animals have the
glossy and silky appearance of young animals. During growth, nor-
mal animals display a greater variability in weight than tethelin-fed
animals.

Extraordinary effects have been observed by Clark51 to be produced
by feeding laying hens with pituitary gland. Thus, by giving to one-
year-old hens, in addition to their usual food, 20 milligrams of fresh
pituitary substance for four days, it was found that the average daily
number of eggs laid by a batch of 655 hens was raised from 273 during
the four days preceding the pituitary feeding to 352 during the four
days of the administration, these results being obtained at a time of
year when the natural egg-production of the hens was diminishing. It
was further observed that not only is the output of eggs greatly increased
as a result of the pituitary feeding, but likewise their fertility, for in
another experiment in which 35 hens were kept along with two cockerels
of the same breed, not only was the output of eggs increased (from 18 up
to 33), but the fertility of the eggs was greatly enhanced.

Functions of the Posterior Lobe (and Pars Intermedia). — As already
mentioned, excision of this part of the pituitary can be tolerably well with-
stood by the animal, so much so indeed that from its behavior after the
operation we can conclude little as to the function of the lobe. On the
other hand, extracts of the posterior lobe injected into normal animals
produce effects that are very striking, indicating that the main function
of this lobe is the production of an autacoid. The extracts have more or less
an epinephrine-like action. Such extracts, rendered protein-free and steril-
ized, are obtainable on the market under the various names of pituitrin,
hypophysin, etc. From them a crystallizable material has been obtained,
but this is probably a mixture of various substances. In discussing the
functions of these various extracts, it must be remembered that the inter-
mediary part (pars intermedia) is included with the posterior lobe in
their preparation.

Although the effect of pituitary extract on plain muscle fiber (and on
glandular tissue) appears, on first sight, to be very like that produced
by epinephrine, it has been found on closer examination that the two
substances really act in different ways. The rise in blood pressure pro-
duced by pituitary autacoid is likely to be more prolonged than that
produced by epinephrine. It stimulates increased cardiac activity, but
after the vagi have been cut or sufficient atropine administered to para-

THE PITUITARY BODY 811

lyze them, the pituitary autacoid continues to stimulate the strength of
•the heartbeat without producing the acceleration noted with epinephrine.
Whereas epinephrine has little or no action on the coronary vessels (page
268) or on those of the lungs, pituitary autacoid usually produces constric-
tion of both types of vessel ; and on the renal arteries the actions of the two
autacoids are entirely different, for epinephrine has a marked constric-
ing effect, while the pituitary autacoid produces dilatation.

Another striking difference in the extracts from the two glands is re-
vealed by repeating the injection after the effect of a previous one has
completely passed off. With epinephrine the original effect is repro-
duced; with pituitrin, on the other hand, the effect of the second injec-
tion is very often the reverse of that of the first; that is to say, the blood
pressure, instead of rising, may fall, or the rise be very much less
marked. Whether this effect of the second dose is caused by the action
of an autacoid having a chalonic rather than a hormonic influence, or
whether it is due to a reversed effect of the same hormone, it is impos-
sible at present to say. The chalonic effect in any case is much more
evanescent than the hormonic, and it is not caused by cholin, as some
have suggested. The effect of epinephrine, it will be remembered, is
abolished by ergotoxin and apocodeine. These drugs, on the other hand,
have no influence on the action of pituitrin. The difference in action
between the two autacoids is usually explained by assuming that the
epinephrine acts on the receptor substance associated in some way with
terminations of the sympathetic nerve fibers in involuntary muscle,
whereas pituitrin acts directly on the involuntary muscle fibers themselves.
Other types of involuntary fiber are also acted upon by pituitrin. The
uterine contractions, for example, are stimulated (Fig. 199), this effect
being unconditioned by the state of the uterus.

A similar effect is produced upon the musculature of the intestine
and bladder (in contrast to the inhibitory effect of epinephrine) and
upon the muscle of the ureter. Pupillary dilatation of the excised frog's
eye, but not of the mammal's, is produced by pituitrin. The effect of this
substance upon the bronchioles is shown in Fig. 200.

The glands upon which pituitrin has the most pronounced action are the
mammary glands and the kidneys. It has no influence upon the salivary
secretion. The effect on the kidney is evidenced by the remarkable increase
in the urinary flow following injection of the pituitrin. This diuresis might
of course be due merely to the vasodilatation that we have seen such extracts
produce — a vasodilatation which is all the more marked because the vessels
elsewhere in the body undergo constriction. But pituitrin continues to cause
increased urinary outflow in the absence of any demonstrable vascular
change ; it also acts after the administration of atropine, so that it is con-
sidered by most observers to act on the excretory epithelium of the convo-

812

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

luted tubules in much the same way as certain diuretics, like diuretin. This
renal hormonic action of pituitrin, would appear to be analogous with that o£.
secretin on the epithelium of the pancreas. Another reason for believ-

Fig. 199. — Tracing showing the action of pituitrin on the uterine contractions and blood pressure
in a dog. Made by Barbour's method. (From Jackson.)

ing that the secretory hormone is independent of that producing vaso-
dilatation of the renal vessels is the fact that a repeated dose of pituitrin,
although, as we have seen, it usually has a depressor action on the blood

THE PITUITARY BODY

813

vessels, still produces a stimulating effect on the excretion of urine.

The work of Knowlton and Silverman58 on the gaseous exchange of the
kidney during pituitrin diuresis is against this view. These observers
could detect no increased oxygen consumption accompanying the in-
creased urinary flow, and ascribe the latter effect purely to augmented
blood flow. The value of pituitrin as a diuretic in clinical practice is now
well recognized.

The work of Cow52 upon the secretory activity of the kidney in rela-
tion to pituitrin administration indicates that the hypophysis normally,

Fig. 200. — Tracing showing the constricting action of pituitrin on the bronchioles and its effect
on blood pressure in a spinal dog. (From Jackson.)

is part of a mechanism for the control of the urinary flow its action
being opposed to that of the adrenal medulla. It is asserted that ingested
fluid taken up by the gastrointestinal mucosa absorbs a substance of a
hormonic nature contained therein, which passing into the general blood
stream calls forth the diuretic principle from the pituitary body.

The effect on milk secretion is best demonstrated by placing a cannula
in the mammary ducts so that the milk may freely flow out. By observ-
ing the rate of outflow during the injection of pituitrin, it will be found
that a remarkable increase occurs. After this increased secretion has
ceased, however, the injection of more pituitrin has no further effect,
indicating that the influence of the first injection must have been, not so

814 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

much to stimulate the secretion of milk, as to accelerate the outflow of
that which previously had been secreted and had collected in the alveoli
and ducts. This effect explains why the pituitary galactagogue should
have very little if any effect on the total production of milk or on the
total amount of fat and other constituents contained in it. Histological
examination of sections of a resting mammary gland and of the same
gland after administration of the pituitrin, bears out the above interpre-
tation of the action. Alveoli in the resting state will be found largely
distended with milk and the epithelium flattened against the basal mem-
brane, whereas alveoli from the gland after pituitary activity show small
shriveled-up alveoli, containing little milk, and with epithelium that is
well marked and stands out prominently from the basal membrane.

These facts taken together indicate that pituitrin stimulates the mus-
cular fibers of the ducts of the mammary glands, thus squeezing out the
milk contained in them. Muscular fibers have been described as existing
between the basal membrane and epithelial cells, much in the same way
as they do in the case of the sweat glands. At least Schafer has suc-
ceeded in demonstrating in this position rod-shaped nuclei which prob-
ably belong to muscular fibers.3 By their contraction, the milk in the
alveoli is expelled into the ducts. The observation of Maxwell,53 namely,
that the alveolar contour of a lactating gland failed to show any change
when irrigated with pituitrin, is opposed to the foregoing view. It has also
been found that pituitrin stimulates the secretion of cerebrospinal fluid
and that this stimulation is independent of a rise in blood pressure.

Recently Abel and Kuboto54 have brought forward evidence to show that
the depressor effect of pituitrin and its stimulating action upon plain
muscle are not specific, but are due to the presence of histamine (/3-imi-
nazolethylamine) a substance we have seen to be produced by the de-
carboxylation of histidine (page 536). These authors have isolated the
depressor and the plain-muscle stimulant principle from the posterior lobe
of the pituitary in the form of a di-picrate. With regard to crystalline
form, solubility, melting point and the method of its isolation, this sub-
stance is identical with the di-picrate of histamine ; since the physiological
actions of the two substances are also the same their unity is believed to be
established.

Pituitrin has a distinct effect on carbohydrate metabolism. After its
intravenous or subcutaneous injection, a marked lowering in the toler-
ance for sugar is observed (page 685), usually to such an extent that
glycosuria becomes established. Gushing and his pupils have concluded
that the posterior lobe contributes an autacoid which stimulates the utili-
zation of sugar in the body. Confirmatory evidence for this view is fur-
nished by the observation that mechanical stimulation of the posterior
lobe, such as is produced by puncturing it with a needle, is followed by

THE PITUITARY BODY

815

a temporary glycosuria, which is said to be as pronounced as that fol-
lowing puncture of the diabetic center (page 704), provided glycogen is
present in the liver. The production of this carbohydrate autacoid would
appear to be under the control of the sympathetic nervous system, for it
has been found by Gushing and others that stimulation of the superior
cervical ganglion, which has been known for many years to be fre-
quently followed by glycosuria, has this effect only provided the posterior
lobe of the pituitary is intact. Even surgical manipulation of the pitui-
tary may excite a hypersecretion of pituitrin, which would account for
the glycosuria often observed after experimental excision or partial

A.

B.

Fig. 201. — A, To show the appearance before the onset of acromegalic symptoms; B, The ap-
pearance after seventeen years of the disease. (After Campbell Geddes.)

destruction of the pituitary. A similar irritation may be set up in disease
of the gland.

The glycosuria which is usually observed after partial hypophysectomy
soon passes off, to be followed by a permanent condition of increased
tolerance for sugar, because now less pituitrin is being produced. It is
said that during the stage of increased tolerance diabetes can not be pro-
duced even by excision of the pancreas. The glycosuria produced by
irritation of the posterior lobe is accompanied by a marked polyuria (dia-
betes insipidus), which may outlast the glycosuria.

The extract of the pars intermedia has an action similar to but not
identical with that of the posterior lobe, seme of the effects of which it
lacks, for example, it possesses no pressor action or influence upon the
kidney, and, though it exhibits galactogogue and oxytocic qualities, these

816 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

are considerably less potent than in the case of extracts of the pars nervosa.
The active principle of the pars intermedia, on account of these differences,
is looked upon by Herring55 as representing an immature stage in the manu-
facture of the active principle of the gland, the final product of which is
represented by the extract of the posterior lobe. The fact that the cells
of the pars intermedia are, apparently, the ultimate source of the pituitary
autacoid (see page 806) supports this view.

Clinical Manifestations of Deranged Pituitary Function

Because of their importance from a physiological standpoint, we shall
now proceed to review briefly some of the more important facts that have
so far been brought to light by clinical observations. The pathological
condition most frequently observed affecting the pituitary is an adenom-
atous growth particularly located in the anterior lobe. Besides pro-
ducing general symptoms of pressure, such as diminution of the visual
field and, perhaps, headache, a shadow can usually be observed when the
patient is examined by means of the x-rays. General symptoms, com-
monly ascribed to a hypersecretion of the autacoid of the anterior lobe of
the pituitary — hyperpituitarism — begin sooner or later to show them-
selves. These symptoms are almost exactly opposite in character to those
observed in animals after removal of this portion of the gland. Thus,
the bones of the extremities become stimulated to increased growth,
so that if the patient is young, and the epiphyses therefore'
not ossified, remarkable elongation of the long bones occurs, pro-
ducing the condition known as gigantism. On the other hand, if the dis-
ease does not develop until after ossification is complete, its effects be-
come most marked in the bones of the face, the lower jaw becoming
enormously hypertrophied and the supraorbital ridges very prominent.
The long bones also become enlarged at their extremities, and there may
be some increase in length of the vertebral column, although the stature
does not increase because of kyphosis (bowing of the spine). The
condition is called acromegaly. Nutritive disturbances of the skin and
hairs also become marked, causing the skin to become dry and yellowish,
and the hairs to undergo, abnormal increase over the body. An early
symptom of the condition is a failure of the sexual power (Figs. 201 and
202.)

After a time the disease begins to affect the pars intermedia et nervosa,
and disturbances in carbohydrate metabolism come to be observed, con-
sisting usually in a diminished tolerance accompanied by glycosuria, in
the early stages of the disease, followed by increased tolerance in the
later stages. The glycosuria is usually accompanied by marked polyuria.

It should be observed that sometimes tumor of the pituitary has been

THE PITUITARY BODY 817

found to exist postmortem though none of the above symptoms had been
recorded during life. In these cases it is probable that the disease from
the start had been of such a nature as to produce a tendency to hypo-
pituitarism rather than hyperpituitarism, for the symptoms are very like
those observed in animals after partial or complete removal of the gland.
If the condition commences before adolescence, the body fails to grow,
although the child may continue to increase in weight because of the

Fig. 202. — Hand of a person affected with acromegaly.

remarkable deposition of fat in the tissues. Sexual development is strik-
ingly interfered with, and the secondary sexual characteristics fail to
show themselves. In boys, for example, the pubic hairs fail to extend up
to the umbilicus; and the hairs on the chin do not develop, whereas the
hair of the scalp grows profusely. The bones remain of the female type,
and a broad pelvis, rounded limbs, small feet and hands are often ob-
served. In these cases there is usually excessive tolerance for carbohy-
drates, which may explain the adiposity, sugar being converted into fat.
In the light of the experimental results, the effect on carbohydrate

818 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

metabolism may be explained as due to involvement of the posterior
lobe. Mental development is retarded, and psychic derangements are
sometimes observed.

Where the hypopituitarism does not develop until after adolescence,
some of the above symptoms will of course be missed, but many will be
observed, such as dryness of the skin, loss of hair, and the tendency in
the male to adopt certain of the female characteristics, particularly with
regard to the growth of hair. Obesity and increased tolerance for sugar
are also evident, and pigmentation of the skin, something like that of
Addison's disease, is said often to be a p-rominent feature. These clinical
types of hypopituitarism (both the preadolescent and the postadolescent)
were first described as entities by Frohlich, and are grouped under the
term dystrophia adiposo-genitalis. They are due undoubtedly to involve-
ment of both lobes of the pituitary.

In contrast to the foregoing, a form of infantilism associated with hypopi-
tuitarism occurs, in which the subjects are not obese but rather the reverse.
There is a markedly retarded development of the skeleton and the sexual
organs, while the patient presents to the casual observer the appearance
of an ill-nourished child. When stripped, however, it is seen that he or
she, is in reality, except for the sexual immaturity, a man or a woman in
miniature. The form possesses the lineaments of the adult, the relative
bodily proportions of the child being absent. This type, which is usually
known as that of Lorain, is probably due to disease affecting chiefly the
anterior lobe. Operative interference in the early stages in many cases
of hypopituitarism as well as of hyperpituitarism is of undoubted benefit,
as is shown by the brilliant work of Harvey Gushing, to which the reader is
referred for further information.

The Relationship of the Pituitary Gland with Other Endocrine

Organs

The relationship of the pituitary gland with other endocrine organs
seems to be an intimate one.

1. With the Thyroid and Parathyroid Glands. — That enlargement of
the pituitary occurs after thyroidectomy in man has been known for a
considerable number of years. The enlargement affects more particu-
larly the pars anterior, although changes are also described in the pars
intermedia et nervosa. Accompanying the enlargement of the anterior
lobe, vesicles containing colloid-like material often become developed in
it, but even after the hypertrophy has proceeded to a considerable de-
gree, this colloid does not contain iodine, nor does an extract have the
same physiological effect as one of the thyroid gland. It can not replace
thyroid extract in the treatment of patients with goiter or myxedema,

THE PITUITARY BODY 819

or ameliorate the symptoms produced in animals by the removal of the
thyroid gland. Deposition of colloid-like material in the pars anterior
also occurs in myxedema. Histological changes in the pars intermedia et
nervosa, although less pronounced than in the pars anterior, are never-
theless said to be perfectly distinct following thyroidectomy, and to con-
sist in an increase in the hyaline and granular masses which have already
been described as present to a certain extent in the normal gland.

Less direct evidence of an association in function between the pituitary
and the thyroid is furnished by the similarity of the effects produced on
the sexual functions and on the general development of young animals
by the removal of either gland. In both cases the animals fail to grow
properly; the sexual organs remain undeveloped; and the mental func-
tions are infantile in type. In hypophysial deficiency, however, extreme
adiposity is likely to be more marked than is the case in cretinism.

2. With the Sexual Organs. — That the pituitary gland has much to do
with the development of the sexual organs has already been shown. Fur-
ther evidence of a relationship between the sexual glands and the pitui-
tary is furnished by the following observations. After castration en-
largement occurs in the pituitary, and on histological examination the
gland is found to contain a large number of oxyphile cells, particularly
in the pars anterior. This influence of the sexual glands on the pituitary
is believed to depend on the interstitial cells present in them, for it has
been found that if the ovary or testis is transplanted into other parts of
the body after the castration, the changes in the pituitary do not occur,
although, as we shall see, the transplanted gland becomes entirely
atrophied except for the interstitial cells. The enlargement of the pitui-
tary during pregnancy — an enlargement which often brings it to two or
three times its normal weight — is further evidence of its association
with the ovary.

3. With the Suprarenals. — Association of function is suggested in this
case by the fact that extracts of suprarenal and pituitary have very much
the same effects on involuntary muscular fiber and glandular structures,
and it is said that the two extracts mutually facilitate each other 's
action in this regard. It should be remembered, however, that pituitrin
and epinephrine do not appear to act on exactly the same peripheral
mechanism (see page 811).

4. With the Isles of Langerhans. — Since pituitrin affects carbohydrate
metabolism, which is thought to be primarily controlled by the Isles of
Langerhans, it is claimed by some observers that a relationship also
exists between the pituitary and these structures. Injections of duodenal
extracts are also said to cause a hypersecretion of pituitrin into the
cerebrospinal fluid.

CHAPTER LXXXVIII

THE PINEAL GLAND, THE GONADS, AND THE THYMUS
THE PINEAL GLAND

This peculiar structure lies between the anterior corpora quadrigem-
ina, and weighs about two-tenths of a gram. It is largest in the early
years of life, and undergoes retrogressive changes after puberty. Micro-
scopically it consists of epithelial cells arranged loosely in trabeculae,
with large sinus-like capillaries between them; neuroglia and sometimes
muscle-fiber cells are also present. Curious globules of calcareous mat-
ter (brain-sand) are also found, especially in the pineal gland of man.
The gland is developed from an evagination of the third ventricle, and
it is homologous with the so-called median eye of reptiles.

The functions of the pineal gland are obscure. In cases where its
extirpation has been successfully accomplished (in the fowl), it has been
found that the body growth is stimulated and that the sexual characteris-
tics develop more quickly. This result would seem to indicate that the
clinical observation that tumors of the pineal gland associated in
young boys with abnormal growth of the skeleton and with early
development of the secondary sexual characteristics, depends on the
fact that a new growth produces destruction of the gland with consequent
hypopinealism. The immediate effects of the injection of extract of pineal
gland are not characteristic, consisting merely of a fall in blood pressure,
which is, however, obtainable when an extract of practically any cellular
organ is injected. Prolonged administration of an extract to growing ani-
mals is said to accelerate the growth and to bring about a precocious develop-
ment 'of the sexual organs; but this result is somewhat difficult to inter-
pret, for, as we have just seen, similar changes occur after experimental
removal of the gland. It is stated by McCord and Allen56 that the pig-
ment cells (melanophores) of tadpoles become contracted after pineal
feeding. As the receptors of the reflex governing such color reactions of
various animals are situated in the retina, these investigators give signi-
ficance to their observations by correlating them with the fact that the
pineal gland, as stated above, is the representation of a reptilian eye.

820

THE PINEAL GLAND AND THE GONADS 821

THE GONADS OR GENERATIVE ORGANS

The Generative Glands of the Male

The structures which are responsible for the well-known influence of
the testicles on the development of the male sexual characteristics are
the so-called interstitial cells of Leydig, which consist of polygonal-
shaped epithelial-like cells, with well-marked nuclei and nucleoli. Lipoid
granules, staining black with osmic acid, are also present in the cyto-
plasm. The degree of development of the interstitial cells varies in dif-
ferent animals, being marked in the cat and man and ill-marked' in the
rat and rabbit. In animals which show seasonal changes in sexual activ-
ity, the cells are most prominent between the periods of sexual activity,
when the semeniferous epithelium is less evident. They also become
prominent in cases where the semeniferous epithelium is atrophied,
either as a result of disease or following ligation of the vas deferens done
in such a way that the artery and nerves to the testicles are not included
in the ligature. When the testicle or a portion of it is grafted into
another part of the body, the semeniferous epithelium degenerates, but
the interstitial cells remain alive and become quite prominent. It is
believed that the interstitial cells are responsible for the production of
an autacoid that has to do with the development of accessory sexual
characteristics.

The effects of castration are not significant in animals below the verte-
brata. In all of these, however, they are very pronounced. The cas-
trated male frog fails to show development of the thumb pad, but this
development immediately ensues if portions of testis from another frog
be placed in the dorsal lymph sac. In birds the results are more pro-
nounced; in the castrated male chick the comb, spurs, wattles, etc., fail to
develop, but will usually do so if some testis from another bird is trans-
planted into its tissues. In mammals the effects are most striking in
animals that develop marked male characteristics, such as the growth
of antlers in stags. These fail to develop properly and are prematurely
shed after castration. In man also, as is well-known from a study of
eunuchs, castration has a very profound effect. Hair fails to grow on the
face; the larynx remains undeveloped; the epiphyses are a long time in
ossifying, so that the stature may become great, but at the same time
the limb bones may be more delicate than usual ; the sutures of the skull
are slow in closing ; and the whole architecture of a castrated male comes
to be very like that of the female. Confirmatory evidence of the influ-
ence of the testicles on the development of secondary sexual character-
istics is afforded by the observation that malignant tumors of the testes
in boys are associated with the premature development of the secondary

822 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

sexual characteristics, and that these may recede after the removal of
the tumor.

As a result of castration, interesting changes have also been observed
in other ductless glands. Thus, the suprarenal cortex and the thymus
become enlarged, whereas the thyroid and pituitary become atrophied.
The metabolic functions also become tardy, as is evidenced by a tendency
to the deposition of fat.

When the castration is performed on an adult man, the above changes
in the. sexual characteristics are of course not so evident, although the
prostate, etc., atrophy. The effect on the metabolic functions is, how-
ever, very marked, there being a striking tendency to increased forma-
tion of fat. It is interesting that accompanying this there should usually
occur a lowering of the assimilation limit for carbohydrate, so that glyco-
suria is very readily induced. We can not assume, therefore, as Gush-
ing has done in the case of hypopituitarism, that the fat deposition is
attendant upon an improper combustion of carbohydrate.

These remarkable effects of castration have naturally prompted ob-
servers to study the influence of injection of testicular extract on the
development of sexual characteristics in different animals, but the re-
sults have in general been considered to be of a negative character.

The Female Generative Organs

It is well known that, besides their function in producing ova, the
ovaries also produce autacoids that have to do not only with the fixa-
tion of the embryo in utero, but also with the changes that occur during
pregnancy in the maternal organism. It is however at present uncertain
as to where these autacoids are produced in the ovary. The two most
likely sources are the stroma cells and the corpus luteum. In the stroma
of the ovary of certain animals, groups of cells have been described
having a different appearance from those of ordinary stroma cells.
They have been called the interstitial cells of the ovary, and are believed
to be analogous with the similar structures found in the testicle. It is
possible, however, that these interstitial cells are nothing more than
cells derived from previous corpora lutea. The latter are formed by
proliferation of the follicular epithelium which remains after extrusion
of the ovum, and by the ingrowing into the follicle of the so-called theca
cells and blood vessels. The fully developed corpus luteum in most
animals consists of cells arranged in trabeculae converging toward the
scar which formed at the place where the follicle had burst. The luteal

THE PINEAL GLAND AND THE GONADS 823

cells, as they are called, are characterized by containing considerable
quantities of lipoid material.

That the ovary produces some autacoid is evidenced by both clinical
and experimental observations. Thus, if both ovaries are removed in a
young animal (oophorectomy or spaying), it is well known that not
only does the uterus fail to develop properly, but the external changes
characteristic of puberty in the female fail to materialize, although act-
ually the general effects are not so pronounced as they are in the male
after castration. Menstruation does not set in ; the mammary glands fail
to develop ; and there is a tendency for the hair to grow as in the male.
When the operation is performed in adult life, the changes are not very
pronounced, except that menstruation ceases and the uterus and mam-
mary glands atrophy. Metabolism also becomes altered, causing a
tendency to the deposition of fat, and in the case of the human animal at
least, there is frequently evidence of mental disturbance.

Attempts to acquire more definite information regarding the physio-
logical effects of the ovarian autacoid have recently been made by Schafer
and Itagaki.3 Extracts were prepared from the corpus luteum or Graafian
follicles or from the hilum ovariae, and observations were made on the
effect produced on the behavior of the chief forms of unstriated muscle
by adding the extracts to isolated preparations of uterus or intestine
or by injecting the extracts into animals. Applied to the isolated, prepa-
rations, extract of follicular tissue or of liquor folliculi was found to
increase the force and rate of the rhythmic contractions of the uterus as
well as its tone, whereas inhibition was produced when extract of the
hilum was used. Extract of corpus luteum, when injected into the
veins, was found to cause the uterus to increase its contraction or if
quiescent to begin contracting. It was further noted that extracts of the
hilum caused a fall in arterial blood pressure, whereas those of the corpus
luteum had little or no effect. It would appear from these observations
that the extracts contain two different autacoids, one having a hormonic
and the other a chalonic action on plain muscular fiber.

Extract of corpus luteum when intravenously injected also stimulates
the outpouring of the milk from the mammary glands, although not so
markedly so as extract of pituitary gland. This pituitary-like action is
not obtained with extracts of ovary that do not contain corpora lutea.
Besides being concerned in the outpouring of milk, corpus luteum has
also been shown to be related in some way to the development of the
mammary gland during pregnancy. These glands become developed in
young virgin rabbits after the continuous administration for a month
or so of extract of corpus luteum, and they also develop in unimpreg-

824 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

nated animals when the corpus luteum is made to develop by artificial
means such as puncturing the Graafian follicle. Furthermore, destruc-
tion of the corpora lutea in a pregnant rabbit arrests development of
the mammary glands. The corpus luteum has also an important func-
tion in connection with the formation of the uterine decidua and the
fixation of the embryo. Thus, after destruction of the corpus luteum at
an early period in pregnancy, the embryo fails to become adherent to
the uterus.

THE THYMUS*

The structure of the thymus is of a lymphoid nature consisting of a
cortex composed of closely packed masses of lymphocytes and a medulla
made up of a cellular reticulum, in the meshes of which are seen large
bodies possessing a concentric configuration — the corpuscles of Hassel.
The gland is developed £rom outgrowths of the third branchial pouch
on either side, which, meeting in the midline, unite to form a solid block
of cells, this later, becoming hollowed out and branched. In the walls of
the tubules, so formed, lymph nodes appear which ultimately form the
cortex. The walls of the tubules themselves break up, their cellular
elements subsequently forming the reticulum and concentric corpuscles
of the medulla. Though prominent in early childhood the thymus un-
dergoes progressive involution with advancing years, until in adult life
it is more or less vestigial in character. It is still a question whether this
body should be included with the organs of internal secretion, and though
many views, mostly of a more or less speculative nature, have been ad-
vanced to justify its consideration as an endocrine organ, the proof that
it possesses an internal secretion, in the generally accepted sense, is
wanting. It is wiser perhaps to state that its functions are obscure, and
that we do not know what role it plays in the animal economy. The re-
sults of feeding the gland to animals or of ablation experiments are con-
flicting and of little help in arriving at any conclusion in this regard.
Attention, however, should be drawn to certain significant facts regarding
its behavior. First, its involution is arrested or retarded after castration,
a fact suggestive of an endocrine function ; secondly, it is believed to be a
source of the lymphocytes, and possibly also of the granular leucocytes.
Examinations of the blood, with a view to the lymphocytic counts, show,
from infancy to puberty, a declining curve, the gradient of which follows
closely that of thymic involution. On this account it is believed by some
that "the thymus functions as a lymphoid organ in infancy and child-
hood when a large number of lymphoid cells and leucocytes are needed
to combat infection." (Hoskins, E. R.).

*For a review of the literature, the reader is directed to a recent article by Blatz.57

THE PINEAL GLAND AND THE GONADS 825

DUCTLESS GLANDS REFERENCES

(Monographs)

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3Schafer, Sir E. A.: The Endocrine Organs, Longman's, Green & Co., New York and
London, 1916.

(Original Papers)

^Guthrie, L., and Emery, W. d' E. : Trans. Clin. Soc., London, 1907, xl, 175; also Bul-
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i2Addis, T., Barnett, G. D., and Shevky, A. E.: Am. Jour. Physiol., 1918, xlvi, 39.
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islloskins, R. G.: Am. Jour. Physiol., 1912, xxix, 363.
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417.
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513.
isGruber, C. M.r and Fellows, A. P.: Am. Jour. Physiol., 1918, xlvi, 472; and Gruber,

C. M.: ibid., 1914, xxxiii, 335; Gruber, C. M., and Kretschmer, O. S.: ibid.,

1918, xlvii, 179.
is>Stewart, G. N., and Rogoff, J. M.: Jour. Lab. and Clin. Med., 1918, iii, 209. See

full bibliography by Rogoff in this paper.
2oElliott, T. R. : Jour. Physiol., 1912, xliv, 374.

2iSte-wart, G. N.: Jour. Exper. Med., 1911, xiv, 377; ibid., 1912, xv, 547; ibid., xvi, 502.
22Meltzer, S. J.: Deutsch. Med. Wchnschr., 1909, xiii.
2-Stewart, G. N. : Rogoff, J. M., and Gibson, F. S. : Jour. Pharm. and Exper. Therap.,

1916, viii, 205.

24Hoskins, R. G., and McClure, C. W.: Arch. Int. Med., 1912, x, 343.
25Stewart, G. N.: Jour. Exper. Med., 1911, xiv, 377.
26Cannon, W. B., et al: Am. Jour. Physiol., 1911, xviii, 64; ibid., 1914, xxxiii, 356; also

Bodily Changes in Pain, Hunger, Fear and Rage, D. Appleton & Co., 1915.
27Stewart, G. N., and Rogoff, J. M. : Jour. Exper. Med., 1917, xxvi, 637 ; Jour. Pharm.

and Exper. Therap., 1917, x, 49; Am. Jour. Physiol., 1917, xliv, 543.
2«Stewart, G. N., and Rogoff, J. M.: Am. Jour. Pliysiol., 1920, li, 366.
29Cannon, W. B.: Am. Jour. Physiol., 1919, 1, 399.
soLevy, A. G. : Heart, 1913, iv, 342.

siGasser, H. S., and Meek. W. J.: Am. Jour. Physiol., 1914, xxxiv, 63.
s^Redfield, A. C.: Jour. Exper. Zool., 1918, xxvi, 275.
ssCannon, W. B., and Cattell, McK.: Am. Jour. Physiol., 1916, xli, 74.
s^Macleod, J. J. R., and Pearce, R. G.: Am. Jour. Physiol., 1912, xxix, 419
3sMarine, D. : Personal communication.
seMarine, D. : Jour. Exper. Med., 1914, xix, 89.
37Marine, D., and Lenhart, C. H. : Jour. Exper. Med., 1910, xii, 211; ibid., 1911, xiii,

455; also Bull. Johns Hopkins Hosp., 1910, xxi, 95.
38Kendall, E. C. : Boston Med. and Surg. Jour., 1916, clxxv, 557; also Proc. Am.

Phys. Soc., 1918, xliv.

soMarine, D., and Kimball, O. P.: Jour. Lab. and Clin. Med., 1917, iii, 41.
4oGudernatsch, J. F.: Am. Jour. Anat., 1913, xv, 431.

4iRogoff, J. M., and Marine, D. : Jour. Pharm. and Exper. Therap., 1916, ix, 57.
42Kendall: Endverin, 1918, ii, 81; ibid., 1919, 3, 156.

Also Plummer, H. S-: Am. Jour. Physiol., 1918, Proc. Am. Soc. Phys., 1918.

826 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

43Marine, D., and Lenhart, C. H.: Arch. Int. Med., 1911, viii, 265.

44Wilson, L. B.: Am. Jour. Med. Soc., 1916, elii, 799; ibid., 1913, cxlvi, 731; also

Wilson, L. B., and Durante, L. : Jour. Med. Besearch, 1916, xxxiv, 273.
4-r.paton, Noel, and Finlay, J.: Quart. Jour. Exper. Physio!., 1917, x, 203; also Paton,

Noel, Finlay, J., and Watson, A.: Ibid., 233, 243, 315 and 377.
46MacCallum, W. G., etc.: Jour. Exper. Med., 1909, xi, 118; ibid., 1913, xviii, 646; Jour.

Pharm. and Exper. Therap., 1911, ii, 421.

47Howland, J., and Marriott, W. McK.: Bull. Johns Hopkins Hosp., 1918, xxix, 235.
48Cushing, Harvey: Pituitary Body and Its Disorders, J. B. Lippincott Co., 1912.
49Horsley, V.: Brit. Med. Jour., 1885, i, 111.
soKobertson, Brailsford, and Bay, L. A.: Jour. Biol. Chem., 1916, xxiv, 347, 363, 385,

397, 409.

01 Clark, L. N.: Jour. Biol. Chem., 1915, xxii, 485.
ssCow, D.: Jour. Physiol., 1914, xlviii, 443.
ssMaxwell, A. L. J.: Jour. Physiol., 1915, xlix, 483.
5*Abel, J. J., and Kuboto, S.: Jour. Pharm. and Exper. Therap., 1919, xiii, 243. See

also Cow, D.: ibid., 1919, xiv, 275; and Dudley: ibid., 1919, xiv, 295.
soHerring, P. T.: Quart. Jour. Exper. Physiol., 1914, viii, 267.
seMcCord, C. P., and Allen, F. P.: Jour. Exper. Zool., xxiii, 207.
"Blatz, W. E.: Jour. Lab. and Clin. Med., 1919, v, 3.
ssKnowlton, J. P., and Silverman, A. C. : Am. Jour. Physiol., 1918, xlvii, 1.

PART IX

THE CENTRAL NERVOUS SYSTEM AND THE CONTROL
OF MUSCULAR ACTIVITY

(Contributed by A. C. REDFLELD)

CHAPTER LXXXIX
THE EVOLUTION OF THE NEUROMUSCULAR MECHANISM

Disease of the nervous system confronts the physician with a complex
group of symptoms, a syndrome due to more or less sharply localized
disturbances in its function. The province of physiology is to analyze
the fundamental activities of the nervous system and assign to various
parts a functional significance, so that the complicated picture presented
by disease may be recognized as the logical result of a lesion of definite
nature, location, and extent. Thus we find the symptoms or nervous dis-
ease grouping themselves as disturbances (1) of sensation (anesthesia,
etc.) (2) of movement, both volitional and reflex (paralysis, etc.) (3)
of postural coordination (muscular spasms and flaccidity, ataxia, etc.)
(4) of the mechanisms of integration in the nervous system including the
higher mental functions of association, memory, and attention, etc.

Corresponding to each of these groups we can recognize a definite as-
pect of nervous activity, the successful performance of which depends
on the continuity of more or less precisely known groups of cells within
the nervous system, and disturbances of any of these aspects can be as-
signed to lesions affecting some part of the group of nerve cells on which
they depend.

The fundamental function of the nervous system is to correlate the
activities of the body so that its many parts may act harmoniously and
as a unit in preserving the welfare of the individual. What the basis
of this integration of activity which manifests itself so remarkably in
the behavior of the higher animals, is, can best be illustrated by a consid-
eration of its evolutionary development.

Primitive Neuromuscular Mechanisms

In the unicellular organisms three processes occur when a response is
brought about by a stimulus. These are (1) excitation, or the. setting up
of a physiological disturbance; (2) conduction, or the spread of the dis-

827

828 CENTRAL NERVOUS SYSTEM

turbance to parts of the cell remote from the point of excitation; and (3)
response on the part of the protoplasm to which the disturbance has spread.
Thus when a paramecium swims against a hard object, an excitation is set
up by the contact at its anterior end ; the disturbance so produced spreads
to other parts of the cell and causes the reversal of the direction of the
stroke of the cilia in relatively remote regions, with the result that the
paramecium backs away from the obstacle, and then starts off in another
direction. The three fundamental processes of excitation, conduction, and
response occur whenever the neuromuscular system of an animal is brought
into play. The case of multicellular animals differs from that cited above
only in that the conduction is intercellular, so that the disturbance set up by
an excitation spreads from one cell to another.

There exist in multicellular animals many examples of cells independent
of the influence of nervous tissue which respond directly to stimuli.
These are known as independent effectors. The most primitive muscle cells
known are those which close the terminal pores of sponges, thus regulating
the flow of water through these animals. Parker1 has shown that these
muscles respond to a variety of stimuli in spite of the fact that no nerve
cells can be found in association with them. Ciliated epithelial cells, such
as occur in certain ducts and passageways in man are also independent ef-
fectors, acting independently of nervous control. The ameboid white blood
corpuscles also must be quite comparable in their mechanisms of response
to the protozoa.

The forerunning of nervous conduction is seen in the activities of these
independent effectors. If a field of ciliated epithelium is examined micro-
scopically, it is found that the cilia are not beating in a disorderly way, but
that definite waves are passing across the field, each cilium beating a mo-
ment later than the preceding one. The appearance is quite like that pro-
duced by gusts of wind sweeping across a field of grain. In the sponges,
also, a stimulus applied several centimeters from the terminal pore will
cause its muscles to contract in spite of the absence of nervous tissue con-
necting the muscles with the point of stimulation. This type of intercel-
lular conduction by nonnervous tissue is called neuroid transmission. It
illustrates the significant fact that conductivity is not a specific property
of nervous tissue, but is displayed by many other tissues as well.

Nervous tissue makes its first appearance in the Coelenterates (Fig.
203). A most primitive condition is found in the tentacles which sur-
round the mouth of the sea anemone. At the base of certain epithelial
cells fibrous processes are developed which connect with underlying mus-

EVOLUTION OF THE NEUROMUSCULAR MECHANISM

829

cles. The epithelial cell serves as a receptor for stimuli, and transmits
the disturbances set up by them to the muscle or effector. Such a mecha-
nism is called a receptor-effector system. The responses which it brings
about are purely local, since there is no provision for conducting the
disturbance to remote parts of the animal, but the introduction of the
receptor serves a valuable purpose in increasing the sensitivity of the
system. Moreover, the arrangement is adequate for the purpose for

i>

Fig. 203. — The evolution of the nervous system. A, the independent effector as illustrated by
the muscle cells of the sponge; B, a receptor-effector system such as occurs in the tentacles of sea
anemones; C, the neuromuscular mechanism of the trunk of the sea anemone, in which a network
of nerve cells is interposed between receptor and effector; D, the nerve net surrounding a small
blood vessel of the frog; E, the nervous system of the earthworm, illustrating a typical reflex arc
and the occurrence of association neurons; a, within the ganglion; r, receptor; nn, nerve net; an,
afferent neuron; en, efferent neuron. (Modified after Parker, Prentiss and Bayliss.)

which it is employed, which is to cause the tentacle to bend toward a
particle of food situated between it and the mouth, so that the currents
set up by the cilia with which the tentacle is covered may sweep the food
into the mouth. An arrangement not remotely analagous to the receptor
effector system of the Coelenterates is found in the case of man in the axon
reflexes by which local vasodilation is produced as the result of a local
irritation of the skin (page 898).

830 CENTRAL NERVOUS SYSTEM

The Nerve Net

In the trunk of the sea anemone nervous tissue assumes a much more
important role. Between the receptors of the epithelium and the muscles
there is interposed a layer of nerve cells arranged as a network. This
network can transmit disturbances set up in the receptors to quite dis-
tant muscles, with the result that a local stimulus may bring about a gen-
eralized contraction of the trunk. The primitive nervous system is thus
seen to consist of a network of nerve cells or nerve net. Its charac-
teristic consists in the fact that the nerve cells are joined together by
continuous fibers so that the structure is essentially a syncytium. No
cell membranes can be distinguished separating the fibers of the constit-
uent nerve cells. The result of this structure is that nerve impulses set
up in one region can spread at random to all parts of the nerve net. The
responses produced by such a mechanism are necessarily diffuse in char-
acter, since large groups of muscles will be brought into play at one time.
Since conduction is not limited to definite paths in the nerve net, local in-
jury will have little effect on the reactions of the organism because the
nerve impulses can pass around the injured region through other parts
of the nervous network. The rapidity with which impulses are conducted
by the nerve net is not great, being only 146 centimeters a second, or about
two hundred times less than the velocity of the nerve impulse in the motor
nerves of the frog.

The nerve net is retained in many parts of the higher animals. Wher-
ever it occurs it is usually very closely associated with the muscles which
it innervates. The most important nerve net in man is found in the
intestine (myenteric plexus). In this structure an important modifica-
tion in behavior has developed. While the reactions of the intestine
maintain the sluggish, diffuse character seen in the coelenterates, con-
duction no longer proceeds as readily in all directions. Excitation pro-
duces a contraction of the muscles above the point stimulated and relax-
ation below it (the myenteric reflex page 501). Waves of contraction
travel along the intestine usually only in one direction, from pyloric end
downward. The nerve net has developed a definite polarity, a property
which is fundamental in the central nervous system of the higher animals.

The Central Nervous System

A typical central nervous system appears in simple form in the seg-
mented worms. The nerve cells of which it is composed do not form
a syncytium, as in the nerve net, but are separated from one another at
the points at which their fibers meet by a specialized structure called
a synapse. A definite membrane may be seen at this point separating
the protoplasm of one fiber from that of the other. The nerve cell con-

EVOLUTION OF THE NEUROMUSCULAR MECHANISM

831

sequently acquires a certain individuality, and can become specialized for
special kinds of activity, and is called a neuron. The neuron is the fund-
amental unit of structure and function in the central nervous system. It
consists typically of a nerve cell body containing the nucleus, from which
extend numerous short fibers, or dendrites, and one long fiber, or axon.
The axon may be branched, such branches being called collaterals.

Fig. 204. — Normal cell from the anterior horn, stained to show Nissl's granules. a, the axon.

(From Howell.)

The arrangement of neurons in the central nervous system of the
worms is characteristic. Most of the nerve cell bodies are collected to-
gether in centrally located masses or ganglia. Fibers pass from the
receptors in the epithelium to the ganglion of the same segment in defi-
nite nerve trunks, while other fibers originating from nerve cell bodies
within the ganglion pass in other trunks to the muscles. In addition

832

CENTRAL NERVOUS SYSTEM

fibers pass from one ganglion to the next in trunks known as intergan-
glionic connectives.

In order that a muscular response may result from a stimulus applied
to the skin of a worm, a disturbance must pass through the following
structures: (1) the receptor with its afferent fiber, (2) a motor neuron
with its efferent fiber, to (3) the muscle (or other effector). This group
of structures is called a reflex arc. It is the simplest anatomical arrange-
ment in the central nervous system, capable of bringing about a signi-

Fig. 205. — Arborization of collaterals from the posterior root fibers around the cells of the
posterior horn. A, ascending fiber in posterior columns; B, collaterals; C, cells of posterior hor/i;
E, synapses. (From Ramon y Cajal.)

ficant motor response. The activity produced by such a mechanism is
called a reflex.

The reflex arc as we have described it lies frequently within a single seg-
ment of the worm. Consequently it can provide each segment with a
great degree of autonomy, so that many of its activities are undisturbed
by the removal of other parts of the animal. No provision is made by
such an arrangement for correlating the activities af adjacent segments.
The ganglia of worms contain, as a matter of fact, an additional type
of neuron which makes the correlation of the activities of different seg-
ments possible. These are neurons which lie entirely within the central
nervous system. Their axons lie in the interganglionic connectives and

EVOLUTION OF THE NEUROMUSCULAR MECHANISM

833

Fig. 206. — Part of an anterior cornual cell from the calf's spinal cord, stained to show neurofibrils.
ax, axon; a, b, c, dendrites. (From Bethe.)

Fig. 207. — Schema of simple reflex arc; r, receptor in an epithelial membrane; a, afferent fiber; s,
synapses; c, nerve cell of motor neuron; c, efferent fiber; tn, effector organ.

834

CENTRAL NERVOUS SYSTEM

serve to connect afferent fibers in one segment with motor neurons in some
distant segment. They are called association neurons because they asso-
ciate the activities of remote parts of the body.

The fundamental characteristics of the central nervous
system as it appears in the worms consists in (1) the
individuality of the component nerve cells and their
specialization for certain functions, (2) the arrangement
of the neurons in such a way that the impulses must
pass over definite paths or reflex arcs in order to reach
an effector, (3) the introduction of neurons specialized
to associate the activities of reflex arcs in remote parts
of the body, and (4) the segregation of the greater part
of the nervous tissue into a centrally located chain of
ganglia, from which fibers pass to peripheral structures
in definite nerve trunks. These characteristics persist
in the central nervous system in the higher animals, in-
cluding man.

Certain modifications of the simple arrangement found
in the worms have been introduced into the nervous sys-
tem as the motor activities of organisms became more
precise and complex. Of minor importance may be men-
tioned the introduction of an afferent nerve cell distinct
from the receptor between the latter and the central
g<mglionic mass, (see the Evolution of Receptors page
854) and the introduction of an outlying neuron between
the termination of the primary motor neuron and the
effector organ (see the autonomic system page 894). Of
far greater importance is the great increase in the num-
ber of association neurons which become the salient fea-
ture of the vertebrate nervous system. In the worms the
inter-ganglionic connectives are scarcely more bulky
than the peripheral nerves from a single ganglion,
whereas in the central nervous system of man the num-
ber of the fibers extending from segment to segment ex-
ceeds by many times the number of fibers in any single
pair of spinal nerves. This increase in the mass of the
central portion of the nervous system is not distributed
equally in all parts, but tends to concentrate itself par-
ticularly at the anterior end. Even in the worms the most
anterior ganglion, the supraesophageal ganglion, is larger than the others,
while this tendency finds its culmination in the great bulk of the brain in
man. This condition is obviously correlated with the development

Fig. 208.— Dia-
gram of nervous
system of seg-
mented inverte-
brate; a, supra-
esophageal g a n-
glion; b, subeso-
phageal ganglion;
oe, esophagus or
gullet.

EVOLUTION OF THE NEUKOMUSCULAR MECHANISM 835

of special sense organs at the anterior end of the animal: the sense
of taste at the mouth, the tactile organs found on the tentacles which
adorn the head of many invertebrates, and of special receptors for stim-
uli originating at a distance, such as the eye and ear. The development
of association neurons for the correlation of activities initiated by the
stimulation of these receptors has made this portion of the central nervous
system the natural place for the seat of the higher mental functions as
they evolved.

CHAPTER XC

THE CONDUCTION OP THE NERVOUS IMPULSE

We have seen that the activity of the neuromuscular mechanism in-
volves the three processes of excitation, conduction, and response. These
processes may be regarded as fundamental properties of protoplasm
which may all be exhibited by a single cell. The evolution of the cen-
tral nervous system is the history of a gradual specialization of cells
each for the execution of one of these processes. Thus in a reflex arc
the receptor is a cell primarily fitted to react to slight changes in its
environment, the neurons are especially adapted to the conduction of im-
pulses, and the effector is constructed for the sole purpose of carrying
out some motor response or producing some specialized secretion. It
would appear as though a single cell could not develop the ability to
perform all of these functions with perfection and as a consequence a
high degree of division of labor has been established.

It should be remembered, however, that this specialization for one
process has deprived the cells to only a limited degree of the ability
to be the seat of the other processes. Thus although excitability is pri-
marily a property of the receptors, nerve cells must also retain the abil-
ity to become excited by disturbances set up in the receptors, and muscles,
must be able to be excited by impulses reaching them from motor neurons
Similarly conduction must occur not only in nerve cells, but in receptors,
so that a disturbance set up at the distal end of the receptor cell may
reach the nerve fibers which terminate about its proximal end. Muscle
cells also must be able to conduct disturbances set up in the myoneural
junction to all parts of the muscle fiber, so that they may contribute to
the response. It has been seen that the conductivity of the cardiac mus-
cle is of great importance in the co-ordination of the action of the heart
(page 182). Even contractility which would appear at first sight to be a
function of the effector alone is displayed occasionally by the other parts
of the reflex arc. Thus embryonic nerve fibers have been observed to
perform ameboid movements and the rods and cones of the retina, which
are the receptors of light, become shorter or longer in response to changes
in illumination.

While excitation, conduction, and response are seen to occur in all
parts of the reflex arc, when we come to study these processes it is con-
venient to examine each in that tissue in which it is most highly developed
and where the other processes will introduce a minimal complicating ele-

836

THE CONDUCTION OF THE NERVOUS IMPULSE 837

ment. Thus excitation is best considered in connection with the recep-
tors and a consideration of it may be postponed until we are ready to
take up the aspect of central nervous activity which leads to sensation
and the phenomenon of consciousness. Response must be studied in mus-
cular tissue and its treatment may be put off until we have seen what
the nervous mechanism initiating muscular activity consists of. Con-
ductivity is readily studied in nerve, and since this process forms the
base of all nervous activity, it must be treated before the study of the
activity of the nervous system as a whole can be undertaken.

Conduction in the Nerve Fiber

When a nerve fiber supplying a muscle is stimulated, the response of
the muscle is so prompt that for many years physiologists despaired of
determining the rate at which the nerve impulse traveled along the
nerve. Helmholtz succeeded, however, in devising a simple method by
which the velocity of the impulse could be measured and found that
in the sciatic nerve of the frog the rate of propagation was about 30
meters a second. Later determinations have shown that in the nerves
of man the velocity of the impulses is three or four times as great, a dif-
ference which may be attributed to the higher temperature of the human
body. It is seen from this that very little time is lost in the transmission
of impulses along nerve trunks, and rapid responses to stimulation are
thus insured. Although nerve fibers are closely bound together within a
nerve trunk, impulses cannot spread in a lateral direction from one fiber
to its neighbor. Consequently if a branch of the lumbar plexus is stim-
ulated, contraction occurs in a more limited group of muscles than if
the nerve trunk is stimulated below the junction of the various parts
of the plexus. The response of muscles to the artificial stimulation of
a nerve trunk also differs in its distribution from responses induced
reflexly or volitionally. These facts show that the constituent fibers
of a nerve trunk are completely isolated from one another.
. Within the single nerve fiber nervous impulses may travel in either
direction along its length irrespective of the direction in which con-
duction normally takes place. Thus if a collateral of a motor neuron
is stimulated close to its termination in a muscle, the impulse will travel
up the collateral to its point of junction with a second collateral, and
down the latter to cause a contraction of the muscles which this in-
nervates. The polarity which is such an important feature of the activ-
ity of the reflex arc as a whole is not exhibited by the conduction within
a single neuron, which thus preserves one of the fundamental proper-
ties of the primitive nerve net,

The All or None Nature of Conduction. — Activity cannot occur in the
body without the expenditure of energy. It is pertinent to inquire what

838 CENTRAL NERVOUS SYSTEM

is the source of the energy expended in the conduction of a nerve im-
pulse. It was perhaps natural for physiologists to assume that this
energy was derived from the stimulus, much as the energy of a pro-
jectile is derived from an explosion. That this is not true has been
shown by important experiments by Adrian.2'3 The intangible nature
of the nerve impulse makes a measurement of its strength difficult. One
cannot use the muscular contraction produced by it as a measure of
its strength, because the degree of muscular response will be determined
by the number of nerve fibers brought into action as well as by any
variation which may occur in the intensity of the nerve impulse. Adrian
chose as a criterion of the strength of the nerve impulse its ability
to traverse a region of nerve fiber in which conduction had been rendered
difficult by the application of a narcotic. Whether a nerve impulse
can emerge from such a region depends on the distance which the im-
pulse must travel before coming to the normal part of the fiber. This
indicates that in passing through the narcotized area the impulse becomes
weaker and weaker, and if it fails to emerge in time it may become
completely extinguished. If the nerve impulse derives its energy from
the stimulus, it should be impossible for it to regain its strength after
dissipating its energy in a region in which conduction is difficult. This
point can be tested by passing the impulse through two equal narcotized
areas separated by a region of normal nerve. If the length of each of
these areas be not quite great enough to extinguish an impulse, but if
their combined length be sufficient for this purpose, and if no recovery
occurs in the intervening region of normal tissue, then the impulse
will be unable to pass through both areas. In passing the first area
the intensity will be reduced in part; on passing through the normal
region there will be no recovery, and in the second area of narcosis, the
strength of the impulse will be reduced to extinction. As a matter of
fact Adrian found that the nerve impulse does not behave in this man-
ner. Impulses which would be completely extinguished by a given area
of narcosis could pass through two areas one half as long if these were
separated by a short length of normal tissue. In passing through the
normal tissue the strength of the impulse recovered so that it was as
great on entering the second region as it was when it came to the first,
and consequently it was able to pass through one as well as the other
(Fig. 209).

From this observation several important conclusions can be drawn. The
energy of the nerve impulse is derived not from the stimulus, but from
the nervous tissue through which it is passing. Consequently the strength
of the impulse depends on the condition of the tissue, and it will vary
only as the condition of the tissue varies. If a nerve conducts an im-
pulse at all, it will be of the maximum strength possible for the con-

THE CONDUCTION OP THE NERVOUS IMPULSE

839

ditioii of the nerve at that time. This conception is known as the all
or none law of conduction, because the tissue acts with all its power or
none at all. It is quite comparable to the all or none action of cardiac
muscle with which we have already become familiar (page 177).

The importance of the conclusion that the energy of the nerve im-
pulse is derived from the nerve fiber itself is this. No matter in how
complex a fashion a neuron may be subdiveded into collaterals or den-
drites an impulse set up in it may pass with undimiiiished intensity along
each of these subdivisions. Since each collateral may be united with
other neurons, the impulse may spread from the one neuron to several
others without becoming attenuated by the multiplicity of the paths

A

B

r

n n

Fig. 209. — Diagram illustrating the effect of areas of narcosis (n) on the strength of the nerve
impulse. A indicates the gradual decline in the strength of the impulse as it penetrates an area
just long enough to cause its complete extinction. B and C illustrate the two possible results of
sending an impulse through two shorter areas, separated by a length of normal nerve. If no re-
covery occurs in the normal tissue, the impulse may be extinguished in the second narcotized area,
as B indicates. If recovery occurs in this area, the impulse may reach the muscle in undiminished
strength. Adrain showed the latter alternative to be true.

in which it is traveling. Hence the conception of the older physiology
of the presence of special reinforcement centers in the central nervous
system for the purpose of reinforcing the strength of the impulse as it
spreads may be dispensed with, since every part of every nerve fiber
contributes the energy necessary to keep the impulse going as it travels
along.

The Refractory Period. — Although the nerve impulses induced by ar-
tificial stimulation may be momentary in duration the activity* of the
reflex arc brought about by normal conditions in life is usually main-
tained for some time in order to achieve continuous contraction of the

840

CENTRAL NERVOUS SYSTEM

appropriate groups of muscles. Such continuous activity on the part
of nerve cells might be due to either (1) the passage of a series of dis-
tinct impulses along the nerve fiber, or (2) to a continuously main-
tained activity. Experiment has shown that the first conception is the
correct one. Two impulses set up in rapid succession in the nerve
fibers of a nerve muscle preparation from the frog may cause a greater
contraction in the muscle than a single impulse. If the interval between
these stimuli is decreased to less than 0.0025 of a second the effect due
to the second stimulus disappears and it has evidently failed to initi-
"ate a second nerve impulse. This result occurs whether the two stimuli
are applied to the same, or to different parts of the nerve fiber, showing
that it is not due to the impossibility of setting up the process of ex-

100

50

•01 -02

Time since previous stimulus (seconds)

03

Fig. 210. — The recovery of excitability in the nerve fiber after the passage of a nerve impulse.
After a brief time in which no second excitation is effective, the excitability gradually returns to
normal, and then becomes temporarily greater than normal. The changes in conductivity following
the passage of a nerve impulse over the nerve follow a similar course. (From Adrain and lyucas.)

citation in one place twice in such rapid succession, but that the nerve
fiber is incapable of conducting a second nerve impulse until a sufficient
period of recovery has intervened. Moreover by cooling the nerve be-
tween the point of stimulation and the muscle, without affecting the
temperature at which the process of excitation occurs, the period of
recovery may be increased three fold, because at a low temperature it
takes longer for the nerve fiber to regain its power to conduct an im-
pulse. This period of recovery during which a second impulse cannot
pass along a nerve fiber is called the refractory period of conduction. It
is quite analogous to the refractory period which occurs in the heart
(page 179) and like it imparts certain, characteristics to the tissue in
which it occurs.

THE CONDUCTION OF THE NERVOUS IMPULSE 841

Because of the refractory period the continuous activity of nerve must
consist of a series of nerve impulses occurring at brief intervals. Nerv-
ous discharge consequently has a discontinuous or rhythmic character.
The actual rate of this rhythm has not been determined precisely for
the voluntary movements of man, but the length of the refractory period,
which is shorter in the nerves of warm-blooded animals than in the frog,
renders it unlikely that it is greater than 3000 impulses per second, while
certain experiments indicate that it is at least 300 impulses per second.
The nerve fiber has been found to be unfatigued even by continuous stim-
ulation for twenty-four hours, a fact which is explained by the discovery
that the nerve will not conduct an impulse until it has recovered from
the fatiguing effects of the preceding impulse. The rhythmic character
of nervous activity also suggests a way in which' nerve impulses set up
by different stimuli may differ from one another and consequently bring
about different reactions. Although the all-or-none law of conduction may
preclude the possibility of nerve impulses differing in strength or inten-
sity, there is no reason why the rate at which impulses follow one another
in normal nervous activity may not vary greatly, and this difference may
be a determining factor in the spread of the impulses through the spinal
cord and brain.

Conduction between Neurons

So far conduction has been considered only with regard to the spread
of a nerve impulse through a single nerve cell. In passing from one
neuron to another the nerve impulse must pass through the synapse
which is the structure uniting their respective fibers. The presence of
synapses in the path of conduction imposes certain characteristics on
the activities of the reflex arc which do not appear in conduction within
a single nerve fiber. The key to an understanding of reflex activity and
the higher mental processes by which reflex acts are controlled undoubt-
edly lies in the physiology of the synapse.

The Polarity of the Reflex Arc. — In nerve fibers it has been seen that
impulses may spread in either direction along the axon. In the reflex
arc as a whole the passage of the impulse is in one direction only, from
the receptor to the effector organ, because a nerve impulse can pass in
one direction only through the synapse, which acts as a valve to prevent
impulses passing back in the opposite direction. This fact is demon-
strated by the classic experiments of Bell and Magendie, who found
that no muscular response followed stimulating the central end of the
cut ventral root of a spinal nerve. The motor neurons whose axons
compose the ventral root can transmit impulses only to the muscles
which they innervate, and in this experiment they were separated by
the operation from the point of stimulation. That impulses do not

842 CENTRAL NERVOUS SYSTEM

spread backward from the motor neurons to the afferent neurons can be
demonstrated by attaching a galvanometer to the afferent nerve, when
it will be seen that no action current is set up in the afferent neuron
if the stump of the ventral root is stimulated. Impulses set up in
these fibers can not pass to other neurons within the spinal cord, be-
cause the synapses will not allow them to spread in that direction.

Thus it is seen that the polarity which is characteristic of the central
nervous system is imposed upon it by the synapse. In the primitive
nerve net, in which synapses can not be demonstrated, polarity does
not exist.

Resistance to Conduction due to Synapse. — The synapse is also a re-
gion which offers some resistance to the passage of the nerve impulse
and may, prevent its passage altogether. It is usually impossible to
cause reflex response by applying a single induction shock to a sensory
nerve, although the stimulus may be quite strong enough to excite a nerve
muscle preparation. Not until the stimulus is repeated several times,
setting up a series of nerve impulses, will the resistance of the synapses
in the reflex arc be overcome so that an impulse can pass through to the
muscle.

The synapses in which the collaterals of a single neuron terminate
differ considerably in the resistance which they offer to the passage of
the nerve impulse. If a series of weak stimuli are applied to the foot
of a frog from which the brain has been removed a flexion of the leg
may be induced. If the stimulus is increased in strength movements
of the opposite leg will occur, while still stronger stimuli will cause the
excitation to spread to the muscles of the trunk and forelimbs. This
observation indicates that the impulses set up by a weak stimulus can pass
only through those synapses which connect the afferent neurons with
the motor neurons of the same limb, while stronger stimuli are required
to set up impulses which can pass to the synapses leading to the motor
paths -to more remote muscles. This graded synaptic resistance is con-
sequently an important mechanism in determining what paths an im-
pulse shall follow in its course through the greatly branching systems
of nerve fibers which occur in the nervous system.

Summation in Reflex Conduction. — The resistance presented to the
passage of the impulse by the synapse suggested to Lucas that con-
duction in a synapse is comparable to 'that in a narcotized area of nerve.
A second point of resemblance is that the impulse travels slower through
both synapse and through a length of nerve treated with alcohol. lie
consequently studied with care the conditions of conduction through
narcotized nerve and discovered several facts which are of value in
understanding the peculiarities which the synapses give to reflex conduc-
tion. If an area of narcosis is just deep enough to check the passage

THE CONDUCTION OF THE NERVOUS IMPULSE 843

of a single nerve impulse, it is found that a second impulse can pass
through it, provided it is produced immediately after the termina-
tion of the refractory period. For a short interval after the passage
of one impulse into a region in which conduction is difficult the nar-
cotized nerve becomes better able to conduct a second impulse. The
effects of two impulses added together is thus able to produce a re-
sponse which a single impulse alone cannot accomplish. This phenom-
enon is known as summation in conduction. Such summation is a
characteristic of reflex conduction, as we have seen in the experiment
in which stimulation with an induction shock fails to bring about a
reflex act unless it is repeated several times. In some cases as many
as 40 or 50 stimuli must be applied before reflexes are established.

Two characteristic phenomena of reflex conduction closely related
to summation which may be explained on the assumption that one im-
pulse can alter the ease with which a second impulse can overcome
the resistance at the synapse are Induction and Facilitation.

Induction is the production of a reflex response by the application to
different afferent nerves of two stimuli each of which alone is incapable
of setting up impulses which can break through the resistance of the
reflex arc. Induction may occur when the stimuli are applied at the
same time or when one stimulus is commenced after the other has been
discontinued. Facilitation resembles induction except that the stimuli
are each capable of producing the response when applied independently.
Their combined effect is to produce a greater response than either can
elicit when acting alone.

The underlying assumption in these cases is that the afferent paths
over which the impulses travel in to the nervous system impinge upon
a common motor path in the synapses of which summation in conduction
occurs.

Inhibition. — In studying the heart we have seen that nerve impulses
traveling over the vagi may depress or inhibit the action of the cardiac
muscle. Inhibition is also an important process in the action of the
central nervous system, and is of great importance because when cer-
tain groups of muscles are made to contract the activity of opposing
groups must be depressed in order that movement may be made without
opposition. Coordination in the nervous system depends on the in-
hibition of certain reflex activities in order that other reactions may
be carried out without confusion. Certain forms of inhibition can be
explained by considerations quite similar to those employed in the ex-
planation of summation. We have seen that immediately after the pas-
sage of a nerve impulse along a nerve a period occurs during which
a second impulse cannot be conducted by the nerve fiber. This is the
refractory period of conduction. Later still there is a period during

844 CENTRAL NERVOUS SYSTEM

which the conductivity of the fiber is supranormal, and although the
first impulse has failed to pass through a region of resistance such as
a narcotized area or a synapse, the second impulse falling in this period
of supranormal conductivity may be powerful enough to pass through
and excite the muscle. This is the phenomenon of summation. Between
the refractory period and the period of supranormal conduction the
nerve fiber is recovering its ability to conduct. Impulses set up at
this period will be of subnormal strength and will be less able to pene-
trate regions in which conduction is difficult. Consequently if the rhythm
of nervous discharge is such that each impulse falls in the period of
subnormal conductivity which follows the passage of the preceding im-
pulse, the discharge will be of impulses of subnormal strength. Such
a series of impulses may be unable to pass through the resistance of the
synapse and no activity can result. Whether a series of impulses will
produce summation or inhibition depends on the relation between their
frequency and the time required for the conducting tissue to recover
from the effects of each impulse, that is, on whether each impulse falls
in the period of supranormal or of subnormal conduction set up by its
predecessor.

If the synapses connecting a single afferent path with two motor
neurons have different rates of recovery, the impulses might fall in the
period of supranormal conductivity of one synapse and be summated
and cause a contraction of the corresponding muscle, while they might
fall in the period of subnormal conductivity of the other synapse and
be inhibited, the corresponding muscle remaining inactive. In this way
we obtain a picture of how the reciprocal inhibition of antagonistic
groups of muscles may be accomplished.

It must be remembered that physiologists have just made a beginning
in analyzing nervous activity from this point of view, and that our present
ideas are no doubt crude and subject to revision. Also the facts on which
our conception of the nature of nervous conduction is based have been made
out chiefly by a study of the motor nerves. It is conceivable that the im-
pulses conducted by sensory nerves are of a different nature from those
motor impulses, but so far as they can be studied they appear to be the
same. It is also possible that the impulses set up by electrical stimulation
of motor nerve trunks are different from those arising through voli-
tional or reflex activity.

Canalization. — The frequent use of a path through the nervous system
appears to lower permanently the resistance of the synapses along its
course. This process is known as canalization, and results in a greater
facility in bringing about movements of the muscles to which the path
leads. The bearing of this property of the synapse on the development
of skill in mechanical manipulation and in habit formation is obvious.

THE CONDUCTION OF THE NERVOUS IMPULSE 845

The conductivity of the synapse can be altered not only by the pas-
sage of nerve impulses through it, but by many other agents. Certain
chemical substances such as strychnine and tetanus toxine have a selec-
tive action upon the synapse, lowering the synaptic resistance, and con-
verting inhibition into active contraction (see page 941). In those
invertebrates which possess an asynaptic nervous system, or nerve net,
strychnine is without such effect. Nicotine has a selective action upon
the synapses of the sympathetic nervous system, increasing the resist-
ance so that impulses are unable to pass (page 895).

Reflex activity is very easily abolished by lack of oxygen, as will be
indicated in the next chapter. In this regard it differs from nerve trunk
conduction to a marked degree. Since conduction can be shown to be
quite independent of the nerve cell body, it must be the synapses which
are rendered impassable by asphyxia. Fatigue occurs readily in re-
flex conduction, and must also have its seat in the synapse, since the
nerve trunk itself is quite indefatigable.

The Miyoneural Junction. — The synapse is a region of tissue at the
junction of two nerve fibers having properties quite distinct from those
of the nerve fibers themselves. The myoneural junction, interposed be-
tween nerve fiber and muscle is an analogous structure, the properties
of which are different from both muscle and nerve. Certain drugs have
a selective action upon it, such as curare, which decreases the conductiv-
ity of the myoneural junctions of skeletal muscles and thus results in
their paralysis. Curare is a poison which is used by certain savages on
their arrow heads. Its fatal effects are due to its action in paralyzing
the respiratory muscles by blocking the passage of nerve impulses across
the myoneural junction. Epinephrine, the secretion of the adrenal glands,
has a specific affinity for the myoneural junctions of certain autonomic
nerves, exciting the junctional tissue to action similar to that produced by
the nerve impulses (see page 776). The most prominent characteristic
of the myoneural junction is its resemblance to the synapse. Like it,
it is a region in which conductivity is difficult and readily modified, so
that it may be the seat of summation, inhibition, and fatigue.

CHAPTER XCI
THE NUTRITION OF NERVOUS TISSUE

The Function of the Nerve Cell Body

In the preceding chapter we considered the physiology of the nerve
fiber and the synapses in which it terminates. We must now inquire
what part the nerve cell body, containing the nucleus of the neuron, takes in
the conduction of the nervous impulse. In the crayfish it is possible to
remove the cell bodies from the motor neurons of the antenna' without
disturbing the reflex connections of the nerve fibers. This can be done
because the motor neuron possesses a single axon which divides at some
distance from the cell body into two collaterals, one connecting with the
afferent neurons of the reflex arcs which control the movements of the
antenna?, the other passing directly to the muscles of that organ. Cutting
away the part of the cephalic ganglion which contains the cell bodies
of these neurons does not interfere with the reflex excitation of the
muscles of the antennae, provided that the continuity of the collaterals
is not destroyed. The nerve fibers, deprived of their cell bodies are able
to function normally for two or three days. Conduction does not then
depend primarily upon the presence of the nerve cell body. On the days
following the operation the reflex is elicited with greater and greater
difficulty, and fails altogether on the third or fourth day. The nerve cell
body is consequently necessary for maintaining the conductivity of its
nerve fibers, that is, it is concerned with the nutrition of the outlying parts
of the neuron.

Degeneration and Regeneration of Nerve Fibers.4 — The nutritive func-
tion of the nerve cell is also illustrated by the phenomena which follow
the section of a peripheral nerve trunk or of the tracts of fibers in the
central nervous system. When a man's motor nerve is severed, the
excitability of the peripheral part may be increased for one or two days,
but will then decline rapidly and disappear completely by the end of
the second week. Microscopic examination reveals the fact that such
a nerve, the fibers of which are cut off from their cell bodies, has under-
gone degeneration. The fibers have broken up into ellipsoid segments
of myelin, each containing a piece of the axis cylinder, and these seg-
ments later fragment very irregularly into smaller pieces which are
eventually absorbed. In animals such as the rabbit, in which the process
occurs slowly, it can be seen that the degenerative changes begin at the

84t>

THE NUTRITION OF NERVOUS TISSUE

847

wound and proceed peripherally, although in the dog, in which the degen-
eration is rapid, it appears as though the process occurred synchro-
nously in all parts of the fiber.

In the fibers on the central side of the wound degeneration also oc-
curs, but it is limited to the several internodal segments which lie just
above the point of injury. Nearer to the nerve cell body the fibers re-
main for the most part unchanged. An influence, however, is exerted

lri

I

IV

V

VI

Fig. 211. — Degeneration and regeneration of a sectioned nerve fiber, I. Fibrillation of the axis-
cylinder and swelling of the myelin. II. Segmentation of the axis-cylinder, swelling and displace-
ment of the myelin. Proliferation of neurilemma cells. III. Disappearance of the axis-cylinder;
myelin bulbs; proliferated connective tissue cells. Retrograde degeneration. IV. Formation of
granular bodies; elimination of degenerated myelin by phagocytes. Soldering of fragments by
proliferated connectve tissue cells. Retrograde degeneration. V. Beginning of regeneration in the
central end. VI. Progression of the regenerated axis-cylinder in the empty sheath of the peripheral
end. VII. Regeneration of the peripheral segment. Commencement of myelin reconstruction.
(After Tinc-1.)

on the cell body by the peripheral injury. The chromatic substance of
Xissl's granules becomes modified so that they lose their staining power
(chromatolysis), the cell becomes swollen, and the nucleus may assume
an eccentric position. Peripheral to the wound the destruction of the
tissue is complete, a fiber separated from its cell body being unable to
continue to live. The changes which occur on the central side of the
injury are usually of a temporary nature, and are restored by the process

848 CENTRAL NERVOUS SYSTEM

of regeneration, by means of which the nerve cells reestablish a func-
tional connection with the muscles. If such reestablishment is impos-
sible, as in the case of amputation, disuse may be accompanied by an
atrophy of the neurons so that the number of cells in the anterior horn
of the cord decrease and their fibers degenerate.

While degeneration of the nerve fiber is doubtless influenced greatly
by the presence of the nerve cell body, a major part in the process is
attributed to the cells of the neurilemmal sheath. The process of re-
generation occurs coincidently with that of degeneration. It commences
with activity of the nuclei of the neurilemma, which divide rapidly and
form about themselves strands of protoplasm which replace the frag-
ments of the degenerated fiber as it is absorbed. While it has been
claimed that the fibers of the new nerve are actually formed by the neu-
rilemma, it seems more probable that they grow out along the strands
of this tissue from the central stump pf the nerve, the neurilemma fur-
nishing them with guidance, support, and perhaps nutrition as they
grow. The importance of the neurilemma in the process is supported
also by the fact that in the spinal cord and brain, where the neurilemma
is absent, nerve fibers do not display an ability to regenerate. And herein
lies an important principle in prognosis, for injuries to peripheral nerves
may be repaired by regeneration, whereas the severance of fibers in the
central nervous system results in a permanent injury which can be
corrected only by developing the use of new paths for the control of
the functions which are disturbed.

It should be obvious that these facts form the basis for understanding
the clinical treatment of peripheral nerve injuries. Although the periph-
eral end of a severed nerve is doomed, its neurilemma will form the
guiding path in the establishment of a connection between the new fiber
and the muscle. It is consequently desirable to reunite the ends of the
fibers in order to facilitate the regeneration by allowing the nerve fibers
to establish a connection with the neurilemma of the peripheral stump.
Even when the stumps are not brought into direct contact it is very
remarkable to observe with what surety the new fibers grow out into
the intervening cicatrix and establish a relation with the neurilemmae
of the peripheral trunk.

The phenomenon of degeneration has provided an invaluable tool for
the study of the anatomical relationships within the nervous system
and the function of its parts. By destroying the cells of a nerve center
and observing which fibers degenerate, one can ascertain the distribu-
tion of the fibers which arise from the center, while a study of the
disturbances in the activity of the animal produced by the lesion tells
us what functions are dependent on the neurons which are involved.
Since degeneration does not extend beyond the synapses of the neuron

THE NUTRITION OF NERVOUS TISSUE 840

affected by the lesion, it is possible to learn by this method just how
far the axons from any group of nerve cells extend. The atrophic
changes which occur in the nerve cell bodies after section of their
nerve fiber may also be used to show from what nucleus any tract of
fibers originate. The fact that regeneration does not occur in the brain
or cord after degeneration forms the basis of a method known as suc-
cessive degeneration by which the anatomical paths followed by reflexes
may be made out. For example the scratch reflex, by means of which the
dog relieves itself of irritation set up by parasites on the skin may be
initiated through afferent impulses entering the cord in the thoracic
region. The problem is to discover what neurons conduct these impulses
to the motor neurons of the leg which lie in the lower segments of
the cord. Section of the lateral column of the cord abolishes the
reflex, but we know that in this column lie also fibers descending from
centers in the cerebrum, midbrain, and medulla, and it is desirable
to differentiate these from the propriospinal fibers whose cell bodies
lie within the cord itself. By making a transection of the cord, above
the afferent path of the reflex, all these fibers will be caused to de-
generate. After a year the degenerated fibers will have disappeared
and their paths will be occupied by a neuroglial scar. A section is now
made of the lateral column just below the entrance into the cord of the
afferent path of the reflex. Degeneration will now set in in those de-
scending fibers whose cell bodies lie between the primary and secondary
lesion, and the course of these fibers may be traced to their junction with
the motor neurons. By methods such as these the paths followed by
the nerve impulses involved in the various functions of the nervous
system, with which we are to become familiar, have been made out.

The nutrition of the nervous system is a subject of great importance
because of the fact that many manifestations of nervous disease are the
result of nervous lesions, secondary to some primary disturbance in
the circulation of the spinal cord or brain. Thrombosis or hemorrhage
may produce a mechanical block in the course of vessels supplying the
nervous tissue, or pathological modifications of the blood vessel walls
may interfere with the metabolic exchange between blood and tissue. In
myelitis, disseminated sclerosis, and poliomyelitis the nervous lesions
may have a close relation to the distribution of the blood vessels. In
this connection the section on the circulation of the brain may be re-
viewed with profit (page 254). Certain regions of the central nervous
system are supplied with blood from two sets of arteries so that occlu-
sion of one does not interfere with the nutrition of the part. We will
see that this is a characteristic of the foveal part of the visual center,
which consequently is rarely affected by the vascular lesions of civil
life (page 882). The importance of the nervous system to the existence

850 CENTRAL NERVOUS SYSTEM

of animals and its limited power of regeneration is correlated with the
fact that in prolonged starvation its metabolism is maintained at the
expense of other organs of the body with the result that, excepting the
heart, it is the organ which least and last undergoes a diminution in
weight.

The Metabolism of the Nerve Fiber

The all-or-none nature of the nerve impulse has given reason to be-
lieve that the energy of the nerve impulse is derived from processes
going on in each part of the fiber which it traverses. The refractory
period in conduction is occupied with processes which restore the nerve
fiber to its original state of conductivity. These processes constitute
the metabolism of activity in the nerve fiber ; in addition to them we may
expect a certain amount of metabolism concerned with the maintenance
of the normal condition of the tissue.

With regard to the chemical exchange in nervous tissue, practically
nothing is known except regarding the consumption of oxygen, the
output of carbon dioxide, and the effects of disturbances in these proc-
esses produced by abnormal conditions of circulation and respiration.

Some uncertainty exists regarding the production of carbon dioxide
during the activity of the nerve fiber. It is maintained by Tashiro,5
who has used a very sensitive method for its detection, that the carbon
dioxide production of nerve is distinctly increased while it is being
stimulated. On the other hand A. V. Hill6 has failed to detect any heat
production occasioned by the passage of nerve impulses 'through a nerve,
although he used a method capable of detecting a change of one hundred-
millionth of a degree in the temperature of the tissue. If any oxidative
process had occurred in the nerve, such as might have resulted in the
liberation of carbon dioxide, it should have been accompanied by a
heat production readily detected by this method. The presence of dis-
agreement on this point at least emphasizes one point, that the carbon
dioxide production in nerve fibers, both at rest and in activity, is small and
must contribute a minor share to the metabolic requirements of the
body as a whole.

The nerve fiber is dependent on a supply of oxygen to only a limited
degree, its requirements being apparently small. A nerve trunk of
the frog may retain its ability to conduct for three to five hours in an
atmosphere of pure nitrogen, but at the end of that time its ability
to transmit an impulse will come to an end. On supplying it with oxy-
gen its conductivity is restored again in a few minutes. Oxygen is
consequently necessary for the continued function of the nerve fiber,
which can, however, be deprived of its oxygen supply for long periods
without losing its ability to recover.

THE NUTRITION OF NERVOUS TISSUE 851

Metabolism of the Central Nervous System

The synapses are regions in which conductivity is modified by a va-
riety of conditions. It is to be expected consequently that nutritional
defects will influence the ease with whi<?h impulses may pass through
these regions. The cell body is the nutritive center for the neuron as a
whole. In the reflex arc, of which the synapses and nerve cell bodies
form a part it is logical to expect that deficiencies in nutrition would
show themselves more promptly than in the isolated nerve trunk. This
is indeed the case. While a nerve trunk will retain its conductivity
in an atmosphere of nitrogen for several hours, the reflexes of the frog,
deprived of oxygen supply, disappear in thirty minute. In the warm-
blooded mammal all reflexes disappear within a few minutes after fail-
ure of the blood supply, and in man unconsciousness may be the im-
mediate result of disturbance in the cranial circulation or of asphyxia.

We have already seen how dependent the activity of bulbar centers,
which control the heart beat, the blood pressure, and the movements of
respiration, are on certain conditions, such as the hydrogen-ion concen-
tration of the blood, which must be profoundly altered by disturbances
in the circulation of the brain. In the same way the excitability of
the spinal centers concerned with reflex conduction is modified by asphyx-
ial conditions. Spasmodic contractions of skeletal muscles, or convul-
sions, commonly precede death from asphyxia. These occur in animals
in which the brain has been removed and are consequently due to the
activity of the spinal cord. In spinal animals in which reflexes may be
elicited with difficulty a mild degree of asphyxia frequently causes
a reflex to appear, which could not be produced previously. Deeper as-
phyxia will cause certain reflexes, i. e., the scratch reflex, to take place
spontaneously. When death is threatened, general convulsions of the
skeletal muscles of the trunk and limbs are invariably set up. These
effects show that asphyxia may increase the excitability of the spinal
centers of skeletal muscle and may result in the spontaneous contraction
of the muscles which they supply. The heightened excitability is of short
duration, however, if the asphyxia is complete, and passes into a
condition of depression, followed by the complete failure of the re-
flexes, which may be restored, however, if the respiration of air or oxygen
is established in time (Mathison7).

The responses of the spinal centers for movement of skeletal muscle
do not differ fundamentally from those of the medulla, which are con-
cerned with the regulation of the circulation and respiration. The dif-
ference in their behavior consists in the fact that the bulbar centers
react to smaller changes in the condition of circulation. Thus the vaso-
motor center reacts to thirty seconds of oxygen lack or to breathing 5 per
cent of C02 whereas the spinal centers require two minutes of oxygen

852 CENTRAL NERVOUS SYSTEM

lack or 30 per cent of CO2. The significance of the difference in sensi-
tivity of the spinal and bulbar centers to changes in the composition
or flow of the blood lies in the fact that stimulation of the latter tends
to bring about automatically reactions which restore the blood to its
proper condition. As a result the spinal centers are rarely confronted
in healthy life with a circulatory condition which might modify their
activity.

After all activity of the central nervous system has been suppressed by
anemia, or asphyxia, complete recovery may result if the circulation is
restored to a normal condition soon enough. The respiratory reflexes are
the first to reappear, then the excitability of spinal reflexes is regained,
and finally cerebral function is restored. Less prompt recovery occurs
if the circulation remains inadequate for a longer period, manifesting
itself chiefly in a failure of the cerebrum to regain its normal function
completely. A pregnant cat, which had been subjected to anemia of
the brain and upper cord for 10 minutes, regained her ability to walk,
to clean her paws, and to lap up water or milk, but her movements were
poorly controlled. On the twelfth day she gave birth to kittens. To these
she paid no attention unless one of them came in contact with her
nose when she would lick it with her tongue. She allowed the kittens
to suckle and fondled them with her paws when nursing very much as
a normal cat would do, but if one of them wandered away she would
make no attempt to bring it back. The picture was one of the automatic,
reflex aspects of motherhood deprived of the discriminative attributes
which depended on cerebral processes.

The central nervous system exhibits a difference in the nutritive re-
quirements of its different parts. It is interesting to see how long dif-
ferent groups of nerve cells will resist complete anemia without losing
their ability to revive. Considerable variations occur in different ani-
mals, but the following figures may be taken as typical. They represent
the time beyond which anemia cannot be extended without producing
changes in the nerve cells which cannot be recovered from.

Cerebrum, small pyramidal cells 8 minutes

Cerebellum, Purkinje cells 13 minutes

Medullary centers 20-30 minutes

Spinal Cord 45-60 minutes

Sympathetic ganglia 3-3% hours

Myenteric plexus 7-8 hours

The great susceptibility of the cerebral cells explains the ease with
which consciousness is lost as the result of circulatory failure or as-
phyxia. In illuminating gas poisoning permanent mental defects fre-
quently ensue if resuscitation is not prompt, because of the reduced oxy-

THE NUTRITION OF NERVOUS TISSUE 853

gen-carrying power of the blood which follows the inhalation of carbon
monoxide. Similar mental disturbances may result for a similar reason
in pernicious anemia.

A prolonged condition of low blood pressure may result in the failure
of the medullary centers because of the insufficiency of the blood supply.
This is perhaps one of the limiting factors in the resuscitation of patients
suffering from low blood pressure induced by hemorrhage or secondary
traumatic shock. Bayliss has found that if the blood pressure of the
cat is maintained at a low level for an hour or two the vasomotor center
loses its reflex excitability and the respiratory center fails to maintain
a ventilation of the lungs sufficient to support life. Restoration of the
blood pressure by transfusion may come too late to cause these centers
to recover. In the cat the respiratory center loses its power of revival
before the vasomotor center, but the relative susceptibility no doubt
varies in different species of animals. The cells of the outlying ganglia
of the sympathetic system and, particularly, those of the myenteric
plexus are able to withstand a prolonged disturbance in their blood sup-
ply much better than the neurons of the central nervous system. For
this reason a strangulated loop of intestine which appears hopelessly
damaged, by the prolonged circulatory statis to which it has been sub-
jected, may recover its normal function with remarkable success.8

A close relation probably exists between the distribution of the cap-
illaries in the nervous system and the nutritional requirements of its
various parts. Measurements indicate that the grey matter, in which the
nerve cell bodies lie, is much more richly supplied with capillaries than
the white matter. The grey matter is more adequately supplied in the
medulla than in the cord, and the same relation holds true between the
white matter in these regions. Among the nuclei of the medulla it
appears that sensory nuclei are, in general, more richly vascularized than
motor nuclei. This relation is perhaps explained by the almost con-
tinuous activity of the sensory neurons as contrasted with the more inter-
mittent activity of the neurons concerned with motor acts.

CHAPTER XC1I
THE RECEPTORS

Having reviewed the fundamental conditions of conduction in nerve
fibers and in the reflex arc, we are now in a position to consider the
arrangements of neurons which form the basis of the principal aspects
of central nervous activity. We will consider the afferent part of the
reflex arc, the activity of which gives rise to the discharge of impulses
over motor neurons in reflex activity, and to the phenomena of sensa-
tion and discrimination which determine the nature of volitional acts.
Disturbances in these arrangements give rise to the sensory symptoms of
nervous disease. Such a consideration must start with the study of the
receptors or sense organs.

The Evolution of Specialized Receptors

The receptor is a cell specialized in such a way as to be excited by
minute changes in the condition of its environment. As a result of
such excitation reflex actitity is set up which causes the animal to re-
spond, usually in a way which is to its advantage, and sensations are
produced which give information concerning the nature and position of
the stimulus and its probable consequences. The primitive type of re-
ceptor, which appears in the coelenterates and occurs generally in most
invertebrates consists of an epithelial cell from which a fiber extends
into the central nervous system. Such an arrangement persists in the
olfactory sense organs in man. With the development of longer nerve
trunks in the vertebrate nervous system the cell body is no longer found
at the termination of the afferent fiber, but has taken up a position
nearer to the central nervous system, in the spinal ganglion. The fibers
of such an afferent neuron terminate peripherally in a number of fine
branches which extend along the cells of the epithelium, forming a sense
organ known as a free nerve termination. The sense of pain in man
can be definitely associated with receptors of this type. The highest
degree of sensitivity cannot be attained by such an arrangement. For
this purpose special cells in the skin become modified into receptors, and
about these terminate the fibers of the sensory nerves. Thus one cell
serves as a receptor, while the other is concerned primarily with con-
ducting the disturbance set up in the receptor to the central nervous
system. The receptors of the ear, the eye, the sense of taste and probably
other cutaneous sensations are of this type. (Fig. 212.)

854

THE RECEPTORS 855

Just as a division of labor has been necessary betAveen the receptor
and afferent fiber in order that the former may become as sensitive as
possible to Aveak stimuli, so we find a specialization among the receptors,
each being adapted to respond to some particular kind of physical or
chemical change in its surroundings. Thus AVC may classify receptors
Avith respect to the stimuli to which they respond most readily. We
may speak of chemo-receptors which respond to chemical changes
(taste, smell), tango-receptors which respond to pressure (touch), photo-
receptors which respond to light (sight), phono-receptors which respond
to sound (hearing), and caloro-receptors Avhich respond to temperature
changes (heat and cold). This does not mean, however, that these sense
organs respond only to the type of stimulus to Avhich they are especially

III

Fig. 212. — Evolution of the sense organs. I. Receptor of coelenterate. II. Type of receptor
found in many invertebrates and in gustatory epithelium of vertebrates. III. Simple afferent
neuron of vertebrate with free nerve terminations in skin. IV. Specialized sensory mechanism of
vertebrate, typified by the organ of the sense of taste. It consists of specialized receptor cells in
the integument, about which terminates the axon of an afferent neuron. (After Parker.)

attuned. Pressure upon the eyeball may stimulate the retina, an elec-
tric current may give rise to the sensation of taste, a temperature of 45°
C. will excite the sense organs not only of heat but of cold and pain. But
in the latter case, for example, the heat receptors alone are responsive
to temperatures between 45° C. and the temperature of the body. The
characteristic of the specialized receptor is that its threshold or lower
limit of stimulation, is much lower for one type of stimulus than for any
other.

The Quality of Sensation and Its Local Sign

Whatever the form of stimulus which excites a given receptor, the
quality of the sensation is always the same. A temperature of 45° C.

856 CENTRAL NERVOUS SYSTEM

produces a sensation, not of warmth, but of cold when applied to a re-
ceptor for cold, and of pain when applied to a pain receptor. Pressure
applied to the eyeball gives similarly a sensation of light. This is be-
cause the quality of a sensation depends on the part of the brain to
which the nerve impulses set up by the stimulus are conducted. All
the fibers from a given type of receptor group themselves together in
the spinal cord or brain stem and lead to a common group of cells, or
sensory area, in the brain from which the sensation arises. The im-
pulses traveling over these fibers are apparently the same in quality
no matter what form of physical or chemical disturbance has set them up.
Consequently on reaching the brain centers, no difference can be recog-
nized between them, and they all give rise to a common quality of sen-
sation. The quality of a sensation depends on two factors: (1) the low
threshold of a special group of sense organs for the particular stimulus,
and (2) the anatomical arrangement by which the impulses from such
a group are conducted to a common region in the brain. From whatever
source impulses reach this region the character of the sensation will
be the same. These considerations give rise to the law of the specific
properties of nerve, which is to the effect that, however excited, each
nerve of special sense gives rise to its own peculiar sensation.

The sensations which are set up by the stimulation of receptors not
only have a definite quality, but are recognized as coming from a defi-
nite region of space. They are said to have a local sign. Certain sensa-
tions are referred to parts of our body, as we recognize when we say
our feet are cold, our tooth aches, or our skin itches. Others are referred
to objects recognized to be in contact with the body, as when we assert
that a bed is hard, or a piece of ice cold. Still others are referred to
distant objects, as when we recognize the color of a picture, the sound
of a bell, or the odor of a flower. In all these cases the process of ex-
citation is located actually in a sense organ within or at the surface of
the body, and the phenomenon of sensation is set up somewhere within
the brain. The reference of sensation is a psychological phenomenon
depending on the past experience of the individual. We have learned,
for example, that whenever impulses arrive in certain regions of the
brain, giving rise to characteristic sensations, that they have come from
stimuli set up in some particular group of receptors located in some par-
ticular part of the body and excited by a disturbance which we have
discovered can come only from some particular region in space. Thus
experience tells us that a certain sensation is associated with an object
in contact with the foot. Whenever the afferent paths from the foot
are brought into play, the same sensation results, and we learn to asso-
ciate the resulting sensation with the foot and refer all such sensations
with accuracy to the foot. If the sensation is one commonly associated

THE RECEPTORS 857

only with the obvious contact of some object with the foot, i. e., if it
results from a combination of the sense of touch and sensations of other
quality, the sensation as a whole is referred to the external object, and
.we speak of the object being cold, hard, etc. When components of such
a sensation occur without the obvious contact of some object, the sensa-
tion is referred to the part of the body in which the stimulation arises,
and we speak of the foot being cold or in pain. Similarly we have learned
to associate sensations resulting from stimuli arising in certain sense
organs with objects at a distance from the body. We have learned for
example to associate sensations which arise from stimuli falling upon
particular parts of the retina with the particular regions in space from
which light may come which can stimulate that particular retinal area.
Unconscious of the mechanism of the optical system, or of the arrange-
ment of the afferent paths of vision, we have simply learned that cer-
tain visual sensations can always be attributed to objects occupying a
certain position in space, and we can consequently assert with assurance
that the upper part of a picture is blue. The local sign of sensation is con-
sequently largely a matter of experience or learning.

Reflex acts also bear an accurate local sign, although they may be carried
out by parts of the nervous system apparently devoid of consciousness or
of the ability to learn. Thus a frog, from which the brain has been re-
moved will raise its hind leg and attempt to sweep away an irritating ob-
ject placed on any part of the body, directing its foot to the point of stimula-
tion with the utmost accuracy. A spinal dog will carry out a scratch reflex
which differs considerably in its objective point, depending on the part of
the back to which the stimulus is applied. How the mechanism has come
about which enables stimulation of receptors in one part of the body to
bring about these reflex movements of an appropriate sort is a fundamental
problem in evolution which we cannot take up.

The basis of the recognition of quality and local sign in sensation is
of the utmost importance in interpreting the sensory manifestation of
disease in the central nervous system. It rests on the fact that sensation
of definite quality and local sign depends ,011 the arrival at a certain sta-
tion in the brain of impulses which are set up ordinarily in a group of
sense organs specialized for the reception of one particular type of
stimulus and located in a definite region of the body. Loss of sensation
may result from the interruption of the path of conduction anywhere
between, and including, the receptor and the sensory center in the brain.

Sensations of definite quality may be set up by stimulation of the
nerve fibers at any point along this path, or of the sensory center itself.
One must exercise great care before accepting the location to which the
patient attributes the source of sensation, for he has only the experience
of healthy life to guide him. Consequently he may be misguided into

858 CENTRAL NERVOUS SYSTEM

ascribing sensations to definite parts of the body, which in fact are
hallucinations arising from some functional disorder of the brain which
is affecting directly the sensory centers of the cortex.

Referred Pain. — The accuracy of sensory location seems to be corre-
lated with the abundance of sense organs in different parts of the body
and with the frequency of their employment. On the hands, the lips,
and tongue localization is extremely accurate, for these organs are in
frequent use in examining the nature and position of various objects.
Localization is good on the soles of the feet, which are used to sound
out the ground in walking. On the other parts of the limbs, the trunk,
and particularly the back, stimuli can be localized only in a rather rough
way. Particularly interesting is the phenomena of localization of sen-
sations arising from the viscera. In healthy life these organs do not
give rise to sensory manifestations, but in disease of the viscera acute
pains may be set up. Because visceral sensations arise from organs
within our body, we have no way of knowing just where the trouble
lies and consequently have no basis for localizing the disturbance accu-
rately. In the case of stationary organs such as the heart, the pain
may be referred at times to the proper internal region, but in the case
of movable organs such as the intestine, the reference is most inexact.

DISTRIBUTION OF REFERRED PAIN FROM VISCERAL ORGANS (AFTER POTTENGER)

The eight cervical segments are indicated by Cl, C2-C8; the twelve dorsal or thoracic
segments by Dl, D2-D12; the five lumbar segments by LI, L2-L5; and the four sacral
segments by Sac. 1, Sac. 2, Sac. 4. The areas of the head are indicated as follows:
N — nasal or rostral area; FN — f ronto-nasal area ; MO — medio-orbitalarea; FT — fronto-
temporal area; T — temporal area; V — vertical area; P — prietal area ; O — occipital area ;
NL — naso-labial area; Max/ — maxillary area; Man. — mandibular area; M — mental area;
L. S. — Superior laryngeal area; LI — inferior laryngeal area; TO — hyoid area.

AREA IN THE TRUNK

AND LIMBS

AREA IN THE HEAD

Heart

03, C4— D2— D8 1^*^

« and aorta, N, FN, MO, FT
FT T, V P

Lungs

03, C4 — D4 — D9

N FN MO FT T V P

Stomach

D7— D9 _

FN MO T V P

Intestine

D9 — D12

V P O

Rectum

Sac. 2— Sac. 4 ,

Liver
Gall bladder

C3, C4— D7— D10
D8— D9

FN, MO, T, V, P, O
T V

Kidney and urethra
Bladder (mucous membrane
and neck)
Detrusor vesica3
Prostate
Epididymis
Testicle

Dll— LI

Sac. 3— Sac. 4
Dll— L2
DIG— D12— Sac. 1— Sac.
Dll — D12
D10

3

0

Ovary

1)10

o

Ovarian appendix
Uterus
Neck of uterus
Mammae
Spleen

Dll— LI
D10— LI
^e. 2— Sac, 4
D4— Do
1)6

THE RECEPTORS 859

Very commonly pain arising in the internal organs is referred to some
remote region on the surface of the body. This phenomena is known as
referred pain. Such pains are sharp or aching in character, whereas pain
which seems to come from the internal organs is dull or heavy (Head13).

The afferent nerves from the viscera apparently terminate in the cord
in close association with afferent nerves from certain skin areas. Just
how one group of afferents affects the other is not known, but the fact is
that the sensation from the viscus is referred to the 'peripheral distribu-
tion of those fibers which terminate in the same segment of the spinal
cord. The nerves of cutaneous sensation have a definite segmental dis-
tribution (Fig. 214) and consequently the reference of internal pain
will be to one or another of these segmental regions. Not only is the
visceral pain referred to these segmental areas, but these parts of the
skin become hypersensitive, so that the sensation of pain and sometimes
of heat and cold arising from them is greatly exaggerated. Thus the
location of the referred pain and of hypersensitivity may be taken as an
accurate indication of the internal situation of the source of irritation.
The table on page 858 indicates the segmental distribution of referred
pain from the major viscera.

The sensitivity of the viscera is of a low order. When the sensitivity
of a region of the skin is reduced to a similar condition by disease, sen-
sations arising therefrom may be referred to other parts, just as the vis-
ceral pains ordinarily are. This phenomenon is known as allocheiria.
If the hyposensitive area is limite'd to one side of the body, the sensation
arising from it is referred to the corresponding part of the other side
of the body. If both sides are hyposensitive, the reference is to the
next segment above or below. Like the reference of visceral pain, this
condition must be attributed to the' central relationship between the
tracts carrying afferent impulses from symmetrical points on the skin
and from neighboring segments to the sensory centers. When the mecha-
nism of sensation for one part is depressed, the sensation is referred to
the most closely associated normal region.

Cutaneous and Deep Sensibility

'The physiology of receptors may be illustrated by a consideration,
of sense organs which have a general distribution throughout the body.
These comprise the receptors of chief interest in practical neurology,
and will serve to illustrate principles which apply as well to the spe-
cial sense organs of the head (of the eye, ear, gustatory and olfactory
epithelia), the consideration of which space will not allow. They may
be divided into organs of cutaneous and of deep sensibility, depending
on whether the receptors lie in the skin or in the internal parts of the
body. We can recognize four primary qualities in the sensations to

860

CENTRAL NERVOUS SYSTEM

which they give rise. These are touch, heat, cold and pain. When an
area of skin is examined carefully it is found that these sensations
are not elicited with equal readiness from all parts, but that definite
spots exist which may give rise to one or another of these sensations.
Some give, rise to touch alone, others to the sensation of warmth, others
to that of cold, and still others to a feeling of pain. Each spot evidently
marks the location of one or more receptors for the stimulus in ques-
tion. The spots giving rise to the four different qualities of sensation
frequently do not coincide, nor do their numbers correspond, i.e., cold
spots are more numerous than heat spots. In many regions of the
body one quality of sensation may be lacking altogether. Thus pain is
absent from the inner surface of the cheek opposite the second molar;
it alone occurs on the cornea. These facts furnish proof that the qual-

Fig. 213. — Cold spots (A) and heat spots (S) of an area of skin of the right hand. In each
case the most intense sensations were experienced in the black areas, less intense in the lined,
and least in the dotted. The blank areas represent parts where no special sensation of either
kind was experienced. (From Goldseheider.)

ity of the cutaneous sensations depends on the stimulation of sense or-
gans which are specialized each for a different type of stimulus.

Touch. — Touch spots are stimulated by pressure which deforms the
tissue. This may be seen to be so by dipping a finger into mercury
when it will be found that the sensation arises only from a band of
skin at the surface which is bent by the pressure of the mercury. The
skin deeper down is pressed upon uniformly and consequently is not
deformed and no sensation is set up. Touch spots are not uniformly
distributed on all parts of the body, as we have already indicated. On
the hairy regions it is found that they are most numerous at the base
of the hairs, especially on the " windward" side. These spots are stim-
ulated when the hair is bent, and since the hair acts as a lever, very

THE RECEPTORS 861

light pressures will excite them. Consequently the threshold for touch
is lowered on the hairy parts of the body.

The examination of the sense of touch in the skin is important in the
study of nervous disease. The presence or absence of the sensation is
tested by touching the skin with a pledget of cotton or a soft paint
brush. If the sensation is impaired but not destroyed, more exact in-
formation can be obtained by measuring the threshold, i. e., the smallest
pressure which will stimulate the touch spots by repeating the test with
a series of hairs or brushes of graded stiffness. The ability to localize
the spot touched is known as spot finding or one dimensional localiza-
tion. Two dimensional localization is the process of recognizing that
stimulation is being applied to two spots at the same time. If the points
of a pair of compasses are applied to the skin at once they will be recog-
nized as distinct points only if separated by a certain distance. This
distance becomes greater as the number of touch spots becomes fewer,
it apparently being necessary that a certain number of unstimulated
spots should separate them before the points of stimulation are recog-
nized as distinct. This process of recognizing the distinctness of two
spots is called two dimensional localization. The compass test is use-
ful in detecting deficiencies in the process which may result from de-
struction of the afferent paths for the sense of touch.

Very closely associated with the sense of touch are the sense organs,
which give us knowledge of the position and movements of the parts of
our body. These are located in the muscles, tendons and joints, and are
doubtless stimulated by deforming pressures arising from the contrac-
tion of muscle and the movement of the bones at the joints. The senses
are tested by the ability of a patient to touch one part of the body with
another, the eyes being shut and the affected member being moved into
various positions. Quantitative measurements can also be obtained by
determining through how many degrees a joint may be bent before the
patient recognizes that the limb is being moved. The ability to recog-
nize the position and movement of the parts of the body is called three
dimensional localization.

Heat and Cold. — The heat and cold spots are stimulated by abnormal
temperatures, heat spots being excited by temperatures above and cold
by temperatures below that previously existing in the skin. Whether
one or the other sensation will be felt depends not so much on the ab-
solute temperature to which the heat and cold spots are brought as to
the relation of this temperature to that of the skin. If the skin is
chilled luke warm water will feel warm to it, whereas the same water
will feel cool if the skin has previously been brought to a high tempera-
ture. Thus if one finger is placed in cold water and the other in hot
water for a few minutes and then both are thrust into water at an

862 CENTRAL NERVOUS SYSTEM

intermediate temperature the sensation of warmth will be felt in the
former finger and of cold in the latter. The sense organs thus become
adapted to the conditions to which they are exposed, and become ex-
cited again only by a change in these conditions.

Adaptation is a quite general sensory phenomenon. It occurs prom-
inently in the retina, with the result that an eye which has become used
to the dark is dazzled momentarily by the ordinary daylight. Adapta-
tion is also a marked feature of the touch sense, as is the experience of
every one who has worn flannel underclothing or a plate of false teeth.
It serves to protect the organism from the fatiguing effects of over-
stimulation from conditions to which it is continually exposed. Sensory
adaptation must be borne in mind not only when examining the senses
of others, but in making judgments with our own sense organs. Thus if
the hands are cold, the skin of another may feel warm and feverish, even
though its temperature is not above normal.

Pain is of particular importance to the physician, whose services are
judged by the community largely by his skill hi suppressing this sen-
sation. Unlike the other receptors, the pain spots are not specialized for
the detection of any particular form of stimulus, but may become excited
by any condition which threatens to harm the tissues. Pain may be pro-
duced by excessive pressure, the caustic action of chemicals, excessive ex-
posure to light as in sunburn, temperatures above 45° C. and the effects
of extreme cold, as in frost bite. The threshold for these stimuli is high,
so that in the strengths at which they are ordinarily experienced the
sensation of pain does not arise. All stimuli of sufficient intensity to
threaten the welfare of the tissues and give rise to pain are called
noxious stimuli, It was thought at one time that pain resulted from
the overstimulatio-n of any type of receptor. This conclusion was natural
when one considered the great variety of conditions which might give
rise to painful sensations. Undoubtedly the overstimulation of any
sense organ may produce sensations of unpleasant character, but that
specific sense organs for pain exist can no longer be doubted. This is
shown by the presence of pain spots in regions from which other sense
organs are absent, as the cornea, the absence of pain in regions in which
other sense organs occur, as the inside of the cheek opposite the sec-
ond molar, by the existence of special tracts in the central nervous sys-
tem for the conduction of the impulses which give rise to pain, .and by
the fact that certain drugs such as cocaine may abolish the excitability
of the receptors for pain without disturbing the reception of other
sensations.

Pure sensations, arising from the stimulation of a single type of re-
ceptor, rarely occur in life except under the artificial conditions which
we employ in the laboratory. The sensations which we experience are
the composite result of the simultaneous combination of a variety of

THE RECEPTORS 863

stimuli, acting together on sense organs which give rise to sensations of
different quality. The nature of the resulting sensation is consequently
modified. Water heated to 40° C. feels warm to the hand and stimulates
only the heat spots. At 45° C. the cold spots and pain spots are also
excited, and the resulting sensation takes on a distinctly different qual-
ity which we call "hot." Since pain is excited only by extreme in-
tensities of stimuli which can set up other qualities of sensation, it is
natural to find painful sensations varying considerably in their quality,
depending on the sensations which occur in association with them.
Thus a throbbing pain is due to the simultaneous pressure produced by
dilated blood vessels.

It is interesting to find that certain qualities of sensation are incompa-
tible with one another. When stimuli capable of setting up two such incom-
patible sensations occur at once, one sensation is suppressed or inhibited by
the other. An interesting experiment is described by Head which illustrates
this. The tip of the glans penis is supplied with receptors for cold and pain,
but may be devoid of heat spots. If it is dipped into water at 40° C. the
pain spots alone are stimulated and a disagreeable, painful sensation re-
sults. If the temperature is raised to 45° C. the cold spots also are stimu-
lated, the pain is displaced by a vivid sensation of cold. About the corona
of the penis heat spots also occur. If this region is also immersed, the
quality of the sensation changes to one of exquisitely pleasant warmth. If
the water employed in the experiment is at a temperature higher than
45° C. the painful sensation persists and no sensation of warmth is felt.
The sensations of pain and pleasant warmth are incompatible and cannot
occur simultaneously. Which one will succeed in gaining control of
consciousness and in suppressing the other depends on the relative
strength of their stimuli. An entirely analogous phenomenon occurs in
the competition of incompatible reflexes for the control of a common
motor path (page 947).

Noxious stimuli give rise to an exceedingly impelling sensation and
to reflexes which can dominate over any others which may be set up
at the same time. The response to painful stimulation is of a protective
character and it is imperative that such stimuli and their sensations
should control the activity of the organism when they arise with in-
tensity. On the other hand, if the noxious stimuli are near the thresh-
old value of intensity, and little danger is threatened, it is an advan-
tage that its effects be suppressed so that the organism may react with
a discretion based on data derived from other sensations as well.

The Distribution of Sensitivity in the Body

fSensations of touch, heat, cold, and pain are felt generally throughout
the surface of the body, with the exception of certain limited areas such
iis we have referred to, from which one or another quality of sensation

864 CENTRAL NERVOUS SYSTEM

may be lacking. The presence of these cutaneous senses is obvious to
any one, and the sensations which they arouse form the basis of many
volitional acts. The presence of receptors in the deeper parts of the
body, on the other hand, may be recognized only by careful introspec-
tion, as when some pathological condition produces deep pain, or de-
ranges the unconscious motor responses which depend on the receptors
of deep sensibility. That afferent nerve impulses may arise from the
muscles, connective tissue, tendons and joints is shown by a number of
considerations. We are accurately aware of the position of our limbs
and of any change in their position, whether made actively or passively.
This knowledge does not depend on the cutaneous sensibility because the
sense of position is not impaired when the cutaneous sensibility is
destroyed by cutting the sensory nerves to the skin. When this is done
sensations of pain and pressure may still be felt if the limb be pressed
upon forcibly. Painful sensations which are referred directly to the
muscles may arise during a muscular cramp or in the soreness which fol-
lows the severe use of muscle groups which are unaccustomed to such
activity. The fibers conducting afferent impulses lie in the trunks of
the motor nerves, and when these are damaged muscular sensibility is
lost. On cutting the dorsal root of a spinal nerve, it is found that a
number of fibers in the motor nerve trunks to the muscles undergo
degeneration. The receptors in the muscles, connective tissue, tendons,
and joints may give rise to sensations of pain and touch and give in
addition information which we shall see is invaluable in coordinating
the movements of the body (page 914).

The receptors of the internal organs of the trunk may give rise to
sensations of pain, referred either to the inside of the body or to some
region of the skin. That the sensibility of these organs is of a low or-
der is attested by the fact that in healthy life we are rarely aware of
their presence in spite of the almost continuous activity of many of these
organs. The study of the distribution of the internal receptors for pain
has been made by Lennander14 during operations performed under local
anesthesia. It has been found that the connective tissue about the ten-
dons, the synovial membranes, periosteum, and perichondrium, are all
very sensitive to pain. The parietal peritoneum is very sensitive to
pain, especially from traction. On the anterior abdominal wall, at least,
it is not endowed with end organs of pressure, heat, or cold. The mesen-
teries are free from pain when cut, but are sensitive to traction. When
free from connective tissue periosteum or perichondrium, the bone sub-
stance and marrow, cartilage, and arteries and veins are insensitive to
cutting, except those bony structures such as the maxilla and teeth which
are traversed by sensory nerves. The muscles are insensitive to cutting,
although excruciating pain may arise in them as the result of a cramp.

THE RECEPTORS 8G5

The brain substance and pia arachnoid are insensitive on the convexity
of the brain and beneath the occipital bone, but pain may arise from it
beneath the frontal bone and toward the zygomatic arch. In the thoracic
cavity the visceral pleura, which is innervated by the vagus and sym-
pathetic, is insensitive to the pressure of a stiff wire. The parietal
pleura, innervated by the intercostal nerves, is the seat of pain which is
accurately localized. The peripheral portion of the diaphragmatic pleura
is innervated by the intercostal nerves over a band about two inches
wide. Pain arising in this region is referred to the lower thorax, the
abdomen and lumbar region. The central portion of the diaphragmatic
pleura, innervated by the phrenic nerve, is the seat of pain referred to
the neck. The lungs are insensitive, as is the heart, except under trac-
tion. In the abdomen all organs receiving a nerve supply only from the
sympathetic nerves and from the vagus below the branching of the re-
current nerve have no sensation. The substance of the stomach, intes-
tines, and liver may be cut into without causing discomfort. The fibrous
capsule and parenchyma of the kidney do not give rise to sensation if
the fatty capsule is removed. The bladder may be cut or pinched, but
not pulled, without giving pain.

It must be remembered that these observations have been made on
individuals undergoing operation with local anesthetic. Sensitivity may
have been modified by exposure of the organs to the air, or by spread of
the anesthetic. They give valuable information from a surgical point
of view, but do not tell us about the conditions which give rise to sen-
sation during the normal or pathological activity of the viscera. It
will be noted that the most adequate stimulus for visceral pain is trac-
tion, which may produce discomfort when cutting is ineffective. It is
probable that the pains of labor, menstruation, colic, gastric ulcer, etc.,
are set up by tension within the muscles of the uterus, or gastrointes-
tinal tract, or to traction upon the mesenteries and their insertion into
the parietal peritoneum by the arching of these organs when their walls
attempt to contract while in a distended condition.

The sensibility of the mucosa of the stomach has been made the ob-
ject of extensive study, particularly in men possessing gastric fistulas.
The mucosa is quite insensitive to pain, when pricked with a pin or
pinched. Pain is felt as the result of such stimuli only when they are
sufficiently severe to spread to underlying structures. The mucosa is
also insensitive to touch. A stiff test tube brush may be thrust into
the stomach and moved about vigorously without producing any sen-
sation. On the other hand, the temperature senses are represented in
the wall of the stomach. The introduction of water below 10° C. pro-
duces a sensation of cold, and above 50° one of heat. Intermediate tem-
peratures are without effect.

CHAPTER XCIII
THE AFFERENT PATHS OF SENSORY IMPULSES

The insulation of conduction in the nerve fiber, and the fact that im-
pulses can pass from neuron to neuron in one direction only, makes the
arrangement of neurons in the nervous system a matter of great sig-
nificance. We have already seen that the recognition of the quality and
location of a stimulus depends upon the connection of each receptor in
the skin with a definitely corresponding part of the brain. The ana-
tomical arrangement of the paths conducting afferent impulses from
receptors for each quality of sensation and from the different parts of
the body is of importance in elucidating the sensory phenomena of
disease.

The Segmental Distribution of Afferent Nerves

The vertebrate embryo develops as a segmented organism, at least
so far as its nervous, muscular, and skeletal structures are concerned.
The primitive segmentation of the vertebrate embryo is preserved in the
arrangement of the spinal nerves of man. Each dorsal root of the spinal
nerves contains afferent fibers coming from a definite segmental area
of the skin. This may be shown by cutting all of the dorsal roots except
one and then determining what parts of the skin retain their sensitivity.
The areas innervated by adjoining roots overlap considerably, so that
most parts of the skin receive a double innervation. Consequently
damage to a single dorsal root does not produce a considerable loss of
sensation. The areas supplied by each dorsal root agree closely with
the segmental areas to which visceral pain is referred, with the exception
that the latter do not overlap (Fig. 214). The areas of referred pain
appear to represent the central portion of the segment innervated by a
single dorsal root in which the overlapping is less considerable.

The position of the skin areas do not correspond to the level of the
dorsal roots which innervate them because of the downward slope of the
spinal nerves. The skin areas, particularly of the lumbar and sacral
roots, are somewhat below the corresponding segments of the spinal
cord. In the limbs the segmental arrangement becomes obscure, until
considered with respect to the segmental origin of the limb buds in the
embryo. The areas innervated by the different roots contributing to the
brachial and lumbar plexuses are nevertheless quite distinct.

SG6

THE AFFERENT PATHS OF SENSORY IMPULSES

807

The dorsal roots contain afferent fibers not only from the skin, but
from the receptors of deep sensibility located in the muscles and viscera.
We will see that the primitive segmentation of the muscles is consider-
ably disturbed in the course of development (page 890). The afferent
nerves from the muscles enter the cord, however, in the segment from
which the muscles originally arose. The same is also true of the viscera.
The heart, for example, which arises in the cervical part of the embryo
has moved to a lower position, retaining, however, its innervation from

Fig. 214. — Diagram showing the segmental arrangement of the sensory nerves. (From Purves

Stewart.)

the cervical segments. Pain from the heart is referred consequently to
the neck and arm.

Because of this separation of the muscular and cutaneous distribution
of the fibers composing a single dorsal root', injuries to the peripheral
nerves may destroy cutaneous sensibility without affecting deep sensi-
bility. This is particularly liable to occur because of the collection to-
gether in nerve trunks, especially in the limbs, of fibers from adjacent
dorsal roots which have a common (overlapping) distribution. When
this occurs the cutaneous sensibility to light touch, two dimensional
localization, heat and cold, and the prick of a pin, may be destroyed over

868 CENTRAL NERVOTTS SYSTEM

an area which is still sensitive to deep pressure and the resulting pain,
and in which the sense of position of the part remains normal. Such a
lesion is said to cause a dissociation of sensation. Dissociation between
cutaneous and deep sensibility occurs only in the case of peripheral nerve
lesions. Since the fibers of deep sensibility in muscles lie in the trunks
of motor nerves, a lesion affecting it is usually accompanied by certain
disturbances in motor function.

Ascending Pathways in the Spinal Cord

Our knowledge of the course of afferent impulses in the cord is gained
by determining which tracts degenerate when the dorsal roots are cut,
by destroying certain regions of the cord in animals and attempting to
correlate the resulting degeneration with such disturbances in sensation
as can be made out, and by studying the disturbances in sensation which
result from injuries or disease of the cord in man. The latter method
especially has been profitable because by it alone can accurate informa-
tion concerning sensation be acquired (Head and Thompson,15 Holmes16).
Unfortunately, however, an exact knowledge of the site of the lesion can-
not usually be had in these cases, so that at present the course of the
afferent impulses concerned with the various qualities of sensation from
different parts cannot be stated with the precision which will ultimately
be attained. On entering the spinal cord the course of the dorsal root fibers
branch. A few fibers pass posteriorly in the fasciculus inter fascicularis
of the dorsal column. The majority, however, extend upward in the
ascending tracts of the dorsal funiculus. As these proceed upward their
number becomes less and less, because most of the fibers pass into the
gray matter and terminate within a few segments of their point of
entrance into the cord. As fibers enter the ascending tracts of the dorsal
funiculus from higher spinal nerves, they lie lateral to those which have
entered lower down, so that the funiculus takes on a laminated structure.
Upon entering the gray matter of the cord the afferent fibers undergo
synapse with association fibers which function as secondary afferent
neurons conducting the impulses either to the motor neurons within the
cord which are involved in spinal reflex acts, or leading to higher cen-
ters in the brain, some of which give rise to sensation. The fibers of
the secondary afferent neurons which are concerned with sensory im-
pulses cross to the opposite -side of the spinal cord and pass upward to
the brain in the ascending tracts (dorsal and ventral spinothalmic) of the
spinal lemniscus. Studies of the sensory disturbances due to lesions of
the spinal cord in man indicate that on entering the cord the impulses
which give rise to the various qualities of sensation undergo a charac-
teristic grouping. All fibers conducting impulses which give rise to pain
whether from the cutaneous or deep distribution of the sensory nerves

THE AFFERENT PATHS OF SENSORY IMPULSES

869

SENSE OF

POSITION

MOVEMENT

[TOUCH

PAIN

HEAT

COLD

Fig. 215. — Diagram of the afferent paths followed by sensory impulses within the spinal cord and

brain.

870 CENTRAL NERVOUS SYSTEM

become grouped together in a single tract which is composed of second-
ary afferent fibers situated on the side of the cord opposite to that by
which they have entered. The impulses giving rise to the sensation of
heat, and those giving rise to the sensation of cold are also each col-
lected into separate tracts ascending through secondary afferent neurons
on the opposite side of the cord.

All impulses concerned with the tactile aspect of sensation, including
the sensations involved in the recognition of position and passive move-
ment are grouped together in the cord irrespective of their origin from
cutaneous or deep lying receptors. These impulses, however, pass up the
cord in two distinct groups. Impulses concerned with the recognition
of touch and pressure and the recognition of the location to which these
stimuli are applied eventually pass on to secondary afferent neurons and
cross to form a definite tract ascending the opposite side. But whereas
the impulses from painful stimuli, heat, and cold cross within five or six
segments from their point of entrance into the cord, these tactile im-
pulses may not have all crossed until the upper cervical region is reached.

Impulses upon which depend the recognition of two dimensional local-
ization, the sense of position, and passive movement pass up the cord on
the side on which they have entered it, in the fibers of the primary affer-
ent neuron which lie in the dorsal funiculas and terminate in the nucleus
gracilis and cuneatus of the medulla.

As a result of this arrangement of the afferent fibers in the cord, cer-
tain characteristics are imposed upon the sensory disturbances which
result from spinal cord lesions. A lesion which destroys the greater part
of one half of the cord will obliterate the sensation of heat, cold, and
pain on the opposite side of the body in those parts whose nerves arise
below the level of the lesion. The ability to recognize touch and pres-
sure may be unimpaired by such a lesion, because the impulses on which
this depends cross over gradually as they ascend the cord, and conse-
quently there exists at any one level two paths over which such impulses
can travel. If the lesion is located high in the cervical region, a point
at which the crossing over of these tactile impulses is complete, this qual-
ity of sensation will also be lost from the opposite side of the body. Dis-
turbances in the recognition of the position of the limbs and of passive
movement and the distinctness of two points applied to the skin at once
(two dimensional localization) occur, in the case of a considerable uni-
lateral lesion, on the the same half of the body as the lesion, because the
ascending tracts for the impulses involved in these sensations are
uncrossed. On the contralateral half of the body dissociation occurs
between heat, cold and pain, which are obliterated, and the tactile sen-
sations which persist. On the homolateral half of the body the dissocia-
tion is between the sensations of two and three dimensional localization,

THE AFFERENT PATHS OF SENSORY IMPULSES 871

which are obliterated, and touch, heat, cold and pain which remain
normal.

Lesions of more limited distribution may produce dissociations of a
more simple character. Because the fibers conducting the impulses for
pain, heat, and cold are grouped together into separate tracts for each
quality of sensation a limited lesion may destroy one of these qualities
without affecting the others. The close association of the three groups,
however, makes it probable that a lesion affecting one will affect them
all, so that in the majority of cases heat, cold and pain will all be affected
together. When dissociation occurs as the result of spinal lesions, cu-
taneous and deep sensibility of any given quality suffers alike, and as a
result these dissociations have a distinctly different character from those
due to peripheral nerve lesions.

The loss of sensation which results from interruption of the afferent
tracts in the cord affects parts which may be remote from the lesion.
But if the destruction involves only the gray matter of the cord, it will
not disturb those impulses which pass through either the crossed or
uncrossed tracts of the cord at the level of the lesion, but only those
whose paths entered the gray matter and cross the cord. As a result the
sensation of heat, cold, and pain may be absent from a segmental area on
the side of the body corresponding to the lesion, or if the destruction is
more extensive, these sensations may be absent from a segmental band
completely encircling both sides of the body, without any disturbance
affecting the sensation of the lower segments, impulses from which have
crossed the cord at a lower level and pass the lesion in the tracts of the
lateral column. Segmental disturbances of this type are distinguished
as the local effects of an intermedullary lesion. If the lesion is exten-
sive so that both white and gray matter is destroyed on one side of the
cord, a combination of the local and remote effects occur, with the re-
sult that pain and the temperature senses are lost over the entire half of
the body opposite to and below the lesion and also over a local segment
at the level of, and on the same side as, the lesion.

Afferent Paths in the Brain Stem

On reaching the medulla all impulses producing sensations of pain,
heat, cold, and touch (including one dimensional localization) have
crossed the cord. . They continue without interruption through the brain
stem in the tractus spinothalamicus lateralis to terminate in the nuclei
of the optic thalamus. In their course they are joined by impulses from
the cranial nerves, which have also crossed to the side of the brain stem
opposite to that from which they have entered. Impulses which give rise
to the recognition of posture, passive movement, and two dimensional
localization reach the medulla 011 the side from which they have origi-

872 CENTRAL NERVOUS SYSTEM

nated. They have been conducted along fibers of primary afferent neurons
which terminate in the nucleus gracilis and nucleus cuneatiis, from which
arise the secondary afferent neurons which carry them to the optic thal-
amus. These fibers cross the medulla immediately and take up a position
in the medial lemniscus close to those which are conducting impulses for
the sensations of pain, temperature, and touch. In their passage through
the brain stem impulses for all qualities of sensation follow tracts which
are grouped together closely in the opposite side from that which they
have originated. Lesions in the brain stem consequently tend to produce
a complete, contralateral anesthesia. Impulses for any one quality of
sensation are still grouped together in tracts which are distinct from
those carrying impulses for other qualities of sensation. Consequently
lesions of limited extent may abolish sensation of any one quality with-
out disturbing the other qualities of sensation. Observations on cases
of lesions of this sort indicate that impulses involved in the recognition
of posture and movement, which have been associated with those for the
two dimensional localization in their passage up the spinal cord, become
separated in the brain stem, so that the power of recognizing posture and
passive movement can be effected independently of the discrimination
of two points applied simultaneously to the skin.

Afferent Impulses Which Fail to Produce Sensation

Those impulses which are destined to give rise to sensation will be
traced in their course beyond the termination of the secondary afferent
neurons in the nuclei of the optic thalamus, but we shall first consider
the courses followed by those afferent impulses which do not reach the
level of consciousness. These are of three types: (1) the afferent im-
pulses of spinal reflexes, (2) the afferent impulses of visceral reflexes,
(3) the afferent impulses of cerebellar reflexes.

The Afferent Paths of Spinal Reflexes. — The connections within the
cord for spinal reflexes are undoubtedly very primitive. They do not,
however, appear to have been worked out in many cases or in great de-
tail. The simplest reflexes probably involve neurons lying in a single
segment and on one side of the cord. The flexion reflexes which result
from noxious stimuli applied to the limbs are of this type. In other cases
the reflex pathway may extend through many segments, but lie totally
within one half of the cord. An example is seen in the scratch reflex ol;
the brainless dog. The method by which its course was worked out by
Sherrington was described on page 849. It was found to consist of an
afferent neuron connecting the skin of the shoulder with the grey matter
of the cord in the upper thoracic region, a propriospinal neuron having
its cell body in this part of the cord and its axon descending in the lateral
column of the same side to connect with the motor neurons of the limb

THE AFFERENT PATHS OF SENSORY IMPULSES 873

muscles which are involved in the scratching movements. Other reflexes
are executed through paths which cross the cord. In addition to pro-
ducing a flexion of the foot to which it is applied, a strong noxious stim-
ulus causes an extension of the opposite limb. This is known as the
crossed-extension reflex. Crossed reflexes also involve paths which trav-
erse considerable lengths of the cord. Thus a flexion of the hind limb,
produced by a noxious stimulus applied directly to it, is frequently ac-
companied by a flexion of the fore limb on the opposite side of the body.

The Afferent Paths of Visceral Reflexes. — The visceral reflexes are con-
cerned chiefly with the regulation of the circulation, respiration, and the
motor activities of the internal organs. Such reflexes are set up by af-
ferent neurons extending to the visceral organs themselves as well as
to the skin and muscles.

Visceral afferent fibers are found in the ninth and tenth cranial nerves
and in the spinal nerves. Their cell bodies lie in the ganglia of the
medulla and in the dorsal root ganglia of the spinal nerves. The fibers
reach the viscera by following the course of the pre- and postganglionic
fibers of the autonomic nervous system, passing through the ganglia and
plexes without interruption. In spite of this close anatomical associa-
tion with the autonomic nervous system, the visceral afferents are analo-
gous in function and homologous in origin and structure with the affer-
ent neurons from the skin and muscles. It is logical to classify the vis-
ceral afferents with the latter, rather than with the autonomic system
which is wholly motor in function. While certain impulses from the
visceral afferents reach the sensory centers of the brain and give rise to
visceral pain and the other sensory symptoms of visceral disease, the
greater number never affect consciousness. They take part rather in the
execution of visceral reflexes, which modify the activity of the muscles
of the internal organs and regulate the blood flow through them in ac-
cordance with the varying demands of their functional activity. The
most important visceral afferents are those which modify the action of
the cardiovascular and respiratory centers of the medulla. The depres-
sor nerve and the afferent fibers of the vagus which extend to the lung
are examples with which we are already familiar (pages 243 and 227).
The centers regulating blood pressure and respiration are also influenced
by impulses which have their normal origin in the receptors of the skin
and which may be initiated by stimulating the nerve trunks in the limbs.
Ranson and von Hess have studied the location of the afferent pathways
in the cord over which such impulses travel.

Two kinds of vascular reflexes were studied, pressor and depressor,
the former being elicited by strong and the latter by very feeble stimu-
lation of the central end of the sciatic and brachial nerves. They found
that the pathways for the pressor and depressor afferent impulses were

874 CENTRAL NERVOUS SYSTEM

quite different. Thus, after lateral hemisection of the cord, the depres-
sor reflex obtained by weak stimulation of the sciatic on the same side
as the lesion was normal, whereas it was greatly reduced when the sciatic
nerve on the opposite side from the lesion was stimulated. On the other
hand, the pressor reactions that were most markedly diminished were
those from the sciatic on the same side as the lesion. The depressor fibers
evidently cross in the cord, whereas the pressor do so only to a limited
degree. Further it was found, after cutting across the posterior part of
the cord, that the pressor reflexes were interfered with but not the de-
pressor, thus indicating that the former are transmitted either by the
posterior columns of white matter or by the gray matter of the posterior
horns. To determine which, experiments were also performed in which
the posterior columns were alone destroyed and the results compared
with others in which the tip of the posterior horn was included. Since
it was only in the latter experiment that any interference with pressor re-
flexes was found to occur, it was concluded that the posterior horn alone
is concerned in the transmission of pressor impulses.

Regarding conduction of the afferent impulses which in consciousness
produce pain and of those concerned in the reflex changes in respiration,
it was found that the posterior horn of gray matter is not concerned,
from which it is inferred that such impulses are conducted by the same
afferent path that is involved in the depressor reflex; that is to say, as
we have indicated above, the impulses cross in the cord to the opposite
side and ascend in the lateral funiculus.

The Afferent Paths of Cerebellar Reflexes.— The cerebellum is con-
cerned with the coordination of muscular movement, and must be in con-
tinuous receipt of information concerning the changes in the position of
the limb's which result from voluntary and reflex movement. The pri-
mary afferent neurons of cerebellar reflexes are doubtless those which
extend to the muscles, joints, and tendons along with the afferents of
deep sensibility. Inasmuch as cerebellar injuries produce no loss of
sensation, impulses extending into the cerebellum probably produce their
effects without entering into consciousness. Consequently we can learn
about the afferent paths of cerebellar reflexes only by inference from
the anatomical arrangements and by observing the disturbances in co-
ordinated movement which result from various lesions in the nervous
system.

The chief tracts in the cord which degenerate in an anterior direction
and extend into the cerebrum are the tractus spitwcerebellaris dorsalis
and the tractus spinocerebellaris ventralis. The fibers of both these
tracts lie in the lateral column of the cord, and many of their fibers ex-
tend directly into the cerebellum, the former by way of the inferior

THE AFFERENT PATHS OF SENSORY IMPULSES 875

peduncle, the latter by way of the superior peduncle. Experiment shows
that after cutting the tractus spinocerebellaris dor sails a slight degree
of ataxia and loss of tone in the muscles innervated from below the lesion
may result, thus confirming the inference from the anatomical arrange-
ment that this tract is one of the afferent paths of cerebellar reflexes.
Head suggests that in their passage up the cord within the dorsal funicu-
lus, the primary afferent neurons concerned with the conduction of im-
pulses for the regulation of posture and movement give off collaterals
which lead part of these impulses into the direct cerebellar paths, and
that this is the reason why such afferent paths for deep sensibility remain
uncrossed until they reach the medulla.

CHAPTER XCIV

THE SENSORY CENTERS OF THE BRAIN

Sensory experience and the recognition of the quality and location of
stimuli acting upon the receptors of the body depends upon the arrival
of impulses at certain stations in the brain which correspond to the re-
ceptors in question. Knowledge concerning the location of the centers
involved in the perception of sensations arising from each kind of recep-
tor and from each part of the body has been gained by inference from
the anatomical arrangements of the fibers connecting the sense organs
with the various parts of the brain and from studies of the reactions of
animals which have had certain parts of the brain removed. But this
information is of slight value, since we can learn about a sensation di-
rectly only through the verbal report of the person who is experiencing
it. Consequently the important contributions to the sensory physiology
of the brain have come from the clinical study of individuals who have
suffered injury in some part of the cerebrum. Gushing12 induced two
patients in whom part of the brain was exposed to allow him to stimulate
it while they were in a conscious state. As the result of the stimulation
of the postcentral convolution definite sensory impressions were experi-
enced, consisting of a sensation of numbness, deadness, or tactual im-
pressions. No muscular groups underwent movement unless the precen-
tral convolution was stimulated, when no sensations were experienced
by the patient except those which accompanied the change in the posi-
tion of the part that was moved. The sensations which were thus shown
to be represented on the cortex are those of touch discrimination and
those relating to the position and movements of the muscles. A com-
prehensive analysis of sensory localization has been made by Head9 from
observations on soldiers suffering from the wounds of war.

The Sensory Center of the Optic Thalamus

It has long been recognized that the cerebral cortex is the site of cen-
ters concerned in the perception of many qualities of sensation. Ex-
periments by Goltz on a dog from which the cortex had been removed,
suggested that certain subcortical centers might also give rise to sensa-
tion, since this animal responded to various sensory stimuli, and when
hungry gave evidence, so far as his actions were concerned, of experienc-
ing sensations of hunger. Head's clinical observations have led him to

876

THE SENSORY CENTERS OF THE BRAIN 877

assign a very important part in the origin of certain aspects of sensation
to a center which he terms, the essential organ of the optic thalamus.

According to this view, afferent impulses may affect consciousness in
two distinct ways on arriving in the optic thalamus. They may act upon
this sensory center of the thalamus, or they may pass on to the sensory
areas of the cerebral cortex. The presence of a sensory center in the
thalamus, and the nature of the sensations aroused as the result of its
activity, are indicated by the sensations which are experienced by in-
dividuals in whom the sensory areas of the cortex have been destroyed.

In their path through the cord and brain stem afferent impulses have
been grouped on a strictly physiological basis, all impulses arising from
a common type of receptor traveling together. On reaching the optic
thalamus, a regrouping occurs on a psychological basis, the subsequent
course of the impulse depending on the kind of appeal which it is to
make to consciousness. The thalamic organ is the center for "aware-
ness," responding to all stimuli capable of producing sensations of a
change of 'state. The cerebral centers, on the other hand, are recipients
of impulses which give rise to the discrimination of the detailed qualities
of a sensation.

A patient suffering from the destruction of the cerebral sensory area
will exclaim, "Something is happening to me, I am being hurt," instead
of "You are sticking a pin into me," because he fails to recognize the
distinctive characters of the stimulus in question. The cerebral cen-
ters, on the other hand, are concerned with the recognition of fine detail
in sensation, enabling us to perceive not only the presence of a stimulus
and its gross quality, but also to discriminate between stimuli of differ-
ent intensities, to recognize the shape, size, weight, and texture of the
stimulating object and to recognize the position of the hand as it explores
its surface. Thus, to compare the sensations evoked by stimuli of each
of the primary qualities in individuals who have lost the function of the
cerebral centers with normal individuals, it is found that contact is rec-
ognized, but the distinction of differences in /the intensity of the stimulus
cannot be made by the unaided thalamus. The special aspects of tactile
sensation, including the impulses involved in one, two, and three dimen-
sional localization make no thalamic appeal, so that neither the location
of the point stimulated, nor the position of the parts of the body are
recognized. Painful stimuli affect the thalamic center powerful^, giving
rise to sensations of discomfort, deprived of the distinctive qualities
which we recognize in painful sensations when the cortex is intact. The
recognition of gradations of pain cannot be accomplished by the thala-
mus alone. The thalamus can distinguish between heat and cold, as
such, but makes no distinction between various degrees of warmth or
coolness. Thus if a glass of hot water is placed in the hand of an in-

878 CENTRAL NERVOUS SYSTEM

dividual whose cortical area corresponding to the hand is damaged, he
will recognize the contact of the object, and will know that it is unpleas-
antly hot. He will be unable, however, to perceive the roundness, size,
or weight of the vessel, to know how hot it is, or to recognize the posi-
tion of the hand which grasps it.

. The Sensory Centers of the Cerebral Cortex

The Area of Cutaneous and Deep Sensibility. — Impulses giving rise to
cutaneous and deep sensibility which pass from the termination of the
secondary afferent neurons in the optic thalamus to the cerebral cortex
divide themselves into seven afferent streams, which may be affected by
cortical lesions more or less independently. These comprise impulses
concerned with the appreciation of (1) touch, (2) one dimensional local-
ization, (3) two dimensional localization, (4) three dimensional local-
ization, (5) pain, (6) heat, (7) cold. They pass to areas in the cortex
which are more or less distinct for sensations arising from different parts
of the body, and for sensations of different psychical quality. The sen-
sory area for these sensations consists of the pre and post central convo-
lutions, the anterior part of the superior parietal lobule and the angular
gyri. Afferent impulses arising from one half of the body cross the
cord or medulla in their ascent and affect this part of the cortex of the
opposite side of the brain, so that the sensory disturbance which arises
from a unilateral injury of the cortex expresses itself by a loss in sensory
discrimination in contralateral parts of the body. Each of these parts
is represented in a definite part of this sensory cortex. The lower ex-
tremity is represented in the upper part of this area, the upper extrem-
ity in the middle portion and the head in the lower portion. The extent
of the cortical area corresponding to the different parts of the body is
proportional to the functional complexity of their acts and sensations.
Consequently the hands are represented by a very large region; the feet
and face by extensive areas compared with which the representation of
the proximal parts of the limbs and trunk is insignificant. The chances
are consequently greatly in favor of an injury to the sensory cortex, af-
fecting one of these parts of the body, and it is very rare that a prox-
imal part of a limb is affected without the distal part sharing in the dis-
turbance. In the sensory area for the hand, distinct regions exist for
each finger and the, corresponding proximal part of the hand. The area
for the little finger adjoins the area for the lower extremity, with the
result that loss of sensation involving the little finger also usually is
accompanied by a disturbance of sensation in the foot. The ring, mid-
dle, index fingers and thumb are represented one below the other in the
sensory cortex, the thumb area adjoining that for the face, so that sen-
sory disturbances in the thumb and face are apt to occur together.

THE SENSORY CENTERS OF THE BRAIN 879

When sensory loss is occasioned on any part of the body as the result
of a limited injury to the cortex, all aspects of sensation are not affected
equally, with the result that the ability to respond with accuracy is lost
more completely and over a larger area in the case of certain tests than
in others. Such dissociations in the sensations which depend on cor-
tical activity conform to two general principles. First: The more com-
plex and difficult the psychical act required for an accurate ansAver to
the test, and the more completely the test appeals to the cortical center
in contrast to the thalamic 'center, the greater is the area of disturbed
sensibility, and the more complete is the sensory loss in any one part of
this area. Thus the extent and degree of disturbance is greater in the
case of recognition of posture and movement than In the case of two
dimensional localization, and is least for one dimensional localization,
which obviously involves a simpler psychical judgment. Sensibility to
touch is modified more than to temperature, and temperature more than
to pain, because these sensations depend in this order on the cortex as
contrasted to the optic thalamus.

Second: The various aspects of cortical activity depend upon the in-
tegrity of different parts of the sensory area. These aspects are (1) spe-
cial recognition, typified by the sense of posture and movement, which
is dependent chiefly on the part of the sensory cortex which occupies the
precentral convolution; (2) the recognition of similarity and difference,
on which depends the comparison of weights held in the hand, etc., which
resides in the postcentral convolution; and (3) the recognition of the
intensity of the sensation, whether it be of touch, temperature or pain,
which is centered in the foot of the postcentral convolution, and in those
parts of the sensory area lying behind this convolution. It appears that
the sensory area of the cortex may be divided into certain horizontal
zones which are each involved in sensation arising from stimuli acting
on various parts of the body and into three nearly vertical zones involved
each in the three fundamental aspects of discrimination. The cortical
localization is based therefore, not on purely anatomical relationships
by which each part of the body would be represented in all its sensory
manifestations by a single part of the cortex, but on functional require-
ments, according to which each psychical act of sensory discrimination
is centered in a different group of cortical cells. Since these processes
are distinct for the different parts of the body, these parts have a sepa-
rate representation in the cortex, but the magnitude of the area devoted
to each part of the body is dependent solely on the degree in which sen-
sation arises from it.

The Olfactory, Gustatory, and Auditory Areas. — The cerebral cortex
contains in addition to these centers for cutaneous and deep sensibility
certain areas on which depend the perception of olfactory, gustatory,

880 CENTRAL NERVOUS SYSTEM

auditory, and visual sensations. Very little of importance can be said
of the physiology of the olfactory and gustatory centers, which are
thought to lie in the hippocampal convolution of the median aspect of
the temporal lobe, the former occupying the more distal position. The
auditory center lies in the lateral side of the temporal lobe. Complete
destruction of both temporal lobes causes deafness, but if one lobe only
is destroyed, hearing is not impaired in either ear. It appears from this
that the afferent paths from each ear lead to both temporal lobes, so that
if the auditory center in one lobe only is injured, the center in the other
lobe can carry on auditory perception for both ears. Consequently it is
very unlikely that deafness will result from a cerebral injury.

The Visual Areas. — The visual centers are known with much greater
precision. In order to explain the disturbances in vision which result
from lesions in the visual centers, a word must be said about the
formation of images upon the retina and the course of the afferent fibers
which pass from the retina to these centers. The optical mechanism of
the eye is such that the image of any object at which one looks is in-
verted when it falls upon the retina. Consequently the upper part of
the visual field falls on the lower part of the retina, the left half of
the visual field falls on the right half of .the retina, etc. The optic nerves
from the two eyes meet at the optic chiasm, and there about half the
fibers in each nerve cross to the opposite side of the brain and follow
a course which leads to the visual center, which is contralateral to the
eye in which they arose. The other half of the fibers in each nerve do
not cross in the chiasm, but continue through the brain by a path which
leads to the visual center on the same side of the body as the eye in which
they arose. The remarkable thing about this arrangement is that the
fibers which cross in the chiasm are those which arise from the median
half of both retinas. As a result, the left visual center receives all im-
pulses which arise from the left halves of the retinas of both eyes, and
since these impulses are set up by objects whose images are inverted
upon the retinas, this visual center is affected by the right half of the
visual field. Conversely the right visual center is affected by the left
half of the visual field. A consideration of Fig. 216 will make this rather
complicated situation more clear. This arrangement is associated with
binocular vision, that is, the simultaneous use of both eyes in viewing
a single object. In the lower vertebrates, in which the eyes are on op-
posite sides of the head and consequently have different visual fields
the crossing in the chiasm is complete. The arrangement in man is of
obvious importance in causing the images formed by the two eyes to
effect simultaneously the same sensory centers in the brain.

Because of this arrangement certain characteristics appear in injuries to
the various parts of the optic tracts. A lesion located distal to the chiasm

THE SENSORY CENTERS OF THE BRAIN

881

Visual Field

Occipital Lobes

Fig. 216. — Afferent paths connecting the retina with the visual area of the cerebral cortex.

will cause blindness in one eye alone. Lesions, such as those produced
by the pressure of a pituitary tumor upon the chiasm, may destroy the
function of those fibers which are crossing in the chiasm, and as a re-
sult a type of blindness known as bitemporal,hemianopsia results. This
is a loss of sight in the temporal half of both visual fields, occasioned
by destruction of the decussating fibers, which, as we have pointed

882 CENTRAL NERVOUS SYSTEM

out, arise in the nasal half of each retina. Complete destruction of
one of the visual tracts between the chiasm and the sensory area of the
cortex produces a condition called homonymous hemianopsia, or blindness
in the same half of the visual field of both eyes. Thus destruction of
this part of the left optic tract which contains fibers from the left half
of both eyes will produce blindness for the right half of their visual field.
The visual area of the cortex is located about the calcarine fissure on
the median and posterior surface of the parietal lobes. Its area is
sufficiently great to make it probable that a lesion will involve only cer-
tain parts of it, and as a result produce blindness in only part of the
visual field. By correlating the position of lesions with the resulting
loss of vision it has been possible for Holmes and Lister10 to determine
what part of the visual area corresponds with each part of the retina.
They found that the center of each retina, or macula, is represented in
the posterior part of the visual area. The superior quadrant of each
eye is represented in the upper, and the inferior quadrant in the lower
half of the visual area anterior to the center for macular vision. It
has previously been held that the center of each retina was represented
in the visual area of both sides of the brain. This was because in the
lesions of civil life homonymous hemianopsia rarely affected the center
of the visual field in the blind half of the eyes. Holmes and Lister
found, however, in cases where the visual area of one occipital lobe
was completely destroyed that vision was lost in the central part of the
corresponding half of the retina quite as completely as in the more
peripheral portions: They conclude consequently that the macula, like
the rest of the retina, is not represented bilaterally in the cortex. The
discrepancy in the condition, as they observed it, in wounded soldiers,
and as it occurs in civil life, depends upon the fact that in the latter
case the cause of the lesion is usually a disturbance of the circulation
of the cortex as the result of thrombosis, hemorrhage, etc. The macular
part of the visual area is supplied with capillaries from two sets of ar-
teries, those of the median and of the lateral surface of the occipital
lobe. An occlusion of the median supply would destroy the visual area
for the peripheral half of the retina, but would leave intact the macular
region which would be sufficiently nourished by the blood from the
lateral arteries.

Riddoch11 has noted that in case of injury to the occipital lobe, disso-
ciations in visual sensations occur which are quite comparable to the dis-
sociations which may occur in lesions of the sensory cortex for cutaneous
and deep sensibility. These manifest themselves in the case of patients
who are recovering from a functional disturbance of the visual areas.
The first visual perception to appear is the recognition of the movement
of an object in the visual field, which occurs long before the object as

THE SKNSORY CENTERS OF THE BRAIN 883

such can be recognized. A case is also described in which vision persisted
in one half of the visual field on recovery from an occipital injury, and
yet things which were seen quite well could not be oriented in space,
and thickness and depth found no place in the visual perception.

The sensory areas of the cortex and thalamus are the end points to
which we trace the afferent impulses which give rise to sensation. We
are not justified, however, in concluding from this that they are the
regions in which the phenomena of sensation and consciousness occur.
Rather should they be thought of as important junction points on the
afferent side of the complex network of neurons which links up the
various centers of the cerebrum and in which are carried out our mental
processes, which give rise to consciousness. In a similar way the motor
centers which we are to consider in the next chapter are the junction
points from which start out the efferent impulses for voluntary move-
ment.

Sensory Hallucinations. — It seems probable that under pathological
conditions disturbances may be set up locally in the sensory centers
which resemble closely those naturally occurring as the result of peri-
pheral stimuli. Thus in Jacksonian epilepsy the irritation arising from
a splinter of bone pressing upon one of the sensory centers may give
rise to vague sensations or aura, such as flashes of light, loud noises, or
tingling in the skin. If such disturbances resemble closely enough those
occurring naturally, they may give rise to those conscious phenomena known
as hallucinations and the sensory disturbance manifests itself as a definite
vision, or the sound of a bell or whistle. Use has been made of the
fact that hallucinations may be set up by cortical stimulation, in tracing
out the sensory areas in animals. If an irritant such as strychnine be
applied locally to the cortex, the sensation is referred by the animal to
the corresponding portion of the body and an effort made which is di-
rected toward removing the irritant from this region. Thus irritation
of certain regions in the cortex will cause the animal to shake one paw
and attempt to brush away from it the supposed source of the sensation.

CHAPTER XCV

THE MOTOR AREAS OF THE CEREBRUM AND THE EFFERENT
PATHWAY TO SKELETAL MUSCLE

It is a debatable question whether motor acts are ever initiated by the
nervous system except in response to some stimulus which sends afferent
impulses into the brain or cord, or as the result of changes in the im-
mediate environment of the nerve centers due to abnormal conditions in
the circulation. There are, however, a large group of responses the nature
of which is conditioned not only by the immediate stimulus which calls
them forth, but by the previous experience of the organism. Situations
which have existed in the past leave their mark upon the nervous system
in the form of memories, associations and the like, and these determine
how the animal or man will behave when new groups of stimuli, or sit-
uations, arise. We shall see later, how previous experience may alter the
nature of even involuntary responses to simple stimuli, when we
take up the formation of conditioned reflexes (page 954). In the present
place it will suffice to point out that unless we have considerable knowl-
edge of the past experience of an animal it is impossible to predict how
it will respond to certain situations. Responses of this type consequently
are not obviously and invariably related to any particular stimulus, as
are the simpler reflex responses, and consequently appear to arise spon-
taneously in the nervous system. They are consequently called voluntary
acts, which we shall take to imply that their nature and occurrence is
related quite as closely to preexisting conditions in the nervous system
as to the immediate situation which brings them ijorth.

In animals from which the cerebrum has been removed, motor responses
of a very perfect nature may still be carried out. A pigeon in this con-
dition can walk, fly, coo, etc., quite normally, and if fed may live indefi-
nitely. A dog from which the cerebral cortex is removed shows strik-
ingly little difference in its behavior from a normal animal. Its equilib-
rium is good, it moves easily, avoiding objects in its path, swims when
thrown into water, feeds himself if food is brought into contact with
his nose and rejects food of disagreeable taste. The reactions of such
animals become almost strictly predictable, because they show no signs
of being influenced by past experience. The pigeon is no longer fright-
ened by a loud noise or sudden movement, nor does it suddenly become
active for no obvious reason as a normal bird would. The dog shows no

884

MOTOR AREAS OF THE CEREBRUM

885

sign of affection or memory of its master, it does not recognize food as
good to eat by its mere appearance, nor does it give signs of dreaming as
normal dogs do. The mechanism by which the retention and association
of the effects of past experience modifies behavior and produces acts of
an apparently spontaneous and volitional nature evidently resides in
the complicated meshwork of neurons which compose or connect the
various parts of the cerebral cortex.

The Motor Areas of the Cerebral Cortex

Just as we saw in the last chapter that there were certain junction
points, or sensory areas, by which afferent impulses are led into the

Anus & Vagina

Toes/?'

Ankle ;

Knee

,Sulcus centralis

-Abdomen

Shoulder-

Fingers
sthum

YES

Sulcus centrolis

Fig. 217. — Outer aspect of the brain of the chimpanzee, showing the position of the motor centers.
Electric stimulation at the parts indicated causes coordinate movements of the corresponding mus-
cle groups. (After Sherrington.)

cerebral cortex so there are certain foci from which efferent impulses
leave the cortex to initiate movement in the skeletal muscles. ' These
are the motor areas of the cortex. Their situation and the groups of
muscles related to each part of the motor area have been made out by
two methods. In animals, and, under exceptional conditions, in man, the
cortex may be excited locally, preferably by some method of unipolar
electrical stimulation, and the groups of muscles brought into action
may then be noted. By this method the most precise data has been
obtained, especially in experiments upon the higher apes, the topography

886 CENTRAL NERVOUS SYSTEM

of whose brains most closely resembles that of man. Conversely parts
of the cortex may be removed and the distribution of the muscles which
are then no longer under voluntary control may be determined. By
these methods it is learned that the principal motor area lies in the
cortex immediately in front of and extending into the fissure of Rolando.

The Representation of Functional Activity in the Motor Area. — When
this area is explored with a localized electrical stimulus it is found that
definite parts of the body are excited by the stimulation of definite
parts of the motor area. There is then, just as in the case of sensory
areas, a region corresponding to each anatomical part of the body.
Movements of the muscles of the head are occasioned by excitation of
the lower portion of the area; above it the neck, arms, trunk, and legs
are represented in turn. Again, like the sensory areas, the representation
is in respect to the functional use of the parts, so that each part of the
cortex is the focus for impulses giving rise to an orderly act rather than
to the contraction of a single muscle. This is shown by the fact that a
weak, sharply localized stimulus gives rise to a coordinated movement
such as the animal might make volitionally, in which certain groups
of muscles contract while their opponents relax by virtue of a reciprocal
inhibition. Thus stimulation of an appropriate area in the motor area
of the monkey will cause the fist to be clenched, an act which involves
the setting of the extensors of the wrist, the relaxation of the extensors
of the fingers, and the contraction of the- flexors of the fingers. Because
the thing represented in the motor area is a complete functional act,
the areas related to each region of the body vary in size with the num-
ber and complexity of the acts performed by these regions. Consequently
the head and arm occupy a large part of the cortex because of the
intricacy of the muscular acts which may be carried out by the face,
tongue, and fingers. The leg likewise has a large representation when
compared with the trunk, the functional reactions of which are obviously
limited. In the cat the sensory and motor areas of the cortex for the
head, limbs and trunk also coincide in their position, but in the higher
apes and man they have become separated for the most part. Only
those aspects of sensation which are concerned with the recognition of
spacial relationships, particularly of the muscles and joints are repre-
sented in the part of the cortex which lies in front of the fissure of Ro-
lando, and in which the motor functions lie. This is an obvious relation-
ship since a very close association is to be expected between the func-
tions of coordinated movement and of recognition of the position and
movement of the limbs, etc.

The Visuo-Motor Areas. — In addition to the large motor area there are
two smaller areas, excitation of which gives rise to movements of the
ocular muscles. One of them, the frontal visuo-motor area, is located

MOTOR AREAS OF THE CEREBRUM 887

on the frontal lobe. Its excitation causes conjugate deviation of both
eyes to the opposite side. The second area lies in the occipital lobe
coinciding approximately with the center for visual sensation. Stimula-
tion of it also causes eye movements, and these are not simply the result
of referred sensations which result in movements initiated from the
frontal visuo-motor center, since they persist after the latter has been
destroyed. Consequently the occipital visual center is both sensory and
motor in function.

Physiological Bases of the Clinical Effects of Lesions in the Motor
Area of the Cortex. — Stimulation of the motor area of the cortex causes
usually a response on the part of the muscles on the opposite side of the
body. From this it appears that the connections between the two halves of
the cortex and the muscles they control is a crossed one. In agreement with
this is the fact which has been known since very ancient times that in-
jury to one side of the brain frequently results iri paralysis of certain
voluntary movements on the opposite side of the body.

But since cortical lesions are usually small in comparison to the area
of the motor regions, the derangement more commonly affects muscular
acts represented in a limited area of the cortex and as a result the move-
ments of a single arm, of one side of the face, or of one leg are removed
from voluntary control. Such a limited, unilateral paralysis is called
monoplegia.

Jacksonian Epilepsy. — When the strength of the stimulus applied lo-
cally to the cortex is increased, its influence spreads so that adjoining
motor cells are brought into activity and larger and larger groups of
muscles take part in the response. This progressive " march" of the
response to cortical stimulation is usually limited in its spread to the
opposite half of the body, in this way differing markedly from the
spread of spinal reflexes, which we have seen occurs when the stimulus is
increased (page 842).

The foregoing results obtained by experimental stimulation in animals,
are very similar to the symptoms observed in man when the cerebral
cortex is stimulated by the pressure on it of a meningeal tumor or a
spicule of bone. Such stimulation causes contraction in the correspond-
ing muscular area; the contraction then spreads to neighboring groups
of muscles, and may ultimately involve the whole musculature of the
body in a convulsive fit. This is known as Jacksonian epilepsy, and
it is to be distinguished from ordinary epilepsy by the fact that the
patient does not become unconscious during the fit. Like ordinary
epilepsy, however, the Jacksonian type is usually preceded by a pe-
culiar sensation of numbness or tingling in the area that is to show
the first contraction. One of the greatest achievements of modern
brain surgery is the cure of a Jacksonian epilepsy, by trephining the

888 CENTRAL NERVOUS SYSTEM

skull over the affected center and removing the meningeal tumor or
spicule of bone which is responsible for the stimulation. To enable
the surgeon to locate exactly the position of the irritating body, it is
necessary to examine the patient very closely as to the muscular group
which is initially affected during the convulsions, and then to examine
an outline map of the cerebral hemisphere indicating the position of
the various motor and sensory areas as deduced mainly from experi-
ments on the higher monkeys and verified by the experience gain'ed
by previous operations. Topographic maps indicating the surface mark-
ings corresponding to the various convolutions of the cerebrum must
also be used. In such operations the surgeon often has the opportunity
of experimentally verifying the position of various centers.

The entire cortical representation of motor acts does not follow
this strictly crossed unilateral arrangement. Voluntary movements which
involve muscle groups limited totally to one half of the body for their
completion are generally represented in the cortex of the opposite side.
Certain symmetrical muscle groups which commonly operate in syn-
chrony such as those involved in mastication also are represented in
and controlled by the contralateral cortex. On the other hand stimula-
tion of the frontal visuo-motor area of one side causes deviation of
both eyes towards the opposite side so that the movement of each eye
must be represented on both halves of the brain. When the motor
area of one side of the brain is destroyed, the movements of certain
bilaterally acting muscles, such as those of inspiration, of movements
in the diaphragm, intercostal and abdominal muscles and those of the
larynx are not affected on either side. This may be due to a bilateral
representation of these muscles in the cortex, as in the case of the ocular
movements, to the fact that certain of the efferent fibers connecting the
cortex, with the lower motor neurons do not cross to the opposite side
of the cord, or to the commissural connections which link one half of
the cortex with the other.

The Efferent Pathway in the Brain and Cord

The crossed connection betAveen the cerebrum and the functional
groups of muscles which it controls is due to the arrangement of the
efferent neurons which link it with the motor neurons of the cord and
brain stem. The most important tract involved in conducting efferent
impulses from the motor areas arises from the large pyramidal cells
(Betz cells) which are characteristic of the motor areas of the cortex
and do not occur in its other parts. This is the pyramidal tract (tractus
cortico-spinalis). Its fibers converge from the various parts of the motor
area as they approach the internal capsule of the cerebrum, and pass
through the midbrain without crossing. At the level of the pons fibers

MOTOR AREAS OF THE CEREBRUM 889

are given off which cross to the nucleus of the facial nerve 011 the op-
posite side of the body. Similarly fibers leave the main tract in the
upper part of the medulla to cross and connect with the hypoglossal
nucleus. The main decussation of the pyramidal tract occurs in the
lower part of the medulla. A small bundle of fibers continue beyond this
point uncrossed and descend the cord in the direct pyramidal tract,
(tract us cortico-spinalis ventralis) in the ventral column of the cord. The
fibers which enter the decussation in the medulla descend the cord in
the crossed or lateral pyramidal tract (tractus cortico-spinalis lateralis)
in the lateral column of the cord. In these tracts the pyramidal fibers
descend to the level of the motor neurons of the peripheral nerves. The
connection between cortex and muscle is consequently probably con-
summated by no more than two nerve cells, the pyramidal and the lower
motor neuron. It is quite conceivable that other descending tracts in
the cord may be involved in voluntary acts, but their relationships are not
clearly enough understood to enable us to base our explanations of the
motor symptoms of nervous disease upon their action.

The Paralysis Resulting from Injuries to the Pyramidal Tract.— The
arrangement of the pyramidal fibers in their descent through the cord
imposes certain characteristics on the distribution of the paralysis which
results from lesions in different parts of their course. We have seen
that lesions in the cortex rarely result in a complete destruction of the
motor area, so that the resulting paralysis is usually limited to a few
groups of muscles on the opposite side of the body. Such monoplegia
would be accompanied by no loss of sensation, or by impairment in the
special aspects of sensation in a limited region. In deeper parts of the
brain the pyramidal tracts converge with the result that a lesion the
size of a pea in the internal capsule will result in a complete destruction
of the tract. Monoplegia is consequently rare at this level, the paralysis
usually involving the entire opposite side of the body. Such a condi-
tion is known as hemiplegia. If lesions in this region affect sensibility,
the discriminative aspects of it will be destroyed, but those sensations
which make a thalamic appeal will persist. Lesions in the brain stem
as far back as the pons will similarly produce complete contralateral
hemiplegia, accompanied usually, if they affect the afferent paths of
sensation, by complete anesthesia on the paralyzed half of the body. At
the pons the first group of pyramidal fibers cross to the opposite side to
connect with the facial nerve. Lesions in the lower part of the pons
consequently do not involve these fibers and the facial muscles of the
opposite side do not share in the paralysis. This lesion, however, will
interrupt the tracts from the opposite cerebral hemisphere which have
crossed to join the facial nucleus on the side of the lesion. Consequently
the face becomes paralyzed on the same side as the lesion. The decussa-

890 CENTRAL NERVOUS SYSTEM

tion of fibers to the hypoglossal nerve produces a similar alternating
paralysis of the muscles of the tongue and of the limbs in case of lesions
in the medulla. The tongue is paralyzed on the same side as the lesion,
the arms and legs on the opposite side, while the facial muscles of
both sides escape. Such a condition is rare, however. Unilateral lesions
below the decussation in the medulla which affect the pyramidal tracts
cause paralysis which may affect those muscles whose motor neurons lie
below the level of the lesion and on the same side of the body. If the af-
ferent paths in the cord are affected also, sensation will be disturbed,
and, as we have seen, heat, cold and pain may be lost over the opposite
side of the body, the sense of position, passive movement, and two di-
mensional localization will be impaired over the same side of the body,
while touch may be unimpaired on both halves.

The Peripheral Distribution of Efferent Nerves

The motor neurons which conduct impulses for voluntary movement
from the central nervous system to the muscles have their cell bodies
in the ventral horn of the grey matter of the cord. Like the primary
afferent neurons they have a segmental origin, and are distributed to those
muscles which arose in the corresponding segments of the embryo. The
segmental arrangement of the muscles has become greatly obscured dur-
ing development, especially in the limbs, so that only in the case of
the intercostal muscles does it remain perfectly evident. By the careful
study of comparative anatomy and by correlating lesions, such as may
occur in anterior poliomyelitis, which affect only a single segment of
the grey matter, with the resulting muscular paralysis, it has been pos-
sible to make out the segmental origin and innervation of the various
muscles of the body.

In man the distribution of the anterior root fibers according to seg-
ments for the cervical and lumbosacral regions is as follows:

05 Deltoid, biceps, brachialis, supinators, rhomboids. Occasionally
radial extensors. Barely pronator radii teres.

C6 Pronators, radial extensors, pectoralis major (clavicular fibers),
serratus anticus.

07 Triceps, extensor carpi ulnaris, extensors of fingers, pectoralis

major.

08 Flexors of wrist and fingers.
Tl Intrinsic muscles of hand.

S3, 4 Levator ani, sphincter ani, perineal muscles.

S2 Glutei, biceps, semitendinosus and semimembranosus.

SI Intrinsic muscles of foot, tibialis posticus, and muscles of calf.

L5 Muscles of ventrolateral leg (except tibialis anticus).

L4 Extensors of leg and tibialis anticus.

MOTOR AREAS OF THE CEREBRUM 891

The knowledge of the segmental innervation of the limb muscles, as
furnished in the above table, is of value in the localization of spinal
lesions. Paralysis of the extension movements of the wrist and fingers,
along with the triceps, for example, usually indicates a lesion of the
seventh cervical. It is more particularly in the trunk, however, that
the segmental innervation of the muscles is evident. The innervation
of the intercostal muscles being unisegmental, one may diagnose the
level of a lesion of the upper thoracic region of the cord by observing their
behavior during deep inspiration. If the fingers are placed in the in-
tercostal spaces, the paralyzed muscles will feel limp and the fingers
sink into the space during the act.

Localization may also be shown by studying the parajyses of the
abdominal muscles when the lesion involves one of the lower six thoracic
segments. When the patient with a lesion of the eleventh thoracic raises
his head from the bed or coughs, the rectus contracts, but the iliac re-
gions bulge owing to paralysis of the lower portions of the obliques. Under
the same conditions, when the ninth segment is involved the rectus contracts
from about one inch above the umbilicus, whereas below this level it remains
uncontracted, so that the umbilicus is pulled up.

The motor fibers leave the ventral horn and pass through the ventral
roots of the spinal nerves into the nerve trunks which supply the muscles.
In the case of those roots which contribute to the cervical and lumbo-
sacral plexus fibers from several segments may be combined into a sin-
gle trunk. These trunks moreover break up into branches in which the
fibers are sorted out so that motor fibers become separated from sensory
fibers to the skin, and so that all fibers from several segments which
are passing to neighboring groups of muscles may become combined.
Consequently lesions to the nerve trunks of the limbs may show disso-
ciation between the paralysis and the loss of cutaneous sensation, and at
the same time certain muscles originating from several segments may
be affected while other muscles derived trorn the same segments remain
under normal control.

Spinal Reflexes

In addition to voluntary movements, activated by impulses descend-
ing through the pyramidal tracts from the brain, many reflex responses
of the skeletal muscles may occur which owe their initiation to afferent
impulses which never reach consciousness. These impulses are conducted
through the cord by propriospinal neurons, and reach the muscles by
traveling over the same peripheral motor neurons which complete the
path for voluntary acts. Consequently if paralysis is due to an injury
to the motor neurons, either in the ventral horn of the gray matter, or
along the peripheral course of their fibers, the muscles can be excited

892

CENTRAL NERVOUS SYSTEM

neither reflexly nor by volition. Injuries to the pyramidal tracts, how-
ever may cause paralysis without affecting the reflex response of the
muscles. Consequently an examination of the reflex excitability of the
paralyzed muscles will reveal whether the injury involves the motor neu-
ron or not. Since, as we shall see (page 951) impulses from the cere-
brum may have an inhibitant effect on certain reflexes, disease which
cuts off this influence may cause an exaggeration of certain reflex re-
sponses. Moreover since these reflexes are carried out over arcs which
lie within definite segments of the cord the failure of a reflex may
indicate in what part of the cord the lesion lies.

The segments involved in the more important reflex tests are indicated
in the following table :

LOCALIZATION OF MUSCULAR REFLEX ACTS IN THE SPINAL CORD

(After Starr)

Pupillary reflex through the sympathetic: Dilatation
of the pupil produced by irritation of the neck.

Scapular reflex: Irritation of the skin over the scapula
produces contraction of the scapular mucles.

Biceps and supinator longus: Tapping their tendons
produces flexion of the forearm.

Triceps reflex: Tapping tendon produces extension of
forearm.

Scapulohumeral reflex: Tapping the inner lower edge
of the scapula causes adduction of the arm.

Tapping extensor tendons at the wrist causes extension
of the hand.

Tapping flexor tendons at the wrist causes flexion of the
hand.

Palmar reflex: Stroking palm causes closure of fingers;
finger clonus.

Abdominal reflex: Stroking side of abdomen causes
retraction.

Genital reflex: Squeezing the testicle causes contraction
of the abdominal muscles.

Patella tendon: Striking tendon at knee causes exten-
sion of the leg; "knee-jerk."

Achilles tendon reflex: Tapping the Achilles tendon
causes flexion of ankle.

Foot clonus: Extension of Achilles tendon causes flex-
ion of the ankle.

Plantar reflex: Tickling sole of foot causes flexion of
toes, or extension of the great toe and flexion of the
others.

Fourth cervical to first dor-
sal.
Fifth cervical to first dorsal.

Fifth and sixth cervical.

Sixth cervical.

Seventh cervical.

Sixth to eighth cervical.

Seventh to eighth cervical.

Eighth cervical to first dor-
sal.
Ninth to twelfth dorsal.

First to third lumbar.
Second and third lumbar.
First to third sacral.
First to third sacral.
First to third sacral.

CHAPTER XCVI

THE AUTONOMIC NERVOUS SYSTEM, OR THE EFFERENT PATH-
WAY TO SMOOTH MUSCLES AND GLANDS

The development of complex masses of association neurons in the cen-
tral nervous system of the higher animals is associated with the acquisi-
tion of more and more specialized motor mechanisms and of a diversity in
the responses which these muscular structures can make. The organs con-
cerned with nutrition have retained many of their primitive characters
such as walls of smooth muscle and innervation by nonmedullated neu-
rons, arranged in some cases, at least, as a nerve net. The nervous
mechanism for the control of skeletal muscle has developed, consequently
as an adjunct to the visceral system, and has reached such a dominating
position that the latter has been rather neglected in the hands of neu-
rologists. There can be little doubt, however, as the interesting book
of Pottinger18 suggests, that the study of visceral neurology will con-
tribute greatly to elucidating the symptoms of disease. Because the
neurons of the autonomic nervous system are organized somewhat differ-
ently than are the efferent paths to skeletal muscle, and innervate organs
of a different function, the mistake should not be made of thinking that
it functions independently of the central nervous system. There is no
evidence that afferent impulses play upon these neurons except after
passage into the central nervous system. We have seen that afferent
impulses from the viscera may give rise to sensory effects in the central
nervous system (page 873). Similarly reflex change in the viscera may
be set up through impulses having an efferent path in the autonomic
nervous system, but originating from stimuli acting upon the surface
of the body. The pupillary reflex elicited by pinching the neck is a case
in point as is the psychic secretion of gastric juice, the voluntary
emptying of the bladder, and the syndrome of gastrointestinal and
circulatory changes which accompany great emotion. The autonomic
nervous system comprises the group of neurons which carry impulses
to the smooth muscles and glands of the body. It owes its interest and
importance to the functions to which these tissues contribute (nutrition
and reproduction), rather than to any supposed autonomy it may possess.

The Organization of Efferent Nerves to the Viscera

The reflexes in which the autonomic neurons take part are conducted
over reflex arcs. While the afferent side of such arcs may arise from

893

894

CENTRAL NERVOUS SYSTEM

somatic as well as visceral sources, it is interesting that the functional
acts which these reflexes may perform find no representation in the
motor areas of the cerebral cortex, and that in only exceptional cases
can they be initiated voluntarily.

The efferent side of the arc is interesting because of its anatomical
organization. The motor path connecting the spinal cord with the
smooth muscles and glands of the viscera consists of two neurons. The
cell body of the first lies in the lateral horn of the gray matter of the
cord. It is known as an internuncial neuron and its fiber, which is med-
ullated, is called a connector fiber or preganglionic fiber. These fibers
terminate in synapse with the cell body of the second neuron or effector

Post root
gang.

Fig. 218. — Diagram illustrating the different arrangements of the internuncial neurons of the
voluntary and autonomic nervous systems. In both systems the afferent fiber terminates (by col-
laterals) around a cell of the gray matter of the cord. In the voluntary system this cell is sit-
uated in the posterior horn, and its axon travels to an anterior horn cell. In the autonomic
system, on the other hand, it is located in the lateral horn, and its axon leaves the cord by the
anterior root and travels by the white ramus into a sympathetic ganglion, where it connects with
a nerve cell, whose axon forms the postganglionic fiber. (From Gaskell.)

neuron, which lies in an outlying ganglion. These neurons give off
fibers known as postganglionic fibers which extend to the effector which
is innervated. The postganglionic fibers are not medullated (except in
the case of the path to the sphincter pupillae from the third nerve).

Connector fibers are given off from three distinct regions of the cen-
tral nervous system. The anatomical arrangements and physiological
activities of these regions are distinctive. The bulbar outflow consists of
connector fibers lying chiefly in the vagus, but also in the third, seventh,
ninth, and eleventh cranial nerves. The sacral outflow consists of fibers,
leaving the cord with the second to fourth sacral nerves, which join
to form a common nerve trunk (the pelvic nerve or nervus erigens)

Fig. 219. — Diagram of the autonomic nervous system. The preganglionic fibers are in red, and
the postganglionic in black. S.c., superior cervical ganglion; I.e., inferior cervical ganglion; T,
stellate ganglion; S.p., great splanchnic nerve; C, ganglia of solar plexus; m, inferior mesenteric
ganglia; h, hypogastric nerves; N.E., nervus erigens. The arrows indicate the direction of nerve
conduction. The numerals indicate the spinal nerves. (From Howell.)

THE AUTONOMIC NERVOUS SYSTEM 895

on each side. Because they have certain characteristics in common these
two outflows are classed together as the bubo-sacral (sometimes called
the parasympathetic) division of the autonomic nervous system. The
thoracico-lumbar outflow consists of connector fibers leaving the cord
between the first thoracic and second or third lumbar segment. This out-
flow is sometimes called the sympathetic division of the autonomic
nervous system.

The terminology applied to these systems is confusing because of the
different usage of the same name by different authors. The following
table indicates the classification adopted in this book, together with the
synonymous terms in current use.

THIS BOOK

SYNONYMS

(Langley)

(Meyer)

(Gaskell)

Autonomic
Nervous
System

Autonomic
Nervous
System

Vegetative
Nervous
System

Involuntary

Nervous
System

1. Thoracico-lumbar
Autonomic
2. Bulbo-saeral
Autonomic

1. Sympathetic
2. Parasympathetic

1. Sympathetic
2. Autonomic

1. Sympathetic

2. Enteral
Oculomotor

While the details of the anatomical courses of the fibers to the great
variety of structures innervated by the autonomic system is beyond
the scope of a textbook of physiology, it is appropriate to outline certain
generalities concerning the arrangement of the connector and effector
neurons which supply different organs. In addition to the obvious meth-
ods for tracing the paths of nerve fibers by degeneration and by stimu-
lating the roots of the motor nerves knowledge of the course of the
connector neurons has been gained by the use of a special method dis-
covered by Langley. This depends upon the fact that nicotine in cer-
tain concentrations specifically blocks the passage of nerve impulses
across the synapse between the connector fiber and the effector neuron
without disturbing conduction in the course of the nerve fibers unin-
terrupted by a synapse; Consequently when nicotine is painted, upon an
outlying ganglion it is possible to determine, by stimulating the con-
nector fibers, whether they pass through the ganglion without inter-
ruption or not. In this way it has been learned that the motor paths in
the autonomic system fall into three groups with regard to the position
of the synapse between the connector and the outlying neuron.

Position of the Effector Neuron. — The outlying neuron lies wholly
in the walls of the organs innervated by the vagus nerve, the sacral
outflow, and that part of the thoracico-lumbar outflow which supplies the
organs which have developed from the Wolfian and Mullerian ducts,
i. e., the ureters, uterus, and vas deferens. The cells of Auerbach's
ploxus in the gastrointestinal tract represent outlying neurons from

896 CENTRAL XKKVOUS SYSTEM

the vagus, while the sacral plexus is composed of the postganglionic
fibers from the sacral outflow. The remaining parts of the thoracico-
lumbar outflow undergo synapse in one of two sets of ganglia. The seg-
mental chain of sympathetic ganglia contain the cells of the outlying neu-
rons of those thoracico-lumbar paths which follow the course of the spinal
nerves to smooth muscles and glands located in the skin and muscles,
and of those which innervate the organs of the thoracic cavity. The
typical arrangement of this group is shown in Figs. 218 and 221. The
connector fiber reaches the ganglion through the white ramus and the
postganglionic fiber passes back to the trunk of the spinal nerve in
the gray ramus and follows this trunk to the peripheral structure which
it innervates. Many connectors do not terminate directly in the ganglion
of their own segment, but send collaterals forward or backward through
the sympathetic chain to the other ganglia, where they connect with ef-
fector neurons. The third group of thoracico-lumbar paths leads to the
organs of the abdominal viscera, including their blood vessels. The
connector fibers of these paths pass out over the white rami and through
the segmental sympathetic ganglia without interruption to terminate
in one of the mesenteric ganglia in connection with an effector neuron.

The Double Innervation of the Visceral Organs. — The innervation of
the smooth muscles and glands is peculiar in that each effector may be
acted upon by two neurons which effect its activity in opposite ways.
Impulses from one neuron tend to increase the secretion of these glands,
or augment the tone or degree of contraction of the smooth muscles,
while impulses from the other neuron set up changes in the other direc-
tion which inhibit or depress these activities. Because of this double
innervation of structures supplied by the autonomic system, the activ-
ity of any of them will depend on the balance which is struck between the
effects of these antagonistic neurons.

The details of this arrangement may be learned in the case of any
particular organ from Fig. 221.

In general it may be stated that the bulbar and sacral outflows do not
overlap. In the gastrointestinal tract all parts cephalad of the ileocolic
sphincter are innervated by the vagus and other cranial nerves, and
are replaced below this point by the sacral outflow. At the same time,
the thoracico-lumbar outflow supplies this entire tract below the cardiac
part of the stomach with fibers which act upon it in the opposite sense.
The action of the bulbo-sacral outflow on the gastrointestinal tract is
excitatory, except for the ileocolic, and internal anal sphincters which
are inhibited. It consequently favors the movement of food along the
digestive tract and the secretion of the digestive fluids of the pancreas
and salivary glands, and the emptying of the gall bladder. The thora-
cico-lumbar outflow, on the other hand, tends to diminish the activities

Tr^-rr

Head c Neck

fJ \V /fMedu.1.

Splanchnic

(Post-gang.)

= Key —

PreGangilonic Sympathetic
PostGanglfonic Sympathetic
Pre GanglionicBulbo-Sacral

(Para-Sympathetic)
Post GanglionicBulbo-5acraf

•L 1

Arm

(Post
gangj

Heads-
Neck

"(Pregang".)""
Sympathetic
Ganglia

Thoracic
6planchnic
nerve

^Coeliac Plexus &
5yp.Mes.Gang.

Leg

Pr

Arm

(Pregang.)

Lumbar
Splanchnic nerve

Abdominal

Viscera

(Pregang.)

Inf. Mes.Gang.
(.Leg

V (Post-
gang.)

Pelvic visceral nerve

Fig. 220. — Diagram showing the main parts of the autonomic nervous system. For the sake of
clarity several of the preganglionic fibers of the sympathetic autonomies are omitted, but the posi-
tion of their egress from the cord is indicated in the side notes. The diagram shows clearly the
distribution of the bulbosacral autonomic system by way of the vagus and the first, second and
third sacral nerves.

THE AUTONOMIC NERVOUS SYSTEM 897

of the gastrointestinal muscles and of the salivary glands and to close
the sphincters of the lower tract. These systems of fibers also act in an
antagonistic way on the heart, bladder, and interocular muscles. The
bulbar outflow through the vagus inhibits the action of the heart, through
the third nerve constricts the sphincter pupilla? and probably inhibits
the radial fibers of the iris. The sacral outflow through the nervous eri-
gens causes contraction of the bladder musculature and inhibition of
its sphincters. In each of these cases the thoracico-lumbar outflow acts
on these muscles in the opposite sense.

A large group of smooth muscles are innervated only through the
thoracico-lumbar outflow. Some of these, i. e., the pilo-motor muscles
and the muscles of the sweat glands, receive so far as we know only ex-
citor fibers from this system. Others receive both excitor and inhibitor
fibers from this system, so that an antagonism exists in the action of
different neurons from the same outflow. This fact has been 'discovered
by the use of a drug, ergotoxine, which prevents the excitor fibers from
acting upon the muscles but does not impair the action of the inhibitor
fibers. After the application of ergotoxine to these organs the stimula-
tion of their nerves results in an inhibition of the muscles rather than
the normal excitation. Inhibitory fibers are found in the thoracico-lum-
bar supply to the cutaneous blood vessels of the bucco-facial region and of
the kidney and their activity results in a vasodilatation in these re-
gions. The smooth muscles of the uterus also receive inhibitory fibers
from the thoracico-lumbar system, and in the virgin uterus these ma;v
dominate the activity of the organ, so that its muscles relax upon stimu-
lation of their nerves. In the pregnant uterus, on the other hand, the
constrictor fibers in these nerves predominate and a contraction follows
their excitation. Further details of the organization of the Autonomic
system may be obtained from the Monograph by Gaskell.17

The Function of the Autonomic Nervous System

When we examine the contribution which the autonomic nervous
system makes to the organization of bodily activity, we are struck by
the fact that these nerves regulate the activity of a group of organs and
tissues which possess a high degree of autonomy, so that their various
functions can be carried out quite successfully when they are completely
isolated from the central nervous system. The heart is perhaps the most
complex organ under autonomic control, yet not only will isolated strips
of this organ contract in the rhythmic fashion characteristic of the heart 's
activity but the entire organ will beat in a perfectly coordinated way
when freed from nervous control. The tonic contraction of the arter-
ioles, essential to the maintenance of blood pressure, is only temporarily
deranged by the destruction of their nerves. The musculature of the

898 CENTRAL NERVOUS SYSTEM

gastrointestinal tract carries out its rhythmic movements and maintains
polarity in its action after it is separated from its extrinsic nerve supply.
Even the mechanism for operating the pyloric sphincter does not de-
pend on nervous connections extending beyond the gut wall. The secre-
tion of the gastric, pancreatic and intestinal juices is also brought about
by hormones of the secretin type so that nerves are unnecessary for this
activity.

Goltz and Ewald have succeeded in keeping dogs alive and in good
condition for long periods after removal of the spinal cord below the
cervical region. After such animals have recovered from the immediate
effects of the operation, the skeletal musculature of the posterior part
of the body is paralyzed and soon atrophies. The organs under auto-
nomic control recover their normal function to a surprising extent. The
tone of the blood vessels recovers, and they react to temperature changes
much as a normal vessel would. The digestion becomes normal, defeca-
tion takes place regularly, and the bladder is emptied periodically and
spontaneously. A pregnant bitch gave birth to puppies a few hours
after 9.4 cm. of cord had been removed, and suckled one of them suc-
cessfully. In these animals it appeared that the organs innervated by
the autonomic nervous system could function successfully after the cord,
and with it the connector neurons, had been destroyed. The experiments
suggest that the autonomic system may contain reflex arcs within itself,
which do not pass into the central nervous system. A difficulty arises
here because it has not been possible to demonstrate any connection in
the outlying* ganglia between the afferent fibers passing through the
autonomic nervous system and the effector neurons.

A type of reflex which may operate here is that known as the axon
reflex. The only axon reflex which is known to function, except under
laboratory conditions of stimulation, affects the cutaneous blood vessels,
and causes a local inflammation to be set up in the skin when mustard is
applied to it. This reaction was shown by Bruce to persist after cutting
the dorsal roots of the spinal nerves and consequently could not be attributed
to a spinal reflex. After the sensory fibers had degenerated, however,
the effect could no longer be elicited. It appears from this that the
mechanism depends on the integrity of the peripheral end of the sensory
fibers. It is believed that these send off collaterals which connect with
the cutaneous blood vessels. Impulses set up by the mustard in the
sensory termination pass up the fiber to these collaterals and down them
to the blood vessels where dilation is produced. This mechanism also
explains the observation of Bayliss that stimulation of the peripheral
stump of the dorsal root of a spinal nerve causes a local vasodilatation
in the skin. A similar axon reflex has been found to occur in certain
connector fibers of the thoracico-lumbar outflow which supply the smooth

Pi/o motor muscle
Lachrymalqland

Sublingual
gland

-'JSpheno-palatgang. QJ^
Parotid gland

3ubmaxJlldry(5ubHngual)

Iliocecal
sphincter

B/a

Vesical sphincter
Urethral sphincter,

Cranial and Sacral nerves
motor = red
inhibitory = blue

Thoracico-lumbar nerves

inhibitorv =oreen
Postganglionic fibers
are dotted, thus —

N.XI

Sup. cervical ganglion

Thyroid gland

Inf.cervical ganglion
%-Ansa subclavia

-Stellate (&• Thoracic)
ganglion

Sweat gland

so-motor
fibers

P/'/o motor muscle

Celiac (Semilunar)

ganglion(5olarplex)
Splanchnic nerves

Sympathetic chain

iiumbarsplanchnics

* Sup. Mesenteric

ganglion

Inf. Mesenteric
gangUon

hypogastric nerves

Pelvic(Hypoqastricjnterilidc) < sphincter
plexus. (Ye$icalS( rectal portions) Pelvic 'nerves (Nervus erigens)

7? P Haileck

Vig. 221. — Schematic representation of the autonomic nervous system. (From Jackson.)

THE AUTONOMIC NERVOUS SYSTEM

891)

muscles of the bladder, the blood vessels of the rectum, and the internal
anal sphinctor. These fibers send collaterals to the bladder through
the hypogastric nerves. When one of these is cut and stimulated cen-
trally, the muscles innervated by the collaterals in the other hypogastric
nerve are seen to respond. There is no evidence, however, that this
mechanism is brought into play in normal life.

The organs supplied by the autonomic nervous system appear to be
able to carry out their functions in an orderly way by virtue of their
inherent properties, of the presence of the primitive nerve network
which makes up their intrinsic nervous supply, and possibly by the assist-
ance of simple axon reflexes through the postganglionic fibers of the
thoracico-lumbar outflow. Since their reactions are simple and either

Post, roof
gang.-

Fig. 222. — Diagram of an axon reflex in a sensory nerve fiber of the skin. A stimulus applied to
the skin is transmitted by the sensory fiber (N), part of it going to the spinal cord (SC), and
part of it passing by the collateral (C) to the arteriole (A), which it causes to dilate.

strictly local or generally diffuse, a simple nervous mechanism suffices,
just as it does for the simple activities in the coelenterates (page 829).
Function of the Bulbo-sacral Division. — The function of the connector
fibers in -the autonomic system would appear to consist largely in adjust-
ing the activities of these structures as a whole to the conditions of
activity brought about in the somatic musculature under the influence of
the central nervous system. Correlation takes place between visceral
activity, and somatic activity, so that the closest cooperation can ob-
tain between the organs of the body. This is brought out by considering
the way the three divisions of the autonomic system manifest themselves.
The bulbar outflow is concerned with conserving the resources of the
organism. Its action on the heart is to reduce its activity so that there

900 CENTRAL NERVOUS SYSTEM

may be a reserve power for .times of need. The gastrointestinal tract
is brought into activity by the vagus which thus contributes to the nu-
tritional processes of the body. When an animal has acquired food, cer-
tain rather specific reflexes take place through the bulbar outflow which
result in the psychic secretion of salivary and gastric juice and the re-
flexes of swallowing, and thus initiate the process of digestion. The
succeeding stages in the process can no doubt be executed by the intrinsic
mechanisms of the gastrointestinal tract, but activity of the vagus fibers
should be expected to counterbalance the inhibitory influence of the thorac-
ico-lumbar outflow and thus to reinforce the action of the gastrointestinal
muscles.

The bulbar outflow brings about those reactions in the sphincters
and muscular walls of the bladder and cloaca which result in the dis-
charge of waste materials from these receptacles. Although these re-
sponses may occur automatically w^hen the spinal connections are de-
stroyed, under normal conditions these acts are made volitionally at
the convenience of the individual. In them a close cooperation occurs
between the action of voluntary and involuntary muscles in which affer-
ent impulses from these viscera play an important part.

The mechanism for emptying the bladder illustrates this correlation
between voluntary and involuntary action. Reflex micturition is set
up when, through the accumulation of urine, the intervesical pressure
reaches 15 to 18 cm. of water. As the tension increases, rhythmic con-
tractions of the bladder musculature occur which increase in strength and
result in afferent impulses being set up in the pelvic nerves which pass
to the sacral cord and to the higher parts of the central nervous system.
Reflexes are thus set up through centers in the lower cord which result
in excitation of the sacral autonomic supply to the bladder, causing
a contraction of the bladder walls and inhibition of the sphincter. The
pressure within the bladder rises to 20 or 30 cm. and forces the urine
through the neck of the bladder and through the urethra. Normally
the emptying of the bladder is accompanied by a voluntary effort ini-
tiated by the afferent impulses which ascend to the cerebrum, and there
give rise to the sensations aroused by the distended vesicle as well as to
efferent impulses wrhich contract the respiratory and abdominal muscles,
so as to increase the intraabdominal pressure, and help squeeze the urine
out of the bladder. Reflex emptying of the bladder depends then on the
development of a certain tension in the vesicular muscle. It may be in-
hibited to a certain extent by voluntarily contracting the striated peri-
neal muscles which help in the closure of the urethra, either before or
during the reflex act. Micturition may be initiated before the bladder
is full enough to start the reflex, either volitionally or by virtue of im-
pulses arising through sensory nerves from other parts of the body.

THE AUTONOMIC NERVOUS SYSTEM 901

These types of micturition must be set up by impulses which affect the
spinal centers in much the same way as impulses arising from the blad-
der itself. The bladder may consequently be emptied by three mecha-
nisms, (1) by its intrinsic activity as in Goltz and Ewald's dogs; (2)
by a purely spinal reflex through visceral afferent and efferent impulses,
and (3) through voluntary effort acting on the spinal centers and re-,
inforced by the contraction of skeletal muscles. The former mechanism
is relatively inefficient, as is seen in the behavior of the bladder during
the failure of the reflex mechanisms which results from the shock of
a spinal cord injury. The urine is retained until the intervesicle pres-
sure becomes great enough to force the sphincter, and then it dribbles
out feebly. The bladder is not completely emptied and the residual
urine is apt to putrefy, giving rise to cystitis and other infections which
constitute the chief danger in such injuries. If the local condition of
the bladder remains good, the automatic emptying of the bladder may
become periodic and complete whenever about 225 c.c. of fluid accumu-
lates, even though the injury has completey destroyed the reflex con-
nection between badder and cord. If the injury to the cord does not
interfere with the reflex centers, recovery makes automatic reflex mic-
turition possible and the bladder is emptied completely at periodic in-
tervals as it becomes full, but is no longer under voluntary control
(Fearnside,19 Head and Riddoch20).

The Function of the Thoracico-Lumbar Division. — The thoracico-lum-
bar outflow, in contrast to the bulbo-sacral, inhibits the activity of the
digestive tract and brings about changes in the organs of circulation
which are appropriate to increased activity of the skeletal musculature
and of the nervous system which controls them. Whereas the different
parts of the cranial and sacral outflow are brought into activity sep-
arately, so that the digestive secretions may be stimulated without the
heart or iris being affected at the same time, and micturition may occur
independent of defecation, discharge over the thoracico-lumbar system
frequently has a diffuse nature, affecting all of the organs controlled
by it simultaneously. A definite syndrome consequently results which
is brought about under conditions of great emotion, as in fear, pain,
and rage. It consist of acceleration of the heart rate, constriction of
the arterioles in the skin and splanchnic viscera, inhibition of the mus-
cular activity of the gastrointestinal tract, inhibition of the salivary se-
cretion, erection of the hair and secretion of the sweat glands. These
changes occur under conditions when severe muscular effort is apt to
be exerted by the animal, and are appropriate because they tend to shift
the circulating blood to the muscles and nerves of the body at the ex-
pense of the viscera so that the maximum energy may be devoted to

902 CENTRAL NERVOUS SYSTEM

muscular acts. For this purpose the diffuse activity of this system is
an obvious advantage.

In this connection the relation of the adrenal medulla to the thoracico-
lumbar outflow is of interest. Its cells are derived in the embryo from
the same neuroblasts which give rise to the effector neurons of the sym-
pathetic ganglia. They are innervated directly by the connector neurons
of the thoracico-lumbar outflow so that they are strictly homologous
with the effector neurons of this system. It has been shown that without
exception the effects produced on any organ by epinephrine, the secre-
tion of these glands, is the same as that produced by the excitation of its
thoracico-lumbar innervation. These gland cells may be considered as
nerve cells which have changed their mode of acting on their effectors, but
still produce the same effect through their secretion. If these glands are
brought into action, as Cannon21 has shown them to be during emotional
conditions, they will reinforce the action of the thoracico-lumbar nerves
and because their hormone is distributed through the blood, ensure the
general, diffuse response characteristic of the action .of the thoracico-
lumbar system.

It must not be supposed that the reactions of the thoracico-lumbar
system always has this diffuse character. The regulation of vasomotor
reactions is largely carried out through its neurons, and it is possible
for vasoconstriction to occur in one part of the vascular bed without
affecting other parts. The shifting of the mass of the circulating blood
from one part of the body to another in response to the varying needs
occasioned by the varying conditions of each organ must be controlled by
these nerves. The local reflex response of the cutaneous blood vessels to
temperature changes is a case in point (page 744).

The Effects of Impulses from the Viscera upon Central Nervous Ac-
tivity.— Just as the visceral organs may be inhibited through the thora-
cico-lumbar outflow in adaptation to the activity of the skeletal muscles,
so visceral conditions may influence the state of the central nervous
system and the muscles which it controls. We have considered the effects
of afferent impulses from the viscera in producing pain (page 864). In
the presence of visceral disease afferent impulses tend to produce " de-
pression" in the central nervous system, so that muscular activity is
avoided and the sufferer seeks retirement in which to recover. The dis-
agreeable mental conditions produced by constipation are probably also
nervous in origin, as is indicated by their prompt relief following a satis-
factory movement of the bowels. The vigorous contractions of the stom-
ach musculature in hunger not only give rise to this sensation, but make
the subject restless and irritable. Certain reflex acts are reinforced by
impulses set up during hunger, as the knee jerk. The cough attending
diseases of the pulmonary region is believed by Pottenger18 to be due to

THE AUTONOMIC NERVOUS SYSTEM 903

irritability set up reflexly in the pharynx in much the same way as is the
hypersensitivity of the skin in regions of referred pain. Spasms in skele-
tal muscles are also produced in tuberculosis by reflexes arising from
the lung. These are reactions depending on visceral afferent fibers.
Reflex conditions arise from the viscera which affect other viscera
through the autonomic efferents. Dmitrenko accelerated the respira-
tion and pulse in dogs and raised their blood pressures by stimulating
the stomach in various ways, as by distention with balloons. The vom-
iting of pregnancy, menstruation, and the menopause, and of whooping
cough, the gastrointestinal disturbances which may follow injury to the
testis, etc., are attributed by certain clinicians to reflex effects carried
out through the autonomic nervous system.

CHAPTER XCVII
MUSCULAR CONTRACTION

Voluntary and reflex nervous activity expresses itself in the reactions
of the muscles of the body. In order to interpret the normal working
of the motor mechanism, and the abnormal manifestations which dis-
ease of the nervous system imposes on the muscles of the body, the na-
ture of the contractile processes in skeletal and smooth muscle must be
understood.

A muscle is an elastic body. That is to say, for every length to which
it is stretched it will exert a definite tension on its origin and insertion,
tending to pull them together until it has returned to its unstretched
length. When a muscle "contracts," it does not assume a smaller vol-
ume; rather it tends to change its shape so as to become shorter and
thicker. The contracted muscle has become a body with new elastic
properties, i. e.*, for each length to which it is stretched, it now exerts
a greater tension on its origin and insertion than it did in the "uiicon-
tracted" condition. Consequently if opposition is presented to the short-
ening of the stimulated muscle it will exert a tension on the opposing
object equivalent to the tension necessary to stretch the contracted mus-
cle to its resting length. The muscle's length does not change, and hence
it is said to contract isometrically. If, however, the opposition is not
strong, i. e., is due to a light weight, the tension developed on contraction
will overcome the opposition, and the muscle will shorten, thus lifting
the weight. Since the tension exerted by the weight is the same at all
times during the contraction of the muscle, such a contraction is called
isotonic. When it shortens against a weight the muscle assumes a new
length at which it exerts a tension equal to the weight which is lifted.
A muscle is consequently a machine for developing tension, and this
tension may or may not do work in lifting a weight, or moving a joint,
depending on whether or not the tension developed is great enough to
overcome the opposition.

The elastic properties of skeletal muscle may be modified in two dis-
tinct ways which differ in respect to the energy required for the processes
which cause the muscle to tend to shorten. A tonic contraction is one in
which the processes which cause the muscle to change its elastic con-
dition so as to take on a shorter length when at a given tension (or
to exert a greater tension at a given length) are maintained with great

901

MUSCULAR CONTRACTION 905

economy. A tetanic contraction, or tetanus, is one in which the new elas-
tic condition is maintained by processes which require a considerable
expenditure of energy. The properties of these two forms of contraction
will now be considered in some detail, together with the uses to which
they are put by the organism.

The Tonic Contraction of Skeletal Muscle

The skeletal muscles of the body are normally maintained in a state
of slight tension even when at rest. This condition, to which the word
tone or tonus is applied, is due to the action upon the muscle of nerve
impulses which come to it over reflex arcs which we will describe in the
next chapter. When these reflex arcs are interrupted the muscles loose
their tone, that is, their elastic properties change and they can now
extend from origin to insertion without developing any tension. Limbs
in which the muscles have lost their tone become " loose jointed" and
readily assume under the influence of gravity, a variety of postures
which a normal limb would not exhibit. Consequently it is easy to dis-
tinguish between death and sleep by the postures of the limbs, since the
tone of the sleeper's muscles is retained. Tonic contraction is thus seen
to be connected with the maintenance of posture in the limbs. The posi-
tion of the body, and particularly of the limbs is constantly changing,
and with each change the muscles assume new lengths, maintaining
meanwhile the same tension which they exerted before. To do this a
new elastic state must be set up in the muscle so that the muscle can
exist at its new length without exerting a greater tension on its inser-
tion. The tone of the muscles consequently may be changed to fit the
new position of the joint and to maintain this new posture. It is conse-
quently called plastic tonus, (Sherrington27). Since the greatest ten-
sion must be exerted by those muscles which support the weight of our
limbs, or the weight of the body which falls on the limb, these muscles
have developed the greatest powers of tonic contraction. Consequently
they become affected most in conditions which tend to increase the tone
of the muscles.

Tonic contraction, as contrasted with tetanus, is characterized by the
economy with which the elastic state of the muscle is maintained. Roaf
was unable to detect any difference in the respiratory exchange of cats
during the highly developed tone of decerebrate rigidity when com-
pared with the same animals in which all muscular contraction was abol-
ished with curare. Evans has found that the metabolism was less after
curare, but the gaseous exchange was clearly much less in the state of tone
than if the muscles had been thrown into tetanic activity. Bayliss also
found a slight heat production in muscles in decerebrate rigidity, which
varied with the degree of tonic contraction, but very much less than

906 CENTRAL NERVOUS SYSTEM

would have been produced by a tetanic contraction of the same height.
Since the metabolic changes underlying tonic contraction are not great,
it is not surprising that tension can be maintained by this form of con-
traction for long periods without fatigue.

It is a peculiar fact that although tonus is maintained in skeletal
muscle only by means of a reflex arc, it is impossible to produce it by
any known form of artificial stimulation applied to either the efferent
or afferent nerve trunks. Under the normal reflex control the tonic re-
action may involve either a shortening or a lengthening to a new state
of tone, in which the tension remains the same.

In the tonic contraction of skeletal muscle only a comparatively low
degree of tension can be maintained. Consequently it does not require
much force to move a joint out of the posture in which it is held by
the tone of its muscles. In certain muscles the tension exerted by the
tonic contraction is not inconsiderable, however. In the tonic rigidity
which certain muscles assume after the cerebrum is removed the ex-
tensors of the limbs may exert a tension well in excess of that required
to support the weight of the animal. In order to exert the maximum
tension, however, muscles must resort to the tetanic mode of contraction.

Tetanic Contraction of Skeletal Muscle

When a skeletal muscle is stimulated directly, or through its nerve
with a single shock from an induction coil, it gives a momentary con-
traction or twitch. On page 178 it was explained that if a series of
stimuli -are applied to a muscle the resulting twitches may follow one
another so rapidly that the muscle does not relax between them, and
a maintained or continuous contraction results to which the name teta-
nus is applied. That tetanus is really a series of discrete contractions
is shown by the nature of the electrical changes, or action currents set
up by a muscle contracting in this way, for it is found that each part
of the muscle becomes alternately positive and negative as each twitch
is set up in it (see page 188). It is extremely unlikely that the volun-
tary and reflex contractions of our muscles ever consist of single twitches,
since a nervous discharge must usually consist of a series of impulses,
in order that, summation may occur and the resistance of the synapses
be overcome. Whenever our movements are not due merely to changes
in muscular tone, they are tetanic in nature.

The action currents produced by the voluntary contraction of skel-
etal muscle enable us to discover the rate at which component twitches
of the tetanic contraction occur, which is about 50 per second. This rate
is determined by the fact that immediately after one contractile process
has occurred a second cannot take place until a brief time, known as the
refractory period, has elapsed. In the case of skeletal muscle one fit'-

MUSCULAR CONTRACTION

907

tieth of a second is required after one twitch has been initiated before
the tissue has recovered sufficiently to respond to a second nerve impulse.
Forbes and Bappleye22 have shown that the rhythm is not due to the
rate of discharge of nerve impulses from the higher centers, by observ-
ing that the rate of the oscillations of the electromyograph is slowed by
chilling the muscles of the arm in ice water. Since this procedure does

Fig. 223. — Electromyogram of the voluntary contraction of the flexor muscles of the forearm.

(From Forbes and Rappleye.)

not alter the body temperature as a whole, it cannot be supposed that the
temperature of the centers in the nervous system are changed, or that
the diminished rate of the rhythm is due to any change in the rate of
discharge of nerve impulses from these centers. They give evidence
to show, moreover, that the rate at which nerve impulses follow one an-

Fig. 224. — The contraction of a single fiber of the sartorius muscle of the frog. The appearance
before stimulation is shown at the left; during stimulation at the right. Note the tense appearance
of the muscle fiber (X), the slight pull on the deep blood vessel (V), and the change in the relative
position of the surface capillaries which are indicated by the heavy, wavy lines. (From F+isenberger.)

other down the motor nerves is much faster than 50 per second. Many
nerve impulses must reach the muscle while it is still refractory and con-
sequently do not take effect upon it.

Since tetanic contractions are composed of a series of twitches it is
instructive to study the conditions which produce and modify this form
of contraction in skeletal muscle. These muscles are composed of large
numbers of fibers, each one of which may contract quite independently

908 CENTRAL NERVOUS SYSTEM

of any of the others. This may be shown by applying an electric stimu-
lus to a single fiber, by means of the very delicate technic devised by
Pratt,23 when it will be observed that this fiber alone responds to the
excitation (Fig. 224). The fibers of the muscle are insulated from one
another in such a way that the disturbance set up by the stimulus in
one of them does not spread to any other. In this respect skeletal mus-
cle differs markedly from cardiac muscle (see page 177). The unit of
function in skeletal muscle is consequently the twitch of the individual
fiber.

The All-or-none Law. — The question obviously arises how the strength
of contraction of the fiber is affected by the strength of the stimulus ap-
plied to it. As soon as it was realized that a single nerve impulse did
not vary in strength, except under conditions which affected the con-
ducting power of the nerve fiber, it was difficult to imagine how the
nerve impulse could be made to alter the degree of contraction of the
muscle fiber which it excited. It was consequently suspected that the
all-or-none law applied to the activity of the individual fiber of skeletal
muscle just as it does to heart muscle as a whole. The final direct proof
of this view is supplied by the experiments of Pratt and Eisenberger
who showed that when a single muscle fiber is excited its response is
maximal if it responds at all. This fact is shown in Fig. 225, in wliich
the movement of a droplet of mercury placed on the contracting fiber
has been photographed. On increasing the strength of the stimulus
no change occurs in the amount of contraction until the current strength
becomes strong enough to affect an adjoining fiber. At this point the
amount of movement increases by a definite step, and then continues
at the new level until a third fiber is brought into action and another
step-like rise in the record occurs. As the strength of stimulus is de-
creased again the contractions fall off through the same series of steps.
It is consequently believed that if a skeletal muscle fiber contracts- at
all, it does so to the full extent to which it is capable. Graded series of
muscular contractions in response to graded strengths of stimuli, such
as are shown in Fig. 45, are due to the fact that as the stimulus is in-
creased in strength more and more fibers, each contracting maximally,
are brought into play until finally all are excited and the contraction
of the muscle as a whole becomes maximal and cannot be further in-
creased. The adjustment of the strength and degree of muscular move-
ment consequently depends on bringing into action the proper num-
ber of muscle fibers. If the fibers were not insulated from one another,
so that one could contract without the others joining in, graded muscular
movements would be impossible and our skeletal muscles as a whole
would act in- an all or none way just as the heart does.

Although the skeletal muscle fiber contracts to the utmost if it con-

MUSCULAR CONTRACTION 909

tracts at all it must not be supposed that under all circumstances the
maximal contraction is of the same magnitude. The ability of the fiber to
develop tension varies from time to time and may be shown to depend
on a variety of factors. The energy set" free in the contractile process
is greater, the longer the muscle at the time when it begins to contract.
This is shown by the fact that a muscle which is stretched at the moment
when it begins to contract is able to develop a greater final tension
than an unstretched muscle. The heat liberated in the act of contraction,
which measures the total energy set free, increases in a similar manner
with the initial length of the muscle. This observation is of importance

Fig. 225. — The all or none nature of the contraction of a single fiber of skeletal muscle. Tht
lower line represents the strength of the stimulus applied to the muscle, which rises to a maximum,
and then is reduced to its initial level. The upper record is of the movement of a drop of mercury
resting on the contracting fiber. The amount of contraction does not change as the stimulus is in-
creased until the point A is reached, when a second fiber became excited causing a pronounced,
step-like increase in the record. Later a fiber responded and produced another step. The same steps
are observed as the stimulus strength is gradually decreased. (From Pratt and Eisenberger.)

/

because it shows that the strength of the contraction is dependent upon
the surface area of the contractile elements in the muscle fiber, which
naturally becomes increased as the muscle is elongated, and not on the
volume of muscle substance, which is unchanged by stretching. We have
seen on page 217 the importance of this principle in enabling the heart
to compensate for an increased load by dilating.

The previous history of the muscle fibers also has a great influence
upon the magnitude of the contractions of which each fiber is capable.
We have seen on page 178 that if a muscle is excited to a maximal

910 CENTRAL NERVOUS SYSTEM

contraction several times in rapid succession each twitch is somewhat
higher than its predecessor. This phenomenon is known as treppe and
is explained by the fact that chemical changes arising from one con-
traction make the muscle better able to contract the next time. If
the successive stimuli are continued for some time the height of the
contractions soon reaches a maximum and then begins to fall off as the
muscle becomes fatigued. Fatigue is due, in part at least, to the fact
that after prolonged activity each fiber in the muscle is able to develop
less tension when it contracts.

The Chemistry of Tetanic Contraction. — In order to understand the
nature of fatigue, the chemical changes which occur during the activity
of muscle must be considered. When a muscle is excited, energy is lib-
erated which sets up a state of tension. The tension may result in doing
external work, as in lifting a weight, or it may dissipate its energy
as heat if the muscle is not allowed to shorten. In either case a supply
of potential energy stored in the muscle has been drawn upon. It has
been shown by Roaf that the hydrogen-ion concentration of muscle
substance becomes increased at the moment of contraction, and chemical
analysis shows that lactic acid appears in muscle as the result of pro-
longed excitation. It is consequently believed that the liberation of
lactic acid in the muscle substance is connected with setting free the
energy for contraction.

In the process of recovery which follows the activity of muscle when
it is allowed to rest, it is found that the lactic acid disappears provided
a supply of oxygen is available. Since at the same time carbon dioxide
is set free from the muscle, one might suspect that the disappearance
of the lactic acid is due to its being oxidized to carbon dioxide and water.
This, however, cannot be the case, for it is known that after the repeated
fatigue and recovery of an isolated muscle the total quantity of lactic
acid which may be extracted from it is undiminished. In other words
lactic acid does not disappear from the muscle during rest, but is re-
stored to the condition in which it occurred before contraction took
place. Further evidence that lactic acid is not oxidized is afforded by the
fact that the disappearance of 1 gram of lactic acid from fatigued mus-
cle is accompanied by the production of 450 calories of heat, whereas
the oxidation of 1 gram of lactic acid would set free 3700 calories.
Apparently the oxidation of some other substance is necessary in order
to restore lactic acid to the percursor condition, and to replace the po-
tential energy lost in the contractile process, and in the course of the oxi-
dation of this substance — carbon dioxide is liberated and heat is given
off. The nature of the substance oxidized is not definitely known, but
it is presumed from the high respiratory quotient of muscular work that
it is chiefly carbohydrate. (Bayliss,24 Fletcher and Hopkins.25)

MUSCULAR CONTRACTION 911

Treppe and Fatigue. — Applying these facts to the phenomenon of
treppe and fatigue, we see that the continued use of a muscle will be
attended with an increase in the hydrogen-ion concentration as the re-
sult of the liberation of lactic acid in the muscle substance. For all tis-
sues there is an optimal concentration of hydrogen-ions at which their
activities are carried out to the best advantage. The initial change in the
hydrogen-ion concentration which accompanies the first few contractions
brings the muscle into a more favorable condition arid treppe results.
On further production of lactic acid the optimal condition is exceeded
and the muscle fibers become successively less and less able to perform their
work. If the muscle is supplied with an adequate circulation a point is
soon reached at which the excess of lactic acid is restored as fast as it
is formed, by virtue of the oxygen supplied by the blood, and beyond
this point fatigue does not proceed further, successive contractions fol-
lowing one another for a long time with undiminished force. The mus-
cle is then said to have reached a fatigue level in Avhich the constructive
processes during the rest between contractions just balance the destruc-
tive processes during activity. If the circulation is inadequate, or lack-
ing, as it is in an isolated nerve muscle preparation, the increase in
the hydrogen-ion concentration goes on as the result of the accumula-
tion of lactic acid until the contraction of the muscle becomes impossible.

The fatigue of muscle is consequently due to the accumulation of lac-
tic acid and probably other waste products in the muscle substance,
and in protracted exertion to the using up of the materials which upon
oxidation restore the energy lost in the act of contraction and replace
the lactic acid in the condition in which it existed in the rested muscle.

Under normal circumstances skeletal muscle is protected from the
development of any harmful degree of fatigue. This is because its ac-
tivity is initiated through the nervous system, parts of which become
fatigued long before this condition comes on in the muscles. We have
already seen that the nerve fiber is unfatigable. The synapses, on
the other hand, and the myoneural junction are easily fatigued and
cease to conduct excitations to the muscles long before the muscle it-
self becomes too fatigued to respond to direct stimulation. A further
protection against fatigue in protracted muscular activity is afforded
by the fact that the threshold of excitation of the individual muscle
fibers is raised by repeated stimulation. It is quite possible that as
the result of this tendency each fiber may fail to respond to the nerve
impulses reaching it as soon as it becomes fatigued, and consequently
it has an opportunity to rest, while other fibers in the muscle carry on
the work in hand. The falling off in the height of the successive con-
tractions of a muscle which is being fatigued is probably due not only to
the reduction of the degree of contraction of which each fiber is capable,

912 CENTRAL NERVOUS SYSTEM

but also to the cessation of activity on the part of many fibers as their
thresholds rise above the level of the exciting stimulus.

Smooth Muscle

The smooth muscles of the mammalian body differ markedly in their
histological appearance from the skeletal muscles. Their origin in de-
velopment is also different as they arise from the mesenchyme, and not
from the mesodermic somites as the skeletal muscles do. It is not sur-
prising consequently to find that the properties of smooth muscle differ
markedly from those of the skeletal muscles.

The contraction of smooth muscle is sluggish and never develops very
great tension. In this respect it resembles closely the tonic contraction
of skeletal muscle, as contrasted with the tetanic contraction. The most
outstanding feature is the ability of this tissue to alter its tonic condi-
tion so that it may exist now at one length, now at another, under equal
degrees of tension. This is seen to be a most important property when
it is considered that smooth muscle forms the walls of the various hollow
viscera and that these organs must constantly alter their capacity to
fit the varying volume of their contents. In the stomach and urinary
bladder, especially, the muscular walls must be capable of relaxing as
the organ becomes filled, so that the tension exerted on the contents
may not increase unduly. The pressure in the urinary bladder is much
the same whether its contents be 50 or 150 c.c. of urine. Similarly after
injecting 400 c.c. of water into the stomach of a dog the pressure within it
returns almost immediately to its original level through a change in the
condition of the gastric musculature. The conditions in the blood vessels
differ only in degree, for here the smooth muscles adjust their tone to
the requirements of maintaining a uniform pressure of the blood, and
differ from the smooth muscles of the abdominal viscera only in the
relatively high degree of tension which they can maintain.

Like the tonic contraction of the skeletal muscles, the contraction of
smooth muscles is maintained with very little expenditure of energy and
consequently without fatigue. The sphincters of the gastrointestinal tract
and bladder remain closed almost continuously and the muscles of the
arterioles support the relatively great pressure of the blood unremit-
tingly and without becoming exhausted in the least. The smooth mus-
cles which hold the shells of the mollusca closed can support great weights.
The muscle of the fresh water clam, Anadonta, can support a weight of 3
kilos for three hours without consuming any oxygen in excess of its re-
quirements when at rest. The economy of this is seen when it is considered
that the gastrocnemius of the cat consumes when supporting a similar load
by tetanic contraction 4500 times as much oxygen as does the Anadonta
muscle.

MUSCULAR CONTRACTION 913

Like the heart, smooth muscle is capable of setting up automatic con-
tractions of a rhythmic nature even when removed from the body. This
automatic rhythmicity is probably a fundamental property of the smooth
muscle cells, just as it is of heart muscle, for it has been shown by Gunn
and Underbill'2" in the case of intestinal muscle that it continues after
the nerve plexus which lies between the layers of muscle has been removed.
It is also to be seen in isolated smooth muscle cells grown in tissue cultures
in which nervous elements can be observed to be absent.

CHAPTER XCVIII
POSTURAL COORDINATION

The maintenance of posture is accomplished by the tonic contraction
of the skeletal muscles. Not only must the muscles assume a new tonic
state in each new position of the body, but the tone of the muscles must
alter rapidly and in harmony with voluntary and reflex contractions
of a tetanic nature. Each voluntary act must also be made with reference
to the preexisting posture of the parts involved. The smooth continuity
of the normal movements of the body is dependent on the mechanism
which correlates postural with voluntary and reflex tetanic contraction,
and disturbances in this mechanism give rise to incoordinated movement,
ataxia, and the abnormal states of contraction seen in the muscles of
sufferers from nervous disease.

The Reflex Adjustment of Tone. — The tonic contraction of skeletal
muscle is maintained only in the presence of a reflex arc. The afferent
neuron of this arc arises from the muscle itself. This is shown by the fact
that after cutting all the nerve trunks to neighboring muscles and the
skin the tone of the muscle persists, but it disappears at once on sever-
ing the dorsal root through which the afferent fibers from the muscle
pass. The receptors of the afferent neuron which lie in the muscle
substance are called proprioceptors, and the reflexes which they ini-
tiate proprioceptive reflexes. The efferent path of the arc is completed
by the motor neurons of the muscle. In the presence of this arc tone
is not only maintained, but plastic changes in tone may be induced by
impulses traveling over it.

Two types of reaction are recognized which bring about changes in
the postural tone of skeletal muscle. If the knee of a spinal or decere-
brate mammal is flexed by pushing the foot with the hand, the resistance
which the tone of the extensors opposes to the movement may be felt to
give way, almost suddenly, as the joint moves into its new position.
On releasing the limb, it will now remain in the flexed condition as the
result of a reflex change in the tone of its muscles. The explanation
of this is that stretching the extensor muscle has stimulated its proprio-
ceptors and set up a reflex which causes a lengthening reaction of the mus-
cle. If the knee is now extended forcibly by hand a similar phenomenon
occurs and the tone of the muscles adjusts itself to the extended position.
The proprioceptors of the extensors have in this case been excited by a
decrease in the tension of these muscles and have given rise to a short-

9i4

POSTURAL COORDINATION 915

ening reaction. By this mechanism the tension which muscles exert on
their insertions is kept approximately constant, in spite of the changes
in their length which are occasioned by alterations in the position of
the body (Sherrington27).

The plastic tone of a skeletal muscle is effected not only by afferent
impulses arising in its own proprioeeptors, but by impulses arising from
other muscles as well. When the lengthening reaction of the extensors of
one limb is produced, a shortening reaction occurs in the extensors of the
opposite limb. Conversely the stimulus which sets up a shortening re-
action of one limb causes a lengthening reaction of the opposite exten-
sors. The crossed lengthening and shortening reactions may be seen
to be appropriate to the normal mode of using the two legs, for under
usual circumstances when one limb is flexed the opposite leg becomes
extended to support the weight of the body. The arrangement is conse-
quently one which ensures a certain degree of harmony in the tonic ad-
justments of muscles of parts which are used synchronously. A similar
adjustment of the tonic condition of the muscles must also be made
when the position of the body is changed through voluntary or reflex
movement. When such movements are produced tone changes of two
types occur: (1) The tone of the muscles which oppose the movement is
inhibited; (2) the muscles which produce the movement enter into a tonic
contraction which maintains the limb in the new position after the ex-
citation has come to an end.

The first phenomenon is seen when the leg of a spinal or decere-
brate mammal is thrown into flexion by stimulating a sensory nerve, or
the pain receptors of the foot*. The tone of the extensors, which in
the decerebrate cat is strong enough to support the animals weight,
might be expected to offer some resistance to the bending of the joints.
It may be shown, however, that at the moment the flexors contract,
the tone of the extensors vanishes, so that they do not oppose the flexion.
This is demonstrated by separating the flexor muscles from their insertion
at the knee and attaching them to a weighted lever, by which changes
in their length may be recorded. Since they are freed from their
insertion, any increase in their length cannot be due to stretching by
the flexors, but must be due to a loss in tone. When flexion is pro-
duced, it is found that the extensor muscle lengthens and the lever falls,
in synchrony with contraction of the flexor (Fig. 226). This is an exam-
ple of the phenomenon of reciprocal inhibition of antagonistic muscles,
which ensures their cooperative action.

The maintenance of the new position of a limb after the stimulus which
caused the change has subsided is called the after-discharge of the re-
flex. It is due in certain cases at least to a tonic shortening reaction
which is set up during the response to a stimulus — applied to receptors

OKI

CENTRAL NERVOUS SYSTEM

Fig. 220. — Reciprocal inhibition. Tracings made by myographs connected with E, and ex-
tensor muscle (vastus crureus), and F, a flexor muscle (.semitendinosus), of a decerebrate cat.
At signal / the homolateral peroneal nerve was excited, causing contraction of the flexors and in-
hibition of the tone of the extensors. At signal // the flexors were again thrown into contraction by
exciting the homolateral peroneal nerve, and (without removing this stimulus) the contralateral
peroneal nerve was excited (as shown in the lower signal), with the result that the contraction
of the flexors was inhibited at the same time that the extensors contracted. On removal of the
latter stimulus, the former one reasserted 'its influence. This experiment demonstrates very clearly
the accurate coincidence of the reciprocal action. (From Sherrington.)

POSTURAL COORDINATION 917

other than the proprioceptors of the muscles (called exteroceptors). Fig.
227 shows how greatly the reflex contraction of the extensors of the
knee of the cat may outlast the stimulus. If the afferent fibers from
this muscle are destroyed by cutting the dorsal roots the reflex contrac-
tion scarcely outlasts the stimulus. It appears that the reflex contrac-
tion is accompanied by a tonic shortening reaction which is maintained
after the exciting stimulus has come to an end. Its occurrence is de-
pendent on the proprioceptive reflex arc of the muscle, so that if this
is interrupted the contraction of the muscle cannot be maintained. The
reflex response fuses with the proprioceptive reaction so that it cannot
be said where one ends and the other begins. It is obvious that this is
a mechanism which greatly facilitates the "smoothness" of muscular

Fig. 227. — Records of the contraction of the isolated extensor muscle (vasto crureus) of the knee
of the cat produced by stimulating the popliteal nerve of the opposite leg. Periods of stimulation
indicated by the signal below the record. A, illustrated the after-discharge in the normal muscle;
D, the absence of after-discharge following the cutting of the afferent nerves from the muscle.
(From Sherrington.)

acts, enabling the limbs to remain in the position assumed under the
effects of certain stimuli, until other stimuli cause new postures to ap-
pear.

The Posture of the Body as a Whole,— When the position of the body
changes as the result of voluntary and reflex activity the tone of its
entire musculature must be modified so that each part may make a har-
monious contribution to the act as a whole. Part of the function of the
central nervous system is consequently to correlate the simple proprio-
ceptive reflexes such as we have described, not only with one another, but
with the voluntary and reflex acts which are initiated through the ex-
teroceptors. The afferent impulses which give rise to these harmonious
changes in the posture of the body as a whole arise in part from the pro-

918 CENTRAL NERVOUS SYSTEM

prioceptors of the muscles and tendons, and in part from the labyrinth.
The former are influenced by the position of the parts of the body, the
latter by the position of the body as a whole in space. The attitude con-
sequently depends* not only on the harmonious a'djustment of the posture
of its parts, but all these are brought into relation with the position
of the body in space, whether right side up, inverted, etc. The in-
teraction of these two sets of proprioceptors is illustrated by ex-
periments on the decerebrate cat. The tone of the extensors of such
animals is sufficient to support the body's weight. If the head of the
standing animal is forcibly flexed, the postural contraction of the ex-
tensor muscles of the fore limbs is inhibited, and the forequarters sink,
while at the same time the postural contraction of the extensor muscles
of the hind limbs increases, raising the hind quarters. The animal as-
sumed the appropriate attitude for looking under a shelf. On the other
hand, if the head is passively tilted up and back, the postural contrac-
tion of the extensor muscles of the fore limbs increases, raising the fore
quarters, and at the same time the postural contraction of the extensors
of the hind limbs is diminished so that the hind limbs sink. The at-
titude is now that of a cat looking up at a shelf. These reactions per-
sist after the labyrinths have been destroyed and consequently must
be due to proprioceptors in the muscles of the neck. The influence of
the labyrinth was studied by rendering the neck immobile with a plas-
ter cast, or by cutting the afferent roots of the upper cervicle nerves.
On changing the position of the head the same adjustments occurred
in the position of the limbs, so that the labyrinth must reinforce the
proprioceptors of the neck in their action. In addition the labyrinth
affected the posture of the neck in such a way that it would, had its
afferents been intact, have set up the appropriate change in the limb
posture. It has long been known that destruction of the labyrinth causes
very abnormal postures to be assumed and these can be attributed to
unusual positions set up in the neck muscles. In case of destruction of
both labyrinths a great loss in tone results. If the organ on one side
only is destroyed, tone is diminished on the opposite side, with the re-
sult that the trunk is curved and the animal tends to roll over and over.
Compensatory Movements of the Eyes, — The position of the eyes is
very markedly influenced by stimulation set up in the labyrinth. This is
of obvious importance, since as our bodies move, compensation must be
made by the eye muscles in order that the gaze may remain fixed on any
object. This relationship is nicely demonstrated in the dogfish where
the labyrinth is large and easily experimented upon. As the head of the fish
is turned from side to side, as it is in swimming, the eyes move so as
to compensate for the change in position. When the head turns to the
left the left eye is turned forward, the right eye backward so as to re-

POSTURAL COORDINATION

919

tain the original point of fixation. On rotating the head to one side,
the eye of that side is turned upward, that of the other side downward
in compensation. Similar movements can be induced by stimulating the
sense organs in the semicircular canals directly. Stimulation of the hori-

A

^\

I)

Fig. 228. — Compensatory movements of the eyes and fins of the dogfish. A and C illustrate the
position of the fish when at rest. B shows the compensatory movements of the eye.c w.hich occur
during swimming, or on bending the tail into the position indicated. D illustrates the compensatory
movements which occur on rotating the fish about its horizontal axis.

Fig. 229. — The semicircular canals of the ear, showing their arrangement in the three planes of
space. (From Howell's Physiology.)

zontal canal, Avhich is normally excited by a movement in its plane, i. e.,
by turning the head to one side, causes the eye of the same side to turn
forward; similarly the anterior vertical canal causes a rotation of the
eye upward and forward, the posterior vertical canal a rotation upward
and backward (Lee28). Appropriate movements of the fins accompany

920 CENTRAL NERVOUS SYSTEM

these reactions. In the dogfish the positions of the eyes is also con-
trolled by the proprioceptors of the tail muscles, for if the tail is bent
from side to side compensating movements of the eye are produced of
the same nature as those which accompany the movements of the tail
in swimming (Lyon29). Eye movements of a compensatory character are
also seen in man during rotation of the body. As the body turns the
eyes swing slowly in the opposite direction so as to maintain their fixa-
tion. Having turned as far as possible, they swing quickly back in the
opposite direction to fix a new object which in turn they follow by a slow
deviation. This slow deviation alternating with a rapid movement in
the opposite direction is called nystagmus. It also occurs during the sen-
sation of turning which persists for some seconds after the rotation of the
body has come to an end, and in certain pathological conditions.

Clinical Tests of the Labyrinthine Mechanism. — The influence of the
labyrinth on the postural coordination of the eye and limb muscles, forms
the basis for certain useful clinical tests by which the condition of the
labyrinth and of its central connections can be determined. These have
been developed chiefly by Barany. In normal individuals when the semi-
circular canals are stimulated in addition to the turning sensation and
nystagmus, a phenomenon known as past pointing occurs. If the sub-
ject is directed to close his eyes, extend his arm, raise and then lower
it in a vertical plane he will have no difficulty in bringing it back to its
original point. If he attempts to do this while the labyrinth is being
stimulated he will, if normal, return the arm 'to a position which de-
viates from the original point in the direction from which he thinks he
is turning, i. e., in the rotation test in the direction toward which he has
been spun.

The methods used to excite the canals are called the rotation test and
the caloric test. The rotation test is performed by spinning the subject
about two or three times in a pivoted chair, with the head held so that
the pair of canals to be tested lie in the plane of rotation. The caloric
test depends on the fact that if warm (112° F.) or cold (68° F.) water
is poured into the external auditory canal it will set up convection cur-
rents in the semicircular canal which lies in a ventrical position, and
there give rise to excitation. By holding the head in various positions
any one of the three canals can be stimulated. The caloric test has
the obvious advantage that it excites the canals of one labyrinth only.
If labyrinthine stimulation by these methods does not produce after
turning sensations, nystagmus, or past-pointing it is concluded that a
lesion occurs in the sense organ or some part of the nervous system in-
volved in the reaction. The past-pointing test is particularly useful,
since it can be applied to any joint and in any plane, and consequently
it has been possible to study the localization of the centers in the .cere-

POSTURAL COORDINATION 921

bellum which are concerned with the postural tone of each of these parts.
(Black.30)

Other Clinical Tests of the Proprioceptive Reflex Mechanism. — Certain
phenomena may be considered at this point which form the basis for
practical tests of the integrity of the mechanism by which posture and
tone is maintained. The posture of the body is adapted to the position
which it occupies in space, i. e., equilibrium is maintained, not only by
virtue of afferent impulses arising from the semicircular canals, but
as the result of visual sensations and of information supplied to the
central nervous system by the receptors of deep sensibility in the limbs.
Loss of function in any of these three groups of sense organs may be com-
pensated by the other two. As a result sufferers from a destruction of
the deep sensibility of the legs have little difficulty in maintaining an
upright position, so long as they are aided by the use of their eyes.
In the dark, however, their balance is kept with great difficulty. It is
consequently possible to test the integrity of the afferent paths from
the limbs involved in the maintenance of equilibrium by noting the
ability of the subject to stand with the feet close together and the
eyes shut. Under these circumstances a normal person will stand quite
steadily, but a sufferer from locomotor ataxia, in whom the afferent
neurons from the limbs are diseased, will sway violently and tend to
fall. This test is known as Romberg's sign.

The tendon jerks are a group of reactions which result from tapping
the tendons of the muscles of the knee, ankle, elbow and wrist. The
contraction of the muscle which results is not solely one of postural tone,
but it depends for its elicitation on the integrity of the reflex arc between
the proprioceptors of the tendon and the muscle. It may consequently
be used as a test for the condition of the afferent neurons from the deep
structures in the limbs and for the condition of the lower motor neurons
to the muscles, i. e., for the integrity of reflex arcs quite similar to
those involved in the maintenance and adjustment of tone. When a
lesion affects either the afferent neuron, as in locomotor ataxia, or the
lower motor neuron, as in anterior poliomyelitis, the tendon jerks and
tone alike are wanting. The character of the tendon jerks is also pro-
foundly modified by conditions in the central nervous system which affect
the tone of the muscles. In the normal individual when the patellar ten-
don is tapped, the response of the extensor muscles is prolonged by a
tonic contraction which gives way slowly as the flexors draw the leg back
into its original position. The tone of the antagonistic muscles checks
the limb 011 its return to this position, with the result that there is little
tendency for the leg to bounce up and down after the response is over.
When, however, the tone of the muscles is reduced as the result of in-
jury to remote parts of the central nervous system, as in cerebellar le-

922 CENTRAL NERVOUS SYSTEM

sions, or the later stages of spinal shock, the knee jerk is much more
brisk in character because the contraction of the muscles is unimpeded by
the tone of their antagonists. The return of the leg to its original posi-
tion is very rapid since there is no tonic prolongation of the contraction
of the extensors, and the shank tends to bounce up and down in the
absence- of any constraining tonic action on the part of the muscles

Fig. 230. — A, tracing of the knee-jerks of a normal man. B, tracings of the knee-jerks of the
hypotonic leg of a man with a cerebellar injury of eight years' duration. The records should be
read from right to left. (From Holmes.)

(Fig. 230). Under these conditions the return is a passive act produced
by the weight of the leg, and not by a compensating flexor contraction,
for if the limb is supported on a bed when the knee jerk is elicited, it
shows no tendency to flex again after the extension has been produced.
Impulses from other parts of the nervous system may prevent the
occurrence of the tendon jerks by preventing the afferent impulses set

POSTURAL COORDINATION 923

up by tapping the tendons from controlling the activity of the motor
part of the reflex arc (see the Final Common Path, page 945). If the
leg of an animal be thrown into flexion, the extensor muscles are in-
hibited from contraction and the knee jerk can no longer be elicited,
even though the extensor muscles are separated from their insertion
and consequently do not have to pull against the contraction. In a
similar way the knee jerk may be inhibited by influences arising in
the cerebrum, and consequently it is frequently necessary to distract
the subject's attention before the response can be brought out.

CHAPTER XCIX

THE CENTRAL CONTROL OF POSTURAL REACTIONS; THE

CEREBELLUM

The prime essential for muscular tone and its plastic reactions is the
integrity of its own proprioceptive reflex arc. Certain centers in the
brain exert a modifying influence upon the degree of tone which this
arc maintains, but if the afferent fibers from the muscles are damaged,
these centers cannot replace them in their effect on the motor neuron
of the proprioceptive reflex arc. Thus the exaggerated tone of the ex-
tensor muscles which is produced by the action of the centers in the
brain of animals from which the cerebrum is removed disappears at once
if the afferent roots are cut.

Since the proprioceptive reflex arc is necessary for the production
of tone in muscles, conditions of diminished tone or flaccidity appear
in disease affecting either the afferent fibers from the muscle or its
motor neurons. If the former alone is damaged tone will be dimin-
ished or lost without paralysis of the muscle. This is an unusual con-
dition since the afferent and efferent paths are only separated during
their passage into the cord through the spinal nerve roots. It occurs,
however, in locomotor ataxia, in which the primary lesion lies in the
posterior spinal ganglia, and in the ganglia of the cranial nerves. If the
motor neuron alone is affected the loss of tone will be accompanied by
paralysis of the muscles, that is a flaccid paralysis will result. This is
an important principle in determining where the lesion which gives rise
to paralysis is situated, since paralysis produced by lesions of the higher
motor centers and tracts is rarely accompanied by permanent flaccidity.
A typical flaccid paralysis occurs in anterior poliomyelitis in which
the lesion is situated in the ventral horn of the gray matter of the cord,
involving the cell bodies of the motor neurons.

The Influence of the Brain on the Local Tonic Reflex

When the proprioceptive reflex arc is isolated from the brain by com-
plete section of the spinal cord, a condition called spinal shock inter-
venes for a period during which reflexes may not be elicitable and the
muscles become atonic. After a period of time, which is longer the
higher the animal in the evolutionary scale, the reflexes return and tone
is regained, but not quite in normal degree. This condition holds true

924

CENTRAL CONTROL OF POSTURAL REACTIONS 925

for complete transections of the cord at levels up to the medulla. It
appears that the higher centers exert a reinforcing effect on the local
tonic reflex, which may be compensated for when these influences are
removed, but never with complete success. The reinforcement of the
tone of skeletal muscles by the higher centers of the nervous system
represents the resultant of two opposing tendencies, one augmenting the
tonic contraction, the other inhibiting it.

The augmentation of tone is seen in the condition known as decere-
brate rigidity, to which we have already referred, in which the tone of
the extensor muscles is greatly exaggerated. Experiments on animals
show that the rigidity is not the result of separating the cerebrum from
the central nervous system, as the name would imply, for if successive
slices of the brain be removed from above downward the condition does
not develop until the section separates the optic thalamus from the mid-
brain. The researches of Sherrington,31 Thiele,33 and particularly of
Weed,32 indicate that the mechanism supporting the rigidity is probably
somewhat as follows. The afferent impulses on which the " reflex stand-
ing" depends arise in the muscles themselves, since cutting the posterior
roots of the spinal nerves supplying the muscles in question abolishes the
rigidity. They pass up the cord in the ventrolateral column of the same
side and probably enter the cerebellum through the superior cerebellar
peduncles and pass to the cerebellar cortex. From thence the path leads
back through the same peduncles to the midbrain in which lies the main
center for maintaining this condition, probably the nucleus ruber. From
there the paths descend through the cord in extrapyramidal tracts, prob-
ably the rubrospinal. Afferent paths also probably lead directly to the
midbrain center without passing through the cerebellum, for in some
animals removal of the cerebellum is not followed by loss of rigidity or
its loss is not immediate.

The Inhibition of Tone.— The rigidity may also be inhibited, once it
has developed, by stimuli applied to various parts of the nervous system.
If the "decerebration" is limited to one side of the body rigidity may
develop on that side only and it becomes possible to study the effect of
stimulating the cortex of the other half of the cerebrum. Stimulation of
the sensory-motor area inhibits the existing tone in the extensors mus-
cles. Excitation of the cerebral peduncles also inhibits the rigidity.
Weed32 considers that the cerebellum forms an essential link in the path
over which these inhibitory impulses pass from the cerebrum to the
centers which maintain the rigidity, because severence of the middle
cerebellar peduncles eliminates the inhibition which is produced by
stimulation of the cerebral peduncles. In support of this observation is
the fact that excitation of the anterior part of the superior vermis or of

926 CENTRAL NERVOUS SYSTEM

the stump of the middle cerebellar peduncle inhibits the rigidity of the
limbs.

The maintenance of the excessive extensor tonus known as decere-
brate rigidity consequently depends upon the reflex connection of a cen-
ter in the midbrain with the muscles. Normally the activity of this
reflex mechanism is held in abeyance by the inhibitory influence of the
fore brain. The fact that both the afferent impulses from the muscles
and the inhibitory impulses from the cerebrum pass through the cere-
bellum suggests strongly that this organ must have a very important
relation to the regulation of postural tone, and that this is the case is
indicated conclusively by what is known of the physiology of this
structure.

The Function of the Cerebellum. — The function of the cerebellum has
been the subject of exhaustive study, particularly on the part of Luci-
ani.36 Stimulation of the cortex of the cerebellum with an electrical
current does not give rise to any detectable reactions unless the current
is so strong as to spread to the deeper ganglia of the brain. Conse-
quently it has been necessary to study the effects of removing all or
part of the cerebellum and to attempt to deduct from the resulting dis-
turbances the function which the ablated parts perform. When this is
done it is found that three stages can be distinguished in the condition
of the animal, following the operation. In the initial stage a definite
group of symptoms are presented which are presumably due to certain
immediate effects of the operation. These effects change quite com-
pletely after several days and a set of conditions present themselves
which appear to be the permanent result of the loss of the cerebellar
tissue. Finally, however, a certain improvement in the behavior of the
animal occurs which may be attributed to the compensatory action of
other parts of the nervous system which modify their activities so as
to correct for the loss of cerebellar influences. The second stage is ob-
viously of chief interest in the interpretation of the normal function of
the cerebellum. The conditions existing in this stage in man, following
gunshot injuries, have been exhaustively described by Holmes,35 and as
they agree closely with the results obtained on animals and are of greater
interest in human physiology, we may draw our conclusions from them.

The destruction of tissue in one half of the cerebellum manifests it-
self in the condition and behavior of the muscles on the same side of the
body. "When compared to the muscles of the uninjured side, these ex-
hibit several forms of abnormality which may be designated as atonia,
asthenia, astasia, and ataxia. To atonia are attributed those symptoms
which manifest themselves as the result of a diminution in the tone of
the muscles. As the result of this condition the muscles feel soft and
flabby and the limbs tend to assume unnatural positions. When the arm

CENTRAL CONTROL OF POSTURAL REACTIONS 927

is held upright, for example, the wrist is flexed under the weight of the
hand. If the joints are passively bent, their movement is not checked
by the action of the muscles, but continues until the articulations cause
them to lock. The characters which the disturbance in tone imposes on
the knee jerk have been described on page 921.

Asthenia expresses the fact that the muscles of the injured side are
weaker than on the normal side. Not only are the patients conscious
that these muscles feel weaker, but measurement with a dynamometer
shows that they can exert in some cases only 50 per cent of the force
of which the normal muscles are capable. The limbs in which the mus-
cles are asthenic are also unusually subject to fatigue. It should be
emphasized that the muscles which have been deprived of a cerebellar
influence are never paralysed: the asthenia is not a failure of function,
but rather an expression of inefficiency in the act of voluntary contraction.
Closely associated with the asthenia is the discontinuity or irregu-
larity of a maintained muscular contraction known as astasia. The af-
fected muscles frequently tend to give way under the load they bear, so
that objects held in the hand are liable to be dropped, or the leg on the
injured side may suddenly collapse under the body's weight and thus
cause the patient to fall as he attempts to walk. A tremor may occur
in maintaining an attitude, if it requires the exertion of some force, par-
ticularly as the muscles begin to tire. It is a less prominent symptom in
man, however, than in animals. The destruction of the cerebellum seems
to disturb the mechanism by which the individual twitches of the con-
tracting muscle become fused so as to maintain a constant tension. We
have pointed out on page 917 that the continuity of muscular movement
is facilitated by the reinforcement of the primary response by an adjust-
ment in the postural tone of the muscle, and it would seem that this is
the mechanism whose disturbance gives rise to the astasia of cerebellar
injuries.

Under ataxia may be grouped those symptoms which are due to ir-
regularities in the voluntary movements of the body. The limbs of the
affected side are ill directed when an attempt is made to perform some
precise movement. The finger may strike the eye, when its true objec-
tive is the mouth and consequently the patient fears to hold his cigarette
in the affected hand while smoking. It is impossible to stop the move-
ment at the right point, with the result that in trying to reach some ob-
ject, the hand strikes it forcibly or else falls short of its objective. When
voluntary movements are made they are interrupted in their progress
by a tremor, particularly as they approach their objective, and greater
need for accuracy becomes necessary. This jerky character of the mo-
tion is obviously closely associated with the static tremor described as
astasia. Certain abnormalities in movement indicate that difficulty ex-

928 CENTRA!, NERVOUS SYSTEM

ists in the synchronous adjustment of the activities of various muscle
groups which should cooperate for a common end. When the fingers are
flexed the extensors of the wrist normally contract synergically in order
to prevent simultaneous flexion of the wrist. If a patient with a cere-
bellar lesion grasps a small object quickly, the wrist may be extended
excessively so that the hand is bent backwards before the fingers are
half flexed. Movements which involve the activities of several joints
are frequently decomposed into their component parts which are exe-
cuted one at a time instead of all at once. In bringing the finger to the
nose the patient will first depress the arm by a movement of the shoulder,
and then flex the elbow after the first act is complete. Difficulty is also
experienced in making rapid alternate movements such as flexion and
extension of the fingers. The actual movement may be made nearly as
rapidly as with the normal hand, but a considerable delay intervenes be-
tween the successive acts, indicating a difficulty in adjusting the neuro-
muscular mechanism for the new act. In making such rapid alternating
movements groups of muscles not concerned in the desired action may
come into play. When, for example, the ankle is voluntarily flexed and
extended in rapid succession the knee and hip may flex and extend also.
The ataxia produced by the destruction of cerebellar tissue consists then
in a disturbance of the normal harmony and correct cooperation in time
and degree of the various muscular contractions concerned in movements
and in the maintenance of posture.

We may conclude that the cerebellum is actively concerned with
the maintenance of tone and in the adjustment of voluntary contraction
and plastic tone to the posture of the body, not only as it is maintained
in rest, but as it changes when in action. Sherrington37 has accordingly
designated the cerebellum as the main ganglion of the proprioceptive
system. The passage of impulses from the proprioceptors and from the
cerebrum through the cerebellum in their course to the centers of the
midbrain which are involved in the maintenance of decerebrate rigidity
consequently assumes an important functional significance.

No Sensory Disturbances Follow Injury to the Cerebellar Cortex.—
In considering the function of the cerebellum it should be pointed out
that although it receives afferent impulses from the proprioceptors of
the body there is no evidence that it is concerned in any way with sen-
sation. The only sensory tests to which those afflicted with cerebellar
injuries fail to respond with normal accurac}^ are those involving the
comparison of weights placed in the normal and the affected hand. In
this test the weight in the latter is judged heavier than it should be be-
cause of the greater effort required to support it with the asthenic mus-
cles. Although the ability to maintain the equilibrium of the body may
be disturbed as the result of cerebellar injury, this is because the mus-

CENTRAL CONTROL OF POSTURAL REACTIONS

929

cles do not respond properly in the attempt to prevent falling, and not
because the sense of equilibrium is in any way impaired.

Localization of Function in the Cerebellum. — The observations on cere-
bellar injuries in man which we have described indicate that the two
halves of the cerebellar cortex are each concerned with the regulation of
tone and movement in the corresponding half of the body. Beyond that
they do not afford any evidence of localization of function in the cere-
bellum. By studying the correlation between the functional importance
of different muscle groups and the development of the different parts of
the cerebellum in different animals Bolk has assigned the control of each
muscle group to a definite part of the cerebellar cortex, as is indicated
in Figure 231.

Basing his work on these anatomic conclusions, Van Rijnberk has studied
the effect of circumscribed extirpation of certain lobules of the cerebellum

Fig. 231. — Schema of the parts of the mammalian cerebellum spread out in one plane. (After Bolk
by Van Rijnberk from Luiciani. Op. cit.) On the right side of the figure the relation of the
different lobules to the functional development of the musculature is indicated according to the
theory of Bolk noted in the text. (From Davidson Black.)

on the muscular control of the different parts of the body, with the following
results. Total or partial extirpation of the lobulus simplex produces side to
side oscillations of the head, indicating the removal of the influences of the
cerebellum that control the movements of the muscles of the neck. Complete
extirpation of the crus primum of the lobuli ansiformes causes as an imme-
diate— irritative — effect dynamic disturbances of the fore limb of the same
side, replaced later by a condition of atonia, which makes the limb hang
limp, and of asthenia, which makes it feeble in its movement when it
is excited to contract. Extirpation of the crus seeundum has a similar
influence on the muscles of the hind limb of the corresponding side. Extir-
pation of both crura of the lobulus ansiformis causes marked asthenia and
atonia in both fore and hind limb on the same side as the lesion. A char-
acteristic disturbance in walking develops as a late effect of this extirpation.

CENTRAL NERVOUS SYSTEM

It has been termed the "lien's gait." Extirpation of the lobulus para-
medianus causes rotation on the longitudinal axis of the body, with pi euro-
thotonus to the operated side. (Fig. 232.)

Just as in tlie case of cerebral localization, so in cerebellar we find that
within each of the largest centers a more particular localization can be made
out; thus, in each of the centers for the upper and lower extremities,
there is a definite arrangement of subsidiary centers for the direction of
the activities of antagonistic muscle groups concerned in the movements of
particular joints.

Localization of function in the cerebellum of man has been worked out
by Barany by correlating the position of cerebellar lesions with dislurb-

Fig. 232. — Diagrams to represent respectively a ventral view of the left half and a dorsal
view of the right half of the human cerebellum illustrating the scheme of subdivision according
to Bolk. (From photographs of specimens from the Anatomical Museum, Western Reserve Medical
School.) (From Davidson Black.)

ance in the past-pointing tests (described on page 920) which appear
when the action of each joint is examined in turn. Barany 's conclusions
so far may be summarized as follows:

(1) The centers for the extremities are located on the cortex of the
hemispheres in the semilunar (superior and inferior) and digastric lobules
(see Fig. 233). The representation is uncrossed or homolateral, thus con-
trasting with cerebral localization, in which it is crossed or heterolateral.

(2) Within each of these chief centers there is a further localization,
which however does not refer to anatomical groups of muscles but rather to
the functional performances of the different segments of the limb. Thus,
within the arm centers there are subsidiary centers concerned in the
movements of the limb in the various planes in rotation, in pronation

CENTRAL CONTROL OF POSTURAL REACTIONS

031

and in supiiiation. It is a functional rather than an anatomical localization.

(3) When a center concerned in the movements of the limb in a certain
direction, e. g., to the right, is suddenly destroyed, a spontaneous devia-
tion is produced in the opposite direction (to the left).

For further details see, the paper by Black.30

Compensation for Cerebellar Injuries. — The final stage following

Fig. 233.

Fig. 234.

Figs. 233 and 234 represent respectively the inferolateral and the posterior aspect of the human
cerebellum indicating certain cerebellar localizations according to Barany. (After Barany, from
Andre-Thomas et Durupt. Op. cit.) N. VII, Nervus facialis; N. IX, Nervus Glossopharyngeus;
N. XII, Nervus hypoglossus.

The signs in the above diagram indicate the exact localization of the centers for the tonus of
the musculature concerned in some of the movements of the right arm and leg, ® marks the
center for downward movements of the arm; X, for abduction of the arm; O, adduction of the
hand; + adduction of the arm; ±, adduction of the hip. N. V. indicates Nervus trigeminus;
N. VI, Nervus abducens; N. VII, Nervus facialis; N. IX, Nervus glossopharyngeus; N. XII,
Nervus hypoglossus. (From Davidson Black.)

the removal of cerebellar tissue is one in which compensation is made
for this loss by other parts of the nervous system, so that in time the
symptoms gradually tend to disappear. The initial disturbances in lo-
comotion and the improvement which comes with time are illustrated in
Fig 235, which represents the footprints of a dog from which the cere-
bellum has been removed.

932 CENTRAL NERVOUS SYSTEM

It will be of interest to consider for a moment the possible causes for the
ultimate disappearance of the symptoms of cerebellar extirpation. These
are either: (1) an organic compensation by the uninjured parts of the cere-
bellum, or (2) a functional compensation by the voluntary centers of the
cerebrum. Although the former of these methods of compensation may
sometimes develop after partial destruction of the cerebellar cortex, it can
not of course explain the recovery which we have seen to occur after the

, e

Fig. 235. — Footprints after destruction of the cerebellum in a dog: a, before the operation;
b, four days after; c, five days after; d, a month after; e, two months after. (From Luciani.)

entire cerebellum has been removed. The most important compensation no
doubt is effected by the cerebrum, as the following observation clearly in-
dicates. If half of the cerebellum of a dog is destroyed, and the animal
kept alive until the symptoms of cerebellar extirpation have entirely dis-
appeared, it will then be found, if the cerebral center on the opposite side
is removed, that the symptoms return in their original severity. After this
second operation the powers of standing in the erect position and of
walking are permanently lost.

CHAPTER C
THE INTEGRATION OF ACTION WITHIN THE REFLEX ARC

In considering the anatomical arrangements which give rise to sensa-
tion and motor activity, we have taken the risk of creating a false im-
pression that the action of the nervous system is carried out in a rigid
and immutable manner, and that nerve impulses travel over the conduct-
ing paths with the invariability with which an electric current flows over
a fixed system of wires. While the constancy of the anatomical paths
by means of which certain nervous functions are carried out is of ines-
timable value in clinical neurology it must be emphasized that in the
nervous system continuous adjustment is made to the end that the activ-
ity of one part may adapt itself to the activities of other parts, and con-
sequently the results of a given stimulation are not always strictly pre-
dictable. In other words the activity of the various reflex paths is closely
coordinated. Before we can consider how this coordination between
reflexes is accomplished, we must first examine into how the activity of
the various parts of a reflex arc are related so that the reflex may bring
about an act of functional significance; i. e., a response in which a local-
ized group of muscles act in a coordinated way so as to accomplish some
purpose which is related to the exciting stimulus.

The Receptors. — Reflex acts are initiated by the stimulation of recep-
tors. Because each receptor is specialized to respond more readily to
one quality of stimulus than to any other (page 856), each reflex arc is
brought into action only by stimuli of an appropriate sort. The selective
excitability of the receptors of the different reflex arcs consequently
enables the organism to respond in different ways to stimuli of different
kinds when they are applied to the same receptive skin area. As an
example we may consider the reactions which may result from stimulat-
ing the foot of a spinal or decerebrate cat. By pressing against the under
surface of the paw a reflex may be elicited known as the extensor thrust,
consisting of a vigorous extension of hip, knee, and ankle of the corre-
sponding leg. This response cannot be called out by any other form of
stimulus. In life it would be expected to occur when in running the
cat's foot comes in contact with the ground, thus throwing the animal's
Weight on the leg. If a harmful stimulus is applied to the same part of
the foot the response is of a totally different character, consisting of a
flexion of the joints of the limb. The foot is pulled awav ^om the stim-

933

934 CENTRAL NERVOUS SYSTEM

ulating object. This would serve to relieve the cat of pain, such as might
be occasioned if it stepped on a thorn. The receptors for these two
reflexes have their thresholds lowered each to a particular form of stimu-
lus, and the nature of the response is such that the leg moves in a way
which is appropriate to the conditions under which stimulation occurs in
nature.

When nerve impulses are set up in the afferent neuron of a reflex
arc, the path over which they may travel is limited by the insulation of
the fibers of the nerve trunk to those neurons with which the afferent
fiber makes connection through synapses located in the grey matter of
the spinal cord. The characteristics of the synapse, which we have de-
scribed in Chapter XC determine the destiny of the nerve impulse and the
characteristics of the reflex response which results.

Summation. — It was pointed out that a single nerve impulse frequently
fails to pass across a synapse, over which a series of impulses may travel
if they follow one another in rapid succession, so that their effects are
summated. This characteristic of synaptic conduction is of importance in
regulating reflex activity, as may be realized when it is considered that
the organism is constantly in receipt of many unimportant stimuli. Be-
cause of the necessity for summation only those stimuli call forth a re-
sponse which are of some intensity and duration. Consequently mo-
mentary and hence insignificant stimuli do not affect its behavior.

6. The Refractory Period. — This has been well defined by Sherrington
as being "a state during which apart from fatigue the mechanism shows
less than its full excitability." We are already familiar with the re-
fractory period in the cases of the heart muscle and the musculature of
the esophagus and intestine. For example, the application of a stimu-
lus to the quiescent frog heart while it is contracting in response to an im-
mediately preceding stimulus fails to produce any further effect. The re-
fractory period is extremely brief (one thousandth of a second) in a
nerve trunk, but is much longer in a reflex arc, being probably longest
in the case of the scratch reflex, in which it is demonstrated by the
fact that, however frequently we apply suitable stimuli to the sensory
surface, the rhythm of response of the contracting limb is always the
same. After each stimulus, therefore, a refractory period must become
developed during which a repetition of the stimulus has no effect. It
is evident that the existence of the refractory period is the factor
responsible for the rhythm of the movements.

It is interesting to consider what part of the reflex arc is responsible
for the existence of the refractory phase. It obviously can not be a
function of the motor neuron, for through the same motor neuron may
be discharged, at one time, impulses which bring about the scratching
movement and, at another, those causing a tonic flexion of the

INTEGRATION OP ACTION WITHIN THE REFLEX ARC 935

same muscles. Nor can the seat of the refractory period be in the
sensory area of the skin or the afferent neuron, for if a scratch move-
ment is elicited by stimulation at a point A in the proper skin area,
the rhythm of response which it calls forth will not in any
way be altered by the application of a second stimulus applied at B
at some distance from A and having a different frequency (Fig. 236).
There is evidently, therefore, some part of the reflex arc that is common to

Fig. 236. — Tracing from the hind limb of a spinal dog during the scratching movements pro-
duced by applying stimuli at two skin points (A and B), the application of the stimuli being in-
dicated by the signals. Not only were the stimuli applied at different points, but at B they
were of much greater frequency than at A. Although there is a slight change in "local sign," it
will be observed that there is no alteration in rhythm, indicating that this property can not be a
function of the final common path. (From Sherrington.)

impulses starting both at A and at B, for if in each of these spots a refrac-
tory phase occurred, then there would be interference before the two im-
pulses had reached the centers of the spinal cord. By exclusion, there-
fore, "the seat of the refractory phase seems to lie somewhere central
to the receptive neuron in the afferent arc'7 — (Sherrington18).

Many other types of reflex activity illustrate rhythm due to the re-
fractory phase. Two laboratory examples may be given: (1) When

936

CENTRAL NERVOUS SYSTEM

the central end of an afferent root is stimulated in the lumbar region of the
spinal cord, the movement produced is distinctly rhythmic in character.
(2) Upon stimulating the central end of the sciatic nerve in a frog whose
spinal cord has been cut some days previously, a clonic action of the
contralateral foot occurs, and the rate of the rhythm is not affected by
variation in the. frequency of the stimulus.

Fig. 237.- — Diagram showing the reflex arcs involved in the scratch reflex. Ra and R@ represent
the afferent neurons connected with hairs on the skin of the back and flank. The afferent im-
pulses are transmitted by these fibers, and on entering the corresponding segments of the spinal
cord terminate by synapses on cells of the internuncial neurons, whose arrows Pa and P(3 travel
down in the lateral columns to terminate similarly around the cells of the motor neurons that
innervate the muscles of the hind limb. Since afferent impulses coming from elsewhere, par-
ticularly from the skin of the leg (R and L), also terminate on these neurons and may excite
them to a different type of action, the motor neuron is called the final common path (F.C.).
(From Sherrington.)

Fig. 238. — The region of body of dog from which the scratch reflex can be elicited. (From

Sherrington.)

In all the above cases the refractory period may be held responsible
for the rhythmic nature of the contraction. In other reflexes it exists
for another purpose. In the case of the extensor thrust, which it will
be remembered is elicited by pressure applied to the pads of the plantar
aspect of the foot, the momentary extension of the leg lasts only for a
little less than two-tenths of a second, but is followed by a refractory

INTEGRATION OF ACTION WITHIN THE REFLEX ARC 937

period lasting nearly a whole second, during which a second stimulus
elicits no response. The object of this long refractory period is no doubt
that opportunity may be given for the flexor muscles to perform the
contraction that would naturally ensue during the normal occurrence
of the extensor thrust, as in the act of walking. When the animal
places his foot on the ground, the sudden pressure exerted on the pad
of the foot immediately calls forth the extensor thrust, by means of
which the weight of the body is temporarily removed from the ground,
and the muscles perform the contractions necessary to produce flexion
of the limb. Although the refractory period is unaffected by the strength
of the stimulus it is very dependent upon the internal condition of the
reflex arc, such as that caused by changes in blood supply or by narcosis.

Reciprocal Inhibition

It might appear that to bend a joint or to move the eyeball the only
muscular action required would be contraction of the muscles which
flex the joint or rotate the eyeball, and that the antagonistic muscles
would merely become passively elongated. When we remember, how-
ever, that all the muscles of the body are ordinarily in a condition
of slight tonic contraction, and that this tends to become increased
when the muscles are passively stretched, then we see that for effi-
cient movement there must be inhibition of the tone of the muscles
which oppose those that are contracting. This reciprocal inhibition,
as it is called, is a very widespread function throughout the animal
body. Sometimes it is purely peripheral in origin, as in the claw
of the crayfish, where stimulation of the nerve causes an opening of the
claw due to the contraction of one set of muscles and the simultaneous
inhibition of their antagonists. Instances of peripheral reciprocal in-
hibition in the higher animals are not so common, but are illustrated in
the case of the myenteric reflex, where it will be remembered a contraction of
the intestine over a bolus of food is accompanied by inhibition in front of
the bolus. The reciprocal action in this case is probably dependent on
the myenteric plexus.

On the other hand, reciprocal inhibition of central origin is very com-
mon in the higher mammalia. Thus, in the case of the lateral movement
of the eyes, if we cut the third and fourth nerves to one eye, say, the
left, the external rectus of that eye will alone be under the control
of the nervous system, through the sixth nerve; nevertheless, if we after-
ward cause the animal to look toward the right, as by holding some ob-
ject in that direction, it will be found that the left eye as well as the
right folloAvs the object. Obviously there must be an inhibition of the

938 CENTRAL NERVOUS SYSTEM

external rectus muscle of the left eye, an inhibition which is pronounced
enough to bring about a movement of the eyeball, and which exactly cor-
responds in point of time with the contraction of the external rectus of
the right eye. This movement, due to the atonicity of the external rec-
tus, does not however succeed in causing the eye to rotate beyond the
midline of the field of vision. This is an instance of a willed reciprocal
inhibition ; i. e., a reciprocal inhibition brought about by stimuli coming
from the motor centers in the cerebrum. The same result may be
obtained by electric stimulation of the center for eye movements on the
cerebral cortex.

The most important details concerning the mechanism of reciprocal
inhibition have been obtained by studying the flexion reflex in a spinal
animal which has completely recovered from shock. In such an animal
the tonus of the extensor muscles of the knees is well marked. If we pre-
vent the flexors from acting on the knee joint and the leg is held in an ex-
tended position, irritation of the skin of the leg will cause the flexion of the
disconnected hamstring muscles simultaneously with a visible relaxation
of the extensors. If the leg is held properly, this relaxation may be
marked enough to cause a slight flexion at the joint under the influence
of gravity. This experiment is very striking when performed on a de-
cerebrate animal, in which, as we have seen, the extensor muscles of the
limb are in a permanent state of hypertonicity.

Reciprocal inhibition can also be demonstrated by stimulating the
central end of suitable afferent nerves — that is, certain afferent nerves •
acting on the same groups of neurons will produce a flexion reflex, others
an extension reflex; thus, stimulation of the homolateral peroneal nerve
produces a flexion reflex of the hind limb (excitatory for flexors, in-
hibitory for extensors), whereas stimulation of the ccmtralateral peroneal
nerve produces an extension (inhibitory for flexors, excitatory for ex-
tensors). (Fig. 239.)

Before we can conclude that the ,two elements in reciprocal inhibition
are part and parcel of the same reflex it must be shown that under what-
ever conditions the contraction of one group of muscles is brought about,
inhibition of their antagonists must also occur and that the responses
take place at exactly the same time. If records are made of the move-
ments of the flexors and extensors of the knee in an experiment such
as we have just described, it is found that the latent period for the re-
sponse of agonist and antagonist, whether it be contraction or inhibition
exactly coincides (Fig. 226). If the strength of the stimulus is gradually
increased the latent period becomes shorter for the inhibitory and active
reaction alike and the synchrony of the reciprocal responses is still pre-
served. Moreover the receptive field 011 the skin from which contraction

INTEGRATION OF ACTION WITHIN THE REFLEX ARC 939

may be elicited coincides exactly with that for the inhibition of the antag-
onistic muscles, as do also the kinds and strengths of stimuli which are effec-
tive in each case. The inhibition of antagonists may consequently be
considered a part of the same reflex which excites the agonists to contrac-
tion.

It is impossible to demonstrate any trace of inhibition of the skeletal
muscles by stimulation of their motor nerves, thus indicating that in-
hibition is dependent upon the nerve center. Furthermore, since inhibition
occurs along with contraction of the antagonistic muscle, we must assume

Fig. 239.— Record from uiyograph connected with the extensor muscle of the knee. During
the time marked by the lower signal, the skin of the opposite foot was stimulated, thus causing
the crossed extension reflex. While still maintaining this stimulation, faradic shocks were ap-
plied to the skin of the foot of the same side (a? indicated by the upper signal), with the result
that immediate inhibition of the contracted extensor occurred. (From Sherrington.)

that the afferent impulse on entering the spinal cord divides into
two branches, one going to one motor neuron so as to excite it, the other
to another neuron so as to inhibit the tonic stimuli which it is con-
stantly sending to the muscles (Fig. 240). According to this assumption
the effect of impulses carried over each branch depends on the nature of
the synapse which these make with the motor neurons of the antagonistic
groups of muscles.

Since the seat of the inhibition is in the nerve center, it is to be ex-
pected that impulses transmitted from other parts of the nervous system

940

CENTRAL NERVOUS SYSTEM

than the particular level of that reflex, will also be able to induce the
inhibition. In the case of the decerebrate cat this can be demonstrated
by stimulation of the lateral columns of the spinal cord; inhibition of
the extensor muscles of the elbow joint occurs, which is all the more
marked because in such a preparation these muscles are in a state of
hypertonicity. Through the pyramidal tract impulses may descend from
the cerebrum which exercise a marked inhibitory influence over the reflex
activities of the cord.

Finally, it must be pointed out that this mechanism of reciprocal in-
hibition is by no means confined to the voluntary muscles. We have

Fig. 240. — Sherrington's diagram illustrating the mechanism of reciprocal inhibition. The
afferent fibers (d) from the skin of the leg and (a) from the flexor muscles of the knee (in
hamstring nerve) pass to the spinal cord, where each gives off a branch which divides into two
others, of which one in each case goes to a motor neuron of the extensor muscles (£) and the
other to a motor neuron (6) of the flexor muscles (F). Branches also pass across the median
line to similar motor neurons on the opposite side of the cord. As indicated by the plus and
minus signs, the afferent stimuli either stimulate or inhibit the activities cf the motor neurons,
the determination of the exact effect being a function of the synapsis. (From Sherrington.)

already seen that it occurs in the case of the myenteric reflex. It is also
a most important function in the innervation of the blood vessels, dilata-
tion in one vascular area being accompanied by constriction in another.
These facts have been already sufficiently dwelt upon elsewhere (page
247). Sometimes also we may have reciprocal action between differently
acting nervous mechanisms, as for example in the case of the submaxil-
lary glands, which respond to stimulation of the chorda tympani nerve
by dilatation of the blood vessels, an inhibition of their tone occurring
along with stimulation of the activity of the gland cells.

INTEGRATION OF ACTION WITHIN THE REFLEX ARC 941

The Action of Strychnine and Tetanus Toxin on Reciprocal Inhibition

Under certain conditions reciprocal action may fail to occur, as, for
example, at certain stages of strychnine poisoning and during the action
of tetanus toxin. In order to demonstrate this failure of reciprocal ac-
tion, it is necessary to examine muscles which act on one joint only, and
to observe their behavior when an afferent nerve is stimulated which un-
der ordinary conditions would throw them into inhibition. Such a
preparation can be obtained in the hind limb of a dog by cutting all the
muscles that act on the knee joint except the vastus crureus, which in a
normal animal invariably undergoes inhibition when the central end of
the internal saphenous nerve is stimulated. If a suitable dose of strych-
nine is injected, it will be found that stimulation of the internal saphenous
nerve, in place of inhibition, causes contraction of the vastus crureus
muscle. The same result is obtained by injection of tetanus toxin.

The failure of the reflex inhibition explains the symptoms produced
by these substances. It explains, for example, the well-known rigidly
extended condition of the limbs in strychnine poisoning, and the dis-
tressing symptom of lockjaw in tetanus infection. In this latter con-
dition the sufferer is subjected to extreme torture with every endeavor
that he makes to open the jaw for the purpose of taking food or drink.
Firmer closure is the result because the normal inhibition of the temporal
and masseter muscles does not occur, but instead they become excited
and the jaw all the more firmly closed. Not only does, the inhibition fail
to occur, but the above muscles are usually in a state of constant hy-
perexcitability, which it is impossible for the patient to restrain ; indeed,
whenever he attempts to do so the opposite occurs and the excitation
becomes heightened. Chloroform acts on reciprocal innervation in an
opposite way from strychnine and tetanus; namely, it paralyzes the ex-
citation of the contracting muscles.

The Reflex Figure

We have seen in the preceding paragraphs that the afferent fibers of
a single reflex arc make connection with the motor neurons of a con-
siderable group of muscles, exciting some and having an inhibitory in-
fluence on others to the end that all may cooperate in producing an or-
derly movement of some functional significance. The effects of stimulating
a single afferent path may not be limited to the antagonistic muscles ar-
ranged about a single joint, but may extend to the flexors and extensors of
all the joints in a single limb and, further, to each of the other limbs and to
muscles of the head, trunk, and tail as well. The response which follows
the application of a strong stimulus to the receptors of a reflex arc may
consequently involve nearly the whole musculature of the animal. The par-

942

CENTRAL NERVOUS SYSTEM

ticular attitude which is assumed is called a reflex figure, and is the expres-
sion of the complete central connections of the reflex in question. Fig. 241
illustrates three characteristic reflex figures obtained by applying a harm-
ful stimulus to various parts of the skin of a decerebrate cat.

The reflex figure which results from such a stimulus when applied
to the foot of the hind leg consists in a flexion of this leg, an extension
of crossed hind leg (the crossed extension reflex), extension of the
homolateral fore leg, and flexion of the crossed fore leg. This group
of responses may be considered to be a compensatory reaction, inas-
much as the movement of certain parts is adapted to restore a balance
which is disturbed by the movement of other parts, and the result
is an orderly change in the position of the body as a whole which is

Fig. 241. — Reflex figures. A, the position of the cat in decerehrate rigidity. B, C, D, re-
spectively, are the reflex figures resulting from stimulating the left pinna, the left forefoot, and the
left hind foot. (After Sherrington.)

significant in meeting the exigency which has given rise to the reflex
response. The reflex figure which we have just described might be
brought into play, for example, when a cat steps on some object which
hurts its hind foot. The hind foot is lifted from the ground by
virtue of the contraction of the flexors and the compensatory inhibi-
tion of their antagonists. The weight of the hind quarters is thus
thrown on the contralateral hind leg, which extends to support this
weight, preventing the animal from sitting on the source of discom-
fort. At the same time the cat must prepare to move away so that
the stimulus may not be encountered again, and for this act the exten-
sion of the crossed hind leg and of the homolateral fore-foot, with their
backward thrust, tend to throw the body forward and support it while
the flexion of the stimulated hind leg and the crossed fore leg move

INTEGRATION OF ACTION WITHIN THE REFLEX ARC 943

these limbs forward preparatory to supporting the body at the next
step. The reflex figure' is seen from this to. be an integral mechanism
out of which is built the functional act of stepping away from a stim-
ulus which endangers the hind foot.

The entire reflex figure may* be considered to be an unified reflex
act depending on the central connections of a single afferent path, for
much the same reasons which lead us to conclude that excitation and
inhibition of the antagonistic muscles at a single joint are parts of a
single reflex. In all parts of the reflex figure reciprocal inhibition
may be seen to occur, as may be proved by studyingr that component
known as the crossed-extension reflex. As we have pointed out above,
stimulation of an afferent nerve from one foot produces a contraction
of the contralateral extensors and an inhibition of any contraction
which may exist in the flexor muscles (Fig. 226). Certain collaterals
of the afferent paths of the reflex must be assumed to cross the cord
and exert an inhibitory effect upon motor neurons of the flexors of
the crossed hind limb somewhat in the manner which Fig. 240 indicates.
In a similar way the paths which lead to the fore limbs must give
off collaterals which inhibit the contraction of those muscles which
would oppose the assumption of the reflex figure. A single afferent
path may in this way, not only produce contraction in a large group
of muscles, but by the inhibition of the activity of their antagonists
it can preoccupy a large part of the reflex mechanism of the spinal
cord to the exclusion of other reflexes. Because of the compensatory
nature of the component parts of the reflex figure, (including the occur-
rence of reciprocal inhibition in each part), which is brought about by
the connections of the various collaterals of the afferent path, the spinal
cord is enabled, quite independently of the higher centers in the brain,
to effect a high degree of coordination in reflex response.

The various parts of the reflex figure do not respond to the same
threshold value of stimulation. Weak stimulation brings into activity
only those muscles which affect the part to which excitation is applied.
If the strength of stimulation is gradually increased, more and more
parts of the total reflex figure appear. In stimulating the hind foot
with increasing intensity, first the ankle alone is flexed, then the knee,
and finally the hip. The response then spreads to include the extension
of the crossed hind leg and finally involves the fore legs also. The
mechanism which determined the course of this march of the reflex
figure is the graded resistance of the synapses described on page 842.
It may be reemphasized, however, that as the reflex spreads to each
new joint the inhibition of the antagonists occurs coincidently with the

944 CENTRAL NERVOUS SYSTEM

contraction of the active muscles, and the resistance of the synapses lying
in the path to the antagonistic muscle groups must be equal.

Rules for the Spread of Spinal Reflexes

Sherrington37 has laid down the following rules for the spread of
short spinal reflexes, as the components of a reflex figure which in-
volve only a few spinal segments may be designated :

1. The degree of reflex spinal intimacy between afferent and efferent
spinal roots varies directly as their segmental proximity.

2. For each afferent root there exists in immediate proximity to its
own place of entrance in the cord, e. g., in its own segment a reflex
motor path of as low a threshold and of as high potency as any open
to it anywhere.

3. Motor mechanisms lying in the same region of the cord are un-
equally accessible to the local afferent channels, if judged by pressor ef-
fects, i. e., the production of contraction. This rule breaks down, how-
ever, when it is considered that an afferent path may produce inhibition
in many of the motor mechanisms to which it has access.

4. The groups of motor nerve cells contemporaneously discharged by
spinal reflex action innervate synergic and not anergic muscles. As
a consequence the muscular contractions are harmonious with one another
(Reciprocal Inhibition).

5. The spinal reflex movement elicitable in and from any one spinal
region will exhibit much uniformity despite considerable variety of
the locus of incidence of the exciting stimulus.

The spread of long spinal reflexes, which are parts of a reflex figure
involving many segments of the cord, is too inconstant in a single re-
flex figure and varies too greatly in different figures to permit any defi-
nite rules to be laid down.

CHAPTER CI

THE INTEGRATION OF SIMULTANEOUS AND SUCCESSIVE RE-
FLEXES

The Principle of the Final Common Path

A single reflex acting independently of the rest of the central nervous
system does not really occur. An afferent impulse on entering the cord
spreads so as to involve a large variety of motor neurons, each of which
may, however, be excited through other afferent fibers arriving either
from other receptors or from higher nerve centers. The motor neuron
itself may therefore be a pathway occupied at different times by very
different types of nerve impulse. Hence it is appropriately called the
final common path, and its activity at any moment must depend on the
nature of the various afferent impulses that are transmitted to it through
the synapses. That each motor neuron must be at the service of several
afferent neurons becomes evident when it is remembered that in the
spinal nerve roots there are three times as many afferent fibers as there
are efferent fibers, and if the afferent fibers of the cranial nerves are
taken into account the proportion of afferent to efferent fibers becomes
five to one. Reflex connections involve usually one or more internun-
cial neurons, and these may act as a common path connecting several
receptors with a common motor mechanism. The propriospinal neurons
of the reflex arc for the scratch reflex described on page 93'5 act as a
common path for impulses arising from distinctly different parts of the
skin.

The various reflexes which share the final common path leading to a
single group of muscles may cause these muscles to respond (1) in some
definite way — as in the maintained contraction of the flexion reflex;
(2) in some different way, as in the rhythmic response of the scratch
reflex; or (3) inhibition may be produced so that no contraction can be
brought about. Reflexes belonging to any one of these groups are allied
reflexes, because they have a common effect on the motor mechanism.
Reflexes belonging to different groups, which consequently affect the
final common path to different purposes are antagonistic reflexes. Inte-
gration in reflex activity depends on the consequences which follow when
allied or antagonistic reflexes act upon the final common path, either
simultaneously or in rapid succession.

945

946 CENTRAL NERVOUS SYSTEM

The Integration of Allied Reflexes

Simultaneous Combination. — The scratch reflex is well adapted for
the study of this subject since the skin area from which this reflex can be
elicited is very widespread (see Fig. 238). The type of reflex produced
from any given area is in general the same, although "the local sign"
—that is, the point at which the. animal scratches — will vary according
to the point stimulated. If we take point A in the reflex scratch jurn
and apply to it a stimulus which is just inadequate to produce any reflex
at all, and then, while this stimulus is still in progress, apply a similar
subliminal stimulus to point B a little removed from it, the two sub-
liminal stimuli will become effective and produce a typical scratching
movement. In other words, the subliminal stimulus of point A be-
comes added on the final common path with the subliminal stimulus of
point B ; the one has reinforced the other.

In a similar wray two stimuli each of which are adequate to exo.it o
a weak reflex response from a common motor mechanism, will reinforce
one another and produce a strong response if they are applied at the
same time.

The receptors from which these mutually reinforcing impulses are re-
ceived need not, as in the above example, be of the same kind, similar
results being obtained by stimulation of receptors of widely different
kinds, such as exteroceptors and proprioceptors. For example, if a stimu-
lus inadequate to elicit a flexion reflex is applied to the skin of the leg,
and another stimulus, itself also inadequate, is applied to the central end
of some deep afferent nerve in the same leg, then the two subliminal
stimuli will become effective in producing a flexion movement.

We have seen that in the development and maintenance of posture
the closest alliance takes place between the exteroceptive reflexes which
initiate movement and the proprioceptive reflexes which adapt the tone
of the muscles to the new positions of the limbs (page 917). Allied re-
flexes may reinforce one another even though the exciting stimuli arc
applied far apart. The flexion of the fore limb which results from
stimulation of the fore paw is reinforced, for example, by a simultaneous
excitation of the contralateral hind foot — a stimulation that gives rise
to a reflex figure involving flexion of the fore limb as we have seen in the
last chapter. Reflexes which give rise to inhibition may also reinforce
one another in their action on the final common path.

Successive Combination. — The reinforcement which one reflex lends to
a second allied reflex lasts for a short time after the stimulus for the
first response has been removed. Consequently successive allied reflexes
may reinforce one another. This reinforcement also can be illustrated
in the case of the scratch reflex. If a stimulus, inadequate to excite when

INTEGRATION OF SIMULTANEOUS AND SUCCESSIVE REFLEXES 947

acting alone, is applied to a point A on the skin, and immediately after a
second stimulus also inadequate to excite, is applied to a point B, the
combined effect of the two successive subliminal stimuli may give rise
to a reflex response. The threshold of some common part of the reflex
arc has been lowered by the effect of the preceding inadequate stimulus,
even though it was applied to a somewhat remote part of the skin. For
this reason a moving stimulus applied to the scratch area is far more
effective than a stationary stimulus applied over the same extent of area.
This phenomenon is called immediate induction, and it is by no means
confined to the spinal cord. It is well illustrated, for example, in the
case of vision. If a thin line drawn on a white card be looked at so that
it falls on the edge of the receptive field of the retina, it will not be seen
so well as a dot of similar width which is moved through the same
distance as the line.

The Integration of Antagonistic Reflexes

Simultaneous Combination. — Two antagonistic reflexes, which use the
final common path to cross purposes, naturally cannot both succeed in
occupying it at the same time. We must examine what results when two
such reflexes come into competition for the control of a common motor
mechanism. The crossed extension reflex and the flexion reflex are
two responses utilizing a common group of muscles in opposite ways.
If we apply a stimulus to the skin of the leg of a decerebrate animal
while the limb is extended as the result of a stimulus applied to the
eontralateral leg, the extension gives way completely to the flexion
reflex (Pig. 239). By choosing the relative strengths of the stimuli
properly a preexisting flexion reflex may also be interrupted by a crossed
extension reflex (Fig. 226). In a similar way the scratch reflex gives way
before a flexion reflex. The significant fact is that when antagonistic
reflexes are in simultaneous competition for the final common path, one of
them, occupies the path to the exclusion of all others. Accordingly there
is no tendency for a fusion of their effects, and this is most fortunate, for
fusion would only result in confusion, since the response would be ap-
propriate for neither of the simultaneous stimuli. This is perhaps the
most important principle in the integration of spinal reflexes by the
final common path.

In the competition of antagonistic reflexes for the control of the final
common path several principles determine the outcome. These depend on
(1) the nature of the reflexes, (2) the relative intensity of the stimulus,
and (3) fatigue.

The nature of the reflex is dependent on the quality of the stim-
ulus and the purpose to which it is employed. The most prepotent re-
flexes are the flexions wrhich result from the application of harmful

948 CENTRAL NERVOUS SYSTEM

stimuli. Their purpose is to protect the body from immediate danger
and consequently they tend to displace other kinds of reflexes from occu-
pancy of the final common path. The reflex responses to all stimuli which
are capable in the conscious animal of giving rise to strongly affective
sensations tend to prevail over all others and consequently the sexual
reflexes share with the responses to painful stimuli a position of domi-
nance in the competition of reflex activity. At the opposite extreme are
the postural reflexes which arise from proprioceptive stimuli and con-
cern chiefly the extensor muscles which must support the weight of the
body. These give way before competing reflexes of other types with
facility. It is important that they should do so, since postural tone
must always adapt itself to the position into which the body has been
forced in response to the stimuli of the environment.

In the case of antagonistic reflexes of equal potency the result of
competition for the common path depends on the relative strength of
the exciting stimuli. Thus a flexion reflex of the hind leg will usually
displace a simultaneous scratch reflex, but if the stimulus eliciting the
scratch is strong, and that tending to produce flexion is weak, the
scratch reflex may persist and the flexion fail to assert itself.

When a reflex has occupied the final common path for some time
it will become fatigued, and may then be displaced by an antagonistic
reflex which could not previously compete against it successfully. Thus,
ordinarily the scratch reflex is much less readily elicited than the flexion
reflex, and if both are excited at the same time the latter will prevail;
but if the flexion reflex is kept up until it shows signs of fatigue, then
by simultaneous excitation of both reflexes the scratch reflex will obtain
the mastery. The development of successive induction, which is de-
scribed below, also assists the competing reflex in gaining control as its
antagonist becomes fatigued.

The susceptibility of reflex arcs to fatigue is probably of importance
in assuring the development of variety in reflex responses, since it
prevents prepotent responses from occupying the final common path for
too long. Many characteristics differentiate reflex fatigue from the
fatigue of an isolated nerve-muscle preparation. The most impor-
tant of these distinguishing features are as follows: (1) The fatigue
comes on intermittently; thus, when the flexion reflex is persistently
elicited, the first sign of fatigue is an irregular decline in the flexion
movement followed by its entire disappearance for a short time. These
lapses become more and more frequent, until at last complete fatigue
sets in and no flexion occurs. (2) Reflex fatigue soon passes off. (3)
It appears earlier for weak than for strong stimuli. (4) The movement
produced by the reflex action may also change in character during re-
flex fatigue ; thus, the beat of the scratch reflex may become slower

INTEGRATION OF SIMULTANEOUS AND SUCCESSIVE REFLEXES 949

and less steady and the foot be less accurately directed to the spot
stimulated. The locus of the fatigue in the reflex arc can not be the
motor neuron itself, for, after this has been completely fatigued by
stimulation of the scratch area, the same muscles may quite readily
execute the flexion reflex if a painful stimulus is applied to the
skin of the hind leg. It must consequently lie in some part of the afferent
side of the reflex arc. Since we know that the nerve trunk is infatigable,
the natural assumption is that reflex fatigue is due to a change in con-
duction across the synapses of the neurons.

Successive Combination. — If antagonistic reflexes occupy a final com-
mon path in succession it is . found that the use of it by one reflex

Fig. 242. — Successive induction illustrated by the crossed-extensiori reflex. The reflex, elicited
periodically with a stimulus of low intensity, is recorded in A and B. Between B and C a strong
flexion reflex was provoked and maintained for 45 seconds. C illustrates the immediately succeeding
extension reflex, which is greatly augmented by successive induction. The next extension (Z?) is
also slightly augmented, but in the third extension (J3) the augmentation has passed off. The
signal recording the stimulation is above; time is indicated in seconds below. (From Sherrington.)

facilitates its subsequent use in a movement antagonistic to that which
first occupied the motor mechanism. This phenomenon is known as
successive induction.

In the spinal animal successive induction is demonstrated by us-
ing two reflexes that are of a more or less antagonistic character —
for example, the flexion reflex and the knee-jerk, or better still the
crossed extension reflex and the flexion reflex. If we elicit the knee-
jerk in a spinal dog at regular intervals, with stimuli of equal intensity,
the extension movements (the kicks) will be approximately equal. If
now we apply a nocuous stimulus to the skin of the foot and so throw
the leg into flexion, it will be found, after the flexion movement has dis-

950 CENTRAL NERVOUS SYSTEM

appeared, that the knee-jerk is much more pronounced than previously.
Similarly, if we elicit the crossed extension reflex by nocuous stimuli
of equal intensity applied to the opposite limb, the extension movements
will be approximately equal. By now throwing the limb exhibiting them
into the flexion reflex, the extensor movements will of course disappear,
but after the flexion has been discontinued, they will reappear with
increased intensity (Fig. 242).

These facts show us, then, that after the final common path has been
occupied by a reflex of one type, it becomes more available to a reflex
of an opposite type. Successive induction gives rise to a series of re-
sponses which afford a further example of the compensatory movements
produced by the integrative action of the spinal cord. By facilitating
the occupancy of the final common path by reflexes opposite in nature
to those which have just occupied it, movements are brought about which
restore the position which was disturbed by the primary response.
In other words, it is evident that if the two opposite reflexes are
constantly competing with each other for possession of the final com-
mon path, they will tend alternately to occupy it, thus bringing about
a rhythmic movement. Such is the mechanism involved in walking;
the leg is lifted from the ground (flexion reflex) ; it is then brought
on the ground, and the mechanical push given to the plantar surface
of the foot brings out the extensor thrust, the appearance of which
is greatly facilitated by the fact that immediately before the flexion
reflex occupied the final common path.

CHAPTER CII

THE INTEGRATIVE ACTION OF THE CEREBRUM

The motor areas of the cerebral cortex are connected through the
pyramidal" tracts with the various lower motor neurons of the body.
We have seen that the excitation of a localized area in the motor cor-
tex may bring about a response of some localized group of muscles
which is coordinated, involves reciprocal inhibition, and develops
through an orderly march in much the same way as does the reflex
figure which arises from a cutaneous stimulation. These responses
utilize the same motor mechanisms as the spinal reflexes do, and con-
sequently come in competition with them for use of the final common
paths. Consequently cerebral influences may modify profoundly re-
flex responses, reinforcing them when both affect the motor mechanism
in the same way, inhibiting them when their actions are antagonistic.
The inhibitory aspects of the cerebral influence are particularly prom-
inent, and consequently many reflexes are elicited with greater cer-
tainty in animals from which the cerebrum has been removed. In this
competition probably much the same factors determine which influence
shall control the common path as govern which of two antagonistic
spinal reflexes shall prevail. Cerebral influences are apparently prepo-
tent over all but the most intense reflex responses to harmful stim-
uli and those which result from strongly affective sensations. We can,
for example, inhibit the reflex withdrawal of the hand from hot water
unless the pain is particularly intense. On the other hand it is diffi-
cult to refrain from winking when the cornea becomes irritated. Within
limits the respiratory reflex may be controlled by the will, but when
the stimulus to the respiratory center becomes intense, the breath
can no longer be held. A large group of reflex arcs concerned with
the regulation of the visceral organs are not connected with the paths
from the cerebrum and consequently cannot be brought under vol-
untary control.

In describing the motor areas in the cortex it was pointed out that
those were points at which many neurons from widely separated parts
of the brain converge upon paths which lead to the lower motor neu-
rons and their muscles. The pyramidal fibers consequently are com-
mon paths used in many diverse volitional responses. For their con-
trol many different influences come into competition and the unpre-
dictable nature of volitional response is no doubt due to the impos-

951

952 CENTRAL NERVOUS SYSTEM

sibility of determining which of the antagonistic elements in this com-
petition will prevail. Deviation from the " straight and narrow path''
may well be due to the failure of the proper influences to gain control
of the internuncial mechanism of voluntary action to the exclusion of
all others. The paralyses of hysteria are perhaps also due to the con-
trol of the common paths from the brain by an inhibitory influence
which cannot be displaced by ordinary volitional impulses.

The Relation of the Cerebrum to the Distance Receptors. — The de-
velopment of the brain in the leading segments of the body is asso-
ciated in all animals with the acquirement of the distance receptors
of the head, i. e., the eye, ear, and olfactory organ. These sense organs
serve to acquaint the organism with parts of its environment with
which it has not yet come into immediate contact. They are suited
to bring about responses which are anticipatory of the consequences
of more direct contact with objects in the environment, that is, of the
seizure and consumption of food, the appropriation of a mate, or the
avoidance of objects which might prove harmful on closer contact. In
order that responses toward distant objects may be made with dis-
crimination, a mechanism has been evolved which apprehends the dis-
tant object not merely as a stimulus possessing a single quality, but
as a "thing" built up of a number of properties, and the response is
determined by these properties as a group. Since the properties of
such environmental objects appeal to a variety of receptors, the sensa-
tions aroused by each must be combined in the nervous system and built
up into a definite concept by a process of association.

Moreover, since the response to the distant object is of an anticipatory
nature, it must be made with reference to the past experience which the ani-
mal has had with objects presenting a similar group of properties. Conse-
quently the results of contact with the object must be associated as part of
the concept with the various properties which have appealed to the distance
Receptors, in order that when such an object enters the environment at
a later time the results of the previous encounter may be recalled and
behavior modified accordingly. In other words distant objects appeal
to the nervous system by virtue of the meaning which is placed upon the
particular combination of receptors which they excite, and the sensations
which arise as a result. The nature of the response which is thus called
forth depends on the memory of past experience with similar objects.
For this reason the development of distance receptors is associated with
the development of the cerebrum in which association and memory mani-
fest themselves. The modification of behavior through the correlation
of present and past experience is the process of learning, which is one
of the chief characteristics by which responses influenced by the cere-

INTEGRATIVE ACTION OF THE CEREBRUM

953

brum are differentiated from those of the lower levels of the nervous
system.

The relation which the distance receptors bears to the cerebral proc-
esses is well illustrated by a comparison of the responses of .animals of
different kinds toward light. Many of the lower organisms possess eyes
incapable of forming an image such as is produced in the eye of the
vertebrate. Their eyes are so arranged as to be stimulated by light
coming only from a certain direction. Consequently the eye may form
a guide which determines the direction of progression, which will be
either toward or away from the light according to the kind of animal
which is studied. Such an animal obviously cannot act with much
discretion in regard to light from different sources, since the shape of the
source of light and perhaps the color of the light make no appeal to
it. The insects and Crustacea possess eyes which are capable of forming
an image and consequently might be capable of distinguishing between
the light of a candle and that from an open window. The development
of the nervous system of these animals has not kept pace, however, with

Fig. 243. — Postures assumed by the robber fly when the eyes are unequally illuminated: illustrat-
ing the influence of light on the tone of the muscles. A, the lower half of each eye is blackened;
B, the upper half of each eye is blackened; C, the right eye is blackened. (After Garry.)

the optical perfection of the ocular mechanism. Each part of the retina
is connected in a rather inflexible way writh certain parts of the motor
mechanism. Unequal stimulation of the different parts of the retina
causes certain parts of the musculature to become more active than other
parts — in other words sets up a characteristic reflex figure (Fig. 243).
In the robber fly, for example, light falling on the upper half of the
retina, when the lower half is covered by opaque cement, causes the trunk
to be curved upward, the forelegs extended and the hind legs flexed.
On taking flight the insect tends to swerve upward and backward
and consequently loops the loop. Blinding the upper half of the retina
has the reverse effect. If one eye only is covered, the legs of that side
are extended, those of the opposite side flexed, and in walking the fly
tends to circle toward the side on which the eye is exposed to light. By
virtue of the physiological influence of the eyes on the muscles the
Direction of locomotion of these insects is guided with mechanical pre-

954 CENTRAL NERVOUS SYSTEM

cision toward the light. The flight of the moth into a candle is deter-
mined in a similar way. The nervous system of the insects is singularly
incapable of modifying its responses as a result of past experience; it is
weak in the display of association and memory. Consequently the
moth does not learn that contact with a caudle flame is attended by dis-
aster and repeats its flights into the flame until it has achieved its self-
destruction.

It is because of the development of the associative powers of the
cerebrum parallel with the perfection of the ocular mechanism that the
behavior of the mammals and man is adjusted to past experience with
greater success than is that of the insects. The human infant devel-
ops in the fifth month a reaction which leads it to reach for any ob-
ject brought sufficiently close within its field of vision. The response
is elicited by a lighted candle as well as by a harmless object such as
a piece of candy. When reaching for the candle is first developed, the
movement is not checked until the heat of the candle actually reaches
the fingers and sets up a protective flexion deflex. By repeated trials
the baby develops within two months a modified response to the candle,
the reaching reaction being completely inhibited. Reaching for candy
still persists without diminution. The infant has developed an asso-
ciation between the particular configuration of stimuli which the candle
produces upon the retina and the harmful consequences of reaching for
this object, and responds to the stimulus by a response suitable to the
painful effects which have previously attended its experiences with the
candle.

Conditioned Reflexes

The nature of the responses of animals with the cerebrum intact is less
predictable than that of the spinal animal in which the cord is removed
from cerebral control, because these responses are conditioned by
the previous experience of the animal and the associations which it has
formed between various stimulating objects and the consequences which
result from its hereditary types of response. The altered responses
which develop by virtue of the modifying influence which the cerebrum
exerts over reflex action are consequently called conditioned reflexes,
in contrast to the unconditioned reflexes of the spinal cord.

It must be considered as one of the greatest advances of modern
physiology that Pavlov and others should have succeeded in evolving
methods by which we may arrive at conclusions regarding the nature of
certain of the integrations which occur when such conditioned reflexes
are formed, since they show us the elementary nature of the processes
by which the association of the results of sensory stimuli leads to modi-
fied forms of behavior.

INTEGRATIVE ACTION OF THE CEREBRUM 955

The methods employed for the study of these higher integrations of
the central nervous system all depend on the reactions of the animal
that are associated with the taking of food. When the food is actu-
ally placed in the mouth, it excites a secretion of saliva, whatever the
circumstances may be. This is an unconditioned reflex. Suppose, how-
ever, that every time food is given a particular sound is made; after
some time it will be found that the occurrence of the sound alone is
sufficient to cause a secretion of saliva. In other words, a conditioned
reflex has been formed. Similarly, sight or smell or any other type of
sensation may be made the excitant for the conditioned reflex. The
secretion now becomes psychic instead of merely physiological. To quote
Bayliss: "Any phenomenon of the outer world for which the animal in
question possesses appropriate receptors can be drawn into temporary
association with salivary secretion, so that it becomes an exciter of se-
cretion if only it has been frequently presented at the same time with
the unconditioned reflex stimulus, food in the mouth."

Work along lines similar to that devised by Pavlov has more recently
been undertaken by students of animal behavior, who have utilized the
acquired habits of an animal in searching for its food in order to study the
influence of conditioning circumstances on its procedure. The advantage
of this method depends mainly on the fact that it can be applied to all
groups of animals. In carrying out such an observation, the animal is
placed in one compartment of a cage, from which it is then released to
a second compartment, the end of which is divided into two passage-
ways, one leading to food, the other leading to some compartment in
which the animal is punished for its mistake as by receiving an electric
shock. Objects such as colored lights are placed in the different pas-
sageways, and the animal by repeated trial comes ultimately to learn
which particular colored light signifies the passage along which he
will receive food. A reflex has therefore become established conditioned
on the particular colored light.

On account of the unavailability of his publications, it is impossible
at present to give any complete account of Pavlov's discoveries. A few
facts, however, are of such importance that it is necessary for us to
state them here as far as we know them. (See Bayliss, Physiology.) Two
mechanisms seem to be concerned in the conditioned reflexes: (1) that
of temporary association, and (2) that of analysis. Temporary associa-
tion is well illustrated in the above experiment in which the secretion of
saliva is induced by a sound. Temporary association of the sound with
the secretion of the saliva may readily be inhibited by all kinds of ex-
ternal phenomena; thus, if the dog's attention becomes diverted while
the conditioned reflex is being stimulated, the response does not occur.

956 CENTRAL NERVOUS SYSTEM

In a dog that had been trained to secrete saliva at the sound of a par-
ticular metronome beat, inhibition occurred one day because, just as
the dog was being presented with the food, the laboratory servant made
a noise outside of the building which diverted the animal's attention.
The conditioned reflex may also be interfered with by internal inhibi-
tion, which is illustrated by experiments in which, after a dog has been
trained to respond to a given conditional reflex, several occasions follow
when food is not given to the animal after the particular sensation to which
it has been trained to respond. The condition — for example, a sound — loses
its effect. This is internal inhibition, but it is a temporary condition
since the reflex returns of itself after a period of rest.

These experiments illustrate what is meant by the formation of tem-
porary associations occurring in conditioned reflexes, but in order that
there may be a fine discrimination between those stimuli which shall
and those which shall not serVe to call forth the conditioned reflex, an-
other mechanism becomes involved — that of analysis. This is performed
by a sense organ the function of which is to separate and distinguish
the complicated phenomena of the outer world. For example, it has
been proved that small differences in the pitch of a musical note may
determine whether or not a conditioned reflex will be excited or in-
hibited, as in the case of one animal that was trained to respond by
the secretion of saliva to a tuning fork vibrating at 100 per second. It
was found that no secretion was produced by a tuning fork vibrating
at 104 or at 96. Much work has also been done with the skin receptors.
Thus, when a given spot of skin is stimulated every time that food is
presented, this becomes an active spot for the conditioned reflex. At
the same time another spot may be stimulated so as to be associated by
the animal with the nonpresentation of food; it is a conditioned reflex
for no food, and is associated with the absence of salivary secretion.

By comparing the responses from active and inactive spots when both
are stimulated either simultaneously or at close intervals, much can
be learned concerning the delicacy of appreciation for external stimuli
and the influence of the inhibitory on the excitatory process. Bayliss
cites the following experiment. Along a series of spots on the skin
of the leg five devices are arranged for producing equal mechanical
stimulations of the skin. The four uppermost of these are made active
spots for the salivary reflex, and the lowest one inactive — that is, when-
ever it is stimulated no food is presented. Let us suppose that upon
administering mechanical stimuli of equal intensity to each of the four
active spots, a certain amount of saliva is produced in a certain time; if
now the inactive spot is stimulated and then thirty seconds later one
of the uppermost spots, there will be no secretion. The previous stimu-

INTEGRATIVE ACTION OF THE CEREBRUM 957

lation of the inactive spot must have caused an inhibition to be set
up in the nerve centers concerned in the reflex. This inhibition only
gradually passes away, disappearing first in the spot farthest removed
from that made inactive, but it may take several minutes before all the
active spots have reacquired their original sensitivity.

The persistence of the inhibition produced by stimulating the inac-
tive spot in the above experiment indicates an important factor in con-
nection with the production of conditioned reflexes. For example, an
animal can be trained to know that in a certain number of minutes after
the sound of a given bell food will be presented to him ; the condi-
tioned reflex will become established so that he salivates at exactly
the same time after the bell is sounded. Something must be going on
in the centers during this time — something inhibiting the reflex. If
during this interval of inhibition some other sensory stimulus is applied,
it will be likely to cut short the inhibition; in other words, it produces
an inhibition of inhibition, so that the secretion of saliva occurs.

Another most curious combination of conditioned stimuli is illustrated
in the following experiment. Suppose, for example, that a given light
and sound are each separately made a stimulus for a conditioned reflex,
but that when they occur together there is no reflex. Suppose now that
while one of these active stimuli is being presented, the other stimulus
is also presented; the result will be that the secretion produced by the
one stimulus .will stop. Evidently, although each is in itself a stimulus,
acting together they cause inhibition.

By studying the conditioned reflexes after a certain part of the cere-
bral cortex has been removed, it has been found that the power of estab-
lishing certain kinds of conditioned reflexes becomes abolished, while
that for others is retained.

The writing of Sherrington,37 Loeb,38 Watson,39 and Margulis41 should
be consulted for further details concerning the material in this chapter.

CHAPTEE (III

THE HIGHER FUNCTIONS OF THE CEREBRUM IN MAN;

APHASIA

The study of the higher functions of the cerebrum leads us to the border-
land between physiology and psychology, but into this vast and relatively
unexplored field we can not venture here, unless just far enough to gain a
suitable vantage point from which to understand the pathology of the
condition known as aphasia* As we have seen from our studies on cerebral
localization, the cerebrum must be regarded as a great sensorimotor gan-
glion, whose functional activities are indicated by various movements.
These movements may, in general, be classified as objective indications
either of feeling and emotion or of intelligence. Although both classes are
evident in all animals, it is particularly in the case of man that the evi-
dences of intelligent activity are especially prominent, since they include
gesticulation and the muscular activities required in spoken and written
language. The movements that express emotional conditions are evolved
earlier and from lower planes than those of intellectual activity. Thus,
very young infants "make faces" when there is reason to believe they
feel pain, and, as they develop, their power of expressing emotion is
evolved long before they present evidence of intelligent motor activity,
and still longer before they can articulate words.

The phenomenon of human psychic activity which is of greatest im-
portance is that of language, and to understand the nature of the cerebral
integration required to produce it, we must briefly consider the cerebral
processes involved in the intellectual development of the infant. The
first step in this development is the storing away in projection centers of
memories of the sensations which these centers have received. For ex-
ample, when the child looks at a bell, there is stored in the visual center a
memory of the shape of the bell, and when the bell moves so as to produce
sound, this also is stored as a sound impression in the auditory center.
Likewise, when he touches the bell impressions of its hardness and smooth-
ness and temperature are stored in the centers for cutaneous sensations.
At first each of these memory impressions occupies an isolated position;
but later, association tracts open up between them, so that the calling
forth of one memory impression is associated with others, and the child

fFree use of the article by Bolton40 is made in this chapter.

958

HIGHER FUNCTIONS OF THE CEREBRUM IN MAN; APHASIA 959

comes to be able to associate the appearance or image of the bell with a
certain sound and with certain sensations of hardness, rotundity, etc. This
preliminary use of observation is known as perception. It involves the
fusion of direct sensations as well as their correlation with memory im-
pressions of former sensations. The number and variety of the latter
called into activity by a particular sensation will obviously vary at dif-
ferent times. On seeing a bell, for example, a child may associate it with
sound on one occasion, and on the next with the feeling of the bell. On
account of this difference in the detail of the method of association, it is
evident that perception must be a product of cerebral integration rather
tli an one depending on memory impressions stored in the isolated centers.
It is a complicated process with an infinite variety of possibilites as to the
exact way in which it is integrated on each occasion.

The act of perception, however, becomes considerably simplified in the
higher animals by the laying down of short-cut paths of association.
These are formed first of all with the auditory center, in which the memory
impression of an articulated sound representing the object — for example,
the word "bell" — is stored away. The child comes to learn that this par-
ticular word is to be associated with the memory impressions it has stored
away of the sound, the sight, and the feeling of the bell. Similar short-cut
paths later become developed in connection with the visual centers, where
a certain symbol, like the word "bell," is presented to the child as signi-
fying all the other attributes of bell. In its most highly developed form,
therefore, perception may be described as the act of calling up one or
more sensorimemorial images when a name is seen or heard.

Having acquired the ability to integrate sensorimemorial impressions
in the above described manner, the child next learns to integrate the motor
centers concerned in the control of the articulatory apparatus so as to
produce a sound. This sound is the word indicating the object involved
in the integrating process. It is the integration necessary to produce the
sound which symbolizes the particular object.

When the power of understanding and producing language has been
acquired, the crowning process of intellectual development — the forma-
tion of a concept, or general notion — becomes evolved. Thus, the evolu-
tion of a general name will include a number of particular objects or acts.
''This process of conception involves the revivification of numerous seii-
Roriniemorial images which present common points of similarity" — (Bol-
ton). It is relatively a simple process for such general objects as animal,
man. building, but becomes very complex for such abstract concepts as
heaviness, beauty, etc. It is obviously a process to which no one cerebral
center can be assigned. The outward manifestation of the conception is
spoken or written language.

960 CENTRAL NERVOUS SYSTEM

Language consists, therefore, in an extremely complex symbolic system,
involving various centers and association tracts in the cerebrum, and
capable of an almost infinite degree of development by the laying down
of new symbolic systems. Language, indeed, becomes the instrument of
thought, practically all of the higher intellectual processes being dependent
on its evolution. In this connection it is interesting to note that a great
number of individuals, especially those who do not read, depend on the
sense of hearing for the acquisition of the impressions required for their
psychic development, while others depend on the -sense of sight for the
same purpose.

At least four different types of center are involved in the integration
of language; namely, auditory, visual, chirographic, and articulatory. We
may call these "word centers," and we must assume that they lie near to
the auditory, visual and general sensory projection areas of the cortex.
To understand and to be able to produce spoken and written language, it
is necessary that all these four word centers participate through associa-
tion tracts, although the meaning of a word may be perceived without all
of them being involved.

PSYCHOPATHOLOGICAL APPLICATIONS

In the study of mental diseases the most important conclusion which
we can draw from the above facts is that language is essentially a sym-
bolic mechanism for the integration of sensorimemorial images. It is
therefore the symbolic system of the integrated processes of the brain; it
is the servant of thought. When, as is often the case, language is used
without the proper exercise of thought, it becomes merely an automatic
affair. A practical deduction from these facts is that any considerable
derangement of the language mechanism must necessarily involve some
interference with the complicated processes of association that go to make
up the psychic function.

These considerations naturally lead us to the subject of aphasia. It has
been usual to distinguish three varieties of this; namely, motor aphasia,
sensory aphasia, and anarthria. In motor aphasia the patient, although
he understands what is said to him, is unable to speak, and the intellectual
powers are little, if at all', impaired. In sensory aphasia speech is possible
in a more or less intelligible manner, but there is a distinct impairment of
intelligence. In anarthria, or subcortical aphasia, the only disability is the
loss or impairment of the power of articulate speech because of some lesion
existing in the center coordinating the lower neurons concerned in the
movements of the laryngeal and tongue muscles. Pierre Marie, as a
result of very extensive experience in Paris, has shown that this classifi-
cation is unjustified. He maintains that there is only one true form of

HIGHER FUNCTIONS OF THE CEREBRUM IN MAN; APHASIA 961

aphasia, and that such a thing as pure motor aphasia as above defined
does not exist, the condition being invariably accompanied by intellectual
impairment.

Marie points out that the various claims that aphasia may exist without
intellectual impairment have been made without sufficient investigation of
the intellectual status of the patient. He shows that many patients suf-
fering from aphasia if asked to do ordinary things, such as cough or spit
or raise the hand, can do them as well as a normal individual, but that
these after all are very crude acts in the ordinary performances of a normal
individual. To test the intellectual powers it is necessary to require the
patient to perform acts which entail a considerable amount of cerebral
integration. We must ask him to perform some sequence of events such
as walking several times in one direction, then in another, touching cer-
tain objects, etc., or better still we should observe the patient closely in his
business transactions and everyday routine of life to see whether he does
things exactly as he did them before. It is always possible by such tests
to show that in aphasia the mental powers have become distinctly de-
preciated.

The portion of the cerebral cortex affected in aphasia is always in the
neighborhood of the so-called area of Wernicke, which is closely related to
the visual and auditory centers. In making this sweeping conclusion,
Marie admits that cases of pure word-blindness but not of word-deafness
may exist ; that is, a patient still retaining his intellectual powers may lose
his ability to interpret correctly what he sees, although he can still interpret
accurately what he hears.

This conclusion conforms exactly with those of the psychophysiologists
regarding the difference in the language mechanisms of educated and un-
educated persons. Language is learned through the sense of hearing, -and
it is only by later education that more is learned by the sense of sight;
that is to say, a person learns to read only after he has learned to under-
stand spoken language. Word-blindness may therefore occur as a pure
symptom, and is less likely than word-deafness to be associated with ab-
normal integrative functions of the cerebrum. Word-deafness however de-
pends upon a lesion involving the auditory center; it necessarily means
disturbance in the association functions of the cerebrum, and is always
accompained by a certain amount of mental derangement.

In corroboration of these facts may be cited the well-known fact that
a deaf-mute is mentally far inferior to one that is congenitally blind.
Loss of hearing leads to more serious cerebral disability than loss of sight.
To quote Bolton again, ' ' In such cases deafness is therefore a more serious
deprivation than blindness, as, for the evolution of the functional activity
of the cerebrum, an entirely new development of associational spheres to

962 CENTRAL NERVOUS SYSTEM

replace those normally employed for auditory and spoken language has
to be acquired. In the case of congenital or early-acquired blindness, on
the other hand, the complex sphere of language, with all its psychic com-
ponents, can be employed in a perfectly normal manner and almost ex-
actly as it is brought into use in the case of persons who neither read nor
write."

It would be beyond the scope of this work to go into the clinical and
pathological evidence upon which Marie bases his far-reaching conclusions.
Suffice it to say that it is definitely shown that the old contention of Broca,
that a special speech center exists, is entirely unjustified by the facts of
clinical and pathological experience. Broca, it will be remembered, con-
tended that motor aphasia is always due to destructive processes occurring
in the lower portion of the ascending frontal convolution on the left side,
and he concluded that this portion of the cerebrum represents the speech
center. Marie has shown, however, that a patient may show distinct evi-
dence of aphasia without any lesion involving this so-called Broca area,
and, on the other hand, that cases not infrequently occur in which this is
completely destroyed without any evidence of aphasia. Important though
this discovery of the inaccuracy of Broca 's conclusion is, by far the most
important conclusion which we may draw from Marie's work is that, since
language is a product of an extended integration of impressions and
memories stored in different parts of the cerebrum, it is not so likely to be
interfered with by destruction of any one of the centers as it is by destruc-
tion of the paths which connect the centers with one another. As a matter
of fact, Marie has shown that in cases of aphasia the lesion is nearly
always located in the course of the pathway connecting the visual and
auditory centers with the other centers of the cerebrum ; it lies around the
upper end of the fissure of Sylvius in the region which in previous years
had been considered particularly associated with the condition known as
sensory aphasia. Those interested in this subject should consult Bolton's
article.

CHAPTER CIV

SUMMARY OF THE ORGANIZATION OF THE MAMMALIAN NERV-
OUS SYSTEM; SPINAL SHOCK

The activity and organization of the nervous system is so complex
that it has been necessary to treat each aspect of it separately and with
little reference to its relation to the organization of the whole. We will
now consider briefly how the various parts of the nervous system are com-
pounded to form a unified machine for coordinating the activities of the
body. The evolutionary development of the nervous system has indi-
cated that two primitive types of nervous organization came into
existence at an early stage and persist in certain parts of the mammalian
body. The most primitive of these was the nerve net which was evolved
by the coelenterates and whfch persists in the mesenteric plexus of
man. The other is the segmental synaptic nervous system of the worms,
which finds its representative in the spinal reflex system of the verte-
brates. We have seen that these systems are not independent, but that
the spinal reflex mechanism exerts a controlling influence over the
peripheral nerve net through the autonomic nerves. Vertebrate evolution
has brought to perfection two additional functional systems which
modify and regulate the activity of the spinal reflexes, and through them,
to a certain extent, the organs controlled by the peripheral nerve net.

These systems are (1) the mesencephalicospinal system for the con-
trol of postural tone, excited by the proprioceptive impulses which
arise in the muscles, joints, and from the labyrinth and (2) the cortico-
spinal system for the execution of voluntary movements initiated by im-
pulses received in large part by the distance receptors of the head and
conditioned by the previous associations and memories which the stimula-
tion of the distance receptors calls up. The corticospinal system not
only controls the activity of the spinal reflex mechanism through the
connections afforded by the pyramidal tracts, but to it the system for
regulation of postural tone is also subservient. The arrangement of the
different levels of nervous activity in their relation to the effectors of the
body is somewhat as shown in the diagram on page 964.

In the intact organism we see the entire mechanism at work ; in the
experimental animal and in the lesions of warfare and civil life we see
the activity of the residual parts of the mechanism which are left in-
tact after mutilation has freed them from control by the higher centers.

963

964 CENTRAL NERVOUS SYSTEM

When a lower level in the organization of the nervous system is
freed from control by a superior level we observe, not only the inde-
pendent activities which this level carries on in the normal animal,
but certain additional activities commonly held in check by the higher
centers. Injury to the nervous system consequently results in certain
positive as well as negative symptoms, and these are attributed to the
removal of an inhibition from the lower levels which is exerted normally
by influences from higher levels now cut off by the lesion. Thus we have
seen in the decerebrate animal that the removal of the control of the high-
est level allows the postural tone of the extensor muscles to become
greatly exaggerated. The spastic paralysis which accompanies many

Cerebral Cortex

Cerebellum and Midbrain

Spinal Reflex

Nerve Net

Skeletal Muscle Smooth Muscle and

Glands

— — — — — /

cerebral and spinal lesions is probably a positive symptom due to a
similar cause (Walshe34). In the decerebrate animal many reflexes may
be elicited with a certainty and to a degree unobtained in the unmutilated
organism because of the removal of cerebral inhibition. The symptoms
of cerebellar injury give a picture of the activity of the nervous system
deprived of the normal influence of the mesencephalic regulation of tone.
Voluntary movements can still be executed, but no longer with the cus-
tomary smoothness or precision, because the mechanism which governs
the coordination of muscular movement and tone is no longer effective.
In the isolated visceral organs, and particularly in the bladder, indepen-
dent activity of the peripheral nerve net is demonstrated. We have
seen that these organs may function in an adequate way, but their ac-

SUMMARY, MAMMALIAN NERVOUS SYSTEM; SPINAL SHOCK 965

tivities are no longer correlated to the activities of the body as a whole.
The extent to which the spinal cord is capable of carrying out co-
ordinated neuromuscular activity, when isolated from the higher centers
of the brain is a matter of great interest. We have seen in considering
the mechanisms by which reflex action is governed that the spinal cord
contains arrangements capable of producing highly integrated responses.
We will consequently examine the activities of the isolated spinal cord
in laboratory animals, and compare them with similar conditions which
are observed in man, in order to obtain an idea of the relative importance
of the spinal cord and brain which show some diversity in their devel-
opment.

Spinal Shock and the Recovery of Reflexes in Animals

In animals the spinal cord may be separated from the brain by an
incision made in the cervical region. Immediately after the operation
a profound condition of depression sets in, involving all the reflex arcs
in the separated portion of the cord. This condition is known as spinal
shock. It supervenes in all classes of animals having a spinal cord, but is
much more profound in the higher than in the lower animals. As a result
of this depression, the part of the body below the section exists in a limp
and flaccid condition, and the application of even very strong stimuli to
the skin will evoke no form of reflex movement. In the case of the lower
vertebrates, such as the frog, the condition begins to pass off in from twenty
minutes to half an hour, after which a stimulus applied to the skin of the
foot is followed by a typical flexion movement at knee and hip, the so-
called flexion reflex. In the rabbit very little reflex response is elicitable
for several hours after the operation, but in a few days the reflexes return
completely below the level of the section. In the dog, on which a great
deal of work has been done, the involved regions of the body are pro-
foundly paralyzed. The skin is in a more or less unhealthy, unnatural
condition, the surface cold, the hairs ruffled; and if care is not taken, the
slightest abrasion of the surface may result in a nasty ulceration. On
account of the paralysis of the centers of micturition and defecation,
there is also incontinence of urine and of feces.

With reasonable attention, however, the dog makes a wonderful re-
covery. After an interval of two weeks the hind limbs, although com-
pletely paralyzed so far as voluntary movement is concerned, begin to
show considerable signs of improvement. The first reflexes to return
are those concerned with the deeper structures, such as the vascular
reflexes, thus bringing the skin back to its normal temperature and
condition. The reflexes of micturition and defecation also soon return,
so that the animal no longer suffers from the continuous discharge of

966 CENTRAL NERVOUS SYSTEM

urine and feces. About the same time the knee-jerk becomes elicitable.
This reflex is obtained by tapping the tendon which connects the patella
with the tibia, the response being a smart contraction of the extensor
muscles of the knee joint. The flexion reflex also begins to reappear.
This is elicited by applying a pinprick or other hurtful stimulus to
the skin of a lower extremity, and when fully developed consists in a
flexion of the knee and hip joints. The evident object of this move-
ment is that the stimulated parts may be removed from the source of
stimulation, and it is plain that all stimuli that produce the flexion
reflex are such as would cause in the intact animal a sensation of pain.
Such stimuli are thus classified as nocuous, and the reflex is styled a
nociceptive reflex. Accompanying flexion of the stimulated limb the op-
posite or contralateral limb usually undergoes a definite extension,
called the crossed extension reflex. That the nociceptive reflexes should
be among the first to return after spinal transection is of considerable
interest as indicating their importance in the protection of the animal
from injury. They are the essential reflexes of defense, and it is con-
siderably later in the recovery of the animal before reflexes dependent
upon stimulation of other tactile receptors begin to show themselves.
The most important of this latter group of more special reflex move-
ments include the so-called scratch reflex and the extensor thrust. The
scratch reflex, as its name implies, is the scratching movement of flexion and
extension of the hind limb at a rate of about four contractions per second
that occurs when a mechanical stimulus is applied to the flank and shoulder
area of the animal. For example, if we gently draw a pencil or the fingers
backward and forward among the hairs 011 this region of the spinal animal,
the corresponding hind limb will be brought up so that the claws are
approximately at the place stimulated, and the limb thus directed will
undergo a series of flexions and extensions, designed evidently for the
purpose of scratching the area of skin that has been stimulated. If the
stimulus is a weak one, only the initial stages of the movement may
occur, such as the preliminary flexion of the leg. As we have already
stated, the receptive stimulus calling forth this reflex is very specific
in nature. A pinprick or rough friction of the reflex area will not produce
it, neither will the application of heat, nor a single electric shock. The
most adequate stimulus is one simulating as nearly as possible the con-
dition which would be produced by the movement on the flank of the
animal of some insect. This more or less complicated scratch reflex can
of course also be elicited in animals whose spinal cord has not been cut,
but we can not predict in such cases whether the reflex will occur. The
brain may inhibit the reflex arc and prevent the movement. In a spinal

SUMMARY, MAMMALIAN NERVOUS SYSTEM; SPINAL SHOCK 967

animal, however, the reflex always occurs provided an adequate stimulus
is applied.

The extensor thrust is elicited by applying pressure to the pad of the
paw or the sole of the foot. It consists of a quick extension movement
of the corresponding limb usually with a flexion of the opposite limb.

After complete recovery from shock, the paralyzed parts of the body
are capable of performing even more complex movements than those al-
ready mentioned. For example, if the animal is held up with the hind
legs hanging down, these will often exhibit rhythmic flexion and exten-
sion movements, with the two limbs acting alternately, as they would
in walking or running. This is sometimes called the mark-time reflex.
Another complicated movement may be produced by placing the animal
in water, when it may make the movements of swimming, but its swim-
ming will not be sufficient to keep it on the surface. These swimming
movements are more perfect in the spinal frog.

After complete recovery from spinal shock, the hind limbs are more
or less in a condition of extension contracture; the vascular and other
visceral reflexes are in perfect condition, and a marked rise in blood
pressure occurs when one of the sensory nerves of the hind limb is
stimulated — an experiment which can be performed in such animals
without the administration of any anesthetic, since the animal feels
no pain. In female spinal animals impregnation may occur and preg-
nancy proceed in normal fashion accompanied by the usual secretion
of milk.

Spinal Shock and the Recovery of Reflexes in Man

The potentialities of the spinal cord of man have not been fully
realized until recent years when investigations by Head and Eiddoch42 on
men who had been shot through the spine have shown just how complete
a recovery can be made from such an injury if the patient is given proper
care. In cases of complete transection of the cord there usually re-
sults in man, as in the other mammals, a complete loss of reflex activity
and of tone in those parts of the body innervated from segments of the
cord which lie below the lesion. Occasionally the cremasteric and
bulbocavernous reflexes may still be elicited. Below the lesion there is
complete anesthesia, the skin is dry and readily becomes gangrenous,
and the urine and feces are retained. After a period varying from one to
three weeks the first reflexes reappear. These are the flexion reflexes in
response to harmful stimuli. At first they can be elicited only from the
part of the receptive field which normally is most sensitive, i. e., the sole
of the foot, and involve those muscle groups which are normally brought
into play by the weakest stimuli. Movements of the toes are conse-
quently the only part of the reflex figure to display itself in the earliest stage

968 CENTRAL NERVOUS SYSTEM

of recovery. Later the receptive field becomes more and more extensive
and the response spreads to additional groups of muscles until the entire
!<•»• is thrown into flexion. As it does so the reciprocal inhibition of
the muscles antagonistic to the flexors takes place in a normal manner,
just as it does in the spinal cat or dog. Finally, however, a stage of
recovery is reached in which a phenomenon occurs which is quite unlike
anything seen in these animals. It is called the mass-reflex and consists
in an extensive spasm of the flexor muscles of the abdomen and lower
extremities which is brought about by harmful stimuli applied almost
anywhere to the parts of the body affected by the injury. Accompany-
ing the response there is a pronounced outburst of sweating in the af-
fected regions and if the bladder is as much as half full, a reflex discharge
of the urine. The mass-reflex shows that the spinal reflexes have lost
their local signature and have consequently become diffuse in their dis-
tribution, resembling in this regard the generalized responses of those
animals such as the sea anemone (page 830), which possess a nervous
system consisting of an asynaptic nerve net.

In one to five weeks after the flexor responses first appear the tone
of the muscles of the limbs begins to recover and may be restored to
nearly, but never to equal, the state found in the normal individual. The
posture of the limbs is one of slight flexion. At the same time the ten-
don jerks become elicitable. These are the only types of extensor re-
sponse which have been observed in cases of complete transection of the
human spinal cord. During this stage of recovery the contents of the
rectum and bladder are voided automatically (Head and Eiddoch20' 42).

The chief difference in the condition of the spinal man and of the
spinal cat or dog consists in (1) the character of the flexor response,
which in man has lost its local signature, is diffuse, and is elicited from
an abnormally extensive receptive field, (2) the flexor position of the
limbs at rest; and (3) the absence of extensor responses, i. e., of those
responses significant in maintaining the upright position and in progres-
sion. It would appear from this that in man the higher centers in the
brain have taken over control of the integration of spinal reflexes to the
extent of determining the local signature and limiting the spread of
these responses and of governing the activities of the extensor muscles
in maintaining postural tone and the extensor movements of progres-
sion; whereas in the lower mammals these phenomena may be executed
by the spinal cord alone. Further evidence from this view is afforded by
cases in which the human spinal cord is incompletely divided. In these
individuals, although paralysis and anesthesia is complete, the reflex
activities may not differ markedly from those of the lower animals. The
mass-reflex is absent, flexor responses retain their local signature, and arc
accompanied by crossed extension in the opposite limb. The postural

SUMMARY, MAMMALIAN NERVOUS SYSTEM; SPINAL SHOCK 969

tone of the extensor muscles holds the resting limbs in slight extension.
Responses comparable to the extensor thrust and the mark time reflex
of the spinal animal occur.

The Cause of Spinal Shock

It would seem natural to suppose that the cause of the depression in
reflex activity which follows transection of the spinal cord, and which
is known as spinal shock, is the irritation set up directly in the tissues
injured by the lesion. This irritation might be thought to have an in-
hibitory influence on spinal reflexes. That this supposition is incorrect
is shown by the fact that after the shock induced by a cervical tran-
section of the cord has worn off, a second transection at a lower level
does not cause its reappearance. The abnormal character of reflexes
recovering from spinal shock does not resemble that of reflexes which
are being inhibited, but rather those which have experienced fatigue.

Spinal shock might be thought to be due to the disturbance in the cir-
culation which follows the spinal transection, but this cannot be the case
because all parts of the body would suffer alike from the fall in blood
pressure, whereas only those parts of the nervous system below the lesion
exhibit shock. This aboral incidence of shock is a very striking character.
So slight is the effect of a spinal transection upon the higher centers that
men who have been shot through the spine may not even lose conscious-
ness. They are aware that sensations from the lower limbs have sud-
denly been cut off, and their first impression is that they have been blown
in two. Sherrington has described a monkey the cord of which was
cut below the cervical region, and which immediately after the opera-
tion amused itself by catching flies with the anterior extremities, whereas
the posterior extremities were in a condition of the profoundest shock.

The most probable explanation of shock, which is in accord with the
preceding facts, is that it is due to cutting off from the spinal reflex
arcs of some influence normally exerted by fibers descending from the
brain. Just what this influence is, or how it facilitates reflex activity
is impossible to state, but it would appear that once this influence is .cut
off, some time is required before the cord can acquire the power of
carrying out its reflex functions without its assistance. We have seen
that a parallelism exists between the depth and persistence of spinal
shock and the development of the nervous system, particularly of the
brain, in vertebrate evolution. This fact consequently supports the
view that spinal shock is due to isolating the cord from the influence
of the higher centers. Moreover those neuromuscular mechanisms are
affected which are normally under control of the brain centers. Dis-
turbances in the visceral activities controlled by the automatic nerv-
ous system are insignificant except in the case of the discharges of

970 CENTRAL NERVOUS SYSTEM

urine and feces, functions which are normally controlled by spinal
reflexes and volitional activity.

The centers, whose influence is cut off when spinal shock appears,
lie in the brain-stem," probably in the nuclei of the pontine or mid-
brain region. Consequently removal of the cerebral hemispheres does
not produce anything like the severe spinal depression which occurs
when the transection passes behind the level of the pons (Sherrington37).

REFERENCES TO

MONOGRAPHS AND ORIGINAL PAPERS ON THE NERVOUS

SYSTEM

Evolution of the Nervous System

iParker, G. H. : The Elementary Nervous System, Philadelphia, 1919, J. B. Lippincott
Co.

Fundamental Properties of Nervous Tissue

2Adrian, E. D. : Brain, 1918, xli, 23.

sLucas, K. : The Conduction of the Nervous Impulse, revised by E. D. Adrian, Lon-
don, 1917, Longmans, Green & Co.

iTinel, J. N. : Nerve' Wounds, English Trans., London, 1918, Bailliere, Tindall and
Cox.

^Tashiro, S.: Am. Jour. Physiol., 1913, xxxii, 107.

effill, A. V.: Jour. Physiol., 1912, xliii, 433.

vMathison, G. C. : Jour. Physiol., 1910-11, xli, 416.

^Cannon and Burkett : Am. Jour. Physiol., 1913.

Sensation and Sensory Localization

0Head, H.: Brain, 1919, xli, 57.
"Holmes, G., and Lister: Brain, 1916, xxxix, 34.
uRiddoch, G. : Brain, 1917, xl, 15.

isCushing, H. : Proc. Am. Physiol. Soc., Am. Jour. Physiol., 1909.
isHead, H.: Brain, 1893, et seq.
34Lennander : Keen's Surgery, v, 156.

, H., and Thompson: Brain, 1906, xxix, 537.

, G. : Brit. Med. Jour., 1915, ii, Nov. 27, Dec. 4, Dec. 11.

Autonomic Nervous System

, W. H. : The Involuntary Nervous System, London, 1916, Longmans, Green

& Co.

isPottenger, F. M. : Symptoms of Visceral Disease, St. Louis, 1919, C. V. Mosby Co.
isFearnside, E. G.: Brain, 1917, xl, 149.
soHead, H., and Biddoch, G. : Brain, 1917, xl, 188.
^Cannon, W. B. : Bodily Changes in Pain, Hunger, Fear and Rage, New York, 1915,

D. Appleton & Co.

Muscle

22Forbes, A., and Eappleye, W. C. : Am. Jour. Physiol., 1917, xlii, 228.

23p'ratt, F. H., and Eisenberger, J. P.: Am. Jour. . Physiol., 1919, xlix, 1.

24Bayliss, W. M. : Principles of General Physiology, London, 1915, Longmans, Green

& Co.

25Fletcher, W. M., and Hopkins, F. G. : Jour. Physiol., 1907, xxxv 247.
26Gunn, J. A., and Underbill, J. F. : Quart. Jour. Exper. Physiol., viii, 275.

SUMMARY, MAMMALIAN NERVOUS SYSTEM; SPINAL SHOCK 971.

Tone and Postural Coordination

2TSherringtcn, G. S. : Quart. Jour. Exper. Physiol., 1909, ii, 109; Brain, 1915, xxxviii,

191.

28Lee, F. S.: Jour. Physiol., 1894, xv, 311; 1894-5, xvii, 192.
29Lyon, E. P.: Am. Jour. Physiol., 1900, iv, 77.
soBlack, D.: Jour. Lab. and Clin. Med., 1916, i, 467.
siSherrington, C. S. : Jour. Physiol., 1898, xxii, 319.
32Weed/ L. H. : Jour. Physiol., 1914, xlviii, 205.
ssThiele, H. : Jour. Physiol., 1905, xxxii, 358.
34Walshe, F. M. E. : Brain, 1919, xlii, 1.
ssHolmes, G.: Brain, 1917, xl, 461.
-sLuciani, L. : Human Physiology, iii, (English trans.), London, 1914.

Integrative Action of Nervous System

s"Sherriiigton, C. S. : The Integrative Action of the Nervous System, New York, 1906.
ssLoeb, J. : Forced Movements, Tropisms and Animal Conduct, Philadelphia, 1918.

The Cerebrum.

39Watson, J. B. : Psychology from the Standpoint of a Behaviorist, Philadelphia, 1919.

Psychological Review, 1916, xxiii, 89.
4°Bolton, J. S. : Recent Researches on Cortical Localization and on the Function of the

Cerebrum in Further Advances in Physiology, ed. by Leonard Hill, London, E.

Arnold, 1909.
lis, S. : Jour. Animal Behavior, 1914, iv, 142 ; ibid., 1914, iv, 362.

Reflex Functions of the Spinal Cord in Man

42Riddoch, G.: Brain, 1917, xl, 264.

INDEX

Abdominal respiration, 324
Abnormal pulses, 291
Absorption, in general, 13

from stomach, 490

of fats, 722
Acapnia, 306

Accessory food factors, 618
Acetoacetic acid, 715, 738
Acetone, 715, 738
Acid :

buffer action, 36

excretion of, by kidneys, 47

chemistry of fatty, 718

total concentration of, 32
Acidity, actual degree of, 23
Acidosis :

ammonia-urea ratio during, 650

compensated, 39

in diabetes, 715

in nephritis, 715

in starvation, 602, 603

relation to alveolar CO,, 371

relationship to breathing, 371

theory of, 38

uncompensated, 39
Acids, of urine, 558
Acromegaly, 816

Action currents in skeletal muscle, 906
Actual degree of acidity and alkalinity,

23

Adaptation, sensory, 862
Addison's disease, 772
Adenine, 667, 669
Adenosine, 671
Adrenal glands, 768

and diabetes, 708, 790
assaying content of, 779
cortex of, 776
disease of, in man, 772
medulla of, 770
sexual precocity and, 776
Adrenaline (see Epinephrine)
Adsorption, 66

compounds, 71

conditions influenced by, 68

effect of chemical forces on, 69

effect of electric changes on, 68

everyday reactions depending on, 67

of gases, 67

Afferent nerves, segmental distribution
of, 866

Afferent paths:

in spinal cord, 868
in brain-stem, 871
of spinal reflexes, 872
of visceral reflexes, 873
of cerebellar reflexes, 874
After discharge, 915

effect on creatinine excretion, 657
Alanine, 634, 635, 636, 639, 698
Albolene absorption, 723
Albuminuria, 552

Alkali retention, determination of, 48
Alkaline buffer, 36
Alkaline reserve, 38

measurement of, 41
Alkaptonuria, 536
Allantoin, 668, 672, 678
Allied reflexes, simultaneous combina-
tion of, 945, 946
successive combination of, 946
Allocheiria, 859
All-or-none law:

of conduction, 837, 839

of contraction of skeletal muscle,

908

of contraction of heart muscle, 177
Alloxan, 668
Alveolar air:

clinical investigation of, 364
estimation of gases in, 361
Fridericia method, 357
Haldane method, 357
Pearce method, 362
tension of CO2, 46, 361, 373

during breathing in confined space,

366

tension of oxygen, 362
Ambard's equation, 562
Amboceptor, 97
-Amino acids, 634
in blood, 641
chemistry of, 634
determination of, 635
fate of, 645
groups, 636, 638
in growth, 609
in tissues, 642
in urine, 564, 654
structure of, 638, 639
Aminoacetic acid (see Glycocoll}
Aminopropionic acid (see Alanine)

973

974

INDEX

Ammonia :

ammonia-urea ratio :

influence of acidosis on, 657
in disease, 661
influence of liver on, 658

as reserve alkali, 657

excretion of, 656

excretion of acid in combination with,
47

of urine, 562

Ammonium carbamate, 657
Ammonium carbonate, 657
Amylases, 81, 91, 525
Amylolysis, 525

in stomach, 489
Amylopsin, 525, 689
Anacrotic wave, pulse, 203
Anaphylactic reaction, 632, 638, 755
Anaphylaxis, 90
Anarthria, 960
Anastomosis, intestinal, 504
Anemia, 94

bloodflow in, 298
Aneurism, bloodflow in, 299

pulse in, 144, 200
Angina pectoris, fibrillation in, 196
Animal calorimeter, 572
Anions, 16, 60
Anoxemia :

acid excretion in, 381

acidosis and, 380

alkalosis and, 381

alveolar CO, tension in, 374

ammonia excretion in, 381
' as a stimulus to respiratory center,
380

changes in body in, 378

general effects of, 374

in mountain sickness, 415

lactic acid in relation to, 379

pneumatic cabinet and, 377
Antagonistic muscles, 915
Antagonistic reflexes, 945
Anticoagulants, 100
Antidromic impulses, 239
A^ntiferments in blood, 90
Antiperistalsis in cecum, 503
Antithrombin, 105, 113
Antitoxins, 70
Antitrypsin, 91

Aortic regurgitation, pulse in, 133
Apex beat, tracing of, 289
Aphasia, motor, 960

sensory, 960

subcortical, 960
Apnea, 349, 382

nervous element in, 384
Apparatus for measuring respiratory ex-
change, 589
Appetite, 506

Appetite juice, nature of, 470, 474
Arc, reflex, 832
Arginase, 81, 650

Arginine, 640, 650, 660
Aromatic sulphates, 665
Aromatic oxyacids in urine, 564
Arrhythmia of sinus, 278, 292
Arterial pressure, 124
Arteries, bloodflow in, 200
Arteriosclerosis, diastolic pressure in,

144

Aspartic acid, 640, 699
Asphyxia, 366
Assimilation limit, 685
Association neurons, 834
Astasia, cerebellar, 927
Asthenia, cerebellar, 927
Asthma, dead space in, 328
Ataxia, cerebellar, 927
Atonia, cerebellar, 926
Atophan, 684
Atr opine, effect on glands, 457

effect on heart, 231
Auditory area, 879
Auricle, pressure in, 146

propagation of beat in, 191
Auricular curve, contour of, 153
Auricular fibrillation, 196, 281, 295
Auricular flutter, 196, 281, 293
A uriculo ventricular orifice, 149
bundle, 183
node, 183

Auscultatory method (of blood pres-
sure), 130
Autocatalysis, 77
Autocoids, 767
Autonomic nerves, cerebral, 458

sympathetic, 458
Autonomic nervous system, 893

axon reflexes in, 898

bulbosacral outflow, 894

connector fibers of, 894

functions of, 897

general plan of construction, 893

parasympathetic, 882, 895

sacral outflow, 494

thoracicolumbar outflow, 895
Axon, 831

reflexes, 829, 898
Azelaie acid, 740

Bacillus coli communis, 534
Bacteria, in intestine, 533, 690

in stomach, 516
Bacterial digestion, 533
Balance, energy, 571

carbon, 582

material, 579

sheet of body, 579
Banting cure, 605
Basal heat production, 574
Basal ration, 610
Basophile cells, 97
' ' Bends ' ' in caisson workers, 425

INDEX

975

Benedict's method for respiratory ex-
change, 580
Benzole acid, 664, 738
Benzoyl chloride, 663
Beriberi, 619

Beta-hydroxy butyric acid, 738
Bile, 526

and fat digestion, 721
chemistry of, 528
constituents of, 526
from gall bladder, 526
functions of, 527
pigments of, 529
salts, 528
Bilirubin, 529
Biliverdin, 529
B-imidazolylethylamine, effect on blood

vessels, 253, 413
as a factor in shock, 307
Birds, removal of liver from, 652
Bladder, emptying of, 900
Blood :

absorption into, 13
amino acids in, 641
amount in body, 85
antiferments of, 90
circulation of, 124
dissociation curve of, 396
epinephrine content of, 780
fat of,

estimation, 726
variations in, 727
ferments of, 90
gases of, transportation, 392
general properties of, 85
mass movement of, 296
means by which gases are carried, 403
oxidation in, 412
proteases of, 90
proteins of, 88

origin, 89

quantity of, in body, 85
refractive index of, 89
specific gravity of, 87
sugar level of, 690

regulation, 703
transfusion of, 94, 131, 194
viscosity of, 141
volume of, 138
in shock, 306
water content of, 87
Blood cell, red, fate of, 95
origin of, 93
regeneration of, 94
stroma of, 92
white, 97
Blood clotting, 99
in diseases, 111

in physiological conditions, 111
influence of calcium on, 104
influence of tissues on, 105
intravascular, 108

Blood clotting — Cont 'd

methods of retarding, in drawn

blood, 100

negative phase of, 109
theories of, 107
time of, 101, 109
visible changes during, 99
Blood corpuscles in mountain sickness,

419
Bloodflow :

clinical conditions affecting anemia,

298

cardiovascular diseases, 299
fever, 298

diseases of nervous system, 300
mass movement of, 208
measurement of, 209, 296
movement in veins, 214
normal flow, 297
variations in, 297
velocity of, 206
visceral, 212

Blood gas manometer, 395
Blood platelets, 98
Blood pressure, 124
diastolic, 129, 133
effect of hemorrhage on, 136
effect of pleural pressure on, 323
factors maintaining, 135
H-ion of blood on, 248
mean arterial, 125
measurement of, 129
in shock, 303, 304
systolic, 129
tracing, 126
Blood vessels:

elasticity of, 143
tone of, 241

Body fluids, reactions of, 35
Body surface and energy production, 575
Body weight and energy production, 575
Botulism, 537
Bowman, capsule of, 541
Bradycardia, 193
Brain :

circulation in, 254
vasomotor nerves, 262
volume of, 256

Breathing, in compressed air, 420
in rarefied air, 374, 415
periodic, 385, 386
Brownian movement, colloids, 58
Bruits, 158

Buffer action of blood, 388
Buffer substances, 36
Building stones of protein, 609
Bulbocavernosus reflex, 967
Bulbosacral outflow, 894
Butyric acid, 737

976

INDEX

Cadaverine, 662
Caffeine, 668, 681
Caisson disease, 420
cause of, 421

decompression of workers, 424
prevention, 422
symptoms, 420
working conditions in, 425
Calcium ion, influence on clotting, 104

influence on heart, 167
Calcium rigor, 167
Calomel electrode, 30
Calorie, 571

Calorie requirement, 625
Calorie test of labyrinth, 920
Calorimeter, 571
animal, 572
Benedict, 573
bomb, 573
hand, 296
respiration, 572
Russel-Sage, 573
Calorimetry, direct, 572, 580

indirect, 580
Caloro-receptors, 855
Canalization, 844
Canals, semicircular, 918

removal of, 918
Cannabin, 611

Capillary analysis of colloids, 57
Capillary circulation, 251

during muscular contraction, 252
Krogh on, 251
Carbamino reaction, 635
Carbohydrates, absorption of, 689
assimilation limits, 685
digestion of, 689
and growth, 617
metabolism of, 685
production from protein, 699
saturation limit, 685
Carbon balance, 582
Carbon dioxide, combining power, 42
effect on respiratory center, 366,

368

estimation in blood, 403
output, 585

volume percentage in blood, 404
Carbon dioxide tension, 354

in alveolar air, after exercise, 435
estimation of, 357, 361
in mountain sickness, 416
in periodic breathing, 388, 389
in arterial blood, 354
in venous blood, 359 N

Carbonic acid (see Carbon dioxide)
Carboxyl group, 634
Cardiac decompensation, dead space in,

328
Cardiac depressor nerve, 243

Cardiac muscle, physiologic characteris-
tics of, 176

Cardiac pouch (stomach), 487
Cardiac sphincter, 482
Cardiorenal disease, bloodflow in, 299

energy output in, 578
Cardiograms, 289

Cardiovascular disease, bloodflow in, 299
Casein, 521, 611
Caseinogen, 521
Castration, 821
Catabolism, 571
Catalase, 91
Catalysts, 73
Cations, 16
Catalytic power, 23
Caval pocket, 784

Coelenterates, nervous system of, 828
Cellulose, digestion of, 533
Centers :

diabetic, 704

motor, 885

sense,

auditory, 879
visual, 880

sensory, 878

word centers, 960
Cephalin, 720
Cereals and growth, 615
Cerebellar ataxia, 927
Cerebellum :

ablation of, 926

clinical observations, 926

functions of, 926

lobes of, 929

localization of function of, 929
Cerebral circulation,, 254
Cerebral compression, 258
Cerebral cortex, stimulation of, 885
Cerebral localization, 886, 878
Cerebral vessels, ligation of, 254
Cerebrin, 720

Cerebrospinal fluid, 121, 255
Cerebrum, functions of, 951, 958, 963

relation to distance receptors, 952

relation to spinal reflexes, 951
CH method of expressing, 27
Chemo-receptors, 855
Cheyne-Stokes breathing, 385, 390
Chlorides, urine, 565
Chalone, 767
Chlorophyl, 530
Cholesterol, 528, 688, 720

estimation of, 726
Choline, 720

Chorda tympani, 236, 239, 412, 458
Chromaffin cells, 771
Chromatolysis, 847
Chromatine, 670
Chromosomes, 670
Chyme, 490, 516
Circle of Willis, 254

INDEX

977

Circulation of blood:

control of, 221

influence of gravity on, 248

mass movement of blood, 208

through the heart, 267

through the liver, 265

through the lungs, 264

time of, 206, 214
Circulation time, 206, 214
Clinical application, circulation, 270

respiration, 364, 393
Clotting of blood (see Blood clotting)
Coagulative ferments, 82
Cod-liver oil, nutritive value, 735
Coefficient of oxidation, 408
Coefficient of solubility of gases, 354
Coefficient of utilization, 410
Cold, sensation of, 860
Cold spots, 860
Collaterals, 831
Colloids :

Brownian movement, 58

capillary analysis, 57

characteristic properties of, 51

diffusibility of, 52

dispersion means, 55

dispersoid, 55

electric properties of, 56
osmotic pressure, 58

electrophoresis, 57

external phase, 55

gelatinization, 62

heterogeneous, 52

homogeneous, 52

imbibition, 63

internal phase, 55

isoelectric point, 65

lyophobe, 61

mutual precipitation of colloids, 57

osmotic pressure of, 142

size of colloid particles, 54

suspensions, 54

suspensoids and emulsoids, action of
electrolytes on, 64

Tyndall phenomenon, 52
Compensated acidoses, 39
Compensatory movements of eyes, 918
Complemental air, 317
Compressed air sickness, 420

cause of symptoms, 421
prevention of, 422, 424
treatment of, 424
Concentration cell, 30
Concentration point, auricles, 185
Concept, 952, 959
Conditioned reflexes, 466, 954
Conduction :

all or none law, 837, 839

betAveen neurons, 841

energy of, 838

in nerve trunk, 827

in reflex arc, 841

Conduction — Cont 'd
polarity in, 841
refractory period in, 839
Conductivity, determination of, 17
equivalent, 19
molecular, 19
specific, 17
Conductivity cell, 18
Conglutin, 612

Construction of autonomic nervous sys-
tem, 893

Contraction of skeletal muscle :
isometric, 904
isotonic, 904
tonic, 904
tetanic, 905, 906

chemistry of, 910
Contracture, extension, 967
Cooking, 630

Coronary circulation, 267
Coronary vessels, vasomotor nerves, 268
Corpus luteum, 822
functions of, 822
Corpuscles of blood, red, 92

white, 97

Cortico-spinal system, 963
Coughing, 317, 351
Cranial cavity, pressure in, 258
Creatine, 647, 656
chemistry of, 656
estimation of, 657
in disease, 661
metabolism of, 658
origin of, 660
Creatinine, 647
chemistry of, 656
coefficient, 658
estimation, 657
in urine, 563
metabolism, 658
of blood in disease, 683
origin of, 660
Cremasteric reflex, 967
Cretinism, 795
Critical concentration, 8
Crossed extension reflex, 966
Cuorin, 720
Curare, effect on myoneural junction,

845
Current of action, of heart, 188

of skeletal muscle, 906
Cyanosis, 378, 444
Cysteine, 639
Cystine, 611, 629, 639
Cystosine, 667
Cytases, 497

D

Dalmatian dog, purine metabolism of,

673, 679

Walton's law, 353
Dead space, 319, 327
Deafness, 880

978

INDEX

Deamidization, deaminization, 535
Deaminizing enzyme, 671
Decerebrate rigidity, 925
Decolorization of liquids by charcoal, 67
Decompression of caisson workers, 424
Defecation, 504

blood pressure during, 529
Defibrinated blood, 102
Degeneration of nerve fibers, 846
Degeneration, successive, 849
Deglutition, 479
Delayed conduction, 282, 291
Delirium cordis, 196
Denervated iris, 784
Dendrites, 831
Depression of freezing point, 10

of urine, 557

Depressor nerve, 243, 244, 245
Depressor substances, 253, 415
Dessert, physiologic value of, 472
Detoxication compounds, 662
Detoxication process, 535
Dextrins, 525, 689
Dextrose (see Glucose)
Diabetes :

acidosis in, 715

and the ductless glands, 710

assimilation limits in, 685

blood examination in, 691

blood fat in, 726

center, diabetic, 704

early diagnoses of, 685, 692

energy output in, 578

experimental, 704

fat metabolism in, 715

insipidus, 815

ketosis, 715

pancreatic, 712

nervous, in man, 706

permanent, 707

phlorhizin, 697

postprandial hyperglycemia, 691

renal, 693

starvation treatment in, 716

treatment of, 623, 686
Diabetic acidosis, 715
Diabetic center, 704
Diabetic gangrene, 300
Dialurie acid, 678
Dialysate, 53
Dialysis, 12

method, colloids, 52
Diaphragm, action of, 337, 338

physiology of, 341
Diastasis, 219

Diastolic filling of heart, 153, 217
Diastolic pressure, 129, 133

measurement of, in man, 129
Dicrotic notch, 203

wave, 203
Diet at different ages, 627

of different communities, 626
Dietetics, 625

Differential manometer, 394
Diffusion, 12

Digestibility of foods, 630
Digestion, by pancreatic juice, 523
in intestine, 523
in stomach, 515
mechanism of, 478
Digestive glands :
control of,
hormone, 460
nervous, 458

general physiology of, 453
microscopic changes during activity,

423

Disaccharides, 689
Dispersion medium, colloids, 55
Dispersoid, colloids, 55
Dissociation, 16, 17
Dissociation constant, 19, 401
Dissociation curve :
of blood, 396
of hemoglobin, 397

influence of salts on, 398
influence of H-ion concentration

on, 339

influence of temperature on, 399
Dissociation of sensation, 868
Dissociation hypothesis, applications of,

21

Dissociation, rate of, 399
Distance receptors, relation to cerebrum,

.952
Diuresis, 552

and pituitrin, 811
Diuretics, 552
Diver's palsy, 420
Douglas method, 489
Dropped beat, 282, 291
Du Bois formula, 576
Ductless glands, 766
in diabetes, 710
Dudgeon's sphygmograph, 201
Dyspnea, 330, 366
Dystrophia adiposo-genitalis, 818

E

Earth-worm, nervous system of, 830

Eck fistula, 651

Eclampsia, 654

Edema, 63, 120

Edestin and growth, 611

Effectors, 829

independent, 828
Efferent pathways:

in brain and cord, 888
to viscera, 893
Effort syndrome, 441

epinephrine in, 442
Elastin, digestion of, 520
Electric conductivity, 16
Electric currents, development of, 29
Electric properties of colloids, 56

INDEX

979

Electrocardiograms, 159, 270
normal, 272
standardization of, 271

ventricular complex, 273

waves of, 272
P-wave, 189, 272
T-wave, 225, 274
Electrocardiograph, 271
Electrocution, cause of death in, 195
Electrolytes, 16

action of, on colloids, 64
Electrolytic solution pressure, 29
Electrophoresis of colloids, 57
Electrostatic attraction, 29
Emboli, 108
Emetics, 484

Emotional glycosuria, 706
Emphysema, 328, 330, 341
Empyema, 341
Emulsions, 719
Emulsoids, colloids, 61
Endocrine organs, 766
Endoenzyme, 71
Endogenous metabolism, 649, 656

of purines, 676
Energy balance, 571
Energy output, and age, 597
and body weight, 575
and disease, 578
and muscular work, 586
and sex, 577
and surface area, 575
and temperature, 586
in starvation, 602
Enterokinase, 477, 523
Enzymes, 72

action of temperature on, 75

amylases, 82

and catalysis, 73

antienzymes, 82

arginase, 82

coagulative ferments, 83

conditions of activity, 83

endoenzymes, 72

glyoxylase, 83

invertases, 82

lipases, 82

nature of, 73

oxidases, 83

peculiarities of, 81

peroxidases, 83

properties of, 94

proteases, 81

reversibility of action of, 25, 78

specific action of, 74

types of, 80

urease, 83

velocity constant, 75
Epilepsy, Jacksonian, 883, 887
Epinephrine, 241, 502, 536, 773, 902

and diabetes, 708

emergency hypothesis of, 786

estimation of, 779, 785

Epinephrine — Cont 'd

methods of determining, 779, 785

physiological action of, 774

reversive action of, 777

secretion of, in fright, 786

variation in action of, 779
Equilibrium, nitrogen, 605
Equivalent, conductivity, 19
Erepsin, 520, 524, 525
Ergastoplasm, 455
Ergot, 536

Ergotoxine, 236, 538, 776, 897
Erythrocytes, 92

fate of, 95

regeneration of, 94
Escapement, 223
Esophagus, during swallowing, 480

inhibition of, 482

peristaltic wave in, 482
Esters, 718
Ester value, 719
Ethereal sulphates, 535, 665
Ethylamine, 536, 662
Excelsin, 612
Excitation, 827
Exogenous metabolism, 649
Exophthalmic goiter, 799

energy output in, 578
Excretion of acid combined with am-
monia, 47

Excretion of urine, 541
Extension contracture, 967
Extensor thrust, 967
Exteroceptors, 917
Extrasystole, 278, 292
Eyes, movements of, 887

Facilitation, 843

Factor safety, in diet, 629

Fatigue level, 911

Fatigue of muscle, 910, 911

Fatigue of reflexes, 845

Fats:

absorption of, 722
chemical theory, 723
•mechanistic theory, 723
and growth, 617
blood, 726, 727

destination of, 729
determination, 726
during absorption, 728
during fasting, 728
variations in, 727
chemistry of, 721
depot fat, 729, 730

destination of, 731
desaturation of, 734, 740
digestion of, 722
fat dust, 726
liver fat, 729, 731
metabolism of, 718, 726, 736

980

INDEX

Fats — Cont 'd

tissue fat, 729, 735
transportation to liver, 732
Fatty acids, 718

acid number, 719

breakdown of, 737

ester value, 719

formation from carbohydrates, 730,

736

in liver in disease, 733
iodine value, 719
melting point, 719
Eeichert-Meissl value, 719
saponification value, 719
Feces, 533, 555
Ferments (see Enzymes)
Ferments in blood, 90
Fever, bloodflow in, 298
body changes in, 750
causes of, 748
cold-bath treatment, 299
purine excretion during, 680
Fibers, anterior root, 238
connector, 894
internuncial, 894
postganglionic, 894
preganglionic, 894
Fibrillation, auricular, 196, 281, 295

ventricular, 195
Fibrin, 100

fibrin needles, 100
source of, 102

Fibrin ferment (see Thrombin), 103
Fibrinogen, 89, 102, 104, 112
Filtration, 13
Final common path, 945
Fistula, biliary, 526
gastric, 468
salivary, 466
Flexion-reflex, 966

Flutter, auricular, 269, 196, 281, 293
Food:

accessory factors of, 618, 630
cooking, importance of, 630
effect of, on circulation, 247
effect on creatinine excretion, 657
laxative qualities, 631
palatability, 630

Food factors, accessory, 618, 630
Food factors of growth, 608
Foodstuffs, rate of leaving stomach, 492
Forced breathing, 341
Formaldehyde titration, amino acids, 521
Formation of solid surface films, 67
Free nerve termination, 854
Freezing point, constant, 10
Freezing point, depression of, 10
Fridericia's method for alveolar air, 357,

358

Fructose, 698
Fundus of stomach, 485

G

Gallstones, 528

Galvanometer, string, 187, 270

Ganglia, 831

Gas in stomach, 496

Gas laws, 3, 353

Gases, adsorption of, 67

coefficient of solubility, 354

estimation of, 361

partial pressure of, 353

solution of, 353

tension of, 353

transportation in blood, 392
Gaskell's clamp, 175
Gastric contents, regurgitation of, 483
Gastric digestion, 515

rate of, 521
Gastric fistula, 468
Gastric juice, quantity secreted, 474

strength of, 475
Gastric secretion, 467

hormone control of, 472
local stimulation of, 472
nervous control of, 469
Gastric tube, 487
Gastric ulcer, 490
Gastrin, 474, 490
Gastroenterostomy, 494
Gastrointestinal contents, reaction of,

. 539

Gelatinization, 62
Glands, changes during activity, 453, 456

electric changes, 457

normal conditions of activity, 465

oxygen consumption of, 408, 411, 456

respiration of, 408, 411
Globulin, 611
Gliadin, 612
Glomerulus, 541
Gluconeogenesis, 694, 708, 712

direct method, 695

indirect method, 696

in normal animals, 699
Glucose :

fate of absorbed, 694

glucose to nitrogen ratio, 696

injections, intravenous, 687
subcutaneous, 688

parenteral assimilation, 688

tolerance for, 688

utilization of, in tissues, 708
Glutamic acid (see Glutaminic acid)
Glutaminic acid, 640, 699
Glutein, 611
Glutelin, 611
Glycol aldehyde, 697
Glycerol, 697
Glycoholic acid, 528, 664
Glycine, 494, 639
Glycinin, 611
Glycocoll, 637, 639, 664, 699, 738

INDEX

981

Glycogen, 694

fate of, 701

sources of, 694
Glycogenase, 694
Glycogenolysis, 701

hormone, 707

nervous, 704

postmortem, 702
Glycolaldehyde, 697
Glycolysis, 702

Glyconeogenesis (see Gluconeogenesis)
Glycosuria, alimentary, 690

emotional, 702

postprandial, 691

relation to sugar of blood, 692

renal, 693
Glycuronates, 665
Glycuronic acid, 665, 666
Glyoxal, 664
Glyoxylase, 82, 698
Glyoxylic acid, 664
G-N-ratio, 696
Goiter, exophthalmic, 799
Gonads, 821

of female, 822

of male, 821
Gout, 681, 683

etiology of, 683

guanine, 673

uric acid excretion in, 681
Gram molecule, 3, 5
Gram molecular solution, 22
Gravity, on circulation, 248

compensation for, 249
Growth, 608

accessory factors, 618

basal ration, 610

carbohydrates and, 583

curves of, 610, 611

curves of inhibition, 614

fats and, 617

inorganic salts and, 618

lysine and, 612

proteins and, 609

trypanophane and, 612

vitamines, 618
Guanidine, 640, 656, 804
Guanine, 667

gout, 673
Guanosine, 671
Giinsberg reagent, 521
Gustatory area, 879

H

Haldane-Barcroft apparatus, 45
Haldane gas apparatus, 593
Haldane's method for alveolar air, 357
Hallucinations, 883
Heart :

action of, 145

auricular curve, 153

diastole of, 146

isometric period in, 150

Heart— Cont 7d

law of, 216

minute volume of, 218

muscle, properties, 176

nutrition of, 161

opening and closing of valves, 154

output of, 216

in relation to venous inflow, 216, 217

oxygen requirements of, 408, 411

oxygen supply of, 166

perfusion of outside body, 161

postsphygmic peripd, 150

presphygmic period, 150

pressure in, 146

pumping action of, 135, 145

resuscitation in situ, 165

rhythmic power in, 170/174

sounds of, 156

systole of, 146

tone of, 220

utilization of glucose in, 713

vagus control of, cold blooded, 222

vagus control of, mammalian, 225

vagus terminations in, 230

ventricular curve, 151

work of, 213
Heart beat:

arrhythmia of, 278, 292

disorders of, 278, 291

myogenic hypothesis of, 170, 171

neurogenic hypothesis of, 170, 172

origin of, in cold-blooded animals, 170

origin of, in mammalian, 182, 189

pace maker of, 174

propagation of, 191

sympathetic control of, 232

ultimum moriens, 185

vagus control of, 222, 225
Heart block, 174, 282, 291

effect of vagus on, 224
Heart disease, vital capacity of lungs in,

330

Heart-lung preparation, 163
Heat production and age and sex, 577
and body weight, 575
surface, 576
disease, 578
sensation of, 861
Heat spots, 860
Heat value of foods, 571
Hematin, 530
Hematoerit, 7
Hematoporphyrin, 530
Hemiplegia, 889
Hemodromograph, 207
Hemoglobin, 92

dissociation constant, 401

dissociation, curve of, 396,398,399

estimation of, 93

rate of dissociation, 399

relationship to bile pigments, 530

specific oxygen capacity of, 392

transportation of O, by, 392

982

INDEX

Hemolysis, 7, 96

Hemolytic jaundice, 94

Hemophilia, 113

Hemopoietic activities of bone marrow,

94
Hemorrhage, 95, 138

immediate effects of, 138
recovery from, 139
Hemorrhagic diseases, 113
Henle, loop of, 541
Hepatic artery, flow in, 265
Heterocyclic compounds, 640
Hexone bases, 638
Hexoses, 685

Hibernating animal, metabolism of, 584
Hibernation, breathing during, 389
Higher functions of cerebrum, 951, 958,

963

H ion or hydrogen ion, 168
H-ion concentration, 22
after hemorrhage, 143
catalytic power 'of, 23
determination of, 31
of intestinal contents, 539
law of mass action and, 26
method of expressing, 27
method of measurement :
electric method, 29
indicator method, 32
standard solutions for, 34
H-ion concentration in blood:

effect on dissociation curve, 398, 401
effect on respiratory center, 352
Hippuric acid, 564, 663, 738
Hirudin, 101
Histamine, 536

as a factor in shock, 307
effect upon capillaries, 253, 413
Histidine, 639, 641, 656
Homogentisic acid, 536, 565
Hordein, 612
Hormones, 3, 766

in control of circulation, 221
respiratory, 352, 366
Howell theory (blood clotting), 107
Hunger, 506
Hunger contractions:

alcoholic beverages and, 512
control of, 511
during starvation, 510
in esophagus, 509
inhibition of, 511
in stomach, 506
nerve centers and, 513
remote effects of, 509
rhythmic, 506
splanchnic nerve and, 511
vagus nerve and, 511
Hiirthle manometer, 128, 147
Hydrocephalus, 255, 263

Hydrochloric acid, amount of, 516

and emptying of stomach, 491, 494
functions of, 516
source of, 517

Hydrogen ion (see H ion)

Hyperacidity, 495

Hyperglycemia, in pancreatic diabetes,

712

postprandial, 691
splanchnic, 704

Hypernephroma, 769

Hyperpituitarism, 816

Hyperpnea, 366, 371, 377

Hyperthyroidism, 798

Hypertonic solution, 6

Hypopituitarism, 817

Hypothyroidism, 797

Hypotonic solution, 6

Hypoxanthine, 667, 671

Ignition juice, 473

Ileocolic sphincter, 501, 503

Imbibition, 63

Imidazole and growth, 639, 656

Imidazole ring, 656

Imidazolylethylamine, 253, 413, 461, 536

Immediate induction, 947

Impulses, nature of, 837

Indican, 565, 665

Indicator method, list of indicators, 33

Indole, 535, 639, 665

Indoxyl sulphate of potassium, 665

Induction :

immediate, 947

successive, 949
Inhibition, 843

reciprocal, 914, 937
Inhibitory effects of autonomic nerves,

896
Innervation, double of visceral organs,

896

Inorganic constituents of urine, 565
Inorganic salts and growth, 618
Inosine, 670, 671
Inosinic acid, 668
Inspiration, negative pressure during,

322

Integration of allied reflexes, 945, 946
Intercostal muscles, 336
Interganglionic connectives, 832
Internal respiration, 391
Interstitial cells of ovary, 822
Intestinal bacteria, 533, 690
Intestinal ballast, 631
Intestinal juice, control of, 477
Intestinal muscle :

metabolic gradient of, 500
rhythmicity of, 499
segmenting movements of. 497
Intestinal obstruction, 505, 538
Intestinal secretions, 476

INDEX

983

Intestine :

absorption from, 13

anastomosis of, 504

bacterial digestion in, 533

digestion in, 523
law of, 501

movements of:
large, 503

clinical conditions affecting, 504
small, 497

nature of, 501
nervous control of, 501
Intracardiac pressure curves, 146, 151
Intracranial pressure, 258
Intragastric pressure, 488
Intrapleural pressure, 321
Intrapulmonic pressure, 316
Intra vitam anticoagulants, 101
Intravascular clotting, 108
Inulin, 696

Invertase, 82, 526, 689
Iodine value of fats, 719
lodothyrine, 798
lonization, 16

Irradiation on to respiratory center, 430
Iris, denervated, 784
Isoelectric point, 64
Isoleucine, 639
Isomaltose, 79
Isometric period, 150
Isotonic solution, 6

J

Jacksonian epilepsy, 883, 887
Jugular pulse tracing, 285
Juice, gastric, 467, 516

intestinal, 476

pancreatic, 476, 523

K

Keith and Flack, conducting tissue in

heart, 185
Keith, Eowntree, and Geraghty method,

85

Kent, bundle of, 183
Ketosis, 715
Kidney, oxygen requirements of, 408,

412

removal of, 655
structure of, 541
Knee-jerk, 966

L

Labyrinth, 918

clinical tests of, 920

Lactalbumin, 611

Lactam, 682

Lactase, 525, 689

Lactic acid, 413, 639, 689, 697, 708
effect on respiratory center, 379
in relation to anoxemia, 379
produced by exercise, 431, 435

Lactim, 682

Language, 958

Laws of gases, 353
of mass action, 23

applied measurement of H-ion concen-
tration, 26
Lead poisoning, 684
Lecithin, 720

estimation of, 726
in bile, 532
in blood, 726, 728
Leech extract, 101
Legumelin, 612
Legumin, 612
Leucine, 640, 698
Leucemia, 681
Leucocytes, 97

sensitizing of, 70

transitorial, 98
Levulose, 698

Levy and Eowntree method, 41
Leydig cells, 821
Limulus, heartbeat of, 173
Lipase, 25, 91, 522, 525, 719
Lipemia, 728
Lipoids of blood, 728
List of indicators, 33
Litten's diaphragm phenomenon, 338
Liver :

circulation through, 265

disease of, 654

glycogen in, 695

metabolism of fats in, 731

perfusion of, 652

removal of, 651

urea formation in, 651
Local irritants, 248, 253
Localization :

one dimensional, 861

two dimensional, 861

three dimensional, 861
Locke solution, 168
Loven reflex, 248
Lungs, circulation through, 264

mode of expansion of, 342
Lymph :

absorption into, 13

electric conductivity, 16

filtration in, 118

formation and circulation, 115

formation of, 15
Lymph spaces, 115
Lymphagogues, 119
Lymphatics, 115
Lymphocytes, 97
Lyophobe colloids, 61
Lysine, 629, 640
Lysine and growth, 612, 614, 616

M

Maintenance, diets for, 616
Maltase, 525, 689
Maltose, 525, 689

984

INDEX

Manometer :

blood-gas differential, 395

Hiirthle, 128, 147

mercury, 125

optical, 147

spring, 128

valved mercury, 152
Mark-time reflex, 967
Mass action, 23

Mass action and H-ion concentration, 26
Mass movements of blood, 208

measurement of, 296
Mass-reflex, 968
Mastication, 478
Mechanics of respiration, 316
Mechanism of urine excretion, 544
Megacaryocytes, 104
Melting point, fats, 719
Mercury manometer, 125
Mesencephalico-spinal system, 963
Metabolism :

calculations, 596

endogenous, 649

exogenous, 649

general, 570

in starvation, 600

normal, 604

of carbohydrates, 685

of central nervous system, 851

of fats, 718

of nerve fibres, 856

of proteins, 632

of purines, 676

special, 570
Methyl glyoxal, 698
Methyl group, 634
Methyl purines, 668
Methylation, 660
Methylglyoxal, 698
Mett's method, 521
Microcytes, 95
Microtonometer, 356
Mid-capacity of lungs, 328
Milk, clotting of, 521
Miniature stomach, 468
Minimal air, 317
Mononuclear leucocytes, 97
Monoplegia, 887
Monosaccharides, 689
Morphogenetic, 767
Morawitz theory, blood clotting, 108
Motor areas:

representation of function in, 886
stimulation of, 885
Mountain sickness, 378, 415

acid and ammonia excretion in, 420
acid-base equilibrium in, 416
adaptation to, 418
alveolar CO2 in, 416
blood corpuscles in, 419
symptoms of, 417
Movements, of intestine, 497

of stomach, 485

Municipal food statistics, 628
Muscarine, action on heart, 232
Muscle, cardiac, properties of, 176

refractory period, 178

respiration in, 408, 409

staircase phenomenon (treppe), 177
skeletal, 177

respiration in, 394
Muscular exercise, 248, 574

circulatory changes during, 427

effect on metabolism, 586

effect on respiration, 427

H-ion during, 431, 432

purines during, 480

redistribution of blood during, 433

respiratory changes during, 427

temperature of blood during, 433
Mutual precipitation of colloids, 57
Myenteric reflex, 830
Myogenic hypothesis of heartbeat, 171
Myoneural junction, 845
effect of curare on, 845
effect of epinephrine on, 845
Myxedema, 796

energy output in, 578

N

Narcotics and blood fat, 727
Necrosis of liver, 654
Negative pressure in ventricle, 152
Nephelometer, 726
Nephrectomy, 655
Nephritis, 683, 684
acidosis in, 715
urea retention in, 562
Nerves :

degeneration of, 846
regeneration of, 846
specific properties of, 859
vasodilator, 239

Nerve cell body, function of, 846
Nerve fiber:

conduction in, 837
degeneration of, 846
direction of conduction in, 837
fatigue of, 841

isolation of conduction in, 837
metabolism of, 850
regeneration of, 846
Nerve net, 830
Nervi erigentes, 239
Nervous control:

of gastric secretion, 469
of ileocolic sphincter, 503
of intestinal glands, 477
of intestinal movements, 501
of pancreas, 462
of respiration, 344
of salivary glands, 458
of stomach movements, 492
Nervous conduction, polarity in, 830, 841

INDEX

985

Nervous impulse:

conduction of, 836

rhythm of, 841
Nervous diabetes, 704

in man, 706
Nervous system:

autonomie, 893

bulbar outflow, 894
enteral, 895
internuncial fibres, 894
oculo-motor, 895
sacral outflow, 894
thoracico-lumbar outflow, 895

evolution of, 827

influence on excretion of urine, 563

integration of, 945, 951

metabolism of, 851

nutrition of, 846, 849
Network, nerve, 830
Neurogenie hypothesis, of heart, 172
Neurons, 830

association, 834

effector, 894

internuncial, 894
Neuroid transmission, 828
Neurolemma, 848
Neutrality, regulation of, 36
Nicotine :

action on vagus, 231
Nitrogen :

action on synapse, 238, 844, 895

excretion of, premortal rise, 600

in starvation, 600

undetermined, urine, 647, 662
Nitrogen balance, 605
Nitrogenous constituents of urine, 560
Nitrogenous equilibrium, 605
Nitrogenous metabolites, in starvation,

602
Nociceptives :

reflex, 966
Noeud vital, 344
Nonelectrolytes, 16
Nonthreshold substances, 546
Normal acid, 22
Normoblasts, 94
Noxious stimuli, 862
Nuclease, 671
Nucleic acid, 669, 720
Nuclein ferments, 91
Nucleins, 669
Nucleoside, 670
Nucleotide, 670
Nystagmus, 920
Nutrition, 608

of nervous tissue, 846, 849

O

Obesity, Banting cure for, 605
Oleic sicid, 718
Olein, 719
Olfactory area, 879

Oncometer, 235
Opsonins, 70

Optic thalamus, sensory center of, 876
Organs, loss of weight during starva-
tion, 602

perfusion of, 652
Ornithine, 650, 664
Ornithuric acid, 664
Orthopnea, 329, 335

Oscillatory method of blood pressure, 132
Osmometer, 5
Osmosis, 4
Osmotic pressure, 4, 10

and formation of lymph, 13
and hemolysis, 7
and plasmolysis, 8
measurement by depression of freez-
ing point, 11

in physiologic mechanisms, 13
in production of urine by kidneys,

14

of transfusates, 142
Ovary, 822

Ovalbumin, as food, 611
Ovovitellin, as food, 611
Oxidases, 82
Oxidation of blood, 400
Oxybutyric acid, 650, 715, 740
Oxygen :

coefficient of oxidation, 408
coefficient of utilization, 410
determination of, 596
estimation in blood, 403
requirements of tissues, 408
tension in alveolar air, 361
tension in arterial blood, 354, 356
therapeutic value of, 445
transportation by blood, 392
volume percentage in blood, 403
Oxygen insufficiency, (see anoxemia)
Oxygen supply of heart, 163, 166
Oxyproteic acid, 662

Pacchionian body, 256

Pain :

referred, 858
sensation of, 862

transmission in cord, 868
sense, 862

Palatability, 630

Palmitic acid, 718, 736

Pancreas :

hormone control of, 460
histologic changes of, 464
oxygen requirements, 396
nervous control of, 462
sugar metabolism and, 710

Pancreatic diabetes, 712

Pancreatic digestion, 523

986

INDEX

Pancreatic juice, 476

and fat digestion, 721

secretion of, 460
Pancreatin, 524
Parasympathetic system, 895
Parathyroids, 800

disease of, 800

injury of, 800

removal of, 800
Paralysis, flaccid, 924
Paroxysmal tachycardia, 281, 293
Partial dissociation, 283
Partial pressure of gases, 353
Past pointing, 920
Pelvic nerve, 895
Pelargonic acid, 740
Pentose, 670, 696
Pepsin, action of, 519

products of, 520
Pepsinogen, 519
Peptides, 636
Peptone, 106, 520
Perfusion, of kidney, 664

of liver, 652

Perfusion fluid, of heart, 166
Perfusion of heart, 161
Periodic breathing, causes of, 385, 386

types of, 385
Peripheral resistance, 135, 234

as cause of shock, 304
Peristalsis :

in esophagus, 481

in large intestine, 503

in small intestine, 497

in stomach, 486, 489
Peristaltic rush, 500, 505
Peristaltic wave, 499

Pernicious anemia, energy output in, 578
P'eroxidases, 82
PH, 27

Phagocytes, 98
Phenaceturic acid, 738
Phenol, 534
Phenolacetic acid, 536
Phenolphthalein, 516, 558
Phenylacetic acid, 664, 738
Phenylalanine, 639
P'henyl group, 639
Phlorhizin, 695, 696
Phono-receptors, 855
Phosphates, excretion of, 47
Phosphate solutions for H-ion, 34
Phosphates of urine, 566
Phospholipins, 720

in bile, 532
Photo-receptors, 855
Phrenic center. 345

isolation of, 345
P'hysiochemical basis, 1
Physiological processes depending on ad-
sorption, 70

Pigments, absorption of, 117
Pilocarpine, action on heart, 232

Pilomotor fibers, 897
Pineal gland, 820
Pituitary gland, 806

anterior lobe of, 808
disease of, 816
functions of, 807
pars intermedia of, 815
posterior lobe, 809
Pitot's tubes, 201
Pituitrin, effect on vessels, 811

effect on carbohydrate metabolism,
814

effect on kidney, 812

effect on milk secretion, 813
Plasma, 100
Plasmolysis, 8
Plastic tonus, 905
Platelets, of blood, 98, 107
Plethora, 87

Plethysmograph, 209, 235, 320
Pleurisy, 341

Plexus of Auerbach and Meissner, 500
Pneumothorax, 322
Poikilocytes, 95
Polarity, in conduction, 841

in reflex arc, 841
Polygraph, 286
Polynuclear cells, 97
Polypeptides, 520, 636
Polyphosphoric acid, 670
Polysaccharides, 522
Polysphygmograms, 285
Portal vein, bloodflow in, 265
Postdicrotic wave, pulse, 203
Postprandial hyperglycemia, 691
Postsphygmic period, 150
Postural co-ordination, 914

central control of, 924
Posture of body, 917
Potassium, microchemical test for, 456
Potassium ions, on heart, 167
Potential acidity of urine, 559
P'recipitins, 632
Predicrotic wave, pulse, 203
Premature beats, 278, 292
Premortal rise, 600
Presphygmic period, 150
Pressor impulses, 243, 244, 245
Pressure :

intragrastric, 488

intrapleural, 321

effect of, in blood pressure, 323

intrapulmonic, 316

negative, 322

osmotic, 10
Pressure pulse, 129
Principle of Willard Gibbs, 66
Proline, 640
Proprioceptors, 914

clinical tests for, 920
Prosecretin, 461
Proteases, 90
Protein sparers, 636

INDEX

987

Proteinases, 81
Proteins :

as colloids, 64
bacterial digestion of, 535.

chemistry of, 633

metabolism of, "631, 647
end products, 647

minimum requirement, 606, 629

of blood, 88

relative value of, for growth, 646

salting out of, 61
Proteose, 520

Prothrombin, 104, 107, 112
Psychopathology, 960
Ptomaines, 536, 662
P'tyalin, 525, 689
Pulmonary circulation, 264
Pulmonary ventilation, 367
Pulses, 198

abnormal, 291

alternans, 181

bigeminus, 181

contour of wave, 200

length of wave, 199

palpable, 202

pressure, 129

pulse curves, 202

pulse waves, 198, 199, 200, 202

rate of transmission, 199

velocity, 200

venous, central, 205, 285

venous, peripheral, 205
Purkinje fibers, 184
Purine bodies (see Purines)
Purines :

chemistry of, 563, 647, 667, 674

endogenous, 676, 677

exogenous, 674

metabolism of, 667

in starvation, 603

synthesis of, 677

in urine, 563

Putrefaction, intestinal, 535, 565
Putrescine, 662
Pyloric canal, 485
Pyloric sphincter, control of, 490
Pyloric vestibule, 485
Pyrimidine bases, 669, 670
Pyruvic acid, 635

R

Kami communicantes, 238

Raynaud's disease, bloodflow in, 300

Eeaction of urine, 558

Reactions depending on adsorption, 67

Reactions of body fluids, 35

Receptor-effector system, 829

Receptors, 829, 854, 933

chemo, 855

distance, 952

extero, 917

evolution of, 854

Receptors — Cont 'd

of skin, 859

phono, 855

photo, 855

proprio, 914

tango, 855

temperature, 861

touch, 860
Reciprocal inhibition, 915, 937

action of strychnine on, 941

action of tetanus toxin on, 941
Reciprocal innervation of blood vessels,

247

Red blood corpuscles, origin of, 93
Reduction of blood, 400
Referred pain, 858
Reflex, 832

conditioned, 466, 954

unconditioned, 466
Reflex arc, 832

integration within, 933

polarity of, 841
Reflex conduction:
canalization, 844
facilitation, 843
induction, 843
inhibition, 843
summation, 843
Reflexes :

abdominal, 892

Achilles tendon, 892

allied, 945

simultaneous combination of, 946
successive combination of, 946

antagonistic, 945

axon, 829, 898

bulbocavernosus, 967

conditioned, 854

cremasteric, 967

crossed extension, 966

extensor thrust, 967

flexion, 966

genital, 892

mark-time, 967

mass-reflex, 968

myenteric, 830

nociceptive, 966

palmar, 892

plantar, 892

proprioceptive, 914

pupillary, 892

scapular, 892

scratch, 966

triceps, 892

unconditioned, 466
Reflex fatigue, 948
Reflex figure, 941

spread of, 943
Refractive index, blood, 89
Refractory period, 839, 934
Refractrometric methods, 89
Regeneration of erythrocytes, 94

of nerve fibres, 846

988

INDEX

Eegulation of neutrality, 36
Eegurgitation of gastric contents, 483
Eeichart-Meissl value of fats, 719
Kenal diabetes, 693
Renal function, theories of, 545
Eennin, 521

Eeserve alkalinity, measurements of, in-
direct methods, 41, 46
measurement of, titration methods,

41

Eesidual air, 317, 328
Eespiration :
abdominal, 324
beyond the lungs, 391
during muscular exercise, 427
external, 391
in compressed air, 420
in rarefied air, 415
internal, 391
mechanics of, 316
movements of diaphragm in, 337
movements of ribs in, 332
Eespiration calorimeter, 572
Eespiratory center, 344

afferent impulses to, 348, 350
automatieity of, 346
hormone control of, 352, 366
reflex control of, 348
sensitivity to alveolar CO2, 371
stimulation by C02, 366, 367
subsidiary, 345

Eespiratory changes in muscular exer-
cise, 427
Eespiratory exchange:

according to body weight, 585

and body temperature, 586

and muscular exercise, 586

and temperature of environment,

586

clinical method for determining, 589
in diabetes, 709
in tissues, 408, 412
Eespiratory hormone, nature of, 366
Eespiratory movements, 322, 325
Eespiratory passages, pressure of air in,

sie

Eespiratory quotient, 582
in diabetes, 709
influence of diet on, 582
influence of metabolism on, 584
influence of muscular activity on,
435

Eespiratory tracings, 320

Eespiratory valves, Pearce's, 589

Eeticulated erythroblasts, 94

Eeversible action of enzymes, 25

Eibs, movements of, 332
musculature of, 336
undulatory movements of, 334

Eight lateral connection, heart, 185

Eomberg's sign, 921

Eotation test of labyrinth, 920

Rhythmic segmentation, 497

S

Sacral outflow, 894
Salicylates, 681

Saline injection, effect on blood pres-
sure, 139

Saliva, control of secretion, nervous, 458
psychic, 466

normal secretion, 466
Salt, dietetic value, 618
Salted blood, 101
Salting of proteins, 61
Saponification, 719
Sarcosine, 656
Saturation limits, 685, 687
Scratch reflex, 966
Scurvy, 622

Sea anemone, nervous system of, 828
Second wind, 438
Secretory fibers, varieties of, 459
Secretion, 460

chemical nature of, 461

mechanism of action of, 455
Secretion (see under various glands)

general considerations, 453
Segmentation movements, 497
Semicircular canals, 918
destruction of, 918
eye movements and, 918
Semilunar valves, 150, 155
Semipermeable membrane, 4
Sensation :

afferent paths of, 866

distribution of, 863

local sign of, 856

quality of, 855
Sense, temperature, 861

touch, 860

pain, 862
Sensibility :

cutaneous, 859

deep, 859

Sensory adaptation, 862
Sensory area of cutaneous and deep

sensibility, 878
Sensory centers, 876
of brain, 876
of cerebral cortex, 876
of optic thalamus, 878
Serine, 639
Serum albumin, 88
Serum globulin, 88
Sex, effect on creatinine excretion, 658

effect on energy output, 577
Sham feeding, 469
Shell shock, 302
Shock, 301

action of heart in, 305

anesthetic, 302

blood pressure in, 303

experimental investigations, 304

gravity, 301

INDEX

989

Shock — Cont 'd
hemorrhagic, 302
histamine as a factor in, 307
nervous, 302
prognosis of, 311
oligemia in, 306
recovery from, 312
secondary symptoms of, 310
shell, 302

spinal, 302, 924, 965
surgical, 303

toxemia as a cause of, 309
trauma as a cause of, 309
treatment of, 311
vasomotor control in, 304, 305
Sinoauricular node, 185, 278, 293
Sinus arrhythmia, 278, 292
Sinus bradycardia, 278, 292
Skatole, 535, 665

in urine, 565

Skeletal muscle, respiration in, 408, 409
Skin, receptors of, 859
Smooth muscle:

contraction of, 912
fatigue of, 912
metabolism of, 912
rhythmicity of, 913
Soap, 718
Sodium ions, 166
Solution of gases, 353
Solutions :

gas laws and, 3
gram molecular, 5, 22
hypertonic, hypotonic, and isotonic, 6
nature of, 3
Sorensen method for estimating amino

groups, 635
Sounds, cardiac, 156

recording of, 158
Specific conductivity, 17
Specific dynamic action, 574
Specific gravity of urine, 557
Sphingomyelin, 720
Sphygmic period, 290
Sphygmograph, Dudgeon's, 201
Spinal cord:
section of, 849

in laboratory animals, 965
in man, 967
hemisection of, 870
sensory pathways in, 868
successive degeneration in, 849
Spinal reflexes, 965
Spinal shock, 924, 965
cause of, 969
in animals, 965
in man, 967
Spirometer, 556

Splanchnic circulation in shock, 305, 306
Splanchnic nerve, 238, 704
Sponges, nervous system of, 828
Spot finding, 861
Stalagmometer, 66

Standard of neutrality, 26

Standard solutions, preparation of, 34

Stannius' ligature, 176

Starvation, 600

acidosis during, 602, 603

cause of death, 604

effect of creatinine excretion, 658

energy output during, 602

excretion of nitrogen, 600

loss of weight, 602

nitrogenous metabolism, 602

purines during, 603 .

secretion of gastric juice during, 511

sensations during, 510

sulphur during, 603

treatment of diabetes, 716
Statistical method, in diet control, 626
Stearie acid, 718
Stilling, "Summer cells" of, 769
Stomach:

arrangement of food in, 489

digestion in, 515

emptying of, 490

effect of pathological conditions on,

494
rate of, 492

gas in, 496

miniature, 468

movements of, 485
effect on food, 488

tonus rhythm of, 506
Stroma of red cell, 92
Stromuhr, 207

Strychnine, action on reciprocal inhibi-
tion, 941

action of, on synapse, '844
Subarachnoid space, 116, 255
Subcostal angle, 338
Subcostal borders, 338
Subdural space, 116
Submicrons, 55
Successive degeneration, 949
Sugar, storage of, 694
Sugar level in blood, 690
Sugar metabolism (see Carbohydrates),

685

relation of pancreas to, 710
Sulphates, ethereal, 535, 665
Sulphates, of urine, 566
Sulphur, excretion of, 648

in starvation, 603
Summation, 934

in conduction, 843

in reflexes, 842
Superior laryngeal nerve, influence on

respiration, 351
Supplemental air, 317
Surface area, and energy output, 575
Surface tension, measurement of, 65
Surgical shock, 303
Survival period, 615
Suspensions, 52
Suspensoids, colloids, 61

990

INDEX

Swallowing, 479

center, 481

of liquid food, 482

nervous control of, 481

sounds produced by, 483

x-ray during, 483
Sympathetic control of heart, 232

afferent, 228
Sympathetic nerve, 458
Sympathetic system, 895
Synapse, 830, 841
Synaptic fatigue in shock, 311
Synaptic resistance, 842
Syntonin, 520
Systolic index, 134
Systolic pressure, 129

measurement of, in man, 129

Tabes dorsalis, 300

Tachycardia, paroxysmal, 293

Tango-receptors, 855

Taurine, 528 •

Taurocholic acid, 528

Temperature :

effect on dissociation curve, 399

effect on metabolism, 586

sensation of, 861

transmission in cord, 868
Tendon jerks, 921
Tension of CO2 in venous blood, 359

of gases in alveolar air, 46, 356, 373
Testicles, 821
Tetanus, 905, 906

in stomach, 507

Tetanus toxin, action on reciprocal inhi-
bition, 941
Tetany, 802

calcium deficiency in, 804

cause of, 804

electrical excitability in, 803

experimental, 800

guanidine metabolism in, 804

symptoms of, 802
Theine, 668
Theobromine, 668
Thirst, 514

Thoracic operculum, 333
Thoracicolumbar outflow, 895
Threshold :

of receptors, 855

of touch, 861
Thrombin, 103
Thrombogen, 107
Thrombokinases, 107
Thromboplastin, 107, 112
Thrombosis, 108
Thrombus formation, 113

Thymic acid, 682
Thymine, 669
Thymus, 824
Thyroid gland, 791

disease of, 795

removal of, 794
Thyroidectomy, 794
Thyroxin, 798
Thymus, 824
Tidal air, 317
Tissot method, 580, 591
Tissue fluid, 116
Tissue juice, 117
Tissues :

amino acids in, 641

influence of, on clotting, 105

oxygen requirements of, 408, 412 .

utilization of glucose by, 708
Titrable acidity and alkalinity, 22
Tonometer, 356, 393
Tone, 905

inhibition of, 925

influence of brain on, 924

of heart, 220

reflex adjustment of, 914
Tonus, 905

plastic, 905

Tonus rhythm, of stomach, 506
Torcular herophili, 259
Touch :

localization, 861

sense, 860
Toxins, 70

Transfusion of blood, 142, 179
Trephining, 263
Treppe, 178, 910, 911
Trichlorlactamide, 668
Trimethylamine, 629, 662
True colloidal solutions, 52
Trypsin, 461, 463, 638

action of, 523
Trypsinogen, 461, 463
Tryptic digestion, products of, 524
Tryptophane, 629, 633, 640, 665

and growth, 614, 615
Tubules, uriniferous, function of, 54J>
Tumors and diet, 616
Turbidity of colloids, 52
Tyndall phenomenon, colloids, 52
Tyrodes solution, 168
Tyrosine, 640, 665, 698, 773

U

Uncompensated acidosis, 39
Unconditioned reflex, 466
Undetermined nitrogen, 629, 647, 662
Undulatory movement of ribs, 334

INDEX

991

Urea, 561, 643, 650

in blood, 645

during disease, 683

excretion of, 561, 649

retention of, in nephritis, 562
Urease, 82, 645
Uric acid, 563, 564, 667, 681
amount of, 556
chemical nature of, 667, 671
endogenous excretion, 680
in disease, 683
metabolism of, 667, 676
of blood, 681

salts of, 564

synthesis of, 677
under drugs, 681
Uric acid diathesis, 667
Uricase, 673
Uricemia, 683
Uricolytic index, 674
Urine :

acids of, 563, 564

amino acid, 564

amount of, 556

aromatic oxyacids of, 564

chlorides of, 565

composition, 560

creatinine of, 563

depression of freezing point of, 557

excretion of, 544

H-ion concentration of, 558

in disease, 567

hippuric acid, 564

homogentisic acid, 565

inorganic constituents of, 565

nitrogenous constituents of, 560

normal organic salts of, 560

phosphates, 566

physical processes involved in produc-
tion of, 14

purine bodies of, 563

rate of excretion, 675

reaction of, 558

skatole, 565

solid constituents of, 560

specific gravity of, 556

sulphates of, 566

total potential acidity of, 559

urea of, 561
Uriniferous tubule, 541
Urobilin, 529
Urobilinogen, 530
Utilization limit, 688

Vagus :

control of heart, 222
impulses, afferent, 227
Vagus center, effect of nicotine on, 231
location of, 227
tonicity of 226

Vagus nerve, influence on respiration,

348

Valine, 640, 641

Valves, cardiac, mechanism of, 154
auriculoventricular, 154
semilunar, 155

Van Slyke method for acidosis, 42, 43
Van Slyke method for amino groups, 636
Vascular reflex, 297
Varicose veins, 215
Vasoconstriction, 236
Vasoconstrictor fibers, 237
methods of detecting, 236
of extremities, 238
of head, 238
of viscera, 238
origin of, 237
Vasodilator fibers, 239

methods for detecting, 236
origin of, 239
Vasomotor center:

afferent impulses, 243, 244
ehiSf center, 240
effect of H-ion of blood on, 242
hormone control of, 242
subsidiary centers, 240
Vasomotor fibers, 236

origin of, 237
Vasotonic impulses, 241
Veins, disappearance of pulse in, 205
Velocity constant, enzymes, 75
Velocity, mean lineal, 206

pulse, 200

Venous blood, tension of CO2 in, 359
Venous inflow, 216
Venous outflow, 235
Venous pulse tracing, 285
Venous sinuses, intracranial, 255
Ventilation :

chemical conditions of air and, 754
physical conditions of air and, 757
physiological principles of, 754
susceptibility to infection and, 759
Ventilation of lungs, 367
Ventricle, curves of pressure in, 146, 148,

151
Ventricles :

conductivity tissue of, 182
fibrillation, 195
spread of beat in, 192, 194
Vignin, 612

Viscera, blood supply of, 254
Visceral bloodflow, 212
Viscosity of blood, 141
Visual area, 880
Visuo-motor areas, 886
Vital activity, 14

992

INDEX

Vital capacity, 317, 329

in disease, 329

Vital theory of urine excretion, 545
Vitamines, 618
Vividiffusion, 641
Vomiting, 483

W

Water content of blood, 87
Water hammer, in blood pressure meas-
urement, 134
Wheatstone bridge, 18
White crescentie line, 231
Wiggers manometer, 147
Willard Gibbs, principle of, 66

Word blindness, 861
Word centers, 860
Word deafness, 861

Xanthine, 667, 671

Xanthine oxidase, 671

Xanthosine, 671

X-rays, in study of stomach, 469

movements of stomach seen by aid of,
485, 489

Zein, inadequacy for growth, 612
Zymogen granules, 454, 455, 464

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