YALE UNIVERSITY
MRS. HEPSA ELY SILLIMAN MEMORIAL
LECTURES
RESPIRATION
SILLIMAN MEMORIAL LECTURES
PUBLISHED BY YALE UNIVERSITY PRESS
ELECTRICITY AND MATTER. By Joseph John Thomson, d.sc, ll.d.,
PH.D., F.R.S., Fellow of Trimty College and. Cavendish Professor of Experi-
mental Physics, Cambridge University. {Fourth -printing.)
THE INTEGRATIVE ACTION OF THE NERVOUS SYSTEM. By Charles
S. Sherrington, d.sc, M.D., HON. ll.d. tor., F.R.S., Holt Professor of Physi-
ology, University of Liverpool. {Sixth printing.)
RADIOACTIVE TRANSFORMATIONS. By Ernest Rutherford, d.sc, ll.d.,
F.R.S., Macdonald Professor of Physics, McGill University. {Second printing.)
EXPERIMENTAL AND THEORETICAL APPLICATIONS OF THERMO-
DYNAMICS TO CHEMISTRY. By Dr. Walter Nernst, Professor and
Director of the histitute of Physical Chemistry in the University of Berlin.
PROBLEMS OF GENETICS. By William Bateson, m.a., f.r.s.. Director of
the John Innes H orticultural Institution, Merton Park, Surrey, England. {Sec-
ond printing.)
STELLAR MOTIONS. With Special Reference to Motions Determined by Means
of the Spectrograph. By William Wallace Campbell, sc.d., ll.d., Director of
the Lick Observatory, University of California. {Second printing.)
THEORIES OF SOLUTIONS. By Svante Arrhenius, ph.d., sc.d., m.d., Di-
rector of the P hysico-C hemical Department of the Nobel Institute, Stockholm,
Sweden. {Third printing.)
IRRITABILITY. A Physiological Analysis of the General Effect of Stimuli in
Living Substances. By Max Verworn, m.d., ph.d.. Professor at Bonn Physio-
logical Institute. {Second printing.)
PROBLEMS OF AMERICAN GEOLOGY. By William North Rice, Frank
D. Adams, Arthur P. Coleman, Charles D. Walcott, Waldemar Lind-
gren, Frederick Leslie Ransome, and William D. Matthew. {Second
printing.)
THE PROBLEM OF VOLCANISM.'^j/ Joseph Paxson Iddings, ph.b., sc.d.
{Second printing.)
ORGANISM AND ENVIRONMENT AS ILLUSTRATED BY THE PHYSI-
OLOGY OF BREATHING. By John Scott Haldane, m.d., ll.d., f.r.s.,
Fellow of New College, Oxford University. {Second printing.)
A CENTURY OF SCIENCE IN AMERICA. With Special Reference to the
American Journal of Science 1818-1918. By Edward Salisbury Dana,
Charles Schuchert, Herbert E. Gregory, Joseph Barrell, George Otis
Smith, Richard Swann Lull, Louis V. Pirsson, William E. Ford, R. B.
SosMAN, Horace L. Wells, Harry W. Foote, Leigh Page, Wesley R. Coe,
and George L. Goodale.
THE EVOLUTION OF MODERN MEDICINE. By the late Sir William
OsLER, BART., M.D., F.R.S.
RESPIRATION. By J. S. Haldane, m.d., ll.d., f.r.s.. Fellow of New College,
Oxford, Hon. Professor, Birmingham University.
w
RESPIRATION
BY
.^ '^
MIX
J?^ S" H ALDAN E
M.D., LL.D., F.R.S.
FELLOW OF NEW COLLEGE, OXFORD
HON. PROFESSOR, BIRMINGHAM UNIVERSITY
':}^
\\
NEW HAVEN
YALE UNIVERSITY PRESS
LONDON : HUMPHREY MILFORD : OXFORD UNIVERSITY PRESS
MDCCCCXXII
COPYRIGHT, 1922
YALE UNIVERSITY PRESS
OP
THE SILLIMAN FOUNDATION
In the year 1883 a legacy of eighty thousand dollars was left to the
President and Fellows of Yale College in the city of New Haven, to be
held in trust, as a gift from her children, in memory of their beloved and
honored mother, Mrs. Hepsa Ely Silliman.
On this foundation Yale College was requested and directed to estab-
lish an annual course of lectures designed to illustrate the presence and
providence, the wisdom and . goodness of God, as manifested in the
natural and moral world. These were to be designated as the Mrs. Hepsa
Ely Silliman Memorial Lectures. It was the belief of the testator that
any orderly presentation of the facts of nature or history contributed to
the end of this foundation more effectively than any attempt to empha-
size the elements of doctrine or of creed ; and he therefore provided that
lectures on dogmatic or polemical theology should be excluded from the
scope of this foundation, and that the subjects should be selected rather
from the domains of natural science and history, giving special promi-
nence to astronomy, chemistry, geology, and anatomy.
It was further directed that each annual course should be made the
basis of a volume to form part of a series constituting a memorial to
Mrs. Silliman. The memorial fund came into the possession of the Cor-
poration of Yale University in the year 1901 ; and the present volume
constitutes the fourteenth of the series of memorial lectures.
PREFACE
When Yale University invited me to deliver the Silliman Lectures
for 191 5 I was asked to deal with the physiology of breathing
and include a general account of the long series of investigations
with which I had been associated on this subject and its practical
applications in clinical medicine and hygiene. Owing to the war I
was unable to give the lectures in 191 5, but in 191 6 delivered four
lectures which dealt only with some of the more general conclu-
sions to which I had been led, and were published early in 191 7
by the Yale University Press under the title ''Organism and
Environment as Illustrated by the Physiology of Breathing."
The war has greatly delayed the appearance of the present
book, which treats the physiology of breathing fully in accordance
with the original plan. I have, however, abandoned the lecture
form, and what I had written four years ago has had to be largely
recast owing to the rapid advance of knowledge. The book is not
a mere compilation, but contains much that has never previously
been published, and is an attempt to give a coherent statement
and interpretation of what is known of the subject at present. I
fear that I may sometimes have unwittingly overlooked observa-
tions by others which would have added completeness to my
account. Yet I hope that what may have been lost in this way
will be made up for by the fact that the book embodies the results
of a continuous series of investigations leading to very definite
and consistent conclusions.
About the middle piJast.ceatury the younger physiologists
broke away from the vitalistic traditions which had been handed
down to them, and set about to investigate living organisms
piece by piece, precisely as they would investigate the working
oTa complex mechanism. This method seemed to them to promise
success, and was popularized by such masters of clear and force-
ful expression as Huxley. It is still the orthodox method of physi-
ology, but the old confidence in it has steadily diminished in
proportion as exact experimental investigation has shown that the
various activities of a living organism cannot be interpreted in
isolation from one another, since organic regulation dominates
them. The keynote of this book is the organic regulation of
breathing and its associated phenomena.
viii RESPIRATION
The mechanistic theory of life is now outworn and must soon
take its place in history as a passing phase in the development of
biology. But physiology will not go back to the vitalism which
was threatening to strangle it, and from which it escaped last
century. The real lesson of the movement of that time will never
be lost.
The book belongs to a transition period, but the transition is
forward and not backward. My treatment of the subject may
possibly be looked on askance in some quarters as reactionary :
for I have been largely influenced by the ideas and work of older
physiologists. If, however, I have gone backward, it is only to
pick up clues which had been temporarily lost; and all of these
clues lead forward — forward to a new physiology which embodies
what was really implicit in the old.
The leaders of the mechanistic movement of last century got
rid of vitalism, but in doing so got rid of. life itself. I have tried
to paint a picture of the body as alive. Though the picture is
imperfect, others will soon paint it more completely. The time
has come for a far more clear realization of what life implies.
The bondage of biology to the physical sciences has lasted more
than half a century. It is now time for biology to take her rightful
place as an exact independent science : to speak her own language,
and not that of other sciences.
The endeavor to represent the facts of physiology as if they
would fit into the general scheme of a mechanistic biology has
led, it seems to me, to the present estrangement between physiology
and medicine. Since the time of Hippocrates the growth. ,Gf.
scientific medicine has in reality been based on the study .of Ihe
manner in which what he called the "nature" ( <^wis ) of the
living body expresses itself in response to changes in environ-
ment, and reasserts itself in face of disturbance and injury. The
underlying assumption is that organic regulation and mai.ntenance
represent something very real, and that only through th.^_stu3y
of It can we recognize and interpret disturbance of .heMtli,_and
eifjectively aid maintenance or restoration of health. I have en-
deavored to return to what seems to me the truly scientific Greek
tradition, and to give it a form which is not only consistent with
modern science and philosophy, but brings physiology and medi-
cine into that close and special relation indicated by the common
etymology of the words "physician" and "physiology."
Most of the investigations specially referred to in the book
have been carried out on man. It W^s only by human experiments
RESPIRATION ix
that the almost incredible delicacy of the regulation of breathing
was discovered; and human experiments have revealed to us in
other ways how rough many of the experiments on animals, or.
oiT^^preparations" from the bodies of animals, have been. Organic
regulation, witF its all-important relations to practical medicine
and surgery, was often entirely overlooked. I hope that the book
may contribute towards establishing human physiology in its
rightful place, which has been usurped too long by experiments
on fragments of frogs and other animals, or on the mere super-
ficial physical and chemical aspects of bodily activity.
I wish to offer my sincere thanks to Yale University for the
honor it has done me in inviting me to give the Silliman Lectures.
Between Oxford and Yale Universities there is a traditional
association, and to me in particular the association stands for
friendship, hospitality, and community of ideas. My only regret
is that in coming to Yale to lecture on the physiology of breathing
I seemed to be doing what an Englishman calls bringing coals
to Newcastle, since I had to refer so frequently to the results
reached at Yale by Professor Yandell Henderson and his pupils.
The book sums up the results of more than twenty years of my
own experimental work, thought, reading, and discussion. To the
old pupils and other friends who have worked and thought with
me, including friends in the mining and engineering professions
and in the Navy and Army, I wish to express my debt. Their
names are often quoted in the text, but I should like to say how
much I have been aided more particularly by Professor Lorrain
Smith, Professor Pembrey, Professor Boycott, Commander Da-
mant, Mr. Mavrogardato, Dr. Priestley, Dr. Douglas, Professor
Meakins, and my son. In connection with the Pike's Peak Scien-
tific Expedition, the results of which occupy such a prominent
place in the book, Dr. Douglas and I had the great advantage
of being associated with Professor Yandell Henderson and another
Yale graduate, Professor Schneider of Colorado Springs. The
book owes much to the talks we had on the Peak in the summer
evenings when our work was over and the lights were twinkling
over the prairie far below from Denver to Pueblo.
Readers will easily see how many gaps remain to be filled up.
To fill these gaps the observations and experiments required are
not yet available. The words of Hippocrates are as true now as
when he wrote them more than two thousand years ago:6/8tosj8pa-
Oxford, May 1920.
X RESPIRATION
Owing to the aftermath of the war there has been considerable
delay in printing the book, and meanwhile a good deal of new
work has appeared on the subjects of certain chapters. Where
this could not be incorporated without serious recasting in the
proofs it is referred to in addenda to the chapters in question. j
May 1921. I
CONTENTS
PREFACE vii
CHAPTER I. Historical Introduction . . . i
Early theories of respiration, i. — Boyle and Mayow, i. — Black and Priestley,
2. — Lavoisier's interpretation of respiration and the source of animal heat, 2.
— Mayer and the source of vital energy, 3. — Discoveries as to the composition of
animal food and excreta, 3. — Discoveries as to the blood gases and the part they
play, 4. — Theories and. discoveries as to physiological regulation of vital oxida-
tion, 4. — Work of Liebig, Voit, Rubner, Pfliiger, and others, 5. — Discoveries
as to physiological regulation of body temperature, 6. — The "energy require-
ments" of the living body, 6. — The problem of regulation of breathing, 8. —
The respiratory center. Work of Legallois and others, 8. — The vagus nerves and
breathing. Work of Hering and others, 9. — Chemical excitation of breathing.
Work of Rosenthal and others, 10. — Theories of "vagus apnoea" and "chemical
apnoea," 11. — Conclusions as to various chemical and other excitants of breath-
ing, 13. — Criticism of these conclusions and starting point of the investigations
described in succeeding chapters, 14.
CHAPTER II. Carbon Dioxide and Regulation
OF Breathing 15 7
Effects of varying proportions of CO2 and oxygen on breathing in man, 15. —
Importance of the alveolar air, 16. — Method of sampling the alveolar air, 17.
'^ — Relative constancy of the alveolar CO2 percentage, 19. — Effects of varying
oxygen percentage of the alveolar CO2 percentage, 20. — Effects of varying CO2
percentage in the inspired air on the alveolar CO2 percentage, 21. — Extreme
sensitiveness of the respiratory center to variation in alveolar CO2 percentage,
22. — Apnoea after forced breathing is due simply to lowering of alveolar CO2
percentage, 24. — Constancy of mean alveolar CO2 pressure in spite of great
variations in rate and depth of breathing, 27. — Rise of alveolar CO2 percentage
during muscular exertion, 29. — Effects of varying barometric pressure on alve-
olar CO2 percentage, 30. — Constancy of alveolar CO2 pressure with varying
barometric pressure, 31. — Individual differences in alveolar CO2 pressure, 32.
— The anatomy of bronchioles and alveoli, 33. — "Alveolar air" is air of
Miller's ''pir-rsac" system, /3 5, — The "effective" or "virtual" dead space in
breathing/^^j^ — Great variations in effective dead space with varying depth of
breathing, 37. — "Alveolar" and true respiratory quotients, 38. — Errors due to
ignorance of the variations in the effective dead space, 39. — Gas pressures of
alveolar air and arterial blood, 41. — Question as to varying composition of
air in different alveoli, 42. — General conclusion from Chapter I, 42.
CHAPTER III. The Nervous Control of Breath-
ing (43
Voluntary and reflex disturbances of breathing, 43. — Experiments on man
xii RESPIRATION
showing the non-existence of "vagus apnoea," 47. — Afferent vagus excitations
coordinate the phases of breathing, 48. — The depth and vigor of breathing de-
pend on the chemical stimuli to the respiratory center,/^?g:=^Effects of resistance
on the rhythm of breathing, 50. — Artificial respiration-atid the vagus coordina-
tion of breathing, ,^0 .-^Normal breathing and afferent nervous control, 53. —
Evidence that the activity of the respiratory center depends on locally acting
chemical stimuli in the medulla oblongata, 53. — Physiological significance of
this fact, 54. — Fatigue of the respiratory center, 56. — The breathing in "sol-
dier's heart" and allied conditions, 52£;7'-"Neurasthenia" and fatigue, 56. —
Variations in individual susceptibility to fatigue of breathing, 57.
CHAPTER IV. The Blood as a Carrier of Oxygen. 59
General chemical properties of haemoglobin and oxyhaemoglobin, 59. — Meth-
aemoglobin and its properties, 59. — Action of ferricyanide in liberating oxygen
or CO from combination with haemoglobin, 60. — Oxyhaemoglobin and CO
haemoglobin are molecular compounds, 61. — The ferricyanide method of de-
termining the oxygen capacity of haemoglobin, 61. — The oxygen capacity of
haemoglobin is exactly proportional to its coloring power, 61. — The Gowers-
Haldane haemoglobinometer, 62. — Normal variations in haemoglobin percentage
of blood, 63. — Haemochromogen and its modifications, 64. — Relation between
oxygen capacity and iron of haemoglobin, 64. — Relation of haemochromogen
to haemoglobin, 66. — Ferricyanide method for ordinary blood-gas determina-
tions, 66. — Amount of available oxygen, in human arterial blood, 67. — Funda-
mental importance of the partial pressure of oxygen in the blood, 67. — "Partial
pressures," "vapor pressures," "diffusion pressures," and "concentrations" of
substances in the living body, 67. — Investigations of the laws of dissociation
of oxyhaemoglobin in blood, 68. — Work of Paul Bert, Hiifner, Loewy and
Zuntz, Bohr, Barcroft, 70. — Effects of salts, CO2, and acids or alkalies, 72. —
Physiological importance of the shape of the oxyhaemoglobin dissociation curve,
72. — Properties and dissociation curves of CO haemoglobin, 72. — Nature of
alterations produced by CO2 on the dissociation curves of CO haemoglobin and
oxyhaemoglobin, 76. — Relative affinities of oxygen and CO for haemoglobin,
74- — Evidence of differences in the chemical structure of haemoglobin in differ-
ent individuals and species, 77. — Use of haemoglobin for estimating partial
pressures of CO or oxygen, 79. — Explanation of the peculiarities of the dissocia-
tion curve of oxyhaemoglobin in blood, 80. — Equations for the dissociation
curves, 82.
CHAPTER V. The Blood as a Carrier of Carbon
Dioxide 84
Amount of CO2 in normal human and dog's arterial blood, 84. — Amounts in
simple solution and chemical combination, 85. — The CO2 is combined with
alkali as bicarbonate, 84. — Why the bicarbonate dissociates appreciably with a
small fall in the partial pressure of CO2 in the blood, 85. — Haemoglobin and
other proteins act as acids in the living body, and do not combine with CO2,
though they play a most essential part in its carriage, 88. — The dissociation
curve for CO2 of human blood, 89. — Constancy of this curve for the same indi-
vidual, and relative constancy in different normal individuals, 89. — Evidence
that oxygen has a chemical action in liberating COj in the lungs, 92. — The de-
RESPIRATION xiii
oxygenation of the blood in the tissues helps the blood to combine with CO2 and
thus partly prevents the pressure of CO2 from rising, 90. — CO2 may be given off
in the lungs although the CO2 pressure is lower in the venous blood than in the
alveolar air, 91 — Approximate mathematical treatment of the dissociation curve
for CO2, 92. — Effect of the CO2 in blood on the dissociation of oxyhaemoglobin
in the systemic blood, 94. — The physiological buffers which prevent abrupt rise
or fall of CO2 pressure in the respiratory center, 96. — Effects on the alveolar
CO2 pressure of holding the breath or forced breathing, 96. — Abruptness of
rises or falls of oxygen pressure in the respiratory center, 100. — This abrupt-
ness is the cause of periodic breathing when the alveolar oxygen pressure is low,
103. — Artificial production of periodic breathing in healthy persons, 103. —
Why shortage of oxygen and consequent periodic breathing do not occur nor-
mally, 104. — Addendum. Discussion of some recent theories of the carriage of
CO2 by blood, 105. — Interchange of acid between plasma and corpuscles, 106.
CHAPTER VI. The Effects of Want of Oxygen. io8
Immediate dependence of the body for its oxygen supply on air, 108. — Anox-
aemia produced by lowered pressure of oxygen in the air, 10 9. ^Effects, on the
breathing, 109. — These effects largely transitory, 109. — Lowering of the thresh-
old of alveolar CO2 pressure, but alveolar CO2 pressure still regulates the
breathing, no. — Variability of the effects in different individuals, ill". —
Death from anoxaemia caused by excessive removal of CO2 from the blood, 112.
— Excess of CO2 in the air counteracts the effects of deficiency of oxygen, ii2.>
— Mere increase of breathjng does not diminish the anoxaemia, though it dirnih-
ishes the cyanosi^7_JJLA)^--Yrhe peculiar symptomsproducedby forced breathing
are apparently due mainly to anoxaemia, 115. — Subsidiary effects of CO2 in re-
lieving anoxaen3,ia, 117 . — Periodic breathing at high altitudes is caused by
anoxaemia^^Li?.- — Effects of anoxaemia on the frequency of breathing, 118. —
Effects in causing fatigue of the breathing, 121. — Effects of anoxaemia on the
circulation, 121. — Increase in pulse rate is largely transitory, 12 3, ---Cyanosis
and anoxaemia not the same thing, 125^— ::^Effects on the nervous system, 125. —
Insidious character of these effects, ^5.— -^Effects on muscular power, senses,
memory, and powers of judgment, i26T^^^Personal experiences, 128. — Moun-
tain sickness and conditions of its production, 128. — Nervous after symptoms
following severe anoxaemia, 129. — After effects on heart, J29. — After effects
on respiratory center, 130. — Adaptation to want of oxygen, 130.
CHAPTER VII. The Causes OF Anoxaemia. . .132
Defective saturation of arterial haemoglobin, 132. — One cause of this is
defective distributioji_.pf air in the lungs, 133. — Experimental proof and ex-
planation of this, 133.— rEffgcts of holding the breath, and explanation of the
anoxaemia produceoTM^ i . — Cause of difference between clinical Cheyne- Stokes
breathing and periodic breathing produced artificially in healthy persons, 141.
— Significance of rapid breathing in cases of illness, 142. — Danger of sudden
attacks of restricted and rapid breathing, ijL^^^j^auses of anoxaemia in em-
physema, bronchitis, and asthma, 145. — Orthopnoea and its causes, 146. — A
second cause of arterial anoxaemia is defective pressure of oxygen in the in-
spired air, 146. — Immediate effects and after effects, 147. — The percentage
saturation of the arterial haemoglobin is lower than corresponds to the oxygen
xiv RESPIRATION
pressure of the mixed alveolar air, 148. — With the same alveolar oxygen pres-
sure there is less anoxaemia at low atmospheric pressures than at normal atmos-
pheric pressure, 148. — Anoxaemia due to hindered diffusion of oxygen into the
blood, 149. — Poisoning by lung-irritant gases, 150. — Arterial anoxaemia in
pneumonia, 150. — Observations of Stadie, Harrop, and Meakins, 151. — The
clinical administration of oxygen, 152. — Description of apparatus for the pur-
pose, is^^^Anoxaemia during muscular exertion, 156. — Exjyeriments of Briggs
on oxygen inhalation during muscular exertion, 157. — Anoxaemia and
velocity of chemical reaction in the formation of oxyhaemoglobin, 158. —
Anoxaemia due to defective oxygen-carrying power of the blood, 158. — Evidence
that the symptoms of CO poisoning are due to anoxaemia, 160. — CO is not
oxidized in the body, but passes in and out by the lungs, 160. — Popular errors
as to the effects of CO poisoning and anoxaemia generally, 160. — Relation be-
tween percentage of CO in air and percentage saturation of the blood with CO,
160. — Relation between percentage saturation of the blood and symptoms, 161.
— Causes of certain differences between the symptoms of CO poisoning and
those of anoxaemia produced in other ways, 162. — Alteration of the dissociation
curve of oxyhaemoglobin in CO poisoning, 165. — Acclimatization to CO poison-
ing, 166. — Occurence of NO haemoglobin in the body, 166. — Methaemoglobin-
forming poisons, 166. — Evidence that with these poisons death is due to anox-
aemia, 167. — Recovery from methaemoglobin-forming poisons, 167. — Hae-
molytic poisons, 168. — Anaemia and anoxaemia, 168. — Reasons why no anox-
aemia is present during rest in ordinary anaemia, 169. — Anoxaemia due to de-
fective circulation, 169. — Gum-saline injections in defective filling of the vessels
•with blood, 170.
CHAPTER VIII. Blood Reaction and Breathing. 171
Ordinary physiological indications of maintenance of a normal blood reaction,
171. — Walter's experiments on acid poisoning and the defenses against it, 171.
— Diabetic coma and acid poisoning, 173. — "Titration alkalinity" and alkalinity
of the blood, 173. — The "buffer substances" in the living body, 174. — Modern
conceptions of alkalinity and acidity, 175. — Osmotic pressure, molecular con-
centration, and molecular diffusion pressure, 176. — Ionization of molecules, 177.
— Ionization and reaction, 177. — Electrometric measurement of reaction, 179. —
Theories of acidosis and anoxaemia, 179. — Hasselbalch's electrometric de-
terminations of relation of CO2 pressure to reaction in blood, 182. — Experiments
showing that variation of alveolar CO2 pressure in the living body compensates
for variations in blood reaction which would otherwise occur, 183. — Barcroft's
experiments on the Peak of Teneriffe, 183. — Quantitative relation between varia-
tions of breathing and of blood reaction, 184. — Extreme delicacy of regulation
of blood reaction, 185. — Very small difference between the reactions of arterial
and venous blood, 185. — Difference in reaction between oxygenated and fully
reduced normal blood, 186. — Error in electrometric method, 188. — Summary of
evidence as to the means by which blood reaction is regulated, 188. — Dis-
turbance of blood reaction by anoxaemia, 189. — Physiological evidence that the
\/blood becomes more alkaline, 189, — Gradual, but incomplete, compensation for
this by the kidneys and liver, 192. — This compensation mistaken for an
"acidosis," 192. — Relief of the anoxaemia by the compensation, 193. — Com-
pensatory blood changes brought about by exposure to excess of CO2, or by ex-
^ cessive removal by CO* from the body, 193. — The amount of "alkaline reserve"
in the blood is no certain index of "acidosis" or "alkalosis," 194. — Experiments
RESPIRATION xv
on the urine excreted during forced breathing, 195. — True acidosis caused by
excessive muscular exertion, 196. — Disturbance^ of blood reaction in nephritis,
196. — Ammonium chloride acidosis in man, ig^ — Remarks on indirect methods
used for measuring changes of reaction in the blood, 199. — Method depending
on the dissociation curve of oxyhaemoglobin, 199. — Method depending on ratio
of combined CO2 to free CO2 in blood, 200. — Need for more delicate methods
than we possess at present, 202. — Question as to the constancy of blood reaction
during normal life, 202. — Action of drugs on the regulation of blood reaction,
204. — Reasons why the alveolar CO2 pressure is not perfectly steady during
rest, 204. — Effects of meats, 204. — Effects of starvation and carbohydrate-free
diets, 205. — The regulation of breathing in man during rest is practically
speaking regulation of blood reaction, 205. — Addendum. Recent literature on
acidosis and alkalosis, 205. — Definition of acidosis and alkalosis, 206. — Ex-
treme delicacy and physiological importance of regulation of reaction in the
tissues, 207.
CHAPTER IX. Gas Secretion in the Lungs. . . 208
Question as to active secretion of gas by the lung epithelium, 208. — Oxygen
secretion by the swim bladder epithelium, 208. — Function of the swim bladder,
208. — Biot's discovery of oxygen secretion, 209. — Experiments of Moreau, Bohr,
and Dreser, 210. — Jager's discovery of the "oval" in the swim bladder, 211. —
Histology of the swim bladder wall and "red body," 214. — Probable function of
the "red body," 214. — Gas secretion in Arcella. Experiments of Bles, 216. —
Implications of secretion generally, 217. — Ideas of Johannes Miiller on secre-
tion, 218. — Apparent gas secretion in Corethra larvae, 220. — Ludwig and
Pfliiger on gas secretion by the lungs, 220. — Experiments of Bohr and Fredericq,
221, — Method and experiments of Krogh, 222. — Carbon monoxide method of
measuring arterial oxygen pressure, 224. — Fallacies in earlier measurements,
225. — New experiments on animals. Conclusions, 226. — New experiments on
men. Method, 229. — Result that secretion is completely absent during rest
under normal conditions, but present under conditions producing want of oxy-
gen in the tissues, 233. — Experiments after acclimatization on Pike's Peak, 236.
— Evidence of constant active secretion, 237. — Indirect evidence of oxygen
secretion, 238. — Experiments of Briggs, 240. — Experiments in a respiration
chamber at normal atmospheric pressure, 241. — Acclimatization experiments in
a steel chamber, 242. — Cause of difference between results by carbon monoxide
and aerotonometer methods, 243. — Reason why the percentage of oxygen satura-
tion of the arterial blood is considerably less at high altitudes before acclimatiza-
tion than corresponds to the oxygen pressure of the alveolar air, 244. — Bohr's
method of measuring the rate of diffusion of gases from the alveolar air into
the blood, 245. — Experiments of A. and M. Krogh by this method, 246. —
Paralysis of oxygen secretion under pathological conditions, 247. — Direct evi-
dence that during hard muscular work at normal atmospheric pressure diffusion
of oxygen is quite insufficient to saturate the arterial blood with oxygen, 247. —
Question of active excretion of CO2 by the lungs. Krogh's experiments, 247. —
Reasons for suspecting that active secretion of CO2 may occur under certain
conditions, 248. — Comparison of oxygen secretion by the lungs with glomerular
secretion by the kidneys, 250. — Reply to some recent criticisms of the evidence
for oxygen secretions, 251. — Addendum. Recent experiments of Barcroft and his
co-workers, 253.
xvi RESPIRATION
CHAPTER X. Blood Circulation and Breathing. 257
Intimacy of connection between circulation and breathing, 257. — The most
immediate need for circulation is the need for oxygen and for removal of CO2,
257. — The local circulation rates must be correlated in the main with these
needs, 258. — Special value of experiments on man, 259. — Experiments of Loewy
and von Schrotter with lung catheter, 260. — Experiments of Krogh and Lind-
hard by the nitrous oxide method, 2^2. — Yandell Henderson's experiments on
dogs, 263. — Experiments on "heart-lung preparations," 264. — New method in
which the whole of the lungs are used as an aerotonometer, 254. — Results in
man during rest and work, 265. — The circulation rate is rapid during rest, and
does not increase in direct proportion to work, 268. — The oxygen consumption
per heartbeat and its significance, 269. — The venous blood from different parts
of the body, 270. — Significance of this as regards the mixed venous blood under
different conditions, 270. — General conclusion as regards local regulation of
blood flow, 271. — Yandell Henderson's experiments on local circulation and
CO2 pressure, 272. — Evidence that excessive artificial respiration causes slowing
of the circulation and great local anoxaemia, 272. — With moderate increase of
CO2 percentage in the inspired air the circulation does not increase with the
breathing, 273. — But with great increase of CO2 percentage the circulation in-
creases, 274. — Increase in oxygen pressure slows the circulation, 274. — With
V great deficiency of oxygen there is increase in the circulation, (^^^>-^Effects of
—y forced breathing and muscular exertion on venous blood pressure, 275. — Gen-
eral conclusion as to regulation of local and general circulation, 276. — Com-
parison of regulation of circulation with regulation of breathing, 277. — Part
played by the heart in the circulation, 278. — Regulation of heart's action, 278. —
Coordination of contraction of muscular fibres of auricles and ventricles, 278. —
Start, spread, and frequency of each contraction, 279. — Regulation of filling of
ventricles, 279. — Nervous regulation of frequency of heartbeat, 279. — Regula-
tion of blood distribution, 281. — Contractility of arteries, veins, and capillaries,
281. — Vasomotor regulation of arterial and venous blood pressure, 283. —
Abnormal defects in circulatory regulation, 284. — Valvular defects and breath-
ing, 286. — Nervous defects and breathing, 286. — Loss of blood and its treat-
ment by gum-saline injections, 287. — The condition of "shock," 288. — Yandell
Henderson's investigations, 288. — Shock from absorption of poisonous disin-
tegration products, 289. — Regulation of blood volume, haemoglobin, and rate
of pulse and respiration in animals of different sizes, and after loss of blood or
transfusion, 290. — Evidence that the haemoglobin percentage of the blood de-
pends on the oxygen pressure in tissue capillaries, 293. — Chlorotic "anaemia"
and breathing, 297. — Addendum Further experiments on the circulation in
man, 298.
CHAPTER XI. Air of Abnormal Composition. 300
Outside air of country and towns: effects of impurities, 300. — Air of occupied
rooms. Common impurities and their effects, 302. — Effects of temperature,
moisture, and movement of air, 303. — General standard of air purity, 305. —
Critical wet-bulb temperature, 305. — The katathermometer, 306. — Escape of
lighting gas and conditions determining their danger, 306. — Importance of pro-
portion of CO in lighting gas, 310. — Air of mines. Abnormal constituents
present, 3 1 1 . — Black damp : composition, sources, and properties, 3 1 1 . — Fire
damp: composition, sources, and properties, 313. — Afterdamp from explosions
RESPIRATION xvii
causes death by CO poisoning, 315. — Causes and prevention of colliery ex-
plosions, 316. — Composition of pure afterdamp and practical test for CO, 316.
— Self-contained breathing apparatus for miners, 318. — White damp and spon-
taneous heating of coal, 319. — Smoke from fires and blasting: nitrous fumes,
319. — Treatment of CO poisoning, 320. — Wet-bulb temperature in mines, 321.
— Effects of dust inhalation in mines, 322. — Varying effects of different kinds of
dust. Miner's phthisis, 322. — Physiology of dust excretion from the lungs, 323.
— Air of wells. Barometric pressure and dangers of well sinkers, 325. — Oxida-
tion processes in underground strata, 326. — Air of railway tunnels, 326. — Air
of sewers. Accidental impurities and their dangers, z^T- — Air of ships, 329. —
Lung-irritant gas poisoning in warfare, and treatment, 329.
CHAPTER XII. Effects of High Atmospheric
Pressures. 334
Paul Bert's work on the physiological action of barometric pressure, 334. —
The diver's equipment and the method of using it, 335. — The diving bell and the
caisson, 336, — Tunneling in compressed air, 337. — Effects of air pressure on the
ears and voice, 338. — Effects due to pressure of CO2 in diving, and their
avoidance, 339. — Compressed air illness or "caisson disease," 340. — Investiga-
tions of Paul Bert and others, 341. — Medical recompression chambers, 343. —
Theory of stage decompression and experiments on the subject, 345. — Tables for
guidance of divers, 350. — Treatment of compressed-air illness, 351. — Diving
operations at a great depth off Honolulu, 351 . — Management of air locks in
tunnels, 353. — Paul Bert's experiments on effects of increased oxygen pres-
sure, 355. — Effects of oxygen in producing pneumonia, 356.
CHAPTER XIII. Effects of Low Atmospheric
Pressures. 358
Occurrence of low atmospheric pressures at high altitudes, "Mountain sickness,"
358. — Summary of Paul Bert's fundamental experiments on the pressure effects
of gases, 358. — His experiment on man in a steel chamber, 360. — Reason why
a given lowering of alveolar oxygen pressure has less physiological effect at a
low atmospheric pressure than at ordinary atmospheric pressure, 362. — Effect
of CO2 pressure in diminishing the anoxaemia of a low atmospheric pressure,
362. — Mosso's "acapnia" theory, 363. — Acclimatization to low atmospheric
pressures, 364. — Effects of high altitudes in increasing the haemoglobin per-
centage of the blood, 364. — Effect of increased atmospheric pressure in dimin-
ishing the haemoglobin percentage, 365. — Beneficial effect of increased haemo-
globin in anoxaemia, 365. — Increased breathing in acclimatized persons, 366.
— Physiological effect of a mere increase of breathing, 367. — The acclimatiza-
tion change is a compensation of alkalosis, 369. — Alveolar CO2 pressure in
persons acclimatized at various altitudes, 370. — Conclusions from the Duke of
Abruzzi's Himalayan Expedition, 372. — Active secretion of oxygen in the lungs
after acclimatization, zTZ- — Relation of physical training to power of oxygen
secretion, 373. — History of high ascents in balloons, 375. — High ascent by
Glaisher and Coxwell in 1862, 375. — Fatal ascent of the Zenith in 1875, 376.
— High ascent with use of oxygen in 1901, 378. — Experiments of von Schrotter,
379-— -Recent high American aeroplane ascent, 379. — Limits of height attainable
with use of ordinary oxygen apparatus, 379. — Apparatus required for indefinitely
great heights, 380.
xviii RESPIRATION
CHAPTER XIV. General Conclusions. . . . 382
The breathing and circulation are so regulated as to keep the diffusion pres-
sures of oxygen, and of hydrogen and hydroxyl ions, in the tissues normal, 382.
— Breathing and circulation are responses to tissue activity, and do not pri-
marily determine it, 383. — Claude Bernard and the regulation of internal en-
vironment, 383. — Diffusion pressures and Bernard's "conditions of life,"383. —
Diffusion pressure of water on the same footing as that of other blood constitu-
ents, 384. — The blood constituents are in continuous active relation with the
living tissues, 385. — Comparison of living tissue elements with dissociable
chemical molecules, 386. — Conception of the living body as the seat of a system
of mutually dependent reversible reactions, 386. — Defects of the mechanistic
and "hormone" theories of physiological inter-connection, 387. — The dividing
line between biology and the physical sciences, 388. — The fundamental con-
ception of biology, and the real work of the biological sciences, 389. — This
work illustrated by the investigations detailed in previous chapters, 389. —
Real nature of organic identity, 390. — The existence of active maintenance of
organic identity is the foundation of medicine and surgery, as well as of physiolo-
gy and morphology, 391. — Examination of the argument that the physical con-
ception of Nature is truer and more scientific than the biological, 392. — The
previous question which is fatal to the physical conception, 394. — Physical
reality a superficial sensuous appearance, 394. — In describing biological phe-
nomena and putting her questions to Nature, biology must use her own working
hypothesis and not those of the physical sciences, 394. — Nature as seen by the
biologist, 396. — Supposed evolution from "inorganic" conditions, 396. — Indi-
vidual life and life in association, 396. — It is impossible to describe or define
conscious activity in either physical or biological terms, 397. — Neither the
physical nor biological interpretation of Nature is, in the last resort, more than
a practical makeshift, 398. — The rightful practical sphere of physiology does not
include distinctively conscious activity, 399.
Appendix 400
A. Determination of oxygen capacity of blood haemoglobin by ferricyanide, 400.
— B. Determination of oxygen capacity of blood haemoglobin by haemoglobin-
ometer, 404. — C. Determination of oxygen and carbon dioxide in blood by ferri-
cyanide and acid, 407. — D. Colorimetric determination of percentage saturation
of haemoglobin with CO, 418. — E. Determination of blood volume in man
during life by CO, 424.
CHAPTER I
Historical Introduction.
In the history of physiological discovery the growth of knowledge
as tojhe. physiology of breathiag was comparatively late. Before
the middle of the seventeenth century hardly anything was known
about breathing except its muscular mechanism and the facts
that if the breathing of a man or higher animal is interrupted
for more than a very short time death ensues, and that the breath-
ing is increased by exertion and by some diseases. The discovery
by Harvey of the circulation threw no positive light on the physi-
ology of breathing, and it ^was still generally believed that, the^
main function of respiration is to cool the blood. Progress was
impossible without corresponding progress in chemistry.
" The first beginnings of a better knowledge date from the work
at Oxford of Robert Boylei and Mayow^ a young doctor. Boyle
showed with the air pump that air is necessary to life, and Mayow
Investigated and compared together the influences of niter in the
combustion of gunpowder, and of air in respiration and ordinary
combustion in air. He drew the conclusion that in all of these
processes a "nitro-aerial spirit" combines with ''sulphur" (com-
bustible matter). As regards respiration he concluded that the
nitro-aerial spirit Is present in limited proportion in air, and is
absorbed from the air in the lungs by the blood, carried by the
circulatioajto the brain, where it is separated off in the ventricles,
and thence passes down the supposed nerve- tubules to the-muscles^
where it unites with "sulphur" and produces muscular contraction
by the resulting explosions. He explained the increased breathing
which accompanies muscular exertion as a necessary accompani-
ment of the increased consumption of the nitro-aerial spirit.
It will thus be seen that he had practically discovered oxygen^,
in so far as the rudimentary chemical ideas which he had formed
permitted the discovery. He had also formed a sound physiological
conception of the relation between muscular wpiTc arid increasS_.
breathing. Mayow's conception of oxygen passing down the
^ Boyle, New exferiments fhysico-mechamcal, touching the Spring of the Air,
Oxford, 1666. Particularly Experiments XL and XLI, "with the accompanying
"Digression containing some Doubts touching Respiration."
''Mayow, Tractatus Quinque Medico-physici, Oxford, 1673. In particular
Tractatus II, De Respiratione (2d Edition).
2 RESPIRATION
nerves was of course only a modification of the idea then current,
and elaborated by Descartes among others, that muscular-con-
traction depends upon the ''animal spirits" passing down thp
supposed nerve tubules from the brain. This conception was ap-
parently confirmed by the effects of cutting or ligaturing nerves ;
and Lo.wex>^ another Oxford physician^ performed the striking
experiment of completely disturbing the action of the heart by a
ligatur£_on the vagus nerve. He had stumbled upon inhibition
and misinterpreted it in favor of Mayow's theory.
About the same time another significant observation was made
by Hooke,* the Secretary of the Royal Society. He fqund^jthat
when the"chest of an animal was opened so that theJ,ujigs_£Qlc
lapsed, it could be revived and kept alive by artificial respiration^
and, if holes were pricked in the lungs so that air could pass
through them, the animal could still be kept alive if a stream of
air was continuously blown through the lungs, although they^did
not move.
The foundations thus seemed to be laid of our present knowl-
edge of the physiology of breathing; but unfortunately the sig-
nificance of the discoveries made at Oxford was not appreciated,
and indeed the study of physiology and other branches of natural
science there was practically allowed to die out for the succeeding
two hundred years.
The next important step in connection with respiration was
the discovery, about the middle of the eighteenth century, by
Joseph Black of Edinburgh, that ''fixedLair** X^arbon dioxide)
which he had found to be liberated by acids from mild alkalies
(carbonates) is given off by the lungs in respiration. Briestley
discovered soon afterward that what, in accordance with Stahl's
phlogiston theory, he called "dephlogisticated air" (oxygen) dis-
apj)ear£j)oth in ordiimxy, combustiqn^and in animal respixaiion,
while it is produced by >green plants in sunlight. Lavoisier then
followed up Black's and Priestley's work by showing that in"
combustion what he for the first time called oxygen combines"
with carbon and other substances, and that carbon dioxide Is"
produced by the combination of carbon and oxygen, while wateF
is produced by. the combinatioji_gfjixdrogea^^^a^^ He and"
Laplace^ also showed that the carbon dioxide produced by an
animal is nearly equivalent to the oxygen consumed, and that
'Lower, Tractatus de Corde, p. 86, 1669.
*Hooke, PAH. Trans., II, p. 539, 1667. Hooke had been assistant to Willis
and Boyle at Oxford.
Lavoisier and Laplace, MSmoires de V Academic des Sciences, p. 337, 1780.
RESPIRATION 3
the amount of heat formed by an animal is nearly equivalent to
that formed in combustion of carbon when an equal quantity of
oxygen is consumed in respiration and combustion. He thus made
it clear that in the living body, just as in combustion, oxygen
combines with carbon and other substances, producing carbon
dioxide and other oxidation products : also that this combination
is the source of animal heat.
He found in the course of experiments on man that during_^
muscular work the consumption of oxygen and output of carbon
dioxide is increased. Curiously enough, he expresses regret that
this should be so, as the laboring classes, who have least money
for buying food, consume more food than those wiio, are better,
off.^ The essential connection between physiological work and
consumption of oxygen was still hidden from him, although, as
already~"seen, Mayow had fairly correct ideas on this subject.
It was not until 1845 that Mayer,''' a German country doctor,
pointed out in connection with the general formulation of the
doctrine of conservation of energy, that in living animals, as in
steam engines, ordinary kine;tic energy as well as. heat has its.
source in the potential energy liberated in the process of oxida-
tion. Oxidation is thus the ultimate source of the energy of animal
movements. Every exact experiment made since then on this >
subject has confirmed Mayer's conclusion, and the increased
consumption of oxygen during muscular work became as intelli-
gible as it was on Mayow's crude theory.
The discoveries with regard to the chemistry of respiration
raised the further question as to what the exact nature of the
combustible material is, and where the combination of oxygen
with combustible matter occurs. As regards the first question it
was evident that since on an average the composition of the adult
living body remains constant, and the excreta, as compared with
the food taken, contain very little combustible material, the
material oxidized must correspond to the oxidizable matter of
the food. This material was classified by Prout as belonging almost
entirely to one or other of three groups of substances, known now
under the names of proteins, carbohydrates, and fats. Of these
the former alone contains nitrogen, which is excreted in the urine
in the form, mainly, of urea when the protein is oxidized. Only
water and carbon dioxide are formed in the oxidation of carbo-
' Lavoisier and Sequin, Mem. lie I' Acad., p. 185, 1789.
Mayer, Die organisc/ie Bewegung in ihrem Zusammenhange mit dem Stoff-
•wechsel, Heilbronn, 1845.
4 RESPIRATION
hydrates or fats, and by the ratios and amounts in which nitrogen
compounds and carbon dioxide are excreted and oxygen consumed
we can calculate how much protein, carbohydrate, and fat is
being consumed in the body.
As regards the second question there was for long much doubt.
It was, however, definitely shown by Magnus^ in 1845 that much
gas is liberated from blood on exposing it to a vacuuin, and that
less oxygen and morje. carbon dioxide are given off from venous
than from arterial ^blood. The mercurial blood gas pump was
"^hie'n gradually perfected, mainly by Lothar Meyer, Ludwig, and
Pfliiger; and it was gradually established that the oxygen which
disappears in the lungs is taken up by the blood almost entirely
in the form of a loose chemical compound with haemoglobin, the
colored albuminous substance In the red corpuscles. This corripbund
yields up part of its oxygen as the blood passes round the systemic
circulation, and returns to the lungs for a fresh charge, the charg-
ing being due to the higher partial pressure of oxygen in the
lungs, while the partial discharging in the systemic circulation
jis due to the lower partial pressure there in consequence of con-
Jsumption of oxygen. The discharging is accompanied by a change
of color from scarlet to dark purple. Similarly carbon dioxide is
taken up mainly in the form of a loose chemical combination with
alkali, and discharged in the lungs as a consequence of the lower
partial pressure of the gas in the lungs. For a considerable time
there was much doubt as to how far the actual oxidation occurs in
the blood or in the tissue elements; but the investigations of
Pfliiger^ about 1872 showed clearly that practically all the ox;JLda-
tion occurs in the tissues.
So far I have discussed from an abstract physical and chemical
standpoint the main outlines of discovery relating to respiration.
It is now necessary to consider these discoveries more closely, and
from a physiological standpoint. For a long time the brilliance
of Lavoisier's discovery as to the relation between respiration and
animal heat carried physiologists to some extent off their balance,
as it came to be believed that heat production is a more or less
blind mechanical process under no direct organic control, and
presumably dependent simply upon the supply of oxygen and
oxidizable material. Thus Liebig, who was not only a great
chemist but also a great chemical physiologist, concluded that
every increase in the food consumed or the amount of oxygen
• MagnUs, Annalen der Physik, XL, 1838, and LXVI, 1845.
"Pfliiger, Pfiuger's Archiv, VI, p. 43, 1872.
RESPIRATION 5
introduced into the lungs must increase the rate of oxidation and
heat production. ^^ This conclusion seemed to be confirmed when
he introduced his well-known method for the determination of
urea in urine and it was found that every increase in the amount
of nitrogenous food eaten was followed by a corresponding in-
crease in the amount of urea excreted, although during complete
starvation the excretion of urea was not diminished below a certain
minimum. He inferred that it is only the ''vital force" which pro-
tects the body against indefinite oxidation, and that when more
food is introduced than is really required this protection is not
extended, so that the food material falls a prey to oxygen. In
assuming this influence of the 'Vital force" he was only applying
to the phenomena of physiological oxidation the ideas held by
the majority of contemporary physiologists.
When, however, the phenomena of physiological oxidation
came'to be studied more closely by Bidder and Schmidt, Voit, and
other physiotogists, it was found that although the excretion of
urea might fall greatly during starvation there was very little
Jail in the consumption of oxygen. It thus became evident that any
diminution in the consumption of protein was accompanied by
increase in consumption of the fat and of any carbohydrate
remaining in the body. Further investigation of the ratios in which
protein, carbohydrate, and fat replaced one another in the oxida-
tions occurring in the body resulted in the striking discovery by
Rubner that within wide limits of variation in their supply to the
body they replace one another in proportion to the energy which
they liberate in their oxidation within the body.^^ Thus i gram of
fat furnishes as much energy as 2%. grams of protein or carbohy-
drate, and I gram of fat from the reserve in the body takes the
place oi 2%. grams of protein or carbohydrate when the supply
of the latter in the food is cut off. The idea that the rate of oxida-
tion in the living body is determined by the rate of food supply
is thus erroneous. On the contrary the oxidation is regulated with
marvelous accuracy in accordance with its energy value in.satis-
^'cEon of what are commonly called the "energy requirements"^
of the body. Rubner's discovery is one of the main physiological
foundations of scientific dietetics.
Just as the rate of physiological combustion, other things being
equal, is not determined in the higher organisms by the supply of
food material, so it is not determined by the abundance of the
"Liebig, Letters on Chemistry, Third English Edition, p. 314, 1855.
"Rubner, Zeitschr. f. Biologie, XIX, p. 313, 1883.
6 RESPIRATION
oxygen supply. Lavoisier himself and afterwards Regnault and
Reiset found that a warm-blooded animal breathing pure oxygen
consumes no more oxygen than an animal breathing ordinary
air; and subsequent investigations have shown that the oxygen
* percentage in air has to be reduced very low before the oxy-
gen consumption is diminished. Pfliiger also found that oxidation
in the tissues is within wide limitsTndependent of the rate of suppjh^
of oxygen through the blood circulation. We are thus again face
to face with "physiological requirements."
When temperature and heat production in the living body came
to be studied physiologically the first striking fact discovered
was that however much the external temperature might vary
I within wide limits, the body temperature of warm-blooded ani-
I mals remained practically the same during health. Similarly,
although the heat production might be increased several times
by muscular exertion there was no material increase of body
temperature, and it became quite evident that the rise of tempera-
ture in fever is not due to increased heat production, but to dis-
turbance in the nervous regulation of heat discharge from the
body. Finally, when the influence of variations in external tem-
perature on heat production in the body was measured, it was
found by a succession of observers, including, besides Lavoisier,^^
, Crawford in 1 788, and Pfliiger and others in more recent times,
that, particularly in small animals, a lowering of external tem-
Tperature evokes through the influence of the nervous system a
i rise in heat production, so that heat production becomes subservi-
ent to the maintenance of body temperature. This maintenance
is therefore one of the factors determining physiological energy
requirements.
When we inquire what determines the energy requirements of
the body as a whole we find that the results of investigation point
us towards a number of associated conditions which we can
identify one by one by observation or experiment, but which ordi-
narily occur in conjunction with one another, and on an average
remain very constant. Thus the activity of the nervous system in
determining various forms of muscular and glandular activity
constitutes one of the chief factors. But the activities of the
nervous system are themselves subject to control in the form of
what we call on the one hand "fatigue," or on the other "exuber-
ance of spirits," finding its expression in man in games and what
appear at first sight to be mere "luxus" activities of all kinds.
" Pfluger, P finger's Archiv, XII, p. 282, 1876.
RESPIRATION 7
Hence apart from seasonal variations the daily nervous activities
are pretty constant in total amount.
Although the internal body temperature is actually very con-
stant, yet a very moderate actual rise or actual fall in body
temperature is sufficient to increase or diminish oxidation very
materially. In fever, for instance, the oxidation in the body is
greater thanlT would be witfiout the rise of temperature buTwi]
other conditions the same. The oxidation in fever is, however^
only a fraction of that during even very moderate exertion.
When we examine still more closely, and in the light of the facts
which are continuously becoming revealed by pathology and
pharmacology, we begin to realize that ''energy requirements"
depend on an infinite multitude of associated ''normal conditions.^^
Anupset in the proportion of, say, calcium or potassium in the
blood, or in that of substances produced in minute amounts in
one or other of the "ductless glands" or supplied to the body
along with the other main constituents in ordinary food, will
dramatically end "energy requirements" by that mysterious phe-
nomenon which we call death, and which we are so familiar with
that we almost cease to speculate about its nature.
At first sight death may seem to become intelligible when we
find that in the higher animals its immediate cause is want of
oxygen in the tissues owing to interruption of the circulation or
breathing. But further examination shows us that death is no mere
stoppage of an engine owing to lack of air or fuel, but also total
ruin of what we took to be machinery. It is a mysterious dissolu-
tion in the association together of the infinitely complex group of
normals which constitute the life — the <f>v(Ti^ — of an organism ;
and an examination of the fragments left has thrown no light on
why the association should have existed at all, or endured so long.
The outward form and internal arrangement and composition of
the dead body tell their story of life to him who can interpret their
hieroglyphics; but there is no life visible. The gulf between the
dead and the living is a gulf across which our present intellectual
vision does not reach, and we only deceive ourselves when we
sometimes imagine that it does. Thus when we ask what determines
those "energy requirements" which determine consumption of
oxygen and output of carbon dioxide in the living body, the only
answer we can at present elicit from experimental investigation
is that the energy requirements are one side of the <f>v<ri^ of the
organism. To those who object that the <f>va-i^ is a mere name,
and that physiology must be simply physics and chemistry I can
8 RESPIRATION
only reply, following the example of Hippocrates who protested
against the intrusion of abstract philosophical speculatTons 'int&'
medicine, that there can be no doubt about the existence. of the
associated and persistent group of appearances which the woriL
<^vsto- designates when applied to life. If we ignore this we reject
the one thing which gives us that grasp of biological phenomena
which enables us to predict them, and renders a scientific treatment
of biology and medicine possible.
The immediate subject of this book is the side of physiology
which concerns the means by which the supply of oxygen and
removal of carbon dioxide are so carried out and regulated that
physiological requirements are met. That this supply and removal
are through the lungs and blood has already been pointed out;
but the development of knowledge as to the means of regulation
must now be traced. Much difficulty arises, however, from the
fact that the problem itself was only recently realized with any
clearness. Respiration and circulation have been to a large extent
treated as if the requirements of the body were on the whole
constant. Actually, however, the consumption of oxygen _aiid.
production of carbon dioxide fluctuate greatly. A heavy exeriioiij
for instance, will increase tenfold the consumption of oxygen and
output of carbon dioxide for the whole body, and must certain,!)^
increase in a far higher ratio the consumption and output of the
muscles actually at work.
It has of course been known from the earliest times that muscu-
lar activity causes great increase in the depth and frequency of
the breathing, and that rebreathing the same air has a similar
effect ; but the very familiarity of these facts seems to have led
to a relative neglect of the problem of how the respiratory activi-
ties are regulated. An undue specialism has led to the investiga-
tion of each form of bodily activity as if it were something
separable from other bodily activities, and not a physiological
activity. Further confusion has arisen through the roughness of
many of the experiments made on animals, and corresponding
failure to detect the delicacy of physiological regulation.
In i8i I it was discovered by Legallois that if a portion of tissue
definitely localized in the medulla oblongata is destroyed respira-
tion ceases and death ensues. ^^ This part of the medulla has come
; to be known as the respiratory center^ and round the responses of"
this "center" to various nervous and other stimuli the physiologi-
cal investigation of breathing has been focused.
" Legallois, Experiences stir la principe de la vie, Paris, 1812.
RESPIRATION 9
It was found by Legallois and subsequent investigators that the
nervous connections botfiabove and below the respiratory center^
can be successively severed without preventing the rhythmic dis^
-charges of inspiratory and expiratory impulses except in so far as
efferent nerves connected with the center are cut off from it. Thus
the rhythmic discharges of the center are not dependent on afferent
nervous impulses and continue regularly so long as normal,arterial
blood is supplied to it. In this sense the action of the center is
automatic. On the other hand the mode of action of the center is
much affected by nervous stimuli.
In the first place its action is to a large extent under voluntary
control. Thus the breathing can easily be suspended for about a
minute, and in the'actions of speaking, singing, etc., is greatly
interfered with. The rate and depth of breathing are also_
iirider voluntary control, and may be much affected by emotion.
Consciously perceived stimuli of all kinds may also affect the
breathing — particularly stimuli affecting the air passages. The
irregularity and variability of the breathing owing to all these
causes tended to direct the attention of physiologists away from
the central problem of how the breathing responds to fundamental
physiological requirements.
It was soon discovered that apart from consciously felt stimuli
the breathing is specially affected by afferent stimuli conducted
by tire~vagus nerve. Early last century it was noticed that when the
vagus nerves are severed the breathing becomes less frequent and
deeper; and on stimulating the vagi various marked effects, de-
pending on the strenj;;th of stimulus, were found to be produced
on the breathing.
In 1868 Hering and Breuer^^ made the striking discovery that
on mechanically interrupting, at the end of inspiration, the ex- 1
pulsion of air from the lungs the rhythm of respiratory effort Is
interrupted for a time, until at last this interruption is broken by
an inspiratory effort, followed by alternating expiratory and in-
spiratory efforts showing that the center has renewed its rhythmic
activity. Similarly if at the end of expiration air is prevented from
entering the lungs there is an interruption before the center re-
turns to its normal rhythmic activity.. These effects are completely
absent if the vagi have been divided. The slow rhythmic dis-
charges of the center go on quite independently of whether the
inflation or deflation of the lungs is prevented or not.
"Hering and Breuer, Sitzber. d. Wiener Akad.. M ath-naturw . CI. {2), LVII,
p. 672 and LVIII, p. 909, 1868.
e
lO RESPIRATION
It was evident from these experiments, and from the marked
slowing and deepening of breathing after the vagi are cut, that
distention of the lungs stimulates the nerve endings of the vagi
in the lungs in such a way as to terminate inspiration and initiate
expiration, while deflation of the lungs produces a corresponding
stimulus acting so as to terminate expiration and initiate inspira-
tion. Thus inspiration seems to be the cause of expiration, and
expiration of inspiration. Hexing described this as the "self-regu-
lation" of breathing.
Another series" of observations relates to chemical stimulation
of the respiratory center. It was^found that if air containing very
little oxygen is breathed, or a small volume of ordinary aif"Ts
repeatedly rebreathed, great panting ensues, followed by general
convulsions and final cessation of breathing. The same result was
found by Kiissmaul and Tenner to follow if the blood supply to
the brain is completely cut off, so that the blood remaining in the
vessels becomes venous. The respiratory center is thus first stimu-
lated to excessive action by imperfectly oxygenated or venous
blood, and later becomes exhausted and finally ceases to act. But
another most significant fact was definitely discovered by Roserj--
thal in 1862.^^ If in an. animal artificial respiration is pushed so
that the ventilation of the lungs is abnormally great the activity
of the respiratory center ceases entirely for a time, and tKis
condition he designated as apnoea. In most persons apnoea can be
produced easily by voluntarily forcing the breathing for a short
time. After a few deep and rapid breaths it will be noticed that
all natural tendency to breathe ceases for a time.
These observations suggested that ordinary breathing is de-
termined by the degree of arterialization of the blood supplying
the respiratory center. If the degree of arterialization is dimin-
ished the breathing is increased, and vice versa, so that the
respiratory center automatically maintains a normal degree of
arterialization. When the venous blood is arterialized in the lungs
two changes occur, as we have already seen. The blood takes up
oxygen, and also loses carbonic acid. It might be one or the other,
or else both, of these changes that determines the activity of the
respiratory center. The most immediately evident change in the
blood during its passage through the lungs is its change in color
from a bluish to a bright scarlet color, and this change, as already
seen, is due solely to its oxygenation and not to loss of carbonic
acid. We thus naturally tend to think of blue blood as venous and
"Rosenthal, Die Athembewegungen, 1862.
RESPIRATION 1 1
scarlet as arterial ; and with the blood pump we can easily prove
that the scarlet blood contains more dissociable oxygen than the
blue.
Rosenthal came to the conclusion that it is solely or almost
solely in virtue of its varying oxygen content that the blood,
stimulates the respiratory center or not.^^ Careful blood-gas de-
termmations showed that when apnoea had been produced by
forced ventilation of the lungs the arterial blood contained a little
more oxygen. On the other hand, when oxygenation was rendered
incomplete by letting an animal breathe air very poor in oxygen
there was an immediate great increase in the breathing, although
the discharge of carbonic acid was in no way interfered with.
Moreover, when air containing; a^verj laj^ejexcess pi_C.O^^^^
breathed byTin aniniar the rate oFbreatliing remained normal.
Rosenthal also brought forward other evidence which appeared^
to point in the same direction ; but the weak point in his argument
was the fact that there is no apnoea when pure oxygen is breathed,
although the arterial blood contains a good deal more oxygen
than usual. The truth is that he had been misled by the fact that a
very high percentage of CO2 in the air breathed has a narcotic
effect, so that the breathing, which is in reality increased at first
by raising the percentage of CO2 in the air of the lungs, quiets
down again when the percentage becomes very high. Pfliiger and_
Hohmen^''' showed that both excess of CO2 (provided that the CO2
is not in too great excess) and want of oxygen excite the respira-
tory center.
A further fact, discovered originally by Traube,^^ but often
overlooked by subsequent investigators, was that apnoea could
big^'pr^HuceH^yeifBy a gas as hitfogen or hydrogen, in whrch
no oxygen was present. Thus if apnoea is due to *'over-arterializa-
fion^^f the arterial blOod"it can be produced by the simple re-
moval of CO2, whether or not the oxygen is also diminished,
although the artificial ventilation of the lungs must be much more
vigorous if apnoea is produced in the absence of oxygen.
Meanwhile another theory of apnoea was put forward, and
has'leH^ as will be shown later, to the utmost corifusion and com-
plete misinterpretation of the facts. When the lungs are distended
there is, as already mentioned, an interruption in the rhythm of
discharge from the respiratory center. The inspiratory muscles,
^"Rosenthal in Hermann's HancLbuch der Physiol., Vol. IV, 2, 1882.
"Pfliiger, Pfluger's Archiv, I, p. 61, 1868.
" Traube, Allgem. Med. Centralzeitung, 1862, No. 38, and 1863, No. 97.
12 RESPIRATION
and specially the diaphragm, are, and remain till the interruption
is broken by an inspiratory effort, relaxed. This interruption of
inspiratory effort came to be interpreted as an apnoea, and appears
so if only inspiratory muscular movements are recorded, as, for
instance, with the method adopted in Hering's laboratory by
Head,^^ in which only the contractions of the diaphragm are re-
corded, or with other methods which do not record tonic expira-
tory effort. Hence it came to be assumed that there exists what is
called "vagus apnoea.'^ The next step was to maintain thaPall
apnoea is in reality vagus apnoea, and this inference was suppoffed
By Th'e "fact That "apnoea" can still be obtained when theaHeffei —
-blood is blue owing to air containing a very low percentage '^5'f
oxygen being breathed, and can also be produced (as Lorrain
Smith and I found) by air very rich in COg. It was also affirmed
by Brown-Sequard that after the vagi are cut apnoea cannot be
produced, though this statement can easily be shown to be com-
pletely mistaken. With an efficient apparatus for increasing the
ventilation of the lungs apnoea can quite readily be produced
after section of the vagi.
On the other hand, increasingly clear evidence accumulated
that apnoea due to over-ventilation of the blood passing through
the lungs exists as a matter of fact. The most striking proof of
this was afforded by experiments in which Fredericq^^ crossed
the circulation of two animals by connecting the vessels ia-sucka
way that the respiratory center of each animal was supplied with
arterial blood from the other animal. He then found that wiien
excessive artificial respiration was produced in one of the animals
apnoea was produced in the other, and when the artificial respira-
tion ceased hyperpnoea continued in the animal which had had
artificial respiration, since its respiratory center was now receiving
blood which was venous owing to the cessation of breathing in the
other animal. This hyperpnoea, on the other hand, maintained
the apnoea in the other animal, so that one of the animals re-
mained apnoeic while the other remained hyperpnoeic.
This experiment showed clearly the existence of a true ".Qhfiaii-
cal ' apnoea ; but, as the existence of vagus apnoea was also,.con-
sidered to be firmly established, the existence of both forms of
apnoea came to be generally assuin.ed. As regards vagus apnoea the
evidence was considered to show that when apnoea is produced by
distending the lungs with air or hydrogen it is vagus apnoea that
"Head, Journ. of Physiol., X, i and 279, 1889.
*° Fredericq, Arch, der Physiol., 17, p. 563, 1901.
RESPIRATION 13
lasts on after the distention ceases, and from this supposed fact
the further inference was drawn that repeated distention of the
lungs produces a summed vagtis effect resulting in vagus apnoea
after the distentions have ceased. Thus the same procedure that
causes chemical apnoea seemed to produce also vagus apnoea,
and the two kinds of apnoea could hardly be distinguished in
practice. Moreover hyperpnoea due to any chemical cause such as
want of oxygen or excess of CO2 must apparently tend to be
prevented by the production of vagus apnoea due to repeated
distentions of the lungs. The two processes by which the breathing
appeared to be regulated acted, therefore, in opposite directions.
As regards the chemical stimuli acting on the respiratory center,
it remains to consider the further evidence as to the relative im-
portance of want of oxygen and excess of CO2 ,* also whether other
chemical stimuli act on the center. In 1885 Miescher^^ showed
by experiments on man that a given small increase in the per-'™
centage of COo in air affects the breathing considerably, while a
corresponding diminution in the oxygen percentage has no such
elTect. He was thus led to the conclusion that it Is the CO^ per-
"cenfage in the air of the lungs that ordinarily determines the
chemical regulation of breathing, and not the oxygen percentage.
Thus CO2 protects the body from want of oxygen so long as
ordinary air is breathed. It will be seen in the sequel how relatively
correct this general view of Miescher's was, although he main-
tained the existence of vagus apnoea and thus shared in the
mistakes of his time.
In 1888 Geppert and Zuntz^^ published the results of a very
careful series of experiments on the effects of muscular work (pro-
duced by tetanizing the hind limbs of an animal after section of the
spinal cord) on respiration. After bringing forward new evidence
that it is the blood which carries the stimulus for increased breath-
ing to the respiratory center they showed that during the work
the, proportion of CO2 in the blood was greatly diminished, and
that there was also a slight increase in the oxygen percentage of
the blood. Hence, they argued, it is neither increase in CO2 per-
centage nor diminution in oxygen percentage that causes the
hyperpnoea accompanying muscular exertion. They believed that
it is some acid substance produced in the muscles, and pointed out
that Walter.iLad found that the breathing is much increased in.,
poisoning by acids.
" Miescher, Arch. f. {Anat. u.) Physiol., p. 355, 1885.
^Geppert and Zuntz, Pfliiger's Archiv, XLII, pp. 195, 209, 1888.
^■rti5»
14 RESPIRATION
From the foregoing review of the knowledge existing up to
the beginning of the present century on the physiological regu-
lation of breathing it will be seen that the conclusions reached
were unsatisfactory in many ways, and to some extent contra-
dictory. On the one hand the nervous regulation through the vagi
and other nerves seemed to have no relation to the requirements
of the body for oxygen and for removal of COg, and in fact to
act antagonistically to these requirements. On the other hand
the excitation of the breathing during muscular work seemed
also, from the results of Geppert and Zuntz, to have no definite
relation to increased requirements for oxygen and CO2. There
was also no definite quantitative information as to why in normal
breathing during rest the composition of the expired air is so
constant as it is. Without more exact and consistent physiological
knowledge it appeared to be very difficult to interpret the ab-
normal breathing so often met with in disease, or to know how to
set about investigating it.
From still another standpoint the existing knowledge was very
unsatisfactory to me personally. From a consideration of the
general characteristics which distinguish a living organism from
a machine I had become convinced that a living organism cannot
be correctly studied piece by piece separately as the parts of a
machine can be studied, the working of the whole machine being
deduced synthetically from the separate study of each of the parts.
A living organism is constantly showing itself to be a self-main-
taining whole, and each part must therefore always be behaving
as a part of such a self-maintaining whole. In the existing
knowledge of the physiology of breathing this characteristic could
not be clearly traced. The regulation of breathing did not, as
represented in the existing theories, appear to be determined in
accordance with the requirements of the body as a whole; and
for this reason I doubted the correctness of these theories, and
suspected that errors had arisen through the mistake of not study-
ing the breathing as one of the coordinated activities of the whole
body. In so far as the investigations detailed in succeeding chap-
ters originated with me, they were mainly inspired by the con-
siderations just mentioned; and, as will be seen in the sequel, the
same considerations have led to a reinvestigation and reinterpre-
tation of other physiological activities besides breathing.
CHAPTER II
Carbon Dioxide and Regulation of Breathing.
My attention was first directed to the regulation of breathing by
a series of experiments carried out by Lorrain Smith and myself^
as to the question whether, as had shortly before been asserted by
Brown- Sequard and d'Arsonval as a result of a very definite and
apparently convincing series of experiments, a poisonous organic
substance is given off in expired air. The results of our experi-
ments, which were made partly on man and partly on animals,
were entirely negative, and left no doubt in our minds that the
apparent positive results described were due partly to undetected
air leaks which led to animals being asphyxiated, and partly to
other experimental errors. In the human experiments we used an
air-tight respiration chamber of about 70 cubic feet capacity, in
which the air became more and more vitiated by respiration.
The effects of the vitiated air on our breathing attracted our
attention specially. When the proportion of CO^ in the air rose
to about 3 per cent, and the oxygen fell to about 17 per cent (there
Seing 20.94 per cent of oxygen and 0.03 per cent of CO2 in pure
atmospheric air) We Breathing began to be noticeably increased.
With further vitiation the increase in breathing became JiiQre aad
more~marked, until with about 6 per cent of CO^ and 13 per cent
of oxygen the panting was very great, with much consequent
"exhiartistion.
When the experiment was repeated, with the difference that
the CO2 was absorbed by means of soda lime, there was no notice-
able increase in the breathing before the oxygen fell below about
I4"pef~cent. When, finally^ the CO2 was left in the air, but oxygen
was first added so that the oxygen remained abnormally Tiigh
jytiroughojjt^iiie panting was just the same as when ordinary air
was used. In short experiments in which the same air was
rebreathed from a large bag till we could no longer stand the
experiment we found tbat_we^had to stop at aboutjo^er cent of
CO2, whether oxygen was added or. not, and that the oxygen per-
centage made no difference tiD. the. distress, produced. In these
experimenfs "there was only about 8 to 9 per cent of oxygen in the
* Haldane and Lorrain Smith, Journal of Pathology and- Bacteriology, I, pp.
168 and 318, 1893.
1 6 RESPIRATION
rebreathed air at the end of the experiment ; but even this made
no difference to the breathing. When, on the other hand, a mixture
containing a greatly reduced oxygen percentage, without any
addition of COg, was breathed, the breathing was increased sensi-
bly, as shown by graphic records, when the oxygen fell to about
12 per cent, and was greatly increased by lower percentages.
With extremely low percentages, such as 2 per cent, consciousness
was lost quite suddenly after about 50 seconds, before there was
time to notice any increase in the breathing.
It was evident from these experiments that when the same air
is rebreathed, or an insufficient proportion of fresh air is supplied,
the increased breathing produced is due simply to excess of CO2,
until, at least, the oxygen percentage becomes extremely low. It
appeared, therefore, that the variations in ordinary breathing in
response to variations in the respiratory exchange must be due
to the increased CO2 produced, and not to the increased consump-
tion of oxygen. This conclusion was the same as that of Miescher,
and supported his views as to the regulation of respiration.
When more than about 10 per cent of CO2 was breathed the
effect of the mixture was to produce stupefaction, which was very
marked with higher percentages. This effect was already well
known in animals, and CO2 was one of the gases tried as an an-
aesthetic by Sir James Simpson before he adopted chloroform.
The effect of excess of CO2 in producing ataxia, stupefaction, and
loss of consciousness has become very familiar to me in connection
with experiments with mine- rescue apparatus and diving appa-
ratus. These effects are readily produced in the presence of a large
excess of oxygen, and are therefore quite independent of the
effects of want of oxygen. The narcotic effect of a large excess of
CO 2 quiets down the respiration, and this effect in animals led
many previous observers to overlook almost entirely the ordinary
effects of CO2 in stimulating the breathing.
During the next few years after our first experiments I was
engaged in the investigation of other problems connected with
general metabolism, respiration, and blood gases, but in 1903
returned to the regulation of breathing in a long series of experi-^
ments carried out in conjunction with Dr. J. G. Priestley, who^
was then a student at Oxford.
It seemed pretty evident that in order to reach clear ideas on
the regulation of breathing it was necessary to study very care-
fully the composition of the alveolar air which is in contact,
through the alveolar epithelium, with the blood passing through
RESPIRATION 17
the lungs ; also that this could be best done on man. The composi-
tion of human alveolar air under different conditions had already-
been calculated by Loewy^ and Zuntz from the volume occupied
by a plaster cast of the respiratory passages in a dead body and
the average composition and volume of a breath of expired air.
The expired air is evidently a mixture of air from the alveoli with
the air which remains in the respiratory tubes at the end of inspira-
tion. This air is presumably but little altered by diffusion through
the walls of the respiratory tubes, and so far as respiratory ex-
change is concerned the volume of the lumen of these tubes must
constitute a "dead space" in breathing. The dead space is occupied
by alveolar air at the end of expiration, and by more or less pure
atmospheric air at the end of inspiration.-^*^
If we know the volume of the dead space, and the volume and
composition of the air expired at each breath, we can calculate
the average composition of the alveolar air. It is, however, im-
possible to estimate directly the volume of the dead space in a
particular individual with any accuracy, or to be sure that it
remains the same under different physiological conditionsfiThe
bronchi and bronchioles are provided with a muscular coat by
means of which their lumen is capable of contracting or dilating. fp j
Apart from this the air in the alveoli which are nearest to the end
of a bronchus will contain purer air during inspiration than during
expiration, and this introduces a further complication.
To get a reliable knowledge of the composition of alveolar air
it seemed desirable to make direct determinations. The method
introduced by Priestley and myself^ is simply to make a sharp and
deep expiration through a piece of hose pipe about four feet long
and one inch in diameter, and provided with a plain glass mouth-
piece which is closed by the tongue at the end of the expiration
(Figure i). By means of a narrow bore glass tube filled with
mercury and introduced air-tight into the hose pipe near the
mouthpiece, a sample of the last part of the expired air is then \
at once taken directly into the gas analysis apparatus as indicated \
in Figure i,"* or else into a vacuous sampling tube.^ If the sample Nw^
is to be a normal one the breathing must be quite normal before
' Loewy, Plfliiger's Archiv, LVIII, p. 416, 1894.
• Haldane and Priestley, Journ. of Physiol., XXXII, p. 225, 1905.
• For physiological work methods of air analysis which are both accurate and
rapid are required. A description of the methods which I introduced with this in
view will be found in my book, Methods of Air Analysis, London, Charles Griffin
& Co., Third Edition, 1920.
• If the sample is too large some pure air may be drawn in.
i8
RESPIRATION
the deep expiration ; and it requires some care to secure this. Under
normal resting conditions the depth of expiration needed in order
to give a reliable sample at the end of inspiration is at least 800 cc.
With less than this the sample is likely to be mixed with air of
Figure i.
Apparatus for obtaining and analysing alveolar air.
the apparent dead space; for though with normal breathing the
volume of the apparent dead space is far less than 800 cc, at least
three or four times its volume of alveolar air is needed in order
to flush it and the breathing tube out thoroughly. If more than
about 800 cc. are expired, the composition of the sample is the
same whatever the depth of the expiration, and we designated
air of this constant composition as ''alveolar air" although, as
will be shown later, the composition of the air in the alveoli is by
no means such a simple matter as we thought. The following are
the averages of results which I obtained on this point when the
samples were taken just at the end of inspiration.*
Vol. of air expired
Per cent
of CO2 in sample 1
through tube
taken from tube ||
190 CO.
3.03
335
4-37
510
5-04
650
5.19
950
5-51
1350
5.48
As soon as this method of sampling the alveolar air was applied
on ourselves and others it became evident that the alveolar CO2
and O2 percentage during rest under normal conditions are sur-
• Haldane, Amer. Journ. of Physiol., XXXVIII, p. 20,
:91s.
RESPIRATION 19
prisingly constant for each individual. As the depth of breathing
cannot be kept absolutely steady and the composition of the al-
veolar air varies slightly with inspiration and expiration it is
best to take at least two samples — one just at the end of inspiration,
and another just at the end of expiration. The following tables
give the CO2 percentages in samples of our normal resting
alveolar air, taken in the sitting position during rest at intervals
over about 20 months in 1903 to 1905. Since then we have made
many further determinations, but the percentages have remained
nearly the same. They are slightly lower or higher on some days
than on others, and other observers have noticed this in them-
selves.
J. i
3. H.
Barometric
COi fer cent,
COi per cent,
COi per cent,
pressure in
end, of
end of
mean
mm. of Hg.
inspiration
expiration
759
5-33
576
5.545
747
5.47
5.69
5.56
748
5.56
570
5.63
748
S.59
5.87
573
748
5.38
5.60
5.49
748
5.33
•5-94
5-40
749
5-8o
5.51
5.87
749
5.66
5-59
5.585
765
5.63
5.83
5.61
759
5.42
572
5.625
758
5.74
572
571
765
5-53
572
5.62
Mean 754
5-54
572
5.63
It will be seen that, as might be expected, the inspiratory
samples give on an average a somewhat lower result than the
expiratory ones. The average for one subject is 5.63 per cent and
for the other 6.28. The slight variations of individual results
from these averages are evidently not due merely to changes in
barometric pressure.
When ordinary air was breathed the oxygen percentage in the
alveolar air was nearly as steady as the CO2 percentage. When,
however, the oxygen and CO2 percentages in the inspired air
were varied it became quite evident that the breathing is regu-
20
RESPIRATION
J-
G. P.
Barometric
€0% fer cent,
COt -per cent,
CO2 per cent,
■pressure in
end of
end of
mean
mm. of Hg.
inspiration
expiration
759
6.18
6.43
6.305
754
6.51
6.63
6.57
747
6.10
6.70
6.40
753
6.81
6.86
6.835
758
5.95
6.74
6.35
758
5.82
6.23
6.025
758
5-93
6.21
6.07
754
6.12
6.33
6.215
754
6.26
6.20
6.23
754
6.23
6.05
6.14
751
5.66
6.75
6.205
751
5.98
5-99
5.985
762
6.37
6.29
6.33
762
6.24
6.09
6.165
765
6.39
6.43
6.41
Mean 756
6.17
6.39
6.28
lated so as to give a constant percentage of CO2 and not of oxy-
gen. The following results were obtained with oxygen percentages
varied at intervals in the same subject.
OXYGEN PERCENTAGE
CO2 PERCENTAGE |
Inspired air
Alveolar air
Inspired air
Alveolar air
80.24
72.21
0.20
5.84
63.67
57.57
0.14
5.41
20.93
14.50
0.03
5-54
16.03
10.39
0.05
5.62
15.82
10.59
0.05
5.60
15.63
10.60
0.07
5.45
12.85
8.34
0.06
S.37
12.78
7.80
0.07
5.28
11.33
8.96
O.IO
3.85
11.09
7.10
O.IO
4.89
6.23
4.30
0.09
3.57
This table shows that increase in the oxygen percentage over
short periods had no noticeable influence on the alveolar CO2
percentage, and that not until the oxygen percentage in the in-
RESPIRATION 21
spired air was lowered to about 12 or 13 and the alveolar oxygen
percentage to about 8 was there any marked decrease in the CO2
percentage. With a greater lowering of the oxygen percentage
than this, however, the breathing was so much increased as to
lower the CO2 percentage considerably.
When the CO2 percentage in the inspired air was increased,
on the other hand, the effect was strikingly different. Instead of
the alveolar COg rising in any direct correspondence to the rise
in the inspired CO2, the increase in alveolar CO2 was so slight as
to be hardly appreciable even with a rise of 2 or 3 per cent in the
CO2 of the inspired air. This is evident from the following ex-
periments, made in the air-tight chamber.
SUBJECT
CO2 PER CENT
CO
J PER CENT IN RELATIVE
IN INSPIRED
ALVEOLAR AIR RATES OF ||
AIR
ALVEOLAR
VENTILATION
End of
End of
Mean
inspiration
expiration
J. S. H.
0.03
SA2
5-83
5-62
100
"
2.07
5.60
153
>>
3.80
6.03
5.92
5.97
258
»>
0.03
5.74
5.72
5-71
100
>>
1.74
5-59
5.71
5.65
143
>>
3.98
5-99
6.16
6.03
277
>»
5.28
6.44
6.66
6.55
447
J. G. P.
0.03
6.85
6.28
6.31
100
)f
5.29
6.92
6.86
6.89
392
»
6.66
7.62
7.72
7-(>7
622
}>
7.66
8.34
8.56
8.45
795
The evident effect of adding CO2 to the inspired air was so to
increase the breathing that, if the percentage added was not too
high, the CO2 percentage in the alveolar air was kept nearly
constant. Of the delicacy of this reaction it is easy, from the fig-
ures, to form a fair estimate. With a moderate amount of hyperp-
noea, and provided that, as was actually the case, sufficient time
has elapsed to eliminate the influence of any temporary damming
back of CO2 within the body, the discharge of CO2 by the lungs
is about the same during hyperpnoea as during rest. Hence it
is possible to calculate how great a relative increase in the alve-
olar ventilation is brought about by a given increase in the alveolar
22 RESPIRATION
CO2 percentage. We found that about 0.23 per cent increase in
the alveolar CO2 gives 100 per cent increase in the resting alveolar
ventilation. For instance with 4.16 per cent of CO2 in the inspired^
air, the alveolar CO2 percentage would rise to about 6.06 per
cent, if it had been about 5.6 per cent when pure air was breathed.
As the difference between 4.16 and 6.06 is only a third of the
difference between 0.0 and 5.6, it follows that the alveolar ventila-
tion is thrice as great with the slightly raised alveolar CO2 per-
centage.
A more precise measure of the effects of raising the alveolar
CO2 percentage on the lung ventilation has more recently been
obtained by Campbell, Douglas, and Hobson,'' who found that for
an increase of 10 liters per minute in the volume of air breathed
there was an increase of 0.28 per cent (or 2 mm. of mercury
pressure) in the alveolar CO2. An increase of 0.17 per cent was
sufficient to double the alveolar ventilation during complete rest
in a deck chair.
If an increase of 0.2 per cent in the alveolar CO2 is sufficient
to double the alveolar ventilation it might be expected that a
decrease of 0.2 per cent would cause the breathing to cease. As
already mentioned, forced breathing or excessive artificial respira-
tion causes temporary cessation of natural breathing, or apnoea.
After forced breathing for about a minute the subsequent apnoea
commonly lasts for about i^ minutes in man. The alveolar CO2
percentage is markedly diminished for a few seconds by even a
single extra deep breath of pure air, and correspondingly in-
creased by a breath of air containing more than 5 or 6 per cent of
CO2. It is easy to show, however, that the full effect of the dimin-
ished or increased percentage of CO2 on the respiratory center is
not immediate. This is just what might be expected. The arterial
blood leaving the lungs at any moment is doubtless saturated with
CO2 to a point corresponding with the existing percentage of CO2
in the alveolar air; but when this blood reaches the tissues it
comes in contact with tissue and lymph saturated with CO2 to the
normal extent, but possessing a considerable capacity for absorbing
more COg. In consequence of this the tissues, including the res-
piratory center, take some time to get into equilibrium with the
new level of saturation with CO2 in the arterial blood. Hence in
order to measure the real effect of any increase or diminution in
the alveolar CO2 percentage, it is necessary to maintain this per-
centage constant for some time. When air containing an excess
'Campbell, Douglas, and Hobson, Journ. of Physiol., XLVIII, p. 303, 19 14.
RESPIRATION 23
of CO2 is breathed, the alveolar CO2 percentage naturally be-
comes constant after a few minutes ; but with forced breathing of
ordinary air it is not possible to maintain an alveolar COg per-
centage which is below the normal by some required small amount.
To get over this difficulty we employed forced breathing with
air to which CO2 had been added, and found that on successive
trials with increasing percentages of CO2 in the inspired air
the duration of apnoea following forced breathing diminished
until, when there was more than about 4.7 per cent of CO2 in the
inspired air, no apnoea at all was produced. It was thus evident/
that a very small diminution in the alveolar CO2 percentage/
produces apnoea. The actual composition of the alveolar air at the
end of forced breathing in similar experiments was determined
later by Douglas and myself.^ It was found that with more than
4.7 per cent of CO2 in the inspired air no apnoea could be produced
by forced breathing, however hard, in a person whose normal
alveolar CO2 percentage was about 5.6, and that apnoea was only
produced if the alveolar CO2 was reduced by more than 0.2 per
cent below the normal. When, however, the CO2 in the inspired
air was lower, so that the alveolar CO2 percentage was reduced
by more than 0.2 per cent, apnoea was produced.
Itis thus clear that the cause of the apnoea following forced
breathing is reduction in the CO2 percentage in the alveolar air,
and that a reduction of as little as 0.2 per cent is sufficient to cause_
apnoea. The astounding sensitiveness of the respiratory center to
CO2 is thus clearly established in both an upward and a downward
direction. A mean increase or diminution of .01 per cent in the
alveolar CO2 will evidently produce an increase or diminution of %
5 per cent in the alveolar ventilation, or of about 400 cc. per minute «*
in the lung ventilation.
It may be useful to review briefly the sources of error in the
views current until recently with regard to the causes of the apnoea
produced by excessive ventilation of the lungs. One view was
that the excess of oxygen in the arterial blood causes the apnoea.
This theory had so little evidence to support it that it is very
surprising that it should have remained current so long. It is
true that during excessive artificial respiration the arterial blood
contains slightly more oxygen than usual; but there is a still
greater excess during the quiet normal breathing of pure oxygen,
which causes not the smallest sign of apnoea. Rosenthal^ laid great
' Campbell, Douglas, Haldane, and Hobson, Journ. of Physiol., XLVI, p. 312,
1913-
* Rosenthal in Hermann's Handbuch der Physiologie, IV, 2, p. 266.
24 RESPIRATION
stress on an experiment in which on slightly raising the pres-
sure in a spirometer from which an animal is breathing, the an-
imal stops breathing; and he attributed this to increase in the
partial pressure of the oxygen in the spirometer. The real cause
was quite evidently the distention of the animal's lungs by the
pressure, as in the experiments of Hering and Breuer. When a
man or animal has been rendered hyperpnoeic from want of oxy-
gen, and the hyperpnoea has reduced the normal percentage of
CO2 in the alveolar air and blood, apnoea is produced by supply-
ing more oxygen; but this apnoea is of course dependent on de-
ficiency of CO2, and cannot, therefore, be cited in support of the
oxygen theory of ordinary apnoea.
The other erroneous theory — that apnoea following forced
breathing is due to a summation of inhibitory vagus stimuli aris-
ing from distention of the lungs in the forced breathing —
was based on two fallacies. The first was that intact vagi are
necessary for the production of apnoea by artificial respira-
tion. This is certainly not the case; for apnoea can be produced
quite promptly and easily after section of the vagi. It is necessary,
however, to make sure that the excessive artificial ventilation is
really effective in ventilating the lungs, since after section of the
vagi the natural breathing does not follow the rhythm of the
artificial respiration, and may thus partly annul the effects of
the latter.
The other fallacy connected with the vagus theory of ordinary
apnoea was that when air containing little or no oxygen is used
for artificial respiration an apnoea due to excessive aeration of
the blood is impossible. Advocates of the vagus theory wrongly
thought only of oxygen want in connection with aeration of the
blood. They thus attributed to vagus excitation any apnoea which
was produced in presence of defective oxygenation of the blood,
ignoring the fact that deficiency of CO2 was present along with
defective oxygenation, and that this fact explained the observed
apnoea. Provided that the alveolar CO2 percentage is sufficiently
reduced, apnoea can be produced readily in spite of great defi-
ciency of oxygen in the alveolar air.
The fact that apnoea is produced when forced breathing reduces
the alveolar CO2 percentage by as little as 0.2 per cent (with the
alveolar oxygen percentage not abnormally low), and that if this
reduction is prevented no amount of excessive lung ventilation
1 will produce apnoea, affords, in conjunction with the other facts
already referred to, conclusive evidence that the apnoea following
RESPIRATION 25
excessive lung ventilation is due to lowering of the alveolar CO2
percentage, and not to either of the other causes to which the
apnoea has also been attributed. The vagus theory of the apnoea
caused by increased lung ventilation involved the very great
improbability that a special arrangement exists in the body for
bringing increased breathing to an end, regardless of whether a
continuance of the increased breathing is physiologically required
or not. It seemed almost incredible that such a theory could be
correct.
The ease with which apnoea due to reduction of COg in the
alveolar air might be taken for an apnoea due to the after effect
of mere distention of the lungs is clearly shown by the stetho-
graphic tracings of human breathings reproduced in Figures 2
to 7.-^^ Figure 2 shows apnoea as an after effect of inflation of the
lungs, while Figure 3 shows that when the inflation is made with
air containing 4.6 per cent of CO2, so as to prevent reduction of
the alveolar CO2 percentage, no apnoea succeeds the period of
inflation. The apnoea appearing as an after effect in Figure 2 is
therefore due to reduction of the alveolar CO2 in consequence of
the distention with pure air.
Figure 2.
+ +
AAAA/Vn fVWVWVV
Figure 3.
Effects of distention for 8 sees. Crosses show beginning
and end of distention. To read from left to right. In Fig. 2
pure air is used for distention ; in Fig. 3 air containing
4.62 per cent CO2.
Figures 4, 5, and 6 illustrate the same point. In Figures 4 and
5 there is apnoea succeeding a short distention, but not immedi-
ately, since a few seconds were needed before the **apnoeic" blood
"Christiansen and Haldane, Journ. of Physiol., XLVIII, p. 274, 19 14.
26
RESPIRATION
could affect the respiratory center. In Figure 6 the distention wa^
sufficiently prolonged for the "apnoeic" blood to affect the center
before the end of distention. The effect is therefore similar to
that in Figure 2.
v^wwn
^A/'vvvvw^
Figure 4.
finrr«i»«»'''»nf«»»**»»i»»'ni mnr>»'>vi»» i>»»'»<<»»>» irt'» »vt» »>»>?« t»
.j,^
^'^aaAaAAA/
Figure 5.
Tnn»»»f >»r*»'ri
»»»ni<i>r»<«»wr»'fwin»»t>«»f<i rr» rr*'i »
4^r
Figure 6.
Effects of distention with pure air for increasing short
periods. Crosses show beginning and end of distention. To read
from left to right. Fig. 4 distention for i sec. ; Fig. 5 for 3 sees. ;
and Fig. 6 for 5 sees.
The regularity of ordinary breathing is constantly being inter-
fered with in various ways, as for instance during talking or
singing; and the breath can if necessary be held for about a minute
by voluntary effort. The readiness with which these interruptions
occur has given rise to the popular idea that the supply of air to
the lungs is to a large extent under voluntary control, and can be
increased or diminished by proper training. In reality the mean |^
ventilation of the lungs is not affected by ordinary interruptions.
RESPIRATION 2^
This is strikingly shown by experiments which we made on the
effects of voluntarily varying the frequency of breathing.
The frequency of breathing varies considerably among normal
individuals, or in the same individual at different times ; and it is
easy to vary the frequency while leaving the depth of breathing
to regulate itself in a natural manner. On making experiments of
this kind Priestley and I found the following percentages of CO2
in the alveolar air :
ALVEOLAR CO2 PERCENTAGE
RESPIRATIONS
End of
End of
Mean
PER MINUTE
. inspiration
expiration
J. S. H.
9
5-59
5.87
5.73
19
5.56
570
5.63
J. S. H.
9
5-33
5-47
5-40
20
5-44
5.60
5.52
J. G. P.
10.5
5.95
6.74
6.35
30
5.98
6.05
6.02
In a recent series, made on myself ten years later,^^ the fre-
quency was varied within much wider limits, with the following
results :
ALVEOLAR CO,
PERCENTAGE
'
RESPIRATIONS
End of
End of
Mean
PER MINUTE
inspiration
expiration
p:
5.66
5-70
5.62
5.24
6.09
5.66
11
5.48
5.49
5.48
5.40
5.73
5.56
r 36
5.63
5-73
5-68
J 4
5.II
6.34
5.72
^ 3
5.10
6.24
5.71
L 60
6.17
6.16
6.16
It will be seen that in spite of variations from 3 to 36 per minute
in the frequency of breathing the alveolar CO2 percentage re-
mained constant, since increased or diminished depth of breathing
" Haldane, Amer. Journ. of Physiol., XXXVIII, p. 20, 191 5.
28 RESPIRATION
compensated for diminished or increased frequency. The manner
in which this correspondence between depth and frequency is
brought about will be discussed in the next chapter.
During any considerable muscular exertion the discharge of
CO2 from the lungs is enormously increased; and in view of the
facts already described we should expect to find the breathing
similarly increased, with a rise in the alveolar CO2 percentage
corresponding to the rise observed when the breathing is corre-
spondingly increased by breathing air containing an excess of
CO2. Priestley and I obtained the following mean results during
work on a somewhat primitive bicycle ergometer.
ALVEOLAR CO2
PERCENTAGE
CALCULATED
End of
End, of
Mean
RESPIRATORY
EXCHANGE
inspiration
expiration
J. S. H.
Rest
I
5-54
5.70
5.62
Work
4.9
5.44
6.05
5.75
J. G. P.
Rest
I
6.17
6.39
6.28
Work
3.8
6.45
6.98
6.72
Mean
Rest
I
5.85
6.045
5.9s
Work
4.3
5.945
6.545
6.235
In this series there was thus only a mean rise of 0.285 per cent
in the alveolar CO2, whereas we had expected to find a rise of
about 0.6. The correspondence was, however, in the right direc-
tion, and we endeavored, mistakenly as afterwards appeared, to
explain the lack of exact correspondence.
A more complete series was carried out later with much im-
proved apparatus by Douglas and myself, with Douglas as sub-
ject.-^^ The accompanying table shows the data for volume of air
breathed, oxygen consumed, CO2 given off, composition of ex-
pired air, and of alveolar air. In these experiments we used the
now well-known bag method of Douglas for determining the
respiratory exchange. -^^
It will be seen from this table that with a CO2 production in-
creased from 264 cc. per minute during rest standing to 1398 cc.
per minute during walking at 4 miles on grass the alveolar COg
percentage rose from 5.70 to 6.36, i.e., by 0.66 per cent. The vol-
ume of air breathed per minute was increased from 10.4 to 37.3,
" Douglas and Haldane, Journ. of Physiol., XLV, p. 235, 1912.
"Douglas, Journ. of Physiol., XLII, Proc. Physiol. Soc, p. xvii, 191 1.
RESPIRATION
29
CO2 per cent in alveolar
air
10
0
10
Tj- Tj- Tt 0 COVO Th 0 00 0
q 0 w ""i ^. <^ "^ ^. <^ "I
vovo^VO^vOVOvovovC)
CO2 per cent in expired air
M M
U-3
4
OsOO 01
CO COVO
rf ^ rt-
10 tx
ILOVO
0 01 0 C\
10 txoq tx
Tt- Tt Tt rf
Vol. of each breath in cc.
(it 37 °C. moist, and pre-
vailing barometric pres-
sure.
On
•H ro m
tX CO CO
01 Tf U-)
0 r^
M VO
0 0
01 01
in Tf 0 10
irj 01 M Tj-
0 1000 HH
01 01 01 CO
00
IX
^N On 01
Tl- 01
01 10 CO 10
Bifeaths per min.
\o
tx
01
Tf TtVO
M l-l H-(
Tf 00
M M
txOO 00 0\
|_| M l-l HH
Liters of air breathed per
min. at 37° C. moist, and
prevailing barometric pres-
t^ 6
covq Choq
vd 00 6 '^
M M CM cs
0 CO
01 CO
01 VO CO Os
-^^ hh" d
CO '^ 100
sure.
CO2 production in cc. per
min. at o*C and 760 m7n.
ONVO
M 01 tx (N txOO w 00 0 VO
VO VO CO M 10 a\ 1000 0 00
lOVO lXO\O<^01txOco
W M M M 0» 01
O2 consumption in cc. per
■ min. at o^C. and 760 m,m.
txoo
fO c^
<N CO
VO
0 tx 10
01 ^
00 0\
l-l M
CO 10 10 CO
C\ 0 01 -^
Tt 0 w 10
w 01 01 01
f
u
(grass)
(laboratory)
(grass)
0
II
(laboratory)
(grass)
(laboratory)
(grass)
bJD
II
0
^ 0.
:::;::
;; !5
; :; 2 s
01 CO CO
Tf Tt
Tj- Tj- to 10
30 RESPIRATION
or by 26.9 liters. This corresponds very closely to the estimate by
Campbell, Douglas, and Hobson of an increase of 10 liters per
minute in the breathing for every .26 per cent of increased alveolar
CO2 at normal barometric pressure.
When, however, the CO2 production was increased still further,
the alveolar CO2 percentage, instead of continuing to increase,
began to diminish, and was only 6.10 per cent with the maximum
CO2 production (2386 cc.) and volume of air breathed (60.9
liters). Quite clearly, an additional factor or factors besides mere
increase in the alveolar CO2 percentage was coming into play;
for with the higher rates of CO2 production the lung ventilation
is not merely increasing in the same fixed proportion as before to
the increased production of CO2, but at a slightly higher rate.
What this additional factor is will be discussed later; but mean-
while we may rest content with the broad fact that the increased
ventilation is almost in proportion to the increased production of
CO2, just as we should expect from the other facts already dis-
cussed with regard to the regulation of breathing.
It was shown by Paul Bert^* that the physiological actions of
CO2, oxygen, and other gases present in the air breathed depend
on their partial pressure. It is only when the barometric pressure
is constant that their action depends on the percentage proportions
in which they are present in the air. The method of calculating
the partial pressure of the CO2 in the alveolar air may be illus-
trated by an example. Let us suppose that the barometric pressure
is 760 mm., and that 5.6 per cent of CO2 is found in the alveolar
air. In the first place allowance must be made for the aqueous
vapor present in the alveolar air, which in the living body must be
saturated with aqueous vapor at the body temperature. The pres-
sure exercised by this aqueous vapor is 47 mm. Hence the remain-
ing gas pressure is 760 — 47=713 mm. Of this pressure 5.6 per
cent is due to CO 2 (the results of the gas analysis being always in
terms of dry air) . Hence the pressure of CO2 is
760 — 47
5.0 x = 39.9 mm., or 5.25 per cent of an atmosphere,
since 39.9 is 5.25 per cent of 760.
From Paul Bert's results it might be confidently predicted that
it is not the mere percentage but the pressure of CO2 in the alve-
olar air which regulates the breathing, and our experiments left
no doubt on this point. On descending one of the deepest mines,
and ascending the highest hill in Great Britain, we found that the
" Paul Bert, La Pression barometrique, Paris, 1878.
RESPIRATION
31
pressure of CO2 in the alveolar air remained about constant, while
the percentage varied. A more conclusive experiment was made in
a large steel pressure chamber, employed at the Brompton Hospi-
tal, London, for the treatment of asthma. In this chamber — ^the
only one then existing in England of the kind — we compared
our alveolar air at normal atmospheric pressure, and at the highest
pressure which the chamber would stand. The mean results were
as follows :
Barometric pressure
COi i>er cent
COi -pressure in
in mm. Hg.
in dry alveolar
per cent of
atr
one atmosphere
J. G. P.
1261
3.64
5.83
765
6.41
6.05
J. S. H.
1258
3.42
5.46
765
5.62
,S.3i
Mean
1260
3.53
5-64
765
6.01
5.68
It is quite clear from these results that it is the pressure of COj
in the alveolar air, and not its mere percentage, which regulates
the breathing. It is also as evident from these experiments as
from those already mentioned in which the oxygen percentage
was varied, that the oxygen pressure in the alveolar air may be
increased very greatly "without at the time affecting the regula-
tion of the CO2 pressure. The actual alveolar oxygen pressure
was 13.0 per cent of an atmosphere in the observations at ordinary
pressure, and 26.8 per cent in those at the high pressure.
Still more striking results were obtained by Leonard Hill and
Greenwood,^^ and by Boycott^^ in steel chambers erected later
for the investigation of the effects of high atmospheric pressures.
Hill and Greenwood obtained the following results.
They considered at the time that their results showed that the
production of CO2 remained unaltered during the expe ri merits ;
and it is evident that had the volume of air breathed and the mass
of CO2 produced remained the same the results would have beenj
as they found. But the constancy of the partial pressure of CO2I
was certainly due, not to the cause which they suggested, but tol
the fact that the breathing was regulated so as to keep the partial
pressure of CO2 steady.
"Hill and Greenwood, Proc. Roy. Soc, 1906, B, LXXVII, p. 442, 1906.
"Boycott and Haldane, Journ. of Physiol., XXXVII, p. 365, 1908.
32 RESPIRATION
ATMOSPHERIC
ALVEOLAR CO2
ALVEOLAR CO2
PRESSURE
PRESSURE IN
PERCENTAGE
IN MM
Hg.
IN MM. Hg.
Hill
Greenwood
Hill
Greenwood
760
4.7
5.3
33-5
37.8
4640
0.75
0.9
34.4
41.3
3860
0.95
I.O
36.2
38.1
3090
1.2
1.3
36.5
39.5
2310
1.8
1.8
40.7
40.7
1540
2.5
2.7
37.5
40.5
760
5.0
5.4
35.6
38.5
The results of Boycott and Haldane with Boycott as subject
are shown graphically in Figure 7. It will be seen that, provided
that the alveolar oxygen pressure was prevented from falling so
low as to cause want of oxygen, the alveolar CO2 pressure re-
mained steady with variations of the barometric pressure from
300 to 2800 mm. and corresponding variations in the alveolar
CO2 percentage from 15 to 1.5.
The daily variations of atmospheric pressure at any one place
are not sufficiently great to cause any considerable variations in
the alveolar CO2 percentage, and there are other causes, discussed
below, which cause distinct variations in the alveolar CO2 present.
Even, therefore, if we take into consideration the daily variations
of atmo.spheric pressure, the resting alveolar CO2 pressure is not
quite constant at different times in the same individual, and varies
considerably in different individuals.
The differences in the alveolar CO2 pressure in different indi-
viduals; and in different sexes and at different ages, were investi-
gated by Miss Fitz Gerald and myself. We obtained the following
results from a number of different persons,^^ living at Oxford.
ALVEOLAR COa
PRESSURES IN MM. OF MERCURY
Mean
Maximum
Minimum
Men
39.2
44.5
32.6
Women
36.3
41.0
30.4
Boys
37.2
42.1
30.6
Girls
35.2
40.1
31.2
"Haldane and FitzGerald, Journ. of Physiol., XXXII, p. 491, 1905.
RESPIRATION
33
The investigations of Priestley and myself brought out the
remarkable fact that the composition of the alveolar air is the
same no matter how deep the breath may be from the last portion
of which the sample is taken. According to descriptions commonly
600
200 0
3000 2600 2200 1800 14 00 1000
air pressure mm Mg
Figure 7.
Effects of variation in barometric pressure on alveolar gas pres-
sures and percentage of CO2 in A. E. B. The dotted lines show results
when oxygen was added to the air.
current of the anatomical relations of bronchioles to alveoli one
would have expected that the deeper parts of a breath, coming
from alveoli far from the bronchioles, would contain more CO2,
since these alveoli must get less fresh air than the alveoli near a
bronchiole. It was somewhat of a puzzle that this was not the case.
I was unaware of the anatomical investigations which had been
carried out ten years earlier by a distinguished American investi-
gator, W. S. Miller, who by using the laborious "reconstruction"
method had discovered the true anatomical arrangement.^^ Figure
8, modified from a colored plate in Miller's latest paper, shows
" Miller, Journ. of Morphoh, VIII, p. 165, 1893, and XXIV, p. 459, 1913.
34
RESPIRATION
diagrammatically this arrangement. The finest ordinary bronchi-
oles divide up to form "respiratory bronchioles" with alveoli in
Figure 8.
Diagram showing arrangement of three lung lobules, with their
bronchiole, respiratory bronchioles, alveolar ducts, atria, and air-
sacs. (After colored plate by Miller, Journ. of Morphol. 24, p. 459,
1913)
their walls, and the respiratory bronchioles branch into "alveolar
ducts" lined with ordinary alveoli, and each opening into from
RESPIRATION 35
two to five distributing chambers which he named "atria," and
which are also lined with alveoli. From each atrium a number of
openings lead onwards into what he calls "air-sacs," which are
main cavities of which the walls are also constituted of alveoli or
air cells. By far the greater part of the alveoli belong to the air-
sac system, but a certain number belong to the respiratory bron-
chioles, alveolar ducts and atria; and the latter act partly as air
passages to the air sacs, and partly perform the same respiratory
functions as the air sacs themselves.
With this anatomical arrangement the whole of an air-sac sys-
tem is about equally well ventilated with fresh air, the only alveoli
which receive an undue supply of fresh air being those of the
respiratory bronchioles, alveolar ducts and atria. We can thus
understand why it is that the deeper parts of a very deep breath
have exactly the same composition as the middle parts. Evidently
however what Priestley and I called "alveolar air" is air-sac air.
The fact that the atria, etc., have partly a respiratory function,
and partly act as air passages to the air-sac system, enables us
also to clear up some otherwise unintelligible facts with regard
to the "dead space" in breathing. The dead space was first esti-
mated roughly by Loewy from the volume of a cast of the
respiratory passages, taken in a human lung after death. As this
method seemed uncertain, Priestley and I made determinations by
comparing the composition of a whole breath of expired air with
the composition of what we took to be the whole alveolar air. We
calculated the expired air as a mixture of this alveolar air with
fresh air occupying the dead space. In this way we found that
during rest the volume of the "effective dead space" is about
30 per cent of the volume of the average tidal air. For greater
certainty Douglas and I collected the whole of the expired air
over a certain period, and made the same calculation from the
average volume arid composition of each breath, compared with
the composition of the alveolar air.^^ We then found that the
"effective dead space" is far greater during the hyperpnoea of
hard muscular work than during rest. As we were then still un-
aware of Miller's work we interpreted our observations as indicat-
ing that the bronchi or other respiratory passages become wider
duringl^yperpnoea, ]so as to enable air to enter the lungs more
easily. Any one who examines a section of lung must be struck at
once by the fact that the mucous membrane of the bronchi is
usually in folds, indicating that if the muscular coat relaxed the
"Douglas and Haldane, Journ. of Physiol., XLV, p. 235, 19 12,
36 RESPIRATION
folds would open out and the lumen of the bronchi would greatly
increase. We thought it probable that such a relaxation occurs
during hyperpnoea, and that this explains the increase of the dead
space.
Using a method which Siebeck first introduced, Krogh and
Lindhard^^ then redetermined the dead space, and concluded that
it does not appreciably increase during hyperpnoea. Their method
was to take in a small measured breath of a hydrogen mixture;
they then made a deep expiration, which was measured, and
from the deeper part of which a sample of the alveolar air was
taken. From the percentage of hydrogen in the alveolar air, as
compared with the higher percentage in the whole expired air, the
volume of the dead space could be calculated on the assumption
that it was filled with the original hydrogen mixture.
The question was then independently reinvestigated about the
same time by Yandell Henderson, Chillingworth, and Whitney at
Yale, and myself at Oxford. We reached the same conclusion —
namely that the apparent effective dead space is enormously in-
creased during hyperpnoea, as Douglas and I had found, but that
the increase is due simply to mechanical causes, and occurs
whether or not the respiratory center is excited by excess of CO2
or other causes. Our papers appeared together in the American
Journal of Physiology.^'^ In their determinations Krogh and
Lindhard had inspired the same volume of the hydrogen mixture
whether there was air hunger at the time or not, and consequently
they got the same dead space; whereas our experiments were
made with the very deep breathing which is naturally associated
with air hunger, and consequently the dead space was increased.
Miller's investigations enable us to explain the great increase
of the "effective dead space" with deep inspirations. Considering
the relative thickness and stoutness of the bronchial walls it seems
very improbable that the bronchi, surrounded as they are by very
yielding lung tissue, could passively dilate appreciably owing to
a deeper inspiration, and this consideration led Douglas and
and me to believe that they must dilate owing to a relaxation of
their muscular walls — a theory negatived by the later experi-
ments. What dilate during deep breathing are evidently not the
bronchi but Miller's "alveolar ductules" and "atria," which serve
as air passages to the "air sacs," and which must expand along
"Krogh and Lindhard. Journ. of Physiol., XLVIII, p. 30, 1913-
" Yandell Henderson, Chillingworth, and Whitney; also Haldane, Amer. Journ.
of Physiol., XXXVIII, pp. i and 20, 1915.
RESPIRATION
37
with the general expansion of the lungs. In addition, they are more
completely washed out by fresh air during inspiration. It also fol-
lows that the "effective or virtual dead space" is neither a definite
anatomical space nor a fixed dead space in any sense, but a value
dependent on several variable factors. These factors include the
rates at which CO2 passes outwards and oxygen passes inwards
between the air and blood at different points in the alveolar sys-
tem. For this reason the "effective dead space" is different for
oxygen and CO2. The over-ventilation of the atria, etc., removes
from the blood circulating round them an extra proportion of
carbon dioxide, but cannot, for a reason which will be discussed
later, give to the blood any appreciable extra amount of oxygen.
During inspiration this extra proportion of CO2 passes on to the
saccular alveoli, but not during expiration. The "respiratory
quotient," or ratio between the volume of carbon dioxide given
off and of oxygen absorbed, is thus abnormally high in the air
expired from the atria, etc., and as a consequence abnormally
low in the air sacs, so that the "effective dead space," as calculated
from deficiency of oxygen in the expired air, compared with that
in the "alveolar air," is greater than when the dead space is calcu-
lated from the relative CO2 percentages. The respiratory quotient
for the "alveolar air" is also below the correct value as calculated
from the composition of the mixed expired air.
The following table, giving results on myself, shows the varia-
tions in the "effective dead space" with varying depth of breathing
as calculated both from CO2 and from oxygen, and also the differ-
ences between the respiratory quotient as calculated from the
expired air and from the alveolar air. Using a slightly different
method, Henderson, Chillingworth, and Whitney got similar re-
sults.
It will be seen from this table how enormously the apparent
dead space varies with the depth of breathing and how much
greater the dead space calculated from the oxygen is than that
calculated from the CO2. A further point which comes out is that
with deep breathing the difference between the alveolar CO2
percentages at the beginning and end of expiration is far less than
the difference between the oxygen percentages. This is mainly
because the extra CO2 washed out of the alveolar ductules and
atria passes on into the saccular alveoli during inspiration. A
further point is that the true respiratory quotient is about a sixth
higher than the alveolar respiratory quotient. The fact that the
alveolar respiratory quotient is a good deal lower than the true
38
RESPIRATION
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RESPIRATION
39
quotient had been noticed by us before this in the work of the
Pike's Peak Expedition (to be referred to later), but had not been
explained. It is quite evident from the table that the composition
of the deep alveolar air cannot be exen approximately calculated
from that of the expired air by assuming the existence of a con-
stant dead space. The latter assumption has caused great confusion
in recent years, particularly in the work of the Copenhagen School.
It was shown by Yandell Henderson and his coadjutors that
when air passes along an air passage the axial stream is much
faster than the peripheral stream, and that as a consequence of
this the air in the dead space is not pushed out bodily in front of
the alveolar air during expiration. Some of the tracheal and
bronchial air is at first left behind, and before pure alveolar air
issues at the nose or mouth the air passages have to be washed out
by three or four times their volume of alveolar air. This is illus-
Figure 9.
(a) Shows a "spike" of smoke moving through a glass tube, (b)
Shows the condition when the current is suddenly stopped and mixing
instantaneously occurs, (c) Shows clear air drawn in.
Bi^
Figure 10.
Shows how a column of smoke crosses a bulb with little mixing
or sweeping out of the air within it.
trated by Figures 9 and 10, taken from their paper, and drawn
from experiments made with smoke. Both they and I found also
that a pause before expiration diminishes the volume of the ap-
parent dead space. This is easily understood, as the air in the
atria, etc., will during the pause come nearer in composition to
that of the saccular alveoli. With care in avoiding a pause I found
40
RESPIRATION
that during rest with normal breathing it was necessary to expire
about 800 cc. of air before a reliable alveolar sample could be
obtained at the end of inspiration. If the breathing was deep and
slow much more air had to be expired. At the end of a normal
expiration, however, the air issuing from the mouth is practically
alveolar in composition.
The conclusion reached by Priestley, Douglas, and myself that
increased production of CO2, and consequent rise in the alveolar
CO2 percentage, determines increased breathing during muscular
work was afterwards questioned by Krogh and Lindhard,^^ on
the ground that our determinations of the alveolar COg percentage
were fallacious, and that the real alveolar CO2 percentage during
muscular work is not only lower than we found, but also con-
siderably lower than during rest. Their argument is mainly
based on the assumptions, which have already been shown to be
wrong, that the "effective dead space" is not largely increased
during deep breathing, and that reliable samples of alveolar air
can be obtained at the end of a deep inspiration, without more
than a very shallow expiration to clear the extra dead space. This
part of their argument falls to the ground. They point out, how-
ever, what is a real source of slight error — namely that a delay of
fully half a second occurs during the taking of an alveolar sample,
and that during this interval the alveolar CO2 percentage must
rise appreciably. It was shown above that the difference in CO2
percentage between samples of alveolar air taken at the beginning
and end of expiration during work corresponding to an increase
of 4.3 times in the CO2 production was about 0.6 per cent. As an
expiration took nearly 2 seconds, there would be a rise of 0.15 per
cent in half a second, corresponding to the delay in taking the
alveolar sample. During rest, according to a similar calculation,
there would be a rise of 0.05 per cent. The net error in comparing
rest with work would thus be only about o. i per cent, a difference
too small to affect the conclusions materially. Owing to their
defective methods of estimating and directly determining the
alveolar CO2 percentage at the beginning of expiration Krogh
and Lindhard enormously overestimated the error due to a delay
of half a second in obtaining a sample. The fact remains, however,
that when the work was pushed in the case of Douglas, and even
without pushing the work in my own case, the rise in alveolar CO2
percentage was less than corresponded to the increase in breathing.
This significant fact will be discussed later.
** Krogh and Lindhard, Journ. of Physiol., XLVIII, p. 30, 19 13.
RESPIRATION 41
It will be shown in Chapter IX that during rest under normal
conditions the gas pressures in the alveolar air and blood passing /
through the alveoli come into exact equilibrium. Now it has just j
been shown that in a very appreciable part of the lung alveoli
(those in the respiratory bronchioles, alveolar ducts, and atria)
the CO2 pressure is lower, and the oxygen pressure higher, than
in the air-sac alveoli. We might therefore be led to infer that in
the mixed arterial blood the CO2 pressure will be lower, and the
oxygen pressure higher, than in the blood from the air-sac alveoli,
and that in consequence of this the mixed arterial blood will have
a lower CO2 pressure than that of the deep alveolar air. Further
consideration shows, however, that this will not be the case. The
walls of the alveoli of respiratory bronchioles, etc., are in contact
on the one side with the air of air-passages, but on the other with
air in the air-sac alveoli. Hence the extra proportion of CO^
extracted from the blood in the air-passage alveoli is practically
taken from the air-sac alveoli, and this is why the apparent respira-
tory quotient of the air-sac alveoli is lower than the true respira-
tory quotient. We should be counting the lowering twice if we as-
umed that in consequence of the extra discharge of CO2 in the re-
spiratory bronchioles, etc., the CO2 pressure of the arterial blood is
lower than corresponds to that of the air-sac alveoli. The same
argument applies also as regards the oxygen pressure of the air-
sac air, although under normal conditions hardly any extra oxy-
gen can pass into a given volume of blood in its passage through
the alveoli of respiratory bronchioles, etc. Hence the gas pressures
of the air-sac alveoli represent truly the mean gas pressures to
which the arterial blood is saturated in the various alveoli. This
is why the gas pressures of the deep alveolar air as determined by
the method which Priestley and I introduced are of so much
importance.
Krogh and Lindhard^^ still maintain that the mean gas pres-
sures to which the blood is equilibrated in passing through the
lungs is given, not by the composition of the deep alveolar air,
but by that of the alveolar air as calculated from a fixed, or almost
fixed, dead space. This involves the conclusion that during deep
breathing, including the deep breathing of muscular exertion, the
arterial CO2 pressure is far lower than is shown by the direct
method of Priestley and myself. As, however, there is no cor-
responding apnoea, the whole theory of regulation of breathing in
accordance with the CO2 pressure of the arterial blood must be
^ Krogh and Lindhard, Journ. of Physiol., LI, p. 59, 1917.
^2 RESPIRATION
abandoned if Krogh and Lindhard are correct. Their reasoning
is quite logical, but their premises are unsound. They have failed
to take into consideration the anatomical relations of the air-
passage alveoli to the air-sac alveoli.
The fact that the mixed air from all the air sacs of the lungs is
the same in composition however much of this air is expelled in
taking a sample led us to assume almost unconsciously that the
composition of the air in practically all the air sacs is the same.
Nevertheless all that the experiments prove is that the average
composition of the air expelled from the air sacs is the same, while
in individual air sacs the composition may vary widely.
It is evident that in any particular air-sac system the mean
composition of the contained air will depend on the ratio between
the supply of fresh air and the flow of blood. If the supply of
fresh air is unusually small in relation to the supply of venous
blood there will be a lower percentage of oxygen and higher
percentage of carbon dioxide in the air of the air sac, and vice
versa. It seems probable that by some means at present unknown
to us a fair adjustment is maintained normally between air supply
and blood supply. For instance, the muscular walls of bronchioles
may be concerned in adjusting the air supply, or the arterioles
or capillaries may contract or dilate so as to adjust the blood
supply. In any case what seems to matter is the degree of arteri-
alization, not of the blood from individual air sacs, but of the
mixed arterial blood; and if the composition of the mixed air-sac
air served as a reliable index of the arterialization of the mixed
arterial blood we might dismiss as a. matter of only academic
interest the question whether the air in individual air sacs varies
in composition.
It will be shown below that there can be little doubt that under
normal conditions the air in different air sacs varies appreciably
in composition, and that under abnormal conditions the variation
may be considerable. It will also be shown that the latter fact
is one of great importance in pathology and therapeutics.
Meanwhile it is clear from the experiments described in the
present chapter that under normal conditions, excluding heavy
work, the breathing in man is on an average regulated by the al-
veolar COo pressure; and a very slight increase or diminution in
the alveolar COj pressure suffices to cause a very great increase or
diminution in the breathing. This conclusion has thrown a flood
of clear light on the physiology of breathing.
CHAPTER III
The Nervous Control of Breathing.
It is now necessary to discuss more closely the influence of nervous
control on breathing. The rhythmic activity of the respiratory
center is for short periods of time very completely under volun-
tary control — a fact evidently connected with the very delicate
use of the lungs in phonation, as well as in other voluntary acts not
directly connected with "chemical" respiratory functions. Excita-
tion of various afferent nerves may also excite or inhibit inspira-
tion or expiration. Most of the effects thus produced appear to be
protective in various ways, or preparatory to some particular
effort, and they only disturb the main regulation of breathing
occasionally, just as voluntary interference does. In view of the
facts with regard to the control of breathing by chemical stimuli,
we might thus be led to the conclusion that the respiratory center,
when not interfered with by voluntary or other occasional nervous
disturbances, acts simply by producing rhythmic inspiratory and
expiratory discharges, determined in extent and frequency by
nothing but chemical stimuli dependent on the blood supply.
This simple conception is entirely inadequate, in view, more
particularly, of the facts discovered originally by Hering and
Breuer, and already referred to. These facts, apart from the
results of section of the vagi, can be observed very fully in man,
without the complications introduced by anaesthetics, and were
so studied in 191 6 by Mavrogordato and myself.^ We employed
a very simple arrangement which enabled us to breathe through
a wide-bored tap, and observe by a water manometer the pres-
sure between the mouth and the tap when the latter was closed,
the nostrils being closed by a clip. If the tap was closed at
the end of natural or forced inspiration or expiration, or in
any other phase of respiration, the phenomena could be studied.
By connecting the far end of the tap with a reservoir containing
pure air or air containing any required percentage of CO2, we
could observe the influence of hyperpnoea due to CO2, and by
suitable volume recorders connected with the far ends of the
reservoir and gauge the breathing and pressure could be recorded.
If wtpiration is interrupted by turning the tap, and all voluntary
^ Journ. of Physiol., L; Proc. Physiolog. Soc, p. xli, 19 16.
44
RESPIRATION
effort is suspended, the previous rhythm of the respiratory center
is interrupted by a prolonged expiratory phase, as indicated by
the gauge. The expiratory pressure is at first slight and constant,
but afterwards rises gradually and at an increasing rate, until,
if expiration is still prevented, there is at length an inspiratory
effort, as shown in Figure ii. Similarly, if the breathing is ob-
RESPIRAVON
/NTRAPULMONARY PRESSURE
B.
RESPIRATION
f NTRAPULMONARY PRESSURE
Figure 1 1 .
Effects of interrupting natural breathing. A, Respiration inter-
rupted during inspiration — near end. B. Respiration interrupted
during expiration — near end. Respirations — inspiration up, expira-
tion down. Intrapulmonary pressure — ^positive pressure down, neg-
ative pressure up.
structed during expiration there is a prolonged and increasing
inspiratory effort (Figure ii). The initial inspiratory pressure
is somewhat greater than the initial expiratory pressure, and this
is in accordance with the opinion generally held that while ordi-
nary quiet inspiration is always an active process the correspond-
ing expiration is mainly passive.
With interruption at the end of an extra deep inflation or de-
flation of the lungs the phenomena are still more marked. If
apnoea has previously been caused by forced breathing, the initial
expiratory or inspiratory pressures are still produced as before,
but a long interval elapses before they begin to increase, and the
duration of the expiratory or inspiratory phase is much prolonged.
RESPIRATION
45
If, on the other hand, the inflation or deflation was made during
the hyperpnoea caused by breathing air containing an excess of
CO2 the expiratory or inspiratory pressures mount up at once.
The mounting up of the initial pressure is thus dependent on the
accumulating chemical stimulus to the respiratory center. If the
breathing is interrupted, not just after, but before the completion
of inspiration or expiration, the inspiratory phase is continued if
inspiration has been interrupted, and the expiratory if expiration
has been interrupted, as shown in Figure 1 1.
If, instead of interrupting the breathing by means of a tap or
other obstacle which cannot be overcome, the only interruption
is by a limited adverse pressure capable of being overcome by
the breathing, the apparent "apnoea" is terminated by an expira-
tion if the pressure is positive, or an inspiration if the pressure is
negative. This simply means that with a positive pressure the
expiration occurs at the moment when the expiratory effort has
increased sufficiently to overcome the adverse positive pressure,
and similarly with a negative pressure. This is illustrated by
Figures 12 and 13, which reproduce stethographic tracings ob-
tained in man.^ The subject at first breathed quietly through the
limb of a wide-bore three-way tap open to the air. At the end of
an inspiration the tap was suddenly turned so that the mouth of
the subject was connected with the air of a bag under a pressure
of about 3 inches of water. The consequence of this was that the
jlJ\_UJUjm\f^^^
Figure 12.
yi_j^_jljy{j[0im^
Figure 13.
Effects of prolonged distention of the lungs. To be read from left to right. Time
marker =; seconds. Distention continued between the two crosses. In Fig. 12 pure
air was used for distention; in Fig. 13 air containing 7.3 per cent of COa and
8.2 per cent of oxygen.
lungs were suddenly distended with a large volume of air. It
will be seen that after about half a minute the apparent pause in
'Christiansen and Haldane, /own, of Physiol., XL VIII, p. 272, 19 14.
46 RESPIRATION
the breathing was interrupted by an expiration, repeated after-
wards at gradually diminishing intervals. The diminution in
these intervals was evidently due to the fact that COg was ac-
cumulating in the lungs; and this interpretation is confirmed by
Figure 13.
Figure 14 shows a corresponding effect with a negative pressure
applied, so as partially to deflate the lungs. In this case the ap-
parent pause was much shorter, as CO2 began to accumulate very
rapidly, owing to the facts that not only had no fresh air been
introduced, but the volurne of air in the lungs was diminished.
vvvimW^"^^^^^^^
]j\IWwmNm/\i\i
Figure 14.
Effects of partial deflation. Crosses show beginning and end of
deflation. To read from left to right. Time-marker = i second.
The supposed apnoeic pause produced by distention or inflation
of the lungs is simply a prolonged inspiratory or expiratory effort.
This effect is produced regardless of the chemical stimulus to the
center. Thus Lorrain Smith and I showed that it is even produced
when the lungs are distended with air containing 20 per cent of
CO2, though the prolongation is much curtailed in such a case.'
It is thus clear that the continuance of an inspiratory or ex-
piratory discharge of the respiratory center depends on the extent
to which actual inspiration or expiration accompanies the dis-
charge. If the movements of inspiration or expiration are not
accomplished the ordinary respiratory rhythm is replaced by a
prolonged and increasingly powerful inspiratory or expiratory
discharge, tending to overcome the obstruction. The respiratory
center does not act independently of the lung movements, but
inspiratory or expiratory discharge of the center goes hand in
hand with actual inspiration or expiration, as if the center were
one piece with the lungs. The term "vagus apnoea" is evidently
an entire misnomer, as prolonged inspiratory or expiratory effort
cannot be called apnoea. The tracings which apparently demon-
strate the existence of apnoea are only one-sided, and therefore
misleading, records.
Hering and Breuer found, as already mentioned in Chapter I,
that after section of both vagi the association of discharge of the
•Haldane and Lorrain Smith, Journ. of Pathology. I, p. 168, 1892.
RESPIRATION
47
center with the respiratory movements is annulled, so that infla-
tion or deflation of the lungs has no immediate influence on the
respiratory rhythm. Hence the afferent impulses through which
the discharges of the center are coordinated with the movements
of the lungs are conveyed by the vagi. After section, or better (so
as to avoid excitatory effects produced by actual section), freezing
of the vagi, the breathing, as has been known since early last
century, becomes deeper and less frequent, the inspirations in
particular taking on a dragging character which, until the work
of Schafer, referred to below, was entirely attributed to the ab-
sence of the normal inhibitory effect conveyed through the vagi
on distention of the lungs to a certain point. Nevertheless the
respirations continue to be rhythmic, and to respond in their depth
to the stimulus dependent on varying percentages of COg in the
alveolar air. It was shown by Scott* however, that the control of
the alveolar CO2 percentage when excess of CO2 is present in the
air breathed becomes much less perfect, as the frequency of the
breathing cannot increase.
The analogy between the Hering-Breuer stimuli transmitted
through the vagi and what Sherrington has named the **proprio-
ceptive" stimuli participating in reflex or voluntary movements
of the limbs is evident; though the rhythmic discharges of the
respiratory center are dependent on stimuli, not from the surface
of the body, but from the blood acting on the center.
When, in addition to section of the vagi, the respiratory center
is also severed from its connections above the medulla oblongata,
the rhythmic discharges of the center become still less frequent,
and may be inadequate to prevent death from asphyxia. The
influence on the center of afferent stimuli from the respiratory
muscles has not yet been demonstrated directly; but the fact,
observed by Boothby and Shamoff,^ that an animal in which the
pulmonary branches of the vagi have been severed without injury
to the recurrent laryngeal nerve recovers after a sufficient time
a normal control over respiration seems to point to the existence
of such stimuli. The same conclusion has been still more clearly
reached in a quite recent paper by Schafer,^ who shows that the
slowed breathing after section of the vagi is largely due to ob-
struction caused by laryngeal paralysis.
We must now endeavor to correlate the facts relating to the
* Scott, Journ. of Physiol., XXXVII, p. 301, 1908.
"Boothby and Shamoff, Amer. Journ. of Physiol., XXXVII, p. 418, 1915.
'Schafer, Quart. Journ. of Exper. Physiol., XII, p. 231, 1919.
48 RESPIRATION
Hering-Breuer phenomena with those relating to the governing
of the lung ventilation by the charge of CO2 in the alveolar air
and arterial blood. It seems very clear that the immediate cause of
the arrest of inspiration during ordinary breathing is the disten-
tion of the lungs to a certain point, and a consequent inhibitory
stimulus transmitted up the vagi. The experiments of Head/ in
which the movements of a slip of the diaphragm, the most promi-
nent inspiratory muscle, were recorded, show that this inhibition
produced an instant relaxation of the diaphragm. If the vagi
have been frozen the relaxation is greatly delayed, and even
after the delay is at first very imperfect. The inhibition of inspira-
tion initiates an expiratory phase, which continues until, in its
turn, it also is cut short by deflation to a certain point, at which
the vagi transmit an influence which inhibits expiration and
initiates the inspiratory phase. It appears from Head's experi-
ments that if the vagi are frozen after the inspiratory or expira-
tory phase has been initiated, this phase still continues. If with
vagi intact the breathing is partially obstructed, inspiration or
expiration is continued till either act is complete. The influence
transmitted through the vagi initiates inspiration or expiration,
therefore; and the center persists in the inspiratory or expiratory
phase till the vagus gives the signal which terminates the phase
and initiates the complementary phase. The center behaves as if
it always remembered the last signal; and the analogy between
any act dependent on memory and the duration of the inspiratory
or expiratory phases of breathing is evident. We are equally
reminded of the "refractory period" in the phases of cardiac and
other muscular activity.
Where the "chemical" regulation of the respiratory center
exerts its preponderating influence is in determining the extent
to which inflation or deflation of the lungs must extend in order
that the Hering-Breuer stimuli should be effective, and also the
vigor and consequently the rapidity of the inspiratory and expira-
tory movements. Thus an increased CO2 stimulus causes increased
depth of breathing, since a greater inflation or deflation of the
lungs is required before the stimulus of inflation or deflation
becomes effective. At the same time the movements of the chest
wall become more rapid, so that the frequency of breathing is
not diminished in consequence of the greater distances traveled
by the chest walls. The net result is thus ordinarily increase
in depth without diminution in frequency. But if the frequency
' Head, Journ. of Physiol., X, pp. i and 279, 1889.
RESPIRATION 49
is diminished in consequence of voluntary or involuntary inter-
ference, the depth is correspondingly increased owing to a very
slightly increased CO2 stimulus. This is the explanation of why
the mean alveolar CO2 percentage remains so steady with varying
frequency of breathing. It is only, as a rule, when there is very
considerable increase in the breathing that there is any material
increase in the frequency; and during health the frequency is
hardly affected by moderate muscular exertions or moderate
stimulation by CO2 in other ways. The frequency of breathing
is thus no measure of the amount of air breathed; but undue
frequency of breathing, as will be shown later, is a very important
abnormal sympton.
The response of the breathing to abnormal resistance has re-
cently been investigated by Davies, Priestley, and myself.^ For
recording the depth and frequency of breathing we used the
recording ''concertina" described in Chapter VII (Figure 43).
For a resistance to breathing we sometimes used partly closed
taps, the effects of which could be thrown in suddenly by closing
alternative inspiratory and expiratory air passages. In place of
the taps we also sometimes employed cotton wool resistances, as
with a cotton wool resistance the driving pressure varies directly
as the air flow, while with a tap the pressure varies as the square
of the air flow. The pressure was measured with a water ma-
nometer connected with the tubing between the mouth and the
resistance.
MiJJliiliMJlMi
Figure 15.
Effects of resistance. In this and subsequent figures inspiration = upstroke.
Time marker = 10 seconds. To read from left to right.
It was found that when a resistance is thrown in the immediate
effect is a great slowing of the breathing. After the next breath
the respirations become deeper and less slow, and after several
breaths the breathing settles down to a rhythm in which the
respirations are deeper and correspondingly less frequent. With
a considerable resistance the frequency is often reduced to a fourth
of the normal rate, while the depth is almost correspondingly in-
' Davies, Haldane, and Priestley, Journ. of Physiol., LIII, p. 60, 19 19.
50
RESPIRATION
creased (Figure 15). The explanation of this is obvious from the
foregoing account of the physiology of the Hering-Breuer reflex.
When a resistance is thrown in deflation or inflation of the lungs
is slowed, but continues till the point is reached at which the
phase of respiration is reversed by the reflex. Meanwhile, how-
ever, CO2 has begun to accumulate, so that the next respiration
is not only more vigorous but deeper; and the final result is deeper
and less frequent respiration.
When there is no resistance to breathing the compensation of
diminished frequency by increased depth is almost perfect, as
shown by the experiments already quoted of Priestley and my-
self; but when the slowing is due to resistance the compensation
is less perfect, since the extra work performed by the respiratory
muscles implies a more powerful stimulus of CO2 to the respira-
tory center. Accordingly the alveolar CO2 percentage rises quite
considerably with resistance to breathing. The following table
shows the rises observed by Davies, Priestley, and myself with
varying resistances.
Just as, in the absence of resistance a very slight increase in the
alveolar CO2 percentage, and consequent slight increase in the
chemical stimulus to the respiratory center, increases the depth
of breathing, so a slight diminution in alveolar CO2 percentage
diminishes the depth. It was recently discovered independently by
Yandell Henderson in America and by Liljestrand, Wollin, and
Nilsson in Sweden that if apnoea is first produced and artificial
respiration then carried out by Schafer's or one of the other usual
methods the quantity of air which enters the chest at each artificial
inspiration is only about a third or less of what enters during
artificial respiration when the subject has simply suspended vol-
untarily his own breathing. With voluntary suspension of the
natural breathing, moreover, the volume of air which enters at
each artificial inspiration varies (roughly speaking) inversely
as the frequency of the artificial breathing, so that it is impossible
to produce a condition of true apnoea by increasing the frequency
of the artificial breathing. If, finally, the air artificially inspired
contains an excess of CO2, the volume introduced by the artificial
respiration increases just as it would with natural breathing. It is,
in fact, just as if the subject were himself breathing naturally all
the time, in spite of the undoubted fact that he has suspended his
natural breathing.
These phenomena are completely intelligible on the theory that
the limits within which inflation or deflation of the lungs inhibits
RESPIRATION
51
SUBJECT
ALVEOLAR CO2
RESISTANCE IN
PERCENTAGE
CM.
OFH2O
During
Inspira-
Normal.
resistance
tory.
Expiratory
Remarks.
J.S.H.
5-40
5.34
4^
iH
Slight cotton-wool resistance.
Breathing slowed
J. G. p.
;
5.60
5.80
4/2
i^
Slight cotton-wool resistance.
Breathing slowed
\ H.W.D.
■
5-97
6.24
13
5
Heavier cotton-wool resistance.
Breathing slowed
\
5-99
S.93(?)
6.61
6.21
8
4
Lighter cotton-wool resistance.
Breathing slowed
Lighter cotton-wool resistance.
Breathing slowed
Lighter cotton-wool resistance.
"
"
6.26
"
>>
Breathing slowed
Lighter cotton-wool resistance.
Breathing slowed
7.02
25
14
Heavy cotton- wool resistance.
Breathing slowed
J. S. H.
5.4
6.40
6.60
"
>>
Heavy cotton- wool resistance.
Breathing quickened
Heavy cotton-wool resistance.
Breathing about dS
6.76
?.
?
Resistance lessened by partly
opening taps. Respirations
about 30
J.G.P.
5. 37
5-76
?
?
Tap resistance lessened by
partly opening taps. Respi-
rations about 4
J. S. H.
5.33
6.50
?
?
Tap resistance lessened by
partly opening taps. Respi-
rations about 24
6.80
?
?
Tap resistance increased. Res-
pirations about 40
52
RESPIRATION
inspiration or expiration depend on the alveolar COg percentage.
In apnoea a very slight amount of inflation or deflation is suffi-
cient to cause inhibition of inspiration or expiration. In conse-
quence of this the respiratory movements are nearly jammed in
a mean position during apnoea unless considerable force is ex-
erted, which is not the case with ordinary methods of artificial
respiration. With a normal stimulation of the respiratory center
by CO2 and a normal respiratory frequency, the limits of inflation
or deflation at which the Hering-Breuer inhibition occurs are a
good deal wider, and with a diminished respiratory frequency,
or an increased percentage of CO2 in the air inspired, the limits
are much wider still. Thus the respiratory center tends indirectly
to govern artificial respiration unless the latter is of a specially
vigorous kind.
That the center responds, even during apnoea, with tonic con-
traction of the diaphragm to deflation of the lungs, and with re-
laxation to inflation, was clearly shown by Head's experiments ;
and the inspiratory or expiratory pressures produced by the
diaphragm and other respiratory muscles can easily be demon-
strated in man. The continued control of respiratory movements
during apnoea or voluntary suspension of the breathing, or during
voluntary variations in the frequency of breathing, is thus readily
intelligible. In voluntary forced breathing or in forcible artificial
respiration, this control is broken down. It must not, however, be
assumed that because the ordinary gentle methods of human
artificial respiration have such a small eff'ect during ordinary
apnoea, the eff"ect will be equally small where the suspension of
breathing has been caused by asphyxiation or the action of an
anaesthetic or other poison. In these cases the excitability of the
respiratory center to the Hering-Breuer stimuli is possibly as
much depressed as its excitability to CO2, in which case the
artificial respiration will not be insufficient.
The normal rate and depth of breathing in any individual is evi-
dently an expression of the normal balance between chemical and
nervous stimuli. The normal is fairly constant because the balance
is a stable one. It may, however, be greatly altered under abnormal
conditions, and it can easily be interfered with voluntarily.
It is evident from the foregoing discussion that we cannot
separate the nervous from the "chemical" control of breathing,
since each determines the other at every point. From too exclusive
a consideration of the nervous side of the control it has been sup-
posed, on the one hand, that the center is essentially automatic in
RESPIRATION 53
its action, or that its alternate inspiratory and expiratory dis-
charges are, under normal resting conditions, determined simply
by alternating stimuli transmitted through the vagus nerves. On
the other hand a too exclusive consideration of the chemical side
leads to the erroneous impression that the discharges of the center
are, apart from occasional voluntary or other interferences, de-
termined in strength and duration solely by chemical stimuli. If,
finally, we attempt to determine, one by one, the "factors'* in the
regulation of breathing, the sum of the supposed factors turns
out to be illusory, since no one of them is a constant quantity. The
evaluation of each factor depends on its varying relation to the
others.
The "respiratory center" is a small area situated in the medulla
oblongata. It has been found that when this area is destroyed, all
rhythmical respiratory movements cease, and that so long as this
area is intact and in connection with any efferent nerves supply-
ing respiratory muscles, discharges of the center through these
nerves continue, as shown by the rhythmical contractions of the
muscles, although all the other nervous connections upwards and
downwards have been severed.
It is also now clear that the activity of the center depends upon
the composition of the blood circulating through it, and not on
chemical stimuli acting elsewhere. If the circulation to the medulla
is interrupted by closure of all the four arteries supplying it, so
that its blood has time to become venous, violent hyperpnoea re-
sults, as Kiissmaul and Tenner showed about the middle of last
century; and the crossed circulation experiments of Fredericq,
already referred to, prove that either apnoea or hyperpnoea is
produced, according as the blopd supplied to the central nervous
system is more aerated or less aerated in the lungs.
It has been suspected that although the stimuli dependent on
the composition of the blood act directly within the brain, nervous
end-organs situated elsewhere are also sensitive to these stimuli,
so that the corresponding nerves convey impulses which play an
important part in the regulation of breathing. It was, for instance,
believed by Traube that chemical stimuli are conveyed directly
from the lungs by the vagus nerve, and others have supposed
that stimuli to increased breathing are conveyed by direct nervous
paths from the muscles. This hypothesis was investigated with
great care by Geppert and Zuntz,^ who severed all the nervous
connections between actively working muscles and the medulla,
'Geppert and Zuntz, Pfiiiger's Archiv, XLII, pp. 195, 209, 1888.
54
RESPIRATION
and found that the respiratory response to increased muscular
work was the same as before, but was entirely absent if the circu-
lation from the working muscles was interrupted. Similarly they
found that severance of the nervous connection between the lungs
and the center did not affect the response. Lorrain Smith and I
found, similarly, that when air containing about 20 per cent of
CO2 was supplied to a rabbit there was no difference in the time
required for the onset of hyperpnoea after the vagi were cut.
No definite anatomical group of nerve cells has been defined at
the position occupied by the respiratory center; and the exact
meaning which ought to be attached to the expression "respira-
tory center" is still doubtful. It seems pretty clear, however, that
the center is at about the position which is sensitive to the chem-
ical respiratory stimuli. To judge from analogy the sensitive
elements are probably not the bodies of nerve cells, but end-
organs or arborizations. The central paths for the innervation of
inspiratory and expiratory movements must also be different, but
in what sense the center itself is double is still obscure. Its excita-
tion by chemical stimuli depends more upon the character of the
blood supplied to it than on substances generated by its own local
metabolism. Thus the temporary diminution of blood supply in
fainting does not produce the same prompt effect on the center as
changes in the arterial blood owing to imperfect aeration in the
lungs. In this respect the center is very well suited to fulfill the
function of taking a part in controlling the quality of the general
arterial blood supply of the body. The amount of arterial blood
supplied is controlled in other ways.
Like other parts of the central nervous system, the respiratory
center can easily be fatigued; and, as will be explained later,
fatigue of the respiratory center is of great importance in practical
medicine. Fatigue of respiration was recently studied by Davies,
Priestley, and myself, and its phenomena described in the paper
already referred to. The fatigue was produced by breathing
against a resistance, the breathing being also increased at the
same time, if necessar)^, by muscular exertion. The resistance was
produced by cotton wool in the manner already described.
So long as the center is functioning normally it responds to the
resistance, in the manner indicated above, by producing a constant
slow and deep type of breathing. When, however, the resistance
is excessive and continued for some time, the breathing becomes
progressively shallower and more frequent. At the same time the
alveolar ventilation becomes less and less effective, until at last
RESPIRATION
55
asphyxial symptoms begin to develop. Figure i6 is a tracing
which shows this change. Figure 1 7 shows a similar change pro-
duced, not by resistance alone, but by the combined effects of
resistance and the increased breathing due to muscular work.
iiiiiiiiuufii
iR.
I'R^
Figure 16.
Effects of heavy resistance. To read from left to right.
Wc
if^mtH
Figure 17.
Effects of resistance and gentle work. To read from left to right.
It will be shown later that even a slight deficiency in the oxy-
genation of the arterial blood favors greatly the development of
fatigue symptoms in the respiratory center. But addition of oxy-
gen to the air does not prevent the development of fatigue due
simply to great extra work thrown on. the respiratory center. When
the breathing is quite free, and the oxygenation of the blood
normal, fatigue does not at all readily show itself, and greatly
increased breathing goes on in a normal manner over long periods.
During muscular exertion, however, as will be shown later, the
oxygenation of the blood may become impaired, in which case
fatigue of the breathing may easily show itself, so that the subject
becomes in a literal sense "short of breath," since each breath
is short.
56
RESPIRATION
During the war cases were very common of what, according as
one nervous symptom or another was most prominent, was desig-
nated as "chronic gas poisoning," "soldier's heart," "disordered
action of the heart," "neurasthenia," etc. In these cases "shortness
of breath" on exertion was a common and prominent symptom.
Their breathing was investigated by Meakins, Priestley, and my-
self^^ and we found a marked deviation from normality in its reg-
ulation. In many of these persons the frequency of the breathing
was very abnormally increased during rest, and in nearly all there
was on exertion a quite abnormal increase of frequency, with a
corresponding reduction of the normal increase of depth. The
symptoms were thus the same as those of fatigue of the respira-
tory center, and on extra exertion these patients were liable to
lose consciousness with asphyxial symptoms, just as in ordinary
overfatigue of the center. Another prominent symptom was that
the patients were unable to hold a deep breath for anything like
a normal period, even if they were given oxygen to help. Many of
them were also subject, particularly at night, to attacks of rapid
shallow breathing with a sense of impending suffocation.
The condition of the breathing in these patients was evidently
such as would be produced by an abnormal increase in the readi-
ness with which the Hering-Breuer reflex is elicited, and we
therefore described the respiratory condition as one of "reflex re-
striction" in the depth of breathing. At the time we were not
aware of the symptoms of fatigue of the respiratory center. In the
condition of fatigue the shallow and rapid breathing is just what
would result from an increase in the strength of the Hering-
Breuer reflex, and a similar apparent exaggeration of this reflex
is present, as already seen in connection with the results of artificial
respiration, in the condition of apnoea. In view, therefore, of all
the facts relating to the respiratory movements in fatigue, apnoea,
and neurasthenia, it seems probable that the apparent increased
strength in the Hering-Breuer reflex is due to a diminution in
the persistency of the individual inspiratory and expiratory dis- J
charges from the center, rather than to any real increase in the
inhibitory Hering-Breuer discharges up the vagus nerves. It is
thus only the weakness of the center that enables the Hering-
Breuer reflex to gain the upper hand.
If we apply the same general conception to the other exag-
*• Haldane, Meakins, and Priestley, Reports of the Chemical Warfare Medical
Committee, No. s. Reflex Restrictions of Breathing, 1918, and No. 11, Chronic
Cases of Gas Poisoning, 1918; also Journ. of Physiol., LII, p. 433, 1919.
RESPIRATION 57
gerated reflexes and general failure of nervous coordination in
"neurasthenia," fatigue, and "shock," we seem to render these
conditions more intelligible. Thus the great general nervous ir-
ritability, exaggeration of circulatory reflexes, tendency to sweat-
ing, and occasional instability of temperature, as observed in
"neurasthenia," are probably analogous to the exaggerated re-
flex restriction in the depth of breathing and the inability to hold
a breath. All these symptoms seem to be due to what Hughlings
Jackson called "release of control."
In the causation of military neurasthenia the nervous over-
strain of war, and the shocks to the nervous system in connection
with various incidents of warfare and gross bodily injuries had
evidently played a prominent part; but it was equally evident
that infections of different sorts were also in part responsible for
the condition, the nervous system being apparently weakened by
toxic influences. In the same way ordinary fatigue of the respira-
tory center or other parts of the nervous system may be due not
merely to extra work, but also partly to want of oxygen (as will
be shown later) , or to other chemical influences. Neurasthenia may
thus be regarded as only a more lasting and persistent form of
ordinary fatigue or exhaustion. It will be shown later that a very
important secondary effect of the shallow breathing characteris-
tic of neurasthenia or fatigue of the respiratory center is im-
perfect oxygenation of the blood.
The readiness with which a given resistance to breathing pro-
duces signs of fatigue of the breathing varies greatly in different
individuals. In some persons a comparatively small resistance
suffices to produce shallow breathing and rapid exhaustion of the
respiratory center, though in other quite healthy persons a very
considerable resistance is needed. Men with symptoms of neu-
rasthenia are, as might be expected, particularly sensitive to re-
sistance. This matter is, of course, important in connection with
the design of respirators, etc. A respirator causing any consider-
able resistance may easily disable a man for muscular exertion.
The threshold alveolar CO2 pressure at which the respiratory
center begins to be excited may be altered by various abnormal
conditions which will be discussed further in later chapters. The
threshold may be lowered by want of oxygen or by the presence
in the blood of an abnormally low proportion of available alkali,
or by certain drugs, including, as Yandell Henderson^^ has pointed
" Yandell Henderson and Scarbrough, Amer. Journ. of Physiol., XXVI, p.
279> 1910.
58 RESPIRATIOxN
out, ether in low concentrations, or by massive afferent nervous
stimuli. On the other hand the threshold is raised by such anaes-
thetics as chloroform, morphia, or chloral; and under their influ-
ence the alveolar CO2 pressure is raised^^ and the breathing is
commonly so much diminished that the arterial blood becomes
markedly blue. These facts are of great importance in connection
with the use of anaesthetics. Henderson showed also that morphia
affects the chemical more than the afferent threshold of the res-
piratory center. Rise of body temperature has a marked effect in
lowering the threshold.^^
"Collingwood and Buswell, Journ. of Physiol. (Proc. Physiol. Soc), XXXV,
p. xxxiv, and XXXVI, p. xxi, 1907.
" Haldane, Journ. of Hygiene, V, p. 503, 1905 ; see also Haggard, Journ. of Biol.
Chem. XLIV, p. 131, 1920,
CHAPTER IV
The Blood as a Carrier of Oxygen.
The evidence has already been referred to that nearly all the
available oxygen in the blood is present in the form of a chemical
compound with the haemoglobin of the red corpuscles, and that
this compound has the remarkable property of dissociating with
fall in the partial pressure of oxygen, at the same time changing
its color from bright scarlet to a dark purple. It dissociates com-
pletely when the oxygen pressure is reduced to zero, and the
readiness with which the dissociation occurs is dependent on
temperature and other conditions which will be discussed below.
It is contained in the corpuscles to the extent of about 30 per cent
of their weight, and on liberation from them it can be crystallized
out with comparative ease by the help of cold and of substances
which diminish its solubility. There is considerable variation in
the form of the crystals obtained from the blood of different
animals.
To what extent, and in what directions, the elementary composi-
tion of haemoglobin varies is not yet definitely known; but the
haemoglobin of birds has been found to contain phosphorus, while
none is present in the haemoglobin of mammals. Iron is always
present. A given amount of blood, whether or not the corpuscles
have been dissolved and the haemoglobin liberated and diluted,
takes up, on saturation with air at room temperature, a perfectly
fixed and definite amount of oxygen in chemical combination. No
further measurable quantity is taken up, except in simple physical
solution, on saturation with oxygen. An exactly equal volume of
carbon monoxide or nitric oxide is taken up in combination in
presence of either of these gases. There is no shadow of doubt that
the combination is a chemical one, though some extraordinary
attempts, based on ignorance of well-ascertained facts, have re-
cently been made to explain the combinations of oxygen and CO2
in blood as due to adsorption.
Haemoglobin not only enters into dissociable chemical combina-
tions with oxygen, carbon monoxide and nitric oxide, but also in
presence of various oxidizing agents, such as ferricyanides or
chlorates, or very weak acids, etc., when oxygen is also present,
passes into a modification called by Hoppe Seyler methaemoglobin.
6o RESPIRATION
This substance, which crystallizes in a similar form to oxyhaemo-
globin but has a dull brown color in acid solution and a brownish
red color in alkaline solution, was found by Hiifner to take up in
its formation from haemoglobin just as much oxygen as oxy-
haemoglobin ; but the oxygen is not given off in a vacuum. On the
other hand it yields its oxygen much more rapidly to a reducing
agent than oxyhaemoglobin or free oxygen does, and is thus an
oxidizing agent of some activity. Thus if a drop of ammonium
sulphide solution is mixed with a solution of methaemoglobin in
the absence of free oxygen the methaemoglobin is instantly re-
duced to haemoglobin, as shown by the change of color and spec-
trum. But if free oxygen is present the color and spectrum of
oxyhaemoglobin appear, since the ammonium sulphide combines
far more slowly with free oxygen, or with the combined oxygen
of oxyhaemoglobin, so that the haemoglobin formed instantly
from the methaemoglobin is able to combine with the free oxygen
and remain for a long time as oxyhaemoglobin.
While investigating the action of poisons which form met-
haemoglobin in the living body I noticed that when ferricyanide
and certain other reagents act on oxyhaemoglobin to form methae-
moglobin fine bubbles are liberated, and on further investigation
the liberated gas was found to be oxygen.^ I then measured ac-
curately the liberated oxygen, and found that the volume of oxy-
gen liberated by ferricyanide from blood agrees exactly with the
volume liberated by the mercurial pump from combination in the
blood. Ferricyanide also liberates carbon monoxide from its com-
bination with haemoglobin, and the volume liberated corresponds
with the volume of oxygen liberated by a corresponding quantity
of oxyhaemoglobin. The following figures were obtained.
Combined gas in cc. liberated from
the haemoglobin of lOO cc, of blood
and measured dry at o°C and 760 mm.
By blood pump alone from blood saturated with air
18.18
By ferricyanide from blood saturated with air
18.20
By ferricyanide from blood saturated with CO
18.07
From their behavior, it appears that oxyhaemoglobin and CO-
haemoglobin are molecular compounds in which the molecules of
* Haldane, Journ. of Physiol., XXII, p. 298, 1898.
RESPIRATION 6l
gas are directly combined as such with the molecules of haemo-
globin, just as molecules of water are combined with molecules of
a salt or other substance to form hydrate molecules. In methaemo-
globin, on the other hand, the atoms in the molecules of oxygen
which enter into combination are separately combined just as in
ordinary chemical compounds containing oxygen. When the
oxidation of haemoglobin to methaemoglobin occurs the new
molecule formed loses its capacity for forming the molecular
compounds oxyhaemoglobin and carboxyhaemoglobin. In conse-
quence of this the molecular oxygen and carbon monoxide are
liberated from oxyhaemoglobin or carboxyhaemoglobin by the
action of ferricyanide, and can be measured with the greatest ac-
curacy in the gaseous form by a simple method which I described
in 1900 (see Appendix).^
The ferricyanide method afforded a ready means of measuring
directly the gas combined in the molecular form with haemo-
globin, and for this purpose replaced the complicated procedure
and involved calculations required when the mercurial pump
was used. One of the first discoveries made with the new method
was that the coloring power of haemoglobin or any one of its
molecular compounds with gases varies exactly as its capacity for
combining with gas. Hence the "oxygen capacity" of the haemo-
globin in blood — in other words its power of fulfilling its physio-
logical function of carrying oxygen — can be measured easily by
means of a reliable colorimetric method.^ The following table
(p. 62) shows the results we obtained on this point.
That oxygen capacity and depth of color run parallel also in
various anaemias and other pathological conditions was shown
by Morawitz ;* and Douglas^ showed that even during the rapid
regeneration of haemoglobin after loss of blood this also holds.
At the time when the ferricyanide method was introduced there
existed several well-known forms of "haemoglobinometer." Of
these the apparatus of the late Sir William Gowers was by far the
most convenient. In his method 20 cubic millimeters of blood,
obtained from a prick of the skin, are introduced into a small
graduated tube and diluted with water until the depth of color
is the same as that of a standard solution of picrocarmine in an-
other similar tube. The depth of color of the picrocarmine solution
' Haldane, Journ. of Physiol., XXV, p. 295, 1900.
* Haldane and Lorrain Smith, Journ. of Physiol., XXV, p. 331, xgoo.
* Moiawitz and Rohmer, Deutsch. Arch. f. klin. Med., XCIII, p. 223, 1908.
'Douglas, Journ. of Physiol., XXXIX, p. 453, 1910.
62
RESPIRATION
is that of normal human blood diluted to i/iooth; and the
graduated tube gives the strength of color of the blood under
examination in terms of this normal standard. One defect of the
method was that the picrocarmine standard is not permanent,
and another that the color of the picrocarmine solution is not the
OXYGEN CAPACITY
PERCENTAGE
PER
100 cc.
DIFFERENCE IN
RESULT BY
FerrJcyamde
Colorimetric
COLORIMETRIC
method
method
METHOD
Ox blood
18.51
18.42
—0.5
>>
15.05
15.33
+ 1.9
»»
20.29
19.85
2.2
ft
15.04
15.17
+0.9
Horse blood
18.37
18.39
+0.1
Ox blood
19.75 :
19.90 )
20.00
+0.9
>>
18.94
18.94
+0.0
Rabbit's blood
14.62)
14.55 J
14.58
O.I
Sheep's blood
17.44]
17.44)
17.30
—0.8
Ox blood
21.50)
21.55)
21.42
—0.4
t>
16.16
16.06
0.6
Human blood
Mean
21.08
21.27
18.06
+0.9
—0.055
18.07
same spectrally as that of the blood solution. As a consequence of
this both the depth and the quality of the tints of the two solutions
are differently affected by variations in the quality of the light at
the time of using the instrument. Thus if the tints agree at one time
of day they may be different at another ; and in ordinary artificial
light the results given are totally different from the results by
daylight. Moreover, in consequence of individual differences in
vision, a color match for one person is not the same as that for
another person, even in the same light. To remedy these defects I
substituted for the picrocarmine a one per cent solution of blood
of the average oxygen capacity of the blood of adult men (18.5
RESPIRATION 63
cc. of oxygen per 100 cc. of blood) , and introduced other improve-
ments.®
In the presence of free oxygen haemoglobin is a very unstable
substance, and soon decomposes, owing to the action of bacteria,
etc. ; but in the absence of oxygen the color of haemoglobin is per-
fectly stable, and this is also the case for carboxyhaemoglobin. The
standard solution was therefore saturated with carbon monoxide
in the absence of oxygen, and in this form is permanent. The blood
under examination is also saturated with carbon monoxide by
contact with coal gas or a little carbon monoxide. The two solu-
tions are thus spectrally the same. With these improvements the
Gowers haemoglobinometer became an extremely accurate instru-
ment for ascertaining the oxygen capacity of blood, and the ac-
curacy of any particular instrument could be controlled at once
by the ferricyanide method. Certain ever-recurring criticisms of
the instrument are almost entirely based on want of acquaintance
with the physiological principles of colorimetric methods, or of
the chemical facts on which the method is based. A detailed de-
scription of the method will be found in the Appendix.
The percentage oxygen capacity (or haemoglobin percentage)
in the blood varies quite appreciably from hour to hour and day
to day, according as the total volume of the blood varies from ad-
dition or withdrawal of liquid. There are also variations associ-
ated with age and sex ; and pathological variations may be very
marked and significant. As regards age and sex I found the follow-
ing average relative figures for the percentage oxygen capacity
of the blood.
Men 18.5
Women 16.5
Children 16.1
It has been known for long that when an oxyhaemoglobin
solution is overheated or treated with various simple reagents the
oxyhaemoglobin decomposes into a coagulated protein and a
deeply-colored brown substance soluble in alcohol and certain
other solvents, and known as haematin. The haematin contains ^.J
per cent of iron, and the coagulated protein is free from iron. To
the haematin the formula C34H34Ne05Fe has been assigned. By
the action of reducing agents the haematin loses oxygen and
changes to a purple color, with a corresponding change of spec-
trum, described by Stokes at the same time as he described the
' Haldane, Journ. of Physiol., XXVI, p. 497.
64 RESPIRATION
spectra of oxyhaemoglobin and haemoglobin. To this reduced
haematin Hoppe Seyler gave the very suitable name haemo-
chromogen, as he believed it to be the parent substance of the color
of haemoglobin and its varied derivatives. Thus we can regard
haemoglobin as a compound of haemochromogen with a protein,
also haematin as an oxygen compound of haemochromogen, while
compounds of haemochromogen with carbon monoxide and nitric
oxide are also known.
This conception is confirmed by the fact that the oxygen ca-
pacity of haemoglobin varies as its coloring power, and by another
still more recently established fact. Till a few years ago it still
seemed very doubtful whether there is a fixed and definite rela-
tionship between the iron in haemoglobin and its oxygen capacity ;
and Bohr''^ thought that he had obtained evidence of the existence
of marked variations in the relation between iron and oxygen
capacity; and that this relation differs in arterial and venous
blood. The doubts on this subject turned round the reliability of
the methods of determining iron. But in 191 2 Peters, using a new
and very reliable method of iron determination, found that there
is a fixed and simple relationship between the oxygen capacity and
iron, one molecule of combined oxygen corresponding to one
atom of iron.^
Still other considerations point in the same direction. When we
examine the colors and spectra of the various direct derivatives
of haemoglobin and haemochromogen a striking general cor-
respondence emerges. Methaemoglobin and haematin have very
similar colors and spectra, which differ in a more or less similar
manner in acid or alkaline solutions, and give a similar red color
and corresponding spectrum on addition of hydrocyanic acid.
With carbon monoxide haemochromogen gives the same color
and spectrum and takes up the same volume of carbon monoxide
as haemoglobin. With the nitric oxide compounds there appears
also to be a correspondence. Thus I found that the red color of
raw salted meat is due to the presence of NO -haemoglobin,
formed by the action on haemoglobin of the reduction product of
the niter which is mixed with the salt; and the color is still red
after the meat is cooked and the NO-haemoglobin broken up to
yield a haemochromogen compound on heating. NO-haemoglobin
is also found post mortem in poisoning by nitrites. Between
haemoglobin and haemochromogen there is also more or less of
Bohr, Nagel's Handbuch der Physiologie, I, p. 95, 1905.
• Peters. Journ. of Physiol., XLIV, p. 131, 19 12.
RESPIRATION
65
correspondence; but oxyhaemochromogen, the molecular oxygen
compound of haemochromogen, is missing, and it seems that
haematin is so readily formed by haemochromogen in the pres-
ence of oxygen that oxyhaemochromogen cannot exist. Figure i8
shows the positions of the absorption bands in the spectra of NO-
haemoglobin and NO-haemochromogen.
CD E b F
!
Figure i8.
I. Nitric oxide haemoglobin. 2. Oxyhaemoglobin. 3. Carbonic
oxide haemoglobin. 4. Nitric oxide haemochromogen. 5. Obtained
by action of nitrous acid on haematin.
If haemochromogen has been formed from haemoglobin by
the action of acids or caustic alkali and heat, a substance possess-
ing the spectrum and properties of natural haemoglobin is gradu-
ally re-formed on neutralization.^ As proteins are greatly altered
in properties by heating with alkali it would seem from this ob-
servation that there may be a number of different haemoglobins,
in which, though the haemochromogen part of the molecule is
the same in all, the protein part varies. As will be shown later,
there is evidence that not only in different species, but also in
different individuals of the same species, the protein part of the
haemoglobin molecule varies, thus producing slight variations in
the properties of the haemoglobin as a carrier of gases, although
there is no variation in the oxygen capacity per unit weight of
iron present. The haemochromogen part of the molecule seems,
on the other hand, to be constant in all the different sorts of haemo-
globin, and this brings about the identity of the relations between
oxygen capacity, coloring power, and percentage of iron in all
the different varieties of haemoglobin, although as regards other
properties haemoglobins from different sources vary distinctly.
' See Menzies, Journ. of Physiol., XVII, p. 4x5, 1895, and XLIX, p. 452, 1915.
66 RESPIRATION
The original ferricyanide method for determining the oxygen
capacity of haemoglobin was very accurate, but required a good
deal of blood, and was also slow on account of the time needed
for exact equalization of temperature and gas pressur'es. Mr.
Barcroft was then beginning his important series of investiga-
tions on the metabolism of the salivary glands and other organs.
As he required a blood-gas method suitable for very small volumes
of blood he asked me whether the ferricyanide method could be
adapted for the purpose, and I designed an apparatus which v/e
jointly tested and described, and which turned out so successfully
that, in one form or another, it has now almost displaced the
mercurial blood pump.^^ In this apparatus the oxygen combined
in the haemoglobin of the very small quantity of blood required
is liberated by ferricyanide, and the CO2 by acid. The amount of
gas liberated in either case is determined, not from the increase
in volume which its liberation causes, but from the increase of
pressure when the total volume of gas is kept rigorously constant.
I adopted this principle as the result of much previous experience
in the measurement of small differences in gas volumes. Certain
causes of difficulty are eliminated by the pressure method, and by
the adoption, as in the original ferricyanide method, of a control
arrangement by which the effects of changes i^ temperature and
barometric pressure during the experiment are eliminated. Vari-
ous improvements in the technique of collecting and sampling
blood drawn directly from blood vessels were also introduced by
Mr. Barcroft.
This apparatus has been modified in various ways by different
investigators, and some of the modifications are improvements.
Others, however, seem to me to be the reverse. In the Appendix
there is a description of a new and much more exact method in
which the volumes of oxygen and CO2 are measured directly.
Besides the oxygen chemically combined with haemoglobin,
the blood contains a certain small amount of oxygen in simple
solution. In accordance with Henry's law of solution of gases in
liquids this amount varies with the partial pressure of oxygen in
the atmosphere with which the blood is saturated, which in the
case of arterial blood in the living body is (with certain reserva-
tions discussed in Chapters VTI and VIII), the alveolar air. The
amount of oxygen in free solution can be measured directly when
the haemoglobin is by one means or another put out of action in
respect to its power of entering into molecular combination with
"Barcroft and Haldane, Journ. of Physiol., XXVIII, p. 232, 1902.
RESPIRATION 67
oxygen. Bohr found that at body temperature 2.2 cc. of oxygen
(measured at 0° and 760 mm.) go into simple solution in 100 cc.
of blood when the partial pressure of oxygen is one atmosphere/^
and this is about 8 per cent less than dissolves in water. In the
alveolar air the partial pressure of oxygen is only about 13 per
cent of an atmosphere, and in the mixed arterial blood about 1 1
per cent, or 84 mm., of mercury. Hence the amount of free oxygen
dissolved in the 100 cc. of the arterial blood of a man is only about
0.24 cc. (measured at o°C. and 760 mm. pressure) whereas
about 17.4 cc. are present in combination with haemoglobin, as
will be shown below. It is evident, however, that the amount in
free solution is of great importance ; it depends upon the partial
pressure of oxygen in the atmosphere with which the blood is in
equilibrium; and, as already pointed out, Paul Bert found that
the physiological action of oxygen and of any other gas depends
upon its partial pressure in this atmosphere.
From the standpoint of physical chemistry the "partial pres-
sure" of a gas in solution is simply the vapor pressure of the dis-
solved gas, i.e., its tendency to pass out of the solvent at any free
surface, or the gas pressure which will just balance this tendency
so that the amount of gas in solution neither increases nor de-
creases. But the vapor pressure of a substance in solution, or of the
solvent itself, varies directly, as I showed in a recent paper,^^
with the diffusion pressure of the substance in solution. Hence
vapor pressure is a direct index of diffusion pressure; and this is
the reason why the partial pressure of a gas in solution is of so
great importance. It is owing to differences in diffusion pressure
that water or substances dissolved in it tend, independently of
active "secretory" processes, to pass in one direction or another
in the living body or outside it. For instance, when water passes
through a semi-permeable membrane into a solution of sugar or
salt, this is because the diffusion pressure of the pure water is
greater than that of the diluted water in the sugar or salt solution.
Van't Hoff's brilliant discovery that there is a connection between
the fundamental "gas laws" and the phenomena of osmotic pres-
sure was unfortunately marred by his failure to interpret either
the connection or the experimental facts correctly. As a conse-
quence, osmotic pressure and diffusion pressure were either com-
pletely misinterpreted or confused with one another. There seems
now to be no doubt that it is the diffusion pressures, and not the
"Bohr, Nagel's Handbuch der Physiol., I, p. 62, 1905.
Haldane, Bio-Chemical Journal, XII, p. 464, 1918.
68 RESPIRATION
mere concentration of substances in the body, that are of physio-
logical importance. To illustrate this distinction, the concentra-
tion of water in blood is much less than in a two per cent solution
of sodium chloride ; but the diffusion pressure of water in the blood
is much greater than in the salt solution. Hence water will pass
from the blood into salt solution. Similarly carbonic acid probably
passes by diffusion from the muscular substance into the blood
although the concentration of free carbonic acid in the muscle is
less than in the blood.
Paul Bert's conclusion that it is the partial pressure of a gas
which is of importance as regards its physiological action can thus
be extended to every other substance present in the living body,
not excepting water. The partial pressure of a dissolved gas is of
decisive importance because the gaseous partial pressure, or vapor
pressure, is an index of the diffusion pressure of a substance in
solution ; but where the gaseous partial pressure is so low that it
cannot be measured, we must have recourse to other indices of the
diffusion pressure.
It has been shown how important are the gas pressures in al-
veolar air. But the gas pressures of the blood in the systemic
capillaries are of still more fundamental importance. It is clear
that in order to understand how the oxygen pressure of the blood
is regulated we must know the connection between dissociation of
the oxyhaemoglobin of blood and fall in oxygen pressure. In other
words we must know what is called the dissociation curve of oxy-
haemoglobin in blood.
The history of the growth of knowledge on this subject is some-
what curious. Paul Bert^^ made some rough determinations with
the pump of the amounts of oxygen in dogs' blood saturated with
air in which the oxygen pressure was varied. His results indicated
that in presence of oxygen reduced to a pressure of about 20 mm.
the blood at body temperature had lost half its oxygen. In a living
animal breathing air with an oxygen pressure of about 55 mm. (the
alveolar oxygen pressure being unknown) the blood had also lost
half its oxygen. When the blood was at a temperature below that
of the body the oxygen was dissociated much less readily.
The subject was taken up again by Hiifner, who used a solution
of oxyhaemoglobin crystals in dilute sodium carbonate solution.
As the result, partly of experiments, and partly of calculation, he
published in 1890 a very symmetrical curve, according to which
oxyhaemoglobin does not lose half its oxygen till the oxygen pres-
" Paul Bert, La Pression Barometrique, p. 694, 1878.
i
RESPIRATION
69
sure is reduced to 2.6 mm.-^* This curve was totally at variance
with Paul Bert's results, and made it very difficult to understand
the effects on animals breathing air with a low oxygen pressure.
In 1904 Loewy and Zuntz^^ published further experiments with
defibrinated blood giving results much nearer to those of Paul
Bert. Meanwhile the subject was taken up by Bohr/^ who not only
confirmed Paul Bert in the main, but for the first time showed that
the dissociation curve for blood or haemoglobin solutions has a
very peculiar shape, with a double bend (Figure 19), and that the
100
20 30 40 50 60 70 80 90 100 HO 120 130 \A0 150
Figure 19.
Curves representing the percentage saturation of haemoglobin
with oxygen at different partial pressures of oxygen and CO2.
Dog's blood at 38°C. Ordinates ^ percentage saturation with
oxygen ; abscissae = partial pressures of oxygen in millimeters
of mercury. (Bohr, Hasselbalch, and Krogh.)
curve for a haemoglobin solution differs considerably from that
for blood. For this reason he inferred that the haemoglobin in
blood C'haemochrome") differs chemically from crystallized
haemoglobin. Bohr, Hasselbalch and Krogh^''' then made the
important discovery that the dissociation curve of haemoglobin or
"haemochrome" is greatly influenced by the partial pressure of
the CO2 present (Figure 19), the CO2 helping to expel oxygen
from its combination, so that, as the blood takes up CO2 in its
passage through the capillaries, oxygen is liberated from the oxy-
haemoglobin more readily than would otherwise be the case.
"Hiifner, ArcA. f. (Anat. u.) Physiol., p. i, 1890.
"Loewy and Zuntz, Arch. f. (Anat. u.) Physiol., p. 166, 1904.
"Bohr, Centralbl. f. Physiol., 17, p. 688, 1904.
^^ Skand. Arch. f. Physiol., 16, p. 602, 1904.
70 RESPIRATION
The investigation was now taken up by Barcroft and his pupils,
who have made a number of important advances during the last
few years with the help of one form or another of the ferricyanide
apparatus. -^^
They found that the form taken by the dissociation curve of
oxyhaemoglobin is greatly influenced by the salts present in the
red blood corpuscles, or in a solution of their oxyhaemoglobin.^^
When all the salts were removed by dialysis the curve became a
rectangular hyperbola,^^ as in the curve published by Hiifner. If
the reversible reaction between oxygen and haemoglobin is rep-
resented by the uncomplicated equation Hb -{- 02<=^Hb02, the
curve would, in accordance with the well-known law of Guldberg
and Waage, be a rectangular hyperbola. This is the case when
salts are absent and the solution is neutral, as in the dialysed solu-
tion. When, however, salts are present, the form of the curve is
altered towards the characteristic form given by blood, and the
nature and extent of the alteration was found to depend on the
nature and concentration of the salts. Thus when dialysed dogs'
haemoglobin was dissolved in a salt solution of the same composi-
tion and concentration as in human blood corpuscles the dissocia-
tion curve obtained was similar to that of human blood.
These discoveries rendered it unnecessary to assume with Bohr
and others that there is any essential chemical difference between
the haemoglobin present in blood corpuscles and in a solution of
crystallized haemoglobin. At the same time they furnished a key
to the explanation of the apparently divergent observations as to
the dissociation curve of oxyhaemoglobin. Barcroft and Orbeli^^
found that not only does CO2 shift the curve in the direction dis-
covered by Bohr and his pupils, but that other acids added in
such small quantities as not to decompose the haemoglobin have a
similar effect, while alkalies have the opposite effect. As will be
explained later Barcroft and his associates concluded that this
alteration affords a very sensitive measure of any alteration in the
reaction, or hydrogen ion concentration of the blood; and they
have used it for this purpose.
The form of the dissociation curve of the oxyhaemoglobin in
human blood at body temperature and with a constant pressure of
" A summary of these investigations is given in Barcroft's book, TAe /Respira-
tory Function of the Blood, 19 14.
" Barcroft and Camis, Journ. of Physiol., XXXIX, p. 118, 1909.
"Barcroft and Roberts, Ibid., XXXIX, p. 143. 1909.
"Barcroft and Orbeli, Journ. of Physiol., XLI, p. 353, 1910. Barcroft, Ibid.,
XLII, p. 44, 191 1.
RESPIRATION
71
40 mm. of CO2, as in average human alveolar air, was worked out
by Barcroft, and his results for one individual (Douglas) were
18
L
2
0
21
22
23
24 25
26
il
28
29
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2 3 4 >5 6
PRESiORE OF OXYOEN
7 S O 10 II 12 13
IN PERCENTAGE OF ONE ATMOSPHERE .
Figure 20.
Dissociation curves of oxyhaemoglobin in presence of 40 mm. pressure of
CO2 at 38° (i per cent of an atmosphere = 7.60 mm. pressure).
O Blood of C. G. D., using ammonia in blood-gas apparatus.
• Blood of C. G. D., using Na2C03 in blood-gas apparatus.
n Blood of J. S. H., using ammonia in blood-gas apparatus.
■ Blood of J. S. H., using Na2C03 in blood-gas apparatus.
X Mixed blood of six mice, using ammonia in blood-gas apparatus.
approximately confirmed by Douglas and myself, working with
a different apparatus. Figure 20 shows the curves given by the
blood of Douglas and myself in a very exact series of observa-
tions, with the individual observations marked. Our curves as will
be seen are sensibly the same; but Barcroft has found that the
curves of different individuals may vary very distinctly. With the
blood of Douglas and myself, for instance, half-saturation of
the haemoglobin with oxygen occurs at an oxygen pressure of 4.0
per cent of an atmosphere or 30.4 mm. With that of other individ-
uals, and the same pressure (40 mm.) of CO2, half-saturation
may, according to Barcroft, occur at as low an oxygen pressure as
24 mm.22
Barcroft, The Respiratory Function of the Blood, p. 218, 1913.
72 RESPIRATION
On examining the dissociation curve it will be seen that the
steepest part of the curve is in the middle. In the case of oxy-
haemoglobin dissociating in the living body as the blood passes
through the capillaries, and in doing so taking up CO2, this part
of the curve is still steeper, for the reason given by Bohr and his
pupils. It is clear that with this form of curve the oxygen pressure
in the capillaries must tend, after the first fifth of the oxygen has
been given off, to remain comparatively steady during the giving
off of the next three-fifths : for at this stage a large amount of
oxygen is given off from the oxyhaemoglobin with a compara-
tively small fall in the oxygen pressure. In this way the oxygen
supply to the tissues is maintained at a far higher and also much
steadier pressure than if the curve were a rectangular hyperbola.
As will be seen later, a man would die on the spot of asphyxia if
the oxygen dissociation curve of his blood were suddenly altered
so as to assume the form which Hiifner supposed it to have in the
livmg body. The salts of the red corpuscles and the particular
hydrogen ion concentration of the blood are of essential impor-
tance in connection with the oxygen supply of the tissues.
Haemoglobin, as already mentioned, forms specially colored
dissociable compounds, not only with oxygen, but also with carbon
monoxide and nitric oxide, and the compound with CO is of
special physiological interest, apart from its practical importance
in connection with the frequency of CO poisoning. As compared
with the oxygen compound the CO compound, which was dis-
covered by Claude Bernard,^* is characterized by its relative
stability, which is so great that at one time it was supposed that
CO-haemoglobin is not dissociable.
Blood of which the haemoglobin is saturated with CO has a
scarlet color similar to that of blood saturated with oxygen ; but if
the CO-haemoglobin is highly diluted, or examined in a very thin
layer, its color is pink, as compared with the yellow color of diluted
oxyhaemoglobin. By taking advantage of this fact one can easily
recognize the presence of CO-haemoglobin in blood. This test, as
I have often pointed out, is far more delicate than the older
spectroscopic test, but requires daylight or some similar light. By
adding carmine solution to diluted normal blood one can exactly
match the color of the diluted blood containing CO,^* and by
using a suitable carmine solution I found it possible to estimate
"Claude Bernard, Compt. Rend., XLVIII, p. 393, 1858.
" A detailed description of this method in its latest form will be found in
the Appendix.
RESPIRATION
73
with great accuracy the percentage saturation of haemoglobin
with CO.
With the help of this method Douglas and I worked out dis-
sociation curves for the CO-haemoglobin of human blood at
38°C — in the absence, of course, of oxygen, but in the presence
of varying partial pressure of COo.^^ The results are shown in
Figure 21.
•005 010 015 020 '025 -030 '035 -OA-O -045 '0^0
PRESSURE OF CO IN PERCENTAGE OF ONE ATMOSPHERE.
Figure 21.
Dissociation curves of CO haemoglobin in absence of oxygen, at 38" and
with various pressures of CO2. O Blood of C. G. D. • Blood of J. S. H.
These curves, like the curve for the oxyhaemoglobin of human
blood in Figure 20 are drawn free-hand. On comparing them we
found that, allowing for possible small errors due to insufficient
determinations, they are all the same curve when the scale on
which the abscissae of each are plotted is altered by a suitable
" Douglas, J. S. Haldane, and J. B. S. Haldane, /ourn. of Physiol., XLIV, p.
275. I9I-2-
74 RESPIRATION
constant. It thus appears that the effect of substituting CO for O2,
or of varying the partial pressure of CO2, is only to alter a simple
constant in the equation to the curve. In other words it is only
the affinity of haemoglobin for the gas saturating it. which alters.
With respect to the oxyhaemoglobin curve the same conclusion
was reached by Barcroft and Poulton,^^ who found that variations
in the partial pressure of CO2 had, within wide limits, the same
effects on the dissociation curve of oxyhaemoglobin, as on that of
CO-haemoglobin. In the case of Barcroft's blood it requires a
little over twice as high a partial pressure of oxygen to produce
half-saturation of the haemoglobin in presence of 40 mm. pres-
sure of CO2 as when CO2 is absent; just as in the blood of Douglas
it takes a little over twice as high a partial pressure of CO. Bar-
croft and Means^^ have, however, also shown that in the case of a
salt-free or nearly salt-free solution of haemoglobin the effect of
CO2 is not merely to alter the affinity of oxygen for haemoglobin,
but also to alter the mathematical form of the curve, just as salts
do. Hence it is only in the case of whole blood that the affinity
alone is altered ; and probably we should find that it is only within
definite limits of variations in the hydrogen ion concentration of
whole blood that the mathematical form of the dissociation curve
is sensibly unaltered.
When blood or haemoglobin solution is exposed to a mixture
of CO and air the haemoglobin becomes partly saturated with CO
and for the rest with O2. I found many years ago that with a dilute
solution of blood the curve representing the percentage saturation
of the haemoglobin with CO when increasing percentages of CO
are added to the air in the saturating vessel is a rectangular hyper-
bola.^^ Figure 22 shows curves obtained by Douglas and myself
with undiluted blood at body temperature from two persons and
two mice.^®
It will be seen that in each case the curve is a rectangular
hyperbola, corresponding to the simple reversible reaction HbOo
+ CO?=^HbCO + O2. Thus for my own blood the proportions of
HbCO to Hb02 are I : I with .07 per cent of CO, 2 : i with 2 x .07
per cent of CO, 3 : 1 with 3 x .07 per cent of CO, etc. For each kind
"• Barcroft and Poulton, Journ. of Physiol., XLVI, Proc. Physiol. Soc, p. iv,
1913.
" Barcroft and Means, Journ. of Physiol., XLVII, Proc. Physiol. Soc, p.
xxvii, 1 9 14.
"Haldane, Journ. of Physiol., Vol. XVIII, p. 449, 1895.
^ Journ. of Physiol., Vol. XLIV, p. 278, 19 12.
RESPIRATION
75
of blood the curve remains exactly the same when the blood is
diluted, or rendered less or more alkaline, or when neutral salts
are added. This is of course quite different from what happens
with the simple dissociation curves of oxyhaemoglobin and CO-
haemoglobin.
IOC
A/v
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PERCENTAGE OrCO.
■»30
55
40
•45
Figure 22.
Dissociation curves of CO haemoglobin in presence of air (20.9 per cent
O2) at temperature of 38°. I. Blood of J. S. H. II. Blood of C. G. D. 'ill.
Blood of mouse A. IV. Blood of mouse B. The crosses indicate points deter-
mined in the presence of 40 mm. pressure of added CO2.
When the percentage of CO in the air is kept constant and the
percentage of oxygen is varied the curve is again a complete rec-
tangular hyperbola, as shown in Figure 23, provided that the per-
centage of CO is sufficient to saturate the haemoglobin completely
in the absence of Oo, as in the upper curve.
76
RESPIRATION
It is thus evident that when we have determined the percentage
saturations of a sample of haemoglobin with CO and O2 in a solu-
tion saturated with a gas mixture containing CO and O2 at known
concentrations or partial pressures, what we have really de-
termined is the relative affinities of the haemoglobin for CO and
100
90 -
70
CO
o
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560
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PERCENTAGE OF OXYGEN.
80
90
• 00
Figure 23.
Dissociation curves of CO-haemoglobin in presence of constant percentage
of CO and varying percentage of oxygen, at atmospheric pressure. I. Blood of
J. S. H. : CO =0.0945 per cent. Blood of mouse C: CO = 0.090 per cent.
III. Blood of mouse D : CO = 0.0635 per cent.
O2 (without allowing, however, for the slight difference in solu-
bility between the two gases). In my own blood the haemoglobin
is equally divided between CO and Og when the partial pressures
of CO and O2 are as .07 to 20.9 — i.e., as i to 299. Hence the
affinity of the haemoglobin for CO is 299 times its affinity for O2.
For the haemoglobin of Douglas the corresponding figure is 246.
For his haemoglobin we can also compare the affinities for CO and
RESPIRATION 77
O2 in another way. In presence of 40 mm. of CO2 his blood be-
comes half -saturated with CO (in the absence of oxygen) at a
pressure of .017 per cent of an atmosphere of CO, as shown in
Figure 21, and half-saturated with O2 (in the absence of CO) at
a pressure of 4.0 per cent of an atmosphere, as shown in Figure
20. These pressures are in the ratio of I 1235, which is nearly the
same ratio as when the relative affinities are estimated by the pre-
vious method.
As already seen, we may be able to account for varying dis-
sociation curves of the oxyhaemoglobin in whole blood by the
varying composition and concentration of the salts contained in
the red corpuscles, and by varying alkalinity; but we cannot so
account for the varying relative affinities of different specimens
of haemoglobin for CO and O2, since the curves in Figure 22 are
not affected by varying concentration of salts or degrees of alka-
linity. There seems to be no escape from the conclusion that in
different individuals of the same species, as well as in different
species, the haemoglobin molecules are different. Whether the
haemoglobin in each individual is made up of homogeneous mole-
cules, or is a mixture in some definite proportion of two or more
different kinds of haemoglobin, we do not as yet know. What
seems pretty certain, however, is that each individual has a specific
kind of haemoglobin just as he has a specific shape of nose. At
whatever time we have .investigated my own and Dr. Douglas's
haemoglobin their specific differential characters have appeared
to be sensibly the same. It seems pretty certain that, since the ratio
of oxygen capacity to both the coloring power and amount of
iron in haemoglobin is constant, the difference in the haemoglobin
molecule in different kinds of blood is due to the protein and not
the haemochromogen fraction of the molecule; but as yet there
are no data to indicate more specifically the nature of the differ-
ence. It is of considerable biological significance to have found,
however, that, looking at living organisms from a purely chemical
standpoint, individual differences express themselves, not merely
in the relative amounts of the different molecules which can be
separated from different parts of the body, but also in their chemi-
cal constitution.
Since the dissociation curve of CO-haemoglobin in presence of
a constant pressure of oxygen and varying pressure of CO, or in
presence of a constant pressure of CO and varying pressure of
oxygen, is a rectangular hyperbola, provided that the gases are
present at sufficient pressure to saturate the haemoglobin, it is
78 RESPIRATION
clear that provided we know the relative affinities of the two gases
for the haemoglobin, and the pressure at which one is present, we
can tell from an observation of the percentage saturation of the
haemoglobin the pressure of the other. Hence we can use haemo-
globin solutions for determining small percentages of CO in air.
All that is necessary is to introduce a little blood solution into a
small bottle of the air, shake till the solution takes up no more CO,
and then determine colorimetrically the percentage saturation of
the haemoglobin with CO, and calculate the percentage of CO
present. ^^ Still more important in physiological work is the con-
verse determination of the oxygen pressure by observation of the
percentage saturation of haemoglobin exposed to a constant pres-
sure of CO. By this means, as we shall see later, it is possible to
measure the partial pressure of oxygen in the arterial blood withih
the living body and so decide the question whether active secretion
of oxygen inwards occurs in the lungs.
Douglas and I found that when the combined pressure of Oo
and CO are insufficient to saturate the haemoglobin the dissocia-
tion curve of CO-haemoglobin in presence of a constant pressure
of CO and diminishing pressure of O2 begins to diverge from the
rectangular hyperbola which it would otherwise have followed,
and then proceeds to trace out the peculiar hump shown on the
lower two curves in Figure 23, and in greater detail in Figure 24.
We thus have what seems at first sight a most anomalous fact,
namely that although all other facts show that increase in the
pressure of oxygen tends to keep out CO more and more from
combination with haemoglobin, yet at very low pressure of oxygen
and CO the reverse is the case, and increase of oxygen pressure
helps the CO to combine with haemoglobin. There can be no doubt
that the converse is also the case — namely that at low pressures of
CO the presence of the CO helps the oxygen to combine with the
haemoglobin. This explains a very anomalous fact noticed by
Lorrain Smith and myself many years ago*^ — namely that the
presence of a small percentage of CO helps animals to resist the
effect of a very low oxygen pressure, or at any rate does not make
them worse. We had expected that a given percentage of CO
would become more and more poisonous the more the oxygen
pressure was diminished, and this was the case within certain
limits; but we were then quite at a loss to understand why with
very low oxygen pressures the CO seemed to do no harm.
Haldane, Methods of Air Analysis, p. 119, 19 19.
"Haldane and Lorrain Smith, Journ. of Physiol., XXII, p. 246, 1897.
RESPIRATION
79
The explanation of the anomalous hump in the curves on Fig-
ures 23 and 24 is in reality easy enough in view of the peculiar
double-bended form of the simple dissociation curves of oxy-
haemoglobin and CO-haemoglobin in whole blood. When CO is
present at a pressure insufficient to saturate the blood, and the
s
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PRESSURE OF OXYGEN IN PERCENTAGE OF ONE ATMOSPHERE.
22
Figure 24.
Dissociation curves of CO haemoglobin in blood at 38* and in presence of
40 mm. CO2, with constant pressure of CO and varying pressures of oxygen.
oxygen pressure is gradually raised from zero, the two gases to-
gether will trace out curves representing the total saturation of
the haemoglobin, as shown in the thin lines on Figure 24. These
curves are calculated on the theory that the proportion of oxy-
haemoglobin to CO-haemoglobin is exactly what is required in
view of the known relative affinities of oxygen and CO for the
haemoglobin of the blood used. As, however, the thin curves start
at the steep part of the joint curve a very small addition of oxygen
8o RESPIRATION
will produce such a large effect that not only will a large amount
of oxygen go into combination, but also an increased proportion
of CO. The thick lines show the curve for CO-haemoglobin as
calculated on this hypothesis, and the dots show the actual ob-
servations. There is in reality perfect agreement with the theory
that oxygen and CO combine with haemoglobin in exact propor-
tion to their relative affinities for haemoglobin and their partial
pressures, just as in the upper curve of Figure 23. The great sig-
nificance of this in connection with the explanation of CO poison-
ing will be referred to later.
It remains to discuss the explanation of the various dissocia-
tion curves to which reference has been made. We have seen above
that Barcroft and his pupils found that when a solution of oxy-
haemoglobin is freed, or approximately freed, from salts it gives
a dissociation curve which is a simple rectangular hyperbola, in
accordance with the simple reaction
Hb + Oa^HbOa.
A. V. Hill pointed out in 19 10 that the varying values obtained
for the osmotic pressure of haemoglobin solutions in presence of
salts indicates that the molecules are more or less aggregated to-
gether owing to the influence of the salts ; and he showed that this
fact was capable of explaining the deviation from a rectangular
hyperbola of the dissociation curve. Thus if, in consequence of
the aggregation, the reaction were
Hbs + 202^Hb204,
the curve would no longer be a rectangular hyperbola but would
approximate to that given for oxyhaemoglobin in presence of a
certain proportion of salts. By assuming a suitable proportion of
aggregation of the haemoglobin molecules as Hbg, Hbg, etc., we
can therefore construct equations which will give the actual dis-
sociation curves. He also gave a general form of equation to meet
the varying cases. In this equation there are two constants, which
must be suitably chosen.
The subject was also taken up by Douglas, J. B. S. Haldane,
and myself. We adopted Hill's aggregation theory, but in a dif-
ferent form. It seemed to us that the aggregation in protein solu-
tions is a phenomenon of the same general nature as precipitation,
the precipitate being, however, only formed in very small parti-
cles consisting of only two, three, or at any rate a few molecules.
RESPIRATION 8l
On this view the aggregated haemoglobin molecules have their
molecular affinities saturated, and therefore go out of the re-
action between oxygen or CO and haemoglobin, thus following
the general principle that corpora non agunt nisi soluta. The only
reaction taking place between the haemoglobin and oxygen is thus
the first one mentioned above. To explain the actual form of the
dissociation curve for blood or salt solutions we assumed that the
degree of aggregation depends on the concentration of the haemo-
globin or oxyhaemoglobin in the solution, in accordance with the
reactions
Hb + Hb^Hbs
Hb + Hbs^Hbg etc.
HbOs + Hb02^Hb204
HbOg + HbsO^^HbgOe etc.
Thus reduced haemoglobin and oxyhaemoglobin molecules ag-
gregate separately; and if we assume that reduced haemoglobin
aggregates more readily than oxyhaemoglobin we can explain at
once the distortion of the curve from the primary rectangular
hyperbola obtained by Barcroft. For as the oxyhaemoglobin be-
comes reduced the aggregation of the reduced haemoglobin mole-
. cules must increase more rapidly than the aggregation of the
I oxyhaemoglobin diminishes. Hence at what would, but for the
I aggregation, be half-saturation, there are fewer free reduced
'! haemoglobin molecules and more free oxyhaemoglobin molecules
than would be the case if the oxyhaemoglobin molecules aggre-
gated as readily as the reduced haemoglobin molecules. Hence
the actual saturation will be much less than half, and not just half,
as would be the case if the tendency to aggregation were the same
for the two kinds of molecules. The actual dissociation curve will
also have the double bend which is characteristic of it. We also
assumed that the saturated molecules of HbCO have just as much
tendency to aggregate with one another and with the saturated
. molecules of HbOg as have the molecules of HbOa- For this reason
the dissociation curve of HbCO in blood in presence of oxygen
must be a rectangular hyperbola, as is actually the case, though its
dissociation curve in the absence of oxygen has the same form as
the dissociation curve of HbOs-
By making certain assumptions (for a statement of which I
i must refer to our original paper) J. B. S. Haldane found that the
|, following equation to the curve for human blood in Figure 20
82 RESPIRATION
resulted, and fitted the experimentally determined curve very
closely. ^^
1.65 (9—85)
^ ^ (i_S)(i+25)
where p = pressure in percentages of one atmosphere, and
5 = fractional saturation of the haemoglobin with oxy-
gen.
Thus if 5 be 50 per cent = -^ — = ^, /> will be 4.0, as we actu-
ally found to be the case. To express the result in millimeters of
mercury pressure, p must of course be multiplied by 7.6, and would]
thus become, in the above example, 30.4.
As explained, above, the simple dissociation curves for oxy-
haemoglobin or CO-haemoglobin in normal human blood*^ are,
so far as our present knowledge goes, the same, when allowance
is made for the differing affinities of the two gases for haemo-
globin. The above equation may therefore be generalized in the
form
1. 65 (9-85)
^"-(1-5) (1+25)
taking a as representing the affinity of the gas for haemoglobin
as compared with the affinity represented in the curve on Figure
20, giving half-saturation with a gas pressure of 4.0 per cent of an
atmosphere. Thus for the fourth curve on Figure 21 (dissociation
curve of CO-haemoglobin in the blood of Douglas, in presence of
42 mm. CO2 pressure), at half-saturation pa = 4.0. Hence as p
was .01 7, a was 235, or the affinity of the haemoglobin for the CO
(determined without taking into account the solubilities of CO and
O2) was 235 times its affinity for oxygen in the standard curve of
Figure 20. This is a convenient and easily intelligible method of
putting the results.
" In working out this equation it was assumed that (as found by Barcroft and
Roberts for dogs' haemoglobin) a dialysed solution of the haemoglobin of Douglas
and myself becomes half-saturated with oxygen at 38°C and a pressure of 1.6 per
cent of an atmosphere of oxygen, and that in human blood saturated with oxygen
2/3 of the oxyhaemoglobin is aggregated, and in completely reduced blood 8/9 of
the reduced haemoglobin. The curve of the dialysed solution would give the
i-S
equation p =z — tt:
" For abnormal human blood the curves are probably different, as will be
pointed out in Chapter VIII.
RESPIRATION 83
The corresponding equation worked out by Hill is
where x = oxygen pressure in mm. of mercury,
y = percentage saturation of the haemoglobin,
K z=z a, constant varying for different curves.
For the blood of Douglas (which was the first to be investi-
gated completely by Barcroft, and which was also investigated by
ourselves) the value of K was .000196.^*
Hill's equation gives curves almost identical with ours, and as
he had kindly communicated it to us by letter we should certainly
have adopted it had we seen how the theory on which it is based
could be brought into definite relation with the particular rec-
tangular hyperbola given by dialysed haemoglobin, or reconciled
with the fact that the dissociation curve of CO -haemoglobin in
presence of a constant oxygen pressure is a rectangular hyperbola.
Hill soon afterwards offered a possible explanation as regards the
latter point. ^^ It seems to me that this explanation is improbable,
but so also, it must be confessed, are certain assumptions connected
with the deduction of our own equation. At present the data are
lacking for a decision as to whether either theory is correct, al-
though both equations are for all practical purposes satisfactory.
I cannot see, however, how to escape the conclusion that there is
more aggregation among the unsaturated than among the satu-
rated molecules of haemoglobin. It is evident that far more data
are needed to enable us to understand the dissociation of oxy-
haemoglobin in blood.
With the help of the chemical facts described in the present
chapter we might proceed at once to the discussion of a number of
physiological and pathological problems; but such a discussion
would be incomplete and misleading in the absence of the facts
relating to the carriage of COg by the blood, and this subject will
therefore be considered in the next chapter.
" The value of /^ as calculated from our own results (Fig. 20) is, for the blood
of both Douglas and myself, outside the normal limits given by Barcroft and rep-
resented graphically in Figure 109, page 226, of his book TAe Resfiratory Function
of the Blood. The cause of this discrepancy is not yet clear.
"A. V. Hill, Bio-Chemical Journal, VII, p. 471, 19 13.
CHAPTER V
The Blood as a Carrier of Carbon Dioxide.
We must now turn to the consideration of the blood as a carrier of
COg. Mammalian arterial blood has usually been found to contain
about 40 or 50 volumes of COg per 100 volumes of blood, while
venous blood from the right side of the heart contains several
volumes more. The following average results obtained with the
mercurial pump by Schoeffer^ illustrate the difference between
venous and arterial dogs' blood, although much doubt must exist
as to whether the circulation and respiration were at normal rest-
ing values when the samples were taken. Much more reliable data
will be given for man in Chapter X.
OXYGEN
CO2
Arterial blood
19.2
39-5
Venous blood from right heart
Difference
II.9 •
7.3
45-3
5.8
In man, as will be shown below, normal arterial blood contains
during rest about 53 volumes per cent of CO2 if the blood is satu-
rated with CO2 at the pressure (about 40 mm.) existing in average
alveolar air of adult men. As 100 volumes of blood, according to
Bohr's^ calculation, take up in simple solution about 51 volumes
of CO2 in presence of a pressure of one atmosphere of CO2 at body
temperature, they can only take up-^ x 51 = 2.7 volumes at the
normal alveolar pressure of 40 millimeters or 5.3 per cent of an
atmosphere. Hence only 2.7 volumes per cent of the CO2 are in
simple solution, the other 50.3 volumes being in chemical combi-
nation. As will be shown below, the difference between the partial
pressures of CO2 in human arterial and venous blood during rest
is only about 6 mm. or 0.8 per cent of an atmosphere. Hence the
physically dissolved CO2 given off in the lungs is only 0.4 volumes
Schoefifer, Sitz. ber. d. Wiener Acad, math. not. cl., XLI, p. 589, i860.
' Bohr, Nagel's Handbuch der Physiol., II, p. 63, 1905.
RESPIRATION 85
per cent, while actually about 4 volumes per cent are given off. It
is evident, therefore, that the giving off of CO2 in the lungs is
almost entirely dependent on the dissociation of its chemical
combinations in the blood.
In what form is CO2 chemically combined in the blood? We
cannot answer this question in the same comparatively simple
and definite manner as in the case of the combination of oxygen
with blood. CO2 dissolved in water has acid properties, and by the
addition of other stronger acids to blood the dissociable chemical
combinations with CO2 are entirely broken up and CO2 liberated.
It is thus quite evidently as an acid (i.e., as H2CO3) that CO2
enters into combination with blood. On analysis blood is found to
contain an excess of alkali (for the greater part soda) not com-
bined with mineral acids. In other words hydrochloric, phosphoric,
and small amounts of sulphuric, acids are present in blood, but \ ^
not in sufficient amounts to saturate the alkali. Hence CO2 is ap- ^ ^-^
parently free to combine with the excess of alkali, forming, since
an excess of free CO2 is present, bicarbonates. As Zuntz^ pointed
out, if blood were nothing but a solution of the well-recognized
acids and bases present in it, we could account for the quantity of
CO2 which it is capable of combining with chemically. Zuntz cal-
culated that the excess of alkali present in the blood is equivalent
to at least a 0.2 per cent solution of soda. This could take up as
bicarbonate as much CO2 as blood can take up in combination.
Nevertheless the properties of such a solution in respect to the
carriage of CO2 would not approach to those of blood: for the
soda would remain completely saturated as bicarbonate when ex-
posed to the CO2 in the alveolar air, and there would not be any
appreciable dissociation, so that the solution would be no better
than distilled water as a physiological carrier of C02- This point
has been rendered specially clear by Bohr, who investigated the
dissociation curve for CO2 of a dilute sodium bicarbonate solution.
To reach an insight into the actual behavior of blood as a car-
rier of CO2 we have to take into consideration another factor.
Proteins have the very peculiar property of being able to act either
as weak alkalies towards acids or as weak acids towards alkalies.
This is shown, for instance, by the familiar fact that an ordinary
indicator such as litmus ceases to give a sharp end-point when a
protein is present, and that not only neutral but even slightly acid
* Zuntz, Hermann's Havdbuck ier Physiol., IV, 2, p. 65, 1882. To Zuntz's
admirably clear and thorough discussion of the subject I am greatly indebted. This
discussion is far ahead of most of what has appeared in later textbooks and papers.
^.
86 RESPIRATION
protein solutions will combine with COg. A considerable excess
of acid or alkali must be added to a neutral protein solution before
a marked acid or alkaline reaction is reached. The protein acts as
a ''weak/' or very slightly ionized, acid, such as carbonic acid, and
likewise acts as a correspondingly weak alkali, since the protein
molecule possesses both acid and alkaline affinities. It is thus, like
carbonic acid, or any other weak acid, or weak alkali, a buffer
substance, which prevents any abrupt change from acid to alkaline
reaction or vice versa. Not until all the CO2 combined in a solu-
tion of carbonate has been liberated by acid is there a sudden de-
velopment of acid reaction, or so long as any free COg is present
of strong alkaline reaction. The CO2 acts as a buffer substance on
the alkaline side only, whereas protein is capable of acting on
either side of the neutral point. In the living body, however, blood
is always a little alkaline, so that the combination of CO2 with
proteins does not come into account.
We can now see a reason why blood should act towards CO2 as
it does in the living body and in the vacuum pump. The total
alkali in the blood is combined, partly with strong acids, such as
HCl, partly with carbonic acid, and partly with protein com-
pounds; partly also, perhaps, with other substances capable of
acting, like the proteins, as very weak acids. In the living body,
however, free carbonic acid is always present, and the mass in-
fluence of the free carbonic acid prevents part of the protein from
combining with alkali, while the protein in a similar manner
keeps out the carbonic acid. We have thus a chemical system
which is disturbed at once by any variation in the concentration
I of free carbonic acid present, i.e., by any variation in the partial
^pressure at which the blood is saturated with COg- When the
pressure of COg falls, more of the proteins are at once enabled to
take the place previously occupied by the carbonic acid in the
chemical combinations which constitute the system ; and vice versa
with a rise of CO2 pressure. In the vacuum pump the CO2 pressure
is reduced to zero, since, although the total pressure in the vacuum
chamber of the pump is, owing to aqueous vapor, always above
zero, the COg is carried off in the stream of aqueous vapor passing
away. To recover the whole of this CO2 in the same gaseous form,
however, a perfect and dry vacuum in the receiving chambers of
the pump is needed. Since the COg pressure is zero the whole of the
COjin combination is expelled by the mass influence of protein act-
ing as an acid. Pfliiger showed that even when a moderate amount
of sodium carbonate is added to blood, the additional COg in the
RESPIRATION 87
carbonate is expelled in the vacuum pump, and can be recovered
in the gaseous form with the help of the perfect vacuum of the
Pfliiger blood pump.* This can now be easily understood in terms
of the theory just stated. The blood must be either boiled or
shaken : otherwise the disengagement of CO2 is excessively slow.
When serum alone, and not whole blood, is exposed to the
vacuum of the pump, most of the CO2 can be pumped out, but not
quite all. It is necessary to add some acid in order to obtain the
whole of the CO2 — at any rate within any reasonable time. The
proteins of the serum are not present in sufficient amount to effect
the dissociation of the whole of the sodium carbonate, but the ex-
pulsion is easy when the haemoglobin of the corpuscles is added.
Both haemoglobin and serum proteins act towards sodium carbon-
ate as acids, and it was shown by Sertoli^ that much of the CO2
can be expelled in the pump from sodium carbonate solution if
serum proteins are first added.
Bohr found that haemoglobin solutions, even if they are first
rendered slightly acid, will combine with considerable amounts
of CO2, and he was thus led to what seems to me to be the er-
roneous conclusion that haemoglobin has a specific power, apart
from its alternative acid or basic properties, of combining with
CO2. Equally erroneous, as Priestley^ has recently shown, is a
similar conclusion which was put forward on spectroscopic
grounds.
We have already seen what predominant physiological im-
portance is attached to the pressure of CO2 in the arterial blood,
and with what exactitude this pressure is regulated. We should
therefore expect to find that the pressure of CO2 in the tissues of
the body generally is of the same importance and subject to simi-
lar regulation. To understand this regulation it is of primary
importance that we should know the laws of dissociation of CO2
from its combination in blood. Until quite recently our knowledge
on this subject was very limited, although Bohr''^ had constructed
a tentative dissociation curve from observations partly by Jacquet
and partly by himself, on samples of blood from the ox and dog.
The matter was taken up a short time ago by Christiansen,
Douglas and myself^ with the help of the new method of blood-
* Pfliiger, Ueber die Kohlensdure des Blutes, p. 6, 1864.
'Sertoli, Hoppe-Seyler's Med.-Chem. Unlets., Ill, p. 356, 1868.
"Priestley, Journ. of Physiol., LIII, Proc. Physiol. Sic, p. LVIII, 1920.
'Bohr, Nagel's Handbuch der Physiol., II, p. 106, 1905.
• Christiansen, Douglas, and Haldane, Journ. of Physiol., XLVIII, p. 244,
1914.
88
RESPIRATION
gas determination mentioned in Chapter IV. Warned by previous
failures of physiologists to recognize the exactitude of normal
physiological regulations, we used defibrinated human blood, of
which fresh samples could be obtained at any time from the same
individual under normal conditions. At the outset we wasted much
time, however, through failing to realize that it was necessary to
have the blood fresh for each experiment, as blood outside the
body undergoes slow changes which diminish its capacity for
carrying C02-
Figure 25 shows the results obtained with my own blood.
90
40
.0-
■^
^
■^
-1
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^
^u
^
,0^
^
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• ^
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1
1
10
20
90
100
MO 120
30 AO 50 60 70 80
PRESSURE of CO2 in MM. H^.
Figure 25.
Lower curve — absorption of CO2 by blood of J. S. H. in presence of air and COa.
Upper curve — absorption of COa by blood of J. S. H. in presence of hydrogen and
COa.
Attention may first be directed to the lower curve, showing the
amounts of CO2 taken up in the presence of air and varying pres-
sures of C02- The first, and by far the most striking, point to be
noted is that, although the different determinations were made on
different days covering a period of about six months, they all lie
on one curve. The samples were taken at different times of the day
RESPIRATION 89
during ordinary laboratory work. In regulating the temperature
of the bath containing the saturator, analyzing the samples of air
from the saturator, observing the barometric pressure, measuring
the sample of blood (of which about i cc. was used for each anal-
ysis), and determining the CO2 by means of the blood-gas ap-
paratus (we used Brodie's modification of the original apparatus),
it was impossible to avoid combined errors of I or 2 per cent of
the quantities to be measured, so that we could not say how exact
Nature's regulation of the curve is. At any rate it was so exact
for my blood that the most exact existing chemical methods did
not show any deviations from the curve, any more than they
could show deviations from the oxyhaemoglobin or CO-haemo-
globin dissociation curves. Marked temporary deviations could,
however, be produced by severe muscular exertion ; and probably
very distinct deviations may occur after meals.
With the blood of other persons the results were only slightly
different. Thus the curves, so far as ascertained, for the blood of
Miss Christiansen and Dr. Douglas were slightly below, and
otherwise parallel to mine under normal conditions. The blood of
most persons seemed to take up about 50 volumes of CO2 per 100
volumes of blood at 40 millimeters pressure of CO2; but under
abnormal conditions, as will be shown below, there are great
temporary variations from this standard, corresponding to the
great variations observed under the unfavorable conditions in
experiments on animals.
More than 50 years ago it was suspected by Ludwig that oxygen
may have some influence in turning out CO2 from the venous
blood which comes to the lungs. The experiments made to ascer-
tain whether oxygen helps to turn out CO2 from blood gave, how-
ever, only a negative result, and more recent work by Bohr,
Hasselbalch, and Krogh^ led to similar negative conclusions. We
had been making experiments to investigate the rise of alveolar
CO2 pressure when the breath was held, or when a small quantity
of air was rebreathed. One result of these experiments was to show
that if the alveolar oxygen pressure fell much below normal the
percentage of CO2 in the alveolar or rebreathed air was always,
without exception, lower after any definite interval of time, than
was the case under the same conditions but with the alveolar oxy-
gen percentage high. This brought us back to Ludwig's old ques-
tion, which with the new blood-gas method we could investigate
* Bohr, Hasselbalch, and Krogh, Skand. Arch. f. Physiol., XVI, p. 411, X904.
90
RESPIRATION
far more easily and exactly than when nothing but the blood
pump and the old methods of gas analysis were available.
The first pair of experiments showed us that Ludwig's old
suspicion was correct, and that at the same pressure of CO2 blood
takes up considerably more CO2 in the absence than in the presence
of oxygen. The upper curve in Figure 25 is the absorption curve
for my own blood in the absence of oxygen, and shows that at the
physiologically important part of the curve the blood takes up
from 5 to 6 volumes per cent more of CO2 if oxygen is absent. We
found that the excess of CO2 taken up runs parallel, not to the
partial pressure of oxygen, but to the extent to which the oxy-
haemoglobin of the blood is dissociated. Saturation of the haemo-
globin with CO had just the same effect on the curve as saturation
with oxygen. The effect may be due to saturated haemoglobin
being a less alkaline substance than reduced haemoglobin, but is
more probably dependent on the molecules of reduced haemo-
^ ' globin having a much greater tendency to aggregate than those
of saturated haemoglobin. The reasons for this assumption with
regard to aggregation were given at the end of last chapter.
The aggregated haemoglobin molecules would presumably have
less mass influence in keeping out the CO2 from combination with
alkali than the unaggregated molecules.
Let us now see what physiological deductions can be drawn
from the absorption curves in Figure 25. Human blood contains
about 18 volumes per cent of oxygen, and if all this oxygen were
used up in the tissues about 1 5 volumes of CO2 would be formed.
But during the using up of the oxygen the absorption curve for
CO2 starting from 40 mm. would pass from the lower to the upper
curve of Figure 25, following upwards the thick line shown in
Figure 26.
Hence the COg pressure, instead of rising to 80 mm., as would be
the case if the lower curve were followed, would only rise to 62
mm. Actually, as will be shown later, not more than about a fifth
of the oxygen is used up during rest, so the pressure of COg in the
mixed venous blood rises only about 5 or 6 mm. This makes it
far more easy to understand why the pressure of CO2 in the arte-
rial blood should be so exactly regulated as it is. If it had been the
case that the resting CO2 pressure in the systemic capillaries were
far above the arterial CO2 pressure, the necessity for such exact
regulation of the arterial CO2 pressure would have been hard to
understand.
While the venous blood is being aerated in the lungs, the ab-
RESPIRATION
91
sorption curve for CO2 will follow the thick line downwards. It
will be seen that, if we assume the resting excess pressure of CO2
in the venous blood, the quantity of CO2 given off when the CO2
pressure in the lung capillaries falls to that of the alveolar air
will be about 55 per cent greater than if no oxygenation had oc-
curred. If, on the other hand, we assume a certain excess charge
75
I
§65
70
60
^ 50
I 40
1 1 1 "7'
y^
Z ^^
-^ ^
y^t ^-^
^ ^ y^
^j^ ^
T-tt'^ --"""
/^t^ -^
/ /- '■"'
-/^-■■■'
-,^^ -.^-"
7v^ ■^-
^Z^-' ._
ly __
7^ /
1
80
90
H<).
30 AO 50 60 70
PRESSURE of CO^ m MM.
Figure 26.
Upper curve — absorption of CO2 by blood of J. S. H. in pres-
ence of hydrogen and CO2.
Middle curve — absorption of CO2 by blood of J. S. H. in pres-
ence of hydrogen and CO2.
Lower curve — absorption of CO2 in blood of ox and dog in pres-
ence of air and CO2 (Bohr's data).
Thick line A — B represents the absorption of CO2 by the blood
of J. S. H. within the body.
of CO2 in volumes per cent in the venous blood, the discharge of
CO2 will ordinarily be about 55 per cent greater than if no oxy-
genation had occurred.
We can also see that under abnormal conditions, such as may
easily occur when the breathing is suspended or reduced in
92
RESPIRATION
amount, as after forced breathing, or during excessive artificial
respiration, or other respiratory disturbances, CO2 rnay easily be
given off by the lungs when there is no excess of venous over
alveolar CO2 pressure, or even when the venous CO2 pressure is
considerably lower than that of the alveolar air. For when the
blood reaches the lungs the process of oxygenation so reduces the
capacity of the blood for CO2 that its COg pressure is raised
above that of the air, and diffusion results. If the respiratory
quotient has fallen temporarily to a third or less of its normal
value, the thick line of Figure 26 will become vertical in the living
body, or incline to the left instead of to the right. It is merely
necessary to suspend the breathing for a very short time in order
to realize this condition. Only if air containing a large excess of
CO2 is breathed, will CO2 be absorbed backwards, and the thick
line pass downwards as well as to the left.
The discovery that oxygenation of the haemoglobin helps to
turn out CO2 from blood gives us the key to the proper interpreta-
tion of the fact that, as was found by ourselves in human experi-
ments, and earlier by Werigo,^^ and by Bohr and Halberstadt,^^
more CO2 is given off into the air of the lungs when oxygen is
present. Thus in Halberstadt's experiments it was found that if
one lung was ventilated with air, and the other with hydrogen,
the lung ventilated with air gave off nearly 50 per cent more CO2
than the lung ventilated with hydrogen. This result is precisely
what would be expected in view of the facts just described; but
as Bohr was misled by the apparent results of his experiments
with blood outside the body, he wrongly attributed Halberstadt's
and Werigo's results to the supposed fact that in presence of air
there is a large formation of CO2 in the lungs, owing to a process
of oxidation occurring there. As will be shown later, hardly any
formation of CO2 occurs in the lungs.
In a quite recent paper Parsons^^ has investigated mathemati-
cally the form of the absorption curve of blood for CO2 on the
theory that the blood is a chemical system consisting of carbonic
acid and what may be regarded as one other free acid (consisting
of the proteins present) with a fixed concentration of available
alkali distributed between them. This fixed concentration he
estimated from blood-ash analyses and in other ways, to be about
4.5 x lo-^N. He found that the form of the curve given by calcula-
"Werigo, P finger's Archiv., LI, p. 321, 1892.
" Bohr, Nagel's Handb. der Physiol., I, p. 208.
"Parsons, Journ. of Physiol., LIII, p. 42, 19 19.
RESPIRATION
93
tion corresponded satisfactorily with the curves which both we
and he had obtained experimentally for human blood. This is
illustrated in Figure 27, reproduced from his paper. We had not
attempted to calculate the form of the curve, as several proteins
are involved in the chemical system ; but by the simplifying as-
sumption which he made Parsons overcame this difficulty.
"-ioL
-
_^^^^
^
80
A
,^
-^
10
y^
.^
^
60
v«^
^
y^
^
/
30
20
10
/
/
/
[
•
D.
'
rC
-^x
^
10 20 30 40 50 60 70 80 90 100 HO iZOmm.
Figure 27.
Comparison between the theoretical curve and experimental results for
completely reduced blood of Haldane.
In the previous chapter we have seen that, other things being
equal, a rise of CO2 pressure shifts the dissociation curve of oxy-
haemoglobin to the right if the curve is represented as in Figures
19 or 28. In the living body the pressure of CO2 is constantly
rising as the blood becomes more and more venous in its passage
through the systemic capillaries. The data embodied in Figure 25
gave us the means of calculating this rise, and it will be seen that
it is much less than previously existing knowledge would have
led us to believe. Figure 27 shows the oxygen dissociation curve
of my own blood in the living body, calculated from Figure 26, on
the assumption that the shifting of the curve to the right is pro-
portional to the increase of CO2 pressure in the blood as it passes
along the systemic capillaries.
Bohr believed that the shifting of the dissociation curve to the
right by the influence of increasing CO2 pressure in the systemic
94
RESPIRATION
capillaries is an important factor in facilitating the unloading of
oxygen from the blood ; and this line of argument has been further
elaborated by Barcroft. The actual shifting is, however, very
small under normal conditions, and of much less physiological
importance than the effect of the shifting of the CO2 absorption
curve in consequence of reduction of oxyhaemoglobin.
1.0
-
-
-
-
-
-
-A
-__
:
5
<<i
^
•^ 80
^
5
A
y
C 70
/
7
3-
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f^
/
/
»
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'
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/
1
/
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— 1
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0 20
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//
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h,c
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■^ 10
s
V
C^
„
J
3
/ 2 3 4 5 6 7 8 9 10 1/ 12 13 U 15 16
Pressure of oxt^^en in Percentage of one afmosphere.
Figure 28.
The thick line shows the dissociation curve of oxyhaemoglobin in the blood of
J. S. H. and C. G. D. in the presence of 40 mm. pressure of CO2. The thin line
represents the dissociation curve of oxyhaemoglobin in the blood of J. S. H. and
C. G. D. within the body.
We are now in a position to interpret much more completely
the facts concerning the regulation of breathing by small varia-
tions in the alveolar CO2 pressure. How very small the mean
variations are, we have already seen. On the other hand the
breathing is constantly being interrupted or interfered with in
one way or another during ordinary occupations, such as speak-
ing or singing, and the breath can be held for a few seconds with-
out any noticeable air hunger being produced. During these
interferences the alveolar CO2 pressure must be constantly rising
and falling on either side of the normal limit, but the physiological
effect seems almost nil, and to popular imagination it seems as
if the breathing, instead of being regulated so rigorously as was
shown to be the case in the second chapter, is hardly regulated at
11
RESPIRATION 95
all. We are also familiar with instructions to increase the breathing
so as to "improve the oxygenation of the blood" and with quack
advertisements based on the same idea. How does it come about
that although the regulation is so exact on the average, yet
temporary deviations from this average exactitude do not cause
any discomfort? How is it, also, that when the production of CO2
is suddenly increased to perhaps ten times the normal, as on a
sudden muscular exertion, yet the breathing responds gradually
and easily to the new conditions?
The answer to this question is that there are physiological buf-
fers between the stimulus of increased production of CO2, or
increase in the alveolar CO2 pressure, and stimulation of the
respiratory center, and that if it were not so the respiratory center
would work in a jerky, irregular, and extremely inconvenient
manner. The first of these buffers is the large volume of air always
present in the lungs. Thus in my own case the mean volume of air
in the lungs at the end of inspiration during rest is 3650 cc,
measured dry at o°C., including about 3000 cc. of saccular al-
veolar air containing about 5.6 per cent -of CO2. Let us assume
that the breath is held at the end of inspiration during rest, and
consider what happens. About 250 cc. of CO2 would be normally
given off per minute, or 20 cc. in 5 seconds; and if the latter
quantity were given off with the breath held the mean CO2 pres-
sure in the lung air would rise by 0.6 per cent in 5 seconds. But,
as will be shown later, about 700 cc. of blood will pass through the
lungs in 5 seconds, and as the arterial blood will be more highly
saturated with CO2 if the alveolar CO2 percentage rises, some of
the CO2 which would ordinarily have been given off will be
dammed back in the blood. Figure 25 shows that for every rise of
2.5 mm. or .36 per cent in the alveolar CO2 pressure the blood will
take up, or hold back, i volume per cent of CO2. Hence the actual
rise in the mean CO2 pressure within the lungs cannot be more
than about 0.4 per cent in the 5 seconds during which the breath
is held. The net result is that about two-thirds of the COg which
the suspension of the breathing prevents from escaping from the
body is temporarily accommodated in the lung air, which thus
acts as a first buffer for preventing too sudden a change in the
arterial CO2 pressure.
A second buffer is provided by the tissues and lymph in and
around the respiratory center itself. So far as we know the re-
action in all parts of the body is slightly alkaline, just as in the
blood; and the tissues and lymph have, like the blood, a con-
96 RESPIRATION
siderable capacity for absorbing CO2. Hence it will take some
time for the blood to saturate the tissues and lymph up, or de-
saturate them down, to a new CO2 pressure. Here we have a
second, and very powerful, buffer action, tending to smooth out
the influence on the respiratory center and other tissues of all
variations of short duration in the CO2 pressure of the arterial
blood, and also to prolong the influence of variations of longer
duration.
This subject was investigated by t)ouglas and myself.^^ The
following table shows the results we obtained on determining the
alveolar CO2 pressure at various times after holding the breath.
In order to throw out disturbing eff"ects due to the action of oxy-
gen want on the respiratory center, some of the experiments werel
made after a few normal breaths of oxygen had been taken, so that
there should be plenty of oxygen in the lungs up to the end of the
stoppage of respiration.
PRESSURE IN MM. OF
Hg.
IN ALVEOLAR AIR
CO2 O2
At end of period of holding breath for 30"
49.2 62.6
At fifth expiration following
29.1 -
At ninth expiration following
31.5 -
At twelfth expiration following
32.0 -
At twentieth expiration following
33.8
At thirtieth expiration following
37.0 -
At fortieth expiration following
38.8
At fifth expiration after holding 40"
28.4 117.
At eighth expiration following
29.4 -
At end of holding breath for 130" after oxygen
61.9 274.
At sixth expiration afterwards
24.8 —
At twentieth expiration afterwards
33.3 —
At fortieth expiration afterwards
31.2 —
Normal average
39-75 105.
Figure 29 is a stethographic tracing of the respirations during
an experiment, and shows that the breathing returns gradually
to normal after the hyperpnoea following the stoppage.
The table is extremely instructive, and shows very clearly what
a long period of increased breathing, with the alveolar CO2 pres-
sure distinctly below normal, is required in order to compensate
" Douglas and Haldane, Journ of Physiol., XXXVIII, p. 420, 19 19.
2^
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O CL
98 RESPIRATION
for the cumulative action of the stoppage of breathing. After the
long stoppage of 130 seconds the breathing and alveolar CO2
pressure had not nearly returned to normal, even after the fortieth
breath following the stoppage.
Figure 30 shows the converse experiment. Forced breathing
was continued two minutes so as to wash out CO2 from the lungs,
arterial blood, and respiratory center ; and oxygen had been taken
into the lungs, so as to cut out the effects of want of oxygen. The
apnoea lasted 4^ minutes, and an alveolar sample (the taking of
which is recorded on the tracing and somewhat disturbs it) was
obtained as soon as the slightest inclination to breathe was noticed.
It will be seen that the CO2 percentage in this sample was 7.12
per cent (51.5 mm. of CO2 pressure) a value far above the normal
40 mm. required to excite the center under normal conditions.
Separate experiments showed that by the end of two minutes of
forced breathing the alveolar CO2 pressure had fallen to about
1 3 mm. and during the apnoea rose to normal again at the end of
2^ minutes. During the last 2 minutes the alveolar CO2 pressure
was above normal ; but sufficient CO2 had not accumulated in the
tissues of the respiratory center to stimulate it, till the alveolar
CO2 pressure had gradually risen to 51.5 mm. At this point the
center, which had now just reached its normal CO2 pressure, began
to work quietly and smoothly, reducing the alveolar CO2 pressure
to normal, and picking up the normal regulating activity. The
breathing cannot indicate a gradual return of the CO2 pressure
in the center to normal, corresponding to the gradual return in
Figure 29, since, as is shown by the experiments described in
Chapter II, complete apnoea results from a fall of 0.2 per cent or
1.5 mm. of the CO2 pressure in the respiratory center.
The apnoea following forced breathing can be temporarily
interrupted by sending a block of blood highly charged with CO2
to the respiratory center. The effect of this is shown in Figure 31.
As soon as the breathing and the "apnoeic" venous blood return-
ing to the lungs have removed the extra CO2 introduced into the
lungs the apnoea returns again.
The washing out of CO2 from the body during forced breath-
ing, and its gradual reaccumulation during the next ten or twenty
minutes, were strikingly illustrated in some experiments carried
out by Boothby.^* Thus in an experiment on myself he found that
during ij/^ minutes of forced breathing I had removed about
1,400 cc. extra of CO2 from the body. During the subsequent ap-
"Boothby, Journ. of Physiol., XLV, p. 328, 1912.
RESPIRATION
99
noea of 2 minutes about 600 cc. of CO2 were regained, and about
200 cc. more during two minutes of periodic breathing which
followed. The remainder was regained during the following six
or eight minutes. In this latter period the alveolar CO2 pressure
Figure 31.
Effect of a breath of air containing 9.0 per cent of CO2 during apnoea follow-
ing forced breathing. Crosses show inspiration and expiration of breath. After
an interval there are three deep, and two shallow, breaths, followed by a long
apnoeic interval, after which the usual periodic breathing begins. To read
from left to right. Time-marker := i second.
was practically normal, but the respiratory quotient very low, in
correspondence with the very high respiratory quotient during
the forced breathing.
What approximately happens to the CO2 pressure in the al-
veolar air and respiratory center is represented in Figures 32 and
■50
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g^5
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8
Time in Minufes
Figure 32.
Approximate variations in CO2 pressure of arterial and venous blood dur-
ing and after forced breathing of oxygen for two minutes,
33. The pressure of CO2 in the respiratory center is assumed to be
about equal to that of the mixed venous blood, though it is prob-
ably lower.
lOO
RESPIRATION
The very powerful steadying influence on the CO2 pressure of
the capacity of the tissues for taking up CO2 is evident from these
figures. In consequence of this influence, and in a much less degree
that of the reserve of air in the lungs, variations of short duration
in the alveolar CO2 pressure hardly count, although even the
slightest variations of a more prolonged character count a great
deal.
60
< 50
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Tine in Minutes
Figure 33.
Approximate variations in CO2 pressure of arterial
and venous blood during and after holding the breath
for 130 seconds with oxygen.
On examining Figure 32 it will be seen that, although the
venous CO2 pressure is below that of the alveolar air during most
of the apnoea, CO2 is being given off all the time into the alveolar
air. This is due to the effect of oxygenation in decreasing the
capacity for CO2 and thus raising its pressure in the blood. This
effect is explained by the fact that the thick line of Figure 26 will
be inclined to the left, as very little CO2 is being given off by the
tissues, impoverished as they are of CO2 by the forced breathing.
In order to realize how important the steadying influence just
mentioned is, we have only to turn to what happens when want
of oxygen, instead of CO2, is exciting the center. Oxygen is no
-^ ?.
d <u
3
V rt
;:i S
s I ^
^ > a
J3 O g
'^ 15
u 'a
.2 CO
I02
RESPIRATION
more soluble in the tissues and lymph than in water. They have
thus practically no power of storing free oxygen. In the course of
our investigations on the effects of want of oxygen it became
evident that the center works very jerkily when excited by want
of oxygen, and the subject was studied in further detail by Doug-
las and myself.^^ We found that the effects of regulation of the
center by oxygen want could be observed very conveniently at
the end of the apnoea caused by forced breathing of ordinary air.
When apnoea is produced by forced breathing of air for about
two minutes, the oxygen percentage in the lungs runs down very
low before the pressure of CO2 in the respiratory center has nearly
risen to its normal value. In some subjects there is an alarming
^
E
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A
Ji
I
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k
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V
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^/~
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10
r
i !
4^
K^
^-%
Z*"^
m^
^m^^
mm^^
iV/W.WrVffl
Figure 35.
Variations in alveolar gas pressures after forced breathing
for two minutes. Thin line = oxygen pressure, thick line = CO2
pressure. Double line = normal alveolar CO2 pressure. The
actual breathing is indicated at the lower part of the figure.
appearance of blueness in the face before any desire to breathe is
felt. Ultimately, however, the stimulus of oxygen want (together
with the subliminal CO2 stimulus) suffices to start the breathing.
But the first four or five breaths greatly raise the alveolar oxygen
percentage and thus quiet the center down again, so that apnoea
again follows, which is again followed by breathing and subse-
quent apnoea, this periodic rising and dying away of the breath-
ing going on for about five minutes, as shown in Figure 34, though
not all subjects react alike.
Figure 35 shows the variations of the alveolar oxygen and CO2
"Douglas and Haldane, /ourn. of Physiol., XXXVIII, p. 401, 1909.
RESPIRATION
103
pressure, as determined in samples of alveolar air. Reference to
Figure 31 shows that at no time during the periodic breathing is
the CO2 pressure in the respiratory center more than just suf-
ficient to excite the center by itself.
It is very easy to see what has been happening. The oxygen
want caused by the partially reduced blood coming from the
lungs at the end of the apnoea has, along with the CO2 present,
sufficed to excite the center ; but this oxygen want is at once re-
lieved by the breaths which follow, since the oxygen pressure in
the lungs is raised beyond the exciting point. The result is a
prompt return of the apnoea, till the oxygen in the alveolar air
again returns to the stimulating point. The respiratory governor
is "hunting" just as the governor of a steam engine or turbine
hunts if there is no heavy flywheel or other steadying influence.
The chief flywheel of the respiratory center is the great storage
(f
Figure 36.
• Breathing through soda lime and long tube. Sample of alveolar
air at the end of a dyspnoeis period, O2 = 8.70 per cent, CO2 = 5.48
per cent.
capacity in the tissues for CO2. There is no such storage capacity
in connection with oxygen, so the flywheel has disappeared.
When slight oxygen want, and not merely excess of CO2, is
exciting the center, the breathing very readily becomes periodic.
To realize this condition in a permanent manner we only had to
breathe in and out through a tin of soda lime with a piece of hose
pipe of variable length attached on the far side, so as to give a
suitable dead space. By this means the alveolar oxygen pressure
can be reduced to any required extent. Figure 36 shows the effect
of such an arrangement. This effect is at once knocked out if oxy-
gen is breathed.
104
RESPIRATION
Some years ago it was discovered by Pembrey and Allen^^ that
the well-known pathological form of periodic breathing named
after Drs. Cheyne and Stokes, who described it (though it was
previously described by John Hunter), is abolished by giving the
patient pure oxygen to breathe. This observation indicates with
great certainty that ordinary pathological Cheyne-Stokes breath-
ing is caused also by want of oxygen participating in the excita-
tion of the center. Pathological periodic breathing and that of
hibernating animals will be discussed later.
The normal pressure of oxygen in the alveolar air is about
lOO mm. or 13.1 per cent of an atmosphere. On looking at the
dissociation curve of oxyhaemoglobin in human blood (Figure
20) it will be seen that a fall of 4 per cent of an atmosphere, or
30 mm., makes very little difference to the saturation of the haemo-
globin. Nor has such a fall any appreciable influence on the rest-
ing breathing at the time. It is thus evident that, although there
is no appreciable store of readily available oxygen in the liquids
of the body outside the red corpuscles and certain muscles which
contain a little haemoglobin, there is a store of oxygen, available
without any inconvenience, in the air of the lungs. If the breathing
is temporarily stopped during some occupation this store is drawn
on. Thus if the breath is held for half a minute the oxygen runs
down by about 4 per cent in the alveolar air during rest ; but under
normal conditions it is quite impossible to hold the breath long
enough to imperil seriously the oxygen supply to the tissues. In
spite of the gradual manner in which, as we have just seen, CO2
acts on the respiratory center, there is never, except under very
artificial conditions, any considerable oxygen want. The com-
paratively large volume of air which is always in the lungs gives
sufficient oxygen storage to guard against the temporary want of
oxygen. Were this amount of air much less the danger would be
always present, and, as we shall see later, this danger or incon-
venience is present at high altitudes, when the mass of oxygen in
the lungs is greatly diminished. At a high altitude one cannot
hold the breath for more than a few seconds without feeling an
imperative desire to breathe, and such operations as shaving, or.
reading a barometer, are thus rendered troublesome. Nature sees
to it that ordinary mortals who live under a pressure of about one
atmosphere carry about sufficient oxygen in their lungs to pre-
vent oxygen want; and there seems to be some evidence that
" Pembrey and Allen, Journ. of Physiol., XXXII, Proc. Physiol. Soc, p. xviii,
1905 ; also Medico- Chirurg. Trans., XI, p. 49, 1907.
RESPIRATION 105
persons who inhabit very high parts of the earth develop a greatly-
increased chest capacity.
Addendum. The account given in this chapter of the manner in
which CO2 is carried by the blood represents what I have taught
for many years, and is largely based, as mentioned above, on the
teaching of Pfliiger and Zuntz. A very different view of the
subject has recently been presented by Buckmaster, Bayliss, and
others. According to this view the extra COg taken up in the
venous blood is combined, not with alkali, but with haemoglobin,
and may also be in part adsorbed by haemoglobin and other
proteins. As evidence that haemoglobin and other proteins do
not play the part of weak acids in expelling CO2 from its combi-
nation with alkali, Buckmaster cites experiments in which he
found that, contrary to Pfliiger's statement, blood or haemo-
globin is not capable of expelling CO2 from a weak carbonate
solution in the vacuum of a blood pump at body temperature.^
It seems to me that these experiments were fallacious because the
blood was neither boiled nor shaken. Boiling, shaking, or bubbling
is necessary to remove the COg. When Pfliiger's experiment was
repeated in a simple form by Adolph in my laboratory the ex-
pulsion of CO2 from sodium carbonate by blood was found to
occur quite readily.^ As already mentioned, Buckmaster's con-
tention that haemoglobin gives a characteristic spectrum with
CO2 was also found to be incorrect.
The supposition that an extra amount of gas is adsorbed by the
proteins of blood has no basis. The careful experiments of Bohr
and other previous observers show clearly that apart from chemi-
cal combination blood takes up, not more, but considerably less,
gas than an equal volume of water. The only apparent exception
to this rule was the fact that oxygenated blood (but not reduced
blood) yields slightly more nitrogen than the quantity calculated
from its estimated solubility. The existence of this small surplus
Avas confirmed by Buckmaster and Gardner.* The apparent surplus
is almost certainly due to what is a rather common source of
slight error in gas analysis. When the gas pumped off from oxy-
genated blood is analyzed, the first step is to bring the gas into
contact with potash solution to absorb the CO2. When this is ab-
sorbed a gas mixture consisting almost wholly of oxygen is left
in contact with the potash solution. But the latter is saturated
* Buckmaster, Journ. of Physiol., LI, p. 105, 1917-
'Adolph, Journ. of Physiol.. LIV, Proc. Physiol. Soc. p. XXXIV, 1920.
* Buckmaster and Gardner, Journ. of Physiol., XLIII, p. 401, 19 12.
io6 RESPIRATION
with air, and as a consequence nitrogen diffuses from the potash
solution into the gas mixture, while oxygen diffuses into the
potash solution. The consequence is that the residue of nitrogen
found in the gas after the oxygen has been absorbed is greater
than was originally present in the gas. This source of error is
absent if little or no oxygen is present in the gas pumped off from
the blood. We can thus explain why no extra nitrogen has been
found in reduced blood.
Bayliss* contends that the bicarbonate and the plasma proteins
present in blood play no part in the physiological carriage of
CO2 between the tissues and the lungs, and that haemoglobin is
alone concerned in the carriage, since it does not, under actual
physiological conditions, compete as an acid with CO2 for the
alkali available in the blood. The experiments cited in support of
this conclusion seem to me quite unconvincing; and if it were cor-
rect we should expect to find that blood saturated at the alveolar
partial pressure with CO2 would contain more combined CO2 than
a solution of bicarbonate of the same strength in titratable alkali
as the blood. Actually, the blood, especially at body temperature,
contains far less combined CO2. It seems quite impossible to
reconcile Bayliss' theory with this fact ; and I cannot see how any
other theory than that given in the first part of this chapter i>
capable of interpreting the facts as a whole. It may be that a small
amount of CO2 is combined with free haemoglobin ; but it seems
evident that under physiological conditions -haemoglobin and
other proteins act, for all practical purposes, simply as weak acids.
It is in virtue of this action, and the more powerful action of
oxyhaemoglobin than reduced haemoglobin as an acid, that blood
functions so efficiently as a pysiological carrier of CO2. Campbell
and Poulton, who entirely disagree, and on substantially the same
grounds as I do, with the conclusions of Buckmaster and Bayliss,
have recently shown that an artificial mixture of dialysed cor-
puscles and dilute sodium bicarbonate solution takes up, within
physiological limits of CO2 pressure, much less CO2 than the
bicarbonate alone holds. ^
For the sake of simplicity I did not discuss separately the
action of plasma and corpuscles in combining with CO2 ; but much
attention has been given recently to this subject. Zuntz^ pointed
out that when plasma or serum is separated from blood collected
* Bayliss, Journ. of Physiol., LIII, p. 162, 19 19.
"Campbell and Poulton, Journ. of Physiol., LIV, p. 157, 1920.
'Zuntz, Hermann's Handbuch der Physiol., IV, 2, p. -jt, 1882.
RESPIRATION
107
as it flows from a vessel, the corpuscles are capable of taking up
from pure CO2, more combined CO2 than an equal volume of
the plasma. If, on the other hand, the blood is artificially saturated
with pure CO2, or air containing a high percentage of CO2, and
then separated into plasma and corpuscles, the plasma contains
more combined CO2 than the corpuscles. He concluded that alkali
previously combined with haemoglobin in the corpuscles combines
with CO2 when a high concentration of the latter is present, and
passes out as bicarbonate into the plasma. Further investigation
of this phenomenon by .Giirber''' showed that alkali does not pass
out of the corpuscles, but acid passes in, leaving the corresponding
alkali behind in the plasma. The walls of the corpuscles seem,
therefore, as Hamburger^ in particular has pointed out, to be
practically impermeable to sodium and potassium ions, but per-
meable to chlorine and other anions. Hence the proportions of
alkali to chlorine, etc., in the plasma depend upon the corpuscles,
and are regulated by them according as the pressure of CO2 in
the blood rises or falls. Yandell Henderson and Haggard, who
have quite recently investigated this phenomenon closely from
the physiological standpoint, point out what striking effects this
regulating action may produce.^ During forced breathing, for
instance, the weakly combined alkali of the plasma may be con-
siderably diminished, although the total weakly combined alkali
in the blood need not necessarily be altered.
The relation of the corpuscles to the available alkali in the
plasma suggests at once the question whether there is not a similar
relation as regards other tissue elements. Henderson and Haggard
showed that with vigorous and continued artificial respiration
the available alkali in the whole blood, and not merely in the
plasma, diminishes greatly, and that this diminution is accompa-
nied by signs of irretrievable damage to the body. This suggests
excessive draining of acid from the tissue elements with the
result that the whole body suffers, although the alkalinity of the
blood itself is partly prevented from falling. The matter will,
however, be discussed further in Chapter VIII.
' Giirber, Sitz-ber. d. pAysik-med. Gesellsch. zu Wurzburg, p, 28, 1895.
Anionenwanderungen in serum und Blut unter den einfluss von CO 2, saure und
alkali. Biochem. Zeit. Vol. 86, p. 309-324, 19 18.
'Haggard and Henderson, Journ. of Biol. Chem., XLV, p. 199, 1920.
CHAPTER VI
The Effects of Want of Oxygen.
In the higher organisms, as Paul Bert first pointed out, the im-
mediate cause of death of the body as a whole is practically always
want of oxygen, owing to failure of the circulation or breathing.
This fact arises from the circumstance that the body has hardly
any internal storage capacity for oxygen, but depends from
moment to moment for its supply from the air. We can deprive
the body for long periods of its external supplies of food or water,
or we can prevent for some time the excretion of urinary products
or even of carbon dioxide, but we cannot interfere with the supply
of oxygen to the blood without producing at once the most threat-
ening symptoms. Almost the only appreciable storage capacity
for surplus oxygen is in the lungs. In virtue of this small store
breathing can be prevented for about ij4 minutes in a man at
rest and previously breathing normally before urgent symptoms
of oxygen want appear ; but if the oxygen in the lungs and blood
is rapidly washed out by breathing pure nitrogen, nitrous oxide,
or other gas free from oxygen, loss of consciousness occurs almost
at once. Lorrain Smith and I found that even with quiet breathing
of pure hydrogen, so that some time was needed to wash out the
lungs, sudden and complete loss of consciousness was produced
within 50 seconds.
Even when the oxygen supply, though not cut off, is insuffi-
ciently free, the ill effects develop rapidly, and may very soon
become serious. Hence few things are of more importance in
practical medicine than the causes and effects of want of oxygen.
Want of oxygen in the systemic circulation may be produced
either by deficiency in the available oxygen in the arterial blood,
or by abnormal slowing of the circulation, so that too much of the
available oxygen is used up in the systemic capillaries. It will be
convenient to consider first the effects of want of oxygen or "an-
oxaemia," and afterwards discuss the various ways in which it
may be produced.
The effects of anoxaemia can be observed most conveniently in
persons breathing air from which part of the oxygen has been
removed without the addition of any other gas producing by
itself a physiological effect; or in persons breathing pure air at
RESPIRATION 109
reduced atmospheric pressure. In either case the partial pressure
of the oxygen breathed is reduced, and the haemoglobin tends to
become imperfectly saturated with oxygen in the lungs in cor-
respondence with the dissociation curve for the oxygen in human
blood (Figure 20).
The effects on the breathing have already been touched upon
in Chapter II, but must now be discussed fully. In most persons
the percentage of oxygen in the air breathed, or the barometric
pressure, must be reduced by about a third before any evident
effect on the breathing is produced at the time; and this effect
differs according as the reduction is produced rapidly or slowly.
With a greater reduction the contrast in this latter respect is still
more marked. With rapid reduction there is at first a quite notice-
able increase in the depth, and also in the frequency, of breathing.
In the course of several minutes, however, the increase diminishes
markedly. This phenomenon and the causes of it were described
and investigated by Poulton and myself.^ We found that the in-
creased breathing causes, as could be anticipated, a distinct fall
in the alveolar CO2 pressure. As a consequence, more CO2 than
usual is washed out of the blood, and the respiratory quotient, or
ratio of the volume of CO2 given off to that of oxygen absorbed,
is increased. Thus it increased from the normal of about 0.8 to as
much as 2.8 when there was sudden and considerable oxygen de-
ficiency. Soon, however, the extra discharge of CO2 from the
blood began to cease and there was only a slight further fall in
the alveolar CO2 pressure^Pan passu the breathing quieted down
so as, in spite of the diminished discharge of CO2, to maintain a^
certain level of alveolar CO2 pressure, this level being of course
below the normal level. At the same time the alveolar oxygen
pressure dropped, since the lung ventilation had diminished while
the rate of absorption of oxygen remained undiminished. The
drop in alveolar oxygen pressure tended, of course, to increase the
symptoms of want of oxygen and thus prolong the period of in-'
creased breathing; but finally a balance was struck, for the time
at any rate. When the deficiency of oxygen was produced quite
gradually the initial marked increase of breathing was not notice-
able, as the extra CO2 was washed out gradually.
By further experiments, we found that the new and lower
level of alveolar CO2 pressure had become the regulating level
for the atmosphere breathed. That is to say, a small increase above
this level caused a great increase in the breathing, while a small
*Haldane and Poulton, Journ. of Physiol., XXXVII, p. 390, 1908.
no RESPIRATION
diminution caused apnoea, just as when pure air is breathed. It
was evident, therefore, that the CO2 pressure, though at a lower
level, was controlling the breathing still. The primary marked
increase in the breathing was due to the alveolar CO2 pressure
and the CO2 pressure in the whole of the body being above the
new level, and the quieting down of the breathing was due to
the gradual washing out of CO2 from the whole body till the at-
tainment of the new normal level, which was itself determined
by the alveolar oxygen pressure.
A fuller discussion of these facts, and of the ultimate physio-
logical response to long-continued slight anoxaemia, must be
postponed to Chapter VII, but meanwhile it is evident that they
throw a new light on the physiology of breathing. Hitherto we
have considered the amount of lung ventilation as if it were de-
termined solely by a certain excess of partial pressure of CO2 in
the arterial blood; but now we see that the excess is something
variable and dependent, for one thing, on the pressure of oxygen
in the arterial blood, just as the action of the Hering-Breuer re-
flex depends, not merely on the amount of distention or collapse
of the lungs, but also on the pressure of CO2 in the arterial blood.
Similarly the action of want of oxygen on the breathing depends
on the CO2 pressure. On how many other factors which together
make up "normal conditions" the action of CO2 or want of oxy-
gen on the respiratory center depends we do not know. We always
find normal conditions in a healthy organism, and we are there-
fore apt to overlook their unknown complexity. If we represented
the relation between arterial CO2 pressure, oxygen pressure, and
lung ventilation in the form of an equation, this equation would
only be valid under conditions otherwise normal. In other words
an unknown constant C would have to be set down in the equation.
That this constant exists during life — in other words that living
organisms maintain fundamental normals of structure and ac-
tivity representing the <^voris of Hippocrates — is one basis of
biological science. Apart from this basis physiology would be a
mere chaos of unconnected "bio-physicar' and "bio-chemical"
fragments.
The eff"ect produced on the breathing by a given reduction in
the oxygen pressure of the inspired air or alveolar air varies con-
siderably in diff'erent individuals. Some respond much more
readily by increased breathing than others, and for this reason
seem to be better protected against the other and more serious ef-
fects of want of oxygen, since the increased breathing raises the al-
RESPIRATION 1 1 1
veolar oxygen percentage. In some persons a lowering by as little
as 5 per cent in the oxygen percentage of the inspired air will
sensibly increase the breathing, but in most persons a lowering of
at least 7 per cent (i.e., from 20.94 to 14) is needed to produce a
measurable effect, while in others very little effect is produced
before consciousness is lost from want of oxygen. It is thus for
many persons peculiarly dangerous to pass into an atmosphere in
which the oxygen percentage is very low, or to ascend to a very
great height in a balloon, since increased breathing may give
very little warning, particularly if the change is gradual, so that
the extra CO2 is blown off gradually.
It was discovered in 1908 by Yandell Henderson^ that when
effective artificial respiration in an animal has been pushed to
excess for some time, so that the pressure of CO2 in the blood and
tissues is very greatly reduced, there is not only a prolonged
succeeding apnoea, but the animal dies of want of oxygen without
attempting to draw a single breath. The artificial respiration must
be performed somewhat forcibly, by means of a suction and ex-
haust pump ; and the reason for this will be evident from what has
already been said in Chapter III as to the control of the chest-
movements by the Hering-Breuer refl^ during artificial respira-
tion produced by ordinary means.
This important experiment shows that when the CO2 pressure \
is reduced below a certain point in the respiratory center the latter '
ureases to respond to even the extremest stimulus of want of oxy- I
/gen. The apnoea produced in the ordinary way by voluntary
ri forced breathing is terminated, as shown in Chapter V, by the
I combined stimulus of CO2 and want of oxygen, and in some
persons the oxyhaemoglobin in the arterial blood runs down so
low that the lips and face become alarmingly blue before breath-
ing begins. In the case of Poulton, for instance, his face presented
such an alarming appearance when he demonstrated our experi-
ments at a meeting of the Physiological Society that one or two
members of the Society could hardly be restrained from applying
artificial respiration on the spot. In my own case, and that of many
others, the blueness is much less marked, although, as already
shown, the termination of the apnoea is quite clearly due to want
of oxygen, and not merely to accumulation of CO2.
It is evident from the foregoing account that the respiratory /
response to the stimulus of uncomplicated oxygen want is a com- v
plex one. The anoxaemia tends to increase the breathing, but the
'Yandell Henderson, Amer. Journ. of Physiol., XXI, p. 142, 1908.
J
112 RESPIRATION
increased breathing, by washing out CO2, checks this increase
very quickly, so that the net result for the time is only a small
increase. Where the anoxaemia is only slight this net increase will
be practically inappreciable, and this, as will be shown in Chap-
ter VIII, is due, not to the fact that there is no appreciable anox-
aemia, but to the masking of the natural response to anoxaemia
by the opposite response to the washing out of COg. After a suffi-
cient interval of time the former response, as we shall see, becomes
unmasked by the compensation of the latter response, so that in
the long run there is a very definite response of the breathing to
even a very small fall in the oxygen pressure of the inspired air.
When diminution in the oxygen pressure of the inspired air is
accompanied by a corresponding increase in the pressure of carbon
dioxide, it is evident that within wide limits the pressure of oxy-
gen in the alveolar air will remain almost normal, since the in-
creased breathing due to the extra carbon dioxide will so raise
the alveolar oxygen pressure as to compensate approximately for
the oxygen deficiency in the inspired air. There will thus be no
appreciable anoxaemia, and consequently the oxygen deficiency
in the inspired air will produce no effect at all, although a similar
deficiency in the absence of the excess of CO2 would produce a
marked effect. For instance, by adding CO2 to the inspired air we
can easily compensate within wide limits for the deficient oxygen
pressure which affects airmen at high altitudes. This is not be-
cause, as Mosso^ imagined, the effects of high altitude are due
primarily to excessive loss of CO2 ("acapnia"), but because the
oxygen pressure, as well as that of CO2, is kept approximately
constant by the increased breathing due to the CO2. When, how-
ever, the conditions are such that the extra breathing due to ex-
cess of CO2 does not prevent the alveolar oxygen pressure from
falling very low, the stimulus of anoxaemia is added to that of
CO2, and an enormously greater effect is produced on the breath-
\ ing than by the CO2 stimulus alone. This extra effect, as was
recently shown by Meakins, Priestley, and myself^ is due to in-
crease in the frequency of the breathing; and increased frequency,
provided the depth of breathing is sufficient, is, for a reason which
will appear in the next chapter, particularly effective in prevent-
ing anoxaemia.
A further complication in the effects of anoxaemia and forced
breathing on the respiratory center and the body as a whole is
* Mosso, Life of Man on the High Alps, Chapter XXII, London, 1898.
*Haldane, Meakins, and Priestley, Journ. of Physiol., LII, p. 420, 1919.
RESPIRATION II3
introduced by the fact that, as Bohr discovered (see Chapter V
and Figure 19), deficiency of carbon dioxide causes haemoglobin
to hold on more tightly to oxygen. The consequence of this is, that
when increased breathing lowers the pressure of CO2 in the al-
veolar air and in the body as a whole, on the one hand the haemo-
globin of the blood passing through the lungs is more highly
saturated with oxygen than it otherwise would be; on the other
hand the blood holds this oxygen so firmly that the oxygen pres-
sure in the tissues falls lower than it otherwise would. There may
thus be considerable anoxaemia though the blood is almost as red
as usual, and the existence of this anoxaemia is only revealed by
the immediate physiological effects of raising the alveolar oxygen
pressure.^
On reducing, in a steel chamber, the atmospheric pressure to
half an atmosphere there is a quite appreciable permanent increase
in the breathing, and consequent drop in alveolar CO2 pressure
caused by anoxaemia, but, in my own case at any rate, no very
striking blueness of the lips, although at the time the alveolar
oxygen pressure is only about 34 mm. This pressure would only
be sufficient to saturate the oxyhaemoglobin of the blood to the
extent of 57 per cent if the pressure of CO2 were that of normal
alveolar air (see Figure 20). Blood with this percentage satura-
tion would be very strikingly blue. Owing, however, to the dimin-
ished pressure of CO2, the saturation is much higher, and this
accounts for the color of the lips being nearly normal. The exist-
ence of considerable anoxaemia was, however, revealed at once
by the effects of adding oxygen to the inspired air : for vision and
hearing were at once strikingly improved and the breathing di-
minished. The degree of blueness of the lips is thus only a rough
index of anoxaemia when anoxaemia is taken in its physiological
meaning, as diminution in the oxygen pressure, rather than merely
of the oxygen content, of the blood. It is the diminution in the
amount of free oxygen, whether or not the amount of reserve oxy-
gen combined with the haemoglobin is also diminished, which is
functionally important.
Thus the benefit produced by diminished pressure of CO2 (as,
for example, during forced breathing) in increasing the percent-
age saturation of the haemoglobin in the arterial blood is neu-
tralized by the disadvantage in the tissues owing to the same cause.
The venous blood may, in fact, be as red as usual, although the
venous oxygen pressure is abnormally low : for the saturation of
Haldane, British Medical Journal, July 19, 19 19.
1/
114 RESPIRATION
the arterial blood with oxygen can be only very slightly increased
by the lowering of alveolar CO2 pressure. The oxygen pressure
of the venous blood must in consequence be lowered, so that anox-
aemia might be produced without any diminution, and even with a
slight increase, in the saturation of the haemoglobin of the venous
blood. On the other hand if the haemoglobin of the arterial blood,
with normal alveolar CO2 pressure, were only half-saturated, a
lowering of the alveolar CO2 pressure would considerably in-
crease the saturation of the haemoglobin in both arterial and
venous blood, but without sensible alteration of the venous oxygen
pressure. Only in the practically impossible case of the saturation
of the arterial haemoglobin being much below half would there
be any rise in the venous oxygen pressure. Practically speaking,
therefore, the Bohr effect, the increased oxygen content in blood,
due to lowering of alveolar CO2 pressure, is never of service in
increasing the real oxygen supply to the tissues, and is sometimes
of great disservice, although it always tends to make the venous
blood less blue, and so diminishes cyanosis. On the other hand the
corresponding effect due to raising of alveolar CO2 pressure will
practically never diminish the oxygen supply to the tissues, and
will usually increase it, though the venous blood will always be
more blue.
With forced breathing of normal air there is, as mentioned in
Chapter I, a slight increase in the oxygen present in the arterial
blood. This is due, partly to the Bohr effect and partly to the effect
of the increased alveolar oxygen pressure. Hence the saturation
of the haemoglobin is increased from about 95 to 100 per cent.
There is also a small increase in the free oxygen dissolved in the
arterial blood. On the other hand the amount of CO2 and its
partial pressure are enormously reduced in the arterial blood, and
to a less extent the venous blood, since the circulation rate, as
will be shown in Chapter X, is much diminished. The net result
must be a considerable fall in the oxygen pressure in the tis-
sues. Now it is well known that forced breathing produces a
train of symptoms which, if the forced breathing is pushed,
tend towards unconsciousness, so that forced breathing has
even been used by dentists as a means of producing partial
anaesthesia. In many respects these symptoms are similar to those
of anoxaemia, except for the absence of spontaneous increased
breathing. It was discovered by Hill and Flack^ that when the
forced breathing is with oxygen instead of with air the symptoms
• Hill and Flack, Journ. of Physiol., XL, p. 347, 19 10.
RESPIRATION . II5
are greatly diminished. The most natural explanation of this is
that the oxygen, by increasing largely the amount of free oxygen
in the blood, diminishes the anoxaemia, since an oxygen supply
which is not dependent on the Bohr effect is added to the ordinary
oxygen supply from oxyhaemoglobin. Probably, therefore, the
symptoms referred to are mainly produced by anoxaemia caused
by the Bohr effect. The subject will be discussed further in Chap-
ter X.
It is a very interesting fact that in many persons forced breath-
ing does not produce apnoea at all, although in such persons the
breathing is regulated in accordance with the alveolar CO2 pres-
' sure, just as in other persons. This fact was investigated by Dr.
Boothby some years ago while he was working with meJ He
found that at the end of continuous forced breathing for one or
two minutes there was in himself not only no sign of apnoea, but,
on the contrary, increased natural breathing for a short time. This
soon passed away, but at no time was there any apnoea, though
the excretion of CO2 in the expired air was much diminished for
a considerable period. The cause of this absence of apnoea is not
yet clear. It seemed possible that the stimulus of anoxaemia from
the Bohr effect might, in persons who do not become apnoeic,
account for the absence of apnoea ; but even after forced breathing
j of oxygen the apnoea was absent in one of these persons whom I
! tested. His power of voluntarily holding a deep breath was
markedly increased by forced breathing of air, but natural apnoea
did not occur.
Owing, apparently, to the existence of the Bohr effect, the in-
fluence of CO2 in relieving the general symptoms of anoxaemia
is not due merely to increased breathing and consequent rise in
the alveolar oxygen pressure. Lorrain Smith and I observed that
animals in a semi-comatose state from the anoxaemia of carbon
I monoxide poisoning were revived by substituting expired air for
pure air without alteration of the percentage of carbon monoxide.
With the expired air mixture there could be no rise in the alveolar
oxygen pressure, and there was no alteration in the percentage
saturation of the blood with carbon monoxide. A still more strik-
ing effect is produced by simply adding CO2 to the air inspired
during CO poisoning. At the time we could not understand this
effect, as Bohr's discovery had not yet been made. But this dis-
covery furnishes an explanation of why a rise in the alveolar CO2
I pressure, without alteration of the alveolar oxygen pressure,
' Boothby, Journ. of Physiol., XLV, p. 328, 19 12.
ii6
RESPIRATION
should relieve the symptoms in CO poisoning : for the increased
CO2 pressure will enable the oxygen to come off more easily from
the oxyhaemoglobin present in the blood, and will thus tend to
relieve the anoxaemia. The circulation rate will also be increased,
as will appear in Chapter X. There would seem to be a considerable
future scope for the therapeutic use of CO2 in anoxaemic condi-
^jW^-^ ^AA/v/
^vVV
BREATHING
-^ — ^ — ^ — <m — vw^- — ^^ — w^ — ^j^ — A^- — vw^
Oj OFF
Figure 37. !
Tracing i. (Stethograph) Douglas, July 12. Evening of arrival on Pike's Peak. Natuij
periodic breathing.
Tracing 2. Haldane, July 12. Evening of arrival. Natural periodic breathing with mci
sharply defined periods after making six forced breaths.
Tracing 3. July 16, Haldane. Natural periodic breathing abolished by administration
oxygen. Reappearance of periodic breathing after withdrawing the oxygen.
tions of all kinds, whether or not these conditions are due to im-
perfect oxygenation of the arterial blood.
Even when simple anoxaemia is so extreme that consciousness
is on the point of being lost, the breathing in man, except at first,
is hardly more than doubled, as shown by the fact that the alveolar
RESPIRATION
117
CO2 pressure is only reduced to about half. During heavy muscu-
lar exertion, on the other hand, the breathing may easily be in-
creased to ten or fifteen times its normal amount. The relatively
slight increase in the amount of air breathed during very serious
anoxaemia is frequently lost sight of in the interpretation of
clinical symptoms. There is nearly always a considerable increase
in the frequency of breathing, but the depth of breathing is
usually only slightly increased, and may be diminished, as will
be explained more fully below. In the very dangerous pure anox-
aemia of high altitudes or CO poisoning, increase in the breathing
is not a prominent symptom.
' Tl has been known for long that at high altitudes the breathing
is very apt to be periodic. This phenomenon was fully observed
on Monte Rosa by Mosso,^ who, however, had completely failed
to realize the significance of Paul Bert's researches on the effects
of gases, and thus failed to interpret correctly the cause of the
periodic breathing. The periodic breathing is usually not con-
tinuous, but can easily be started by disturbing the ordinary
rhythm of breathing, as by taking a few long breaths, or holding
the breath. It is also very apt to occur at night. It is distinguished
from ordinary clinical Cheyne- Stokes breathing by the shortness
rtRVALS OF 5 SECONDS
Figure 38.
Henderson, August 13. Quantitative record of the respiration during periodic
breathing. Inspiration upwards.
of the periods. There are usually groups of only about three to
six breaths, followed by a pause, and this periodic sequence con-
tinues almost indefinitely (Figure 37). Sometimes the middle
breath of the group is deepest, sometimes the last breath (Figure
38) or sometimes the breaths are about equal in depth. Some-
times the periodicity only shows itself by periodically recurring
single deep breaths.
The general explanation of this periodic breathing has already
been given in Chapter V. That this explanation is the correct one
is shown by the fact that, as is seen in Figure 37, on adding oxy-
* Mosso, Life of Man on the High Alps, Chapter III, London, 1898.
Ii8
RESPIRATION
gen to the inspired air the periodicity disappears. This experiment
was carried out repeatedly by Douglas, Yandell Henderson,
Schneider, and myself, on Pike's Peak, and never failed.^ Mosso
had attempted to carry it out, but got a negative result owing to a
defective mode of administering the oxygen.
As already seen periodic breathing can easily be produced at
ordinary barometric pressure by suitable means. As the barometric
pressure is reduced the periodic breathing is produced more and
more readily, and is more and more persistent, just as might be
expected; and the same is true if, instead of a reduction of bar-
ometric pressure, there is a reduction in the oxygen percentage of
the inspired air. This form of periodic breathing has no pathologi-
cal significance, and occurs during perfect health.
The special characters of the increased breathing caused by
Figure 39.
(a) Rebreathing — Concertina filled with oxygen — CO3 accumulating,
(b) Rebreathing — Concertina filled -with air — CO2 accumulating.
Time-marker =: 2 seconds. Arrow shows point where lips were distinctly blue.
anoxaemia were recently studied by Meakins, Priestley, and
myself.^^ The differences between increased breathing caused by
excess of CO2 and that caused by anoxaemia, or by anoxaemia
accompanied by excess of CO2, are very striking. Speaking gen-
erally, the effect of excess of CO2 is mainly to increase the depth
of breathing, and only a moderate increase of frequency is pro-
duced. On the other hand anoxaemia produces a marked increase
in frequency and only a moderate increase in depth. But when the
• Douglas, Haldane, Yandell Henderson, and Schneider, Philos. Trans. Royal
Society, B. 203, p. 231.
"Meakins, Haldane, and Priestley, Journ. of Physiol., LII, p. 420, 19 19.
RESPIRATION
119
effects of excess of CO2 and anoxaemia are combined there is
great increase of both depth and frequency, so that far more air is
breathed than when either excess of CO2 alone, or anoxaemia
alone, is the stimulus. In my own case, for instance, when the
breathing was pushed, in short experiments, to as much as seemed
bearable, 131 liters per minute, with a depth of 1.98 liters and a
frequency of 66 per minute, were breathed when the effects of
excess of CO2 and anoxaemia were combined; and only 81 liters,
with a depth of 2.69 and a frequency of 30, when the only stimulus
was excess of CO2.
Figure 39 shows quantitatively the effects of rebreathing a
small volume (about 2 liters) of air or oxygen from the recording
concertina already described. It will be seen that the increase in
frequency was much less when the effects of anoxaemia were cut
out by the oxygen.
Figure 40 A shows the effect on the same subject of similar re-
breathing when the accumulation of CO2 was prevented by inter-
WI|llllllllllllllllll)ll|lllllll||lll)|llll'l|lilllllll|lllllllllllllllllll'llll"'INI|l»l)ll||IIIN^
Figure 40.
Rebreathing through soda-lime from concertina. Time-marker = 2 seconds,
(a) Subject Cpl. M. (b) Subject J. S. H.
posing a layer of soda lime. It will be seen that the frequency
increases, but not the depth. Figure 40 B shows the effects on
another subject, whose respiratory center responds much more
readily to the effects of anoxaemia. In this case depth as well as
frequency are considerably increased. It must, however, be borne
in mind that, in short experiments such as these, the increased
breathing, as already explained, is mainly due to the necessity of
^ CQ
O
. bO
c5°
^ Pi
RESPIRATION 12 1
removing from the body the large amount of preformed COg
which has become superfluous owing to the effect of anoxaemia
in lowering the threshold of CO2 pressure.
Figures 41 and 42 show the effects of anoxaemia combined with
those of the slight resistance associated with the recording ap-
paratus. The effects are complicated owing to the fact that with a
certain degree of anoxaemia, varying greatly for different indi-
viduals, periodic breathing is produced readily, as shown in some
of the tracings. Periodic breathing, or else very shallow breathing,
is also produced invariably after the anoxaemia, as shown in all
the tracings. This is of course due to the fact that so much CO2
has been removed from the body by the hyperpnoea of anoxaemia,
just as it is removed by forced breathing.
In Figure 41 B and Figure 42, A, C, and D, it will be seen that
after an initial increase in depth the breathing became progres-
sively shallower and more frequent just as in fatigue due to ex-
cessive resistance; and after a time asphyxial symptoms were
usually impending owing to the ineffectiveness of the shallow
breaths. When the experiments were made we had not investigated
the effects of fatigue caused by resistance, and there is now no
doubt that the slight resistance due to the apparatus, combined
with the effects of anoxaemia on the respiratory center, accounted
for the specially rapid failure of breathing shown in the figures.
When the breathing is quite free, as in a steel chamber at low
pressures, failure of the respiratory center does not occur nearly
so readily, but the difference is only one of degree; and failure
of the respiratory center, as shown by shallow and frequent res-
pirations, is the inevitable result of serious arterial anoxaemia.
With the increasing shallowness of the breaths the arterial an-
oxaemia increases, owing to causes discussed in Chapter VII.
This increases the failure of the respiratory center; and unless
relief comes the inevitable result of the vicious circle thus pro-
duced is death.
We must now turn to the other symptoms and signs of want of
oxygen, beginning with the circulatory symptoms. Unfortunately
we cannot as yet measure the volume of blood circulated per
minute in the same easy way in which we can measure the volume
of air breathed. Our knowledge of the effects of want of oxygen
on the circulation is thus imperfect as yet. It will be discussed
more fully in Chaper X. When moderate symptoms of anoxaemia
are produced experimentally, as in a steel chamber at reduced
atmospheric pressure, or when air deficient in oxygen is breathed,
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RESPIRATION
123
there is at first an increase of the frequency, and apparently also
in the strength, of the heartbeats. This indicates an increase in the
circulation rate. But just as in the case of the respirations, the
frequency and vigor of the pulse soon fall again, though the fre-
quency remains above normal, just as does the frequency of res-
piration. Thus the pulse may rise to about 120 at first, and then
fall after a few minutes to about 90, and remain steady. With
greater anoxaemia the increase in rate is more marked. The great
temporary increase in blood pressure with acute anoxaemia in
animals is also a well-known phenomenon.
At first sight it might seem that a great increase in both res-
pirations and circulation would be the natural physiological:
response to anoxaemia, since the increased respiration will raise
the alveolar oxygen pressure and the increased circulation rate
will increase the amount of oxygen left in the red corpuscles of
the blood passing through the capillaries. But, as already seen,
^the increased respiration lowers the pressure of CO2 in the respira-
tory center and tissues, and this lowering rapidly reduces the in-
creased breathing to within relatively narrow limits. A similar
lowering of CO2 pressure in the tissues must also be produced by
increased circulation rate ; and the falling-off in the initial increase
of pulse rate is probably at bottom due to the same cause as the
falling-off in the initial depth and frequency of breathing. With
further increase in the anoxaemia the heartbeats, like the respira-
tions, become more and more feeble. A fuller discussion of the
relatively little that is at present known definitely as to the physio-
logical regulation of the circulation will be found in Chapter X.
It is of course evident that the physiology (not the mere physics)
of the circulation is intimately related to that of the breathing.
As a sign of anoxaemia, the appearance of the lips, tongue, and
face is of much importance, but requires careful interpretation.
The bluish color or cyanosis seen in the lips and skin during
ordinary anoxaemia is, of course, due to the fact that in the blood
passing through the capillaries the proportion of oxyhaemoglobin
to haemoglobin is abnormally low. A somewhat similar color may
be produced by the action of poisons which produce methaemo-
globin and other colored decomposition products in the blood;
and this condition, which is of course quite exceptional, and can
quite easily be distinguished, will be referred to in Chapter VII.
Cyanosis may either be due to general or local slowing of the
circulation, or to the fact that the arterial blood is imperfectly
oxygenated, and the latter cause, as will be shown in Chapter VII,
124 RESPIRATION
is far more common than was, till recently, supposed. Portions of
the skin may be blue from local slowing of the circulation due to
cold and other causes; but abnormal blueness of the lips and
tongue points to either imperfect oxygenation of the arterial
blood or general slowing of circulation. According as there is
much or little blood in the capillaries the color is full or unsatu-
rated. Thus in extreme cyanosis the lips may be either almost
black, or only leaden gray; and in slight cyanosis the color may
be either a full or a pale purplish red.
Ordinary cyanosis of one kind or another is commonly seen in
patients who, though suffering from some chronic ailment, are
not particularly ill. Hence the significance of cyanosis under other
conditions is apt to be overlooked unless all the symptoms and
other circumstances are taken into account. It must, in the first
place, be pointed out that the degree of cyanosis is no direct
measure of the degree of physiological anoxaemia. The latter is
due to a lowering in the partial pressure of oxygen in the blood of
the capillaries, while the former is due to a diminution in the ratio
of oxyhaemoglobin to haemoglobin. Under ordinary conditions
the latter effect is an index, though, owing to the form of the
dissociation curve of oxyhaemoglobin (Figure 20), not a direct
measure, of the former effect. When, however, the matter is com-
plicated by an alteration in the Bohr effect of CO2 pressure on the
dissociation of oxyhaemoglobin, the relationship between oxygen
pressure and dissociation of oxyhaemoglobin is at once altered. If,
for instance, the pressure of CO2 in the arterial blood is reduced
by increased breathing, there may be much less cyanosis for a
given degree of physiological anoxaemia than when the CO2
pressure in the blood is normal. Thus there is no fixed relationship
between cyanosis and physiological anoxaemia; and this fact is
of great importance in the clinical interpretation of cyanosis.
Moreover, as Barcroft showed, the Bohr effect is due to the action
of CO2 as an acid. Hence, owing to the adjustments which, as will
be shown in Chapter IX, occur in the living body when time is
given, the CO2 pressure in the alveolar air may be no guide as to
how far the Bohr effect is disturbing the ordinary relations be-
tween cyanosis and true anoxaemia. The word "anoxaemia"
should evidently be taken as signifying a condition in which the
free oxygen in the systemic capillary blood is abnormally dimin-
ished; and this of course, in accordance with Henry's law, comes
to the same thing as diminution in the oxygen pressure.
The symptoms produced in the nervous system generally by
RESPIRATION 1 25
anoxaemia must now be described. A knowledge of them is of
great importance in practical medicine. If a pure anoxaemia is
produced very suddenly, as by breathing pure nitrogen, hydro-
gen, methane, or nitrous oxide, loss of consciousness occurs quite
suddenly and with no previous warning symptoms. Thus a miner
who puts his head into a cavity in the roof full of pure, or nearly
pure, methane drops suddenly as if he had been felled ; and when
he recovers after breathing pure air for a few seconds he some-
times even imagines that he has been knocked down by another
man, and acts accordingly. If the anoxaemia is produced with
only moderate rapidity the marked temporary disturbances, al-
ready referred to, in the breathing and circulation give, as a rule,
some warning of what is coming. But when the onset is gradual
there is little or no preliminary discomfort, and for this reason
the onset of pure anoxaemia is very insidious, and the condition
is, therefore, in practice a dangerous one, as is well seen in CO
poisoning, or in ascents to very high altitudes in balloons or aero-
planes, or in many clinical cases. Thus although CO is not very
poisonous as compared with other gaseous poisons, it is responsible
for a far larger number of deaths than any other gaseous poison
not used in warfare.
As the slow onset of anoxaemia advances, the senses and intellect
become dulled without the person being aware of it; and if the
anoxaemia is suddenly relieved by means of oxygen or ordinary
air, the corresponding sudden increase in powers of vision, hear-
ing, etc., is an intense surprise. The power of memory is affected
early, and is finally almost annulled, so that persons who have ap-
parently never lost consciousness can nevertheless remember noth-
ing of what has occurred. Powers of sane judgment are much
impaired, and anoxaemic persons become subject more or less to
irrational fixed ideas, and to uncontrolled emotional outbursts.
Muscular coordination is also affected, so that a man cannot walk
straight or write steadily. With further increase in the anoxaemia,
power over the limbs is lost; the legs first being paralyzed, then
the arms, and finally the head. The senses are lost one by one, hear-
ing being apparently the last to go. The sense of painful impres-
sions on the skin seems to be lost early. Thus miners suffering from
CO poisoning, but not to the point of losing consciousness, are
often burnt by their lamps or candles without their being aware of
the burn at the time.
In many respects the symptoms of anoxaemia resemble those
of drunkenness, and a man suffering from anoxaemia cannot be
126 RESPIRATION
held responsible for his actions. Without reason he may begin to
laugh, shout, sing, burst into tears, or become dangerously violent.
He is, however, always quite confident that he himself is perfectly
sane and reasonable, though he may notice, for instance, that he
cannot walk or write properly, cannot remember what has just
happened, and cannot properly interpret his visual impressions.
When unable even to stand, owing to experimental CO poisoning
or to anoxaemia produced by low pressures in a steel chamber, I
have always been quite confident in my own sanity, and it was
only afterwards that I realized that I could not have been in a
sane state of mind.
A recent experience of this kind was in a steel chamber in which
Dr. Kellas, who is an experienced climber in the Himalayas and
has exceptional powers of resisting anoxaemia, was with me.^^
We had reduced the pressure to 320 mm., and as I could no longer
write or make any observations I handed him the notebook. He
afterwards told me that I remained sitting, but always answered
his questions quite deliberately and confidently, and insisted on
his keeping the pressure at 320 mm. This went on for an hour and
a quarter, of which time I could afterwards remember absolutely
nothing. At last Dr. Kellas obtained my assent to raising the pres-
sure to 350 mm., after which I took up a mirror to look at my lips,
though Dr. Kellas observed that for some time I looked at the
back instead of the front of the mirror. I had, however, begun to
realize that we had been far longer at the low pressure than we
had intended, and agreed to a rise to 450 mm. On reaching this
pressure my mind had cleared and I noticed a return of feeling
and power in my legs. After coming out I could vaguely remember
taking up the mirror, but nothing before that, after handing over
the notebook. We had no intention of staying at so low a pressure
that it was impossible for me to take notes, and my persistence
was quite irrational. Dr. Kellas was much bluer than I was during
the stay at 320 mm., but could still write quite well, watch the ba-
rometer, and manage the regulating tap ; but whether he was quite
normal mentally seemed rather doubtful. Perhaps he shared to
some extent my irrational desire to continue the experiment:
otherwise I think he would have noticed how abnormal my condi-
tion was. We were both at the time unacclimatized to low pres-
sures.
This personal experience illustrates some of the peculiar dan-
gers associated with atmospheres which produce anoxaemia,
" Haldane, Kellas, and Kennaway, Journ. of Physiol., LIII, p. 181, 19 19.
RESPIRATION 12/
whether in virtue of defective oxygen pressure or of the presence
of poisonous proportions of CO. In the first place it is evident that
a man may advance for some distance into such an atmosphere
before he begins to be seriously affected; for the temporary
marked increase in the breathing may, when the oxygen pressure
is defective, at first prevent an appreciable fall in the alveolar
oxygen pressure. This must, for instance, happen while a balloon
or aeroplane is rising rapidly, or while a miner is advancing with
an electric lamp into an atmosphere very highly charged with
fire-damp. When the breathing begins to quiet down again the
effects of the atmosphere will develop fully and it may then be too
late to turn. At 320 mm., for instance, I was at first quite capable
of making observations and taking notes, including a note of the
increased breathing and its subsequent quieting down.
Another, and often still more serious, danger arises from the
gradual and insensible failure of judgment. A man suffering from
anoxaemia will usually go on, and insist in going on, with what
he set out to do. An airman will very probably continue to ascend,
oblivious to danger ; and a miner engaged in rescue or exploration
work, or in dealing with an underground fire, will insist in going
on when he is suffering from the anoxaemia of CO poisoning,
and will often fight any one who tries to make him desist.
All these considerations apply equally to clinical cases of anox-
aemia ; and for this reason the condition is quite commonly never
recognized till too late. The early recognition of clinical anox-
aemia is a matter of great importance.
Besides the immediate symptoms of anoxaemia there are a
number of delayed symptoms or after effects. They depend partly
on the length, and partly on the severity, of the exposure. A
short exposure, even with loss of consciousness, produces no .
serious after symptoms ; but occasionally a man's behavior is very \y^
abnormal for a few minutes after recovery. One of my ac-
quaintances has twice knocked persons down on waking up from
a short loss of consciousness caused by anoxaemia; and my own
behavior was distinctly abnormal just after coming out from the
steel chamber in the experiment alluded to above. Similar ab-
normalities after slight CO poisoning have often come under my
observation. Thus a well-known inspector of mines, on returning
to the surface after he had been affected by CO from an under-
ground fire, first shook hands very cordially with all the by-
standers. A doctor who was present then offered him an arm ; but
this the inspector regarded as an insult, with the result that he
took off his coat and challenged the doctor to a fight.
128 RESPIRATION
The best-known delayed effect of slight anoxaemia is the train
of symptoms originally called "mountain sickness." This is a
condition in the typical form of which there is nausea, vomiting,
headache, sometimes diarrhoea, and always great depression. The
symptoms appear, as a rule, some hours after the beginning of
the exposure, and may not appear at all till after the exposure is
over. In CO poisoning it is usually after the exposure, and often
after the CO has practically disappeared from the blood, that
these symptoms begin. The duration of exposure required for their
production depends upon the degree of anoxaemia. Thus the
higher a mountain is, or the greater the altitude at which an air-
man has been flying, the shorter is the exposure required. On
Pike's Peak, at 14,100 feet (barometer about 458 mm.) the usual
stay (an hour or two) of visitors by train is too short to produce
mountain sickness, though the ordinary immediate symptoms of
anoxaemia are usually very evident, and even very great cyanosis
and fainting are observed occasionally. A stay of several hours
is usually required to induce mountain sickness, which usually
begins about 8 to 12 hours after the beginning of the exposure.
Thus the symptoms may only develop after the return downwards.
With a sufficient period of exposure mountain sickness may
develop at much lower altitudes than that of Pike's Peak. It is
often observed at even 7,000 or 8,000 feet, where the degree of
anoxaemia is not sufficient to produce any noticeable immediate
effect on the breathing. Similarly a percentage of CO which pro-
duces no noticeable immediate effect will, with sufficiently long
exposure, cause headache, nausea, etc. These facts are of the
greatest significance in clinical medicine, for it is now evident that
even a very slight degree of continued anoxaemia is of much
importance to the patient. Mountain sickness and the effects of
CO poisoning are not isolated phenomena unrelated to the rest of
physiology and pathology, but symptoms of anoxaemia, which is
in reality one of the commonest conditions during illness. At
present we can only conjecture as to the nature of the slight
temporary pathological changes of which the mountain sickness
symptoms are the manifestations.
With severe and prolonged exposure to want of oxygen the
nervous after symptoms are of an extremely formidable nature,
and often end in death. ^^ For a reason which will be explained
" An interesting description of these symptoms by Dr. Shaw Little will be
found in Appendix B to my Report on the Causes of Death in Colliery Explosions
Parliamentary Paper C. 8112, 1896.
RESPIRATION
129
in a later chapter they are most commonly met with after CO
poisoning, and whatever their origin they are often grossly mis-
interpreted. The patient does not recover at once on removal of
the oxygen want, as in short exposures. In cases of CO poisoning
consciousness may not be recovered, although within an hour or
two after removal to fresh air most of the CO has already disap-
peared from the blood. It is exactly the same with men who have
remained unconscious for, perhaps, several hours in air very poor
in oxygen. Or if consciousness has been partially recovered the
patient may lapse again into unconsciousness. During gradual
recovery there is usually a very marked spastic condition of the
muscles, and occasional epileptiform seizures, and there may be
various partial paralyses and other nervous symptoms. Sometimes
the patient lingers on for weeks in a comatose condition with
spastic muscles and occasional opisthotonos. The body tempera-
ture is unstable, and every function of the central nervous system
seems to be more or less affected. Gross hemorrhages in the brain
have been described, and Mott has found small multiple hemor-
rhages. The symptoms are, however, evidently due in the main
to widespread injury to the nerve cells themselves during the ex-
posure. Loss of memory, mental incapacity, and even definite
mania may follow the exposure; but whatever the nature of the
symptoms may be, they nearly always pass off gradually if the
patient survives the first few days. One interesting nervous after
effect occasionally observed is what appears from the symptoms
to be peripheral neuritis.
The heart may also suffer severely in prolonged exposure to
want of oxygen; and if the exposure has been accompanied by
much muscular exertion, as in efforts to escape or to rescue other
men, the after symptoms may be mainly cardiac. In these cases
the pulse is feeble and irregular, the heart dilated, with a blowing
systolic murmur; and any muscular exertion produces collapse. It
may be a considerable time before the heart fully recovers.
Probably every other organ and tissue in the body feels the
after effects of severe exposure to want of oxygen. The patient
often enough dies of pneumonia. Acute nephritis and gangrene of
extremities have been noticed as sequelae to the acute broncho-
pneumonia and oedema of the lungs in chlorine poisoning. As
the patients have been exposed to very grave oxygen want in
consequence of the lung condition, it seems probable that the af-
fections just mentioned are after effects of the oxygen want,
aggravated by the after effects on the heart, and often complicated
by secondary infections.
I30 RESPIRATION
With anoxaemia, as already explained, the respiratory center
becomes very easily susceptible of fatigue, as manifested by di-
minishing depth of the breathing. It is now well known that in
the resuscitation of persons who have been nearly asphyxiated by
drowning, asphyxiating atmospheres, etc., the most effective
remedy is artificial respiration. This is because the respiratory
center has completely or almost completely failed or become
"fatigued," and the patient would die if this condition were not
compensated for by artificial respiration. Respiration seems almost
always to fail before the heart fails. The respiratory center may
also take a long time to recover sufficiently to be able, without
artificial aid, to keep the patient alive. For this reason it may be
necessary to prolong the artificial respiration for hours.
Diminishing depth with increasing rate of respiration is always
a sign of the onset of fatigue of the breathing; and when the
depth continues to diminish without compensation from increased
rate the condition rapidly becomes dangerous, as will be shown
in Chapter VII, since secondary anoxaemia develops. In a person
dying quietly the diminishing depth can be observed until the
resulting anoxaemia ends in death. The immediate cause of death
seems to be failure of the respiratory center. When death from
anoxaemia occurs at very high altitudes (as, for instance, in the
case referred to in Chapter XII, of the balloonists, Tissandier and
Croce Spinelli) it is evidently failure of the respiratory center
which precipitates the anoxaemia, thus making the conditions
so very dangerous; and the same remark applies to asphyxiation
in atmospheres containing a low percentage of oxygen in mines,
wells, etc. In CO poisoning, as will be explained in Chapter VII,
there is not so much danger from this cause, so that extreme anox-
aemia may exist for a long time without death occurring.
After the respiratory center has been over-fatigued in conse-
quence of anoxaemia, the effects may not pass off for a very long
period. The breathing on exertion, or even during rest, is ab-
normally shallow ; and the peculiar group of symptoms observed
in the neurasthenic condition so familiar during the war, and al-
ready referred to in Chapter III, is observed. This condition may
remain for months after severe anoxaemia, and is often mistaken
for organic heart injury.
In considering the effects of anoxaemia a factor comes in which
must always be borne in mind — namely that of adaptation or ac-
climatization. This may act in two different ways. In the first
place adaptation may bring it about that the anoxaemia which
RESPIRATION
131
would, without adaptation, exist is greatly diminished. This form
of adaptation is very clearly seen in persons living at great alti-
tudes, and will be discussed in detail in later chapters. In the
second place the tissues may adapt themselves to a lower partial
pressure of oxygen. About this second form of adaptation our
knowledge is at present very imperfect; but it seems to me
that clinical evidence points strongly to its existence. Perhaps the
clearest evidence is afforded by cases of congenital heart defect,
in which part of the venous blood passes direct to the left side of
the heart without first passing through the lungs. In these cases
of "Morbus coeruleus" the arterial blood is always more or less
blue, and becomes extremely blue on muscular exertion, so that
one can always recognize this condition in persons walking in the
street. The remarkable point, however, is that in spite of the an-
oxaemic condition of the arterial blood these persons may get on
quite well, and be able to walk at a good pace. On account of the
large increase in their haemoglobin percentage, they have plenty
of oxygen in their blood, but at a low partial pressure. It seems
hardly possible to doubt, therefore, that their tissues have become
adapted to the low partial pressure of oxygen; and the same
adaptation probably exists to a considerable extent in many
chronic cases of valvular heart disease, emphysema, etc.
The fact that cyanosis may exist without harm in chronic cases
of disease has certainly contributed greatly to the general failure
to recognize the gravity of anoxaemia in persons not adapted.
Adaptation is a process which always requires time, and the time
factor must, therefore, be taken into account in judging of the
physiological effects of anoxaemia.
CHAPTER VII
The Causes of Anoxaemia.
In the previous chapter anoxaemia has been defined as the condi-
tion in which the partial pressure of oxygen, or, what comes to
practically the same thing, the amount of free oxygen, in the
systemic capillaries generally, is abnormally low. The causes of
this condition must now be examined.
The first and most important cause of anoxaemia is defective
saturation of the arterial haemoglobin with oxygen. This may, as
we shall see, arise from several causes; but the most obvious of
these is defective partial pressure of oxygen in the alveolar air.
It will be shown in Chapter IX that during rest under normal
conditions oxygen passes into the blood through the alveolar
epithelium by a process of simple diffusion, and that the oxygen
pressure in the arterialized blood leaving each alveolus is exactly
that of the air in the alveolus. For the purposes of the present
discussion we may provisionally assume that this is always the
case during rest, so long as the lungs and the inspired air are
normal, although modifications in this assumption must be intro-
duced later.
In the light of this assumption and of our knowledge of the
dissociation curve of oxyhaemoglobin, it might seem at first that
we are justified in assuming that the oxygen pressure of mixed
arterial blood is simply that of mixed alveolar air as ordinarily
obtained for analysis by the methods already described. In favor
of this assumption is the now well-ascertained fact that the
breathing is regulated under ordinary conditions in close ac-
cordance with the pressure of CO2 in the mixed alveolar air, as
explained in Chapter II. Variations in average alveolar CO2 pres-
sure are thus a direct measure of variations in the CO2 pressure
of the arterial blood ; and it was natural to assume, as was done
by myself and others till lately, that variations in alveolar oxygen
pressure must also be a measure of variations in the oxygen pres-
sure of the arterial blood. One known difficulty in this assumption
lay in the fact that the arterial oxygen pressure, as measured in
animals by the aerotonometer (Chapter IX) is nearly always
lower, and sometimes considerably lower, than the alveolar oxy-
gen pressure; but various explanations of this difficulty had been
adopted by myself and others.
RESPIRATION
133
A new and important light was thrown on the whole subject in
the course of a study by Meakins, Priestley, and myself of the
"neurasthenia" produced by gassing and other causes during the
war.^ As mentioned in Chapter III, the breathing in these patients
is abnormally frequent and shallow, particularly on exertion. It
was also found that addition of oxygen to their inspired air was of
considerable service during any ordinary exertion, and that in
some of them the lips became blue on exertion unless oxygen was
given. As there was no sign of anything seriously abnormal in
their lungs, we were led to suspect that the shallow breathing was
somehow causing anoxaemia. This led us to make experiments
<s>=^
m^o
Figure 43.
"Concertina" apparatus for continuous record of respiration.
on the effects of shallow breathing in normal persons, and for this
purpose we devised the apparatus^ shown in Figure 43. The
subject inspires through the mouthpiece and inspiratory valve
from the recording "concertina." The bottom of this moves up-
wards with inspiration, and records the movement by means of
an inked pen on the drum. The bottom comes down on a movable
stop, and by moving this upwards the maximum capacity of the
concertina can be reduced to whatever is desired. During expira-
tion the expired air passes out by the rubber expiratory valve.
At the same time the expiratory pressure is communicated to a
^ Haldane, Meakins, and Priestley, Journ. of Physiol., LII, p. 433, 1919.
* Made by Messrs. Siebe Gorman & Co., 187 Westminster Bridge Road, London.
v:
^
RESPIRATION • 135
tambour the movement of which, as shown, closes a circuit from
an accumulator or from the lighting circuit through a rheostat.
This circuit passes through an electromagnet which instantly
lifts a valve and admits air freely into the concertina, which at
once refills itself. At the end of expiration the circuit is instantly
broken and the valve closes, so that only the volume of air
contained in the concertina can be inspired at the next inspiration.
In this way the amount of air taken in per breath can be limited,
and a continuous record is at the same time obtained of the depth
and frequency of respiration. With the concertina fully open
ordinary records of the breathing are obtained, and any gaseous
mixture can be supplied through a glass cylinder which incloses
the electromagnet and valve. The advantage of this method is
that it is capable, not merely of permitting a study of shallow
breathing, but also of giving a continuous quantitative record of
any sort of breathing. The old stethographic method of recording
the breathing is apt to be misleading, since it does not give a
quantitative record.
When the depth of inspiration is limited by means of this ap-
paratus the natural impulse, at first, is to continue the inspiratory
effort at the end of each inspiration, as the Hering-Breuer reflex
has not given the signal for expiration. With a little practice,
however, the breathing goes quite easily, and the frequency in-
creases in proportion as the depth is diminished. When the depth
is greatly limited the breathing becomes very frequent — 100 or
more a minute.
On observing the breathing when the depth was gradually more
and more limited, we found that the breathing became periodic
very readily. As already explained, periodic breathing is a symp-
tom of anoxaemia, and this fact led us to try the effect of adding
a little oxygen to the inspired air. This promptly abolished the
periodic breathing, as shown in Figure 44. There could thus be
no doubt that the periodic breathing was due to imperfect oxy-
genation of the arterial blood. In some persons, such as myself,
the periodic breathing was produced much more readily, and in a
more striking degree, than in other persons. This, as already
mentioned in Chapter VI, is due to individual differences in the
response of the respiratory center to anoxaemia.
We at first thought that the anoxaemia must be due to the fresh
air not penetrating properly to the deep (air-sac) alveoli when
the breathing was shallow; but on examining samples of the deep
alveolar air during a prolonged experiment, we were disappointed
136
RESPIRATION
to find that in the deepest alveolar air the oxygen percentage, so
far from being lower, was actually higher than usual. There was
thus hyperpnoea from want of oxygen, and yet the deep alveolar
air contained more oxygen than usual. The breathing was, how-
ever, very inefficient and therefore greatly increased in amount,
as the dead space told much more than with normal breathing,
so that the percentage of CO2 in the expired air was very low.
On turning the matter over, we bethought ourselves of some
anatomical observations collected by Professor Arthur Keith in
''Further Advances in Physiology," edited by Professor Leonard
Hill, 1909. He showed in this essay that during inspiration the
.; lungs do not expand equally and simultaneously at all parts,
but open out part by part, somewhat like the opening of a lady's
;; fan. The parts nearest the moving chest walls (for instance the
Ij diaphragm) expand first, and other parts follow. It follows from
■ ^ this, that in shallow breathing the lungs will be very unevenly
ventilated. Only certain parts will expand properly, and on ac-
c5^
i
I
>c^f~
6.6
6.0
PRESSURE OFZO^
PERCENT OF AN ATMOSPHERE
S3 4.6 4.0 3.3 2.6
2.0
/J
0.7
c
90
J
• —
—
— ~
"""
60
/
/■
70
60
SO
40
30
20
10
.
r
-
-
J
T"
-H
f
■**
^
/
"^
^
/
*s,
i
f
\
I
\
90
80
70
60
50
40
30
20
10
0 2 4 6 S 10 12 /4 16 Id 2fr22 2426 28 30 32 34 36 38 40 42 44
PERCENT OF AN ATMOSPHERE
OXYGEN PRESSURE
Figure 45.
Dissociation curves of blood for COj and oxygen.
count of the increased frequency of breathing they will receive
much more than their proper share of fresh air, while the other
parts which do not expand will receive much less.
The consequence of this will be that the venous blood passing
through the unexpanded parts of the lungs will be very im-
perfectly arterialized, whereas in the expanded parts the blood
will be more arterialized than usual. The mixed arterial blood will
thus be a mixture of over-arterialized and under-arterialized
r'
RESPIRATION 1 37
blood. To see what the results of this mixture will be, we must
refer to the respective dissociation curves for the oxygen and the
CO2 present in blood, taking also into account the action of oxygen
in expelling CO2 from venous blood, as shown on the curve in
Figure 26. For convenience' sake the two relevant curves are
plotted together in Figure 45, taken from our paper. It will at
once be seen that the over-ventilation in some parts of the lungs
will wash out CO2 from the blood in the same proportion as the
under- ventilation fails to wash it out. The mixed arterial blood
will thus be normal as regards its content of CO2 if the total al-
veolar ventilation is normal. On the other hand, the over- ventila-
tion will hardly increase at all the charge of oxygen in the blood
from the over- ventilated alveoli, since this blood is on the flat part
of the curve with the alveolar oxygen pressure at perhaps 16 or
18 per cent of an atmosphere. The under- ventilation, on the other
hand, will leave the venous blood nearly venous and on the steep
part of the oxyhaemoglobin curve, with a large deficiency of oxy-
gen. The mixed arterial blood will, therefore, be seriously deficient
in oxygen, and symptoms of anoxaemia will consequently be pro-
duced. As one of these symptoms is increase in the breathing, there
will be some compensation, and the CO2 percentage of the mixed
alveolar air will fall somewhat, there being a corresponding rise
also in the oxygen percentage, as was actually found in our ex-
periments.
There is thus a very complete explanation of our experimental
results, and also of the symptoms of anoxaemia in the neurasthenic
cases ; but clearly it is necessary to modify radically the idea that
the alveolar oxygen pressure gives the oxygen pressure of the
mixed arterial blood. We have no guarantee that even during
quite normal breathing the distribution of air in the individual f
lung alveoli corresponds exactly with the distribution of blood to
them. Unless this correspondence is exact some alveoli will re-
ceive more air in proportion to their blood supply than others,
and as a consequence the mixed arterial blood will be a mixture
of more and less fully arterialized blood, with some of the con-
sequences first discussed. It is probable indeed that in some way
or other the air supply is proportioned to the blood supply,
whether by regulation through the muscular coats of the bron-
chioles or regulation of the blood distribution ; but it is also certain
that this proportioning is only an approximation. The fact that
in animals the aerotonometer gives a lower arterial oxygen pres-
sure than the alveolar oxygen pressure (Chapter IX) is most
138 RESPIRATION
naturally explained on the theory that the proportioning is only
4 approximate, and there are various other facts which point in the
same direction.
One of these facts is as follows. When the breathing is suddenly
interrupted voluntarily the breath can be held for a certain time —
usually about 40 seconds if only an ordinary breath is inspired
before the interruption. Leonard Hill and Flack^ discovered, how-
ever, that if the lungs are filled with oxygen first the breath can
be held for two or three times longer ; also that the alveolar CO2
percentage is considerably higher at the breaking point. On the
other hand, when the same air was rebreathed continuously from
a small bag filled at the start with a breath of alveolar air, the
alveolar CO2 percentage went as high as when the breath was
held with oxygen, though not so high as when oxygen was re-
breathed from the bag. The following table, illustrating these
results, is taken from Hill and Flack's paper.
It was difficult, at the time, to interpret these results satisfac-
torily, since the alveolar oxygen percentages, when the breath was
held after breathing ordinary air, did not seem to be low enough to
stimulate the breathing appreciably. In order to obtain still more
definite information Douglas and I repeated the observations,
but in such a way as to have great variations in the alveolar oxy-
gen percentage.* We then found that the beneficial effects of in-
creasing the alveolar oxygen percentage were still evident, though
to a diminishing extent, till 1 7 per cent of oxygen was present in
the alveolar air. Oxygen in excess of this made no difference. But
1 7 per cent is 3 per cent more than what is present in normal al-
veolar air; and, as we have already seen, there are no effects on
the breathing from want of oxygen when ordinary air is breathed
by normal persons, or even when the oxygen percentage of the
alveolar runs down to 10 or even 8 per cent. The results were
therefore very mysterious at the time, and we were compelled to
. adopt the improbable hypothesis that holding the breath has some
considerable effect on the circulation in the brain, leading to
anoxaemia of the respiratory center. There is, however, no reason
whatever to expect such an effect.
The experiments on shallow breathing have furnished the
solution to this mystery. It is evident that the relation between
blood supply and ventilation in individual groups of alveoli is
not an even one. In some alveoli the oxygen runs down and CO2
'Leonard Hill and Flack, Journ. of Physiol.. XXXVII, p. t^, 1908.
* Douglas and Haldane, Journ. of Physiol., XXXVIII, p. 435, 1909.
IT) o O O lO
M CO <N 01 (N
bo
VO 01
CO 00
o) Looq
a> CO CO
00 d ' *
o o o
o "^
O 01
as M 1 VO o
CO HH 1 CO Tj-
00 liS 00 rf
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■v> 6\
§■§ 1
01 O VO 1 01
01 00 On 1 00
u
OC tx ts. IX
?^1
01 »r> o lo o
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tXVO CO lO C\
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^
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After
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oxy
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O 00 lO M t-^
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IX IX 00 00 00
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01 IT) O LO O
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I40
RESPIRATION
accumulates faster than in others. Hence in some the blood is
less perfectly oxygenated; and if the breath is held for a time
this imperfect oxygenation becomes more and more marked till
at last the mixed arterial blood is very considerably short of oxy-
gen, just as when the breathing is very shallow. Hence the oxygen
percentage of the mixed alveolar air becomes altogether deceptive
as an index of the degree of oxygenation of the mixed arterial
blood, although the CO2 percentage remains, for the reasons al-
ready given, a reliable index of the degree of saturation of arterial
blood with CO2. The results of these experiments on holding the
breath are thus very valuable as furnishing evidence that, even
with normal or increased inspirations, the relation between blood
supply and air supply varies considerably in different alveoli.
That the arterial blood does actually become imperfectly oxy-
genated when the breath is held has been quite recently demon-
strated by Meakins and Davies.^ They found that on holding a
deep breath of air for 40 seconds, the haemoglobin of the arterial
-rSO
M
~^
c
X
E."^
&
.2
(J 40
Vl
<o'
D
i'°
/
i^
Jao
r
20 40 60 80 100 120 140 »bO ISO 200 220 240 260 280 300 320 340 360 380 400 420
Pressure of O^in mm.Hq.
Figure 46.
Alveolar CO2 during breath holding after inhalation of oxygen.
blood drawn from the radial artery was only 83.8 per cent satu-
rated with oxygen, although the mixed alveolar air contained
13.4 per cent of oxygen. Had air of this composition been dis-
tributed evenly throughout the alveoli the haemoglobin would
have been 97 per cent saturated with oxygen.
A further series of experiments which Douglas and I performed
is very instructive in this connection. As already mentioned in
Chapter V, the alveolar CO2 percentage rises high above its
normal value before the end.of an^pnoea after forced breathing
witly extra oxygen. We observed how high the alveolar CO2 pres-
sure went when there were varying pressures of oxygen in the
* Meakins and Davies, Journ. of Pathol, and Bacter., XXIII, p. 451,1920.
RESPIRATION 141
mixed alveolar air at the end of the apnoea produced by two
minutes of forced breathing, and the results are plotted in Figure
46.^ It will be seen that the CO2 pressure (and of course also the
length of the apnoea) rises with the alveolar oxygen pressure
until the latter reaches about 120 mm. (corresponding to about
17 per cent of oxygen in the dry alveolar air), beyond which a
further rise in alveolar oxygen pressure has no effect. In this case
the oxygen pressure in all the lung alveoli would be at a more or
less equal high level at the beginning of an apnoea, but would
fall at unequal rates in the different alveoli. Accordingly at the
end of apnoea the mixed arterial blood would be getting venous
unless the average alveolar air contained more than 17 per cent
of oxygen. And yet as little as 8 per cent would be enough to
prevent this effect if the air was evenly distributed in relation to
the blood supply of the alveoli, or if respiratory movements pre-
vented anything more than comparatively slight variations in
the oxygen percentages in different alveoli.
Judging from aerotonometer experiments on normal animals,
and from direct determinations on human arterial blood, the hae-
moglobin of average human arterial blood is only about 94 to 96
per cent saturated with oxygen — about 2 per cent less than if the
whole arterial blood was saturated to the oxygen pressure of the
mixed alveolar air. A very accurate series of determinations
described by Meakins and Davies in the paper just quoted showed
that in different healthy persons the saturation varies from 94 to
96 per cent. The slight variations seem to be due to the variations
which Barcroft described in the oxyhaemoglobin dissociation
curves of different individuals.
The periodic breathing produced by shallow breathing differs
strikingly from the periodic breathing produced by anoxaemia
in normal persons. As will be seen from Figure 44, the periods
are much longer, and in this respect bear a striking resemblance
to ordinary clinical Cheyne-Stokes breathing. The reason why
the periods are longer is evident enough : for the shallow breath-
ing is very ineffective in raising the oxygen percentage in the
badly ventilated parts of the lungs and so relieving the anox-
aemia. The relief thus comes slowly. The breathing, therefore,
"waxes and wanes" gradually, as in clinical Cheyne-Stokes
breathing. In hibernating animals similar breathing is often ob-
served and can be explained in the same way, as, owing to the
small production of CO2, the breathing is very shallow.
'Douglas and Haldane, Journ. of Physiol., XXXVIII, p. 401, 1909.
142 RESPIRATION
Ordinary clinical Cheyne-Stokes breathing is evidently a symp-
tom of anoxaemia due often to the shallow breathing which char-
acterizes a failing respiratory center. This failure may be that of
approaching death, since the anoxaemia itself tends to hasten the
failure of the center, as already explained in Chapter VI. There
is thus a vicious circle which, unless broken in some way, must end
in death from anoxaemia, just as in the case of an airman at a
dangerously high altitude. The color of the lips, in conjunction
with the diminishing depth of the breathing, points clearly to
what is happening.
It is now evident that the anoxaemia so often present in disease,
but so seldom recognized as such, is due in a large number of
cases to the shallow breathing characteristic of a damaged or
"fatigued" respiratory center, whatever the original cause of the
damage or fatigue may be. It is also evident that frequency of
breathing has assumed a significance which it did not previously
possess, since frequency is very often an index of shallowness of
breathing, damage to the respiratory center, and consequently
impending danger from anoxaemia. The frequent and shallow
breathing in surgical shock, or in various forms of influenza and
pneumonic conditions, or as it may occur in many other forms of
disease, is a symptom of which the possible deadly import will be
evident enough to those who have read the preceding chapter in
connection with what has just been said. In this connection I
should like also to emphasize the fact that, as fully explained in
the last chapter, it is unsafe to judge of the degree of anoxaemia
by the degree of cyanosis. The anoxaemia is, and must be, ac-
companied by alkalosis, so that the oxyhaemoglobin holds on more
tightly to its oxygen, and this alkalosis may become extreme with^
very shallow and rapid breathing.
Chronic fatigue or failure of the respiratory center is seen in^
neurasthenia and various other forms of disease; but failure of
the respiratory center may also occur in acute and sudden attacks,
which are often associated, either primarily or secondarily, with
anginal pain. The patient may feel that he cannot expand his
chest to breathe, just as if it were mechanically constricted; and]
he rapidly develops asphyxial symptoms, with very frequent and'
shallow breathing. In reality, apparently, he is in the grip of the
Hering-Breuer reflex, which, as explained in Chapter III, assumes
exaggerated influence, owing to the failure of the respiratory
center. These attacks, though they usually pass ofi", are sometimes
very dangerous; and many sudden deaths appear to be due to
RESPIRATION
them. They are specially liable to occur at night. The ra)
breathing is apt to produce the impression in a physician that
the heart and not the breathing, that has failed ; and this impre\
sion may be apparently confirmed by the presence of secondar^
anginal pain. In all doubtful cases, the effects of properly admin-
istering oxygen will decide the diagnosis. If the immediate cause
of the symptoms is failure of the respiratory center, the effects
of the oxygen are rapid and prompt, and have been so in cases
which have chanced to come under my own observation.
^Tt is evident that anoxaemia caused by irregular distribution
of oxygen among the lung alveoli may be due to a variety of
causes. One of these is emphysema ; for the emphysematous parts
of a lung will naturally be supplied with far more than the proper
proportion of air to suit their greatly diminished respiratory
surface, while the other parts will receive correspondingly less
air. The arterial blood will thus be a mixture of over-arterialized
lllllilllllllllllllllllllllllllilllllllllillllllllllllilllillllllllll^^
Figure 47.
Subject J. S. H. Rebreathing in and out of 50 liter cylinder. Time markers
2 seconds, i. Sitting. 2. Lying.
and under-arterialized blood, with resulting anoxaemia, which
may or may not be compensated by one or other of the processes
to be described in succeeding chapters.
Another cause of the same general character is bronchitis or
asthma. The irregular partial blocking or muscular constriction
of the bronchi and bronchioles in these conditions must lead to
144
RESPIRATION
irregular distribution of fresh air to the alveoli, even though the
average distribution, as shown by the volume of air breathed, is
greatly increased. Hence the mixed arterial blood will be deficient
in oxygen, and grave anoxaemia may develop. Here, also, the
effects of oxygen administration will decide the diagnosis of the
condition.
We found that the recumbent position greatly favors the de-
velopment of periodic breathing, and therefore of anoxaemia.
We also found that when a normal person assumes the recumbent
position, the usual result is that the breathing becomes slower and
deeper. In my own case, for instance, the frequency diminishes
from about 15 in the sitting or upright position to 7 or 8, while
the depth correspondingly increases, so as to keep the alveolar
CO2 pressure nearly the same (see Figure 47). The cause of this
phenomenon is not altogether clear, but is probably the increased
resistance thrown on the diaphragm in the recumbent position,
as the weight of the liver and other abdominal organs assists the
descent of the diaphragm in the upright position. Rontgen ray
liiailiMiijiiiiiiii
■iMilliMMilBtWil^
Figure 48.
Subject J. G. P. I. Breathing restricted by concertina — lying. 2. Breathing
restricted to same extent — sitting. 3. Breathing further restricted — sitting. Oxy-
gen given. Curves read left to right. Inspiration upstroke. Time marker =
seconds.
photographs which we took to show the position of the diaphragm
favored this explanation ; and, assuming it to be correct, the effect
of the recumbent position may well be similar to the slowing
effect produced by resistance as shown in Chapter III. Whatever
RESPIRATION
145
the cause of the natural increased depth may be, it is evident that
in the recumbent position the tendency to irregular distribution
of fresh air in the lung alveoli with any given depth of breathing
is much increased, so that anoxaemia from this cause, as shown
in normal persons by periodic breathing, is much more readily
produced. In my own case periodic breathing is rapidly produced
in the recumbent position when the breathing is kept at over 20
per minute by artificially limiting the depth by means of our
apparatus, whereas in the upright position there is no such effect.
The effect of the recumbent position is shown in Figure 48.
We have thus a simple explanation of a phenomenon which
has been familiar to physicians since early times, but which has
hitherto never been satisfactorily explained. When patients are
800 700 600 500 400 30Q
Sarometric Pressure m mm of mercury
Figure 49.
Effects of diminished barometric pressure on the
alveolar gas-pressures. The thick lines show the
alveolar CO2 pressure, and the thin lines the alveolar
O2 pressure. The dotted lines refer to the experiment
in which oxygen was added to the air.
short of breath during illness they are often very uncomfortable
in the recumbent position, and may become dangerously worse
if not propped up in bed or in a chair. This condition is known as
146 RESPIRATION
orthopnoea, and its causation now seems evident. With a failing
respiratory center, and consequent abnormal shallowness of respi-
ration, anoxaemia is the natural result of the recumbent position ;
and the prevention of this anoxaemia by keeping the patient in a
sitting position becomes an important part of treatment unless
the same object is attained by oxygen administration.
Defective distribution of air in the lung alveoli is, of course,
only one of the causes of defective oxygenation of the arterial
blood; but I have dealt with this cause first, not only because it
is of very great importance in medicine, but because an under-
standing of it is essential to the understanding of other causes of
defective oxygenation.
A second and hitherto much better known cause of defective
oxygenation of the arterial blood is a deficiency in the partial
pressure of oxygen in the inspired air, and consequent fall in the
alveolar oxygen pressure. As shown in Chapter II, it usually re-
quires a fall in oxygen percentage from the normal of 20.9 to
about 14 per cent, or a third, before any evident effect on the
breathing is produced at the time by the oxygen deficiency. Simi-
larly a fall of about a third in barometric pressure (corresponding
to about 1 1,500 feet above sea level) is required. Figure 49, from
a paper by Boycott and myself,'' shows that until the barometric
pressure in a steel chamber falls by about a third, the normal
alveolar CO2 pressure is very little disturbed. The alveolar CO2
percentage simply goes up as the barometric pressure goes down,
but the pressure of CO2 remains almost the same in the alveolar
air. In the same investigation we found that even when the bar-
ometric pressure was reduced to 300 mm. the alveolar CO2 pres-
sure remained the same, provided that any excessive fall in the
oxygen pressure of the inspired air was prevented by adding oxy-
gen to the air of the chamber. There is thus no trace of foundation
for Mosso's contention^ that the diminished mechanical pressure
of the air produces by itself a diminished saturation of the blood
with CO2.
Since the alveolar air, with the breathing normal, contains about
a third less oxygen than the inspired air, it follows that when the
oxygen percentage or partial pressure in the inspired air is reduced
by a third the alveolar oxygen percentage will be reduced to about
half — i.e., from about 13 per cent of an atmosphere to about 6.5
per cent. On comparing this with the dissociation curve of oxy-
haemoglobin it will be seen that such a diminution corresponds
' Boycott and Haldane, Journ. of Physiol., XXXVII, p. 355, 1908.
' Mosso, Life of Man on the High Alps, London, p. 287, 1898.
I
RESPIRATION 147
to a saturation of about 80 per cent of the haemoglobin with oxy-
gen, and that any further diminution will cause a rapid fall in the
saturation. The air produces at the time no noticeable discomfort,
and the breathing is not sensibly affected, although the lips are
slightly bluish. The natural conclusion is that a diminution of
about 15 per cent in the saturation of the haemoglobin, or a dimi-
nution to half in the arterial oxygen pressure, is of no physio-
logical importance, even though the lips are rather dull in color.
This wholly mistaken idea is, however, rudely shaken by the
effects of remaining for a sufficient time in the atmosphere : for
the observer will be almost certainly prostrated by an attack of
mountain sickness which he is never likely to forget afterwards.
If, now, in order to escape mountain sickness, the pressure of
oxygen in the inspired air is only diminished by one-seventh (cor-
responding to a height of 4,500 feet; or an oxygen percentage of
1 7 at ordinary atmospheric pressure) , there will be no appreciable
blueness, and the corresponding saturation on the oxyhaemoglobin
dissociation curve will be only 3.5 per cent below that for normal
alveolar air. Nevertheless there will, if sufficient time is given, be
quite appreciable physiological responses, which .will be discussed
in succeeding chapters. The truth is that in the long run the body
responds in a fairly delicate manner to quite small diminutions
in the oxygen pressure of the inspired air.
Let us now look at the matter in the light of the new knowledge
as to the somewhat imperfect manner in which air is distributed
in the alveoli. In the course of our investigation on military
neurasthenia, we placed several of the patients in a steel chamber
and observed the effects of diminished pressure. A very slight dim-
inution, corresponding to only about 5,000 feet, was sufficient to
produce in them urgent respiratory and other symptoms, although
they were doing no work. Even in normal persons the dissociation
curve of oxyhaemoglobin and composition of the mixed alveolar
air are, as was shown above, no certain guides to the percentage
saturation of the haemoglobin, or oxygen pressure in the mixed
arterial blood. As a matter of fact the blueness of the lips seen in
persons freshly exposed to very low atmospheric pressure seems
to be often much greater than would correspond to the oxygen
pressure in their alveolar air when due allowance is made for the
Bohr effect of lowered alveolar CO2 pressure. We may thus be
quite sure that at diminished atmospheric pressure the saturation
of the mixed arterial blood with oxygen is or may be distinctly
lower than corresponds to the oxygen pressure of the alveolar air.
148 RESPIRATION
Poulton and I found that when a small quantity of air — about
6 liters — was rebreathed continuously up to the verge of loss of
consciousness, the CO2 being completely absorbed by soda lime,
the inspired air contained only 4.8 per cent of oxygen, and the
alveolar air 3.7 per cent. There was very great hyperpnoea; for
the preformed CO2 had not had time to escape in the manner
already referred to in Chapter VI. The respiratory quotient of
the alveolar air was as high as 2.8. The experiment was then
repeated with a large volume of air, and under such conditions
that the oxygen percentage only fell very slowly. The lowest per-
centage of oxygen that could now be reached in the inspired air
without great confusion of mind was about 9.4, with about 4.6
per cent (or 33 mm.) in the alveolar air. There was no noticeable
hyperpnoea, and the respiratory quotient was normal. The al-
veolar CO2 percentage was only reduced from the normal of 5.7
per cent to 4.6, indicating that the alveolar ventilation was only
increased by about a fourth.
From these experiments we may conclude that air containing
less than 9.5 per cent of oxygen would ordinarily cause disable-
ment within half an hour. At a barometric pressure of 368 mm., or
a little less than half an atmosphere, corresponding to about
20,500 feet above sea level, there would be a corresponding drop
in the alveolar oxygen pressure; but judging from my own ob-
servations the physiological effects are very distinctly less severe.
This is probably due to the fact that in rarefied air the diffusion of
oxygen within the lung alveoli is much more free than at atmos-
pheric pressure.^ As a rule no very serious symptoms are ex-
perienced at the time till the barometric pressure has fallen to
about 350 mm. (corresponding to 21,500 feet) ; but in this respect
different individuals vary considerably. It must also be borne in
mind that nervous symptoms of anoxaemia begin to appear at
altitudes not nearly so great. At 320 mm. (about 24,000 feet)
most persons, including myself, are soon very seriously affected
in the manner described in Chapter VI, unless they are acclima-
tized.
Another cause of imperfect oxygenation of the arterial blood
is that there may not be sufficient time for the required quantity
of oxygen to pass into the blood through the alveolar epithelium.
This cause of anoxaemia came into prominence in connection with
the effects of lung-irritant poison gas during the war. It was evi-
dent from the first cases which I saw in April, 191 5, that there was
* Haldane, Kellas, and Kennaway, Journ. of Physiol., LIII, p. 195, 1915.
RESPIRATION 149
acute anoxaemia due to imperfect oxygenation of the arterial
blood. There were the ordinary chlorine symptoms of acute bron-
chitis, alveolar inflammation, and oedema of the lungs. The faces
of the patients were deeply cyanosed, in spite of considerably in-
creased breathing of adequate depth. At first it was suspected that
the cyanosis was due to "toxaemia," causing the formation in the
blood of methaemoglobin or some similar dark-colored decompo-
sition product; but on diluting a drop of the blood, saturating
with CO, and comparing the solution with the tint of similarly
treated normal blood, I found that there was no abnormal pigment
present, so that the blue color was due simply to anoxaemia. That
this anoxaemia was, in the main at least, due to delay in the pas-
sage of oxygen into the arterial blood was then confirmed by the
fact that on administering oxygen the blue color changed to red,
and the patients improved in other respects. It was evident that
with the greatly increased partial pressure of oxygen in the al-
veolar air, the oxygen was able to pass into the blood at a sufficient
rate to saturate or nearly saturate the blood, and thus maintain
life. The delayed passage was probably due mainly to the fact
that the alveolar walls were swollen and oedematous, so that they
did not allow oxygen to pass inwards at a normal rate. As will be
pointed out in Chapter IX, this condition was produced experi-
mentally in animals by Lorrain Smith. The distribution of air in
the lung alveoli was doubtless also gravely interfered with by the
bronchitis and emphysema caused by the actions of chlorine,
though at the time I was ignorant of the importance of this cause.
To judge by the increased breathing there was also much dis-
turbance in the excretion of CO2 by the lungs; and the great dis-
tention of the veins and other signs in the chlorine cases pointed
in this direction also.
In the cases of poisoning by phosgene and other lung irritants
used later, the symptoms of irritation of the air passages were
much less prominent. The general symptoms corresponded more
closely with those of pure anoxaemia. This was particularly true
in the earlier seen, or less severe, cases, when there was no evi-
dent oedema of the lungs. Thus, at first, the symptoms of acute
anoxaemia were shown only on muscular exertion sufficient to
cause a greatly increased need for oxygen ; and some of the men
who were apparently at the time only slightly affected lost con-
sciousness or died as a result of muscular exertion. Others suf-
fered only from general malaise or symptoms similar to those of
mountain sickness, and apparently due to slight anoxaemia. In
I50 RESPIRATION
the graver cases the anoxaemia was usually unaccompanied by
distention of the lips and veins with blood, and the cyanosis was
thus of the leaden or gray type, just as in cases of slowly advancing
anoxaemia from other causes. In death from gradual CO poison-
ing, for instance, there is no extra distention of the lips or veins
with blood, although, of course, the lips are not gray but light
pink. Death, in the phosgene cases and probably in others, seems
to have been finally due to failure of the respiratory center, the
breathing becoming more and more shallow till the resulting
increase in the anoxaemia ended in death. Orthopnoea was a very
common symptom so long as the men were conscious.
In favorable cases of ordinary croupous pneumonia the lips
remain of a good color, and there are no evident signs of anoxae-
mia; but the breathing is rapid, and correspondingly shallow.
The danger of anoxaemia is therefore not far off. At Cripple
Creek (at an altitude of about 10,000 feet) I was told that cases of
commencing pneumonia were at once put on the train and sent
down to the prairie level, as it had been found that they had a
very poor chance if treated locally. This indicates the danger
from anoxaemia, and led us, in the Report of the Pike's Peak
Expedition, to advocate the use of chambers containing air en-
riched with oxygen for treating pneumonia. The fact that there
is often no cyanosis in spite of very extensive lung consolidation
seems to show that the pulmonary circulation has practically
ceased in the consolidated areas. The blood supply of these areas
may be solely through the bronchial arteries, the high-pressure
supply from which joins the pulmonary circulation. This inference
has recently been confirmed by Gross,^^ who found by means of
X-ray photographs of lungs injected with an injection mass
opaque to X-rays, that the pulmonary vessels are nearly blocked
off in the consolidated parts in pneumonia. In the unaffected parts
of the lungs, the oxygen seems to penetrate the alveolar walls
readily enough in pneumonia. Where anoxaemia becomes danger-
ous in croupous or disseminated pneumonia it seems usually to be
failure of the respiratory center and consequent shallow breathing
that is mainly responsible for the anoxaemia.
The fact that in pneumonias of all kinds the arterial blood is
commonly more or less imperfectly saturated with oxygen has
quite recently been shown directly by Stadie,^^ who examined
"Gross, Canadian Med. Assoc. Journ., p. 632, 19 19.
" Stadie, Journ. of Exper. Med., XXX, p. 215, 19 19.
RESPIRATION 15 1
samples of arterial blood drawn usually from the radial artery by
means of a syringe. In normal persons he found an average of
95 per cent saturation of the haemoglobin with oxygen ; and this
is about what might be expected in view of what has been said
above. In cases of pneumonia the saturation varied from 95 to
42 per cent; and as a rule the cases where the saturation was
below ^6 per cent ended fatally. Cardiac cases were soon after-
wards investigated by Harrop/^ who found that in many of them
there was imperfect saturation of the arterial blood. This was
almost certainly due, frequently, to partial failure of the respira-
tory center and consequent shallow breathing.
The significance of these analyses will be evident from what
has been said in the previous and present chapters ; and the danger
to a patient of permitting any serious arterial anoxaemia to con-
tinue when it can be prevented is, I hope, already evident.
As anoxaemia is such a common and often dangerous condition,
and can frequently be combated by the addition of oxygen to the
inspired air, it will be rfrT^tee'to" refer liere to clinical methods
of administering oxygen. In the first place it is necessary to have
clear ideas as to the objects aimed at, in administering oxygen. If
the oxygen is only given to enable a patient to surmount some quite
temporary crisis due to anoxaemia — produced, it may be, by one
of the sudden angina-like attacks of reflex restriction of breath-
ing referred above — a very simple method of administration will
suffice. A small cylinder of oxygen furnished with an india-rubber
tube by means of which a stream of oxygen may be directed into
the patient's open mouth will suffice; and such an arrangement
would probably often be useful in certain cases, as the oxygen
could be given promptly by a competent nurse at any time.
In the great majority of cases, however, the cause of the an-
oxaemia is one which may last for a considerable time, so that
the administration of oxygen, in order to be useful, must be
continued. In this connection it should be clearly realized that
the object of the oxygen administration is not simply palliative,
but curative. By preventing the anoxaemia we not only avert
temporarily a cause of danger or damage to the patient ; but give
the body an interval for recovery from the original cause, what-
ever it may be, of the anoxaemia, or for adaptation. We also break
a vicious circle : for if the anoxaemia is allowed to continue, it
will itself make the patient worse, or tend to prevent the recovery
which would otherwise naturally occur. We are not dealing with
" Harrop> Journ. of Exper. Med., XXX, p. 241, 19 19.
152 RESPIRATION
a machine, but with a living organism; and a living organism
always tends to return to the normal if the opportunity is given.
Oxygen is still often given by methods which are either quite
ineffective or extremely wasteful. One method is to place a funnel
over the patient's face, and allow some quite indefinite amount of
oxygen to pass into the funnel. By this method the patient re-
breathes a good deal of expired air, but may hardly get any of
the oxygen, as the latter, being heavier, runs out below. A far
better method is to insert a rubber catheter or other soft tube into
the patient's mouth or nose, and pass a stream of oxygen through
the tube. Another good method, when pure oxygen has to be given,
is to allow the oxygen to pass at a sufficient rate into a rubber bag
connected with the inspiratory valve of an anaesthetic mask placed
over the patient's mouth and nose. The patient inhales from the
bag, and exhales to the outside through the expiratory valve in
the mask.
In ordinary cases the patient does not require pure oxygen, but
only a sufficient addition to the air of oxygen to prevent the an-
oxaemia. In any case it would be very undesirable to continue the
administration of pure oxygen for more than a limited time, as
pure, or nearly pure, oxygen has a slow irritant action on the
lungs, as will be shown in Chapter XII. If the mask is left open
to the air, so that the patient can breathe as much air as he likes,
and a stream of oxygen is allowed to pass into the mask directly,
the oxygen which passes in during expiration is of course wasted.
It became evident during the war that an efficient apparatus
for the continuous administration of oxygen with maximum econo-
my in oxygen was greatly needed, particularly in the treatment
of acute cases of poisoning by lung-irritant gas. I therefore de-
vised an apparatus so arranged that by a simple device the patient
inspired through a face piece the whole of the added oxygen,
without waste during expiration, while the proportion of oxygen
could easily be cut down or increased, according as was needful.
The original form of this apparatus was described in the British
Medical Journal, February lo, 191 7, page 181, after it had already
been supplied extensively to the army in France. Its use there for
gas cases was initiated, and the managment of it carefully investi-
gated, by Lieutenant Colonel C. G. Douglas of Oxford. Other
well-known medical officers also made very valuable observations
on the effects of oxygen inhalation. The results, particularly in
gas cases, were strikingly successful; and practically continuous
administration could easily be carried out over the two or three
RESPIRATION 1 53
days during which there was danger from anoxaemia. Patients
can sleep comfortably during the administration.
The apparatus was afterwards simplified, with the special object
of making it both easy for a nurse to handle, and available for
front line and stretcher work, including treatment of "shock"
cases. Figure 50 shows the arrangement of the apparatus. It con-
sists of : ( I ) an oxygen cylinder provided with an easily worked
TAP to
^^/■^^ OPENING
f ^/TOAJR
MAIN
VALVe
Figure 50.
Api)aratus for administering oxygen.
and efficient main valve ; (2) a pressure gauge showing how much
oxygen is in the cylinder; (3) a reducing valve which reduces
the pressure to a small amount which remains constant till the
cylinder is exhausted; (4) a graduated tap indicating the flow of
oxygen in liters per minute; (5) thick- walled rubber tubing con-
veying the oxygen to the patient and a light rubber bag; (6) a
face piece with a minimum of dead space, and provided with
elastic straps and a pneumatic cushion which can be taken off for
disinfection.
The patient can inspire and expire freely through an opening
in which there is a rubber flap to cause a very slight resistance.
During expiration the oxygen collects in the bag, and is sucked
into the face piece at the beginning of inspiration. From the move-
ments of the bag it can be seen at any time whether the patient
is receiving the oxygen. To put the apparatus in action the main
valve is opened freely, and the tap is adjusted to give 2 liters a
minute or whatever greater or less amount suffices. With a de-
livery of 2 liters a minute a 40-foot cylinder would last nearly
ten hours.
154 RESPIRATION
The effects of continuous oxygen inhalation with this apparatus
on the arterial blood in pneumonia and bronchitis have quite
recently been investigated by Meakins.^^ He found that with 2
liters a minute the percentage saturation of the haemoglobin in a
pneumonia case with almost complete consolidation of one lung
rose from 82 per cent to 91 per cent, but went back on stopping the
oxygen to 84 per cent, slight cyanosis returning also. On then
giving 3 liters a minute, the saturation rose to 97 per cent, which
is 2 per cent above the normal value for healthy persons. In a
bronchitis case with slight cyanosis and orthopnoea, the satura-
tion rose from 88.6 to 97.0 per cent on giving 2 liters a minute^
and the cyanosis and orthopnoea disappeared. In a normal man
the saturation rose from 95.6 to 98.1 on giving 2 liters a minute.
The plan of treating patients in an air-tight chamber contain-
ing a high percentage of oxygen was introduced towards the end
of the war at Cambridge under Barcroft's direction ;^* and a
similar chamber was erected at Stoke-on-Trent. Favorable results
were obtained in chronic cases of gas poisoning, as might be
anticipated in view of the disturbed nervous control of breathing,
already described in Chapters III and VII. It now seems evident
that the administration of air enriched with oxygen is likely to
be successfully introduced in the treatment of various illnesses
in which arterial anoxaemia is present.
During considerable muscular exertion the rate at which oxy-
gen has to penetrate from the alveoli into the blood is enormously
increased. Hence it is during muscular work that we should ex-
pect to find any signs of anoxaemia in healthy persons breath-
ing normal air at normal atmospheric pressure. That a certain
amount of anoxaemia is commonly produced can be shown
indirectly in various ways. In the first place the alveolar CO2
pressure, particularly in some persons, does not rise during mus-
cular exertion in the proportion that would be expected if the
increased breathing were simply due to the increased production
of CO2 and consequent rise in the alveolar CO2 pressure. Thus in
the experiments of Priestley and myself, my own alveolar CO2
pressure rose only by .13 per cent, in place of an expected rise of
about .8 per cent, if the increased breathing had been due to CO2
alone; while in the case of Priestley (who was in much better
" Meakins, Brit. Med. Journ., March 5, 1920. A number of further cases have
•till more recently been recorded by Meakins, Journ. of Pathol, and Bacter., XXIV,
p. 79. 1921.
"Barcroft, Dufton, and Hunt, Quarterly Journ. of Medicine, XIII, p. 179,
1920.
RESPIRATION
155
physical training than I was) the rise was .44 per cent in place of
an expected rise of about .56. I have since then frequently found
that my alveolar CO2 pressure does not rise appreciably with
muscular exertion, and falls if the exertion is very great ; though
in younger men there is almost always a marked rise, as in the
experiments on Douglas, mentioned in Chapter II. The absence
of a rise in me when ordinary air is breathed is not due to the
formation of lactic acid referred to in Chaper VIII. I found in
191 7, however, that there is a well-marked rise when a little oxy-
gen is added to the inspired air. The failure of my alveolar CO2
to rise was therefore due apparently to slight anoxaemia during
muscular exertion.
It has for long been well known to engineers that men perform
hard physical work more easily when they are working in com-
pressed air. This was very evident, for instance, during the work
on the Blackwall tunnel under the Thames, which I visited about
25 years ago. At the existing air pressure the alveolar oxygen
pressure would have 3j4 times its normal value. In breathing
nearly pure oxygen while wearing a mine rescue apparatus, I
share the very common experience, that in spite of the weight of
the apparatus, heavy exertion, such as walking very fast, is much
easier. On the other hand, even a very moderate increase in alti-
tude increases considerably the panting on exertion.
Some years ago Hill and Flack^^ published a number of ob-
servations on the apparent effects of oxygen before and after
muscular exertion. Many of their observations were concerned
with very striking effects, already referred to, of oxygen in pro-
longing the time during which the breath can be held. They
showed that this effect is just as marked when exertion is per-
formed with the breath held as during rest. They also found that
oxygen given during the distress immediately following severe
exertion has a distinct effect in raising the blood pressure, improv-
ing the pulse, and alleviating the distress. This indicates that a
raised partial pressure of oxygen in the alveolar air increases the
oxygenation of the blood, and that part of the distress caused by
severe muscular work is caused by deficient oxygenation of the
arterial blood. I am unable to agree, however, with their further
conclusion that when oxygen is breathed a large amount of free
oxygen is stored in the blood and tissues, and that for this reason
a man who has breathed oxygen for a time has a distinct physio-
" Hill and Flack, /ourn. of Physiol., XXXVIII, Pro. Physiol. Soc, p. xxviii,
1909 ; and XL, p. 347, 19 10.
156 RESPIRATION
logical advantage as regards performance of work over a man
who has simply breathed air. Douglas and I found^^ that if oxy-
gen is breathed quietly before an exertion there is no physiological
advantage if the breath is not held. The extra oxygen in the lungs
is quickly washed out by the breathing, and there is nothing to
indicate the existence of any other extra store of oxygen in the
body. If, however, the breathing is forced before the exertion,,
there is considerable advantage whether air or oxygen is breathed
during the forced breathing ; and this advantage is due simply to
washing out of CO2. As will be shown in Chapter XII, the tis-
sues and venous blood cannot become highly saturated with oxy-
gen when this gas is simply breathed at ordinary atmospheric
pressure; and if oxygen had any appreciable effect apart from
that due to the actual presence of an increased percentage of oxy-
gen in the lungs the result would be very unintelligible.
A clear and striking light has been thrown on this subject by
some recent experiments by Dr. Henry Briggs.^*^ He found that
when equal work is done on a Martin's ergometer the percentage
of CO2 in the expired air is, in persons not in good physical train-
ing, considerably higher when air rich in oxygen is breathed than
when ordinary air is breathed. In persons in the best physical
training, on the other hand, there is practically no difference until
the work done is very excessive. The following table is from his
paper. Subject A was out of training, and Subject B in good
training.
PERCENTAGE CO
, IN EXPIRED AIR
Work in foot founds
Subject A
Subject B
per minute
Breathing
Breathing
Breathing
Breathing
Pedaling with brake off
atr
oxygen
atr
oxygen
3.9
4.1
4-4
4.5
3»ooo
4.65
5-25
5.3
5-45
1 6,000
4.7
5.8
6.2
6.2
9,000
4.3
5.8
6.1
6.3
1 10,000
4.1
5.7
6.0
6.2
12,000
""
5.6
6.0
la
Douglas and Haldane, Journ. of Physiol., XXXIX, Proc. Physiol. Soc, p. i,
1909.
"Briggs, Henry — Fitness and breathing during exertion, /. Physiology, Vol. 53,
19 19-1920, Proc. Physiological Soc, p. 38-40.
RESPIRATION
157
The reason why anoxaemia is absent in persons who are in
good training will be discussed in Chapter IX.
There can be little doubt, in view of all the evidence adduced
above, that muscular work produces some degree of anoxaemia
in untrained persons, and that the anoxaemia increases with the
work. The anoxaemia can hardly be due to any other cause than
LITERS GAS INSPIRED PER MINUTE
Subject A
Subject B 1
Breathing
Breathing
Breathing
Breathing
atr
oxygen
atr
oxygen
12
13
14
II
25
22.5
20
18
40
33
27
27
54
43
Z7
37
57
46
40.5
40.5
~
~
50
48
that the blood is passing through the lungs so quickly that suffi-
cient oxygen to saturate the haemoglobin has not time to pass in
through the alveolar epithelium, just as occurs to a far greater
extent even during rest in a case of phosgene poisoning.
Another possible explanation might perhaps suggest itself, and
seems, indeed, to be suggested in Chapter XI of Mr. Barcroft's
book, "The Respiratory Functions of the Blood." This is that the
velocity of the chemical reaction, which occurs when haemoglobin
comes into contact with oxygen at a certain partial pressure of
oxygen, is so low that there is not time for the change to complete
itself in the lungs during muscular exertion. The rate at which
haemoglobin takes up oxygen, or oxyhaemoglobin gives it off,
in presence of a certain partial pressure of oxygen is so extremely
rapid that at present we have no means of measuring it. We can
form some conception of what must be the velocity if we consider
what is happening in the circulation of a small warm-blooded
animal, such as a mouse or bird. As was shown by Dr. Florence
Buchanan-^^ the pulse rate of such an animal is, even during rest,
about 700 to 800 a minute. A volume of blood equal to the whole
"Buchanan, Journ. of Physiol., XXXVII, Proc. Physiol. Soc, p. Ixxix, 1908;
and XXXVIII, Proc. Physiol. Soc, p. Ixii, 1909.
158 RESPIRATION
of that in the animal will pass round the circulation in one or two
seconds during exertion, so that any portion of blood will only be
present for an instant in the pulmonary capillaries in each round
of the circulation. Yet the time is sufficient for the chemical change
to occur in the blood, and doubtless far more than sufficient, since
we have to allow also for the time needed for the passage of oxy-
gen through the layer of living tissue separating the air from the
blood. In man the time available is much greater, so that the
absolute velocity of the chemical change does not come into con-
sideration at all, though of course the relative rates at which oxy-
gen is chemically associated with or dissociated from haemoglobin
at varying partial pressures of oxygen and varying temperatures,
determine the corresponding dissociation curves as experimentally
determined.
A further group of causes of anoxaemia depends not on defec-
tive saturation in the lungs, but on defect in the charge of available
oxygen carried by the arterial blood, so that, with the existing
rate of circulation, the oxygen pressure in the systemic capillaries
falls too low. Of this group, carbon monoxide anoxaemia will be
considered first.
The laws of combination of carbon monoxide with haemoglobin
have already been discussed in Chapter IV. My own interest in
carbon monoxide arose out of my connection with coal mining, as
it had become evident to me that carbon monoxide poisoning was a
common occurrence, and I wished to understand it as thoroughly
as possible. When Claude Bernard discovered the combination of
CO with haemoglobin he attributed death from CO poisoning to
the anoxaemia resulting from the fact that CO displaces the oxy-
gen of oxyhaemoglobin. CO was, however, very generally be-
lieved to have other physiological actions than those of anoxaemia,
and my first experiments were made with a view to clearing this
matter up.
To put the matter to the test, I devised the following experi-
ment^^ (Figure 51). A mouse was dropped into a thick glass
measuring vessel filled with pure oxygen, and the pressure of
oxygen in this cylinder was then raised to two atmospheres by
connecting it with an oxygen cylinder in the manner shown. The
oxygen was then clamped off and another clamp opened, through
which the oxygen was directed into the top of another measuring
vessel full of water, and the water driven over into a third measur-
ing vessel filled with pure carbon monoxide, so arranged that the
"Haldane, Journ. of Physiol., XVII, p. 201, 1905.
RESPIRATION
159
gas was driven into the vessel containing the mouse. The animal
was now in a mixture consisting of two parts of oxygen and one
of carbon monoxide, at a total pressure of two atmospheres of
oxygen and one of carbon monoxide. It could also be killed by
drowning in this atmosphere if water was forced over.
My calculation was that in the presence of two atmospheres of
oxygen the animal would have in simple solution sufficient oxy-
gen in its arterial blood to supply the oxygen requirements of its
tissues, at any rate during rest; and that it would thus be inde-
pendent of the oxygen supply shut off through the action of the
^^'-"vo^'/'v
1
Figure 51.
Apparatus for exposing mouse to atmosphere of oxygen and CO.
CO, with which the haemoglobin would be almost completely
saturated. If, however, the CO had any toxic action apart from
its action in producing anoxaemia this action would certainly
manifest itself at once, since the partial pressure of the CO was
100 per cent of an atmosphere, whereas in CO poisoning as ordi-
narily met with in non-fatal cases, the partial pressure of CO
is not more than about 0.2 per cent of an atmosphere. The amount
l6o RESPIRATION
of free oxygen which would go into solution in blood at the body
temperature with an atmospheric pressure of two atmospheres is
4.2 volumes per 100 cc. of blood, which is just about as much as is
ordinarily taken from the blood as it passes through the tissues
(see Chapter X).
The mouse remained quite normal and seemingly unconcerned,
except that when it exerted itself in climbing up the jar it seemed
to become more easily tired than usual. Thus CO has no appreci-
able physiological action except that of producing anoxaemia.
It is, physiologically speaking, an indifferent gas, like nitrogen,
hydrogen, or methane, and, like these gases, only acts physio-
logically by cutting off the supply of oxygen. Its only specific
physiological action, so far as I am aware, is that it has a slight
garlic-like odor. It is not an "odorless gas" except to those who
are afraid even to smell it on account of the mythical properties
commonly attributed to it. Animals which have no haemoglobin
pay no more attention to CO than to nitrogen. I kept a cockroach
for a fortnight in an atmosphere consisting of 80 per cent of CO
and 20 per cent of oxygen, and it remained perfectly w^ell. CO is
not oxidized or otherwise decomposed in the living body of any
animal. ^^ It passes in by the lungs and passes out — far more
rapidly than is generally supposed — by the lungs, without there
being the smallest loss. For this and other reasons it is a most
valuable physiological reagent.
The popular idea that CO remains for long in the blood is based
simply on failure to realize the nature of the symptoms which fol-
low severe or long-continued anoxaemia. In the light of present
knowledge it is childish to suppose that as soon as anoxaemia is
relieved a patient will recover, or that anoxaemia is in itself a
trifling matter if life is not immediately imperiled. If there were
only one clinical lesson derived from a perusal of this book, I hope
it would be that anoxaemia is a very serious condition, the con-
tinuance of which ought to be prevented if at all possible.
The properties of CO as a poison can now in the main be under-
stood in the light of preceding chapters. As the molecular affinity
of haemoglobin for CO is enormously more powerful than its
affinity for oxygen, it is evident that a very small proportion of
CO in the air is capable of saturating the blood to a noticeable
extent. The proportion of oxygen in dry alveolar air is about 14
per cent, and the affinity of haemoglobin for CO (in my own case
For experiments and references on this subject see Haldane, Journ. of Physiol.,
XXV, p. 221, 1899, and M. Krogh, Pfiiiger's Archiv, 162, p. 94, 19 15.
RESPIRATION i6i
at least) is about 300 times its affinity for oxygen. It follows that,
if we assume for the moment that the oxygen pressure of the blood
is that of the normal alveolar air, the blood will gradually become
half -saturated with CO if air containing = .047 per cent of
CO is breathed continuously for a sufficient time. If the per-
centage is .0235 per cent, the final saturation will only be one
third; and if the percentage is .012 the saturation will be a fourth;
and so on. If pure air were again breathed the CO would be ex-
pelled from the body through the unbalanced action of the al-
veolar oxygen pressure in expelling CO from its combination. The
rates of absorption and of elimination of the CO can also be
calculated on the same principles from the mean percentage of
CO in the alveolar air, allowing for the fact that as the haemo-
globin approaches the balancing saturation the rate of absorption
will gradually fall off; and similarly the rate of elimination will
gradually fall off as the blood loses CO. As will be shown in
Chapter IX, however, this theoretical course of events is pro-
foundly modified by active secretion of oxygen inwards by the
lung epithelium.
It is evident also that in air abnormally poor in oxygen a given
percentage of CO will become more poisonous, and in air ab-
normally rich in oxygen less poisonous. This I verified experi-
mentally on animals. It remained to ascertain in man what effects
corresponded to a given saturation of the haemoglobin ; and this I
ascertained by experiments on myself,^^ using for the purpose the
carmine titration method referred to in Chapter IV, and fully
described in its latest form in the Appendix.
I found in these experiments that no particular effect was ob-
served until the haemoglobin was about 20 per cent saturated. At
about this saturation an extra exertion, such as running upstairs,
produced a very slight feeling of dizziness and some extra palpita-
tion and hyperpnoea. At about 30 per cent saturation very slight
symptoms, such as slight increase of pulse rate, deeper breathing,
and slight palpitations, become observable during rest, and run-
ning upstairs was followed in about half a minute by dizziness,
dimness of vision, and abnormally increased breathing and pulse
rate. At 40 per cent saturation these symptoms were more marked,
and exertions had to be made with caution for fear of fainting.
At 50 per cent saturation there was no real discomfort during
rest, but the breathing and pulse rate were distinctly increased,
"Haldane, Journ. of Physiol., XVIII, p. 430, 1895.
1 62 RESPIRATION
vision and hearing impaired, and intelligence probably greatly
impaired. It was also hardly possible to rise from the chair with-
out assistance. Writing was very bad, and spelling uncertain.
Movements were very uncertain, and it was difficult to recognize
objects distinctly or estimate their distance correctly, so that things
a long way off were grasped at in vain. Attempts to go any distance
caused failure of the legs and collapse on the floor. In one experi-
ment the saturation reached 56 per cent. It was then hardly
possible to stand, and impossible to walk. After each of these
experiments the saturation of the blood fell rapidly when fresh
air was breathed ; and within three hours the saturation had fallen
below 20 per cent.
Shortly after these experiments, I examined the bodies of a
large number of men who had been killed in colliery explosions,
and found that nearly all had died of CO poisoning. The satura-
tion of the haemoglobin with CO was usually about 80 per cent,
but in some cases not more than 60 per cent. In fatal cases of
poisoning by lighting gas Lorrain Smith found similar satura-
tions.
The general similarity between the symptoms of CO poisoning
and those of anoxaemia produced in other ways is evident; and
the after-symptoms appear to be identical with those of mountain
sickness and related disorders. There is, however, a difference
between the symptoms of CO poisoning and those of anoxaemia
produced by imperfect oxygenation of the arterial haemoglobin.
This difference lies in the fact that in CO poisoning fainting, or a
tendency to fainting, is much more prominent than respiratory
distress. A man at a high altitude pants excessively on exertion,
but does not easily faint. A man suffering from CO poisoning
faints very readily on exertion, and the tendency to dizziness and
collapse is far more prominent than the hyperpnoea. The fainting
on exertion is evidently due to the fact that from lack of the mass
of oxygen needed the heart cannot compensate by sufficiently
increased output of blood for the greatly increased flow of blood
through the working muscles. The blood pressure therefore falls,
with the result that the circulation to the brain is diminished and
anoxaemia then causes loss of consciousness. But why does this
occur so much more readily in CO poisoning? The fact that it does
so indicates that relatively speaking the respiratory center is less
affected in the anoxaemia of CO poisoning, in which the mass of
oxygen in the blood is reduced but the pressure of oxygen in the
arterial blood remains normal. That is to say, with a degree of
I
RESPIRATION 163
anoxaemia which would not seriously affect the heart in anoxae-
mia from imperfect oxygenation of the available haemoglobin
there will be marked response to anoxaemia in the respiratory
center, but not in CO poisoning. This points clearly to the very
important conclusion that it is practically speaking to the oxygen
pressure of the arterial blood that the respiratory center responds.
The blood which bathes the receptive end-organs (or whatever
else is sensitive to the respiratory chemical stimuli) of the respira-
tory center must therefore be blood which has lost very little of its
arterial charge of oxygen.
There are other facts pointing in the same direction. Thus in
fainting or dizziness from fall of blood pressure there is no im-
mediate panting, although the anoxaemia which immediately
results in the cerebrum is sufficient to cause loss or impairment of
consciousness. The arterial blood, however, remains normal as
regards its pressures of oxygen and CO2 during fainting; and in
accordance with the conclusion just reached, the breathing is not
stimulated till the stagnation of blood in the respiratory center is
very marked.
It is to be kept in mind that at a moderate altitude the pressure
of oxygen in the arterial blood is diminished far more than the
mass of the oxygen, as expressed by the percentage saturation of
the haemoglobin. With CO it is the mass of oxygen which is
diminished in the blood, while the pressure may be normal.
It also seems a priori probable that the respiratory center should
be continuously sampling and controlling the gas pressures of the
arterial blood. For it has to act for the whole body. Its function
is evidently, not to keep normal the gas pressures in the capillaries
of one particular part of the body, such as the medulla oblongata,
but to keep normal the arterial blood upon which every part of
the body draws in accordance with varying local requirements.
It keeps the gas pressures normal just as the heart keeps the blood
pressure normal, so that every part of the body can always indent
for arterial blood of standard quality and sufficient quantity.
A further peculiarity of CO poisoning is that quite commonly
consciousness is lost for long periods in the poisonous atmosphere
without death occurring. Thus cases of CO poisoning afford strik-
ing opportunities of studying the effects of prolonged general
anoxaemia of the brain and every other organ in the body. The
reason why death does not occur more readily seems to be that,,
although the amount of oxygen transported by the blood is dimin-
ished, the oxygen pressure in the arterial blood remains normal.
1 64
RESPIRATION
and as a consequence the respiratory center does not rapidly fail
in the same manner as it does when the arterial oxygen pressure is
very low, as explained in Chapter VI. This characteristic seems to
be common to all forms of anoxaemia in which the arterial oxygen
pressure remains about normal, including anoxaemia due simply
to a failing heart.
If the action of CO were simply to diminish the oxygen-
carrying power of the haemoglobin, without modification of the
properties of the remaining haemoglobin, the symptoms of CO
poisoning would be very difficult to understand in the light of
other knowledge. Thus a person whose blood is half-saturated
Pressure of 0, in Mm. of Wg.
30 40 50 60 70
80
90
too
3i 4X 55: G2 ^ BX &i m ifi S at
Pressure of 0, in % of an atmosphere
Figure 52.
Curve I, o per cent saturation with CO; II, 10 per cent; III, 25 per cent;
IV, so per cent; V, 75 per cent.
with CO is practically helpless, as we have just seen ; but a person
whose haemoglobin percentage is simply diminished to half by
anaemia may be going about his work as usual. Miners may be
doing their ordinary work though their haemoglobin percentage
is reduced to half or less by ankylostomiasis ; and women may be
going about their duties with their haemoglobin percentage re-
duced to a third by chlorosis. Even in the extremest "anaemia,"
RESPIRATION 165
with the haemoglobin below 20 per cent of its normal value, and
the lips of extremest pallor, the patient is perfectly conscious,
though hardly capable of any muscular exertion.
The key to this seeming paradox is furnished by the discovery^^
that the oxyhaemoglobin left in the arterial blood when it is
partially saturated with CO has its dissociation curve altered in
such a way that the haemoglobin holds on more tightly to the oxy-
gen. The oxygen still present as oxyhaemoglobin is therefore less
easily available, so that the oxygen pressure in the tissues must
fall lower in order to get off the combined oxygen. With a given
amount of available oxygen in the blood the physiological anox-
aemia is thus increased. Figure 52, from a paper by J. B. S. Hal-
dane,^^ shows the alterations in the dissociation curves of the
oxyhaemoglobin with varying percentage saturations of the blood
with CO. It will be seen, for instance, that with 50 per cent satu-
ration of the blood with CO the oxygen pressure must fall to less
than half the usual value, and with 75 per cent saturation to less
than a third, in order to dissociate half the oxygen present in the
arterial blood as oxyhaemoglobin. No wonder, therefore, that the
symptoms of CO poisoning are much more severe than those of a
corresponding simple deficiency of haemoglobin in the blood. It
will be seen also that the shape of the dissociation curve is com-
pletely altered. The characteristic double bend (which, as already
seen, is of such vital physiological importance) in the oxyhaemo-
globin curve tends to disappear altogether, so that an enormous
fall in oxygen pressure is needed to make the bulk of the oxygen
in the oxyhaemoglobin dissociate.
In the investigations which Lorrain Smith and I made on the
effects of continuously breathing a definite percentage of CO all
the experiments were made on ourselves, and in a series which
was more or less continuous from day to day. From the results of
these experiments we estimated that it required about .05 per cent
of CO in the air to produce the 30 per cent saturation of the blood
which was necessary for any very noticeable symptoms of CO
poisoning. In isolated experiments made later, however, we found
the CO much more poisonous, so that it only required about .02
per cent to produce the required saturation. In the original ex-
periments we had become "acclimatized" without knowing it. The
great significance of this "acclimatization" will be discussed in
succeeding chapters.
" Douglas, J. S. Haldane, and J. B. S. Haladne, Journ. of Physiol., XLIV,
293, 1912.
"J. B. S. Haldane, Journ. of Physiol., XLV, Proc. Physiol. Sac, p. xxii, 19 12.
1 66 RESPIRATION
The other gas, besides CO, which enters into molecular com-
bination with haemoglobin is nitric oxide. But as free nitric oxide
combines at once with the oxygen in air to form yellow "nitrous
fumes," and these are intensely irritant and produce very danger-
ous inflammation, nitric oxide poisoning in the same sense as CO
poisoning is impossible. Sir Humphrey Davy nearly killed him-
self when he attempted to breathe nitric oxide (NO) at the time
when he discovered the eff'ects of nitrous oxide, or "laughing gas"
(NgO). NO haemoglobin is, however, formed to some extent in
the living body during poisoning by nitrites, as was discovered by
Makgill, Mavrogordato, and myself ;^* and some time after death
from nitrite poisoning the whole of the haemoglobin becomes
combined with NO. Hence the body is red, just as in a fatal case of
CO poisoning, so that the case might easily be mistaken for CO
poisoning on mere spectroscopic examination of the blood. The
condition can be distinguished at once by the fact that the blood
and tissues remain red on boiling, just as in the case already al-
luded to of salted meat.
Another cause of an anoxaemia analogous to that of CO poison-
ing is present in the case of the action of poisons which produce
methaemoglobin in the living body. The first of these to be dis-
covered was chlorate of potash, which in former times, before the
dangerous properties of chlorates were realized, used to be ad-
ministered freely as an oxidizing agent, and has even been recom-
mended as an antidote for the anoxaemia of high altitudes. The
discovery that in a fatal case of diptheria treated with chlorate of
potash the blood contained much methaemoglobin drew attention
to the possible dangers from anoxaemia in poisoning by any of the
numerous substances which are capable of producing methaemo-
globin in the living body.
The possibilities of anoxaemia being produced were investi-
gated by Makgill, Mavrogordato, and myself. As ferricyanide
does not penetrate the walls of the red corpuscles, and chlorates
do not do so in the animals we were using, we used chiefly nitrites
for the experiments; and we did so for the reason, partly, that
nitrites have other important physiological actions besides that of
producing methaemoglobin (in reality a mixture of methaemo-
globin with a certain proportion of NO haemoglobin). Having
discovered the dose required to produce death we then, as soon
as serious symptoms began to develop after administration of the
dose, placed the animals in compressed oxygen. The result was
•* Makgill, Mavrogordato, and Haldane, Journ. of Physiol., XXI, p. i6o, 1897.
RESPIRATION
167
that the serious symptoms disappeared and the animals recovered.
If, however, they were removed into ordinary air, they died at
once with anoxaemic convulsions. When kept in the oxygen for a
sufficient time, however, they completely recovered and could be
returned to ordinary air. Oxygen at ordinary atmospheric pres-
sure was often sufficient to save the animals.
Having worked out a method for estimating colorimetrically
the proportional extent to which the haemoglobin was altered by
the poison, we then found that the dangerous symptoms depended,
just as in CO poisoning, on the extent of the alteration. It was
thus evident that the cause of death, and of the dangerous symp-
toms, was anoxaemia, just as in CO poisoning. We also found that
the methaemoglobin and NO haemoglobin soon disappeared, leav-
ing the blood quite normal, if death was averted. The methaemo-
too
3
r
«
90
80
70
60
50
40
30
20
to
0
i
s:
!S
5:
!^
s;
//ours a/ter /ny'ech'on
Figure 53-
Methaemoglobin due to sodium nitrate.
globin was simply reduced back again, just as on the addition of
a reducing agent to a methaemoglobin solution outside the body.
It was also evident that the reduction process was constantly going
on and tending to neutralize the poison even while the relatively
large amounts of it were still present in the blood. In proportion
as the poison was destroyed or excreted the reduction process got
the upper hand. There are, therefore, reducing agents of some
1 68 RESPIRATION
kind or another within the corpuscles. Figure 53 shows the per-
centage conversion to methaemoglobin in the blood of a rabbit at
intervals after a non-poisonous dose of sodium nitrite. It will be
seen that after four hours the blood had completely recovered.
The action of methaernoglobin- forming poisons is rendered
evident at once by the marked cyanosis which they produce. The
methaemoglobin has a dark color, and the arterial blood becomes
therefore of a chocolate or coffee color. This form of cyanosis may
become very marked indeed without serious real symptoms of an-
oxaemia being present. Thus in acute poisoning by dinitrobenzol
(an ingredient of certain explosives) a man may become very blue
in the face and yet be going about as usual, although he presents
a most alarming appearance.
Many of the poisons which produce methaemoglobin cause, in
addition, radical decomposition in the haemoglobin, and even
breaking up of the red corpuscles. This is, for instance, the case,
to a large extent, with dinitrobenzol, so that there are other colored
decomposition products present as well as methaemoglobin; and
for the present it is not possible to specify their nature. Their pres-
ence, or that of methaemoglobin, can, however, be detected at once
on diluting a drop of the blood till the color begins to become
yellowish, then saturating with coal gas or CO, and comparing
the tint with that of normal blood diluted to a corresponding ex-
tent and similarly saturated. If any colored decomposition prod-
ucts are present the normal blood solution will be pinker, as the
CO does not combine to give a pink color with these foreign
substances.
When a poison causes solution of the red corpuscles (haemo-
lysis), or decomposes the haemoglobin beyond the methaemo-
globin stage, the haemoglobin is lost to the body, and "anaemia"
is one result of this, as well as jaundice. Thus chronic poisoning
by dinitrobenzol and similarly acting substances causes very seri-
ous anaemia. This also results from chronic poisoning by arsenu-
retted hydrogen, which has the peculiar action of injuring the
walls of the red corpuscles and so causing haemolysis, with re-
sulting haemoglobinuria, jaundice, and often nephritis. We are
thus brought to the consideration of the anoxaemia caused by
anaemia, the word "anaemia" being taken to mean simply a
diminution in the percentage of haemoglobin in a given volume
of blood, whether the blood volume itself is diminished, or normal,
or increased. As a matter of fact the blood volume is usually much
RESPIRATION 169
increased in "anaemia," as was first shown by Lorrain Smith. ^^
It was found by Miss FitzGerald that in ordinary cases of
anaemia there is no appreciable diminution in the alveolar CO2
pressure. ^^ As will be shown more fully in Chapter VIII, a chronic
arterial anoxaemia, however slight, invariably lowers the alveolar
CO2 pressure if time is given, and if the anoxaemia continues
during rest. The absence of a lowered alveolar CO2 pressure in
cases of anaemia is thus clear evidence of the absence of anox-
aemia, in spite of greatly diminished oxygen-carrying capacity of
the blood. It is evident, therefore, that the circulation rate is much
increased in anaemia and this inference is confirmed by the ab-
sence of cyanosis. A little consideration will show that this in-
creased circulation rate, while it serves to maintain the normal
oxygen pressure of the blood in the systemic capillaries, will prob-
ably not reduce too much the pressure of CO2 in the tissues. The
CO2 conveying power of the blood in the living body depends, as
shown in Chapter V, on the concentration of haemoglobin present
in the blood, and this concentration is greatly reduced in anaemia.
Diminution in the actual COo-conveying power of the blood in
the living body will therefore advance pari passu with the diminu-
tion of the oxygen-carrying power. Thus (as shown in Chapter
X) an increased circulation rate is brought about by the combined
stimulus of diminished oxygen pressure and increased CO2 pres-
sure. This is not so in the case of anoxaemia from defective satura-
tion of the haemoglobin in the lungs; nor, for the special reason
given above, in the anoxaemia of CO poisoning. The reason why
imperfect saturation of the arterial blood causes such serious
anoxaemia in the cerebrum and tissues elsewhere, while anaemia
causes so little anoxaemia (during rest) unless it is very extreme,
is probably bound up with this difference as regards effects on
CO2 pressure in the tissues. The matter will, however, be discussed
more fully in Chapter X.
The last cause of anoxaemia to be considered is that due prima-
rily to defective circulation; and it will be referred to very briefly
here, as the relation of circulation to respiration will be discussed
in Chapter X. When the blood pressure is very defective owing to
failure of heart action or failing supply of venous blood to the
heart, the inevitable result is failure in the general circulation rate,
and failure also in the proper distribution of blood within the body.
This must result in anoxaemia in the tissues, together with an
""^Lorrain Smith, Trans. Path. Soc. Lond., LII, p. 315.
^'^ Journ. of Pathol, and, Bacter., XIV, p. 328, 1910.
1 70 RESPIRATION
undue rise in their CO2 pressure. But owing to the combination of
these two conditions the fall in oxygen pressure and rise in CO2
pressure will both be moderate until the slowing of circulation is
excessive : for the oxygen will fall along the steep part of the
dotted curve in Figure 21, while the CO2 pressure will rise along
the thick line in Figure 26. This means that a great diminution in
the charge of oxygen in the haemoglobin, and consequently a very
considerable cyanosis, will be possible with a comparative small
fall in the oxygen pressure or rise in the CO2 pressure. Hence
cyanosis due to slowing of the circulation is not in itself such a
serious indication as cyanosis due to failing saturation of the blood
with oxygen, although of course indicative of possible more
serious failure of the circulation.
When fall of arterial blood pressure is due to defective filling
of the large veins leading to the heart, benefit may be expected
from the intravenous injection of suitable saline solution, as this
will tend to fill up the veins, and to bring about adequate filling
of the heart. A simple salt solution tends, however, to leak out
again very quickly from the circulation. To remedy this defect
Bayliss^''^ has introduced the plan of adding gum to the salt solu-
tion, the gum fulfilling the same function in preventing leakage
as the proteins normally present in blood plasma. This procedure
has proved very successful, and avoids the risks and practical
difficulties associated with transfusion of blood or liquids con-
taining proteins. For the reasons already pointed out, the dilution
of the blood by the saline injection does not cause anoxaemia.
As will be pointed out in Chapter X, failure in the venous return
to the heart may be due to deficient pressure of CO2 in the systemic
capillaries, owing to excessive washing out of CO2 in the lungs ;
and this excessive washing out may be secondary to arterial anox-
aemia. Arterial anoxaemia and deficiency of CO2 may also be the
i cause of failure of the heart muscle. It is probable, therefore, that
1 in many cases the vicious circle may be more effectively broken by
' administration of oxygen or even CO2 than by injection of gum^
j saline solution or transfusion of blood ; but in other cases injection
I or transfusion would quite clearly be required.
" Bayliss, Intravenous Injection in Wound Shock, 19 18.
CHAPTER VIII
Blood Reaction and Breathing.
It has been known for long that the reaction of blood to litmus
paper is always slightly alkaline, while the living tissues are also
alkaline, though they change to acid in dying. Knowledge as to the
connection between the blood reaction and normal breathing is,
however, mostly of very recent origin ; and the same may be said
of knowledge as to the extreme exactitude with which the reaction
of the blood is regulated, and the physiological importance of the
, very slightest deviation from the normal reaction of the blood
and tissues.
That the reaction within the body is physiologically regulated
was originally indicated, not only by the reaction of the blood to
I litmus and other indicators being always the same, but also by the
fact that on administration of sufficient doses of sodium bicarbon-
ate or other alkalies the urine, which is normally acid in man,
'„ becomes alkaline. The same effect is produced by a vegetable diet,
\ which contains a large amount of organic acids combined with
^ alkali. The acids are mostly oxidized with formation of CO2 within
' the bod}^ thus leaving alkaline carbonates, so that the excess of
alkali must be, and actually is, excreted in order that the reaction
within the body may remain normal. In herbivorous animals the
urine is always alkaline. On the other hand, in carnivorous ani-
mals, and in man with his usual mixed diet, the urine is acid. This
is because there is an excess of non-volatile acid formed within the
body by the oxidation of the sulphur, phosphorus, etc., in the
food constituents and this excess is partly, at least, got rid of by
the kidneys, and the normal alkalinity of the blood and tissues
thus preserved.
More than forty years ago an important series of investigations
bearing on the physiology of the blood reaction was carried out
under Schmiedeberg's direction at Strassburg. The effect on rab-
bits of the administration of large doses of dilute hydrochloric acid
was investigated by Walter,^ and it was found, as one result, that
the breathing of the animals was very greatly increased, becoming
extremely deep as well as more frequent — the same sort of effect
as is produced by excess of CO2, as shown in Chapter II. The
^F. Walter, Archiv f. exper. Pathol. PharmakoL, VII, p. 148, 1877.
172 RESPIRATION
animals also ultimately became comatose, just as is the case when
CO2 is in great excess ; and finally there were signs of exhaustion
of breathing, the breathing ceasing before the heart ceased to beat.
Another very important result reached in these investigations
was that when the experiments were repeated on dogs it was much
more difficult to produce the symptoms, and it was found that the
amount of ammonia excreted (in combination with acid) in the
urine was increased greatly. Under normal conditions the amount
of nitrogen excreted as ammonia is small in proportion to the total
excretion of nitrogen. Thus in man the amount of ammonia
usually excreted in 24 hours is only about 0.7 gram (sufficient,
however, to neutralize about 2 grams of H2SO4), so that only a
small fraction of the total nitrogen is excreted as ammonia. In
acid poisoning, however, the fraction becomes a very much
larger one in carnivorous animals and in man. Walter found that
in dogs the ammonia excretion could be pushed up to several
times the normal by giving large doses of acid.
According to the existing evidence, which originated with
Schmiedeberg and his pupils, ammonia is converted into urea in
the liver. It appears, therefore, that when acid is administered to
carnivorous animals or men, ammonia is not converted into urea,
or else nitrogen which normally appears as urea is converted into
ammonia and goes to neutralize the acid. If ammonia is admin-
istered by mouth as carbonate it is wholly converted into urea, and
the excretion of ammonia by the urine may be actually diminished.
If, on the other hand, the ammonia is administered in combination
with a strong acid as a neutral salt, much of this ammonia appears
as salts of ammonia in the urine. Some is, however, converted into
urea in the liver, as was recently shown definitely by perfusion
experiments.^ It was found that during health the proportion
of ammonia which escapes conversion into urea and consequently
appears in the urine depends on the acid-forming or alkali-
forming properties of the diet. Thus with a meat diet the pro-
portion of ammonia is much higher than with a vegetable diet;
and by administering alkalies ammonia may be made to disappear
entirely from the urine.
The varying neutralization of acids by ammonia is therefore
one of the means by which the reaction within the body is regu-
lated in man and carnivorous animals, while variation in the
excretion of acid or alkali in the urine is another. The former
means hardly exists in herbivorous animals. But the significance
'Loffler, Biochem. Zsitschr., LXXXV, p. 230, 19 18.
RESPIRATION 1 73
of the most rapid and effective method of all — varying excretion
of carbonic acid by the breathing — remained hidden till quite
recently, although Walter's experiments showed that there is not
only a great increase in the breathing, but the amount of carbonic
acid present in the arterial blood is reduced in extreme case to
about a twelfth of the normal.
It was discovered by von Jaksch^ in 1882 that where acetone
is present in the urine, as in bad cases of diabetes, verging on
coma, or actually comatose, considerable quantities of aceto-
acetic acid are also present; and soon afterwards Minkowski*
found that oxybutyric acid, a closely allied substance, is likewise
present. The excretion of ammonia had already been shown to be
greatly increased, as well as the depth of the breathing and the
acidity of the urine, just as in acid poisoning; and indeed it was
this that led Minkowski, and Stadelmann before him, to the
search for organic acids. Thus all the symptoms point to acid
poisoning by the acids mentioned. Shortly after Priestley and I
introduced our method of investigating alveolar air, Pembrey,
Beddard, and Spriggs investigated the alveolar air in cases of
diabetic coma at Guy's Hospital,^ and found the alveolar COg
percentage as low as 1. 1 per cent. It went up and down as
the patient emerged from or relapsed into coma; and the ad-
ministration of sodium bicarbonate warded off the attacks of
coma, and at the same time kept the alveolar CO2 percentage from
falling. Investigation of the alveolar CO2 pressure is now a well-
recognized clinical method for estimating the gravity of symptoms
in diabetic coma and other states of "acidosis," as well as for
judging of the effects of treatment.
For a long time the degree of alkalinity of the blood was judged
from the amount of acid which has to be added to a given volume
of it or its serum before an indicator, such as litmus, gives the tint
indicative of neutrality. By this method it was found that the
blood in acid poisoning or diabetic coma is less alkaline than
usual; and ail sorts of similar supposed "acidoses" have been dis-
covered, although the signs of physiological response to the pres-
ence in the body of too much acid might be more or less absent or
even contradictory. A few years ago, however, it became evident
that the amount of acid required for neutralization is no reliable
*Von Jaksch, Berichte der deutschen Chem. Gesellsch., p. 1496, 1882.
* Minkowski, Arch. f. exfer. Pathol. «. Pharmak., XVIII, pp. 35 and 147,
1884.
' Beddard, Pembrey, and Spriggs, Journ. of Physiol., XXXI, Proc. Physiol. Soc,
p. xliv, 1904; also XXXVII, p. xxxix, 1908.
1 74 RESPIRATION
measure of the blood alkalinity. Even a strong solution of sodium
bicarbonate is but feebly alkaline ; but the amount of acid which
must be added to it to render it neutral is as great as if the sodium
were present as caustic soda, and is thus no measure of the actual
alkalinity of the solution. The carbonic acid united with the soda
prevents it from being at all strongly alkaline, but at the same time
does not completely neutralize it, and all weak acids have the same
properties. They may thus be said to be "buffer" substances, since
they prevent a strong acid from neutralizing at once a weakly
alkaline solution. A great deal of the strong acid has to be added
before the weak alkalinity is neutralized. The same applies to weak
alkalies, mutatis mtUandis.
Now the blood and tissues are full of buffer substances. In the
first place, as already seen in Chapter V, carbonic acid is present
in combination. Haemoglobin and various other proteins are also
present ; and it has been well known for a long time that proteins
act as both acid and alkaline buffers, so that the neutral point in a
solution containing proteins is very difficult to ascertain sharply
by means of ordinary indicators. The color alters gradually in
either direction as the neutral point for any particular indicator
is approached. It was shown in Chapter V that in the alkaline
blood haemoglobin and other proteins act as weak acids more than
sufficient in amount to combine with the bases not already com-
bined with strong acids, and that the presence of these proteins
along with carbonic acid determines the manner in which the
alkali in blood takes up and gives off CO2 with varying partial
pressures of this gas. The amount of acid required to produce
neutrality is thus in itself no measure of the degree of alkalinity
in blood, but depends on the amount of the various buffer sub-
stances, including carbonic acid in combination with alkali; and
they may vary considerably in amount under different conditions.
This has been pointed out very clearly by L. J. Henderson.®
It may be desirable at this point to remind the reader as to the
conception of acidity and alkalinity to which chemical and physi-
co-chemical investigation has led during the last thirty years. The
phenomena of electrolysis revealed to Faraday the fact that the
constituents of any "electrolyte," such as copper sulphate, are
torn asunder during electrolysis into definite fragments, of which
one kind travels toward the anode, and the other to the cathode.
These fragments he called "ions," because it is their movement
towards either anode or cathode, and the fact that each of them has
•L. J. Henderson, Ergebn. ier Physiol., VIII, p. 254, 1909.
RESPIRATION
175
a definite electrical charge, that determines the phenomena of
electrolysis and the exact quantitative relationship between the
current passed through a cell containing an electrolyte in solution
and the splitting up of the electrolyte into its constituents. Van't
Hoff and Arrhenius brought Faraday's conception into relation
with osmotic pressure and various other phenomena connected
with solutions.
Osmotic pressure was first measured accurately by the botanist
Pfeffer.'^ He used a semi-permeable membrane (i.e., a membrane
which allowed the solvent water, but not the dissolved substance,
to pass) which had been originally discovered by Moritz Traube
in 1867,^ though Traube had not seen how to apply this membrane
for measuring osmotic pressures. Some years later van't Hoff^
made the brilliant discovery that in dilute solutions of sugar and
other substances, the osmotic pressure is practically the same as
the pressure which the solute would have if its molecules were
present alone in the gaseous form at the same temperature. There
must thus be a fundamental connection between molecular con-
centration, osmotic pressure, and gas pressure ; also between mo-
lecular concentration and the vapor pressures, boiling points and
freezing points of solutions, as had already been empirically shown
by the investigations in particular of Raoult. Van't Hoff believed
that osmotic pressure, etc., were due in some way to the molecular
bombardment of the solute molecules, and therefore vary as their
concentration per liter of solution ; and this theory has served for
the building up of the theory of solutions as it is still represented
in current textbooks of physical chemistry. In reality this theo-
retical interpretation was not even justified by PfefTer's data if
concentration per liter is considered, and breaks down entirely for
concentrated solutions. The theory is also quite unintelligible
mechanically, since the bombardment pressure of the solute mole-
cules would be in the wrong direction for explaining the phe-
nomena. Hence many persons regarded van't Hoff's theory with
the greatest suspicion ; but the fact that it seemed to answer ad-
mirably as a means of prediction in the case of dilute solutions,
and to cover an enormous mass of facts, has led to its very general
acceptance, though other attempts have been made to substitute
for it some more intelligible conception.
In 1918^^ I showed quite clearly, as I think, that van't Hoff's
Pfeffer, Osmotische U titer sue hungen, 1877.
'Traube, Archiv f. {Anat. u.) Physiol., p. 87, 1867.
• Van't Hoff, Zeitschr. f. physik. Chemie, I, p. 481, 1887.
"Haldane, Bio-Chemical Journal, XII, p. 464, 1918.
176 RESPIRATION
conception of osmotic pressure was mistaken. It is neither the con-
centration per liter of the solute molecules, nor that of the solvent
molecules, that determines osmosis, but the diffusion pressure
of the solvent. Water passes through a semi-permeable mem-
brane into a solution, because the diffusion pressure of pure water
is greater than that of the diluted water in the solution. The
osmotic pressure is not the excess of diffusion pressure of water
outside the solution, but the external mechanical pressure required
to equalize the two diffusion pressures, although in sufficiently-
dilute solutions this mechanical pressure is practically the same
as the excess of diffusion pressure of water.
In a solution, just as in a gas mixture, the molecules are free
to move about; and, just as in a gas mixture, the mean free
space round each molecule is the same because the mean energy
of external movement is the same for each molecule. Hence the
free space in which water molecules are free to diffuse is in pro-
portion to the total number per liter of molecules present. This
space is of course greater per molecule of solvent in a solution
than in the pure solvent. Hence the pure solvent diffuses into the
solution unless the external pressure on the solution is raised
sufficiently to equalize the two diffusion pressures.
When osmotic pressure, vapor pressures, boiling points, etc.,
are calculated in terms of this theory instead of van't Hoff 's theory,
the experimentally ascertained values agree with the theory,
whereas this is not the case, as is now well known, with van't
Hoff's theory, except in the case of very dilute solutions. Thus
for solutions of cane sugar, and allowing for the fact that at
temperatures near o°C. cane sugar is present in solution as a penta-
hydrate, the osmotic pressures at o°C. calculated from the con-
centrations on the new theory and the pressures actually observed
by the Earl of Berkeley and Mr. Hartley at Oxford are as follows :
OSMOTIC PRESSURE IN ATMOSPHERES
Grams Cane Sugar
Observed
Calculated
Calculated on
fer 100 cc.
van't Hoff's theory
3-32
2.23
2.24
2.17
959
6.85
6.85
6.29
18.26
14.21
14.17
11.95
25.81
21.87
21.80
16.90
28.13
24.55
24.44
18.41
54.24
67.74
67.66
35-48
RESPIRATION 1 77
The vapor pressures, boiling points, and freezing points of
sugar solutions show a similar agreement between observations
and the new theory, as pointed out in detail in my paper.
To physiologists the main advantage of the new theory is that,
as will be pointed out in detail in later chapters, it enables us to
utilize the kinetic theory of matter in unifying our conceptions
of a great number of physiological phenomena.
The osmotic pressures observed by Pfeifer and others for dilute
salt solutions were far greater than corresponded to van't Hoff's
theory. This became quite intelligible when Arrhenius pointed
out in 1887^-^ that the discrepancy could be cleared up on the as-
sumption that solutions of electrolytes are ionized to a greater or
less extent. Their osmotic pressures are not merely due to the
concentration (or, in terms of the new theory just referred to, the
diffusion pressure) of complete molecules of the solute, but also
to the concentrations of the ions present, as indicated by the vary-
ing electrical conductivities of different strengths of the solutions.
This explanation of Arrhenius was received at first with some
incredulity, but is now universally accepted, as the evidence in
favor of it is overwhelming. A dilute solution of sodium chloride,
for instance, is not now regarded as a solution of NaCl molecules,
but, practically speaking, of sodium and chlorine ions. Similarly
a dilute solution of hydrochloric acid is a solution of hydrogen and
chlorine ions.
Ionization may be regarded as a tearing apart of the molecules
of the electrolyte in solution on account of the molecular affinity
of H2O molecules for the atoms of the electrolyte molecules ; and
in accordance with this conception the ions are not stray atoms or
^other fragments of molecules, but molecular compounds with
molecules of water. In pure water itself the molecules are also to
a certain extent ionized, as indicated by, among other things, the
conductivity of pure water. The products of this ionization are
hydrogen and hydroxyl (HO) ions, combined with molecules of
water.
The acidity of a solution is due to preponderance of hydrogen
ions, and the alkalinity to preponderance of hydroxyl ions; and
when the concentrations of hydrogen and hydroxyl ions are equal
the solution is neutral. As, however, hydrogen and hydroxyl ions
are constantly reacting with one another according to the equation
H + HO ?± H2O,
the product of the concentrations of hydrogen and hydroxyl ions
"Arrhenius, Zeitschr. f. fhysik. Chemie, I, p. 631, 1887.
178 RESPIRATION
remains the same, in accordance with the law of mass action, how-
ever acid or alkaline a solution may be. Hence the concentration
of hydroxyl ions diminishes in proportion as that of hydrogen
ions increases, and vice versa.
All acids and bases combine with one another in chemically
equivalent proportions, but different acids and alkalies vary very
greatly in the extent to which they are ionized. The ''strengths"
of different acids and alkalies were found by the electrical con-
ductivity method to depend upon the extent of their ionization.
The "strong" acid HCl is, for instance, very completely ionized
into hydrogen and chlorine ions, and the "strong" base NaHO is
similarly ionized into sodium and hydroxyl ions; while "weak"
acids, such as carbonic acid, or weak bases, such as ammonia, are
very slightly ionized.
Water itself is slightly ionized into hydrogen and hydroxyl
ions, and can thus act as either a very weak acid towards bases or
a weak base towards acids. In the case of strong or highly ionized
acids and bases this property of water is practically of no account,
as the ionization of water is so very small ; but in the case of weak
acids or bases the water competes appreciably with the acid or
base. For instance in the case of potassium cyanide, a compound of
an extremely weak acid with a very strong base, the following re-
action occurs :
KCN + H2O ^ KOH + HCN.
Thus free KOH and free HCN are both present in a solution of
this salt. But the KOH is highly ionized into K and HO ions,
while the HCN is hardly ionized at all. Hence HO ions pre-
dominate, and the solution is alkaline. Carbonic acid is not such a
weak acid as hydrocyanic acid; but the same relations hold, so
that both carbonates and bicarbonates form solutions which are
distinctly alkaline; and bicarbonate solutions are still slightly
alkaline, even though much free carbonic acid is present, as in the
case of blood in the living body.
The ordinary indicators appear to be extremely weak acids
or bases which change color on combination. When the only
other acids or bases present are strong ones, the change of color
is of course very sharp ; but with other weak acids or bases present,
the change is gradual and the complete color change does not
occur until the solution is distinctly alkaline or acid. This is be-
cause the indicator competes with other weak acids for the base ;
and different indicators compete in varying degrees. Thus dif-
ferent indicators turn with different degrees of slight variation
RESPIRATION 1 79
from the true neutrality point where hydrogen and hydroxyl ions
are equal in concentration, as in pure water.
The relative diffusion pressures, or (to use the incorrect lan-
guage of the still generally accepted van't Hoff's theory of osmotic
pressure, etc.) the relative concentrations of any particular sort
of ion, in different solutions, can be measured by the differences
of potential communicated to a suitable electrode dipped in the
solutions. Thus with a hydrogen electrode hydrogen ion con-
centration can be measured directly; and this method was ap-
plied, soon after its discovery, to the measurement of the hydrogen
ion concentration (and therefore indirectly also of the hydroxyl
ion concentration) of blood. The earlier attempts gave the result
that the blood was neutral in reaction, and remained neutral even
in acidosis. The physiological signs of acidosis were, however,
very clear, as already explained. The electrometric method in its
earlier form was thus far too rough for physiological work.
It was mentioned in Chapter I that the experiments of Geppert
and Zuntz on the hyperpnoea following muscular contractions in
animals showed a great diminution in CO2 and a slight excess of
oxygen in the arterial blood during the hyperpnoea. They there-
fore concluded that neither excess of CO2 nor want of oxygen can
be the cause of the hyperpnoea ; and they sought for the cause in
some acid substance present in the blood, since acids were known
to stimulate the breathing. The search made for the acid substance
did not, however, lead to any definite result ; and the experiments
of Priestley and myself on man brought us back to CO2 as the
stimulus to the increased breathing. The improbability of any
organic acid being the stimulus to the breathing seemed to us to
be in any case very great. No acid other than CO2 is given off in
the expired air, and organic acids, etc., are not appreciably oxi-
dized in the blood itself. It did not therefore seem possible to un-
derstand how the air hunger of muscular exertion could be re-
lieved, as it undoubtedly is, by increased breathing. In any case
the diminished proportion of CO2 in the arterial blood in these
experiments was entirely discounted by the fact that this dimin-
ished proportion continued to exist for at least an hour after the
hyperpnoea had passed off. We thought that in Geppert and
Zuntz's experiments owing to defective circulation in the artifi-
cially stimulated muscles of the animal some lactic acid had been
produced and thrown into the blood, thus greatly reducing its
power of combining with CO2. Thus, although the pressure of
CO2 was perhaps actually higher in the arterial blood and caused
i8o RESPIRATION
hyperpnoea, the amount of CO2 contained in the blood was much
less. We also thought that owing to the diminished CO2 carrying
power of the blood there might be an increased rise of CO2 pres-
sure in the tissues. This explanation was, however, somewhat
strained and unsatisfactory, as was pointed out in Chapter II. We
had correctly divined the main cause of the greatly diminished
proportion of CO2 in the arterial blood in those experiments, but
not the whole cause.
In a series of experiments by Boycott and myself on the effects
of low atmospheric pressure in a steel chamber on the alveolar
CO2 pressure^^ we found that on returning from low pressure
the alveolar CO2 pressure, which had been lowered by the hyperp-
noea caused by the low atmospheric pressure, did not return at
once to normal, but remained low for some time. Ogier Ward,
who was working in conjunction with us, found the same thing
and in much more marked and persistent degree, on returning to
ordinary pressure after a stay on Monte Rosa.^^ Galleotti,-'^* and
also Aggazotti,-^^ had already found that the titration alkalinity of
the blood is diminished by exposure to low pressure in a steel
chamber or at high altitudes. It was also known from older experi-
ments made in Hoppe-Seyler's laboratory by Araki^^ that in con-
ditions of acute want of oxygen (CO poisoning, etc.) large quanti-
ties of lactic acid are produced in the body. Putting together all
these facts, and the results of Walter's experiments on acid poison-
ing, we drew the conclusion that what the respiratory center re-
sponds to is the combined effect of carbonic acid and other acids on
the reaction of the blood. It seemed no longer possible to maintain
the hypothesis that COg acts specifically in exciting the respira-
tory center. The long duration of the lowering of alveolar CO2
pressure after exposure to want of oxygen seemed intelligible on
the theory that excess of lactic acid had been produced owing to
the anoxaemia, and that the sodium or potassium lactate thus
formed had been excreted by the kidneys, thus robbing the body
of alkali and leaving the blood correspondingly less alkaline — a
deficiency which it required some time to make up.
This conclusion was further strengthened by the observation of
Douglas and myself, that after an excessive muscular exertion
" Boycott and Haldane, Journ. of Physiol., XXXVII, p. 355, 1908.
"Ogier Ward. Journ. of Physiol., XXXVII, p. 378, 1908.
"Galleotti, Arch. Hal. de Biol., XLI, p. 80, 1904.
"Aggazotti, Ibid,, XLIV, 1905.
"Araki, Zeitschr. f. fhysiol. Chemie, XV, p. 335, 1908; also XVI, p. 425;
XVII, p. 311; XVIII, p. 422.
RESPIRATION
I8l
the alveolar CO2 pressure remains low for about an hour.^*^ We
attributed this to the effect on the respiratory center of lactic acid
10 tS 20 25 30 3S 40 45 50 55 60 65 70 75
nun CO2
Figure 54.
© Blood, + Serum, O Corpuscles of same sample. 13 Blood,
X Serum of another sample. / Blood of another sample. Q
Another sample of blood. 0 Same sample with acetic acid added.
O 8 parts — NaaHPO* and 2 parts — KH2PO4. □ Equal
15 15
parts — Na^HPO* and KHjPO*. • — KCl solution.
15 10
given off into the blood by muscles in which the work had been
far in excess of the possible oxygen supply. The correctness of
"Douglas and Haldane, Journ. of Physiol., XXXVIII, p. 431, 1909.
1 82 RESPIRATION
this inference was shortly afterwards established by Ryffel/^ who
had meanwhile worked out a new and very convenient method of
determining small amounts of lactic acid in blood and urine.
The methods of determining hydrogen ion concentration in the
blood were at that time still too crude to permit of testing these in-
ferences by direct determinations, but shortly afterwards the elec-
trometric method was greatly improved by Sorensen and particu-
larly by Hasselbalch of Copenhagen. In 191 2 Hasselbalch and
Lundsgaard^^ published curves showing the variations of hydro-
gen ion concentration with variations in CO2 pressure at body
temperature in ox blood, and Lundsgaard^^ repeated the experi-
ments with human blood. Figure 54 shows graphically their re-
sults for blood and other liquids. For convenience* sake the results
for hydrogen ion concentration are plotted, not directly in terms of
gram molecules per liter, but in terms of the negative power of 10
representing this value. This mode of notation, introduced by
Sorensen, is represented by the symbol Ph, and since the negative
power increases with diminution of hydrogen ion, or increase of
hydroxyl ion concentration, the curve rises with diminution of
hydrogen ion concentration.
At body temperature the point of neutrality corresponds to a
Ph about 6.78, as indicated by the thick line in the figure. It will
be seen from the curves that even with a far higher pressure of
CO2 than exists in the living body the neutral point is not
reached. This is partly due to the fact that the proportional ioniza-
tion of carbonic acid becomes less and less with increasing con-
centration, just as is the case with other acids, including even
strong ones. The lower curve (for neutral potassium chloride solu-
tion) shows this clearly. Thus sulphuric acid when pure is quite
devoid of acid properties and does not attack metals, because it is
practically not ionized at all. This can be understood on the theory,
already alluded to, that ionization in aqueous solutions is brought
about through a reversible reaction with the water molecules.
The influence of a buffer substance (disodium phosphate) in
hindering changes of hydrogen ion concentration is shown very
strikingly in the two curves for phosphate solutions. In blood, as
already pointed out, various buffer substances, including haemo-
globin with other proteins, and the phosphate in the corpuscles,
are present. The curve for acidified blood shows that even when
"Ryffel, Journ. of Physiol., XXXIX, Proc. Physiol. Soc, p. xxix, 1910.
" Hasselbalch and Lundsgaard, Biochem. Zeitschr., XXXVIII, p. 77, 19 12.
*• Lundsgaard, Biochem. Zeitschr., XLI, p. 247, 1912.
RESPIRATION 183
blood is rendered distinctly acid these buffer substances still act
very efficiently. The haemoglobin acts as an alkali, whereas it
always acts as an acid in blood within the living body.
In order to test whether it is really to difference in Ph that the
respiratory center normall}'- reacts, Hasselbalch made the experi-
ment of altering the resting alveolar CO2 pressure by changing
the diet. A meat diet, consisting largely of proteins containing
sulphur and phosphorus which break down into free sulphuric and
phosphoric acid, is evidently an acid- forming diet as compared
with a vegetable diet, which contains less protein and a relative
abundance of salts of organic acids which break up in the body so
as to yield carbonates. Hasselbalch found that with the acid meat
diet the resting alveolar CO2 pressure was 4.4 mm. lower, and
then proceeded to compare the Ph of the blood in the two condi-
tions. The results were as follows :^^
Alv. CO2 Pressure Ph of blood Ph of blood at
mm. Hg. at 40 mm. CO2 existing alveolar
pressure CO2 pressure
Meat Diet 38.9 7.33 7.34
Vegetable Diet 43.3 7.42 7.36
It will be seen that at 40 mm. CO2 pressure the blood sample
taken with the meat diet was distinctly more acid than with the
vegetable diet, but that at the existing alveolar CO2 pressure the
two values for Ph were identical, at least within the limit of ac-
curacy of the method of measurement. Hence the respiratory
center had regulated the alveolar CO2 pressure in such a manner
as to keep the Ph of the blood almost constant.
There is other evidence pointing in the same direction. Barcroft
found that on ^he Peak of Teneriffe the dissociation curve of
human blood appeared to be normal, provided that the curve
was investigated, not at the normal sea level alveolar CO2 pressure
of about 40 mm., but at the existing resting alveolar COg pres-
sure.22 We got a similar result at a greater height on Pike's
Peak,^^ as did also Barcroft and his co-workers on Monte Rosa.^*
'^Hasselbalch, Biochem. Zeitschr., XLVI, p, 416, 19 12.
"Barcroft, Journ. of Physiol., XLII, p. 44, 191 1.
"Douglas, Haldane, Henderson, and Schneider, Phil. Trans. Roy. Soc, (B)
203, p. 201, 1913.
"See Chapter XVII, of Barcroft, The Respiratory Function of the Blood, 1913.
1 84 RESPIRATION
As already pointed out this curve is shifted to the right or left with
varying alkalinity, and the shifting is a moderately delicate index
of the variation (Chapter III). Peters,^^ working with Barcroft,
has shown that the shifting with variations in CO2 pressure de-
pends on the shifting of Ph. Hence the constancy of the dissocia-
tion curve appeared to be a direct index of the constancy in Ph of
the blood. The lowering of alveolar CO2 pressure at high altitudes
seemed therefore to be just sufficient to keep the Ph of the blood
steady in so far as direct methods enable us to measure the degree
of steadiness. As will be seen below, however, there is physio-
logical evidence that the blood is actually more alkaline at high
altitudes. More recently Hasselbalch and Lindhard have made
direct electrometric measurement, of Ph in a steel chamber after
exposure of sufficient duration to the low pressure, and their
measurements give practically the same result.^^ The resting al-
veolar CO2 pressure on Pike's Peak was about 27 mm., or 13 mm.
below that at sea level. Raising the alveolar CO2 pressure on Pike's
Peak to 40 mm. would have caused the extremest panting.
As soon as the results of Hasselbalch and Lundsgaard were
published, it was possible to estimate quantitatively the delicacy
with which the respiratory center responds to variations in the
reaction of the blood : for the delicacy of the reaction of the center
to variations of CO2 pressure was known from our previous ex-
periments, while the curves of Hasselbalch and Lundsgaard made
it possible to convert variations of CO2 pressure into variations of
Ph in the blood. Some confusion arose, however, owing to the
fact that Lindhard,^"^ and Hasselbalch and Lindhard,^^ had mean-
while published experiments which seemed to indicate that the
respiratory center in man is commonly far less sensitive to COg
than Priestley and I had found. The matter was therefore rein-
vestigated by Campbell, Douglas, Hobson, and myself.^^ We
found that the Danish observers had been deceived, owing to a
faulty modification of the method of sampling the alveolar air.
The fresh experiments gave practically the same results as Priest-
ley and I had obtained, so we could make the calculation accord-
ingly.
A rise of 0.2 per cent or 1.5 mm. in the CO2 pressure of the
Barcroft, The Respiratory Function of the Blood,, p. 316, 1913.
** Hasselbalch and Lindhard, Biochem. Zeitschr., 68, p. 293, 19 15.
"Lindhard, Journ. of Physiol., XLII, p. 337, 191 1.
"Hasselbalch and Lindhard, Skand. Arch. f. Physiol., XXVIII. 191 1.
"Campbell, Douglas, Haldane, and Hobson, Journ. of Physiol., XLVI, p. 301,
1913-
I
RESPIRATION 1 85
alveolar air and arterial blood causes an increase of about 100 per
cent in the resting alveolar ventilation, and from Figure 54 it
will be seen that this corresponds to a difference of .012 in Ph.
This difference, large as its physiological effect is, cannot be de-
tected with certainty by the electrometric method, or by indicators,
and is quite undetectable by the shifting of the dissociation curve
of oxyhaemoglobin. Nevertheless a twentieth of this difference
would produce an easily measurable effect on the breathing or
alveolar CO2 pressure. The astounding delicacy of the regulation
of blood reaction is thus evident. No existing physical or chemical
method of discriminating differences in reaction approaches in
delicacy the physiological reaction. Unfortunately, however, the
quantitative significance of our calculation has not yet been ap-
preciated. The blood within the living body is still treated as if
its reaction were not only variable, during rest, as it is, but capable
of showing the variations by the existing very rough chemical and
physical reactions. One might as well try to cut delicate histo-
logical sections with a blunt carving knife, as try to demonstrate
ordinary very minute changes in blood reaction by the existing
physical and chemical methods.
It was discovered by Christiansen, Douglas, and myself, as
previously set forth, that the reduction of oxyhaemoglobin, as
this occurs in the course of the circulation, has an effect re-
sembling that of the addition of alkali to the blood. Thus the
CO2 pressure of the blood in the systemic capillaries is pre-
vented from rising nearly as high as it would otherwise do. The
hydrogen ion concentration of the blood is also prevented from
rising in correspondence with the actual greatly restricted increase
in CO2 pressure. Accordingly the actual increase of hydrogen ion
concentration in mixed venous as compared with arterial blood
must be very small. In this way the extraordinarily delicate regu-
lation of the reaction of arterial blood becomes much more intelli-
gible, as venous blood must be very little less alkaline than arterial
blood. In determining the hydrogen ion concentration of blood by
the ordinary electrometrical method it is necessary to reduce the
blood first, as the presence of oxygen interferes with the action of
the hydrogen electrode. ^^ Thus the determination is made on re-
duced, or by Barcroft's method on partially reduced, blood, but
with a CO2 pressure corresponding to that of arterial blood. It is
'"Peters, Journ. of Physiol., 48, Proc. Phys. Soc, p. vii, 19 14. It is probable
that owing to incomplete reduction the values obtained by Hasselbalch have been
slightly too low.
1 86
RESPIRATION
evident, therefore, that the value obtained for the hydrogen ion
concentration is lower than that which exists in either arterial or
venous blood in the living body. To investigate the amount of this
difference Parsons*^ adopted the method of determining the hy-
drogen ion concentration, not in whole blood, but in its serum, of
which the hydrogen ion concentration is not altered when free
oxygen is removed. Using this method, he found that with normal
blood the Ph at a constant pressure of CO2 at anywhere near the
alveolar CO2 pressure is greater by .038 in the oxygenated than
the reduced blood. Figure 55 show his results. From them and
6.^
65
64-
85
82
8/
&0
79
78
77
7.6
75
7-4
73
72
t
.
I
\
\
I
\
^.
s\
V
^
i,.
:^
N.
p*
>k
r^
r^
^
■^
^^
r>^
--H
^
^
^
-A
PiP/="S"5
C/jOA
^
/7- /"/
0 /Aj
' AAA
4 f-/r.
JS.
-rt
^0
^
'' , r
„
— I
10
20
50
60
70
80
30 40
Figure 55.
Curve R, completely reduced blood. Curve O, fully oxygenated
blood. X, direct measurements on reduced blood without removal of
corpuscles. H, Hasselbalch's curve.
from Figure 26 (Chapter V) it is possible to calculate what
the difference for normal blood between the Ph of arterial and
mixed venous blood is, assuming that the venous blood has lost
a certain proportion of its oxygen and simply gained a corre-
sponding proportion of COg. If the venous blood had lost all its
"Parsons, Journ. of Physiol., LI, p. 440, 19 17.
RESPIRATION 1 87
oxygen the difference would be .07, as shown in Figure 56 from
Parsons's paper. Assuming, however, that the mixed venous blood
loses normally a fourth of its combined oxygen (see Chapter X),
the difference is only .0175 — a difference which can hardly be
detected except by physiological methods, and which corresponds
to a rise of only 0.3 per cent in the alveolar CO2 percentage.
It might be supposed that in order to obtain the true Ph of
arterial blood under abnormal conditions all that is necessary is to
add a constant to the value obtained for reduced blood ; and that
consequently the ordinary methods of determining Ph (whether
electrometrically or from indications given by the dissociation
7-6
7-5
7-3
7-2
7-/
^.."X
^
^0
\
■">
NT
_\
Nc
\
1
\
^
"--
TOTAL CO, CONTENT(c.<:f^^^^^ qF BLOOD
Figure 56.
The slope of the line AC shows the rate at which the Ph
of blood increases as its content of COa increases in the
capillaries.
curve of oxyhaemoglobin) give reliable indications of any altera-
tion in the Ph of the arterial blood. There is, however, no evidence
at present that this is the case, and there is in fact other evidence
pointing in the opposite direction.
If, in the first place, the proportion of haemoglobin in the blood
is altered, there will presumably be an alteration in the difference
between the Ph of fully oxygenated and of reduced blood. Apart
altogether from this, however, there may be another kind of al-
teration in this difference. In the paper by Christiansen, Douglas,
and myself, it was pointed out that the probable reason why re-
duced blood appears to be more alkaline than oxygenated blood
is that on reduction the haemoglobin becomes more aggregated
and therefore acts less strongly as an acid. In abnormal blood the
degree of increased aggregation may be either increased or di-
minished. This will alter the difference in Ph between oxygenated
and reduced blood, and will also, if our theory as to the cause of
1 88 RESPIRATION
the peculiar shape of the dissociation curve of the oxyhaemoglobin
in blood is correct, alter the shape of the dissociation curve.
In a quite recent paper Lovatt Evans^^ has shown that the Ph
of blood as determined colorimetrically by an indicator method
is as much as 0.2 higher than when determined electrometrically.
He has also shown pretty conclusively that the electrometric
method has an error owing to the formation of formate from
carbonate by catalytic action at the electrode, so that the Ph of
blood is higher by 0.2 than appears from the electrometric de-
terminations. The new colorimetric method of Dale and Evans^^
seems to avoid several defects inherent in the electrometric method
as applied to blood.
On the existing evidence, and allowing for mistaken inferences
which have been drawn in ignorance of the peculiar properties of
haemoglobin (as it exists in the red corpuscles) in regulating the
Ph of blood, it seems evident that during health the regulation
of the reaction of the arterial blood is carried out with a delicacy
and constancy of which we can at present only obtain a real con-
ception by physiological observations. The foregoing discussions
show that there are at least three regulators of the reaction — the
lungs, the kidneys, and the liver. We can also now form a general
conception of how these regulators act under ordinary conditions.
The part played by the lungs in this regulation is, quite clearly,
to deal rapidly with variations in reaction due to varying pro-
duction of CO2, and particularly to the rapid variation caused by
varying muscular exertion. By keeping the alveolar CO2 pressure
approximately normal, the action of the lungs keeps the arterial
CO2 pressure approximately normal ; and so long as the dissocia-
tion curve for CO2 in the blood is also kept normal by other means
the reaction of the arterial blood is also kept almost exactly
normal. If, however, owing to rapid production of lactic acid in
muscles, rapid secretion of gastric or pancreatic juice, or other
causes, the dissociation curve for CO2 is temporarily disturbed, the
breathing compensates approximately at once for the disturbance
in blood reaction.
The part played by the kidneys seems also clear. They not only
respond to the minutest variations in blood alkalinity by secreting
more acid or more alkaline urine, but also tend to keep normal the
proportion of soda and potash and other crystalloid substances
existing in the blood. In this way the dissociation curve of the COj
"Lovatt Evans, Journ. of Physiol., LIV, p. 353, 1921.
"Dale and Evans, Journ. of Physiol., LIV, p. 167, 1920.
RESPIRATION 189
in blood is kept normal ; and no physiological phenomenon is more
striking than the constancy of this curve under normal conditions.
If the proportion of available alkali is temporarily diminished
by acid poured out into the blood, the kidneys help to restore it
to normal again ; and similarly with excess of alkali. The action
of the kidneys is slow compared with that of the lungs; but is
apparently still more delicate. As L. J. Henderson was the first to
point out clearly^* the Ph of urine is no measure of the total acid
excreted in it, since urine, like blood, contains buffer substances.
Among these phosphoric acid plays the main part in acid urine,
and carbonic acid in alkaline urine. To measure the acid excreted
titration must be employed, and in titrating alkaline urine the
combining CO2 must be allowed to escape.^°
The part played by the liver is to neutralize as far as possible
the disturbing effect of any excess of acid or of alkali introduced
into the body through the intestines, or formed in the tissues. By
allowing more, or less, ammonia to enter the circulation the
liver regulates the reaction of the blood ; and the neutral ammonia
salts are afterwards eliminated by the kidneys as being foreign
substances. The importance of the part played by the liver under
normal conditions is evident enough in view of the fact that in
man the ammonia excreted daily would just about suffice to neu-
tralize all the sulphuric acid formed daily. Like that of the kid-
neys, the action of the liver is slow and delicate as compared with
that of the lungs.
Possibly the intestines also play an active part in regulating
the blood reaction. It is known, at any rate, that alkali may be
eliminated from them in the form of insoluble alkaline phosphates.
We have now to consider how this joint regulation behaves
when the action of one of the regulators is interfered with; and
the case of interference with the lung regulation will be considered
first. This regulation may be disturbed in various ways, but per-
haps most is known at present as to its disturbance owing to the
fact that under abnormal conditions the stimulus of anoxaemia in-
creases the breathing, and thus disturbs the normal relation be-
tween the lung ventilation and the degree of stimulus of the
respiratory center owing to varying reaction of the arterial blood.
The history of the development of knowledge on this point is very
instructive.
"L. J. Henderson, Amer. Journ. of Physiol., 21, p. 427, 1908.
"Davies, J. B. S. Haldane, and Kennaway, Journ. of Physiol., LIV, p. 32,
1920.
IQO
RESPIRATION
It has already been shown in Chapters VI and VII that until
the oxygen pressure of the inspired air is lowered by about a third,
or that of the alveolar air to about half (i.e., from about lOO mm.
to 50 mm.) there is no marked immediate increase in the breath-
ing. The effect on the respiratory center of the very distinct degree
Attihide
750 700 650 600 560 500 450 400 550 ZOO 2SO 20O
Gas pressure
■mm.cf 800
mercwy
in Ft
120
too
300 7SO 100 650 6O0 550 500 4SO 400 3SO 300 250 20O
Atmospheric pressure in mm. of mercury.
, Figure 57-
Alveolar gas pressures in relation to barometric pressure or altitude.
of anoxaemia which is undoubtedly produced, in the manner ex-
plained in Chapter VII, is almost entirely masked by the con-
trary effect due to extra washing out of CO2 and consequent
lowering of the Ph in the arterial blood. But if exposure to the
lowered oxygen pressure is continued, not merely for perhaps an
hour, but for days or weeks, there is a quite marked increase in
RESPIRATION 191
the breathing, as shown by a fall in the alveolar CO2 pressure.
This fact, already referred to in connection with the historical
development of the theory of regulation of the breathing by the
blood reaction, was brought out in full clearness by the investiga-
tions carried out in connection with the Pike's Peak expedition
by Miss Fitz Gerald on persons fully acclimatized at different
altitudes.^® Figure 57 represents graphically her results on this
subject. It will be seen that in such persons the alveolar CO2 pres-
sure falls regularly with increase of altitude. In other words the
breathing increases in a regular ratio with diminution in the oxy-
gen pressure of the inspired air.
What is the cause of this increase? Since the experiments,
already referred to, of Boycott, Ogier Ward, and myself, it has
been pretty generally assumed that in response to the stimulus of
anoxaemia a slight acidosis, sufficient to account for the increased
breathing, develops in the blood. This explanation received strong
confirmation from the discovery by Barcroft in the Teneriffe
experiments that the dissociation curve of the oxyhaemoglobin of
the blood at high altitudes is sensibly the same in presence of the
existing alveolar CO2 pressure as at sea level in presence of the
alveolar CO2 pressure existing there. The extra acid, or dimin-
ished available alkali, present in the blood seemed just to compen-
sate for what would otherwise be increased alkalinity due to the
lowered CO2 pressure. The physiological facts, however, do not
correspond with the lactic acid theory. Moreover no excess of
lactic acid could be discovered by Ryffel in the urine and hardly
any in the blood, of persons exposed to low pressures in a respira-
tion chamber or steel chamber,^"^ or indeed in persons at high
altitudes ;^^ and no other abnormal acid could be discovered in the
blood. Hence the theory of an acidosis due to formation of ab-
normal acids cannot be substantiated. In the report of the Pike's
Peak Expedition we adopted the theory that the anoxaemia alters
the activity of the kidneys in such a way that they regulate the
blood to a lower level of alkalinity.
Another, and essentially similar, theory was adopted by Has-
selbalch and Lindhard as the result of experiments in a steel
chamber. ^^ They found that the excretion of ammonia is markedly
'' FitzGerald, Phil. Trans. Roy. Soc, 203 (B), p. 351, 1913; and Proc. Roy.
Soc, 88 (B), p. 248, 1914- See also, Yandell Henderson, Journ. of Biol. Chem.,
1920.
"Ryffel, Journ. of Physiol., XXXIX (Proc. Physiol. Soc), p. xxix, 19 lo.
^' See Barcroft, The Respiratory Function of the Blood,, p. 260.
'* Hasselbalch and Lindhard, Biochem. Zeitschr., 68, p. 295, 1915.
192
RESPIRATION
diminished at the lowered pressure, and were thus led to the theory
that the acidosis of high altitudes is due to diminished formation
of ammonia by the liver as a consequence of anoxaemia.
The question was again taken up in a series of experiments in
steel chambers by Kellas, Kennaway, and myself, in which care-
ful measurements were made of the excretion of acid and am-
monia.*^ We found that even with a comparatively slight diminu-
tion of pressure there was a great diminution in the excretion of
acid and ammonia, and the urine passed to the alkaline side of
neutrality. The true explanation of the supposed acidosis then
revealed itself to us. The kidneys and liver were responding quite
normally, but to an alkalosis, this alkalosis being produced by the
increase (largely masked) of breathing caused by the anoxaemia.
A similar view of the supposed acidosis of high altitudes was
reached, on independent grounds which will be discussed below,
by Yandell Henderson.*^
The increased excretion of alkali and diminished formation of
ammonia lead gradually towards a compensation of the alkalosis
and simultaneous relief of the anoxaemia, this relief being due to
the increased oxygen supply to the lung alveoli, and to other
causes discussed in Chapters IX and X. But the final result is a
compromise. A certain small degree of anoxaemia and consequent
alkalosis still remains, as evidenced by a continued low excretion
of ammonia and other physiological symptoms and by the fact
that on removal of the anoxaemia there is a quite appreciable
immediate rise in the alveolar CO2 pressure, as was shown for
instance, when we breathed air enriched with oxygen after we had
become acclimatized on Pike's Peak. The extra excretion of alkali
comes to an end, however, as the kidneys cannot reduce the blood
alkali further without very serious alteration of the normal balance
of salts in the blood.
The supposed acidosis is thus not an acidosis at all, but the in-
complete compensation of an alkalosis. The "adaptation" of the
blood so as to relieve the alkalosis and anoxaemia is also nothing
but an extension of the everyday adaptations by which alkalosis
and anoxaemia are continuously being prevented. The reason why
the adaptation takes so long at low atmospheric pressures is simply
that it takes a long time for the kidneys and liver to get level with
the very prolonged and considerable work thrown on them by
progressive increase in the breathing. They are, as it were, pursu-
*" Kellas, Kennaway, and Haldane, Journ. of Physiol., LIII, p. i8i, 1919.
"Yandell Henderson, Science (N. S.), XLIX, p. 431, 1910; see also the series
of papers by Henderson and Haggard, Journ. of Biol. Chem., 1919.-1921 incl.
RESPIRATION 193
ing in a leisurely manner a goal which is constantly receding from
them, so that it is a long time before they finally reach it. The
quantity of alkali which has to be removed from the blood and
tissues is very large, as a simple calculation will show.
With the compensation of the alkalosis there also comes com-
pensation of any secondary anoxaemia caused by the alkalosis as
a consequence of the Bohr effect discussed so fully in Chapters IV
and VI. Owing to the increased breathing the percentage satu-
ration of the arterial blood is (without any allowance for increased
oxygen secretion) as high as at first, while the oxygen pressure in
the systemic capillaries is higher (i.e., nearer normal) on account
of the decreased alkalosis. Cyanosis may be, however, quite as
marked as before. By the administration of acid the adaptation
to a lowered oxygenation of the arterial blood could doubtless
be hastened.
The study of responses to the anoxaemia and alkalosis of high
altitudes is of great medical interest, since, as already explained
in the two preceding chapters, anoxaemia is a very common and
often extremely dangerous clinical condition. There can be no
doubt that the same responses as occur in healthy persons at
high altitudes occur also in patients suffering from anoxaemia. It
is therefore important not to misunderstand these responses.
During the war, for instance, the intensely dangerous anoxaemia
of acute gas poisoning and ''shock" was sometimes treated by the
administration of alkalies, on the theory, based on nothing but the
unintelligent use of a new method of blood examination, that the
patients were suffering from "acidosis." Physiological knowledge
as to the deadly significance of serious anoxaemia, and the (sup-
posed) acidosis as an adaptive change tending towards its com-
pensation, was ignored. It is also important to understand that the
adaptive changes require time, and that so-called palliative treat-
ment, by giving this time, may in reality be curative.
Another cause of interference with the lung regulation of blood
reaction is to place an animal or man in an atmosphere in which
the percentage or pressure of CO2 is so high that the regulation
breaks down completely and there is in consequence an excessive
and lasting fall in the Ph of the blood. This condition was studied
recently in animals by Yandell Henderson and Haggard.*^ They
made the very important and significant discovery that the acido-
sis thus produced gradually brings about a marked increase in the
*" Yandell Henderson and Haggard, Journ. of Biol. Chem., XXXIII, p. 333,
1918.
194 RESPIRATION
capacity of the blood for combining with COg. In other words the
dissociation curve of the CO2 in blood, if plotted as in Figure 25,
would occupy a higher position. This is evidently a change tending
to counteract the diminished blood alkalinity produced by the
excess of COg.
The same observers found that on prolonged and forced arti-
ficial ventilation of the lungs, so as to produce a condition of al-
kalosis, there is a corresponding diminution in the capacity of the
blood for combining with CO2. This is also a change towards
the normal alkalinity. Thus in an alkalosis produced by excessive
\ removal of CO2 the av^ailable alkali in the blood diminished, while
'' in an acidosis produced by excess of CO2 the available alkali
increased. It is clear that in either case the change is of a character
tending to neutralize the change in blood reaction.
What is the significance of this change? It occurs much too
quickly to be capable of explanation as due to an adaptive re-
sponse by the kidneys and liver. The probability is, therefore, that
it is due to exchange of anions between the tissues and blood in
the manner discussed in Chapter IV (Addendum), and is indica-
tive, therefore, of very severe alkalosis or acidosis of the tissues.
This would help to account for the very dangerous symptoms
which Henderson and Haggard found to be an accompaniment of
any considerable diminution of the available alkali of the blood,
when the diminution was produced by excessive artificial respira-
tion. Thus a diminution of about 40 per cent in the capacity of
the blood for combining with CO2 was fatal to the animal. A
similar diminution due to the acidosis caused by running quickly
up a stair is hardly felt at all. In the latter case the diminution in
available alkali in the blood indicates a quite trifling acidosis,
while in the former a similar change in the blood indicates a
severe and fatal alkalosis.
These and other experiments*^ of these investigators brought
out in a striking manner that it is a complete mistake to regard
diminution of the available alkali (or so-called "alkaline reserve")
of the blood as a definite sign of acidosis in the living body. The
"alkaline reserve" of the blood and whole body is only another
name for its "titration alkalinity" ; and it has already been shown
above that titration alkalinity is no measure, and not even a sure
qualitative indication, of the real alkalinity of the blood. In the
experiments of Yandell Henderson and Haggard the animals were
"Haggard and Henderson, Journ, of Biol. Chem., XXXIX, p. 163, 19 19;
and XLIII, pp. 3, 15, and 29, 1920.
RESPIRATION 195
suffering from severe alkalosis although the ''alkaline reserve" or
titration alkalinity of their blood was greatly diminished; and
similarly they were suffering from severe acidosis although the
"alkaline reserve" of their blood was greatly increased.
It was these observations that led Yandell Henderson to the
same conclusion which we reached — namely, that in the anoxae-
mia of high altitudes there is a condition of alkalosis, and not of
acidosis, in spite of the greatly reduced titration alkalinity or
"alkaline reserve" of the blood.
A ready method of interfering temporarily with the regulation
of blood reaction by the lungs is forced breathing. This can be
continued for a considerable time if it is employed in moderation.
Leathes** found that if forced breathing is continued for some
time the urine becomes alkaline to litmus, and the titration alka-
linity has still more recently been investigated by Davies, J. B. S.
Haldane, and Kennaway.^^ The titration alkalinity is, however,
not so striking as after a large dose of sodium bicarbonate has been
taken. The same observers found that after a large dose of sodium
bicarbonate there was not only a rise of as much as I per cent in the
alveolar CO2 pressure for some hours, but the available alkali in
the blood (as shown by the dissociation curve for CO2) was
markedly increased, while there was also a great increase in the
titration alkalinity of the urine. Large quantities of bicarbonate
(readily determined by the blood-gas apparatus) were present in
the urine, which effervesced briskly on the addition of acid, though
the actual alkalinity of the urine was of course only feeble, since
the CO2 acted as a buffer. The titration alkalinity (after removal
of liberated CO2) was equivalent to nearly i per cent of HCl. The
ammonia had completely disappeared from the urine, and this
was also the case after forced breathing, although such a degree
of forced breathing as was practicable did not appreciably dimin-
ish the available alkali in the blood within one and one-half
hours. A stay of several hours in air containing 5 to 6 per cent of
CO2 was also not sufficient to increase appreciably the available
alkali of the blood, although the titration acidity of the urine was
increased, along with increased excretion of ammonia. Collip has,
however, found that, as might be expected from the change in
distribution of acid and alkali between plasma and corpuscles
** Leathes, Brit. Med. Journ., Aug. 9, 1919.
"Davies, J. B. S. Haldane, and Kennaway, Journ. of Physiol., LIV, p. 32,
1920.
196 RESPIRATION
when the Ph of blood is altered, the alkaline reserve of the plasma
was distinctly diminished by forced breathing.^^
The blood reaction may, of course, be disturbed in other ways
than by interference with respiration. One of these ways is by
ingestion of acids or by production within the body of great ex-
cess of some organic acid. Walter's experiments, interpreted in
the light of our present knowledge, showed the effects of acid
poisoning in stimulating to the utmost all the means of diminishing
acidosis, including excessive breathing, greatly increased forma-
tion of ammonia, and secretion, presumably, of an abnormally
acid urine. The titration alkalinity or "alkaline reserve" of the
blood and doubtless also of the whole body was evidently dimin-
ished very greatly.
Christiansen, Douglas, and Haldane produced a temporary true
acidosis by flooding the blood with lactic acid produced by mus-
cular anoxaemia during the heavy exertion of running several
times upstairs. In this case two results followed. In the first place
there was a fall in the resting alveolar CO2 pressure, which was,
in several experiments, about 39 mm. before the exertion, and
30.5 mm. about 10 minutes after the exertion. The blood absorbed
about 49 volumes of CO2 per 100 of blood before the exertion in
presence of the existing alveolar CO2 pressure, and only about
28 afterwards. After one and one-half hours both the resting
alveolar CO2 pressure and the absorbing power of the blood for
COo had returned to normal.
In these experiments the capacity of the blood for absorbing
CO2 at a CO2 pressure of 40 mm. had been reduced by about 40
per cent, and the resting alveolar CO2 pressure by about 20 per
cent, corresponding to an increase of about 25 per cent in the
lung ventilation. There was thus a very distinct acidosis ; but ref-
erence to the calculations already made will show that the acidosis
could not have been detected by any existing method of directly
estimating hydrogen ion concentration.
The great drop in the capacity of the blood for combining with
COo suggests at first that the blood had become correspondingly
inefficient as a carrier of CO2 from the tissues to the lungs, and
that this deficiency could only be made up by a greatly increased
circulation rate, if it was made up at all. The truth, however, is
that the main difference produced was that the dead weight of
CO2 always carried round by the blood was greatly diminished.
As a carrier of CO2 from the tissues to the lungs, the blood was
*'^ Amer. Jotirn. of Physiol., LI, p. 568, 1920.
RESPIRATION 197
nearly as efficient as normal blood. This is due to the fact that, as
already explained in Chapter V, the haemoglobin and other pro-
teins play the essential part in the actual conveyance of CO2 from
the tissues to the lungs, and can still play this part in spite of what,
in a physiological sense, is extreme acidosis.
The experiments were practically a replica in man of the ex-
periments of Geppert and Zuntz on muscular activity in dogs
(Chapter I). In discussing these experiments Priestley and I were
not aware that a very great diminution of the CO2 content of the
blood may be caused by acidosis without any serious diminution
in the capacity of the blood for conveying CO2 from the tissues to
the lungs. The discovery made in 19 14 by Christiansen, Douglas,
and myself has greatly altered the previously existing ideas as to
the conveyance of CO2 from the tissues.
The comparatively rapid recovery of the blood after the flood-
ing of the body with lactic acid was evidently due to the fact that
lactic acid was rapidly oxidized before the slight acidosis actually
produced had time to cause any considerable extra excretion of
acid by the kidneys, or formation of ammonia by the liver. Had
the acidosis been produced by a mineral acid it would probably
have taken far longer to pass off.
Disturbance of the blood reaction may be artificially produced
by the ingestion of acids or alkalies, or even, to a slight extent, by
varying the character of the diet. It requires a very large amount
of acid or alkali to produce any considerable disturbance. This is
partly due to the abundance of buffer substances in the body, but
still more to the effective means (variations in lung ventilation,
ammonia formation, and excretion of acid or alkali by the kid-
neys) which the body possesses of active defence against dis-
turbance of reaction. If the administration of acids or alkalies is
used medicinally as a means of assistance in the regulation of the
blood reaction, the large doses required must be borne in mind.
Small doses cannot but be practically useless. The amelioration of
the physiological symptoms of acidosis or alkalosis will form the
safest guide to what is required; but it is evidently very important
not to mistake alkalosis for acidosis, or the hyperpnoea of acidosis
for the abnormal breathing caused by anoxaemia or an exhausted
or "neurasthenic" respiratory center. There are no short cuts to
decisions on such a subject. A physician must be a real physician,
and must have learned to be one by study of how the living body
behaves — of what its <Awrts is, to use the old expression of Hip-
pocrates.
198 RESPIRATION
As the kidneys are essentially concerned in the regulation of the
reaction within the body, it is evident that failure of the kidneys
may cause serious disturbance of reaction. As, moreover, normal
human urine is acid, and presumably is so in all animals if food is
not taken, the disturbance will naturally be in the direction of
producing acidosis. Hyperpnoea and other symptoms suggestive
of acidosis are commonly met with as an accompaniment of serious
inflammation of the kidneys; and these symptoms are now com-
monly attributed to acidosis. One peculiarity of them is that there
may be little or no increase in the ratio of ammonia to total nitro-
gen excreted.
Considerable new light is thrown on the causes of acidosis by
quite recent experiments of J. B. S. Haldane.^''^ The experiments
consisted in taking large doses of NH4CI during two or three
days, so that an abnormal percentage of ammonia was present in
the blood. As a result there were very pronounced respiratory
and other symptoms of acidosis, including a marked fall in the
available alkali of the blood. Owing to the excess of ammonia in
the blood part of the ammonia of the NH4CI had been converted
into urea, setting free much HCl into the blood. The normal
response in which the liver sets free ammonia into the blood on
the approach of acidosis was of course reversed, and though the
urine was very acid the kidneys were unable by themselves to
cope effectively with the HCl, so that acidosis resulted.
A further result was that the supply of phosphate in the body
began to run short, so that the kidneys could not excrete so much
acid as usual for a corresponding acidosis. When neutralized
sodium phosphate was taken the excretion of acid was much
increased, and the acidosis passed off correspondingly more
rapidly.
These experiments are of special interest, as they revealed a
practicable method of artificially producing marked symptoms
of acidosis in man. Previous attempts to do so by drinking large
quantities of dilute HCl or acid sodium phosphate had failed
owing to the efficacy of the physiological means of regulation.
It seems likely that in the acidosis of Bright's disease the forma-
tion of ammonia by the liver is checked by the accumulation of
ammonia in the blood owing to the inefficiency of the kidneys.
Hence the ratio of ammonia to toal nitrogen in the urine is not
increased.
It follows from the facts brought forward in this chapter that
"J. B. S. Haldane, Journ. of Physiol., LV, 1921.
RESPIRATION 199
the regulation of alveolar and arterial CO2 pressure resolves itself
into regulation of the blood reaction, and that the blood reaction
itself is a normal which is constantly being regulated within
marvelously narrow limits — so narrow that the variations, evident
though they are made by physiological reactions, cannot be fol-
lowed adequately by existing physical and chemical methods.
At this point it seems desirable to consider and criticize some of
the indirect means which have been used for estimating variations
in the hydrogen ion concentration of the blood. In recent years the
capacity of the blood, or of its serum, for combining with CO2 has
commonly been taken as an index of hydrogen ion concentration,
this capacity being also alluded to as a measure of the "alkaline re-
serve" of the blood. It is evident that the "alkaline reserve" of the
blood is only another name for the "titration alkalinity" when COg
is allowed to escape. It is also evident from facts described above
that the alkaline reserve is increased in conditions of acute acidosis
due to excess of CO2, and diminished in conditions of acute al-
kalosis due to excessive lung ventilation caused by artificial res-
piration or anoxaemia. Hence although the alkaline reserve is
diminished in acidosis due to the presence of abnormal acids in
the blood, a diminution in alkaline reserve cannot be regarded as
by itself an index of acidosis. There is, in fact, no necessary con-
nection between diminution in alkaline reserve or titration alka-
linity and diminution in blood alkalinity.
Another indirect method which has been used for estimating
variations in alkalinity is observation of one or more points in the
dissociation curve of the oxyhaemoglobin of the blood in presence
of the existing alveolar CO2 pressure. This method is due to
Barcroft and his pupils, and is based on the following facts. ( I )
As was shown in Chapter IV, each point in the dissociation curve
of oxy- or CO-haemoglobin in blood is simply displaced to a pro-
portional distance to the right or left on varying within wide limits
the partial pressure of CO2. Thus only one constant in the equa-
tion expressing the curve is altered. (2) It was shown by Peters,^^
and this had been completely confirmed by Hasselbalch,*^ that the
alteration in the constant depends, in cases where only the CO2
pressure is varied, on alterations in the hydrogen ion concentra-
tion, and can thus be used as a measure of it. Barcroft and others
have therefore used the alteration in the constant as a measure in
all cases of variation of hydrogen ion concentration in the blood.
** Barcroft, The Respiratory Functions of the Blood, p. 316.
** Hasselbalch, Biochem. Zeitschr., 78, p. 132, 19 16.
200 RESPIRATION
In persons at high altitudes, for instance, the constant is appar-
ently quite normal in presence of the existing alveolar COg pres-
sure; and from this fact it was inferred that the hydrogen ion
concentration of the blood is also normal, as already mentioned.
On the other hand, in persons who have shortly before undergone
some excessive muscular exertion the constant is very markedly
altered ; and from this fact a corresponding increase of hydrogen
ion concentration in the blood is inferred. The same method has
been employed for estimating variations of hydrogen ion con-
centration in the blood of patients.
When, however, the facts are examined more closely it appears
that there must be a flaw in the reasoning. In the case of persons
who have completed some severe muscular exertion in a few min-
utes before, there is no physiological evidence of anything but a
most trifling acidosis, such as could not possibly be detected by
alterations in the constant of the dissociation curve. The breathing
is only increased to such an extent as to reduce the alveolar COo
pressure by about a fifth. This only corresponds to an acidosis
equivalent to what would be produced by a rise of 0.3 mm. in the
alveolar CO2 pressure ; and such a rise would be entirely inappreci-
able in its effect on the dissociation curve of oxyhaemoglobin. The
rise apparently indicated by the alteration in the constant is enor-
mously greater. Hence it appears that there must be some other
cause for the alteration than rise in hydrogen ion concentration.
This other cause is probably operative in many cases of patho-
logical acidosis.
Another indirect method of measuring hydrogen ion concen-
tration has been proposed by Hasselbalch.^^ He showed quite
clearly that when the pressure of CO2 is varied in blood or even
serum the hydrogen ion concentration, as separately determined,
is proportional to the ratio of combined CO2 (which, as already
explained, is a measure of the bicarbonate present) to free COo
when allowance is made for the percentage ionization of the free
COo and bicarbonate. This corresponds with the fact that the blood
behaves as if more alkali were constantly being added to it in pro-
portion as its reaction approaches the neutral point. It is very re-
markable how closel}'- Hasselbalch's law holds for different kinds
of blood and in blood serum, in spite of great differences in the
dissociation curves for COs- Figure 58 from Hasselbalch's paper
is also very interesting as showing (for fresh ox blood) the dif-
ferences in the dissociation curves for serum, blood, and corpuscles.
" Hasselbalch, Biochem. Zeitschr., 78, p. 112, 19 16.
RESPIRATION
20I
These differences are just what might be expected in view of the
action of haemoglobin as a weak acid in alkaline solutions. In spite
of the great differences in the dissociation curves of blood and
serum Hasselbalch's law held good. He therefore applied it as a
means of calculating the hydrogen ion concentration of corpuscles
and of abnormal blood, and seemed justified in doing so.
10 ZO 10 40 so 60 70 80 90 lOOmmCOj
• _ Serum, 38°
e 8 Blood, 18°
« X Blood, 38°
o o Blood corpuscles, 38°
< » Serum, 18°
Figure 58.
CO2 dissociation curves (from Hasselbalch loc. cit.)
Nevertheless this method, like that of Barcroft and Peters,
seems to break down with abnormal blood. As an example of
abnormal blood he took, from the paper already referred to by
Christiansen, Douglas, and myself, experiments in which Douglas
had flooded his blood with lactic acid by running quickly a number
of times up and down the laboratory stairs at intervals during
about a quarter of an hour. As a consequence his blood had lost
about 40 per cent of its normal power of combining with CO2, and
his resting alveolar CO2 pressure was diminished by about a fifth.
The samples were taken about ten minutes after the last ascent of
the stairs, and all sensible hyperpnoea had passed off. From the
data given, Hasselbalch calculates, in accordance with the law
he had discovered for the same blood at varying pressures of CO2,
that the Ph of Douglas's arterial blood had fallen by .12. This
would, in accordance with the data given above as to the effects
of increase of Ph on the breathing, suffice to increase the breath-
ing to about ten times its resting value. Indeed Hasselbalch evi-
dently believed that there must have been such an increase, since
he speaks of the immensely increased breathing being unable to
compensate for the decrease in Ph. The breathing was, however,
perfectly quiet and apparently normal, though the lowering of
202 RESPIRATION
the alveolar COg pressure showed that it was about a fourth deeper
than it otherwise would have been. On the physiological evidence,
therefore, the fall in Ph was only about .003, instead of .12, or
only one-fortieth as much as calculated. From this example it
would seem to follow that Hasselbalch's method, when extended
to abnormal blood, is as unreliable as that of Barcroft and Peters.
Further investigation as to methods of determining hydrogen ion
concentration in abnormal blood seems to be much needed.
Except by observation of physiological reactions, there seems at
present to be no method of estimating in a reliable manner the
small variations in Ph which are of so much physiological impor-
tance. Hasselbalch estimates that a difference of .03 can be detected
in single determinations by the electrometrical method ; but this is
a very large difference, corresponding to an increase of 250 per
cent in the breathing. The colorimetric method by means of indi-
cators is equally rough. Time and effort will continue to be wasted
on futile measurements until the extreme fineness of the physio-
logical regulation of Ph in the blood and tissues is more fully
realized.
REACTION OF THE BLOOD IN EIGHT DIFFERENT WOMEN
BEFORE AND AFTER CHILDBIRTH
Ph. at
CO2 pressure
Alveolar CO2
Ph at alveolar
40 mm.
pressure
CO2 pressure
Before
After
Before After
Before After
7.40
7-44
31.0 42.2
7-44 7-43
7.40
7.48
^7-7 43-5
7.49 7.46
7.45
7.45
35.6 39-8
7.48 7-45
7.39
7.43
32.5 43.5
7.42 7.42
7.39
7-44
32.7 37.7
7.43 7.45
7.38
7-45
27-7 33-5
7.45 7-49
7.38
7-43
30.3 38.3
7.41 7.44
7-35
7.38
33-8 37-3
7.38 7-40
Mean 7.39 7.44 31.3 39.5 7.44 7.44
On account of various sources of error, already alluded to, in
the electrometrical or other measurements of Ph, we are still with-
out much very exact information as to the permanent steadiness
during health of the alkalinity of the blood under resting condi-
tions. In this connection some very interesting observations have
been made by Hasselbalch and Gammeltoft on the Ph of the
RESPIRATION
203
blood during and after pregnancy.^^ It had already been found
by Hasselbalch and others that the alveolar CO2 pressure is much
lower than normal during pregnancy. Taking advantage of this
fact, they determined the Ph of arterial blood before and after
childbirth with the results shown in the accompanying table.
Allowing for the probable errors in determining the Ph and
alveolar CO2 pressure, these figures seem to show that the fall in
alveolar CO2 pressure compensates within the limits of accuracy
of the electrometric method for a fall in the Ph of the blood which
would otherwise occur. The mean of the first two columns shows
that this fall in Ph would have been 0.05, whereas the compen-
sating fall in alveolar CO2 pressure was 8.2 mm. as shown by the
mean for the second two columns. Hence a difference of 0.0 1 in
Ph corresponds to a difference of 1.6 mm. of CO2 pressure, or
0.23 per cent of CO2 in alveolar air. We have already seen, how-
ever, that a change of about this amount in alveolar COg pressure
is sufficient to cause either apnoea or doubling of the alveolar
ventilation according to its direction. Even under the most favor-
able conditions it is hardly possible at present to determine differ-
ences in Ph within the body to within 0.03 in single observations ;
but by measuring the variations in lung ventilation as compared
with production of CO2 we have an index of change in Ph which
is at least 50 times as sensitive as the existing direct electrometric
method, exact as this is in comparison with older methods.
Although the measurements of Ph showed no change in the
alkalinity^ of the blood during pregnancy, yet the fall in alveolar
CO2 pressure indicated that there was an increase of 25 per cent in
the lung ventilation per unit of CO2 given off. This, therefore,
would correspond to an ''acidosis" to the extent of a Ph of 0.003 —
an amount far too small for direct measurement. That it was
acidosis which caused the increase in the breathing was shown by
the fact that the increase was accompanied by an increase of about
20 per cent in the proportion of nitrogen excreted as NH3 to total
nitrogen excreted in the urine. The authors conclude that there is
an increased acid production in the body during pregnancy (or
perhaps an increased drain of alkali from the body of the mother) ,
but that it is compensated by increased breathing and formation
of NH3. It is true that relatively to the degree of accuracy at
present attainable in determining the Ph of blood the compensa-
tion is perfect. But if the compensation were really perfect we
should be landed in the position of the vitalists of assuming effects
"Hasselbalch and Gammeltoft, Biochem. Zeitschr., 68, p. 206, 19 15.
204 RESPIRATION
produced without any measureable cause. In reality the acidosis
is not completely compensated, and the incompleteness is only
hidden by the extreme roughness of the method of measurement
in comparison with the fineness of the physiological reaction.
The table seems to indicate that the normal Ph is not quite the
same, though very nearly the same, in different individuals. For
the present, however, this conclusion is rather doubtful, in view
of the fact that the measurements were for imperfectly reduced
blood. We have seen already that in spite of the accuracy of regu-
lation there are individual differences in the normal alveolar C0«>
pressure, the normal composition of haemoglobin, and the normal
dissociation curve of blood for C02. As regards every detail of
structure and function we may be certain of finding similar differ-
ences when the measurements are made with sufficient accuracy;
and this doubtless applies also to even the Ph of the blood.
We have already considered one cause which alters the Ph to
which the respiratory center regulates. This cause is anoxaemia.
At high altitudes the body is in the long run protected to a large
extent from the effects of the alkalosis thus produced, because the
kidneys and liver still react almost true to the normal Ph. There
can be no doubt that other causes, such as the action of anaes-
thetics or poisons, or of other small changes in the composition of
the blood, would have a similar effect in altering the standard
to which the Ph regulation of the arterial blood is set. This
question, and the question how the Ph is regulated, not merely in ;
the arterial blood, but in the systemic capillaries, will be deferred I
to Chapters X and XIV.
We can now see much more clearly why it is that the resting
alveolar COg pressure is not quite steady in spite of the extreme
sensitiveness of the respiratory center to the minutest variation j
in alveolar CO2 pressure. There are various causes tending to '
disturb the constancy of the reaction of the blood; and the respira-
tory center, and not merely the kidneys and liver, must do its share
in compensating for these disturbances. Hence the alveolar COo
pressure cannot remain completely steady during rest. One of
these causes is the secretion of acid or alkaline digestive juices.
On account of the secretion of acid gastric juices the alveolar
CO2 pressure rises distinctly very soon after a meal. The effects of
a meal on alveolar COo pressure have been investigated recently
by Dodds.^^ He found that there is normally a sharp rise varyingj
in different individuals, but usually amounting to about 4 mm. half
" Dodds, Journ. of Physiol., LIV, p. 342, 1921.
RESPIRATION 205
an hour after the meal. This is rapidly followed by an equally
marked fall below normal, culminating about one and one-half
hours after the meal, with a subsequent rapid return to normal.
Bennett and Dodds^^ have found that the rise of alveolar CO2
just after a meal is closely related to the concentration and rate
of secretion of the gastric hydrochloric acid as indicated by
samples taken from the stomach. In cases where there is little or
no secretion of HCl the rise in alveolar CO2 is absent, though the
fall due to alkaline secretion into the intestine is still present.
Another cause of variation in alveolar CO2 pressure is the charac-
ter of the diet. With an alkali-forming vegetable diet the alveolar
CO2 pressure is quite considerably higher than with an acid-form-
ing meat diet. This was brought out very clearly in some of the
experiments of Hasselbalch alluded to above; and he showed at
the same time that the reaction of the urine varied in correspond-
ence with the changes in alveolar CO2 pressure.
During starvation the body is living on what amounts to an
acid-forming diet, and Higgins^* has shown that during starva-
tion the alveolar CO2 pressure falls. Perhaps the most striking
effects are obtained with a carbohydrate-free diet. This leads to
the formation within the body of a certain amount of aceto-acetic
and oxybutyric acids, as in severe diabetes. Higgins, Peabody,
and Fitz^^ showed that there is a striking fall in alveolar CO2
pressure, together with a very large elimination of oxybutyric and
aceto-acetic acid by the kidneys, and an accompanying large in-
crease in ammonia excretion and excretion of acid.
All the available evidence points, therefore, to the conclusion
that practically speaking the regulation of breathing in man dur-
ing rest under normal conditions is regulation of the blood re-
action. This very important conclusion is the outcome of the
present chapter.
Addendum. Within the limits of the present book it is un-
fortunately impossible to deal in detail with the mass of quite
recent literature bearing on the regulation of blood alkalinity.
Some of this literature is based on assumptions with which, for
the reasons already given, I am unable to agree : while other parts
of it are concerned with details as to which it seems difficult for
the present to form definite judgments. In general, however, it
"Bennett and Dodds, Brit. Journ. of Exper. Pathol., II, p. 58, 1921.
"Higgins, Publication No. 203, Carnegie Institution of Washington, p. 168,
1915.
"Higgins, Peabody, and Fitz, Journ. of Med. Research, XXXIV, p. 263, 19 16.
2o6 RESPIRATION
does not appear to me that anything which has recently been
published, points to any important modification of the conclu-
sions embodied in this chapter. In view of the great confusion
which evidently exists as to the subject, it may, nevertheless, be
useful to indicate more explicitly the reasons for regarding the
words "acidosis" and "alkalosis" as denoting deviations towards
the acid or alkaline side respectively of the normal reaction or
hydrogen-ion concentration within the body.
Acidosis and alkalosis are now frequently regarded as condi-
tions in which, whether or not there is an alteration in actual
reaction, the "alkaline reserve" of the blood plasma is diminished
or increased. This definition originated in a paper by Van Slyke
and Cullen in which they pointed out the ease with which varia-
tions in the "alkaline reserve," or total capacity of the blood
plasma for combining with CO2 can be determined experimentally,
and the advantages of using oxalated blood plasma in place of
whole blood for the purpose. ^^ Though they stated clearly that
variations in alkaline reserve are no direct measure of the varia-
tions in actual reaction of the blood, they, very unfortunately as
I think, proceeded to define "acidosis" as simply a condition in
which the alkaline reserve of the blood is diminished. It is, how-
ever, to variations in reaction, and not in the conveniently meas-
ured alkaline reserve of the plasma that the body is reacting
in conditions of acidosis or alkalosis; and to define acidosis or
alkalosis as anything else than a deviation towards the acid or
alkaline side of the normal reaction seems to me quite unjustifiable.
The confusion has been added to by the general failure to
realize the extreme delicacy of physiological regulation of re-
action, as compared with the comparative roughness of our present
means of directly measuring changes in reaction. Thus in cases
where there are all the physiological signs of acidosis, the avail-
able means of direct measurement may show no sign of the
change; and hence it has been quite wrongly assumed that no
change exists. This has contributed towards an acceptance of the
definition of acidosis as a condition, not of increased hydrogen-
ion concentration within the body, but of diminished alkaline re-
serve. The picturesque expression "alkaline reserve" is evidently
an unfortunate one in so far as it suggests a reserve of alkali not
in actual use. The alkali weakly combined in the body is in reality
always in physiological use, and the most urgent symptoms of
acidosis appear long before the alkaline reserve disappears.
"Van Slyke and Cullen, Journ. of Biol. Chem., XXX, p. 289, 19 17.
RESPIRATION 207
As was shown above, a difference of .012 in the Ph of the blood
is sufficient to double the resting breathing, or cause apnoea. This
difference in Ph corresponds to a difference of only about one
part by weight of ionized hydrogen in a million million parts of
blood. A continued difference of o. I in Ph would in all probability
cause danger to life. This is a much lower limit than has commonly
been assumed. By forced breathing we can, it is true, produce a
greater difference in the Ph of arterial blood, and maintain this
difference for an hour or more without loss of consciousness. The
difference, however, applies only to the arterial blood. As will be
shown in Chapter X, slowing of the circulation protects the tissues
to a large extent from great rises in Ph. It is possible, also, that ac-
tive secretion of CO2 by the lungs, as well as quickening of the cir-
culation, protects similarly against fall in the Ph of the tissues.
Nevertheless, as Yandell Henderson has so clearly shown, when
efficient forced respiration is kept up in animals for a sufficient
time, not only do coma and progressive failure of circulation ensue,
but so much damage is done that it is impossible to recover the ani-
mal on restoring the Ph of the blood by administering CO2, just as
it is impossible to recover a patient who has suffered for a sufficient
time from acute anoxaemia. That progressive and often irrepar-
able damage ensues also during a condition of excessive acidosis
is suggested by the phenomena of CO2 poisoning and clinical
acidosis. To what extent the damage during alkalosis is due di-
rectly to the rise in Ph, or to the accompanying anoxaemia, we
cannot at present say; and perhaps the question is at bottom
merely academic. When the forced breathing is of oxygen instead
of air the effects are much less marked, as mentioned above ; but
this may be because the circulation can be shut down more effec-
tively when oxygen is breathed, and that hence the rise in Ph in
the tissues is diminished.
CHAPTER IX
Gas Secretion in the Lungs.
In the lungs the blood is separated from the alveolar air by two
layers of living tissue, namely the capillary endothelium and the
alveolar epithelium. What part in respiratory exchange is played
by these very thin layers of living tissue ? Is this part purely me-
chanical? In other words, do these layers behave towards the
respiratory gases as any very thin non-living moist membrane
would behave? Or do the living membranes play an active part in
the process? We must now face this interesting, but also contro-
versial subject.
There has been a tendency to assume that because these mem-
branes are very thin they cannot play any active part. But it is not
so long since even membranes consisting of cubical or columnar
epithelial cells were supposed only to play a passive part in the
separation of material; and the presumption that a thinner mem-
brane of flattened cells cannot play an active part has come down to ■
us from the time, about the middle of last century, when physico-
chemical theories became dominant in physiology, and secretion in
general w^as supposed to be a mere mechanical process like filtra-
tion or diffusion. Another prevalent presumption is that though
liquids or dissolved solids may be actively secreted, gases probably
pass through living membranes by simple diffusion.
So little information about gas secretion is usually to be found
in physiological text books that it may be useful, before discussing
gas secretion by the lungs, to give some account of gas secretion
as it is now well known to exist in the swim bladder of fishes.
The swim bladder is morphologically a diverticulum of the
alimentary canal, like the lungs. In some classes of fishes there is
an open duct from the swim bladder into the alimentary canal,
but in other classes this duct is closed. Quite evidently, the mainp
function of the swim bladder is to make the specific gravity of the
fish about equal to that of the water it displaces when the fish is
at a certain depth. With a certain amount of gas in its swim
bladder the fish will just float at a certain depth. It is, however,
in a position of unstable equilibrium : for any movement upwards
will cause expansion of the air, so that the fish will tend to rise
with increasing velocity towards the surface ; and any movement
RESPIRATION 209
downwards from the position of equilibrium will similarly tend
to make the animal sink with increasing velocity to the bottom.
When fishes are stunned by an explosion under water, about half
of them float to the top, and the other half sink to the bottom.
One has only to place a goldfish in a large and tall bottle of
water provided with a perforated cork through which a thick
walled tube containing water passes to another small bottle of
water, in order to see how the fish deals with the situation. If the
pressure in the large bottle is raised by raising the small bottle
the fish will at first begin to sink, but will immediately turn its
nose upwards and swim upwards, so as to reestablish its position
of unstable equilibrium; and conversely if the large bottle be
lowered. It was formerly believed that a fish compresses or relaxes
its swim bladder when it wishes to go downwards or upwards.
That this is not the case was shown by Moreau^ in a series of
beautiful experiments. A fish is really confined temporarily to
about a certain depth by its swim bladder ; for if any cause tends
to make it leave this depth the animal's response to the stimulus
of expansion or contraction of its swim bladder soon brings it
back to its proper depth.
The goldfish has an open duct to its swim bladder, so if the
pressure is greatly diminished, as by connecting the large bottle
to a filter pump, the air of the swim bladder comes bubbling out
of the animal's mouth. If the pressure is now restored to normal
the animal sinks to the bottom, and after a few fruitless efforts
to swim upwards lies helpless on its side. If it is left there for some
time, however, it gradually becomes more buoyant, and after a
certain number of hours it will be swimming about as usual, with
its swim bladder full of gas. If a fish has a closed swim bladder,
and the gas from this is removed by means of a hypodermic
syringe, the fish also sinks at first, but soon refills its swim bladder
with gas. How is this gas produced, and what is it? It cannot have
been swallowed as air, as the fish has been lying in water at the
bottom all the time, or has a closed swim bladder. This brings
us to gas secretion.
About the beginning of last century the eminent French physi-
cist Biot was engaged in survey work in the Mediterranean, and
was attracted by the observation that fishes caught with a line at
great depths come to the surface and lie helpless with their swim
bladders distended with gas and sometimes projecting out through
the mouth. He determined to analyze the gas, and having intro-
* Moreau, Memoires de Physiologic, Paris, 1877.
2IO RESPIRATION
duced some of it, along with excess of hydrogen, into a glass
"eudiometer'' he passed a spark. Instead of the mild explosion
usual in air analyses, there was a violent explosion which broke
his instrument. He then knew that he had made a most significant
discovery, as the gas he was analyzing must be nearly pure oxy-
gen. He got another eudiometer and made a number of analyses of
gas from the swim bladder. The results showed that while the
gas taken from the swim bladder of a fish near the surface often
contained less oxygen than ordinary air, that taken from fishes
caught at great depths contained nearly pure oxygen.^ Biot had
discovered oxygen secretion.
To illustrate the real significance of his observations we may
take an analysis made much more recently by Schloesing and
Richard,^ in connection with which the depth from which the
fish was taken is definitely stated, and was 4,500 feet. They found
that the gas contained 84.6 per cent of oxygen, together with 3.6
per cent of CO2 and 11.8 per cent of nitrogen. The latter gases
are, however, quite likely to have mostly got in by diffusion during
the delay before the sample was taken. Now the pressure at 4,500
feet is 136 atmospheres. Therefore the oxygen pressure in the
swim bladder was at least 136 x — '—= 115 atmospheres, while
the oxygen pressure in the sea water was only about 2 1 per cent
of an atmosphere, and, in the blood circulating in the capillaries
round the swim bladder, certainly very much less. At a moderate
estimate the oxygen pressure on the inside of the wall of the
swim bladder was at least 1,000 times greater than in the cap-
illaries outside.
In the monograph already referred to, Moreau described a
number of experiments showing the conditions under which oxy-
gen secretion into the swim bladder occurs. He found, for instance,
that if a fish confined in an open cage was sunk to a considerable-
depth, so that its specific gravity became greater than that of thej
water, it gradually secreted oxygen so as to restore the balance;
and similarly if its swim bladder had been emptied by puncturing.
The simple experiment on the goldfish which I have just describe<
is of the same nature. Moreau even found that if a weight w<
attached to one fish in an experimental tank, and a float to anothei
fish, so that the first fish was for the time glued to the bottom, an<
the second to the surface, both fishes would soon be swimminj
* Biot, Memoires de la Societi d'Arcueil, 1807.
' Comptes rendus, Vol. 122, p. 615, 1896.
RESPIRATION 21 1
about again quite unconcerned in the tank, their respective swim
bladders having compensated by secretion or absorption of gas
for the disturbance in equilibrium caused by the sinker or float.
Such facts as these pointed to the conclusion that the gas secre-
tion is under the control of the nervous system ; but this was not
clearly demonstrated by Moreau. It was not till sixteen years
later that Bohr showed that the secretion after emptying the
swim bladder by puncture ceases after the branch of the vagus
supplying the swim bladder is cut.^ I well remember the interest
with which I saw this experiment when Bohr showed it while he
was staying with me in Oxford a few months before he published
his paper on the subject. Dreser^ had meanwhile already shown
that the secretion of oxygen, like that of saliva, sweat, etc., is
excited by the action of pilocarpine.
It is clear that a fish may require to get rid of gas from its
swim bladder, as well as to secrete gas. If the duct is open, there
is of course no difficulty in getting rid of gas ; but it is different
Vasculor/^emlr,
rUrte
Figure 59.
Diagram of arrangement of "oval."
if the duct is closed. The oxygen might, conceivably, be secreted
backwards; but often there is a large percentage of nitrogen in
the gas, and there might be trouble about this. It was discovered
by Jager^ that in fishes with a closed swim bladder there is an
oval window-like area on the dorsal side of the swim bladder
(Figure 59). Over this area there is nothing but a thin layer of
flattened cells between the air of the swim bladder and an under-
lying layer containing a close network of capillaries. This thin
layer seems to permit free diffusion outwards of the gas in the
swim bladder. Assuming this to be the case, the oxygen will
freely diffuse into the blood capillaries, where, as already seen,
Bohr, Journ. of Physiol., XV, p. 499, 1893.
"Dreser, Arch. f. Exper. Pathologic, XXX, p. 160.
' Jager, Pfliiger's Archiv, XCIV, p. 65, 1903.
212
RESPIRATION
the oxygen pressure is very low. Nitrogen and COg, on the other
hand, will diffuse inwards if their partial pressure is less inside the
swim bladder than in the blood, and outwards in the converse
case. The pressure of nitrogen in the blood is doubtless about 79
Figure 60.
Section through secreting gland of swim bladder of Sciaena aquila, showing
the epithelial body and underlying layer of capillary network (f) with gas bubbles
distending the gas ducts of the epithelial body (Jager).
Figure 6i.
More highly magnified portion of epithelial body shown in
Figure 60. A distended gas duct, with surrounding secreting
cells (Jager).
RESPIRATION
213
per cent of an atmosphere, as it is in sea water ; so whenever the
oxygen percentage is sufficiently reduced by diffusion to make
the nitrogen pressure in the swim bladder more than 79 per cent
of an atmosphere, the nitrogen will follow the oxygen out through
the "oval" ; as will the CO2, and from a similar cause. But Jager
found also that the "oval" can be opened or closed by the relaxa-
Figure 62.
(X 330) Folds of the swim bladder epithelium of Godius niger.
C.R.M., capillaries of the rete mirabile. I.C.C., intracellular capil-
lary (Woodland).
tion or contraction of a ring of unstriped muscle surrounding its
periphery. When this ring is contracted the "oval" is covered up
by a layer of the ordinary lining membrane of the swim bladder.
Thus not only secretion, but also absorption of gas from the swim
bladder, is under complete physiological control.
214
RESPIRATION
On microscopic section of the wall of the swim bladder we find
that at most parts it is lined by flattened epithelial cells similar in
outward appearance to those covering the oval. At certain parts,
however, this flattened epithelium passes into a layer consisting of
cubical or columnar epithelial cells, and forming the so-called
"epithelial body" (Figures 60, 61), or else a convoluted layer of
columnar epithelium (Figure 62). In the glandular structure
ducts containing gas may be seen (Figures 60 and 61) in certain
species of fishes, and the gland is evidently an oxygen-secreting
gland. The true glandular structure was one of Johannes Miiller's
many discoveries about glands.
ti^t.;
R.M.
G.Z.
Figiire 63.
Diagram of circulation in rete mirabile of eel. R.M. rete mirabile. G.E. gland
epithelium. Arterioles and arterial capillaries continuous lines. Venules and venous
capillaries interrupted lines (Woodland).
Beneath the glandular structure is a mass of red blood vessels,
forming a structure which attracted the attention of anatomists
hundreds of years ago*^ and came to be known as a rete mirabile.
The arrangement of the blood vessels in this "red body" was re-
cently studied by Woodland,^ who established the fact that the
rete mirabile is an arrangement in which the arterioles passing
to the gland break up into capillaries which come into intimate
contact with corresponding venous capillaries from the venules
coming from it (Figure 63). What is the significance of this?
The arrangement reminds us of that in a regenerating furnace,
where the heat carried away in the waste gases is utilized to heat
Redi, Observations sur les animaux vtvans contenus dans les animaux vivans.
Florence, 1684.
'Woodland, Proc. Zool. Soc. of London, p. 183, 191 1.
RESPIRATION
215
^■the incoming air. Nevertheless it seems hardly probable that the
^Rirrangement is for heat regeneration. The blood passes to the
^Kfland with, presumably, the main physiological object of supply-
^Bng oxygen, and venous blood in returning is already spent as
^■regards its supply of oxygen. Nevertheless I think we can now
^^suggest an explanation. It was discovered by Barcroft and King^
' that at low temperatures the influence of CO2 in expelling oxygen
from haemoglobin is much greater, relatively speaking, than at the
temperature of warm-blooded animals. The difference is so great
as to suggest that the dissociation of oxyhaemoglobin in the tis-
sues of cold-blooded animals is practically dependent, not on fall
END
Figure 64.
(X 1000). Transverse section through anterior end of rete mirabile of
Gobius niger, showing the peculiar endothelium (END) of the arterial
capillaries (A) as compared with the venous capillaries. (V) (Woodland).
of oxygen pressure, but on rise of CO2 pressure. It seems probable,
therefore, that the function of the rete mirabile is to enable venous
blood to communicate part of its COg to the arterial blood. The
effect of this will be to raise the CO2 pressure of the blood sup-
plied to the gland, and so raise the oxygen pressure. There may
be active secretion of CO2 into the arterial capillaries; and this
" Barcroft and King, Journ. of Physiol., XXXIX, p. 374, 1909.
2i6 RESPIRATION
hypothesis is supported by the existence in the arterial capillaries
of a very peculiar thickened endothelium figured clearly by Wood-
land (Figure 64).
Another very interesting case of gas secretion occurs in Arcella
discoides, which is a microscopic unicellular organism found in
rivers and ponds. It has a more or less transparent shell, shaped
something like the top of a mushroom, with an opening where the
stalk should come. Through this opening it protrudes delicate
pseudopodia, by means of which it can creep about (Figure 65).
Figure 65.
Arcella raising itself by developing bubbles. Two bubbles
visible through shell, and pseudopodia projecting through
lower opening.
When a living and healthy arcella is examined in a drop of water
under the microscope, the presence of one or more gas bubbles
inside its protoplasm can at times be observed, particularly if by
accident or design the animal has been turned on its back, with
the opening of its shell upwards. The bubbles of course make the
animal lighter, so that it rises towards the surface of the water,
and also comes right-side up, after which they rapidly disappear
again. The occurrence of these phenomena was described many
years ago by Engelmann. Quite recently Dr. Bles took up the
subject again at my suggestion, as it looked as if oxygen want
was in some indirect way the real stimulus to the formation of the
bubbles, just as it is (as we shall presently see) the stimulus to
oxygen secretion in the lungs. He elicited the very interesting
fact that a quite slight fall in the normal oxygen pressure of the
surrounding water is sufficient to cause the immediate formation
of gas bubbles in the arcella, and thus cause it to rise to where
presumably there is more oxygen. It seems probable, also, from
other observations made by him later, that the bubbles which are
apt to develop when the animal is placed on its back are a conse-
quence of stimuli produced by internal want of oxygen owing to
RESPIRATION 217
increased oxygen consumption during its efforts to right itself.
Before going further let us try to form some sort of conception
as to what is occurring in a gland cell during the secretion of
oxygen. On the side of the cell next the lumen of the duct we have
a pressure of oxygen which may be 1,000 times as great as on the
side next the capillaries ; and yet oxygen may be passing inwards
from the capillaries towards the duct. The cell is permeable to
oxygen : for oxygen is passing through it. Yet the oxygen cannot
be free to dissolve in the ordinary way in the "protoplasm" of
the cell : for if this were the case the oxygen would run backwards
through the cell like water through a sieve. At a pressure of 115
atmospheres, to go back to our concrete example, 100 volumes of
water at 10° C would take up 430 volumes of oxygen (measured
at 0° and 760 mm.) ; and if the oxygen were as freely soluble in
the cell water as in ordinary water the swim bladder would leak
outwards at a quite hopeless rate. If we start by looking upon
''living protoplasm" as a mere solution and suspension of colloid
and other material, we may as well give up the attempt to get any
insight whatever into even the most rudimentary physiological
processes.
When we take a broad general view of the phenomena of life,
one of the most fundamental facts that appears is that the com-
position of each organism or part of an organism is distinctly
specific. The percentage and nature of each of the substances
which we can recover on disintegrating the living tissue are spe-
cific ; and the more we learn about the nature of these substances
the more clearly does this specific character emerge. It is evidently
no mere accident that muscle yields so much potassium, so much
phosphoric acid, so much water, and so much of various proteins.
These substances must be present in some kind of combination in
the living ''substance" ; and if so the living substance cannot be
regarded as a mere solution of free molecules. The molecules are
in some sense bound, as they are in a solid ; and in so far as this is
the case the living substance must in certain respects behave as a
solid, impervious to the free passage of material by diffusion.
The layer of thin flattened epethelium lining appears to be gas-
tight (to oxygen at least) except where it covers the oval. At this
point the layer allows gas to pass freely.
From this point of view we can understand why the living cells
of the oxygen-secreting gland should be gas-tight, or nearly so,
against diffusion backwards, but we have not yet considered how
the gas passes forward through them during secretion; and if
2i8 RESPIRATION
"living material" behaved like an ordinary solid no such explana-
tion would be forthcoming. But evidently a living cell does not
behave like an ordinary solid : for it is constantly taking up and
giving off material, not merely during secretion, but at every
moment of its existence. This is evident from a general considera-
tion of the phenomena of nutrition, and becomes still more evident
if by altering the environment of a cell we disturb the labile
balance between living cells and their surrounding liquids. In the
secretion of oxygen and many other substances, such as urea,
sugar, salts, etc., the substance taken up on one side of the cell is
given off in the same form on the other side. In the processes of
ordinary nutrition, on the other hand, the taking up and giving
off may be on the same side of the cell, and the substance given off
may be in a different chemical form from that taken up. We have
no reason to believe, however, that there is any fundamental dis-
tinction between the taking up and giving off during ordinary
nutrition and during secretion. Nearly a century ago Johannes
Miiller, at the end of his famous memoir on secreting glands,-^^
after pointing out that his observations negatived the mechanical
theories of secretion then current, suggested that secretion must
be regarded as a process akin to growth, the only difference being
that whereas in ordinary growth the material deposited tends to
remain where it is, in secretion it is always being carried away
and replaced. Johannes Miiller's theory was bound up with his
vitalistic physiology, and the clue which he was grasping at was
swept from the hands of physiologists by the wave of mechanistic
speculation which passed over physiology about the middle of
last century. But now that we know from nearly a century of
painful experimental investigation what to the genius of a great
biologist like Miiller was evident enough, that mechanical theories
of secretion are impossible, we can take up the clue again.
When oxygen (or indeed any other substance entering into
cell metabolism) is taken up on one side of the cell, we are led by
the experimental facts to assume that the oxygen enters into
easily dissociable chemical combination. Were this combination
not easily dissociable we could not understand why a cell should
be so enormously sensitive, as we shall see later that it is, to
changes in the concentration of oxygen and other substances in
its immediate environment. Now all we know about cell metab-
olism points to the conclusion that the balance of stability at any
one part of the cell depends on the balance of stability at other
Johannes Miiller, De Glandularum Secernentium Structura Penitiori, 1830.
RESPIRATION 219
parts. The taking up of oxygen, for instance, depends on a host
of conditions in the environment, such as the concentrations, or,
more correctly, the diffusion pressures, of ions of different sorts,
and of various other substances which are, or may be, passing
into and out of the cell. A minute trace of pilocarpine, for instance,
will set the oxygen-secreting cell violently taking up oxygen on
one side, and giving it off on the other; and probably we could
paralyze the oxygen secretion at once by reducing the concentra-
tion of calcium ions in the cell environment.
In a secreting cell the rate of secretion, other conditions being
favorable, depends on the concentration of the dissolved material
to be secreted. This we can see with the utmost clearness in the
case of the kidney or intestinal epithelium. The rate of secretion
also depends on the concentration of the dissolved material on
the excretory side, as we can also see in the case of the kidney.
Clear evidence on this point is summarized by Ambard in his
book La physiologie des reins, Paris, 1920. We are thus led
to the conclusion that the stability of the oxygen combination
on one side of the oxygen-secreting cell depends, other things
being equal, on the stability of the oxygen combination at the
other side, and that in proportion as the oxygen combination
at one surface becomes increased, the oxygen combination at the
opposite surface becomes more ready to release oxygen towards
the cell environment. It also seems probable that as we proceed
from the absorbing to the secreting side of the cell, the tendency
to give off oxygen becomes greater and greater. A cell of sub-
stantial thickness is therefore required to produce a large differ-
ence in oxygen pressure. The combination which dissociates itself
on the excretory surface will, if the concentration of oxygen at
that surface is not so high as to stop the dissociation, be constantly
resaturating itself in part from the combination lying deeper in
the cell. Thus oxygen will travel from the absorbing to the se-
creting side of the gland cell, just as urea, or sodium, or phosphoric
acid, will travel from the absorbing to the secreting side of other
kinds of secreting cells. We can also imagine how, in the course
of their passage, chemical transformations may occur in the
transported material, so that, for instance, an intestinal cell which
takes up fatty acid may deliver fat on the other side, or a cell
which takes up sugar may transform it into fat, or amino acids
into proteins, or oxygen into CO2 and water, or may perform any
of the numerous other syntheses or disintegrations with which
physiologists are familiar.
220 RESPIRATION
In the arcella, bubbles, probably consisting largely of oxygen^
appear and disappear within the cell body, according to the ex-
isting physiological conditions. It seems probable that the bubbles,
for the development of which a high internal oxygen pressure
will be needed, occur in interstices of the living substance, due to
the presence of inclosed liquid or solid substances. In these inter-
stices the gas pressure can rise up to the point at which it pro-
duces disruption and bubble formation. Gas bubbles have not
hitherto been observed in the cells of oxygen-secreting glands,
although certain microscopic appearances have been taken for
such bubbles.
The well-known transparent larva of Corethra possesses two
gas floats : one near the anterior, and the other near the posterior
end of the larva. The gas is enclosed in chitinous bladders de-
veloped from the tracheal system and partially rigid, with cells
on their external walls. If the pressure of the water is increased
the larva begins to sink owing to diminution in the capacity of
the bladders, but regains its equilibrium in two or three minutes ;
and conversely if the pressure is diminished. This looks, therefore,
like a case of gas secretion. Krogh showed, however, in a beautiful
series of experiments^ ^"^ that there is no gas secretion, but secretion
of liquid out of or into the bladders, so as to compensate for the
alteration in their capacity. The larva can equilibrate itself in
this way since the bladders are partially rigid. In deep water, for
instance, the gas pressure is kept the same as that of the atmos-
phere, and hence much less than that of the surrounding water.
The gas pressures inside and outside the bladders are thus the
same, and simple diffusion of gases is not modified by gas secretion.
Having to some extent cleared our ideas by the consideration
of undoubted cases of gas secretion, we can now proceed to dis-
cuss the evidence as to gas secretion by the lungs. As mentioned
already, Ludwig had the idea (in which he was right) that prob-
ably something occurs in the lungs to facilitate the escape of COo,
and possibly the absorption of oxygen ; and this idea appeared in
the work of some of his pupils. It was a time when physiological
research was very active in Germany; and friendly, or some-
times anything but friendly, shots were often exchanged between
the leading laboratories. The Leipzig idea was accordingly put
to the test by Pfliiger and his pupils at Bonn, and for the purpose
Pflijger devised an instrument which he called the aerotonometer,
its object being to measure the partial pressures or tensions of the
**^ Krogh, Skand. Archiv. f. Physiol,, XXV. p. 183, 1911.
RESPIRATION 221
gases contained in venous and arterial blood, so that these pres-
sures could be compared with one another and with the corre-
sponding pressures in the air of the lungs. The aerotonometer
consisted of two tubes immersed in a water bath at body tempera-
ture, and closed below by a mercury seal. In one tube was placed
a mixture containing a smaller percentage of CO2 and greater
percentage of oxygen than corresponded to the partial pressures
expected in the blood ; and in the other tube a mixture containing
a higher percentage of COg and a lower percentage of oxygen.
The blood from the animal was then allowed to trickle down the
inside of the tubes, so that it should as far as possible equalize its
gas tensions with those in the tubes, either by taking up or giving
off CO2 or oxygen. In a successful experiment the blood gave off
CO2 and absorbed oxygen in one tube, and vice versa in the other,
so that the gas pressures of the blood were defined within narrow
limits on the analyses of the gases in the two tubes. The sample of
lung air was obtained by another ingenious instrument, the "lung
catheter," by means of which a bronchus could be blocked off and
a sample of the gas in the lungs drawn off as soon as the air thus
confined had reached a constant composition.
The conclusion drawn from the actual experiments by Pfluger
and his pupils was that there was no average difference in gas
pressures between the venous blood and the air inclosed beyond
the blocked bronchus; and therefore no evidence of any giving
off of CO2 or absorption of oxygen except by simple diffusion. ^^
The question was taken up again by the late Professor Bohr of
Copenhagen, one of Ludwig's pupils. -^^ Bohr improved the aeroto-
nometer, so that a large stream of arterial blood could be run
through it and back to the animal, the blood of which had first
been rendered incoagulable by injecting peptone or leech extract.
He obtained the result that while usually the CO2 pressure in the
arterial blood is not less than in the alveolar air, and the oxygen
pressure not greater, yet sometimes this relation is reversed. From
these results he concluded that active secretion of oxygen from
the lung air into the blood, and of CO2 from the blood into the
lung air, may both occur. Owing to the many possibilities of
error the results were not very convincing, however; and Fred-
ericq^^ of Liege soon afterwards made a further series of experi-
ments, all of which seemed to tell in favor of Pfliiger's interpreta-
tion.
" Pfiuger's Archiv, IV, p. 465 ; VI, p. 65 ; VII, p. 23, 1871-1873.
" Bohr, Skand. Arch, of Physiol., p. 236, 1891.
" Fredericq, Arch, de Biol., XIV, p. 105, 1896.
222
RESPIRATION
About fifteen years later the aerotonometer was greatly im-
proved by Krogh, who was then Bohr's assistant. He very greatly
diminished the volume of air exposed to the blood in the aeroto-
nometer, thus rendering it far quicker in its action ; and ultimately
he succeeded in working with a single bubble of air, round which a
stream of blood could play, the bubble being afterwards analyzed
with the help of a graduated capillary tube into which it could be
sucked up and measured before and after its CO2 and oxygen
had been removed by suitable reagents.
Figure 66.
Krogh's micro-aerotonometer, showing inlet and outlet
for blood, lower part of measuring tube, and air bubble.
Before his death Bohr published some experiments made with
Krogh's aerotonometer, and apparently showing distinctly that
the pressure of CO2 in the venous blood could be less than in the
expired air, although CO2 was being given off in the lungs ; and
that the arterial CO2 pressure could also be less than that of the
expired air. Krogh himself, however, took the view that there
were errors in these experiments, and published, along with M.
Krogh, the results of a careful series of experiments on animals
under conditions which were much more nearly normal than in
any previous experiments.^^ The arterial oxygen pressures were
" A. and M. Krogh, Skand. Arch. /. Physiol., XXXII, p. 179, 1910.
RESPIRATION
223
always very distinctly below the oxygen pressures at the same
time in the alveolar air; while the arterial CO2 pressures were
sensibly equal to those in the alveolar air. There was never any
approach to excess of arterial over alveolar oxygen pressure, or
of alveolar over arterial CO2 pressure, even when these pressures
were varied considerably by altering the composition of the in-
spired air. Krogh, therefore, rejected Bohr's conclusions that
there is active secretion of oxygen or CO2 in the lungs, and con-
cluded in favor of Pfliiger's view that the exchange of gases in
the lungs is entirely due to diffusion. The following table shows
the results of a typical experiment in which the alveolar oxygen
pressure was varied during the experiment, the alveolar air and
blood samples being taken nearly simultaneously.
TIME
TENSION OF CO2 IN
TENSION OF OXYGEN IN |
Alveoli
Blood
Alveoli
Blood
1.36-43
3.6
Z-7
12.0
lO.O
2. 10-12
30
3.5
18.0
150
3.03- 3.07
2.5
2.5
12.0
II. 5
Before following this long controversy further, I should like
to point out a fallacy in the interpretation of the aerotonometer
results. The conclusion of Pfliiger that diffusion alone explains
the giving off of CO2 in the lungs was wholly fallacious, as has
already been shown in Chapter V. The oxygen reaching the
blood in the lungs helps to drive out CO2; and under certain con-
ditions which are very apt to occur during physiological experi-
ments on animals, and may easily be produced in man, the venous
CO2 pressure may be lower than that of the alveolar air, although
no secretion at all may be occurring. In the lung-catheter experi-
ments the oxygen supply to the lungs was blocked off, so that the
blood could not take up oxygen. As a consequence the CO2 pres-
sure in the confined air must have been considerably lower than if
oxygen had been present. In reality Ludwig was right, and
Pfliiger was wrong. This source of fallacy does not in any way
invalidate Krogh's conclusion that the arterial CO2 pressure is
not, under normal conditions, lower than the alveolar CO2 pres-
sure. I think this conclusion is correct ; and it agrees, as he points
out, with all the indications given by the work of Priestley and
myself on the regulation of breathing in accordance with the
alveolar CO2 pressure.
224 RESPIRATION
When Bohr's original experiments on the question of secretion
by the lungs were published in 189 1, I was just beginning the
serious study of mine gases and the physiological effects of vitiated
air; and his results interested me greatly. A year or two later
Lorrain Smith and I made a visit of several weeks to Copenhagen,
and carried out some research work in the laboratory under
Bohr's direction, thus learning a great deal which we could not
have learned in England about existing methods of blood-ga-
investigation, and, far more important, getting into personal
touch with Bohr himself. I should like to take this opportunity oi
saying how much we, and indirectly other physiologists in Great
Britain and America, have owed to Bohr and the Copenhagen
School of physiologists.
The difficulties of the aerotonometer method of determining the
oxygen pressure of arterial blood were very evident, and I cast
about in my mind for some better method. Soon afterwards I
began investigating the action of carbon monoxide in mines, and
the results of this investigation, and the colorimetric method of
blood examination, which I worked out during the investigation,
suggested a new means of attacking the problem which Ludwig
had originally suggested.
The general principle of this method has already been ex-
plained in Chapter IV, and depends on the fact that within wide
limits the relative proportions in which haemoglobin is shared
between oxygen and CO are proportional to the relative partial
pressures of the two gases when allowance is made for their rela-
tive affinities for the haemoglobin. Hence if the proportions ir
which oxygen and CO are shared in the haemoglobin of the
blood when equilibrium is established are known, as well as the
pressure of CO, the pressure of oxygen can be calculated. To
measure the oxygen pressure in the arterial blood it is therefore
only necessary to allow a man or animal to breathe a constant small
percentage of CO until absorption of CO stops, owing to a balance
having been struck between oxygen pressure and CO pressure in
the blood passing through the lung alveoli. The percentage satu-
ration of the haemoglobin with CO is then determined, and the
arterial oxygen calculated from a knowledge of the relative affini-
ties of the two gases for haemoglobin, as determined outside the
body.
The method seemed simple in principle, but it turned out to
be as full of pitfalls in practice as the use of the blood pump,
aerotonometer, or spectrophotometer. What misled us most were :
RESPIRATION 225
( I ) the assumption that Hiifner's oxyhaemoglobin dissociation
curve, then and for many years later quoted in every textbook,
was at least approximately correct; (2) the assumption that all
haemoglobin is alike as regards its relative affinities for oxygen
and CO; (3) ignorance at first of the powerful action of bright
light on the dissociation of CO haemoglobin, and of the influence
of temperature; (4) failure at first to realize how long it takes
to saturate blood or blood solution outside the body with air con-
taining low percentages of CO. There were probably also some
errors in the colorimetric titrations, owing chiefly to our not taking
precautions which subsequent experience showed to be necessary,
against decomposition of blood solutions during long experiments.
The first experiments were made by Lorrain Smith and my-
self^^ on men, the subject of the experiment going through the
lengthy process of breathing air containing a definite small per-
centage of CO, until absorption of CO ceased, as shown by the
analyses of blood samples. The results led us to the conclusion
that the normal resting arterial oxygen pressure was considerably
above that of the alveolar air; and corrections, made afterwards
for the causes of error just referred to caused this conclusion to
stand out still more clearly. Subsequent experience leads me to
the conclusion that we had become acclimatized more or less to
want of oxygen by frequently breathing CO, so that at the time
we were no longer ordinary normal subjects. We were at any
rate breathing with complete impunity a percentage of CO which
would under ordinary circumstances cause very unpleasant symp-
toms. On trying the next year and once or twice subsequently to
repeat one of the experiments, we were surprised to find that the
former percentages w^ere too high for us, and we suspected that
there must have been some error about the percentages breathed
in the first series of experiments. On reconsidering the matter I
cannot see how there could have been an error about the per-
centages breathed. It now seems practically certain that we had
become acclimatized, and had consequently developed during
the experiments a considerably higher arterial oxygen pressure
than normal persons would have had, or than we ourselves would
have had, if we had not absorbed so much carbon monoxide as in
the experiments, and thus become somewhat short of oxygen.
Our next experiments^^ were on various small animals —
chiefly mice. Small animals are specially convenient, as their
" Haldane and Lorrain Smith, Journ. of Physiol., XX, p. 497, 1896.
" Haldane and Lorrain Smith, Journ. of Physiol., XXII, p. 231, 1897.
226 RESPIRATION
blood becomes saturated within a few minutes to its maximum
extent for any percentage of CO in the air. These experiments
again gave an apparently higher oxygen pressure in the arterial
blood than in the alveolar air. When the percentage of CO was in-
creased, so that the animals began to show symptoms of consid-
erable oxygen want, the difference between arterial and alveolar
oxygen pressure became much greater. On the other hand, when
the animals were breathing a mixture of oxygen and CO there
was still a large apparent excess of arterial over alveolar oxygen
pressure. This result was a great disappointment to us, as we had
hoped that when oxygen was breathed, active secretion of oxygen
inwards would cease. The fact that it apparently did not do so
ought to have aroused our suspicions of the correctness of the
measurements. The phenomena observed when the oxygen per-
centage, or the barometric pressure, was diminished, led us, apart
from the measurements, to conclude that secretion of oxygen in-
wards became more active; but in our measurements of oxygen
pressure we were depending on the substantial correctness of
Hiifner's dissociation curve; and when this curve was subse-
quently found to be totally incorrect our measurements had also
to be abandoned as incorrect.
During the next few years knowledge as regards the dissocia-
tion of haemoglobin had greatly increased, thanks to the work of
Bohr, Zuntz and Loewy, Barcroft, and others, as well as our own
work, as described in Chapter IV. Douglas and I now took up the
old subject again, but with far more complete knowledge of the
material we were dealing with.^' Dr. Krogh had also kindly in-
formed me in a letter of some experiments he had made (subse-
quently published) ^^ showing that in the blood of a rabbit the
relative affinities for haemoglobin of oxygen and CO were dif-
ferent from those in the ox ; and we found, as already mentioned
in Chapter IV, that this is not only so for different classes of ani-
mals, but also, and in a most marked degree, for different indi-
viduals of the same species.
We therefore had to modify the method. Each animal was ex-
posed for a sufficient time to a definite percentage of CO in a
bottle, and then drowned iti situ. Some of its blood was then
placed, undiluted and at body temperature, in the saturator, and
thoroughly saturated in presence of some of the same mixture of
air and CO that the animal had been breathing. The percentage
" Douglas and Haldane, Journ. of Physiol., XLIV, p. 305, 19 12.
"Krogh, Skand. Arch. f. Physiol., XXXII, p. 255, 19 10.
RESPIRATION
227
saturations with CO of the haemoglobin in the blood taken
straight from the animal, and in that from the saturator, were
then determined, and the arterial oxygen pressure calculated in
the usual way. The following table shows the results.
Duration
Percentage saturation
Arterial oxygen
of exp. in
of haemoglobin
pressure in per-
Animal used
Percentage
minutes
with CO centage of the ex- ||
of CO
^ -^
1 - _,^i
extstmg
In vivo
In vitro
atmosphere^
Mouse
.016
60
2.^.2.
17.2
12.2
>>
.0165
50
26.7
19.5
13-9
>>
.018
45
26.0
18.5
13.5
>>
.019
33
19.7
12.5
12.1
>>
.025
43
25.6
17.6
13.0
"
.046
40
29.1
22.7
15.0
»
.053
40
37.7
30.2
16.2
>>
.100
32
45.0
43.0
19.3
»
.129
31
56.4
56.3
20.8
»
.198
—
57.6
56.5
20.0
»>
213
13
59-1
75.5
44.7t
»
.244
12
67.3
71.7
25.7t
>>
.255
60
60.1
62.8
23.3
»
.260
25
67.0
64.7
18.9
>»
.262
20
66.4
73.7
28.2
»>
.275
25
66.5
76.9
35.9
Rabbit
.029
140
28.0
18.7
12.4
Same rabbit
.191
150
58.2
56.0
19.1
* Calculated without reduction for
aqueous vapor in the alveolar air. |
t Mouse died.
On looking down this table it will be seen that as long as the
percentage of CO did not exceed about .03 per cent, or the per-
centage saturation of the blood did not go over about 28 per cent,
the arterial oxygen pressure was only about that of the alveolar
air, assuming that the alveolar air of a mouse has about the same
composition as human alveolar air. But as the percentage of CO
in the air, or the percentage saturation of the blood, rose, the
arterial oxygen pressure rose, first to about that of the inspired
air, and then, in most cases, far above it — sometimes to double.
We then repeated the old experiments with oxygen which had
disappointed Lorrain Smith and me so much. The results were
as follows :
228 RESPIRATION
EXPERIMENTS WITH MIXTURES OF OXYGEN AND CO ON MICE
Percentage saturation Oxygen pressure in percentage
Duration of haemoglobin with CO of the existing atmosphere*
Percentage of exp. in i^, ' ^ ' * n
of CO minutes In vivo In vitro Arterial blood Inspired, air
0.16 30 31.3 29.6 77.4 83.9
0.61 30 57.0 54.6 66.6 73.5
1. 15 30 71.4 70.8 83.1 85.6
1.47 30 69.0 75.0 96.3 71.5
* Calculated without reduction for aqueous vapor.
It will be seen that as long as the saturation of the blood with
CO did not exceed about 60 per cent, the arterial oxygen pressure
was about 7 per cent below that of the inspired air, just as the
alveolar oxygen pressure would be. With over 60 per cent satura-
tion, however, the animals began to suffer from oxygen want,
and the arterial oxygen pressure went just as high above that of
the inspired air as in animals breathing ordinary atmospheric
air. The old experiments were wrongly calculated, because the
relative affinities of haemoglobin for oxygen and CO are on an
average different in mouse blood from what they are in human
blood or in the ox blood which we then took as a fixed standard.
This led us to calculate the arterial oxygen pressure about 50 per
cent too high in both the "normal" and the oxygen experiments.
Moreover the "normal" experiments were not normal, since the
percentage saturations of the blood were about 40 per cent, and
therefore too high to give normal results such as those of the first
five experiments in the previous table. If one recalculates the
average results of the old experiments in the light of this new
knowledge they give just the same result as the new experiments.
The general, and absolutely sharp and definite, result of these
experiments is that with very low percentages of CO there was
no evidence of active secretion of oxygen inwards, but that with
higher percentages of CO there was perfectly clear evidence of
active secretion. This active secretion began to show itself as soon
as the CO percentage was sufficient to cause symptoms of CO
poisoning, which symptoms, as shown in Chapter VII, are simply
those of oxygen want : moreover the secretion did not appear if
oxygen was breathed along with the CO, until a much higher
saturation of the blood with CO was reached. Pure oxygen, as
RESPIRATION
229
already shown in Chapter VII, provides a certain supply of dis-
solved oxygen to the blood independently of the oxygen carried by
the haemoglobin, and thus prevents, to a large extent, the oxygen
want which would otherwise be caused by the CO.
Now the oxygen want is in the tissues, and not in the lungs.
Hence the stimulus to secretion originates in the tissues. This
stimulus is almost certainly something carried by the blood from
the oxygen-starved tissues to the lungs or central nervous system.
One might perhaps suppose that whenever the respiratory center
is excited, nervous impulses pass down secretory fibers in the vagus
nerve and excite secretion in the lungs. Lorrain Smith and I tested
this hypothesis, and found that when the respiratory center was
excited by excess of CO2 there was not the slightest rise in the
arterial oxygen pressure. Hence the secretion has no direct con-
nection with the ordinary activity of the center in producing
respiratory movements; and the stimulus to secretion is not a
hydrogen ion stimulus.
We also made a series of determinations on man. In view of
the results of the mouse experiments we were anxious to work
with low percentages of CO ; but if we had used the old method
which Lorrain Smith and I had employed, it would have taken
so long before equilibrium was reached between the CO in the
air and that in the blood that our experiment could hardly have
been completed during winter daylight. We therefore adopted
the course of quickly absorbing as much CO as would saturate
the blood to the desired extent, and then breathing in and out of
a small air space, in which the oxygen and CO2 percentage was
kept constant. Under these conditions CO must, of course, be
given off into the air of the space, and as this air is breathed again
and again, equilibrium between the CO in the air and that in the
blood must establish itself very quickly. The method finally
adopted was as follows (see Figure Oy).
The subject, wearing a nose clip, breathes through the mouth-
piece A, inhaling through the inspiratory valve B, and expiring
through the valve C. The expired air passes through a rubber
pipe of large caliber to the tin vessel D, which is filled with small
fragments of solid caustic soda, and is made of such a size (di-
ameter 23 cms., depth 12 cms.) that the whole of the carbonic
acid in the expired air is effectively removed. Another rubber
pipe leads the outgoing air current from D to the bottle E of 12
liters capacity, which is connected by another pipe with the in-
spiratory valve B. The entrance and exit pipes of E are so ar-
230
RESPIRATION
ranged that the incoming air current is directed to the bottom of
the bottle, while the subject inhales air from the top. The arrows
indicate the direction of the air current caused by the subject's
respiration in the main circuit. Two side pipes lead into the rubber
pipe connecting D with E. One of these, G, is of large bore and
Figure 67.
Apparatus for determining the arterial oxygen pressure in man.
short, and is connected with a vulcanized rubber gas bag of con-
siderable size, such as is utilized on Clover's ether apparatus.
This bag serves only to accommodate each expiration, as the rest
of the apparatus is indistensible, and at the end of inspiration
the bag collapses entirely. The other side pipe F serves for the
admission of oxygen. The oxygen supply is so arranged that oxy-
gen enters the main air circuit automatically to fill up the defi-
ciency caused by the absorption of oxygen by the subject at each
breath. It is essential in a closed system of small size that the
oxygen supplied shall be pure; the small amount of nitrogen
contained in ordinary cylinder oxygen renders its use inadmis-
sible. We therefore in all the later experiments used oxygen
made by the action of water on "oxylith" in the generator H. The
current of oxygen is controlled by the tap at the top of the gen-
erator, and passes along a pipe past a blow-off valve to air J,
through a small gas meter K and thence through a water valve
M to enter the main air circuit at F. The height of the water above
the orifice of the pipe in M is about 2 mm. greater than in J, and
the oxygen therefore passes out to air through the valve J unless
RESPIRATION 231
a slight negative pressure is set up in the main air circuit, when
it will pass by preference through M. Such a negative pressure
obtains in the main air circuit only at the end of an inspiration,
and depends upon the fact that the whole volume of air in the cir-
cuit is diminished by the amount of oxygen absorbed at the last
breath of the subject, as the carbonic acid expired is removed. The
meter records, therefore, the actual oxygen consumption by the
individual. Interposed between the meter and the valve M is a
small rubber bag L, such as is used in a small sized football. This
serves as a reservoir for the oxygen, and enables a free and sudden
supply to be drawn into the air circuit. Without this it would be
necessary to run the oxygen from the generator at an excessive
and wasteful rate, and the slight resistance of the meter might
be felt. In practice the oxygen supply is so adjusted that it is just
escaping continuously to air through J, so as to insure that the bag
L is filled to constant pressure; otherwise the readings of the
meter will not accurately represent the oxygen consumption.
A Haldane gas analysis apparatus N is attached directly to the
air pipe leading from the bottle E to the inspiratory valve, so that
samples of the inspired air may be withdrawn at intervals during
the experiment for analysis. The extremity of a vacuous gas
sampling tube O is inserted into the pipe between the expiratory
valve and the caustic soda tin, not far from the former, for the
purpose of obtaining a sample of alveolar air by Haldane and
Priestley's method. By means of the tap P, connected with the
laboratory water supply, a large volume of air can be displaced
from the bottle E through the pipe R, and used for filling satu-
rating vessels, etc. Before each experiment the apparatus is tested
for air-tightness by disconnecting the oxygen supply pipe at F
and substituting a water manometer for it, and then producing a
positive or negative pressure by blowing in air or sucking it out
through the mouthpiece. The whole apparatus is readily blown
out with fresh air by disconnecting the return air pipe from the in-
spiratory valve and blowing through the mouthpiece with a pair
of bellows.
We found that the percentage of oxygen in the air in the ap-
paratus falls by about 0.8 per cent during the first five minutes of
an experiment, doubtless owing to the rise of temperature caused
by the breathing, which will hinder the entrance of oxygen. After
this the oxygen percentage shows oscillations, which however do
not exceed i per cent. Such oscillations are unavoidable, seeing
that the oxygen supply must be influenced in this method by the
232 RESPIRATION
depth of the individual breaths : the percentage could only re-
main absolutely constant if the depth of breathing was itself
constant. For the same reason the oxygen consumption should not
be determined over a shorter period than five minutes.
One great advantage of this apparatus is that it is very easy
to subject oneself to atmospheres containing different percentages
of oxygen by means of it. To obtain an atmosphere poor in oxygen
all that is necessary is to uncouple the oxygen supply from the
valve M and breathe into the apparatus. Air now enters through
F instead of oxygen, and breathing is continued until analysis of
the inspired air shows that the required degree of oxygen de-
ficiency has been produced. If the oxygen supply is now reestab-
lished the artificial atmosphere produced will remain constant.
To obtain an atmosphere rich in oxygen, the gas may be blown in
through the orifice for the alveolar air sampling tube, leaving the
mouthpiece free for the escape of the displaced air from the re-
turn air pipe.
The total volume of the air in our apparatus is about 15 liters,
and we may therefore presume that the whole of it goes through
the alveoli of a resting adult subject in three minutes. We have
on a number of occasions breathed into the apparatus for an
hour with the greatest comfort, the percentage of oxygen mean-
while varying only within the limits mentioned above.
The time during which the subject breathed into the respiration
apparatus in our experiments has varied on different occasions
from twenty minutes to one hour. So far as we could ascertain the
shorter time was sufficient to establish equilibrium of concentra-
tion of the carbon monoxide in the blood and in the air breathed,
though we have as a rule adopted a period in excess of this as a
matter of precaution. In our earlier experiments we passed about
2 cc. of CO into the air in the respiration apparatus before begin-
ning to breathe into it, in order that the percentage of this gas
present at the start might approximate to its final value. As this
procedure had no influence on the result of the experiment we
gave it up, and the respiration apparatus thereafter always con-
tained air free from CO at the commencement of the experiment.
Analyses of the inspired air were made several times during the
course of the experiment, as it was naturally important for our
purpose that the composition of the inspired air should show none
but minimal variations. Shortly before the close of the experi-
ment a sample of blood was withdrawn from the subject's finger
into a capsule, and defibrinated with a platinum wire. Five-hun-
RESPIRATION
233
-dredths cc. of this blood was then introduced into the saturating
vessel in the manner described in our paper. Immediately after-
wards two further small samples of blood were taken from the
subject's fingers — as a rule one from each hand — the blood being
received into small test tubes quite full of water, which were im-
mediately corked. These samples served for the colorimetric
determination of the degree of saturation of the blood with carbon
monoxide. A last sample of the inspired air was then taken, and
a sample of the alveolar air. Breathing into the apparatus was
continued for about two minutes in case the composition of the
air in the respiration apparatus had been altered by the deep ex-
piration necessary to afford the alveolar air sample : some car-
bonic acid, for instance, might have got through the caustic soda
tin. The experiment then terminated, and the mouthpiece of the
respiration apparatus was at once closed. The saturating vessel
containing the blood was as soon as possible filled by displacement
with some of the air remaining in the respiration apparatus, which
was expelled for this purpose from the bottle E by the arrange-
ment indicated at P and R. While the saturating vessel was being
rotated in the water bath at 38° the determination of the degree
of saturation with carbon monoxide of the samples taken from
the fingers was proceeded with. During this time also the analyses
of the alveolar air, and air from the respiration apparatus, were
completed and when necessary the analysis of a sample from the
saturating vessel. After the saturating vessel had been rotated for
half an hour or more, it was removed from the water bath and
the degree of saturation with carbon monoxide of the blood con-
tained in it was determined. All the data for calculating the
oxygen pressure of the arterial blood and contrasting it with that
of the alveolar or of the inspired air were then at our disposal.
Our first experiments on man were taken up with determining
the arterial oxygen pressure under as normal conditions as pos-
sible, and we especially wished to guard against the effects of
deficiency of oxygen. We therefore employed a low saturation
(23 per cent) of the blood with CO and made sure that the res-
piration apparatus contained a normal atmosphere by ventilating
j^ it freely with fresh air before the experiment. All the experiments
were made with the subject sitting at rest.
The results of these experiments are collected in the accom-
panying table.
The figures show quite distinctly that under normal circum-
stances when the subject is at rest the arterial oxygen pressure in
234 RESPIRATION
man corresponds exceedingly closely to the pressure of oxygen in
the alveolar air. In fact in no single instance does the value of the
arterial oxygen pressure differ from the alveolar by a greater
amount than can be accounted for by the experimental error of
the method.
We then tested the effect of raising the alveolar oxygen pressure
considerably above the normal value by filling the respiration
apparatus with an atmosphere rich in oxygen. The results of the
experiments are also given in the table. Here again the figures
show that the arterial and alveolar oxygen pressures have prac-
tically identical values. In these experiments on man we were
content to use only a moderate increase of the alveolar oxy-
gen pressure, for the higher the oxygen pressure is raised the
less proportional difference is there between the inspired air and
the alveolar air. A point will therefore eventually be reached
when the determination of the difference of tint between the blood
withdrawn from the body and that saturated with the inspired
air in vitro will fall almost within the experimental errors of the
method. It should be noted that in these experiments the car-
bonic acid in the alveolar air had precisely its normal value,
namely 5.6 per cent when measured dry, and we have therefore
no reason to suppose that the alveolar air samples were other
than normal.
Having obtained thus results which indicated that during rest
under normal conditions the transference of oxygen through the
pulmonary epithelium occurs without active secretory interven-
tion of the alveolar epithelium, we were naturally anxious to test
the matter further under conditions in which some amount of
deficiency of oxygen- might affect the subject. The necessary de-
ficiency of oxygen was obtained by exposing the subject to an
atmosphere containing a considerably lower percentage of oxy-
gen than the normal. The experimental procedure was precisely
the same as before, save that we filled the respiration apparatus
before the start with an appropriate atmosphere by the method
described above. The results of these experiments are collected
in the middle part of the table.
The partial pressure of oxygen in the air breathed corresponded
to an altitude of 15,000 feet or over; yet we noted that a 23 per
cent saturation of the blood with carbon monoxide was tolerated
without inconvenience. One of the subjects was liable to head-
ache when his blood was saturated to 25 per cent or more with
carbon monoxide, but this was in no wise accentuated in these
RESPIRATION 235
experiments. That deficiency of oxygen was exerting its custom-
ary effect on the respiration is indicated by the low value of the
alveolar carbonic acid percentage. Both the subjects noticed dis-
tinct hyperpnoea for some time after commencing to breathe into
the respiration apparatus, and that this was accentuated on the
slightest movement. The face remained of a distinctly bluish
color throughout the experiment, but the blueness passed away
if the hyperpnoea became exaggerated for a short time by mus-
cular movement. On rebreathing normal air at the close of the
experiment well-marked Cheyne-Stokes breathing was once or
twice observed, indicating that the want of oxygen had induced a
real hyperpnoea which had lowered the general carbonic acid
j pressure in the body considerably.
In calculating the arterial oxygen pressures from the experi-
mental data of these experiments, it was necessary to make allow-
ance for the fact that the arterial blood was not fully saturated
with oxygen and CO, while the blood from the saturator must have
been almost completely saturated, as the oxygen pressure in the
air of the saturator was considerably higher, and hardly any CO2
was present. For the correction required under these circum-
stances I must refer to our original paper.
On looking at the results of the four experiments it will be seen
that in every case the arterial was above the alveolar oxygen pres-
sure. The mean difference seems to be outside the limits of experi-
mental error, but only amounts to 8 mm.
A further series of experiments was made with the subject
doing muscular work. Preliminary experiments made with the
work done on a tricycle ergometer had shown that when the
breathing was greatly increased difficulties arose with the appa-
ratus. We therefore decided to make use of work with only one
arm. This enabled us to push the work to the point of fatigue,
when want of oxygen would be produced in the muscles, with
formation of lactic acid. That lactic acid was actually formed is
indicated by the low alveolar CO2 percentages. The work appa-
ratus which we employed was of the simplest description. It
consisted of a lever which could be moved backwards and for-
wards, and transmitted its motion by means of a connecting rod to
a small table carrying a weight which slid to and fro upon a
smooth plank, to one end of which the lever was pivoted.
The work apparatus was placed upon the ground adjacent to
the chair on which the subject sat, so that he could move the lever
and yet breathe comfortably into the respiratory apparatus. By
236 RESPIRATION
increasing the weight the amount of work done by the subject
could be raised. It was not possible to measure the actual work
done in mechanical units, but we could do so in physiological
units by observing, by means of the small gas meter, the effect
on the oxygen consumption of the subject per minute. What we
term "moderate work" in the tables below was sufficient to raise
the total oxygen consumption to one and a half times its resting
value, while "severe work" doubled the resting oxygen consump-
tion. Work which doubles the resting oxygen consumption is only
equivalent to walking on the flat at two miles per hour, and does
not sound particularly severe, but we found it sufficiently tiring
when it was performed by one arm only, and kept up for half an
hour at a time.
The lower part of Table III shows the results of the work ex-
periments. These results are very striking : for the arterial oxygen
pressure was on an average 4.4 per cent, or 32 mm. of mercury,
above the alveolar oxygen pressure, and in two experiments was
8.5 and 15.6 mm. above the oxygen pressure of the inspired air
(allowing for aqueous vapor).
In the last experiment on the table the effects of muscular work
and low oxygen in the inspired air were combined. It will be seen
that the arterial was 33.5 mm. above the alveolar oxygen pressure,
whereas with a low oxygen in the inspired air and no work the
arterial never exceeded the alveolar oxygen pressure by more than
13 mm. As already mentioned, it was noticed that when work
was done while a low oxygen percentage was being breathed the
lips and face lost the bluish color due to the low oxygen, and
became of a normal red color. It was also noticed many years ago
by Loewy^^ that even a slight muscular exertion produced a
marked improvement in the subjective symptoms of want of oxy-
gen in a steel chamber at low atmospheric pressure. Our results
on the arterial oxygen pressure during muscular exertion furnish
an evident clue to these observations.
In a former chapter I have referred to some of the results of
the expedition to Pike's Peak undertaken in 191 1 by Professors
Yandell Henderson and Schneider, Dr. Douglas, and myself. ^^
Part of our object was to determine whether the want of oxygen
" Loewy. Untersuchungen u. d. Respiration und Circulation, Berlin, 1895,
p. 16. The fact that Geppert and Zuntz {Pfliiger's Archiv, XLII, p. 189, 1888)
found a little more oxygen in arterial blood during work than during rest may
point also in the same direction.
" Douglas, Haldane, Yandell Henderson, and Schneider, Phil. Trans. Roy. Soc,
(B) 299, p. 195, 1913.
RESPIRATION 237
due to the rarefied air at 14,000 feet did not produce active secre-
tion of oxygen inwards. We used the same method as at Oxford,
taking every precaution against errors. The results were quite
unmistakable. We found that as soon as acclimatization to the air
was established the arterial oxygen pressure became considerably
higher than that of the alveolar air. The next table shows our
results. In ordinary resting experiments on acclimatized persons,
the arterial oxygen pressure was on an average about 70 per cent
above the alveolar oxygen pressure. When, however, air extra
rich in oxygen was breathed, so that the alveolar oxygen pressure
rose to about what it is at sea level, the difference between arterial
and alveolar oxygen pressure fell to 8 or 10 per cent, even during
the short period of an experiment. In a subject investigated im-
mediately on arrival at the summit by the cogwheel railway the
arterial was only about 15 per cent above the alveolar oxygen
pressure, whereas three days later, after acclimatization, the ex-
cess was 100 per cent.
The Pike's Peak results threw much new light on oxygen secre-
tion by the lungs, and on the former experiments at Oxford. It
was evident, that not only is oxygen want a stimulus to active
oxygen secretion by the lungs, but that the response to the stimulus
improves greatly with practice or "acclimatization," just as is
the case with other physiological responses. We can now see why
some experiments — for instance those which Lorrain Smith and I
made jointly on ourselves, indicated oxygen secretion, while other
experiments in which the physical and chemical conditions seemed
to be the same gave negative results. It was the physiological con-
ditions which were different. In the latter experiments we were
not acclimatized against anoxaemia.
It is easy to see the physiological advantage of oxygen secretion
as a defense against the anoxaemia of high altitudes and similar
conditions, or against carbon monoxide poisoning; but its uses
under ordinary conditions, where nothing but pure air at about
ordinary atmospheric pressure is breathed, are not so obvious. It
is clear that as the arterial haemoglobin is nearly saturated with
oxygen, during rest, at any rate, without any active secretion,
hardly anything could be gained by secretion, since any additional
oxygen which could be added to the blood would be trifling in
amount unless with an enormous secretory pressure such as has
never been found experimentally. We can thus readily under-
stand why there is no secretion during rest under normal condi-
tions, as our experiments clearly showed to be the case. It was
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RESPIRATION
239
only during work that the experimental results showed secretion;
but as a matter of fact the increase found in the arterial oxygen
pressure above the alveolar oxygen pressure would be of very
little service in charging the blood further with oxygen ; and this
brings us back to the original question.
In the first place it must be pointed out that the experiments
which Douglas and I made on oxygen secretion during muscular
work were carefully arranged in such a way as to demonstrate the
existence of secretion if any secretion occurred during muscular
work. We knew already that the stimulus to oxygen secretion
came from anoxaemia of the tissues. We knew, also, that the
only probable function of oxygen secretion was, not to raise the
arterial oxygen above that of the alveolar air, but to prevent a
serious fall, such as otherwise might take place during work suffi-
cient to increase very greatly the oxygen requirements of the
body. But we had no index of what the fall might be in the absence
of secretion. We therefore made the experiments in such a way
that tiring work, such as would presumably furnish the stimulant
to oxygen secretion, was done with one arm only. The oxygen
requirements of the body were in this way only increased to a
very moderate extent, so that oxygen secretion would have every
chance to raise the arterial oxygen pressure above the alveolar
oxygen pressure, just as in CO poisoning or at high altitudes dur-
ing rest. It was also much easier to make the experiments accu-
rately when the oxygen intake was not greatly increased.
Since our original experiments, and those on Pike's Peak, were
carried out, a good deal of both direct and indirect evidence has
accumulated in confirmation of our conclusions, and must now be
referred to. In Chapter VII the very clear physiological evidence
was summarized, showing that there is, in persons who are not in
good physical training, considerable anoxaemia during hard mus-
cular exertion. This is not merely local anoxaemia in the muscles
with the associated formation of lactic acid described in Chapter
VIII : for if the work is not too hard the respiratory symptoms
indicating anoxaemia are still present during the work, but there
is no trace of a subsequent fall in the resting alveolar CO2 pres-
sure. This fall is the physiological indication of lactic acid, and
runs parallel, as already mentioned, with the presence of much
lactic acid in the blood and urine. As Douglas and his pupils have
found,^^ there is, as a matter of fact, practically no increase in
"Campbell, Douglas, and Hobson, Phil. Trans. Roy. Soc, (B), Vol. 210, p. i,
1920.
240 RESPIRATION
the lactic acid present in the urine during moderate work. Thus the
anoxaemia cannot well be due to anything else but imperfect
saturation of the arterial blood with oxygen; and that this is the
actual cause is directly shown by the fact that a very moderate
increase in the oxygen percentage of the air breathed relieves the
symptoms.
In ordinary persons not in good physical training a very mod-
erate diminution in atmospheric pressure is quite sufficient to
cause a noticeable excess of hyperpnoea on any considerable ex-
ertion, such as climbing or walking fast. This is very evident on
going by train to some place four or five thousand feet above sea
level; and the cause is, without a shadow of doubt, imperfect
oxygenation of the arterial blood. At ordinary atmospheric pres-
sure we are accustomed to a certain degree of hyperpnoea and
exhaustion with a given degree of muscular exertion. That this
is in part dependent on imperfect saturation of the arterial blood
is only revealed by the fact that in air at a higher atmospheric
pressure (as in the case of workers in compressed air, and prob-
ably in deep mines), or when air enriched with oxygen is
breathed, the same work becomes much easier, at any rate to many
persons.
The observations of Dr. Henry Briggs, described in Chapter
VII, show that there is a striking difference in this respect be-
tween men in good physical training and ordinary persons, as the
former class get no benefit from air enriched with oxygen unless
the work is excessively hard, while the latter get great benefit,
shown, not only by the much greater ease and comfort with which
they perform the work, but by the smaller amount of air which
they require to breathe. The corresponding difference at high
altitudes is perfectly familiar to mountaineers. The man who is in
good training is free from the hyperpnoea, mountain sickness, and
other effects of high altitudes to a far greater extent than the man
who is not in training; and this evident fact has often led
mountaineers to the mistaken conclusion that mountain sickness
has nothing to do with altitude or anoxaemia, but is simply a sign
of imperfect training.
All the facts just mentioned confirm the direct evidence in
favor of oxygen secretion in the lungs. Part of the exhaustion of
hard physical work is due to imperfect saturation of the arterial
blood with oxygen and the consequent effects on the respiratory
center and central nervous system as already described in Chap-
ters VI and VII. In persons who are in good physical training
RESPIRATION 241
these effects are in abeyance because as one part of physical train-
ing the lung epithelium has become much more capable of re-
sponding to the stimulus calling forth increased secretion of
oxygen, just as in the case of a man who has become acclimatized
to a high altitude, or to breathing air containing a small per-
centage of CO. It is the training of the lung epithelium, and not
anything else, that makes the specific difference. This is shown
at once by the fact that acclimatization to high altitudes or CO
poisoning takes place whether a man takes exercise or not.
In this connection I may mention the result of an experiment
which I made for a specific object during the war. It seemed
desirable to find out how soon the fall in oxygen percentage in the
air of a submarine would begin to have serious effects. I there-
fore shut myself in an air-tight respiration chamber which was
provided with the same sort of purifier for absorbing the CO2
produced by respiration as was used in British submarines. The
oxygen percentage was also allowed to fall at the same slow rate
as that at which it had been found to fall in the most crowded
submarines then in use. After a few hours a light would no longer
burn in the air, and in a few more hours even a lighted pipe
handed in through a small air lock would no longer keep alight.
After 56 hours the oxygen percentage had fallen below 10. I then
terminated the experiment as the purifier was failing, and the
immediate object of the experiment, which was to find out whether
the air in a submarine would last easily for 48 hours without any
addition of oxygen, had been attained. I had no trace of mountain
sickness or any other symptom of anoxaemia, and my lips were
just as red as usual, though from other experiments described
in Chapter VII, I knew that without acclimatization I should have
broken down hopelessly in the existing atmosphere. A laboratory
attendant who afterwards went into the chamber along with me
became blue and uncomfortable, and finally collapsed and had to
be pulled out hurriedly.
In this experiment the fall in oxygen percentage had been so
slow that acclimatization had kept pace in me with the fall in
oxygen percentage, just as when a man ascends only very gradu-
ally to a high altitude. There is, however, much more in this
acclimatization than mere increase in the power of oxygen secre-
tion, since there is also the gradual adjustment of blood reaction
to increased breathing, as explained fully in Chapter VIII.
In a more recent series of experiments by Kellas, Kennaway,
242 RESPIRATION
and myself^^ these two effects were separated. One of our objects
was to see how far acclimatization to high altitudes could be ob-
tained by discontinuous exposures to low barometric pressures.
This question is of course of considerable importance to airmen,
in whom the exposures are discontinuous. The effects produced
before acclimatization on Dr. Kellas, myself, and others, by an
exposure to 320 or 330 mm. barometric pressure, are described
in Chapter VI. To obtain acclimatization we used the method of
exposing ourselves for six to eight hours to atmospheric pressures
of 500, 430, and 360 mm. on three successive days. We found, how-
ever, that our resting alveolar CO2 pressure had always returned
to normal before the morning after each successive exposure.
Thus there was no lasting adjustment of blood reaction to in-
creased breathing, as any change in this direction had disappeared
by the morning: There was also no lasting increase in our haemo-
globin percentages. Any acclimatization obtained must therefore,
apparently, be due to increased power of oxygen secretion.
The result of the experiment was that there was marked ac-
climatization, but limited in amount. When unacclimatized I had
been totally disabled, and had lost all memory, at a pressure of
320 mm., as already described. But on the last day of the ac-
climatization we stayed at 3 15 mm. for a considerable time, during
which, though we were distinctly blue, I could quite easily con-
tinue to do gas analyses and other operations, and move about
as usual, with no loss of memory afterwards of what had occurred.
In this experiment my son. Captain J. B. S. Haldane, acted as an
unacclimatized control. He came in with us and stayed for some
time at 366 mm. ; but after two hours he was so much affected that
we had to let him out. His breathing had become increasingly
rapid and shallow, and he had gradually sunk into a stupified
condition. After coming out he could remember hardly anything
of the last hour in the chamber.
It is clear from this experiment that airmen, so long as they
retain their health, and remain at high altitudes pretty fre-
quently, must be capable of acquiring a considerable degree of
acclimatization. This acclimatization was long ago noted by
Glaisher in connection with his occasional high balloon ascents.
An equal degree of acclimatization can undoubtedly be main-
tained in a simpler manner by good physical training; and at
heights of less than about 20,000 feet an airman in good physical
"Haldane, Kellas, and Kennaway, Journ. of Physiol., LIII, p. 181, 19 19.
RESPIRATION 243
training should have little difficulty from anoxaemia. It must be
noted, however, that even a small degree of the neurasthenia with
shallow breathing described in Chapter III renders an airman
totally incapable of going to any considerable height without an
oxygen apparatus.
Our acclimatization experiment indicated that with complete
acclimatization, including adjustment of the blood reaction to
the increased breathing, and increase in the haemoglobin per-
centage, a man could probably, if the mere physical difficulties
were not too great, reach the summit of Mount Everest without
breathing anything else than ordinary air, though he would
quite certainly die at this altitude if he were not acclimatized.
It was pointed out in Chapters III and VII that, on account of
the imperfect distribution of air in the lungs, the average alveolar
oxygen pressure is, even during rest under normal healthy condi-
tions, no certain guide to the oxygen pressure of the mixed
arterial blood. During heavy work this must be so to an increased
degree, since, although the expansion of the lungs is much better,
the rate at which oxygen is absorbed is enormously greater.
Meakins and Davies^^ have recently made exact determinations
of the percentage saturation with oxygen of the haemoglobin in
the arterial blood of a number of healthy persons, and found it to
vary from 94 to 96 per cent in different persons, the variation
depending probably on the differences in the oxyhaemoglobin
curves which Barcroft discovered (Chapter IV). In my own case
the saturation was 94.3 per cent. This is not much lower than 96
per cent, the saturation which would be expected if my arterial
blood were fully saturated to the oxygen pressure of the mixed
alveolar air. If, however, we look at the dissociation curve of
the oxyhaemoglobin of human blood, we see that 94.3 per cent
saturation corresponds to an oxygen pressure of only 1 1.2 per
cent of an atmosphere, as compared with 13.2 per cent in the
alveolar air. Thus the oxygen pressure in the mixed arterial blood
is very distinctly less than in the alveolar air ; and this is the sort
of result which the aerotonometer gives, as already explained.
On the other hand the carbon monoxide method gives, during
rest under normal conditions, exactly the same oxygen pressure
in the arterial blood as in the alveolar air. This difference in the
results by the two methods used to be rather a puzzle, and was
explained by me as probably due, either to a process of rapid but
*® Meakins and Davies, Journ. of Pathol, and, Bacter., XXIII, p. 453, 1920.
244
RESPIRATION
slight oxidation in the blood itself, or to a little blood getting
through the lungs without exposure to alveolar air. Our shallow
breathing experiments, and the neurasthenia cases, showed
clearly enough why the mixed arterial blood is not fully saturated
to the alveolar pressure; but why does the carbon monoxide
method not show this? A little consideration will show the reason.
The carbon monoxide method gives the average arterial oxygen
pressure of all the portions of arterial blood leaving the lung
alveoli, just as the "alveolar air" gives the average oxygen pres-
sure of all the portions of air in the alveoli of the air-sac system.
But the oxygen pressure of the mixed arterial blood cannot be
deduced, as fully explained in Chapter IV, from the average of
the oxygen pressures in the blood leaving the alveoli. It is this
average that the carbon monoxide method gives. Hence for the
purpose of deducing the oxygen pressure of the mixed arterial
blood the carbon monoxide method has exactly the same defects
as the method of inferring this value from the oxygen pressure of
the alveolar air on the assumption (perfectly valid for resting
conditions at ordinary atmospheric pressure when pure air is
breathed) that diffusion equilibrium is established between al-
veolar air and blood. For the purpose, however, of deciding
whether or not active secretion of oxygen is occurring, the carbon
monoxide method is perfectly valid. It gives just the information
needed; and for this purpose it is far more reliable than the
aerotonometer method, which has always given misleading in-
formation on the question of diffusion equilibrium for oxygen,
and made it appear as if diffusion equilibrium is never attained,
even during complete rest.
To those who pin their faith, as regards the secretion question,
to the aerotonometer results, I may perhaps point out that if they
were accepted as evidence they would completely wreck the dif-
fusion theory. For if diffusion equilibrium is not even obtained
under resting conditions under normal barometric pressure it
would be quite inconceivable on the diffusion theory that anything
approaching to diffusion equilibrium would be obtained during
muscular work, and particularly at high altitudes. Yet on Pike's
Peak is was possible to do hard muscular work with the lips re-
maining quite red.
It will easily be seen on consideration that as the barometric
pressure, or the oxygen percentage of the inspired air, is pro-
gressively reduced, the difference in percentage saturation be-
tween the mixed arterial blood and blood completely saturated at
RESPIRATION
245
the existing alveolar oxygen pressure will increase more and more
if diffusion alone determines the saturation of the blood in the
lungs, and will tend in the same direction even if active secretion
assists diffusion. We can thus easily explain why some of the
persons who ascended Pike's Peak were very blue in the face, and
why fainting or partial loss of consciousness were common occur-
rences. We can also understand why some persons become more
or less unwell at first on going to an altitude of only four or five
thousand feet, and why in all persons there is a distinct physio-
logical reaction to anoxaemia, as shown by lowering of the al-
veolar CO2 pressure and rise in the haemoglobin percentage. This
physiological reaction would be difficult to understand if there
was uniform saturation of the haemoglobin in all the alveoli. We
tnust conclude that whether or not a person is acclimatized to a
low barometric pressure the percentage saturation of the mixed
arterial haemoglobin with oxygen is distinctly diminished, though
the amount of the diminution is not indicated by the carbon mon-
oxide method.
In the process of oxygenation of the blood in the lungs, the
oxygen has to pass from the alveolar air through a thin layer of
living tissue into the blood and into the corpuscles. This process
must take some time. To the genius of Christian Bohr we owe the
principle of a method by which the time may be estimated, in so
far as the process is one of diffusion. In connection with the ab-
sorption of oxygen by the lungs it is not possible to measure the
rate at which, with a given diffusion pressure, oxygen passes
inwards, because we do not know the mean diffusion pressure.
We can, as will be shown later, measure the oxygen pressure of
the venous blood, as well as that of the alveolar air and arterial
Tjlood ; but we do not know how quickly the blood becomes satu-
rated in its passage along the alveolar capillaries. Hence we can-
not estimate the mean difference in oxygen pressure required for
the diffusion inwards of a given quantity of oxygen in a given
time. In the case of absorption of CO present in the air in a low
proportion the conditions are quite different, however: for we
can determine the percentage of CO in the alveolar air, and the
rate at which the gas is absorbed, while, for short experiments,
the difference in CO pressure between the alveolar air and the
blood is constant. In this way we can tell how much CO is ab-
sorbed per minute with a given pressure difference; and from
this, allowing for the greater solubility and slightly lower dif-
fusibility of oxygen, we can calculate the rate at which oxygen
diffuses in with the same pressure difference.
246 RESPIRATION
Bohr's original calculations (based on rather rough experi-
ments made by myself for another purpose) were not very ac-
curate; but the matter was reinvestigated by A. and M. Krogh,^'
and still more recently by M. Krogh.*^ A. and M. Krogh found
that for adults about 25 cc. of oxygen will diffuse inwards per
minute for every i mm. of difference in oxygen pressure during
rest, and about 35 cc. during work. The estimate of M. Krogh is
considerably higher ; but I do not think that the method which she
used was at all reliable, for the following reasons. The method
consisted in taking in a deep breath of air containing a small
percentage of CO. Part of this breath was then breathed out, and
a sample of the alveolar air taken. The rest of the breath was
held for a measured interval of time, after which a second sample
of alveolar air was taken, and the percentages of CO in the two
samples very accurately determined. From the fall in the per-
centage of CO between the two samples the rate of absorption of
the CO was then calculated.
If the difference between the percentages of CO in the two
samples represented absorption of CO, the method would be a
correct one. Actually, however, it is quite impossible, as I have
convinced myself by repeated experiments with various gas mix-
tures, to secure an even distribution of a gas through the lung air
by taking in a single deep breath. The first alveolar sample con-
tains an undue proportion of the atrial air containing a higher
initial percentage of CO, while the second sample comes ex-
clusively from the alveoli of the air-sac system, in which the per-
centage of CO was never nearly so high as in the atria. Thus the
apparent absorption of CO during the interval of holding the
breath is much greater than the actual absorption. The method is
thus fallacious; and the same criticism applies to a number of
other Copenhagen experiments with regard to alveolar air, the
dead space in breathing, etc.
Taking, however, the earlier estimate of A. and M. Krogh, it
can be calculated^^ that during rest at normal atmospheric pres-
sure, the arterial blood passing through an average alveolus
would easily be saturated by simple diffusion to the oxygen pres-
sure of the air in the alveolus. During considerable muscular work,
however, this would not be the case ; and the arterial blood would
emerge incompletely saturated. That there should be some an-
A. and M. Krogh, Skand. Arch. f. Physiol,, XXIII, p. 236, 19 10.
M. Krogh, Journ. of Physiol., XLIX, p. 271, 1915.
Douglas and Haldane, Journ. of Physiol., XLIV, p. 337, 19 13.
RESPIRATION
247
oxaemia during considerable exertion is therefore exactly what
might be anticipated on the diffusion theory, even without any
allowance for the effects of uneven distribution of air and blood
among different alveoli. When allowance is also made for this
factor, the presence of anoxaemia during even very moderate
exertion at ordinary atmospheric pressure in persons not physi-
cally fit is just what might be expected; and at high altitudes the
anoxaemia would be so serious as to make any considerable ex-
ertion impossible but for active secretion.
All the facts, therefore, and not merely our direct measurements,
go towards showing that oxygen secretion is a most important
physiological factor, not merely under exceptional circumstances,
but during ordinary life at sea level. It is probably also an im-
portant factor under pathological conditions, though on this sub-
ject our knowledge is still almost a blank, owing to lack of
observations. The only relevant observations are those of Lorrain
Smith. ^^ His experiments, when due allowance is made for the
errors already referred to in our calculations, showed that either
a rise of body temperature or a severe infection paralyzed the
power of oxygen secretion in response to CO poisoning. When
lung inflammation was produced by exposing the animals to a
high pressure of oxygen (see Chapter XII) the arterial oxygen
pressure fell to values which, when corrected, are much below
that of the alveolar air. In this case it is evident that not only
active secretion, but also diffusion of oxygen inwards, was. inter-
fered with. The animals were incapable of muscular exertion and
thus showed symptoms similar to those of phosgene poisoning, as
described in Chapter VII.
A significant determination has quite recently been published
by Harrop^^ of the percentage saturation of human arterial blood
with oxygen, first during rest, and then just after exhausting
work. The results were 95.6 per cent during rest, and 85.5 per
cent just after the exertion. The deficiency found in the blood just
after exertion is far greater than could be accounted for by ex-
perimental errors.
As already mentioned, the aerotonometer experiments of Krogh
indicated that the arterial CO2 pressure is the same as that of the
alveolar air. The manner in which the respiratory center responds
to the slightest increase or diminution in the alveolar CO2 pres-
sure, and the quantitative correspondence between rise in alveolar
''Lorrain Smith, Journ. of Physiol., XXII, p. 307, 1898.
" Harrop, Journ. of Exper. Med., XXX, p. 246, 19 19.
248 RESPIRATION
CO2 pressure and response of the respiratory center, point most
clearly to the conclusion that within pretty wide limits there is no
active secretion of CO2 outwards in the lung, or active retention
of CO2 when the lungs are over-ventilated. In individual experi-
ments Bohr obtained results which seemed to point to active
secretion of CO2 outwards. The latest of these were made with
Krogh's small aerotonometer ; but Krogh has pointed out how
easily errors may arise with this instrument; and in view of all
the facts I think his criticism of Bohr's experiments is probably
correct.
If we calculate, by Bohr's method, the rate of diffusion of CO2
from the alveolar air into the blood, the result is that for the same
difference in partial pressure CO2, in consequence of its much
greater solubility, must diffuse outwards about 20 times as rapidly
as oxygen diffuses inwards. Against this, however, must be set the
fact that the initial difference in CO2 pressure between the venous
blood and alveolar air is only about a tenth of the corresponding
difference in oxygen pressure. On balance, however, there is prob-
ably little hindrance, even during hard work, to the establishment
by diffusion of practical equilibrium in CO2 pressure between the
alveolar air and arterial blood. We have already seen that the
giving off of CO2 in the lungs is dependent in great part on the
saturation of the haemoglobin with oxygen. Hence the giving off
of CO2 is to a large extent under the control of oxygen absorption,
and so of oxygen secretion when this occurs.
Apart from this there seem to me to be strong reasons for sus-
pecting that although active secretion of CO2, like active secretion
of oxygen, does not occur under ordinary conditions, it does occur
when high pressures of CO2 exist in the arterial blood, and the
body is threatened by the excess of COg. As yet there is no direct
evidence on this subject ; but the reasons are as follows : ( i ) When
a small volume of oxygen is rebreathed as long as possible, or
even when the breath is held as long as possible after filling the
lungs with oxygen, the percentage of CO2 in the alveolar air
mounts up much higher and more rapidly than can well be ac-
counted for from any probable rise in the pressure of CO2 in the
venous blood. Examples of experiments in this direction are given
in the paper by Christiansen, Douglas, and myself. (2) It ap-
pears that men in good training and with the power of oxygen
secretion well developed are capable of standing a much higher
percentage of CO2 in the inspired and alveolar air than other
men. In my experience with self-contained mine-rescue apparatus,
RESPIRATION
249
and similar devices, I have often been struck with the greater
sensitiveness to CO2 of myself and other sedentary workers in
comparison with men in good physical training, although nearly
pure oxygen was being breathed. These observations suggest very
strongly that along with the power of oxygen secretion the power
of secretion of CO2 is developed by muscular exertion. (3) In the
experiments of Paul Bert^^ on the blood gases when increasingly
high percentages of CO2 were breathed by animals, it appeared
that with increase in the CO2 percentage the CO2 in the arterial
blood often showed little or no increase. It seems very dif-
ficult to explain these results apart from active secretion of CO2
coming into play progressively, and particularly in view of the
experiments of Henderson and Haggard on the increased CO2-
absorbing capacity of the blood when excess of CO2 is breathed
(Chapter VIII).
In view of the absence, as yet, of direct measurements, it seems
unnecessary to discuss this question further; but I may point out
that just as the opponents of the oxygen-secretion theory have
been mistaken in drawing general conclusions from experiments
in which oxygen secretion was either absent or could not be dem-
onstrated, it is very probable that they have been equally mistaken
over secretion of CO2. Bearing in mind Johannes Miiller's argu-
ment as to the analogy between secretory activity and ordinary
metabolic processes, it seems quite likely that the active transport,
not only of oxygen, but also of CO2, is a phenomenon which oc-
curs in all living cells.
Not only do oxygen and CO2 diffuse through the lung epithe-
lium into or out of the blood, but also other gases, such as nitrogen,
hydrogen, methane, carbon monoxide, etc., so that their partial
pressures become exactly equal in the body and the alveolar air.
But how is it that oxygen is sometimes actively secreted inwards,
and that the oxygen pressure may be greater in the blood without
the oxygen leaking back by diffusion into the alveolar air just as
other gases leak in or out? We must, I think, suppose that the
structure of the alveolar epithelium is not homogeneous but may
be divided into a reticulum of living structure and a plasma filling
the interstices, just as is the case with the body as a whole. The
diffusion will take place through the plasma, while the living sub-
stance behaves as a solid towards diffusion, as in the case of the
secreting cells of the swim bladder. Not only oxygen but also
"Paul Bert, La Pression barometriqtie, p. 985.
250
RESPIRATION
other gases will diffuse through the plasma; but during secretion
of oxygen the living substance behaves like the protoplasm of the
swim bladder, taking up oxygen on one side of the cell, and giv-
ing it off at a higher pressure on the other. The oxygen will tend
to diffuse backwards if, as in experiments with a high percentage
of CO, the oxygen pressure becomes higher in the blood than in
the alveolar air; but some, at least, of this oxygen will be caught
on its way and returned.
This general conception throws light in other directions. Forj
let us suppose the direction of the oxygen secretion to be reversed,
so that the lung epithelium, instead of absorbing oxygen, hindei
its passage. Nitrogen and other inert gases will still be able to pass
inwards freely by diffusion. We shall thus have nitrogen going
through, without oxygen. Now let us suppose that the epithelium
has an excretory function ; and let us apply the general concep-
tions, above set forth, to the glomerular epithelium of the kidney.
We can imagine the living substance of this epithelium holding
back, by an active process, all the normal constituents of blood,
particularly water, if their normal diffusion pressures are not ex-
ceeded, but otherwise letting them through. All the known facts
seem to confirm Bowman's original conclusion that the water of
the urine is usually almost entirely separated in the glomeruli. It
seems also clear that as shown by Ludwig and his pupils, the
process of separation is dependent on blood pressure, like a filtra-
tion process. If we suppose that the passages through which the
liquid is filtered are not permeable by the proteins of the blood,
we have an explanation, as pointed out by Starling, of why a cer-
tain minimum blood pressure is needed. The liquid separated might
be little different from pure water, whereas the blood plasma
contains salts in considerable amount. Such a liquid could not be
separated by simple filtration, and numerous other facts are
against the simple filtration theory. I think that all the facts con-
form with the theory that the glomerulus is a filter, but with a
living framework, and that the action of this living framework,
is to pick out and return to the blood what belongs to its normal
composition, the rest being allowed to pass. In this process the
glomerular epithelium will of course be doing work; but every
living tissue seems to be always doing work, even when it is "rest-
ing." During a glomerular diuresis there may be no extra work for
the epithelium to do, and it will simply act as a filter, just as the
lung epithelium during rest under normal conditions acts like a
nonliving membrane. Barcroft and Straub have shown that during
RESPIRATION
251
certain kinds of diuresis there is no increased consumption of
oxygen by the kidney, and therefore presumably no work done by
the kidney in the process of separation of the extra urine formed. ^^
It is probable that under normal conditions a pure filtration
diuresis of this type never occurs at all; but the possibility of
producing it experimentally throws much light on the mode of
action of the glomeruli and also of the lung epithelium. Possibly
the substances carried to the lungs during anoxaemia act in the
same way as a diuretic drug acts on the kidneys.
In concluding this long chapter I must make some reference
to criticisms which have been made on our experiments. Part of
these criticisms are the evident outcome of a natural conservative
desire to save some remnant of the old mechanistic theory of
glandular secretion. The lungs and the kidney glomeruli were
the last remaining strongholds that there seemed much hope of
defending, and I can admire the spirit which has animated the
defenders. It is different, however, with the criticisms made by
my friend Mr. Barcroft in his recent book,^''' as he fully ac-
knowledges the difficulties of the diffusion theory and the inherent
probability of secretory activity in the lungs.
He bases these criticisms on the work of his pupil, Mr. Hart-
ridge. The latter devised a new and thoroughly sound method of
determining the percentage saturation of the blood with CO by
delicate measurements of the shifting in position of the absorption
bands of oxy- and CO-haemoglobin; and he showed clearly that
his method, although it requires elaborate apparatus, is capable
of giving accurate results. Armed with this method he proceeded
to repeat, as he thought, some of the experiments (not yet pub-
lished except in a short abstract) of Douglas and myself on man.
Unfortunately he modified the method in essential respects, neither
taking precautions that the subject was breathing a constant per-
centage of oxygen, nor using whole blood in the saturator, nor
experimenting in a way calculated to elicit any evidence of active
secretion during work. His experiments did not appear to show
any active secretion, and it would have been extraordinary if
they had.
I now come to the main point of Barcroft's criticisms. Hartridge
had at first calibrated his instrument by ascertaining its readings
with what he believed to be known mixtures of oxyhaemoglobin
-and CO haemoglobin. He subsequently found that his calibrations
'* Barcroft and Straub, Journ. of Physiol., XLI, p. 145, 191 1.
" Barcroft, The Respiratory Function of the Blood,, p. 204.
252 RESPIRATION
had been quite incorrect ; and in order to secure correct calibration
he finally had recourse to the very tedious method of pumping^
out the CO and oxygen from the blood mixture after adding
ferricyanide, and determining the CO and oxygen by analysis,
using the general method which I followed in originally testing
the accuracy of the ferricyanide method for blood gases. In his
paper^^ Hartridge says of his first method that "experiments
made since to discover the cause of the error have shown that
with the method of mixture employed complex interactions take
place between the two portions of solvent." Let us expand this
somewhat mystic statement. He was working with blood diluted
with water to about a twentieth. One portion of this he saturated
with CO, and another portion with air. These were then mixed. It
was apparently expected that the result would be a mixture con-
taining half the haemoglobin saturated with CO and the other
half with oxygen. Now if one dilutes blood to a twentieth and
saturates with CO, the solution will contain about one volume of
CO in combination with haemoglobin to two and one-half in
simple solution ; and when this is mixed with an equal proportion
of the solution saturated with air the CO in simple solution in the
first part will straightway combine with the haemoglobin in the
second part, and turn out the oxygen, the result being that prac-
tically the whole of the haemoglobin combines with CO. With
the method first adopted by Hartridge it was clearly impossible
for him to calibrate his instrument.
Our colorimetric method of determining the saturation of
haemoglobin with CO had repeatedly been tested against mix-
tures previously prepared, the most scrupulous precautions (de-
scribed in three different papers) being, however, taken to avoid
errors arising from the solubility of CO. Barcroft, however, infers
that because Hartridge's calibration failed with the method of
mixtures, ours was presumably also inaccurate : whereas Hart-
ridge's final calibrations were made with the blood pump, which
is an "objective method," and therefore the only trustworthy one.
Hence, Barcroft argues, Hartridge's experiments, so far as they
go, furnish the only reliable evidence about oxygen secretion, as
to which they give a negative result. As a matter of fact there is
not a shadow of doubt that our method of testing the colorimetric
method was at least as exact as the final method used by Hart-
ridge.
"Hartridge, Journ. of Physiol., XLIV, p. 9, 19 12.
RESPIRATION
253
Barcroft's reference to objective methods recalls to my mind
what happened when Hartridge came to Oxford to demonstrate
his method. It was apparently an "objective method," dependent,
like Hiifner's spectrophotometric method, on the exact positions
of absorption bands in the spectra of oxyhaemoglobin and CO
haemoglobin — bands of which the "exact positions" can be quite
easily photographed. A solution of blood was prepared for dem-
onstration; and Hartridge, the late Professor Gotch, and I went
into a dark room and proceeded first to determine the zero point
on the scale of the apparatus. First one, and then the others of us
determined the zero point. But the results were all different,
though each one of us always got the same result. We stood there
in the dark, each suspecting the others of want of accuracy, but
afraid to say so. Suddenly the truth dawned on us. Even the
position of an absorption band is subjective !
And then, if our ears could have caught it, we might have
heard a gentle but kindly laugh. It came from a Spirit that flits
round old university walls and even wanders sometimes into
laboratories. It was the Spirit of Humanism that laughed, and it
always laughs when men find out with Socrates that what is ob-
jective is also subjective.
Addendum. Barcroft and his associates'^ have recently made a
ver}^ carefully planned attempt to see whether any evidence of oxy-
gen secretion could be obtained by analyses of the arterial blood.
Barcroft himself was the subject of the experiment, and he re-
mained for a week in a respiration chamber in which the oxygen
percentage was gradually lowered, until on the last day there was
only about 1 1 per cent of oxygen in the air, corresponding to an
altitude of 18,000 feet, or about 17,000 if allowance is made for
the presence in the air of about 0.5 per cent of CO2. There was
thus apparently every chance of acclimatization occurring. On the
other hand very little acclimatization seems to have actually oc-
curred, as the subject was very unwell, with slight rise of tempera-
ture, on the last day or two, and was in a fainting condition at the
end, just before the samples of arterial blood were taken.
Samples of arterial blood were taken, firstly during rest, and
later during work on a bicycle ergometer of about 380 kilogram-
meters per minute, which would increase the respiratory exchange
about three or four times. The haemoglobin of the sample during
rest was found to be %^. I per cent saturated with oxygen. Analyses
" Barcroft, Cooke, Hartridge, T. and W. Parsons, Journ. of Physiol., LIII,
p. 450, 1920.
254 RESPIRATION
of the arterial blood were made, both by the ferricyanide method
and with the pump, and agreed closely. Samples of alveolar air
were also taken, and part of the arterial blood saturated with air
of about the same composition. The saturation of the haemoglobin
of this blood, when corrected for the slight difference in oxygen
pressure between the air in the saturator and the sample of
alveolar air, was found to be 91 to 92 per cent, which is distinctly
higher than the saturation of the arterial blood. The oxygen pres-
sure of the sample of alveolar air was, however, quite unac-
countably high. It was 6S mm., instead of about 45 mm. which was
the value actually found in a determination made a few hours
previously, and was also the value to be expected from the curve
shown in Figure 98 of this book. Had the actual alveolar gas pres-
sures corresponded with those of the sample, the respiratory quo-
tient would have been about 2 ; and such a quotient occurs only
during forced breathing, which could not have occurred. It seems,
therefore, that there must have been some mistake about the al-
veolar sample; but what this was is far from clear. If the actual
alveolar oxygen pressure had been about 45 mm., as would cor-
respond to the alveolar CO2 pressure, the oxygen saturation of
the blood from the saturator would have been considerably lower
than that of the arterial blood. The experiment is thus inconclusive,
apart altogether from the question as to whether the subject was
acclimatized at all, or to what extent.
The experiment during work is much more consistent. The
arterial haemoglobin was found to be only 83.5 per cent saturated
with oxygen. A lower saturation during work of the character
chosen corresponds well with all our observations on Pike's Peak
and at Oxford. Unacclimatized persons became very blue in the
face on Pike's Peak with comparable work ; and even after acclima-
tization there were clear indications of some anoxaemia. In me, for
instance, the alveolar oxygen pressure rose about 8 mm., and the
alveolar CO2 pressure fell, on walking at 4 miles an hour; and
this, as we pointed out, indicated arterial anoxaemia. The haemo-
globin of the blood exposed to the alveolar air in the saturator
gave a saturation of 89.2 per cent, which is 5.7 per cent higher
than the saturation of the arterial blood. This result furnishes no
evidence of secretion, but to show that there was actually no secre-
tion it would, I think, be necessary to make a control experiment
on a person who had spent only a short period in the chamber, and
was undoubtedly unacclimatized.
Barcroft and his associates consider that the results of the
RESPIRATION
255
experiments were against the secretion theory. In this I cannot
agree with them. It seems to me evident that if there was any
acclimatization in these experiments it was very imperfect, and
not comparable to the acclimatization commonly observed at high
altitudes, and closely studied by us on Pike's Peak. Acclimatization
occurs much more readily in certain persons than in others, and
seems also to be greatly affected by accompanying conditions. An
experiment in which marked acclimatization occurred in myself
in a respiration chamber was referred to above. On endeavoring
to repeat this experiment in the summer of 1920 there was no
effective acclimatization, and on account of severe symptoms of
anoxaemia, accompanied by blueness of the lips, etc., I had to
stop before the oxygen pressure had fallen to quite as low a point
as on Pike's Peak, or to nearly as low a point as in the previous
experiment where no pathological signs of anoxaemia were pro-
duced. It was about a week before I recovered from the effects of
this unsuccessful experiment. The weather was hot, and the
chamber correspondingly uncomfortable. I was also several years
older. In this experiment my arterial blood was analysed by Pro-
fessor Meakins, who found the haemoglobin to be considerably
below its normal saturation with oxygen. There was evidently
little or no acclimatization.
I should like to correct here one or two misunderstandings which
occur in the paper of Barcroft and his associates. Through a mis-
reading of the paper by Douglas and myself he concluded that
on lowering the oxygen pressure of the inspired air to what cor-
responded to about the oxygen pressure on Pike's Peak we found
in a short experiment at Oxford that by the carbon monoxide
method the arterial oxygen pressure was 70 mm. above the al-
veolar oxygen pressure. The actual difference was only trifling
(about 8 mm.), as shown in the table reproduced above. It re-
quired prolonged acclimatization to produce as great a difference
as even 35 mm. There is also a misunderstanding as to our experi-
ments on the effects of work. Though we made no observations by
the carbon monoxide method on the effects of work such as was
employed by Barcroft, all the other observations referred to in
the present chapter tend to show that except, perhaps, when physi-
cal training or acclimatization is very effective, the arterial oxygen
saturation during such work is lower than during rest.
Clear evidence is brought forward by Barcroft and his associ-
ates that no appreciable loss of dissociable oxygen occurs in ar-
terial blood which is allowed to stand for a short time. In the
256
RESPIRATION
Pike's Peak report we concluded that such a loss probably occurs.
The chief reason for this conclusion was that the aerotonometer
always gives a lower oxygen pressure than that deduced on the
diffusion theory from the alveolar oxygen pressure, or indicated
by the carbon monoxide method during rest under ordinary baro-
metric pressure. As explained above, however, there is now an-
other and very clear explanation for this ; and since the investiga-
tion by Meakins, Priestley, and myself on the effects of shallow
breathing I have altogether ceased to believe in the presence, to
any extent which would upset a blood-gas or aerotonometer de-
termination, of "reducing substances" in blood. I am in entire
agreement with Barcroft's criticism of the old experiments by
which Pfliiger believed that he had demonstrated the existence
of reducing substances in fresh arterial blood. It may also be men-
tioned here that in some unpublished experiments Douglas and I
were unable to obtain any evidence by blood-gas analysis of the
presence of reducing substances, even in blood which was com-
pletely reduced by prolonged stoppage of the circulation in the
arm.
CHAPTER X
Blood Circulation and Breathing.
Although it does not fall within the scope of this book to deal
in detail with the physiology of the circulation, yet the connection
between breathing and circulation is so specially intimate that a
chapter must be devoted to this subject. Physiology is most em-
phatically not a subject which can be divided off into water-tight
compartments.
We have seen that it is with the composition of the arterial
blood that breathing is essentially correlated ; but it has also been
shown in successive chapters that the amount and composition of
the blood returning from the tissues to the lungs play a most es-
•Sentialpart in determining the composition of the arterial blood,
anH^are thus intimately correlated with breathing. If, moreover,
the~Bloo^^UUUlv to the brain and other tissues is insufficient, or
the blood is abnormal in composition, the breathing is affected in
various ways. On the other^harid circulation is intimately de-
pendent on breathing. If the__breathing is hindered the' circulaHbn
is quickly'^aHected ; and, as Yandell Henderson was the first to
show, excessive breathing brings about failure of the circul^ion.
Thus we cannot at all fully understand how the breathing is regu-
lated and what part it is playing unless we understand the dis-
tribution of the circulating blood and the means by which its
composition in the tissue capillaries is regulated.
It seems evident that the most urgent and immediate need for "\
an adequate blood supply to any part of the body arises from the I
necessity for a continuous supply of fresh oxygen. If the supply
of oxygen to the arterial blood is cut off in a warm-blooded animal
by placing it in nitrogen or hydrogen, loss of consciousness oc-
curs as soon as the store of oxygen in the lungs and venous blood
is washed out. In man eight or ten breaths suffice for this during
rest, and still fewer breaths during exertion. In very small ani-
mals, with their rapid breathing and circulation, two or three
seconds are sufficient; and a few seconds afterwards the heart is
paralyzed also. The important effects of even a slight diminution
in the pressure of oxygen in the arterial blood have been made
clear in preceding chapters.
258
RESPIRATION
A second, but somewhat less urgent, need is for a continuous re-
moval of carbonic acid or any other acid product formed in the
tissues. We can probably express this generally as a need for pre-
venting an abnormal proportion of hydrogen ions to hydroxyl
ions. The effect on the central nervous system of a sudden flooding
with CO2, without deficiency of oxygen, is almost as striking,
though not so immediately dangerous to life, as the effect of
deprivation of oxygen. The results of even a slight variation in
arterial CO2 pressure have often been referred to already.
Other conditions in the blood besides the diffusion pressures of
oxygen and CO2 or other acid products are just as important to
life. For instance there are the diffusion pressure of water (inac-
curately identified with osmotic pressure) and the diffusion pres-
sures of the ions of various inorganic salts, on the importance of
which the investigations of Ringer and many others have thrown
much light. But none of these values vary in the same rapid
manner as the diffusion pressures of oxygen and CO2 do ; and of
ordinary nutrient substances present in blood, the tissues them-
selves appear to possess a store which can be drawn on if the
supply from the blood fails for a time. The results of perfusion
experiments continued with the same blood indicate that if only
the blood is properly aerated it continues for a very long time to
support life in the tissues.
It would seem, therefore, that the regulation of circulation
through the tissues must in the main be determined in correlation
with the need for supplying oxygen and removing CO2. There
are evidently, however, cases where some other factor determines
the circulation rate. For instance, the skin circulation is de-
termined to a large extent in relation to the regulation of body
temperature; and the circulation through an actively secreting;
gland is probably determined to a considerable extent in corre-
lation with local excess or deficiency of water or dissolved solids.
We can form a general idea as to what changes in gaseous
composition determine the circulation rate through the tissues if
we compare the arterial blood with the mixed venous blood re-
turning to the lungs. As regards this point, analyses showing the
difference in composition have already been quoted in Chapter V,
and indicate that, in the animals experimented on, the blood in
its passage through the tissues had lost about a third of its avail-
able oxygen, and gained the amount of CO2 which would cor-
respond to the loss of oxygen when allowance is made for the
existing respiratory quotient of the animal. If we applied these
RESPIRATION 259
results to man, and interpreted them in the light of the thin line
in the dissociation curves of oxyhaemoglobin shown in Figure 28
(assuming that the haemoglobin of arterial blood is 95 per cent
saturated) and the thick line in the corresponding curve for CO2
(Figure 26) it would appear that the average pressure of oxygen
in the venous blood is about 5.2 per cent of an atmosphere, or
40 mm. of mercury, and the average pressure of CO2 about 47 mm.
The experiments were, however, made on animals, while the dis-
sociation curves (the only accurately determined ones) are for
human blood. Moreover the animals, owing to operative disturb-
ances, anaesthetics, etc., were more or less under abnormal con-
ditions. Hence the inferences just drawn are mere approxima-
tions. The very great variability in the CO2 content of the samples
of arterial blood from animals of the same species, as compared
with the constancy of CO2 content in the case of man under normal
resting conditions, is in itself very significant. The history of the
investigations detailed in the preceding chapters is sufficient to
warn us of the necessity for reaching more than rough approxima-
tions in physiological investigation, and for expecting that physio-
logical regulation of the circulation may turn out to be something
just as delicate and definite as regulation of respiration. It is to
measurements in man, rather than in animals, that we must look
for information of sufficient physiological accuracy, just as it has
been through measurements in man that our definite information
as to the regulation of breathing has been obtained.
The difficulty as regards human experiments has till quite
recently been that of suitable methods. We can easily measure
the blood pressure, pulse rate, etc., in man; but the information
thus obtained is extremely limited in value and almost impossible
to interpret satisfactorily in the absence of information as to the
rate of blood flow. Direct measurements of the rate of blood flow
in anim^als have been carried out by means of the Ludwig
"Strohmuhr" and the improved forms of it which have been
applied to measuring the blood flow through the aorta; but the
operative disturbance is far too serious to allow of sufficiently
definite results being obtained. Valuable information of a rough
kind was obtained by Zuntz and Hagemann-*^ in experiments in
which the gases of the venous and arterial blood were determined
in horses, along with the total respiratory exchange, during rest
and work. These experiments seemed to show clearly that the
^ Zuntz and Hagemann, Landwirtsch. Jahrb., 27, Supplem. Bd. Ill, 1898.
26o
RESPIRATION
general circulation rate is considerably increased during muscular
work, so that, in spite of the enormous increase in consumption of
oxygen and production of COg in the body, there is still a good
deal of oxygen in the venous blood.
Other very interesting experiments were made on man by
Loewy and von Schrotter.^ They succeeded in introducing a
modified Pfliiger lung catheter (Figure 68) into a branch bron-
chus or one of the two main bronchi in man. The supply of fresh
Figure 68.
Lung-catheter as used by Loewy and von Schrotter. The lung-catheter con-
sists of a central inner tube open at the lower end, and an outer tube ending
below in a distensible bulb which can be blown up by the rubber bag when the
end of the catheter is placed in position in a bronchus. By means of the syringe
and glass sampling tube a sample of gas from beyond the bulb can be collected
over mercury free of air.
air to the corresponding part of a lung, or whole lung, was thus
completely cut off and remained so for long periods. The breath-
ing, however, went on quite quietly and naturally, just as before,
even though all the air usually distributed to the two lungs was
going to only one lung. It is very significant that so little dis-
turbance in breathing, etc., was produced; but the fact is quite
easily intelligible now in the light of the preceding chapters. The
"Loewy and von Schrotter, Die Blutctrculation beim Menschen, 1905.
RESPIRATION 261
lung which remained connected with fresh air was receiving
much more fresh air than usual, so that the proportion of COg
in the arterial blood from this lung would be reduced practically
in proportion to its increased ventilation. This blood would mix
with the venous blood from the other lung, and in this way form
a mixture in which the proportion of CO2 was about normal. The
arterial blood from the ventilated lung would, in virtue of the
higher pressure of oxygen and lower pressure of CO2, contain
slightly more oxygen than usual, while the blood from the un-
ventilated lung would contain considerably less. The result would
be a mixture containing an abnormally low proportion of oxy-
gen, but not sufficiently low to cause any marked immediate dis-
turbance. Even with a whole lung blocked off, the haemoglobin
of the mixed arterial blood would be at least 85 per cent saturated
with oxygen instead of 95 per cent, so that the effect on the breath-
ing would be no greater than the probable effect, hardly notice-
able at the time, of breathing air containing 14 per cent of oxy-
gen, or ordinary air at a height of about 1 1,000 feet.
Analyses of the air in the blocked lung showed that after a
comparatively short interval of time the percentages of oxygen
and CO2 became steady, and were, in different individuals, about
5.3 per cent of oxygen and 6.0 per cent of CO2, corresponding
respectively to 37.5 mm. and 42 mm. These values are evidently
the pressures of oxygen and CO2 in the venous blood. The low
value of the venous CO2 pressure was quite unintelligible at the
time, since the average arterial CO2 pressure is about 40 mm. as
shown above. The experiments of Christiansen, Douglas, and
myself (Chapter V) showed, however, that the true venous CO2
pressure is in reality only a little higher than the arterial COg
pressure; and if we allow for the fact that the breathing was
presumably slightly increased by the stimulus of want of oxygen
the result is just what might be expected. The venous oxygen
pressure would be somewhat lower than usual, since the arterial
blood was incompletely saturated with oxygen. Hence both the
oxygen pressure and the CO2 pressure would be below normal.
The results of these experiments were nevertheless of the highest
interest.
It is evident that if by any means we can measure the rate of
blood flow through the lungs, and at the same time measure the
intake of oxygen and discharge of CO2 from the blood, we can
calculate how much oxygen a given volume of the blood gains,
and how much CO2 it loses, in the lungs ; and in this way we can
262 RESPIRATION
indirectly calculate how far the gain and loss vary under different
conditions. A rough method devised by Yandell Henderson for
measuring the relative rates of the blood flow was used in the
Pike's Peak expedition, and served to indicate that the rate of
blood flow remained practically normal in spite of the great alti-
tude. Another method, the principle of which was tried, though
without success, by Henderson on Pike's Peak, was about the same
time independently worked out and extensively used by Krogh
and Lindhard at Copenhagen.^ This method gives absolute and not
merely relative results. The principle of the method is that the
lungs are filled by a very deep breath with a mixture containing a
considerable percentage of nitrous oxide, a gas which is very solu-
ble in blood. A sample of alveolar air is taken after an interval of
five seconds to allow the lung tissue to become saturated with the
nitrous oxide, and after a further interval during which the breath
is held, another alveolar sample. By determining the nitrous
oxide in the two samples, and also the total volume of gas in the
lungs, we find out how much nitrous oxide has been absorbed.
Knowing the solubility of nitrous oxide in blood, and assuming
also that the blood leaving the lungs is fully saturated with nitrous
oxide to the existing partial pressure of the gas, we can calculate
from the loss of nitrous oxide how much blood has passed through
the lungs in the given time interval. The experiment must be
carried out so rapidly that the venous blood continues to be free
of nitrous oxide.
There are various sources of probable error in this method, but
in the hands of Krogh and Lindhard it gave fairly consistent
results. They found that during rest the amount of blood circula-
ting through the lungs of an adult man varies from about 2.8
to 5 liters per minute, and that the arterial blood loses about 30
to 60 per cent of its available oxygen on an average, and during
considerable work about 50 to 70 per cent. The following table
gives calculated volumes of blood passing through the lungs, and
calculated percentage losses in the available oxygen of the blood
as it passes round the tissues.
It will be seen that, allowing for the fact that the haemoglobin
of arterial blood is only 95 per cent saturated with oxygen, the
haemoglobin of the venous blood was apparently only 38 per cent
and 53 per cent saturated in the two resting experiments. The
flow of blood through the lungs during work appeared to be a^
' Krogh and Lindhard, Skand. Arch, f, Physiol., XXVII, p. 100, 191a.
RESPIRATION
263
much as six times as great as during rest. As the pulse rate only
went up to about double the normal, the volume of blood expelled
from the heart at each systole must, if these results were reliable,
have been trebled. This would be just as striking an increase as
occurs in the depth of breathing during muscular work. The values
for utilization of the available oxygen of the arterial blood are
Subject
Work in kg.m.
Calculated blood Percentage utilization
■per minute
flow — Liters per
of available 0% of
minute
arterial blood
J.L.
0
2.8
60
»>
458
9.8
73
»
I minute after
work
4.45
44
A. K.
0
2.95
46
"
446
16.0
47
j>
552
17.6
51
not very far from those obtained in the horse by Zuntz and
Hagemann, but do not agree at all well with those of Loewy and
von Schrotter in man. In the case of six experiments on different
individuals where approximate data were available the latter
observers calculated a utilization of rather less than 20 per cent
during rest.
During or since the war several other observers have used the
method of Krogh and Lindhard, and obtained more or less similar
results. These observers include Boothby,^^ as well as Newburgh
and Means^^ in America. Lindhard^^ has also published a
number of additional results, which give, on the whole, a distinctly
higher rate of circulation, and lower percentage utilization of
oxygen, during rest.
The subject had meanwhile been approached by a quite different
method by Yandell Henderson.^ He used dogs for his experi-
ments, and placed a recording plethysmograph round the heart
after removing the pericardium. By this method he found that
the volume of blood discharged per heartbeat was approximately
the same, whether the heart was beating faster or slower. Thus
within wide limits the volume of blood discharged per minute
'^Boothby, Amer. Journ. of Physiol., XXXVIll, p. 383, 1915.
'^ Newburgh and Means, Journ. of Pharm. and Exp. Therap., VII, p. 4, 19 15.
"^ Lindhard, PfHiger's Archiv.
* Yandell Henderson, Amer. Journ. of P/tysioL, XVI, p. 325, 1906.
264
RESPIRATION
appeared to depend almost entirely on the pulse rate. He concluded
that under normal conditions the heart is, practically speaking,
always adequately filled during diastole, although under abnormal
conditions the filling may become inadequate — for instance when
the carbon dioxide of the blood is greatly reduced by excessive
artificial respiration. If we apply Henderson's conclusions to man
it is evident that they cannot be reconciled with those of Krogh
and Lindhard. On Henderson's theory the increased absorption of
oxygen and discharge of CO2 from the blood passing through the
lungs during muscular exertion must be due to a very large ex-
tent to greater utilization of the oxygen in the blood passing
round the body, and a corresponding increase in its charge of COg.
The rate of circulation can only be increased in proportion to in-
creased pulse rate, the discharge of blood per systole remaining
about the same.
There is no question that the systolic discharge may, at least
under abnormal conditions, vary enormously. This was very
clearly shown by the experiments of Starling and Patterson,^ with
a "heart-lung preparation" — i.e., a preparation in which the
only circulation was through the lungs and heart, the lungs being
ventilated so as to insure full oxygenation of the blood. By vary-
ing the venous blood pressure, the systolic discharge could be
varied tenfold, without any variation in the pulse rate. It does not
follow, however, that there are corresponding variations in systolic
discharge in normal men and animals with the organic regulation
of circulation not thrown out as in the case of a heart-lung prepa-
ration.
In the nitrous oxide method there are various sources of pos-
sible very serious error which can hardly be discussed in detail
here. In order to get a more direct and accurate insight into the
venous gas pressures and their relation to blood flow, a new
method was introduced by Christiansen, Douglas, and myself.^
In the first application of this method we simply determined the
COo pressure of the venous blood atter oxygenation but without
its losing any COg. As we had already discovered (see Chapter
V), this pressure is higher by an easily calculable amount than
that for the unoxygenated venous blood. Mixtures containing
about the required percentage of CO2 were prepared by adding
COo to air. A deep breath of one of these mixtures was taken in
•starling and Patterson, Journ. of Physiol., XLVIII, p. 357, 19 14.
"Christiansen, Douglas, and Haldane, Journ. of Physiol., XLVIII, p. 244,
1914.
RESPIRATION 265
after previously expiring deeply. After two seconds part of the
air in the lungs (about i^ liters) was expired, so as to obtain a
sample of alveolar air. The rest of the breath was held for five
seconds and a second sample of alveolar air was then taken. If
these two samples gave practically the same percentage of CO2,
the CO2 in the alveolar air was evidently in pressure equilibrium
with the CO2 of the oxygenated venous blood. If too much CO2
were present in the alveolar air the second sample would contain
less CO2 than the first, and if too little, more. We were thus using
the whole of both lungs as an aerotonometer. For any particular
person it was easy to find the mixture which gave equilibrium.
With the help of Figure 26 (Chapter V) we could then calculate
the CO2 content of the venous blood and the true value of the
venous CO2 pressure. We could also calculate how much CO2 the
blood had taken up in passing round the body if we knew
the normal alveolar CO2 pressure. The following table shows the
results obtained during complete rest in a sitting position with the
four subjects investigated.
Subject
Arterial CO2 pressure
Venous CO2 -pressure
Difference
in mm. Hg.
in mm. Hg.
J. c.
34.9
41.8
6.9
J. S. H.
40.6
45-6
5.0
C. G. D.
39-7
44.4
47
J. G. P.
40.4
45.1
4.7
Mean
38.9
44.2
5.3
Reference to Figure 26 shows that on an average the venous
blood had only-taken up about 24 per cent of the CO2 which it
would have taken up if all its available oxygen had been used up.
Hence the blood had only lost about 24 per cent of its oxygen in
passing round the circulation; and in the three male subjects the
proportion lost was only about 21 to 22 per cent. This indicates a
much faster circulation rate during rest than the nitrous oxide
method had shown.
At the outbreak of war. Dr. Douglas and I were engaged
in carrying these experiments further; but as he volunteered at
once for active service they were interrupted; and owing to the
disorganization following the war they are not yet completed,
though I was able to carry them on up to a certain point with
help from Dr. Mavrogardato, and to communicate a number of
266 RESPIRATION
results to the Physiological Society in 191 5. We had been engaged
in measuring directly both the true venous CO2 pressure and
oxygen pressure just after forced breathing, so as to discover the
effects of lowered CO2 pressure on the circulation. We found that
the apparent venous oxygen pressures were incredibly high —
70 mm. or even more. On further investigation it became evident
that after a single deep expiration, followed by a single deep in-
spiration of the gas mixture, the air in the alveoli was not properly
mixed. At the end of the forced breathing there would be nearly
20 per cent of oxygen in the alveolar air. With one deep inspira-
tion of the mixture, the air in the air-sac system of alveoli was
mingled with air from the inspired mixture, but an even mixture
in all parts of the alveolar system was not obtained, so that the
air-sac alveoli contained considerably more oxygen than the rest
of the alveoli. As a consequence the second alveolar air sample,
taken more exclusively from the air-sac alveoli, contained more
oxygen than the first, in spite of the fact that it had remained
longer in the lungs. It was evidently necessary, therefore, to take
two or, in the case of forced breathing, three successive deep
breaths of the mixture before holding the breath and taking
the samples. When this was done the results were quite consistent,
and showed that the venous CO2 pressures as determined directly
during rest confirmed the calculated values previously obtained ;
while the venous oxygen pressures, when interpreted in the light
of the thin-line curve of Figure 28, corresponded very closely
with the percentage oxygen loss of the blood as calculated indi-
rectly from the venous CO2 pressure. Moreover, not only the
venous CO2 pressure, but also the venous oxygen pressure, was
considerably lower at the end of forced breathing.
The following are examples of two typical experiments carried
out on myself at the end of ten minutes' rest on a chair.
No. I, 26/2/15. Bar. 762 mm.
Mixture used contained 6.21 per cent of CO2 and 5.73 per cent of
oxygen.
First alveolar sample 2" after last deep inspiration, 6.43 per cent
of CO2 and 6.18 per cent of oxygen.
Second alveolar sample 5" after first sample, 6.47 per cent of CO2
and 6.22 per cent of oxygen.
Therefore venous COg pressure = 6.47 per cent = 46.16 mm. and
oxygen pressure 6.22 per cent = 44.5 mm.
Normal alveolar COg percentage (mean of inspiratory and expira-
tory samples) 5.64 per cent = 40.3 mm.
RESPIRATION
267
Metabolism (by Douglas Bag method) = 330 cc. of COg and 379
cc. of oxygen (at 0° and 760 mm.) per minute.
As the venous CO2 pressure was 6.0 mm. above the arterial,
the blood (calculating from Figure 26) had gained 4.2 per cent
by volume of CO2. Hence the circulation rate calculated from CO2
330
was = 7.9 liters per minute. As the venous oxygen pressure
42
was 44.5 mm. and this corresponds, calculating from Figure 28,
to 73 per cent saturation of the haemoglobin, the blood had lost
about 22 per cent of its combined oxygen. Adding the correspond-
ing small amount of dissolved oxygen this corresponds to a loss
of about 4.3 volumes per cent of oxygen. Hence the circulation
rate, calculating from the oxygen, was =8.8 liters per
43
minute.
No. 2. 27/2/1$. Bar. 752 mm.
Mixture used contained 6.26 per cent of CO2 and 5.26 per cent of
oxygen.
First alveolar sample 2" after last deep inspiration, CO2 = 6.26
per cent and Og = 6.25 per cent.
Second alveolar sample 5" after first sample, CO2 = 6.30, O2 =
6.09 per cent.
Therefore venous CO2 pressure =: 6.30 per cent z= 44.4 mm. ; and
oxygen pressure 6.09 per cent ^ 42.9 mm.
Normal alveolar COg pressure (mean) = 5.55 per cent r= 39.1 mm.
Metabolism 332 cc. of CO, and 374 cc. of oxygen absorbed (at 0°
and 760 mm.) per minute.
As the venous CO2 pressure was 5.3 mm. above the arterial, the
blood (calculating from Figure 26) had gained 3.7 volumes per
cent of COg. Hence the circulation rate calculated from COo was
332
= 9.0 liters per minute. As the venous oxygen pressure was
42.9 mm., and this corresponds (Figure 28) to 70 per cent satura-
tion of the haemoglobin, the blood had lost about 25 per cent of
combined oxygen or about 4.9 volumes per cent of oxygen. Hence
the circulation rate, calculating from the oxygen, was -^^ =80
47
liters per minute.
If we take these two experiments together, the circulation rate
determined from the CO2 was 8.45 liters per minute, and from
268 RESPIRATION
the oxygen 8.40 liters, the general mean being 8.4 liters. As my
pulse rate was 80 to 85 per minute this means that just about 100
cc. of blood were delivered at each heartbeat; and as my blood
volume is about 4.8 liters (see p. 280 of the Pike's Peak Expedi-
tion's Report) a volume of blood equal to that in the whole body
was passing round every 35 seconds.
This is a much higher rate than has usually been calculated in
recent years, but not higher than what the data of Loewy and
von Schrotter indicate. There are so many sources of probable
error in the nitrous oxide method,''' that I do not think that much
stress can be laid on the lower estimates which this method has
given during the resting condition. Nevertheless it is already
evident from our experiments that considerable individual dif-
ferences exist in the resting circulation rate in man; and it is
probable that under abnormal conditions both the circulation
rate and the delivery per beat vary considerably even in persons
of the same weight.
At different times we have found very little difference in the
resting venous gas pressures of the same individual. These gas
pressures seem to be not much less steady during rest under
normal conditions than the arterial gas pressures. It is very dif-
ferent, however, during exertion. The smallest muscular exertion
raises the venous CO2 pressure, and the rise is far more than
corresponds to the comparatively slight rise in arterial CO2 pres-
sure as measured in the ordinary way in the alveolar air. Hence
it is now perfectly certain that the general circulation rate does
not increase in anything like direct proportion to increased me-
tabolism. Even with moderate exertion (about a third the maxi-
mum possible) on a Martin's ergometer, the difference between
arterial and venous CO2 pressure became about two and one-half
times as great as usual, so that the venous blood could not be more
than about 45 per cent saturated with oxygen. So far as we can
calculate there is sometimes more increase in circulation than can
be accounted for by increased pulse rate ; but the increase is seldom
' For instance, it seems very probable that while the breath is held in perform-
ing an experiment the blood flow to the heart, and consequently through the lungs,
is temporarily diminished. Krogh and Lindhard, misled, as we believe, by the
imperfect mixture of oxygen in the alveolar air in their experiments, estimated that
there is a greatly increased absorption of oxygen, and a corresponding abnormal
increase in circulation, while the breath is held; and their results are corrected
accordingly. The correction, which is a large one, does not seem to us to be war-
ranted, and without it their results come much closer to ours. This is especially
true for Lindhard's later results.
RESPIRATION 269
great. Roughly speaking, therefore, our results confirm those
obtained by Henderson on the dog.
Henderson and Prince have determined in a number of persons
the oxygen consumption per beat of the heart, or what they call
for brevity ''the oxygen pulse."^ This value is obtained by simply
dividing the oxygen consumption per minute by the pulse rate.
Figure 69 shows graphically a fairly typical example of their
•05 5SS
"2 i^z
25 2500
ZO 2000 ■
15 i&oo
<0 looo
5 500
Pylse 60 70 &0 90 100 110 120 130 140 »50 160
Figure 69.
Subject Y. H., Weight 75 kilos. Haemoglobin 107. In this diagram the
broken line expresses the oxygen consumption per minute, the dotted line the
CO2 elimination, and the solid line the oxygen pulse. During the short periods
of vigorous exertion and rapid heart rates, the CO2 elimination was increased
to a greater extent than the oxygen consumption, the respiratory quotient even
rising above unity in some cases, and indicating an excessive blowing off
of CO2.
results. It will be seen that with low oxygen consumption per
minute the oxygen consumption per beat is low, but increases
rapidly up to a maximum as the oxygen consumption per minute
increases owing to muscular exertion. When, however, this maxi-
mum is reached, further increase of the oxygen consumption per
minute causes no increase in the oxygen consumption per beat.
Interpreting these data in the light of our own experiments on
man, and Henderson's former experiments on the heart of the dog,
the increased oxygen consumption per beat is not due to any
marked extent to increased output of blood per beat, but to in-
creased utilization of the charge of oxygen in the arterial blood.
' Yandell Henderson and Prince, Amer. Journ. of Physiol., XXXV, p. 106, iqM-
2 70
RESPIRATION
When this increased utilization reaches its physiological limit,
further increase in the oxygen consumption per minute can only
be obtained by increase in the rate of heartbeat.
The mixed venous blood returning to the heart comes from
various parts of the body ; but during muscular exertion a very
greatly increased proportion must come from the muscles. Now
there is evidence from a series of experiments by Leonard Hill
and Nabarro that the venous blood returning from the muscles
contains even during rest far less oxygen and more CO2 than at
any rate the venous blood returning from the brain.^ Without
obstructing the vessels they collected venous blood returning from
muscles through the deep femoral vein, and from the brain
through the torcular Herophili in the dog. The following table
shows the average of about eight determinations in each case.
OXYGEN, VOLUMES
Percentage
PER CENT
loss of
Artery
Vein
Difference
oxygen
fMuscle
18.10
5.12
—12.98
72
Rest
Brain
16.81
13.39
— 3.42
20
Tonic
fMuscle
17.05
3.30
—13.75
81
fit
Brain
15-17
10.22
— 4.95
32
Clonic
Muscle
18.66
6.03
— 12.63
69
fit -
Brain
1577
11.46
— 4.31
27
It will be seen ( i ) that during rest the blood lost three and one-
half times as much of its charge of oxygen in the muscles as in
the brain; (2) that during the intense activity of a tonic or clonic
fit (produced by absinthe) the percentage loss of oxygen by the
blood was only slightly increased in either the brain or the muscles.
The animals were anaesthetized with morphia or chloroform, so
it is possible that the circulation was less active than in normal
animals; but the difference between the brain circulation and
that through muscles is none the less striking.
In the light of these experiments we can see what is presumably
happening as regards the mixed venous blood during muscular
•Leonard Hill and Nabarro, lourn. of Physiol.. XVIII, p. 218, 1895.
RESPIRATION
271
activity. The chief reason why the oxygen diminishes and COg
increases so strikingly is that the mixed venous blood contains
a much larger proportion of blood from muscles, and that this
blood is very poor in oxygen whether the muscles are working or
not. During rest the mixed venous blood will contain but little
blood from the muscles, and a large proportion from the brain
and probably other parts which furnish venous blood relatively
rich in oxygen. As indicated by the size of its arteries, the brain
has a very rich blood supply, going mainly to the gray matter.
Its normal oxygen pressure is evidently very high; and this
renders intelligible the fact that it is so sensitive to deficient satu-
ration of the arterial blood with oxygen. The rapid circulation
explains the promptness of its reaction to changes in quality of
the arterial blood.
The fact that during muscular exertion the mixed venous blood
contains much less oxygen and more CO2 explains why, if the
breath is voluntarily held during exertion, the alveolar CO2
percentage shoots up much higher than if it is held for a far
longer time during rest. It also explains what would otherwise
be a very puzzling fact with regard to congenital heart affections
(''morbus coeruleus"). In cases of morbus coeruleus the face
becomes intensely blue on muscular exertion. Quite evidently the
arterial blood is very imperfectly oxygenated ; and Douglas and I
found that the blueness continues even if the patient breathes pure
oxygen during the exertion. The blueness is due to part of the
venous blood short-circuiting through a congenital direct com-
munication between the right and left sides of the heart, so that
the mixed arterial blood always contains a certain proportion of
unaerated venous blood. During rest this venous blood contains
so much oxygen that the cyanosis is only slight ; but during exer-
tion, with much less oxygen in the venous blood, the cyanosis is of
course far more marked, and the breathing of oxygen avails very
little towards redressing the balance.
It is evident from the facts just referred to that the increase in
blood flow through the lungs during exertion is very much less
than the increase in air breathed. At first sight, therefore, it might
seem that the regulation of circulation differs fundamentally from
the regulation of breathing. A little consideration, however, shows
that there are no real grounds for this conclusion. If we take as our
measure, not the blood flow through the heart, but the blood flow
through individual parts of the body, the facts so far discussed do
not point to any other conclusion than that the blood flow, just
2 72 RESPIRATION
like the breathing, is delicately regulated in accordance with the
local requirements for the supply of oxygen and removal of COg.
The idea that the local circulation is regulated in accordance
with the local CO2 pressure was brought forward in a very definite
form by Yandell Henderson in a series of papers on "Acapnia and
Shock."^^ He showed, firstly, that the local circulation and iunc-i
tional activity in the exposed intestines depends upon the main-
tenance in them of a sufficient pressure of CO2, and secondly, that
on the removal of an excessive quantity of CO2 from the body by
excessive artificial or natural respiration the circulation fails,
whereas excessive ventilation with air to which sufficient CO2 has
been added produces no such effect. These are evidently facts of
fundamental importance as regards the regulation of the circula-
tion, and as showing the intimate connections between respiration
and circulation. On these and other observations he also based the
theory that the immediate cause of shock may be excessive res-
piratory activity.
The blood-gas changes caused by excessive artificial respira-
tion were first investigated by Ewald in connection with apnoea.^^
He not only found that there is a slight excess of oxygen and verj^
large deficiency of CO2 in the arterial blood, but also (though of
this he did not realize the significance) that there is great de-
ficiency of both CO2 and oxygen in the mixed venous blood. The
changes in the arterial blood have already been discussed in earlier
chapters, and it was pointed out in Chapter VII that owing to the
deficiency of CO2 a state of anoxaemia must, other things being
equal, be produced by forced breathing. Ewald's analyses show,
however, that there is something more to cause anoxaemia than
mere deficiency of CO2. The latter would not by itself account
for the deficiency of oxygen combined with haemoglobin in the
venous blood. In long experiments Ewald found this oxygen down
to about a third of the normal, and the CO2 down to half the
normal. Taking into account both the direct effect of deficiency
of COo in diminishing the free oxygen present in the venous blood,
and the effect in the same direction of the diminished proportion
of oxyhaemoglobin present, the artificial respiration must have
brought about a condition of very intense anoxaemia in the tis-
sues. But the diminution in the proportion of oxyhaemoglobin
" Vandell Henderson, Amer. Journ. of Physiol., XXI, p. 126, 1908; XXIII,
p. 345. xqoq; XXIV, p. 66, 1909; XXV, p. 310, 1910; XXV, p. 385, 1910;
XXVI, p. 260, 1910; XXVII, p. 152, 1910; XLVI, p. 533, 1918.
"Ewald, Pfluger's Archiv., VII, p. 575, 1873.
RESPIRATION
273
cannot have been due to any other cause than diminution in the
circulation rate ; and this diminution is shown far more directly
by Yandell Henderson's experiments and numerous blood-gas
analyses by the ferricyanide method. The diminution in circula-
tion goes so far that the venous return to the heart becomes quite
inadequate to fill the ventricles. Hence arterial as well as venous
pressure finally falls, and the heart itself is inadequately supplied
with free oxygen or CO2, and gradually fails along with fail-
ure in the brain and other parts of the body.
Slowing of the circulation through the hands during forced
breathing was clearly demonstrated by his calorimetric method by
G. N. Stewart.ii^
By means of the new method for determining venous gas pres-
sures in man we found that though there is a considerable fall,
after forced breathing for about three minutes, in the CO2 con-
tent of the mixed venous blood, there is, relatively speaking, an
even greater fall in the oxygen content. The experiments were
difficult because of the mental state of the subject. I had to be
watched very closely to see that I carried out the proper manipula-
tions, and many experiments failed because of gross errors, such
as taking in a deep breath of ordinary air from the room. The gas
mixture used had to contain less than 4 per cent of oxygen and
less than 5 per cent of CO2. The fall in oxygen pressure was con-
siderably more than could be accounted for as due to the fall in
CO2 pressure on account of the Bohr effect. Hence the circulation
rate was diminished. The mental condition was apparently due to
marked anoxaemia of the nervous centers ; and it may be remarked
that owing to the rapid normal circulation through the brain the
effects of the forced breathing must be felt there sooner than else-
where.
We also investigated the effect on the circulation of a moderate
excess of CO2, sufficient to increase the breathing to about five
times the normal. This was easily accomplished in a respiration
chamber in which the CO2 percentage had been raised to a little
over 5 per cent. Under this condition there was a slight rise in
both my arterial and venous CO2 pressure ; but the difference
between them was not diminished. Thus there had been no ap-
preciable increase in the circulation rate. It was quite clear that
the circulation does not increase with increased arterial CO2 pres-
sure in a manner corresponding to the increase of breathing. The
"'^ G. N. Stewart, Amer. Journ. of Physiol., XXVIII, p. 190, 191 1.
2 74
RESPIRATION
breathing had increased five times or more, but the circulation
had apparently not increased at all. The pulse, etc., were also
hardly affected. With a great excess of COg, however, the ve-
nous return to the right heart is evidently much increased. This
was first definitely observed by Yandell Henderson, who also
makes the, to me, interesting remark that he first noted the signs
of increased circulation rate on myself, while I was nearly over-
come by accumulation of CO2 in a mine-rescue apparatus, without
any deficiency of oxygen. ^^ Similarly, great deficiency of CO2, as
in forced breathing or excessive artificial respiration, will dim-
inish the circulation rate ; and it seemed probable that great in-
crease in the oxygen pressure in the tissues (though this is diflRcult
to produce except under the high atmospheric pressures referred
to in Chapter XII) would have a similar effect.
That this effect is actually produced in man is indicated by the
results of quite recent experiments by Dautrebande and myself.-^*
We found that when pure oxygen was breathed, particularly under
a barometric pressure increased to two atmospheres, the breathing
increases, as shown by a fall in alveolar CO2 pressure, and there
is a simultaneous slowing of the pulse. This indicated a slowing
of circulation through the brain, such as would compensate for
the high oxygen pressure of the arterial blood. The slowing would
of course raise the pressure of CO2 in the brain, and thus increase
the breathing. It would also explain the fact that though oxygen
at two atmospheres pressure has a rapid poisonous action on the
lungs and other living tissues directly exposed to it (see Chapter
XII), there are no evident cerebral symptoms until oxygen at
much higher pressures is breathed.
The responses involved in the chemical control of the venous
return to the right heart were found by Henderson and Harvey to
be peripheral, but independent of the vasomotor nerves and nerve
endings. In the "spinal" cat they found that slow injections of
adrenalin, and other prolonged vasomotor stimulations, cause a
maintained elevation of arterial pressure, but only an evanescent
rise of venous pressure. Ventilating the lungs with air rich in CO2
(with ample oxygen) has, on the contrary, in the absence of the
medullary vasomotor center, no appreciable direct effect upon
arterial pressure, but induces a gradual, sustained and large eleva-
tion of venous pressure. They note also that during this action
"Yandell Henderson and Harvey, Ainer. Journ. of Physiol., XLVI, p. 533,
1918.
"Dautrebande and Haldane, Journ. of Physiol., LV, p. 296, 1921.
y
RESPIRATION
275
1
the veins are always relaxed, as well as distended ; and they con-
sider that the easier escape of the blood from the tissues, due to
relaxation especially of venules, is the cause of the larger venous
return and consequent rise of venous pressure. Recently Hender-
son, Haggard, and Coburn^* have shown that inhalation of air
containing 6 or 8 per cent of CO2 has a powerful restorative effect
upon the circulation, and particularly upon the venous pressure,
in patients after prolonged anaesthesia and major surgical opera-
tions.
" With great deficiency of oxygen there is also at first a very
marked increase in the circulation rate. This is shown by the
greatly increased pulse rate, deep blue flushing of the skin, etc.,
and great rise of venous blood pressure when air very deficient in
oxygen is breathed. In rapid poisoning by CO there is the same
flushing of the skin and distention of large veins, though the color
is now red and not blue. The increased pressure in the great veins
causes the distention of the right side of the heart and rapid pro-
duction of oedema of the lungs so characteristic of acute asphyxia,
although but for the fact that the heart muscle is lamed by the
anoxaemia there would probably be no over-distention. As Star-
ling and Knowlton found, oedema of the lungs and over-disten-
tion of the right side of the heart are very quickly produced by a
quite moderate increase of the ordinary very low venous pressure
at the entry to the heart.^^ With moderate oxygen deficiency, pro-
duced rapidly, there are, just at first, distinct signs of increased
circulation as well as of increased respiration; but very soon the
increased washing out of CO2 from the blood moderates both the
breathing and circulation, and after a short time the circulation,
as well as the breathing, quiets down, so that unless the anoxaemia
is considerable the increased pulse rate and other signs of in-
creased circulation may have practically disappeared.
The circulation during and just after forced breathing in man
was meanwhile investigated by a quite different method by Hen-
derson, Prince, and Haggard. ^^ They measured the venous pres-
sure by observing the height of the column of blood in a vein of
the arm when the subject was placed in a head down position on a
sloping board (Figure 70), thus obtaining a measure of the venous
" Henderson, Haggard, and Coburn, Journ. Amer. Med. Assn., LXXIV, p. 783,
1920.
"^Starling and Knowlton, Journ. of Physiol., XLIV, p. 206, 19 14.
" Yandell Henderson, Prince, and Haggard, Journ. of Pharmac. and Exfer.
Therapeutics, XI, p. 203, 1918.
276
RESPIRATION
blood pressure at the entry to the heart. The effect of forced
breathing was to cause a great diminution in venous blood pres-
sure. Thus the supply of blood to the heart must have become
inadequate to fill the right ventricle. Owing, however, to the
diminished outflow of blood from the arterial system there was
no fall in arterial blood pressure. It seems to be only when the
anoxaemia of forced breathing becomes so intense as to affect the
heart muscle seriously that the arterial blood pressure falls.
Figure 70.
Measurement of venous blood pressure by placing subject in a head-down
position.
Putting all these facts together, it appears that in general the
circulation is so regulated as to keep the pressures of both oxygen
and CO2 approximately steady in the venous blood from any
particular organ. The regulation is evidently of a double kind,
involving both oxygen and COs- If the oxygen pressure goes
down and the CO2 pressure also goes down, as in a pure anox-
aemia, there is comparatively little effect on the circulation rate,
because increase due to the lowered oxygen pressure is at once
counteracted by the effect of diminution due to the lowered CO2
pressure. Similarly, in an atmosphere containing simple excess of
COo increased circulation due to the excess of CO2 pressure tends
to be counteracted by decrease due to increased oxygen pressure.
During muscular work, on the other hand, there is both a rise of
CO2 pressure and fall of oxygen pressure, and consequently a
RESPIRATION
277
great increase in blood flow through the muscles, with a corre-
sponding increase in venous blood pressure, as Henderson and
his colleagues found with the apparatus shown in Figure 70.-^''
The correspondence between blood flow and amount of work
done by a muscle seems to appear clearly in data obtained by
Markwalder and Starling for the coronary circulation with vary-
ing work of the heart in a heart-lung preparation. ■'^'^^ The amount
of blood pumped by the heart, the aortic blood pressure, and the
flow through the coronary vessels, were measured simultaneously.
The data show that if the work done is estimated by the amount
of blood pumped multiplied by the aortic pressure, the coronary
blood flow varied within wide limits in proportion to the work
done. The variations in coronary blood flow might, of course, be
attributed to the variations in aortic blood pressure, but this inter-
pretation does not seem to explain more than a small part of the
facts.
At first sight the regulation of the circulation appears to be
difi"erent from that of respiration, since in the case of the latter
the influence of CO2 predominates. This, however, is simply be-
cause when ordinary air is breathed the oxygen pressure in the
tissues is not increased when the breathing increases. In reality,
there is no fundamental diff"erence. Whenever anoxaemia is pres-
ent the respiratory regulation, as already shown in Chapter VII,
works just like the local circulatory regulation. The breathing is
not then free to increase in such a way as to compensate approxi-
mately for increasing anoxaemia, because increased breathing
lowers the CO2 pressure and this tends to diminish the breathing.
Similarly the breathing cannot increase freely with increased
CO2 pressure, because the increased breathing would diminish
the anoxaemia. Under deep anaesthesia, when the arterial blood
becomes dark, CO2 has very little eff"ect on the breathing.
There can be little doubt that in the case of circulation, just as
in that of respiration, increase in CO2 pressure stands simply for
increase in hydrogen ion concentration. Hence alkalosis due to
deficiency of CO2 in the systemic capillaries, or acidosis due to
excess, will tend to be relieved by the slow acclimatization changes
described in Chapter VIII.
When once the fundamental fact is grasped that the general
flow of blood throughout the body is correlated with the gas pres-
" Yandell Henderson and Haggard, Journ. of Pharmac. and Exper. Theraf.,
XI, p, 197, 1918.
^^^ Markwalder and Starling, Journ. of Physiol., XLVII, p. 279, 19 13.
2 78 RESPIRATION
sures in the capillaries, the whole physiology of the circulation
appears in a new light. It is not the heart nor the bulbar nervous
centers which govern the circulation rate, but the tissues as a
whole; and they govern it with an accuracy and delicacy com-
parable to the accuracy and delicacy with which they govern
breathing. The heart and vaso-motor system are only the executive
agents which carry out the bidding of the tissues, just as the lungs
and nervous system do in the case of breathing.
It appears that the immediate function of the heart is not to
regulate the circulation rate, but simply to pass on at a greatly
increased pressure the blood supplied to it. The problem of the
regulation of the circulation under normal conditions seems in the
main to resolve itself into that of the regulation by the tissues of
the amount of blood supplied to the heart; and this regulation
depends, as we have just seen, to an overwhelming extent on a
linked control by the oxygen pressure and hydrogen ion concen-
tration in the systemic capillaries.
Just as in the case of regulation of breathing, so also in the
case of regulation of the circulation, the dominant facts have been,
and still are, obscured by masses of detail which, in their un-
connected form, simply confuse the mind and lead to wholly
mistaken judgments. It is difficult to pick a way through all these
details, but the salient points concerning the immediate control of
the heart's action must now be referred to.
We owe mainly to Gaskell the demonstration that the muscular
fibers of the heart may continue to contract rhythmically apart
from nervous control and even when they are separated from one
another, just as the rhythmic activity of the respiratory center
continues apart from peripheral nervous control. When, however,
different parts of the heart are separated from one another, the
frequency of the contractions in the different parts is different,
the ventricular contracting less frequently than the auricular
parts. In lower vertebrates the order of frequency in contractions
is sinus venosus, auricle, ventricle, and bulbus arteriosus. More-
over the individual fibers in each separated part contract normally
in unison with one another so long as they are not separated. In a
normal intact heart, however, not only do the individual fibers in
sinus venosus, auricles, ventricles, and bulbus arteriosus contract
in unison, but so also do all the parts of the heart.
The explanation of this contraction in unison has been furnished
by the physiological and clinical investigations of the last few
years. As was shown by Lewis with the help of the string gal-
RESPIRATION
279
vanometer, each normal contraction starts in what is known as
the Keith-Flack node, an island of primitive sinus venosus tissue
in the right auricle. Thence it is conducted by primitive muscular
tissue to the auricles, and by a bundle of similar muscular tissue,
the bundle of Kent or His, to the ventricles. This primitive tissue
is distributed (as the fibers of Purkinje) over the ventricles, and
has a conduction rate far faster than the rest of the muscular tis-
sue of the heart. Thus all parts of the ventricles contract almost
simultaneously, and shortly after the almost simultaneous con-
traction of all parts of the auricles ; while the pace of the whole
heart is set by the contractions starting in the Keith- Flack node.
Impairment or total failure in the conduction from auricle to
ventricle, or from fiber to fiber in auricle or ventricle, explains
many of the peculiarities met with in heart affections.
So long as the contractions of the ventricles are complete, the
volume of blood discharged at each beat must depend on the ex-
tent to which the right ventricle fills in diastole. This, in turn,
depends on the rate at which blood is let through from the arteries
to the veins. The difference between arterial and venous pressure
is so great that accessory factors such as the pumping movements
of respiration can hardly have more than a very minute average
influence on the circulation, though they have a marked tempo-
rary influence. It is therefore the rate at which the systemic
blood is allowed to pass through the tissues into the venous system
that determines the amount of blood pumped by the heart; and,
as already pointed out, the rate at which blood is allowed to pass
through the tissues is determined by their metabolic requirements,
and particularly by the amount of blood required to keep the
diffusion pressures in them of oxygen and carbonic acid approxi-
mately steady.
It is evident that in the carrying out of this regulation, both by
the heart and the blood vessels, the nervous system plays a very
important part, just as in the case of regulation of breathing; but
the main fact must never be lost sight of that the primary factor
in determining the rate of circulation is neither the heart nor the
nervous centers specially connected with the circulation, but the
metabolic activities of the tissues. At bottom the regulation of the
circulation is a chemical regulation, just as in the case of the
breathing.
The frequency and strength of the heartbeats are moderated
through the central nervous system, first by the well-known in-
hibitory impulses passing to the heart through the vagus nerve,
28o RESPIRATION
and secondly by the equally well-known accelerator impulses
passing to the heart through sympathetic branches. Increased
liberation of inhibitory impulses has been found to be a direct re-
sult of rise of arterial blood pressure (so that the inhibition tends to
prevent an excessive rise of arterial pressure and consequent fa-
tigue of the heart or over-distention of arteries), but is certainly
also a result of rise in oxygen pressure and diminution in CO2
pressure in the blood passing through the brain. An increase of
arterial blood pressure will, therefore, owing to the increased
rate of circulation, slow the heart. When the arterial blood pres-
sure is normal there is a considerable amount of vagus inhibition,
so that on section of the vagi the heartbeats quicken. It appears
also that this tonic nervous inhibition of the heart is itself reflexly
inhibited, either directly or indirectly, by increase of pressure on
the great veins opening into the heart. This was recently shown by
Bainbridge,^^ who found that, even if the accelerator nerves are
cut, increase in venous pressure causes marked quickening of the
heartbeats provided that the vagi are still intact. He showed that
any considerable increase in venous pressure causes quickening
of the heartbeat, and that the quickening depends upon the in-
tegrity of the vagus nerves. Part, at any rate, of this effect is due
to inhibition of the tonic inhibitory action of efferent vagus fibers.
Another part is probably due to reflex excitation of accelerator
nerves, but on this point the evidence was not so clear. The action
of the heart is not subject to direct voluntary control, but the ef-
fects of emotional stimuli on the rate of heartbeat are well known
and very evident.
There is no necessary connection between rate of heartbeat and
circulation rate. This has been shown by various experiments, but
most strikingly by the experiments of Starling and his pupils on
the bodies of animals in which an artificial circulation through
the heart and lungs alone had been established, the physiological
connections with central nervous system and rest of the body being
cut off. In such a "heart-lung preparation" the rate of heartbeat
remains steady for long periods if the temperature is kept steady
and artificial respiration is maintained; but the flow of blood can
be varied within very wide limits by simply varying the rate at
which blood is supplied to the right side of the heart. Thus Pat-
terson and Starling found that with a pulse rate which was steady
at 144 the circulation rate in a heart-lung preparation from the
" Bainbridge, Journ. of Physiol., L, p. 65, 19 15.
RESPIRATION 281
dog could be varied from 215 to 2,000 cc. per minute by simply-
regulating the supply of blood to the right side of the heart.^^
The heart is thus a pump which is capable of adjusting its out-
put without any variation in rate of stroke ; and we might imagine
a heart working quite efficiently on this principle, without any
regulation by the nervous system. The circulation would adjust
itself automatically in accordance with the rate at which blood
; was allowed to pass through the systemic capillaries; and the
resistance in the arterioles and capillaries would automatically
maintain a sufficient arterial blood pressure.
It is possible that in certain cases of heart disease, where the
physiological connection between auricles and ventricles through
! the bundle of Kent and His is broken, the circulation is main-
, tained in this way, since in these cases the pulse rate does not
i change during the very limited amount of muscular exertion
which is possible. In normal persons or animals, however, the
, pulse rate increases very markedly during muscular exertion ; and
i in persons in whom, owing to some nervous or cardiac abnormality
'; this increase does not occur, the capacity for exertion is very small.
! We must infer, therefore, that under normal conditions the ca-
pacity of the heart for increasing the circulation rate without
; increase of the rate of heartbeat is very limited — far more so than
li might be inferred from study of a heart-lung preparation. In
< other words the output of the heart during systole is usually
pretty constant under normal conditions, as Henderson was the
first to point out.
We must now consider in more detail how the distribution of
blood is regulated. It has been known since the discovery by
Claude Bernard of vasomotor nerves that the distribution of
blood in the body is regulated through the nervous system. Vaso-
constrictor nerves are known to be widely distributed in all parts
except the central nervous system, and vasodilator nerves have
also been discovered at certain points. There is also a main vaso-
motor center in the medulla from which vasoconstrictor impulses
radiate, and subsidiary vasomotor centers in the spinal cord.
Another and much more direct means of regulating the distribu-
tion of blood has recently been discovered by Krogh.^^ He has
found by microscopical examination of living capillaries, and by
injection of Indian ink, that under resting conditions the great
majority of capillaries in muscular and other tissues are firmly
"Patterson and Starling, Journ. of Physiol., XLVIII, p. 357, 1914.
Krogh, Journ. of Physiol., LII, p. 457, 19 19.
282 RESPIRATION
contracted and impermeable to blood, so that neither blood cor-
puscles nor even the finest particles of Indian ink can pass
through them. Nor is the full arterial blood pressure capable of
forcing them open. Whenever the tissue is stimulated to activity,
however, these capillaries open wide, so that blood can pass
through them freely. He found, for instance, that in muscle of the
guinea pig about twenty times as many capillaries were open
during activity of the muscle as during rest. The active contrac-
tility of capillaries had been directly observed by Roy and Gra-
ham Brown in 1880, but the real significance of this observation
had not been realized.
Krogh's observations have thrown a flood of new light on the
exchange of gases and other material between the blood and the
living tissues : for the opening out of new capillary paths when-
ever a greater exchange of material is taking place must facili-
tate enormously the exchange, and thus furnish a means of keep-
ing the gas pressures in the tissues approximately normal in spite
of great variations in metabolism. During muscular work, for
instance, the immense increase of capillary paths will greatly
facilitate the exchange of oxygen and carbonic acid between the
blood and the muscle fibers. There must be a great tendency to
fall in the oxygen pressure of the blood passing through the
muscle capillaries during muscular work. Unless this fall were
approximately compensated for by the opening out of new capil-
laries, it is difficult to see how a sufficient oxygen supply could be
maintained, as in all probability the oxygen consumption in a
muscle during very hard work is twenty or thirty times as great
as during rest. We can also now understand much better how it
comes about, for instance, that when the skin circulation is cut
down to the utmost by vasoconstriction in the prevention of un-
necessary loss of heat from the body, the skin, though more or
less blue from greatly diminished blood flow, may be still full of
blood, as shown by the full blue color.
Probably it is the stimulus of the presence in excess of certain
metabolic products, particularly carbonic acid, and the deficiency
of others, particularly oxygen, that determines the relaxation of
the capillary walls. There can also be little doubt that the same
stimuli, acting reflexly, determine the activity of local vasomotor
nerves. Temperature stimuli, or irritation stimuli, appear to act
in a similar manner. Stimuli may also act centrally, however, as
in the general regulation of body temperature by variations in the
skin circulation, or in emotional vasomotor changes.
RESPIRATION 283
How very powerfully a local stimulus may act on local blood
circulation is strikingly shown by a recent experiment of Meakins
and Davies.^^^ They found that when the arm was immersed in
cold water the returning venous blood was completely deprived
of oxygen. On the other hand, when the arm was kept in hot water
the haemoglobin of the venous blood was 94 per cent saturated
with oxygen, as compared with 96 per cent for the arterial blood.
The oxygen consumption was doubtless much greater in the warm
than in the cold skin, so the difference in circulation rate must have
been enormous.
If the regulation of blood distribution in the body were simply
a matter of opening the proper sluice gates according to local re-
quirements, the matter would be much more simple than it is.
Actually, however, the contraction and dilatation of various ar-
teries, veins, and capillary tracts must tend to have the effect of
varying the total capacity of the blood vessels, with the result that
the venous blood pressure at the heart inlet varies, and either too
little, or too much, blood is supplied to the heart. As a conse-
quence, the arterial blood pressure would either tend to fall too
much to secure an adequate supply of blood to the brain and other
parts, or else to rise too high.
There appears to be an elaborate nervous defense against such
disturbances. Excessive rise of arterial blood pressure is guarded
against, not only by the reflex vagus inhibition already referred
to, but also by reflex vasomotor inhibition through the "depres-
sor" branch from the cardiac vagus. Excitation of the depressor
fibers causes inhibition of the vasomotor center in the medulla and
consequent dilatation of arteries and probably veins in the splanch-
nic and other areas. Depressor action is brought about (whether
directly or indirectly) by excessive arterial blood pressure, so
that the pressure is relieved. Deficiency in arterial and venous
pressure is guarded against by an opposite "pressor" action re-
sulting in excitation of the vasomotor center and consequent rise in
blood pressure. A normal stimulus to pressor action of the center
is quite evidently deficiency of oxygen combined with excess of
carbonic or other acids in the blood supplying the brain. Thus the
arterial and venous blood pressures rise very markedly in response
to deficiency of oxygen combined with excess of carbonic acid,
whether produced by deficient aeration of the blood or circulatory
failure. A very important effect of this rise of blood pressure is
*°^ Meakins and Davies, Journ. of Path. and. Bact., XXIII, p. 460, 1920.
284 RESPIRATION
to concentrate the available blood flow towards the brain. In mus-
cular exertion there is also a rise of blood pressure, due partly to
the effect on the vasomotor center of excess of CO2 and deficiency
of oxygen in the arterial blood, but perhaps partly also to a gen-
eral pressor action complementary to a local depressor action on
the arteries and veins concerned in supplying the muscles with
blood.
We may compare the action of the bulbar centers controlling
blood pressure and heart rate with that of the respiratory center
in its linked responses to direct chemical and peripheral nervous
stimuli; but data are not yet available for carrying the com-
parison into detail.
From this general survey of the experimental evidence relating
to the regulation of the circulation, it will be seen that the deciding
factor in determining the rate of circulation and local distribution
of blood flow is local or general deficiency or excess in the diffusion
pressures of the substances which enter into tissue metabolism,
and particularly deficiency or excess in the diffusion pressures of
oxygen and carbonic acid. Temperature is also a factor, but per-
haps not a different one, since the diffusion pressure of a sub-
stance varies as its absolute temperature.
The regulation of the circulation may be abnormal in various
ways, and the present chapter would be incomplete without some
reference to this subject. The abnormality may arise from disease
or congenital defect of the heart or from operative interference.
but is very commonly due to disorder of the nervous regulation,
whether or not any organic defect is also present. Another form
of abnormal circulation is due to a deficient volume of blood, or t(.
abnormality in its composition. In all these cases the abnormal
circulation is reflected in abnormal breathing. Owing to the ab-
sence of adequate clinical or experimental investigations it ih
difficult as yet to deal with this subject in a satisfactory manner.
and I can only attempt to discuss it tentatively in the light of what
is already known.
The effect may first be considered of a valvular defect which
either causes narrowing of valvular openings (stenosis) or make>
a valve incompetent so that there is regurgitation. The effect oi
this is that, other things being equal, more work is thrown on one
or another part of the heart. If this extra work is not serious it
may be completely met, and partly by a true hypertrophy of the
muscular substance on which the increased work is thrown; but
if the extra work is serious the action of the heart as a pump will
RESPIRATION
285
be limited, so that the increased circulation required during mus-
cular exertion cannot be produced. The arterial blood pressure
will therefore fall during muscular work of more than a certain
amount. In consequence of this the coronary circulation may also
be impaired, with possibly dangerous consequences under the ex-
isting circumstances; and there will be faintness along with hy-
perpnoea, owing to slowed circulation and hence diminished oxy-
gen pressure and increased CO2 pressure in the capillaries of the
brain. During rest, however, or such muscular exertion as is pos-
sible without abnormal symptoms, the circulation will be carried
, on in a normal manner.
The alveolar CO2 pressure in a number of cases of valvular
heart disease was investigated by Miss FitzGerald, and found to be
normal except in cases confined to bed with serious symptoms.^^
The absence of any fall in the alveolar CO2 pressure constituted
good evidence of the absence of any impairment of the circula-
tion during rest. In cases with serious symptoms even during rest
there was a marked fall in the alveolar CO2 pressure. This is also
the case in congenital heart affections, when the alveolar CO2
pressure may be as low as 20 mm.^^
We can see what is happening in these cases. Owing to the im-
paired or short-circuited circulation the oxygen pressure in the
tissues falls and the COg pressure tends to rise. This, however,
increases the breathing, and so prevents the rise of CO2 pressure
by abnormally diminishing the CO2 pressure of the arterial blood
leaving the lungs. The fall in oxygen pressure cannot, however,
be prevented in this way, as the increased breathing will not
materially increase the oxygen in the arterial blood. Some anox-
aemia will therefore be present, and will probably show itself by
the color of the skin and lips, as well as by more frequent, and
possibly shallower, breathing, and other symptoms of anoxaemia.
The alkalosis produced by the increased breathing due to anox-
aemia will gradually be compensated for by increased excretion
of alkali and diminished formation of ammonia, just as at a high
altitude (see Chapter VII) ; and this will tend to diminish the
real anoxaemia though without diminishing the cyanosis. Unless
the breathing became shallow no material relief could be looked
for owing to active secretion of oxygen inwards by the lupg ep-
ithelium, as this would only slightly increase the oxygen in the
" FitzGerald, Journ. of Pathol, and Bad., XIV, p. 328.
" French, Pembrey, and Ryffel, Journ. of Physiol., XXIX, Proc. Physiol. Soc,
p. ix, 1909.
286 RESPIRATION
arterial blood ; but some relief may come from compensatory in-
crease in the percentage of haemoglobin in the blood. In a bad
heart case the heart has usually broken down owing to either some
more or less acute infection or to too much muscular exertion;
and usually the main question is whether, and to what extent, the
heart will recover with rest and the passing off of the infection.
In many heart affections the defect is in the nervous regulation
of the heart, either without or with a valvular defect. The ac-
celerator, inhibitory, depressor, or pressor reflexes may be acting
excessively. Cases with evident defects of nervous control have
been very common during the war, under such names as "soldier's
heart," "disordered action of the heart," "neurasthenia," etc. In
the commonest form of this defect there is very abnormal increase
in pulse rate on slight exertion or emotional and other stimuli;
and accompanying the increase there is pain and hyperalgesia in
the areas where pain is usually felt in heart affections. The exag-
gerated cardiac reflexes seem to be similar to the exaggerated
Hering-Breuer respiratory reflex in the same cases, and to be due
to the same causes (see Chapter III). Reflexes and nervous or
emotional responses of all kinds are exaggerated in these cases of
neurasthenia; and the exaggeration of cardiac reflexes is fre-
quently only one symptom of a condition of general neurasthenia.
The pain is probably only an expression of fatigue produced by
the over-frequent heartbeats.
A similar condition is very commonly present as an accompani-
ment of valvular defect; and the associated shallow breathing
may cause very serious secondary anoxaemia in the manner al-
ready described in Chapter VII. This seems to be the explanation
of the orthopnoea and Cheyne-Stokes breathing so often seen in
bad heart cases, and also explains the marked effects of oxygen
inhalation in relieving the symptoms. Continuous inhalation of
air enriched with oxygen is likely to prove a very valuable remedy
in promoting recovery where failure of the respiratory center is
complicating defects of circulation.
A very interesting investigation demonstrating a relation be-
tween vasular disturbances in the lungs and the Hering-Breuer
reflex has recently been published by J. S. Dunn,^^^ who wa>
working at the time in conjunction with Barcroft. He produced
multiple embolism of pulmonary arterioles by intra- venous injec-
tion of starch granules. When only a moderate degree of embolismj
was produced (so as not to cause immediate death) he observed
"^ Dunn, Quart. Journ. of Med,, XIII, p. 129, 1920.
RESPIRATION 287
an extraordinary increase in frequency and diminution in depth
(to half or even a fourth) of respiration. At the same time the
rate of circulation (measured by a very perfect blood-gas method
described in the same journal by Barcroft, Boycott, Dunn and
Peters) was not diminished, nor was the venous blood pressure
raised, or the arterial pressure disturbed : nor was there appreci-
able deficiency of oxygen or excess of CO2 in the arterial blood.
But when the vagi were cut the respirations slowed down and
became normally deep at once. It appears, therefore, that the
Hering-Breuer reflex (Chapter III) was enormously exaggerated
as a result of the disturbed pulmonary circulation. Just at first the
breathing was stopped, which suggests that the respiratory move-
ments were jammed completely by the exaggerated reflex. These
experiments throw a quite new light on the intense and exhausting
dyspnoea caused by pulmonary embolism, and also in cardiac cases
where there is rapid breathing without other cause. How the vagus
nerve endings are excited is not yet clear. The discovery of a drug
capable of controlling their action would evidently be an important
advance in therapeutics.
In defective circulation owing to loss of blood the primary
cause of breakdown appears to be that, in spite of contraction of
arterioles and venules owing to pressor reaction of the vasomotor
center, there is not sufficient blood to fill the large veins and ade-
quately supply the right side of the heart. As a consequence the
arterial blood pressure falls and the circulation slows down, with
consequent anoxaemia acting most seriously on the brain, and
affecting the breathing in the manner already explained in con-
nection with valvular affections where compensation is imperfect.
The natural remedy for this condition would appear at first sight
to be a pressor excitation of the vasomotor center, just as the
natural remedy for arterial anoxaemia due, say, to low atmos-
pheric pressure, appears at first sight to be increased breathing
and increased circulation rate. But just as the increased breathing
and circulation rate in arterial anoxaemia is to a large extent pre-
vented by the counter-balancing eff'ect of the alkalosis thereby
produced, so also is the full pressor response to anoxaemia due to
fall in blood pressure. The breathing is already stimulated by the
diminished blood circulation in the brain, so that the arterial
blood is so alkaline as to quiet down the vasomotor center, in spite
of the anoxaemia. Benefit may be expected from the administra-
tion of CO2 or even of acids ; but the main need is for increase in
the volume of the blood. This increase comes naturally, provided
288 RESPIRATION
that fluid is supplied ; and the great thirst which results from loss
of blood is an expression of the need for fluid. But time is required
for this natural process of recuperation, and meanwhile the patient
may die.
Fluid may be supplied quickly by the intravenous injection of
Ringer's Solution, but this plan is rather ineffective, since the
injected liquid leaks out from the vessels quickly. Bayliss there-
fore introduced his now well-known gum-saline solution for use
in cases of loss of blood and similar conditions.^^ The gum does
not leak out at all readily from the vessels, and in virtue of the
osmotic pressure which it produces it keeps the salt solution from
leaking out. The gum thus plays the same part in this respect as
the proteins of the blood plasma, but is free from the occasional
toxic properties of the proteins in blood transfused from another
person, although it seems to be sometimes not free from disadvan-
tages. It might seem at first sight as if the injection of gum saline
must, other things being equal, be very inferior in its effects to
transfusion of blood, since there is no haemoglobin in the salt solu-
tion. But unless the loss of blood has been enormous there is no
great need for haemoglobin. Increased rate of circulation will
make up for diminished power of the blood to carry oxygen and
CO2, as explained more fully on page 293.
The conditions known as "wound-shock," "surgical shock,"
"anaesthetics shock," and shock from burns, have given rise to
much discussion and investigation. When "shock" is fully de-
veloped, the arterial blood pressure is very low, the pulse feeble,
the lips and skin leaden colored, and the breathing shallow and
often rapid, or sometimes periodic. It appears at present as if this
general condition can be brought about in several different ways ;
and Yandell Henderson's investigations have thrown a clear light
on certain of the causes of shock. It will be convenient to consider
these first.
He showed in the first place that a condition of shock can be
brought about in animals by continued excessive ventilation of the
lungs. This of course greatly reduces the CO2 in the arterial
blood, thus producing a state of alkalosis. The response to this ib
slowing of the circulation, and consequent great anoxaemia, as
already explained. The slowing of the circulation tends, of course,
to diminish the alkalosis in the tissues, but only at the expense of
producing most formidable anoxaemia. The alkalosis is also com-
"Bayliss, Intravenous Injection in Wound Shock, 1918.
RESPIRATION 289
bated by the body in other ways, one being the prompt stoppage
of ammonia formation and the excretion of alkaline urine, as
already explained ; and, whether in consequence of this or of other
causes, the so-called "alkaline reserve" of the blood decreases
greatly, as Henderson and Haggard showed (Chapter VIII).
Nevertheless the anoxaemia and alkalosis cannot be overcome.
The circulation rate steadily diminishes ; the heart, in consequence,
probably, of anoxaemia, begins to fail, apart altogether from its
inadequate supply of venous blood ; and finally there is complete
failure of the heart. If, however, the forced breathing is stopped
before cardiac failure has occurred, death may occur from pro-
longed apnoea and consequent acute asphyxia, as mentioned in
Chapter II. When the condition of shock has developed suffi-
ciently, the animal cannot be saved by adding CO2 to the air
breathed; but in the earlier stages this procedure is quite effective.
The hopeless condition to which the animal is reduced by the
forced artificial respiration is probably analogous to the condition
produced in various ways by prolonged anoxaemia, as in very
severe CO poisoning, or in a patient who has been allowed to
suffer for long from severe arterial anoxaemia. It is probably the
anoxaemia rather than the alkalosis that produces the serious
effect, since, as already mentioned, forced breathing of oxygen is
more easily tolerated than forced breathing of air.
A condition of shock produced by forced artificial respiration
is, of course, not a natural occurrence; but Henderson showed
that excessive respiration can be produced by natural means in
two ways : firstly, by powerful afferent stimuli, as by electrical
stimulation of the sciatic nerve, even in the presence of anaesthesia
sufficient to abolish consciousness; and secondly, by the action of
ether in doses not sufficient to anaesthetize an animal completely.
The afferent stimuli, or the ether, increase the breathing to such
an extent as to diminish greatly the CO2 in the arterial blood,
thus producing great alkalosis or acapnia, with concomitant anox-
aemia. By these means, therefore, a condition of shock may easily
be produced in a patient; and it seems probable that in this way
the condition generally known as shock is frequently produced as
a matter of fact.
Clinical evidence seems, nevertheless, to indicate that in many
ordinary cases of wound shock there has been no excessive
breathing. On the other hand there are many facts indicating
that the symptoms are due to absorption from injured tissues of
290 RESPIRATION
harmful disintegration products,^* and Dale and Laidlaw have
shown that similar symptoms are caused by the action of histamine
produced by tissue disintegration.^^ In "histamine shock" the
venous return to the heart is inadequate, just as in acapnial shock,
and blood appears to stagnate in dilated capillaries so that the
rest of the vascular system is imperfectly filled with blood. Dale
and Laidlaw regard the dilatation of capillaries as a primary ac-
tion of the poison. The respiratory center seems, also, to be affected
very quickly, so that artificial respiration is needed to keep the
animal alive. How far the failure of the respiratory center is
consequent on failure of the circulation, or vice versa, it seems
difficult at present to say ; but the shallow breathing and leaden
cyanosis in shock are indicative of advancing failure of the re-
spiratory center, and appear to be clear indications for early
and continuous oxygen administration, if the condition cannot be
dealt with by removing its cause or in other ways. To remedy the
imperfect filling of the vessels and consequent failure of the circu-
lation, there is an equally clear indication for the intravenous
injection of gum-saline solution. Whether the administration of
air containing CO2 would be of service, as in shock due to simple
alkalosis, is not yet known. If the respiratory center is injured by
a poison from the injured tissues it may be unable to respond
properly to the CO2.
Dale found that the danger from histamine shock may be enor-
mously increased by the administration of an anaesthetic. Many of
Henderson's observations seem to point in the same direction as
regards acapnic shock. These investigations throw much light on
the fatal accidents of anaesthesia.
In connection with circulation and breathing it is important to
consider the manner in which the volume and haemoglobin per-
centage of the blood adjust themselves under varying conditions.
They are fairly constant within about five per cent under ordinary
conditions for any individual, and the volume of blood in a mam-
mal bears a pretty constant ratio to the body weight. This propor-
tion does not depend upon size or ratio of body weight to surface,
since it is about the same in large as in small mammals. Thus
in the rat or mouse the proportion is about the same as in man.
In a small warm-blooded animal such as a mouse the metabolism
per gram of body weight is enormously greater than in a large
^Report No. VIII of Surgical Shock Committee (Special Report No. 26 of
Medical Research Committee) , 1919.
"Dale and Laidlaw, Journ. of Physiol., LII, p. 355, 19 19.
RESPIRATION
291
animal such as a man, and roughly speaking is proportional to
the ratio of external surface to body weight. As was shown by
Dr. Florence Buchanan,^^ the pulse rate and respiration rate vary
in about the same proportion. Thus in a canary the pulse rate, as
recorded photographically by means of the capillary electrometer,
was about 1,000 per minute, the rate, as compared with that in
man, being greater in proportion to the more rapid metabolism.
The circulation rate in a small animal is thus enormously greater
than in a large animal, and indeed must be so ; but the proportions
I
I
I,
l?0
\
\
\
10.0
\
\
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\
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5
^
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16
m
"^
-S.
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%
?n
400 600 /ZOO /6pO 2000 2400 Z80O
Wei^ of Rabbiis in Grammes
3200
Figure 71.
Blood volumes of rabbits in cc. of blood per 100 grains of body weight.
The curve shows what the blood volumes would be if they varied in the pro-
portion of body surface to body weight. The dots and crosses show average
results of actual determinations by the modified Welcker method. Dots repre-
sent results of Boycott : crosses of Dreyer and Ray. The numbers indicate
number of determinations for each group of observations.
between the different parts of animals, including the blood, do
not depend on differences in size of the animals. From a very
limited number of experiments on animals, Professor Dreyer of
Oxford^^ drew the extremely improbable conclusion that in ani-
*' Buchanan, Science Progress, July. 1910.
"Dreyer and Ray, Philos. Trans. Royal Society, B, CCI, p. 138, 19 10; also
Dreyer, Ray, and Walker, Skand. Arch. f. Physiol., 28, p. 299, 191 3'
292 RESPIRATION
mals of the same species the blood volume is a function of the
ratio of body surface to mass, and even inferred that the carbon
monoxide method of determining blood volume (appendix)
must be incorrect because it showed no such relation in experi-
ments published by Douglas, ^^ The matter was afterwards re-
investigated in rats by Chisolm,^^ and by Boycott.*^ Figure 71
shows the results of Boycott and of Dreyer (all obtained by the
modified Welcker method) in rabbits of different sizes. It will
be seen that there is no difference between them, and that, al-
though young rabbits have usually a somewhat higher proportion
of blood than older ones, the increased proportion does not vary
with the proportion of body weight to surface. The circulation
rate must, other things being equal, be faster in a smaller animal
with its higher proportional metabolism, but an increased pro-
portional dead weight of blood would be no advantage, but a
disadvantage.
When the volume of blood is reduced by considerable bleeding,
there is at first a fall in arterial, and doubtless also in venous,
blood pressure ; but soon the blood pressure is restored. The first
effect of the bleeding is probably to evoke partial compensation
by a pressor excitation of the vasomotor center. This is probably
due to diminished circulation rate and consequent fall in oxygen
pressure and increase of CO2 pressure in the medulla. Very soon,
however, the blood volume is more or less restored by taking up
of liquid from the tissues and intestines. The blood is thus diluted ;
but the diluted blood fills up the blood vessels and completely re-
stores the blood pressure. After a delay of many days or perhaps
several weeks, the hydraemic blood is restored to normal by re-
production of the missing corpuscles.
Similarly when blood is transfused from another animal of
the same species there is at first a rise of both venous and arterial
blood pressure. Soon, however, the volume of blood is reduced
by disappearance of most of the extra plasma. The remaining
blood then contains an excess of red corpuscles, and these are only
got rid of in the course of some days or weeks.
The changes which occur were followed by Boycott and Doug-
las with the help of the carbon monoxide method of determining
the blood volume in living animals. ^^ They found that on repeated
"Douglas, Journ. of Physiol., XXXIII, p. 493, 1906.
" Chisolm, Quart. Journ. of Exfer. Physiol., IV, p. 208, 191 1.
"Boycott, Journ. of Pathol, and Bacter., XVI, p. 485, X912.
"Boycott and Douglas, Journ. of Pathol, and Bacter., XIII, p. 270, 1909.
RESPIRATION
293
bleeding the reproduction of the red corpuscles becomes more and
more rapid, so that finally the animal can reproduce the lost cor-
puscles very rapidly. Similarly on repeated transfusion the animal
can get rid of the transfused corpuscles more and more rapidly.
It thus becomes adapted to either bleeding or transfusion.
In an animal in which as a result of bleeding or similar causes
the proportion of haemoglobin in the blood is abnormally low the
oxygen pressure must fall more rapidly than usual if the rate of
circulation is unaltered, as the blood passes through the tissues.
In accordance with what has been already said, this will naturally
tend to be more or less compensated for by an increased rate of
circulation. But this can occur freely without the opposing effect
due to the production of alkalosis, since owing to the diminished
percentage of haemoglobin the pressure of CO2 would also be
OXFOQD
1
SUMMIT OF PIKES PEAK
8g
5^
NEW HAVEN
OXFORb
1 1
HALDANB "''^^^
15 19 25 27 51 4 a H l€ 20 24 26 / 5 9 IZ 17 21
AUGUST SEPTEMBER
420
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y^
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Figure 72.
Ordinates represent percentages of the average haemoglobin percentages
obtained before ascending the Peak (Oxford and Colorado Springs) on the
particular subject. Continuous thick line = total oxygen capacity or total
amount of haemoglobin. Continuous thin line = percentage of haemoglobin.
Interrupted line = blood volume. The values in Oxford before the start of
the expedition are plotted without relation to time.
too high unless the circulation rate were increased. An increased
circulation rate is thus the natural response to a diminished haemo-
globin percentage.
We know from observations on persons living at high altitude
that one result of the shortage of oxygen caused by the diminished
barometric pressure is that the percentage of haemoglobin and of
red corpuscles in the blood rises (see Chapter XIII). In different
individuals the rise varies considerably. Thus in persons who had
been living for some weeks on the summit of Pike's Peak we found
that the haemoglobin percentage varied from 113 to 153 per cent
of the normal. The rapidity with which the change occurs varies
also greatly in different individuals. Figure 72 shows the rate
294
RESPIRATION
at which the change occurred and disappeared in one of the
members of the Pike's Peak expedition, and Figure 73 shows the
far faster rate of increase in haemoglobin in Mr. Richards, a
mining engineer who kindly made for me a careful series of
^:i:
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.
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observations on himself on going to a mine in Bolivia at a height
of 15,000 feet. Figure 72 also shows the changes in blood volume
and total haemoglobin in the body (total oxygen capacity). It
will be seen that after the first few days the blood volume in-
RESPIRATION 295
creases, so that the total haemoglobin in the body increases more
than the percentage of haemoglobin. Thus the corpuscles do not
simply increase at the expense of the space occupied by plasma,
but the total space occupied by the blood is increased. It seems
probable, however, that when a rapid increase in the percentage
of haemoglobin occurs, as shown in Figure 73, the increase is
mainly brought about at first by disappearance of plasma owing
to a pressor reaction of the vasomotor center, with consequent in-
creased filling of the capillaries and resulting loss of liquid from
the blood. In acute anoxaemia produced by asphyxial conditions
there appears to be a rapid loss of fluid from the blood, and this
is probably due to a pressor reaction. Schneider and his colleagues
have recently observed that in a considerable proportion of airmen
exposed for a quite short time to low pressures of oxygen there is
a small but quite appreciable rise in the haemoglobin percentage.^^
There appears to be no doubt that the cause of the increased
total amount of haemoglobin and red corpuscles in the body at
high altitudes is increased activity of the bone marrow in forming
red corpuscles. On this point direct evidence was obtained by
Zuntz and his colleagues. ^^ They found that in dogs the blood-
forming red marrow was markedly increased at a high altitude.
The stimulus to this increase was undoubtedly fall in the oxygen
pressure of the blood, and it is doubtless in the same way that in-
creased formation of red corpuscles is brought about by loss of
blood, especially if repeated. From the experiments of Boycott and
Douglas on repeated blood transfusions, we can also infer with
great probability that with increased oxygen pressure in the tis-
sue capillaries, owing to an increased proportion of haemoglobin,
there is a corresponding increase in the blood-destroying tissues.
The proportion of haemoglobin in the blood appears, therefore,
to be dependent on the oxygen pressure in tissue capillaries. This
inference is confirmed by the fact that, as Nasmith and Graham
showed,^^ the haemoglobin percentage rises markedly in animals
which are kept exposed to a small percentage of CO.
In cases of chronic heart disease, and more particularly in cases
of congenital heart defects accompanied by cyanosis, there is often
a great increase in the total haemoglobin and also in the blood
volume. Thus in a congenital case of "Morbus coeruleus," brought
"Gregg, Lutz, and Schneider, Atner. Journ. of Physiol., L, p. 216, 19 19.
*^ Zuntz, Loewy, MuUer, and Caspari, H dhenklima und Bergwanderungen,
Berlin, 1906.
'* Nasmith and Graham, Journ. of Physiol., XXXV, p. 32, 1906.
296 RESPIRATION
to us by Dr. Parkes Weber, Douglas and I found that the haemo-
globin percentage was increased 80 per cent; the blood volume
100 per cent; and the total haemoglobin 260 per cent;^^ and we
found similar increases in another case. Lorrain Smith had al-
ready found a considerable increase in a non-congenital heart
case with chronic cyanosis. ^^
In some cases (so-called idiopathic polycythaemia) where there
is neither exposure to a lowered oxygen pressure nor any heart i
or lung affection, the haemoglobin percentage and number of
red corpuscles per unit volume is greatly increased. On determin-
ing the blood volume in two of these cases I found it greatly in-
creased. Boycott and Douglas examined three other cases with
a similar result.^"^ In the most marked of these cases the haemo-
globin percentage was 176 per cent of the normal, and the blood
volume nearly three times the normal, so that the amount of|
haemoglobin in the body was about five times the normal. Idio-
pathic polycythaemia is accompanied by a bluish tint of the skin,
and this suggests that from some cause there is slowing of the
circulation and consequent anoxaemia of the tissues, to which the
increased haemoglobin percentage is a natural response.
It is clear that increase in the haemoglobin percentage will tendj
to diminish the tissue anoxaemia at high altitudes or in cases of
heart affections; for the blood can pass more slowly (or at a more
normal rate at high altitudes) through the capillaries before a.\
given fall in the oxygen pressure occurs. This compensation is I
never complete, however; for if it were there would be no stimu-
lus to the increased concentration of haemoglobin. An undue rise
of CO2 pressure in the tissues is also prevented by the increased
haemoglobin percentage.
When the red corpuscles and haemoglobin are increased 60 or
80 per cent the viscosity of the blood is very greatly increased,
and a good deal of stress has been laid on this increased viscosityl
as a hindrance to circulation. Nevertheless persons with their hae-'
moglobin percentage increased 50 per cent at high altitudes are
capable of the severest muscular exertion ; and there is no indica-
tion in them of any circulatory impairment. When we consider
the manner in which the circulation is normally regulated, as
*• The details of this case are given by Parkes Weber and Dorner, Lancet,
Jan. 21, 1 9 1 1 .
"Lorrain Smith and McKisack, Trans. Path. Soc. of London. LIII, p. 136,
1902.
" Boycott and Douglas, Guy's Hospital Reports, LXII, p. i57-
RESPIRATION 297
explained above, it seems evident that anything but a very ex-
treme increase in viscosity will at once be compensated for by
more free opening of arterioles and capillaries. The resistance
to flow of blood in the living body is regulated physiologically,
and cannot for a moment be compared to the mechanical resist-
ance in a system of lifeless tubes.
The rapid variations in blood volume from diminution or in-
crease in the vasoconstrictor (pressor) influence of the vaso-
motor center is perhaps shown most strikingly by the eff"ects on
the blood of section of the spinal cord below the vasomotor center
in the medulla. Cohnstein and Zuntz found that very quickly
after section and consequent fall of blood pressure the proportion
of red corpuscles fell to about half, while the proportion rose
rapidly again on stimulation of the cord just below the section,
with consequent rise of blood pressure.*^ The blood appears to
take up or lose plasma rapidly when the capacity of the blood
vessels is diminished or increased.
It was discovered by Lorrain Smith with the help of the carbon
monoxide method that in chlorosis and in secondary "anaemias"
the blood volume is increased without any diminution, or with
only a very slight one, in the total haemoglobin in the blood. The
anaemia is thus in reality a* hydraemia or dilution of the haemo-
globin.^^ Boycott and I found the same condition in the "anaemia"
of ankylostomiasis.^^ Miss FitzGerald found later that in chlorosis
the alveolar CO2 pressure is not diminished but normal, so that
in this form of anaemia there appears to be no anoxaemia during
rest.*^ These facts suggest that the apparent anaemia is due to
some cause leading to abnormal dilation and consequent increased
capacity of the blood vessels, with the natural sequence of hydrae-
mia, but so that the oxygen pressure in the tissues is not dimin-
ished. Possibly, therefore, the anaemia is produced through the
vasomotor nervous system, or through substances, or the deficiency
of substances, which act primarily on the blood vessels. The facts
that salts of iron have a striking curative action in chlorosis, and
that iron is a constituent of haemoglobin, have led to the idea that
the anaemia is caused by the absence of sufficient iron for a normal
formation of haemoglobin; but in the cure of chlorosis by iron
Lorrain Smith could find no appreciable increase in the total
'"Cohnstein and Zuntz, Pfiitger's Arckiv., 88, p. 310, 1888.
''Lorrain Smith, Trans. Pathol. Soc. of London, LI, p. 311, 1900.
*" Boycott and Haldane, Journ. of Hygiene, III, p. 112, 1903-
"FitzGerald, Jo7irn. of Pathol and Bacterial., XIV, p. 328, 19 10.
298 RESPIRATION
amount of haemoglobin in the body. The characteristic dyspnoea
and faintness on exertion in chlorosis, etc., are probably due to
the impossibility of sufficiently increasing during exertion the
already greatly increased circulation.
In pernicious anaemia and the anaemia of haemorrhage, Lor-
rain Smith found a very marked diminution of the total haemo-
globin present ; but often enough the blood volume was increased
above normal.
Although the intimate connection between breathing and cir-
culation is already very evident, many points in the connection
are still uncertain or obscure. There is an abundant field for
clinical and physiological investigation in elucidating this sub-
ject, though it must always be remembered that not only are
breathing and circulation closely dependent on one another, but
they are dependent also on other physiological activities.
Addendum. The experiments by Douglas and myself on the
regulation of the circulation in man have now been completed, and
are in course of publication. A very complete series, in which
Douglas was himself the subject, shows that during complete rest
the mixed venous blood had only utilized about 19 per cent of its
available oxygen, and gained a corresponding charge of CO2.
During hard work, with the oxygen consumption increased about
nine times, about 65 per cent of the arterial oxygen was utilized.
The pulse rate was increased about 2.6 times, and as the utiliza-
tion of the arterial oxygen was increased 3.4 times, the output of
blood per heartbeat was practically the same during hard work
as at complete rest, and the blood flow had simply increased in
proportion to the increase of pulse rate.
Various other subjects, including myself, had a similar high
rate of blood flow (about 8 liters per minute) during rest, but one
or two had a markedly lower rate of flow, with the percentage
utilization of oxygen as high, in one case, as 33 per cent. In this
case the output per beat during rest, and the circulation rate (about
4.7 liters per minute) were a good deal lower than in the other
subjects, but the output per beat increased to about double during
hard work. There are thus considerable individual differences
(quite apart from differences in weight) as regards the rate of
general blood flow and the particular manner in which the circu-
lation adapts itself to varying amounts of work.
As some doubt has arisen lately as to whether oxygenation of
blood within the living body has the same influence on the CO2
RESPIRATION 299
carrying power of blood as after the blood has been removed and
defibrinated, we made careful observations on this point. The
experiments showed clearly that oxygenation produces the same
effect in the living body as outside it.
A full account of the method, and of the results reached by it,
will be found in our paper.
CHAPTER XI
Air of Abnormal Composition.
In the present chapter I propose to describe the mode of occur-
rence and physiological effects of the more commonly occurring
gaseous constituents of air. The number of noxious gases, vapors,
and particulate impurities, which may, under particular circum-
stances, be present in air, is of course very large, and only the
commoner additions to air can be dealt with here.
Outside Air, Pure country air, freed from moisture, contains
20.93 per cent by volume of oxygen, .03 per cent of carbon diox-
ide, and 79.04 per cent of a residue usually designated as "nitro-
gen," although of this 79.04 per cent about .94 per cent consists
of argon. Very minute traces are also present of hydrogen and
various rare gases. Ordinary atmospheric air contains, however,
aqueous vapor in varying proportions ; and about I per cent is on
an average present in a climate such as that of Great Britain. The
composition of dry country air is the same to the second decimal
point all over the world. In summer weather the percentage of
CO2 near the ground may be as low as .025 during the day, and
as high as .035 during the night, owing to the influence of vegeta-
tion, etc. ; and doubtless the oxygen percentage rises or falls
correspondingly, though this has not yet been shown directly.
In towns the composition of the outside air varies surprisingly
little from that in the country. The percentage of COg seldom
rises above .05, nor does that of oxygen fall below 20.9, even in a
large town, like London ; and in summer weather there is hardly
any difference between the oxygen and COg percentages of town
and country air. In a London park on a summer day the per-
centage of COo may fall quite as low as in the country. Consider-
ing the great area of a town like London, and the enormous
quantity of coal and gas burnt, this fact is very striking, and
shows clearly that apart from horizontally-flowing wind there
are very active up-and-down movements of the air, and these
keep the air of a town pure. It is only in foggy weather that these
up-and-down movements cease more or less; and then the im-
purities in the air of a large and smoky town may become very
RESPIRATION
301
appreciable. Russell found, for example, that in London the per-
centage of CO2 might rise to 0.14 during a dense fog.
Along with CO2 there are present in the air of towns a number
of other impurities. From fires a good deal of unburnt CO passes
off. In the air of the underground railways when steam loco-
motives were still used, I found that about i volume of CO was
present for every 12 volumes of COg. If we assume the same pro-
portion for the air of a town, there would be about .01 per cent
of CO present in the air of a bad London fog. This would be
sufficient in time to saturate the haemoglobin with CO to the ex-
tent of about 17 per cent, and might thus produce appreciable
effects on persons already in bad health, though healthy persons
would not notice any effect.
Much more appreciable, however, are the effects of the par-
ticulate impurities. Ordinary coal contains a good deal of sul-
phur; and the sulphur, in the process of combustion, is mainly
oxidized to sulphuric acid, which condenses along with water
in the form of minute droplets and thus helps to form fog. Of the
unpleasant irritant effects of this sulphuric acid one can form a
good idea in passing through a railway tunnel, particularly if the
train is moving slowly up an incline and the coal burnt contains
much sulphur. Those familiar with sulphuric acid fumes in chemi-
cal laboratories or factories will at once recognize them in the
tunnel air. When badly purified lighting gas is burnt in a room,
the same irritant effect is also noticeable to a less degree. In a bad
fog in a large town the choking effects of sulphuric acid con-
tribute largely to the unpleasant effect of the fog and the manner
in which the fogginess of the air persists even when the air is
warmed in the interior of a house. There is no escape from this
effect unless the air is scrubbed or filtered. The sulphuric acid is
also destructive to metal and other materials.
Besides sulphuric acid the smoky air contains particles of black
carbonaceous matter which greatly help absorb the light, and
also contains substances which have an unpleasant odor and more
or less irritant effect on the air passages. As will be shown below,
there is no reason to believe that the continued inhalation of these
particles has any deleterious effect on the lungs, and in ordinary
town air they are not present in sufficient concentration to be of
any direct consequence in other ways to health. Their greatest
importance arises from the inconvenience and expense caused by
their obstruction of light and the manner in which they dirty
clothes, walls, ceilings, and everything else in a house. By the
302
RESPIRATION
substitution of well-purified gas for coal in fires, or by smokeless
combustion of coal, the trouble might be avoided, and indeed has
been much diminished within recent years.
Lower organisms, and particularly plants, are on the whole
far more sensitive to impurities in air and other changes in en-
vironment than higher animals, and particularly man. The real
reason for this is that between the living tissue elements and the
outside environment higher organisms possess an internal en-
vironment which is not only highly developed, but is maintained
with an efficiency which increases with the scale in development.
Plants are extremely sensitive to the particulate and other impuri-
ties in air and the obstruction of light by smoke and opaque fogs.
But few trees and plants can flourish in the air of a town or in-
dustrial area. The traces of acid and other impurities present in
the air can act more or less directly on their tissue elements, which
have very little between them and the external environment.
Air of Occupied Rooms. In rooms of all kinds where men are
present the composition of the air becomes altered, owing to res-
piration and evaporation and to any gas or oil lamps which may
be burning. Both respiration and lamps consume oxygen and pro-
duce CO2 and moisture. The combustion in the lamps is perfect,
so that no CO passes into the air; and unless the gas is badly
purified from sulphur the products of combustion have very little
unpleasant eff"ec.t apart from what may be due to heat. It was
formerly supposed that some volatile toxic substance is given off
in the breath; but the experimental evidence in support of this
belief was found to be fallacious, and all attempts to demonstrate
the existence of such a substance have failed. Some of the most
striking evidence on the subject is afforded by experience in sub-
marines, in which a limited volume of air is quite commonly re-
breathed until after a few hours a light will not burn and 3 per cent
or more of CO2 may be present. Provided the air remains cool, as
it does in a temperate climate owing to the cooling influence of the
water, the only effects observed are those due to COg.
Even in the most crowded and ill-ventilated rooms the pro-
portion of CO2 seldom rises above 0.5 per cent, with, of course, a
corresponding drop in the oxygen percentage. From the account
already given of the physiology of breathing it is evident that a
difference of this order in the composition of the air is in itself of
no appreciable importance. The breathing simply becomes very
slightly deeper and the composition of the alveolar air and
arterial blood remains practically unaffected as regards either
CO2 or oxygen.
RESPIRATION 303
Although apart from COg no appreciable amount of any
poisonous substance is given off to the air by the body, various
substances which affect the olfactory nerves are given off in minute
amounts from persons or furniture in a room. As a rule these sub-
stances are only perceived on entering a room, and are not noticed
after a short time by those who remain in it. In sensitive persons,
however, they may produce an unpleasant reflex effect; and for
this reason apart from any other a good ventilation is desirable.
When, however, there is no musty furniture, and the bodies and
clothing of those present are fairly clean, there is little or no in-
convenience from this cause.
A far more important factor in connection with the physio-
logical effects of the air in rooms is temperature, and along with
it moisture. The maintenance of a constant internal body tempera-
ture depends on constant physiological adjustment between ac-
tual heat loss from the body and variations in environmental con-
ditions which tend to make the heat loss greater or less than the
heat production. The variations in environmental conditions con-
sist in variations in temperature, moisture content, and movement
of the air, and also variations in the radiant heat gained or lost
by the body, apart from the actual temperature of the air. The
actual heat loss is regulated physiologically, apart from conscious
regulation by variation of clothing, etc., partly by varying the
rate of blood circulation through the skin, and partly by varying
the amount of water evaporated by the skin. The latter means of
regulation does not come into play unless the air is warm, or heat
production in the body is greatly increased by muscular exertion.
When the air of a room is so cold, or the movement of the air
is so great, that the skin, or parts of it, become uncomfortably
cold, we are always clearly aware of the cause of discomfort. But
when the air is so warm as to lead to the skin being uncomfortably
warm we are apt to attribute the discomfort to some other cause
than the heat. The matter is also complicated by the fact that in
different persons the air temperature at which discomfort is
felt varies considerably. Thus persons who have been undergoing
"open-air" treatment and are accustomed to rooms with open
windows feel much discomfort in rooms with closed windows
where other persons are just comfortable. Similarly Americans
accustomed to the warm air associated with central heating find
British houses with fires very uncomfortably cold in winter, while
British visitors to America find the warm air of American houses
very trying.
304 RESPIRATION
The discomforts of warm or cold air are not usually associated
with rise or fall of internal body temperature. When suffering
great discomfort from sitting in a very cold room, I have found
the rectal temperature slightly raised rather than lowered, and
on going to an uncomfortably warm room there was a slight fall
in rectal temperature. Persons going unaccustomed into very
warm air may become faint or suffer from nausea or headache
without any appreciable rise of body temperature. There appears
to be a fall of arterial pressure owing to failure on the part of the
vasomotor center to compensate for the increased flow of blood
through the skin in a warm atmosphere, and this probably ac-
counts for the more striking symptoms. In any case persons soon
become more or less acclimatized within limits to the effects of
warm air. One can observe this in miners who become accustomed
to warm places in mines, or in people who become accustomed to
Turkish baths.
It is somewhat noteworthy that men accustomed to hard outdoor
work seem to be much less sensitive to heat or cold indoors than
other persons. This is probably due to the fact that though they
are not accustomed to external heat they are accustomed to what
in this reference comes to much the same thing, namely, greatly
varied internal heat production, which involves the same capacity
for vasomotor adaptation as exposure to external heat or cold.
Those who are most affected by external heat or cold indoors are
persons who are not only unaccustomed to external heat, but are
also unaccustomed to hard muscular exertion.
Part of the discomfort of warm air in rooms is due to its drying
effect on the skin and particularly the upper air passage. Winter
air warmed to a temperature of about 70° F. is very dry; and if
the skin and upper air passages are kept warm by the air they lose
far more moisture than usual and become uncomfortable. With
cold air the inside of the nose is kept cool, and during expiration
moisture condenses in it, so that it is kept moist in spite of the fact
that the cold air contains very little moisture. With warm dry air,
on the other hand, there is much evaporation during inspiration
and little or no condensation during expiration, so that the nose
is apt to become very dry ; and this appears to lead to swelling of
the mucous membrane.
The combination of physiological disturbances produced b}
warm air in a room is apt to be attributed to chemical impurities
in the air. Owing to this fact, and general ignorance as to the
physiology, as distinguished from the chemistry, of respiration,
RESPIRATION 305
too much stress was formerly laid on the chemical purity of the
air in rooms. The chemical purity is nevertheless a very important
index of the chances of infection through the air from person to
person in a room. The more air is passing through the room the
less the chances of infection become ; and for this reason as high
as possible a standard of chemical purity is desirable where a
number of persons, some of whom may be carriers of infection,
are present. A reasonable standard to aim at under these circum-
stances is that the excess of CO2 in the air of the room should not
be over .02 per cent unless lights are burning, or that about 50
cubic feet of air per person and per minute should be supplied.
This standard can easily be maintained in ordinary houses with
natural ventilation ; and even in the case of crowded buildings a
similar standard can be attained by the right application of
modern engineering methods.
When air becomes very warm the regulation of body tempera-
ture becomes dependent on increased evaporation from the skin
and not merely on variation in the blood flow through it. If mus-
cular work is being done this point is soon reached if the air is
fairly still. The amount of moisture in the air then becomes very
important, as the rate of evaporation from the skin depends on the
amount of moisture already present in the air. In still air, or in
air moving at any given rate, a temperature is finally reached at
which in spite of profuse sweating the skin cannot evaporate
water quickly enough to prevent the body temperature from rising.
As I showed experimentally in 1905, this temperature is reached
when the wet-bulb temperature reaches a certain point.^ Thus in
still air and with hardly any clothing, the body temperature be-
gins to rise when the wet-bulb temperature exceeds 88 °F (3i°C).
It does not matter what the actual air temperature is, or the
actual percentage of moisture in the air, provided that the wet-
bulb temperature reaches 88°. Thus it was indifferent whether the
air temperature was 88° with the air saturated, or 133° with the
air very dry, provided that the wet-bulb temperature was 88°.
When the wet-bulb temperature was far above 88° the rate of
rise of body temperature was proportional to the rise of wet-bulb
temperature.^
When even moderate muscular work was being done the criti-
cal wet-bulb temperature was, even with almost no clothing, at
^ Haldane, Journ. of Hygiene, V, p, 494, 1905.
'Haldane, Trans. Inst, of Mining Engineers, XLVIII, p. 553, i9M-
3o6 RESPIRATION
least io° below 88° in still air. With the ordinary clothing of
temperate climates the critical wet-bulb temperature is much
lower than without clothing, especially during muscular work. On
the other hand, with the air in motion, the critical wet-bulb tem-
perature is higher. The beneficial effects of fans, punkahs, etc.,
during heat is well known. With the wet-bulb temperature above
the body temperature, however, the rise of body temperature is the
more rapid the more the air is in motion.
In the climate of Great Britain the wet-bulb shade temperature
very seldom rises above 70°, even on very warm summer after-
noons ; but during heat waves in America a wet-bulb temperature
of 75° is not infrequently reached, and cases of hyperpyrexia
from the heat then become common. W^et-bulb temperatures of
over 80° are of course common in tropical countries, and are met
by proper adaptation of clothing and mode of life ; but the
amount of muscular exertion which is possible with a wet-bulb
temperature over 80°, except in a good breeze, is limited. In
ordinary rooms in a temperate climate, and when ordinary cloth-
ing is worn, a wet-bulb temperature of even 65° becomes oppres-
sive and likely to cause fainting and headaches in persons not
accustomed to heat or heavy muscular exertion.
In order to obtain a simultaneous measure of the cooling action
on the body of air temperature, movement of air, and maximum
evaporation from the skin. Dr. Leonard Hill has devised an in-
strument known as the katathermometer. This consists of an
alcohol thermometer with a very large bulb, which, when an ob-
servation has to be made, is heated to about ioo°F. The flask is
jacketed with an absorbent jacket which can be moistened with
water. By the rate at which the water cools, a comparative esti-
mate can be obtained of the maximum possible combined cooling
action on the human body of movement of air, temperature, and
evaporation. The actual cooling effect of the air depends, of
course, on the physiological responses of the body, but cannot ex-
ceed the maximum shown by the wet katathermometer.
The physiology of temperature regulation lies outside the scope
of this book ; but temperature effects are so liable to be confused
with effects due to chemical impurities in air that it seemed
necessary to refer briefly to the physiological disturbances due to
warm air.
The air of occupied rooms is liable to be contaminated by
escapes of lighting gas; and under certain circumstances fatal or
very serious accidents from this cause may occur and lighting
RESPIRATION 307
gas may be used very easily for purposes of suicide or even
murder. The great majority of accidental deaths from poisoning
by lighting gas have been in bedrooms, owing to the gas being in
some way left turned on after being extinguished. In 1899 ^
Departmental Committee of which I was a member reported on
the influence of the use of water gas in connection with poisoning
by lighting gas, and I investigated the conditions under which
poisoning may occur in bedrooms.^
It might be supposed that the sense of smell would always give
warning of an escape of lighting gas in a room. On going into a
room in which gas is escaping one notices the smell at once, and
long before sufficient gas is present to cause any symptoms of
poisoning; but a person inside the room when the escape begins
may quite probably never notice it. The reason for this is that
the sense of smell for any particular substance becomes fatigued
very rapidly, and if the proportion of the odoriferous substance in
the air is only very gradually increased the smell is never noticed.
In this way an escape of gas in a bedroom is often unnoticed.
When a continuous escape of gas occurs in a room, the per-
centage of gas in the air goes on increasing until the rate of es-
cape through walls, roof, etc., balances the rate of inflow of gas.
In any ordinary room the walls, roof, and floor are permeable to
air, and, if any cause such as pressure of wind or diff'erence of
temperature between inside and outside tends to produce air
currents in and out of the room, the flow of air is surprisingly
free. If, for instance, the door and windows are closed and all
visible chinks pasted up, it will be noticed that when a fire is lit
the chimney draws just as well as before. Large volumes of air
are passing up the chimney, and this air comes in through the
walls, roofs, etc. Brick and stonework, for instance, are fairly
permeable to air, as can easily be shown by suitable means. Small
rooms in a dwelling house do not require artificial ventilation,
provided the passages, etc., are well ventilated, since the ratio of
surface to cubic capacity is high, so that ventilation through the
surfaces of the room counts for more in relation to the cubic space
per person in the room.
It will thus be readily seen that what happens in a room when
gas escapes continuously will depend on various circumstances,
such as the diff'erence in temperature between inside and outside,
the presence of a fire or of central heating by warm air, the
" Report of the Water-gas Committee, Pari. Paper, 1899. Appendix i.
3o8 RESPIRATION
amount of wind, etc. But even if there is little or no cause of ex-
change of air before the gas escape begins, tne escape itself will
furnish a cause, since the gas is much lighter/than air, so that air
to which gas has been added will tend to pjass out by the roof.
Hence even under conditions least favorable to ventilation, the
gas can never accumulate to more than a very limited concentra-
tion in the air of a room.
Another complication in connection with gas escapes is that the
gas may or may not mix evenly with the air of a room. Gas escap-
ing from a burner passes straight upwards to the roof and there
spreads. I found that unless the temperature of the windows and
walls was below the air temperature of the room the gas never
came down again to any very great extent. With a very rapid
escape of gas, as when a burner was completely removed or a
pipe cut, this was very marked. It was impossible to obtain a
poisonous atmosphere at the ordinary breathing level, but there
was a heavy concentration of gas near the roof. The danger of
poisoning was to persons in the floor above, and not to those in the
room where the escape was occurring. Near the floor level, how-
ever, a curious phenomenon was observed. The gas actually
present in the air was found to be nearly pure hydrogen. This
showed that it was only by diffusion, and not by convection cur-
rents, that gas had penetrated downwards. Hydrogen, being much
more diffusable than any of the other constituents of lighting gas,
had diffused downwards much more rapidly ; and in general it was
found that the hydrogen in lighting gas separates off by diffusion
very readily, leaving a mixture containing more of CO and the
other heavier constituents of the gas. At night, when the windows
were cold, and the tendency to convection currents down them
was consequently strong, mixture of the gas by convection was
much more apt to occur, especially if the escape was at a moderate
rate. There was consequently more danger at night to persons
sleeping in the room.
When the percentage of gas was determined at intervals in the
air of a room with gas continuously escaping from a burner and
mixing by convection currents down the windows, I found that,
if the conditions of wind, etc., remained constant, the percentage
became constant after a certain time which depended on the size
of the room among other conditions, and might vary from about
one to three hours according to the size of the room, rate of gas
escape, amount of wind, etc. The maximum percentage obtained
was 2.7 per cent at the breathing level. With larger escapes of
RESPIRATION 309
gas this percentage could hardly be increased, as most of the gas
remained at the roof. The air at all parts of the rooms tested was
examined with a miner's safety lamp to see if the air ever became
explosive; but with such escapes as could be produced when
burners were not taken off, I never succeeded in obtaining an
explosive atmosphere even at the roof. It requires about 8 per
cent of lighting gas to render air explosive.
These experiments had a very definite practical significance in
connection with the composition of lighting gas used for domestic
purposes : for it is evident that whether or not a dangerous result
will ensue from an escape of gas in a room will depend on how
poisonous the gas is, and not simply on the time during which the
escape continues. The poisonous action of lighting gas largely
diluted with air depends exclusively on the CO contained in it.
In every case of persons found dead in air containing lighting gas
the post mortem appearances are those of CO poisoning, and the
percentage saturation of blood as determined by the method de-
scribed in the appendix has turned out to be round 80, just as in
the case, referred to below, of miners poisoned by CO. Thus,
broadly speaking, the danger of poisoning from escape of lighting
gas depends on whether the air will be poisonous from CO when
less than 2 or 2.5 per cent of gas is present.
Lighting gas as originally introduced is made by the distillation
of bituminous coal, and usually contains about 7 or 8 per cent of
CO. With 2 per cent of this lighting gas in the air there would
only be about 0.14 per cent of CO ; and this, though a formidable
percentage, would not, so far as known, produce fatal effects in a
healthy person, as the haemoglobin would, in all probability, not
become much more than about half -saturated. To judge from all
our present knowledge, and from the results of experiments on
animals, about 0.3 per cent would usually be needed to produce
death within a few hours.
Excellent lighting gas can also be made by blowing steam
through incandescent coke or coal. The product is what is called
"blue" water gas consisting roughly of equal parts of hydrogen
and CO. This gives a very hot, though small, flame, and although
the flame by itself is "blue" and practically nonluminous, an ex-
cellent light is given when a properly adjusted mantle is used. On
the other hand the calorific value of a given volume of this gas is
very low as compared with ordinary coal gas ; and as the value of
gas depends mainly on the heating power of a given volume of it,
as well as, to a certain extent, on the luminosity of its flame when
3IO
RESPIRATION
no mantle is used, water gas is usually "carbureted" by the ad-
dition of cheap oil in a chamber where the oil is "cracked" by
means of heat. The product is known as carbureted water gas,
and is very largely used as a substitute for ordinary coal gas. It
has a luminous flame and more or less satisfactory calorific value,
but contains about 30 per cent of CO.
It is evident that with gas containing 30 per cent of CO, poison-
ing will occur very readily with an escape of gas during the night
in a house. On inquiring into the deaths from gas poisoning in
American towns supplied with carbureted water gas, the com-
mittee referred to above found that about 100 to 200 times as
many deaths occurred from gas poisoning with a given distribu-
tion of gas as in English towns supplied with coal gas only. The
gas was also used very extensively for purposes of suicide, and
sometimes also as a means of murder. Apart from actual danger
from poisoning, there was also the constant anxiety as to danger
from gas poisoning. An American mother, for instance, told me
that she regularly got up every night to make sure that gas was
not escaping where her children were sleeping. The result of the
committee's inquiries was to show that if gas is to be used for
domestic purposes the percentage of CO in it should be reasonably
low; and in consequence of this finding the use of undiluted car-
bureted water gas was discontinued in Great Britain, where,
indeed, it had only been introduced in one or two places, though
with unfortunate results which led to the inquiry. It should, how-
ever, be mentioned that with the general introduction of mantles
the danger of poisoning from accidental escapes from burners is
considerably diminished, as less gas escapes, and if there is a
pilot flame the risk is further greatly diminished.
Gas poisoning in houses may not only occur from escapes
within the house, but also from escapes from street gas mains;
and many serious accidents from this cause have occurred, par-
ticularly with carbureted water gas. The danger is much increased
from the fact that in passing through earth the odoriferous con-
stituents (benzene, etc.) of the gas are apt to be more or less
absorbed, so that the gas entering the basements of houses is more
or less odorless. Probably, also, it may have lost a good deal of
its hydrogen by diffusion, and this will make it more poisonous.
A large number of persons in several houses and many different
rooms may be poisoned by one serious breakage of a main.
Pettenkofer recorded an interesting case where, in the times before
clinical thermometers, illness through gas poisoning from a broken
RESPIRATION 31 1
main was mistaken for a peculiar and rapidly infectious form of
typhus. No smell of gas was noticed at first, and the percentage
of CO must have been so low, and perhaps inconstant, that it took
some hours before any distinct symptoms of illness were produced.
At last the smell became noticeable, probably because the earth
through which the gas was escaping had become .saturated with
the odoriferous constituents, and so ceased to absorb them com-
pletely.
Air of Mines. The air of mines is liable to be contaminated by
various gases known to British miners as black damp, fire damp,
afterdamp, white damp, and smoke. Of these, black damp is the
commonest and most universally present; fire damp is hardly
found except in connection with coal or oil; afterdamp occurs
only after explosions ; white damp in connection with spontaneous
heating of coal ; and smoke in connection with fires or blasting.
Black damp is distinguished by miners through its character-
istic properties of extinguishing lamps without exploding and
not causing danger to life provided a lamp will still burn. As
ordinary black damp is heavier than air, it was formerly identi-
fied with COg. Its true composition was first ascertained in 1895
by Sir William Atkinson and myself.^ It is the residual gas of an
oxidation process, and thus consists of nitrogen with anything up
to about 21 per cent of carbon dioxide. It is now evident that
black damp may be formed by several different oxidation pro-
cesses, among which oxidation of timber, of coal, and of iron
pyrites (FeS2) are the most important.
When timber oxidizes in the process of decay, it gives off
nearly as much CO2 as it consumes oxygen. Hence the black damp
formed consists of about 80 parts of nitrogen and 20 of CO2.
Freshly broken coal also oxidizes slowly for some time at ordinary
temperatures, but to a very limited extent. The oxidation process
is a simple chemical one and not dependent on microorganisms;
and extremely little CO2 is formed. In the oxidation of pyrites,
which is also a simple chemical process, no CO2 is directly formed ;
the sulphur is oxidized to sulphuric acid, which partly combines
with the iron to form ferrous and ferric sulphates, but may react
with calcium carbonate to form calcium sulphate, CO2 being of
course liberated.
Black damp of one sort or another is found in practically all
mines, though in coal mines where there is much fire damp its
*Haldane and Atkinson, Trans. Instit. of Mining Engineers, 1895.
312
RESPIRATION
presence can often be detected only by analysis, on account of the
predominance of fire damp. Occasionally there is so little COg
present in black damp that it is lighter than air; or it may be
lighter than air owing to admixed fire damp. I found that the
black damp formed simply in the oxidation of coal at ordinary
temperatures contains small percentages of CO,^ but black damp
as ordinarily found in considerable concentrations in mines is
practically free from CO.
The action of black damp on lamps and candles is of much
practical importance, particularly as a miner trusts to his lamp
to warn him of the presence of black damp or fire damp. A flame
is extremely sensitive to any variation in the oxygen percentage
in air. If the oxygen percentage is increased the flame becomes
brighter and hotter, and substances which are not inflammable
in ordinary air may then become readily inflammable. If the
oxygen percentage is diminished the flame becomes dimmer and
less hot, unless the diminution is due to the addition of an inflam-
mable gas to the air. When the oxygen percentage is dimin-
ished by the addition of nitrogen or black damp to the air, the
light given by a candle or lamp diminishes by about 3.5 per cent
for a fall of o.i per cent in the oxygen percentage.^ With a fall
of about 3 to 3.5 per cent in the oxygen an oil or candle flame is
extinguished. Aqueous vapor is even more eff"ective than nitrogen
in causing extinction of flame. It should be noted that it is to the
percentage, and not the partial pressure, of oxygen that the flame
is so sensitive, whereas it is the partial pressure that is of physio-
logical importance. A fall in the oxygen percentage of 3 per cent
is of very little importance to a man, though it extinguishes a
flame. On the other hand a flame still burns well when the atmos-
pheric pressure is diminished to a third, while a man is soon as-
phyxiated. Gas flames may be much less readily extinguished by
fall in oxygen percentage than oil or candle flames. Thus a hydro-
gen flame may not be extinguished till the oxygen percentage
falls to half or even less, the extinction point depending to a con-
siderable extent on the velocity with which the gas is issuing from
the burner. An acetylene lamp will burn till the oxygen percentage
falls to about 12.
The physiological action of black damp added to air depends
within wide limits on the percentage of COg in the black damp,
^Haldane and Meachem, Trans. Inst, of Mining Engineers, 1899.
Haldane and Llewellyn, Trans. Inst, of Mining Engineers, XLIV, p. 267
1902.
RESPIRATION 313
and can be deduced from the data already given as to the physio-
logical actions of CO2 and oxygen. It should be noted that the
CO2 diminishes greatly the risk that would otherwise exist from
diminution of the oxygen percentage. This risk is greatly di-
minished, owung to the fact that the CO2 firstly increases the oxy-
gen percentage in the alveolar air by stimulating the breathing,
and secondly raises the hydrogen ion concentration of the blood,
thus increasing the circulation rate and assisting the dissociation
of oxyhaemoglobin in the tissue capillaries. There is therefore
little or no danger from lack of oxygen till the oxygen percentage
in the air falls to 6 or 7 per cent; but if the oxygen falls much
lower death occurs from want of oxygen. The very evident effect
of the CO2 on the breathing gives good warning of the danger,
so that apart from the ample warning given by a lamp a man is
not likely to go into a dangerous percentage of black damp unless
he does so suddenly, as in descending a shaft or steep incline.
In former times miners often worked in air containing so much
black damp as to put a great strain on their breathing while they
were at work. Air containing, say, 3 per cent of CO2 doubles the
breathing during rest; but this effect is scarcely noticeable sub-
jectively. During work, however, the breathing is also about
double what it would otherwise be, and the lungs are thus strained
to the utmost, Probat)ly a great deal of the emphysema from
which old miners used to suffer was due to this cause. ''^
The ordinary fire damp of coal mines is, practically speaking,
pure methane (CH4). In a very "fiery" seam as much as 1,500
cubic feet of methane may be given off per ton of coal extracted.
The methane is adsorbed in the coal,^ and may come off under a
pressure of 30 atmospheres or more. Of other higher hydro-
carbons a small amount is also adsorbed in the coal, but held more
firmly, so that only in the last fractions of gas coming off from
coal can their presence be clearly demonstrated by analysis.
No carbon monoxide comes off with the methane, but appreciable
quantities of CO2 and nitrogen are often given off. It occasionally
happens, however, that enormous quantities of CO2 are adsorbed
in coal and may come off in very dangerous outbursts. This is un-
known in British and American coal fields, but has been met with
in France. Sudden outbursts of adsorbed gas, whether methane
or CO2, can only occur, however, where coal has been locally dis-
integrated, as is apt to be the case near a fault. Ordinary solid coal
' Haldane, Trans. Inst, of Mining Engineers, LI, p. 469, 1916.
'Graham, Trans. Inst, of Mining Engineers, LII, p. 338, 19 16.
314
RESPIRATION
is so impermeable to gas that it only adsorbs or gives off gas
very slowly. In the inflammable gas associated with oil fields
higher hydrocarbons are present in considerable amount, so that
the gas may burn with a luminous flame and has toxic properties.
Methane may of course also be produced by the action of bacteria
on old timber or other organic matter in the absence of oxygen ;
and accidents from the explosion of gas from this source have
occasionally occurred in British ironstone mines.
When about 6 per cent of methane is present in air, the mixture
becomes inflammable with an ordinary light, and explodes vio-
lently with a somewhat higher percentage. Curiously enough,
however, an excess of methane prevents explosion, although plenty
of oxygen is still present; and with more than about 12 per cent
5 V
va
/i%
J4%
4-%
2^% 3%
Figure 74.
Diagram showing outlines of caps visible on an oil flame with different
percentage of methane.
of methane the mixture ceases to be inflammable. This fact limits
considerably the direct dangers from explosions of fire damp.
The presence of nonexplosive proportions of fire damp in air
can easily be detected by the appearance of a "cap" on the flame
of a lamp. The cap is a pale, nonluminous flame which appears on
the top of the ordinary flame. In order to see it properly the ordi-
nary flame must be either effectively shaded or lowered till little
else than a blue flame is present, as otherwise the light from the
ordinary flame produces a dazzling effect which renders the cap
invisible, though it can be photographed without difficulty. The
length of the cap depends on the temperature and size of the
flame, and with the very hot hydrogen flame the test becomes far
more delicate, so that as little as 0.2 per cent of methane can be
detected easily. Figure 74 shows the outlines of the cap visible
RESPIRATION 315
with different percentages of methane when an ordinary oil flame
is lowered to the extent required in testing.
To obviate the danger arising from ignition of fire damp mix-
tures by lamps, some sort of safety lamp is now always used in
fiery mines. A safety lamp may be either an oil lamp constructed
on the general principle introduced by Davy, or an electric lamp;
but the latter has of course the disadvantage that it does not indi-
cate the presence of fire damp and black damp.
As regards its physiological properties, fire damp behaves as
an indifferent gas like nitrogen or hydrogen. A mixture of 79 per
cent of methane and 21 of oxygen has the same physiological
properties as air, except that the voice is altered ; and the physio-
logical action of methane is simply due to the reduction which it
causes in the oxygen percentage. Its action can thus be deduced
from the data in Chapters VI and VII. In actual practice the
danger from asphyxiation by fire damp is considerably greater
than from black damp, since a man going with an electric lamp or
no lamp into air progressively vitiated by fire damp has little
physiological warning of impending danger. He is in a similar
position to an airman at a very high altitude, and if he suddenly
falls from want of oxygen he is very likely to die from failure of
the respiratory center.
Afterdamp. Afterdamp is the gas produced as the result of an
explosion, and has been known for long to be specially dangerous.
In 1895 I made an inquiry into the causes of death in colliery
explosions,^ and found that nearly all (about 95 per cent) of the
men who died underground were killed by CO, although a con-
siderable number had received such serious skin burns that they
could hardly have survived in any case. Death was never due to
deficiency in the oxygen percentage of the air, nor to excess of
CO2, nor, apart from exceptional cases, to more than 2 per cent
of carbon monoxide. It was clear that the men had died in air
containing plenty of oxygen, and not much carbon monoxide.
That carbon monoxide was the actual cause of death was clear
from the fact that the venous blood was usually about 80 per cent
saturated with CO ; and that death was slow, and therefore due to
a low percentage of CO, follows from the fact that about the same
saturation was found all over the body. With more than about
2 per cent of CO the venous blood has not time to become evenly
saturated and the saturation is usually a good deal lower.
" Haldane, Report on the Causes of Death in Colliery Explosions and Fires,
Pari. Paper C, 81 12, 1896.
3i6 RESPIRATION
Colliery explosions were formerly attributed simply to ex-
plosions of fire damp. About 40 years ago it was first clearly
pointed out by Mr. Galloway that this explanation is unsatis-
factory, and that the spread of an explosion must be due to coal
dust. Further evidence of the predominant part played by coal
dust in all great colliery explosions was soon brought forward;
and it became clear that many explosions occur in the complete
absence of fire damp, the coal dust being originally stirred up and
lighted by the blowing out of flame in blasting, and the explosion
carried on indefinitely by further stirring up and ignition. In other
cases the starting point is some, perhaps quite small, explosion of
fire damp, caused by a defective lamp, a spontaneous fire in the
coal, or perhaps even by a spark from falling stone. The ease with
which coal dust explosions may be produced by blasting when
even a very little coal dust is lying on a road, and the astounding
violence which they may develop after the flame has traveled
about a hundred yards, were strikingly shown in experiments
made with pure coal dust at Altofts Colliery under Sir William
Garforth's direction.^^ On account of their danger in a populous
neighborhood these experiments were transferred to Eskmeals on
the Cumberland coast; and finally showed that when an equal
weight of shale dust or other similar material was present along
with the stone dust the mixture could not be ignited by blasting
or gas explosions. -"^^
Sir William Garforth's plan of stone-dusting all the roads in
collieries with shale dust, so that at no point is there more than
half as much coal dust as shale dust, has now been adopted very
generally in Great Britain ; and the only serious recent explosions
have been in mines where this precaution was not adopted. Stone-
dusting is far more efficacious and cheaper than watering the
dust; and indeed efficient watering is impossible in many cases,
owing to the eff'ect of water on the roof and sides of a colliery
road.
In the Altofts experiments, samples of afterdamp were analyzed
by Dr. Wheeler. The following is a typical example.
Carbon dioxide
11.9
Carbon monoxide
8.6
Hydrogen
2.9
Methane
3.1
Nitrogen
73.5
^Record of British Coal-dust Experiments, 19 10.
^Reports of the Explosions in Mines Committee, Pari. Papers, 1^)12-1914.
RESPIRATION 317
It will thus be seen that pure afterdamp, free from air, may
contain as much as 8.6 per cent of CO. Fresh afterdamp also con-
tains an appreciable percentage of HgS (not shown in the analy-
sis). This is a very poisonous gas, and o.i per cent will knock a
man over unconscious in a very short time. The most immediate
effect of fresh afterdamp may be due to HgS ; but on this point
there is no definite knowledge as yet.
Considering the deadly composition of pure afterdamp it is at
first sight somewhat surprising that in actual colliery explosions
the men are not killed at once by the afterdamp, and that the CO
is so dilute in the atmosphere that kills them. It must, however,
be borne in mind that along the roads of collieries the coal dust
is never pure, and often contains so much shale dust that an ex-
plosion is not possible. The combustion is probably, therefore, far
from complete, so that much air is left, apart from what is drawn
in as soon as the air cools. Possibly, also, the percentage of CO in
the pure afterdamp is lower.
Afterdamp is, of course, extremely dangerous to rescuers, and
many lives of rescuers have been lost owing to poisoning by CO.
They have gone too far into the poisonous air before becoming
aware of any danger, and the first symptom noticed is usually
faintness and failure of the legs, so that return is impossible.
Moreover the mental condition of men beginning to be affected
by CO is usually such, as already explained in Chapter VT, that
they will not turn back, and are reckless of danger. A lamp is of
course useless for indicating the danger.
In order to give miners a practical means of detecting danger-
ous percentages of CO, I introduced the plan of making use of
a small warm-blooded animal such as a mouse or small bird.^^
Owing to their very rapid general metabolism and respiration and
circulation small animals absorb CO far more rapidly than men.
Hence they show the effects of CO far more quickly, and can thus
be used as indicators of danger, although in the long run they are
possibly rather less sensitive to CO than men are. Thus a danger-
ous percentage which would require nearly an hour to affect a man
at rest will affect the bird or mouse within about five minutes.
This test has now come into very general use, and was, for in-
stance, largely used during the war by the tunneling companies.
It is easier to see the signs of CO poisoning in a bird in a small
cage, as it becomes unsteady on its perch, and finally drops, while
"Haldane, Journ. of Physiol., XVIII, p. 448, 1895.
3i8
RESPIRATION
a mouse only becomes more and more sluggish ; but the mouse is
easier to handle, and less apt to die suddenly and thus leave the
miner without any test. The animals recover very quickly as soon
as purer air is reached and this greatly increases their value as a
test.
After an explosion it is very necessary to have some test for
CO. The ventilation system is thrown out of action owing to doors
and air crossings being blown in. On the other hand it is very im-
portant to get in as soon as possible in case men are still alive, and
in order to deal with any smoldering fires left by the explosion.
When air in a mine is for any reason not safe to breathe, self-
contained breathing apparatus are now frequently employed. It
is beyond the scope of this book to describe these apparatus in
detail ;^^ but it may be mentioned that the usual principle employed
is that the wearer breathes through a mouthpiece into and out of
a bag, the nose being closed by a noseclip. Into the bag there is
directed a stream of oxygen from a steel cylinder carried behind;
and by means of a reducing valve and properly adjusted opening
beyond it the stream is kept steady at not less than 2 liters
per minute. This is as much as a man uses during pretty hard
exertion. If he uses less, the excess is allowed to blow off.
If he uses more, the oxygen percentage in the bag may fall
rather low, or the bag may become flat before the end of a full
inspiration. In the former case he will begin to pant more than
usual, but will not fall over so long as the 2 liters are coming in.
If less than about 2 liters are coming in he will be liable to fall
over, owing to a rapid fall in the oxygen percentage. If the bag
begins to go flat he will notice this, and either turn on more oxy-
gen through a by-pass, or exert himself less. The carbon dioxide
in the expired air is absorbed by a purifier containing caustic
alkali.
In another form of apparatus the delivery of oxygen is gov-
erned by the state of fullness of the bag; but in applying this
principle there is the difficulty that the oxygen may not be quite
pure, and the contained nitrogen may thus accumulate in the bag,
or a little nitrogen may leak in from the air at the mouthpiece.
In still another form use is made of liquid air, of which a large
amount can be carried, so that most of the expired CO2 can be
allowed to pass out and only a small purifier is needed.
" A thorough discussion of the apparatus in use in America and the principles
and practice applicable to it is given in U. S. Bureau of Mines Technical Paper
No. 82, 1917, by Yandell Henderson and J. W. Paul. Numerous investigations,
including two full reports by myself, have appeared in Great Britain.
RESPIRATION 319
Whichever form of apparatus is used it is very necessary that
it should be extremely reliable in its action, and that the users
should be thoroughly instructed and trained in its proper use and
upkeep. A number of lives have been lost or endangered through
defective supervision and mode of use, or defective design, of
apparatus; and as a consequence of these defects men wearing
the apparatus in quite breathable air have often had to be rescued
by men without apparatus. With proper and scientific supervision
these accidents do not occur, as has been shown again and again
during extensive operations in irrespirable air.
By white damp miners understand a poisonous form of gas
coming off from coal which has spontaneously heated. The term
seems to have arisen from the fact that steam commonly comes
off from the warm coal with this poisonous gas and causes a white
mist. By experiments on animals and analyses I have frequently
found that the poisonous constituent of the gas was CO.
Freshly broken coal is, as already mentioned, liable to a slow
oxidation process. This of course produces heat, and if sufficient
coal is present, so that the heat is not lost as quickly as it is pro-
duced, the coal will heat, and the heated coal will oxidize faster
and faster until at last it is red hot or bursts into flame if sufficient
oxygen is present. It is for this reason that coal may be a danger-
ous cargo on long voyages, and that coal cannot be stacked safely
in very high heaps. In many seams there is great trouble and no
little danger from spontaneous heating of broken coal under-
ground ; and the residual gas coming off from heated coal is often
called white damp. The higher the temperature of coal which is
slowly oxidizing, the greater the proportion of CO in the residual
gas. The effects of white damp are thus much the same as those
of afterdamp ; and the same precautions are required.
Smoke in mines may come either from fires or from blasting.
The smoke from a fire is usually, of course, visible and irritates
the air passages and eyes owing to the irritant properties of the
suspended particles. If, however, smoke has slowly traveled some
distance in a mine, the particles have subsided and the smoke has
become a more or less odorless and transparent gas. Many very
serious accidents, involving sometimes the loss of 100 lives, have
occurred through the poisonous action of smoke from fires in
mines. In these cases the deaths have always, so far as hitherto
ascertained, been due to CO poisoning. A large amount of un-
burnt CO is given off from smoky or smoldering fires, so that the
gases from a fire are almost as dangerous as the afterdamp of an
320 RESPIRATION
explosion. Practically speaking, afterdamp and smoke from fires
produce nearly the same effects, and require the same precautions.
A fire in the main intake of a mine is a most dangerous occurrence,
since the poisonous gas is apt to be carried all over the mine, and
to kill all the men in it. To afford a means of dealing with this
danger, the ventilating fans provided at British coal mines are
now so constructed that the air current can be at once reversed, so
as to drive back the smoke.
Smoke from blasting may contain various poisonous gases,
along with CO2, according to the nature of the explosive. Some
explosives, such as guncotton, give much CO, and some very
little ; but all seem, in practice, to give some. Hence there is always
risk of CO poisoning where explosives are used in mines, unless
the proper precautions are taken. Black gunpowder, as used for
blasting, produces both CO and HgS ; and in the cases of gassing
it is often difficult to decide whether CO or H2S has been mainly
responsible for the effects. With explosives containing nitro-
compounds another and very serious danger is met with. When
these explosives detonate properly the nitrogen is given off as
nitrogen gas; but when they burn instead of detonating, the
nitrogen comes off as nitric oxide, along with CO instead of CO2.
In practice, owing to defective detonators or other causes, some
of the explosive is apt to burn instead of detonating. The nitric
oxide then passes into the air and combines with oxygen to form
yellow nitrous fumes. These have a somewhat irritant effect at the
time, but this is not sufficient to give proper warning of their
dangerous properties. The immediate effects are very slight. If,
however, enough of the mixture has been inhaled, the result is
that after a few hours symptoms of very severe lung irritation
appear, and finally oedema of the lungs and great danger to life.
I have found that exposure to the fumes from as little as .05 per
cent of nitric oxide in air may be fatal to an animal. This subject
will be referred to more fully below in connection with poisonous
gas used in war.
Poisoning with CO in mines is so apt to occur, that a few words
may not be out of place as to the treatment of CO poisoning. The
symptoms and their cause have already been dealt with. The first
thing, is, of course, to get the patient out of the poisonous air. In
doing so, however, it is important to keep him well covered and
avoid in any possible way exposing him to cold. For some reason
which is at present not clear, a man suffering from CO poisoning
gets much worse on exposure to cooler and moving air, as in the
RESPIRATION 321
main intake of a mine. If the breathing has stopped artificial res-
piration should be applied promptly; and this can best be done by
Schafer's well-known method. If oxygen is available it should be
given at once. It immediately increases greatly. the amount of dis-
solved oxygen in the blood, and also expels far more rapidly the
CO from the blood, as will be evident considering the properties
of CO haemoglobin. The oxygen will do most good at first, and
may be continued with advantage for at least twenty minutes. Suit-
able apparatus for giving oxygen can now be obtained easily. Hen-
derson and Haggard have recently shown, however, that owing to
the great washing out of CO2 which occurs during the hyperpnoea
produced in acute CO poisoning, or perhaps owing to temporary
exhaustion of the respiratory center, the breathing is apt to re-
main for some time inadequate. ^^^ They found by experiments on
animals that under this condition the removal of CO from the
blood is greatly accelerated by adding CO2 to the air or oxygen
inhaled. The desirability of having some safe and practicable
means of adding CO2 to oxygen used in reviving men poisoned by
iCO seems evident from these experiments.
A man who has been badly gassed by CO, and has been un-
conscious for some time, is sure to have very formidable symptoms,
lasting long after all traces of CO have disappeared from the
iblood. He may never recover consciousness at all; but when he
does his nervous system generally is likely to remain very seriously
affected for days, weeks, or months, so that he requires to be care-
fully watched, nursed, and treated. Mental powers and memory
may be much impaired, and the nervous system seems to be in-
jured in many different directions. Thus the regulation of body
temperature is apt to be imperfect, and symptoms resembling those
of peripheral neuritis are common. A condition of neurasthenia,
similar to that so often seen during the war, appears to result fre-
quently, with the usual affections of the respiratory and cardiac
nervous system. In some cases there seems to be acute dilatation of
the heart ; and probably almost every organ in the body has suf-
fered from the effects of want of oxygen.
As mines grow deeper and warmer, the importance of the wet-
bulb temperature in connection with mine ventilation becomes
more and more prominent. The reasons for this will be evident
from what has already been said on this subject; especially when
the fact that a miner has to do hard physical work is also taken into
"* Yandell Henderson and Haggard, Journ. of Pharmac. and Exper. Therap.,
XVI, p. 1 1, 1920.
322 RESPIRATION
consideration. To this subject I have given very close attention
in recent years, and a full general discussion of it will be found in
the recent Report of the Committee on Control of Temperature
in Mines.^*
Owing to the nature of their work and the dry conditions in
deep and well-ventilated mines, miners are very much exposed
to dust inhalation; and the prevalence of ''miners' phthisis"
among certain classes of miners led me to the investigation of the
effects of dust inhalation. Both men and animals are in general
more or less exposed to dust inhalation. The problem presented
by dust inhalation in mining and other dusty occupations is thus
only a part of a general physiological problem as to how the dust
inhaled along with air is dealt with by the body. It is evident that
if the insoluble dust which is constantly being inhaled by civilized
men, particularly in towns and in dusty occupations, accumulated
in the lung alveoli, the effects would in time be disastrous. There
is, however, no evidence that such effects are ordinarily produced.
The lungs of a town dweller, for instance, are more or less black-
ened by smoke particles, but remain perfectly healthy; and the
same applies to the lungs of coal miners and of persons engaged
in many other very dusty occupations. In other cases, however,
such as certain kinds of metalliferous mining, steel grinding,
pottery work, etc., the effects of continuous inhalation of the dust
are disastrous. Why have certain kinds of insoluble dust no cumu-
lative bad effect on the lungs? Why, on the other hand, have other
kinds such disastrous cumulative effects? When the first question
is answered the second becomes relatively easy.
It is in the production of phthisis (pulmonary tuberculosis)
that the continued inhalation of a dangerous variety of dust shows
its effects most clearly. The following table, which I compiled
from the statistics of the Registrar General for England and
Wales, shows the marked contrast between different occupations
as regards the effects of dust inhalation in producing phthisis.
Two dusty occupations are included — coal mining and tin mining.
Of the two, coal mining is much the dustier occupation. It will be
seen, however, that among coal miners there is not only very little
phthisis, but even less than among farm workers, and much less
than the average for all other occupations. Among tin miners, on,,;
the other hand, there is a great excess of phthisis; and detailed •
" First Report of the Committee on Control of Underground Temperature,
Trans. Inst, of Mining Engineers, 1920.
RESPIRATION 323
investigation has shown clearly that it is to dust inhalation that
this excess is solely due.-^^
A very large proportion of the dust in inspired air is caught on
the sides of the nasal and bronchial inspiratory passages, from
which it is continuously removed by the action of the ciliated
epithelium. It is only the very finest particles that penetrate to the
lung alveoli. Nevertheless large amounts of dust do, as a matter
DEATH RATES FROM PHTHISIS PER 1000
LIVING
AT EACH
AGE PERIOD FOR ENGLAND AND WALES, 1 900-1 902 1
Age period. 15-25
25-35
35-45
45-55 55-65
All occupied and retired males i.i
2.1
2.9
3.2 2.6
'* coal miners 0.7
i.o
I.I
1.5 2.0
" farm workers 0.6
1.15
1-3
1.4 2.6
" tin miners 0.4
7.0
11.7
16.I 16.2
of fact, reach the alveoli. Arnold showed that even what, in human
; experience, is relatively harmless dust, will produce, if inhaled
in very large amount, foci of scattered broncho-pneumonia in the
lungs, and that quartz dust is specially apt to produce inflam-
, matory changes followed by development of connective tissue. ^^
I In connection with the use of shale dust for preventing colliery
explosions Beattie showed that neither coal dust nor shale dust
produce any harm in animals if the dust is inhaled in the moder-
ate quantities comparable to what a miner inhales. On the other
hand, the dust from grindstones produces signs of fibrosis. -^"^ The
subject was followed further in my laboratory by Mavrogardato
in an investigation undertaken for the Medical Research Com-
mittee.^^ This work showed that the very fine particles which
reach the alveoli are rapidly taken up by special cells of the al-
veolar walls. When coal dust or shale dust was inhaled, these cells
soon detached themselves and wandered away with their load of
dust particles. Some pass directly into the open ends of the bron-
chial tubes, and are thence swept upwards by the cilia. Others
pass into lymphatic vessels and are carried to the nodules of lym-
" Haldane, Martin, and Thomas, Report on the Health of Cornish Miners,
Pari. Paper Cd, 2091, 1904.
^^ Arnold, Untersuchungen iiber Staubinhalation und Staubmetastase, 1885.
" Beattie, First Report of Explosions in Mines Committee, Pari. Pai>er, Cd,
6307, 1912.
"Mavrogardato, Journ. of Hygiene, XVII, p. 439, 19 18.
324 RESPIRATION
phatic tissue surrounding bronchi and then pass right through
the walls of the bronchi and are swept out. Others reach the
lymphatic glands at the roots of the lungs, and finally seem to pass
from there into the blood. In this way the dust is removed from
the lungs, and if too much dust is not inhaled the process of re-
moval will keep pace with the introduction of dust. The well-
known ''black spit" of a collier, which continues for long periods
when he is not working underground, is apparently a healthy
sign showing that dust particles are being removed from the
lungs. It seems quite probable, also, that the efficiency of the
physiological process for dealing with dust improves with use,
like other physiological processes. Moreover the dust-collecting
cells appear to be identical with cells which collect and deal
with bacteria in the lungs. Possibly, therefore, the somewhat re-
markable immunity of colliers from phthisis is connected with
their capacity for dealing with inhaled dust particles. ^^
At the end of a few months the lungs of a guinea pig which have
been heavily charged with coal dust or shale dust by experimental
inhalations are again free from dust. On the other hand this was
not the case when the dust inhaled was quartz. Most of the quartz
remained in situ, though mainly within the dust-collecting cells.
Part had, however, been carried onward to lymphatic glands. The
quartz did not seem to excite the cells to wander in the same way
as the coal dust or shale dust did ; and it appeared as if this dif-
ference in the properties of different kinds of dust explained why
some dusts are much more apt than others to produce cumulative
ill effects in the lungs. Presumably the quartz particles are so
inert physiologically that they do not excite the dust-collecting
cells to wander away. Other kinds of dust particles may be equally
insoluble, but may also be charged with adsorbed material which
makes them physiologically active. Coal, for instance, though very
insoluble in water, adsorbs substances of all kinds, and the im-
portance of its power of adsorbing gases has already been pointed
out.
Shale dust was found by Dr. Mellor to contain about 35 per
cent of quartz. Nevertheless the quartz in shale dust does no harm
to the lungs and is eliminated readily. There are many other
kinds of stone which contain still more quartz, but also produce a
harmless dust. In fact nearly all the dust ordinarily met with is
of the harmless variety, and Mavrogardato's investigation indi-
" Haldane, Trans. Inst, of Mining Engineers, LV, p. 264, 19 18.
RESPIRATION 325
cated that quartz dust becomes relatively harmless when it is
mixed with other dust of the harmless variety. The lung cells
appear to clear out the quartz when they are clearing out the other
dust.
It is evident that much further investigation is needed in order
to elucidate completely the physiology of dust excretion from the
lungs. It is equally evident, however, that this process is under
physiological control, just as much as other physiological activi-
ties are.
Air of Wells. The case of the air of wells and other unventilated
underground spaces differs from that of mines owing to the fact
that no artificial ventilation is provided for. It might be supposed
that the air in a well, with only rock or brickwork round it, pure
water at the bottom, and the top more or less open, would never
be more than slightly contaminated. Experience shows, however,
that this is not the case, and that the air in even a shallow well,
only a few feet deep, is sometimes dangerously contaminated.
In 1896 I investigated this subject, visiting various wells where
men had been asphyxiated, in order to see what had happened.^^
I found plenty of foul air, and that its composition was similar
to that of black damp, and not simply CO2, as was then believed.
The composition of the gas varied from about 80 per cent nitro-
gen and 20 per cent CO2 to almost pure nitrogen ; and it was quite
evident that this black damp or choke damp was simply the
residual gas from oxidation processes occurring in the strata
round the well.
Another point which emerged quite clearly was that the state
of the air in any well liable to foul air depended entirely on
changes in barometric pressure. With a rising barometer the air
was quite clear, and with a falling barometer it was foul. Thus
any fall in barometric pressure might make a well very dangerous,
though an hour before the air was quite pure. Moreover with a
falling barometer the well might be brimfuU and rapidly over-
flowing with dangerous gas. The danger to which well sinkers
are exposed is thus evident. At one well an engine house which
covered the top of the well had been built, and sometimes it was
unsafe to enter this building owing to the gas, unless doors and
windows were wide open. The engine man was much comforted
when I lent him an aneroid barometer and thus convinced him that
the outbursts of gas were due to natural and not supernatural
'° Haldane, Trans. Inst, of Mining Engineers, 1896.
326 RESPIRATION
causes. By always carrying a lighted candle or lamp with him, a
well sinker can guard most effectually against the danger from
black damp ; but it is quite unsafe to trust to previous tests.
It is thus evident that a well acts as a chimney communicating
with a large air space in the substance of the surrounding rock,
or in crevices within it. Air may either be going down this chim-
ney or returning; and if the rock contains any oxidizable material
such, for instance, as iron pyrites, the returning air or gas has
lost more or less of its oxygen, and possibly also gained some COo.
If, however, less than about 4 per cent of CO2 were present in
the black damp it would be lighter than air, and thus likely to
escape unnoticed.
An interesting case which came under my notice later may be
mentioned in this connection. While a tunnel was being driven with
compressed air under the Thames it was found that in a large
cold storage on the river bank lamps or candles were extinguished.
The air was analyzed for CO2, but no noticeable excess was found.
On analysis I found the air very poor in oxygen. On further
investigation it turned out that air very poor in oxygen, but with
practically no excess of CO2, was coming up the shaft of a well
belonging to the building.^-"- The flow did not depend on baro-
metric pressure, and nothing of the sort had occurred before the
construction of the tunnel began. It was evident, therefore, that
the flow was due to compressed air escaping deep down through
the London clay from the advancing end of the tunnel, and
forcing a way to the well, but at the same time losing oxygen
owing to the presence in the clay of oxidizable material such as
iron pyrites. The pure black damp contained 99.6 per cent of
nitrogen and 0.4 per cent of CO2.
Air of Railway Tunnels. Although the great difficulties form-
erly experienced in the ventilation of long railway tunnels have
been overcome by the substitution of electric traction for steam
locomotives, it may be worth while to record here some of these
difficulties. Probably the worst cases were those of single-line
tunnels on a stiff gradient in the Apennines. When the wind was
blowing in the same direction as a train was traveling on an up-
gradient the smoke from the engine or engines tended to travel
with the train. Thus the air rapidly became poisonous from the
presence of CO, and the oxygen percentage fell so low that some-
times lights were extinguished and steam began to fail, owing
" Blount, Journ. of Hygiene, VI, p. 175, 1906.
RESPIRATION 327
to the engine fires burning badly. The passengers could partly
protect themselves by closing the windows ; but the engine drivers
were liable to become unconscious, and at least one very serious
accident occurred, owing to a train running on with the men on the
engine unconscious.
In the London Underground Railway there was also much
trouble, owing to the great traffic, although there were numerous
openings to the street along all parts of the system, and a colliery
fan had also been installed at one point. The difficulties were
referred to a Board of Trade Committee of which I was a member,
, and I made numerous analyses of the air.^^ It was never so bad
as appeared to have been sometimes the case in the Apennine tun-
nels, and the trouble from sulphuric acid and smoke was largely
mitigated by the use of Welsh steam coal containing very little sul-
phur. The air was often, however, very unpleasant, and many
persons were unable to use the railway. At busy times the per-
centage of CO2 might rise as high as 0.8, and of CO to .06 ; but of
course passengers and railwaymen were not long enough exposed
to this air to suffer from the effects of CO, and repairing work on
the line was not carried out except at night. At the end of the
inquiry it was agreed to introduce electric traction, and since this
was done there has been no further difficulty. The tunnels are close
to the surface, and the trains push abundance of air out and in
(through openings to the outside air.
In the (London) tubes, which lie much deeper, the ventilating
action of the trains proved insufficient by itself to prevent the air
from becoming rather unpleasant; and systematic ventilation by
fans was therefore adopted. In various other railway tunnels
simple shafts are provided; and in the Severn Tunnel there is a
nearly central shaft provided with a powerful fan. By these
means the air is kept fairly pure.
Air of Sewers. The air of sewers is perhaps mainly of interest
in connection with the time-honored belief that "sewer gas"
spreads infection. Some of my earliest scientific work was con-
cerned with the air commonly present in sewers, and was started
by the late Professor Carnelley and myself^^ at the request of a
House of Commons' Committee appointed in consequence of alarm
as to the sewers of the House of Commons.
The air of a sewer has, of course, an unpleasant smell, which,
however, is hardly noticed except at the manhole by which access
^Report of the Committee on Tunnel Ventilation, Pari. Paper, 1897, Appendix i.
" Carnelley and Haldane, Proc. Roy. Soc, 42, p. 501, 1887.
328 RESPIRATION
is gained to the sewer. The air is saturated with moisture, and
may be somewhat warm if much warm water flows into the sewer.
Chemically speaking, however, the air is very little contaminated.
Even in the sewers of Bristol, where ventilating shafts were re-
duced to a minimum, I found only about 0.2 per cent of COg. On
determining the number of bacteria in the air we found that
fewer were present in the sewer air than outside, but of much the
same kinds. In sewers which were well ventilated there were far
more than in badly ventilated sewers; and it was evident that
nearly all the bacteria came from the outside through the venti-
lators. Where there was much splashing, however, a few were
thrown into the air. These results, which have been confirmed by
other investigators, are just what might be expected. Particulate
matter is not given off from moist surfaces apart from mechani-
cally acting causes, and any bacteria or other particles driven
into suspension in the air of a sewer will tend to fall back again.
It is conceivable that infection might be carried by sewer air ; but
innumerable other paths of infection are much more probable.
Although ordinary sewer air is chemically very pure, and not
even a trace of HgS can be found, accidents to sewermen from
foul air are not very uncommon ; and there is no doubt that most
of these accidents are due to HgS. I investigated one case of this
kind where five men had lost their lives at a manhole — the last
four in attempts at rescue. ^^ All the symptoms described, includ-
ing irritation of the eyes, were those of HgS poisoning ; and though
the air was not poisonous when I descended, a little HoS was
present. When some of the sewage was put into a large bottle and
shaken up, HoS was found to be present, and a mouse lowered
into the bottle showed severe symptoms of HgS poisoning. These
symptoms were absent when lead acetate was added before shak-
ing, or when caustic soda was added.
It is only when sewage stagnates or deposits solid matter that
HoS is formed. Any cause that stirs this sewage, or liberates HoS
from it, may make the air dangerous. About 0.2 per cent will kill
an animal within a minute or two; and o.i per cent will rapidly
disable it. HoS is thus a good deal more poisonous than CO, and
far quicker in its action.
Another source of danger is lighting gas from leaky street
mains. Lighting gas is frequently met with in sewers, and I have
several times smelt it in sewers. In one recent case which I in-
vestigated two men were killed by CO poisoning from lighting
** Lancet, Jan. 25, 1896.
RESPIRATION 329
gas. There seems to be no evidence of accidents in sewers from any
other gas than HgS or CO ; but many strange smells are en-
countered, and we were once much alarmed by chlorine coming
from a bleaching factory.
Air of Ships. In the compartments of a ship air is specially
liable to become foul owing to the air-tight conditions which
often exist. In a double bottom compartment, for instance, the
whole of the oxygen may disappear, owing to rusting or to ab-
sorption of oxygen by drying paint. In an ordinary compartment
battened down the same thing may also occur owing to slow ab-
sorption of oxygen by articles of cargo, such as grain, wool, etc.
Accidents from this cause are not infrequent if men descend with-
out first testing the air with a lamp or giving time for ventilation
to occur. In coal bunkers fire damp may accumulate in the absence
of proper ventilation, or else the oxygen may fall very low. Coal
trimmers are occasionally also affected by what appears to be CO
poisoning due to small quantities of CO formed at ordinary
temperatures in the slow oxidation of coal, as described above.
The ventilation of passenger and crew spaces on ships was very
defective, particularly in rough weather, until fan ventilation was
generally introduced. It was forgotten that the rooms in a ship
do not ventilate themselves naturally through walls and roof, as
a house ashore does. Owing to the close quarters, it is often diffi-
cult to ventilate the spaces in a ship properly without causing
intolerable draughts. In the mess decks of warships this is specially
difficult, as there are hammocks everywhere at night. The matter
was investigated recently by an Admiralty Committee of which
I was a member and a system introduced by which equal amounts
of air can be made to issue from a large number of louvres on the
sides of ventilating ducts. In this way the men are supplied with
an average of 50 cubic feet of air each per minute, without any
unpleasant draught impinging on any one. The temperature, and
particularly the wet-bulb temperature in warm weather, can also
be controlled very efficiently by this plan. With men perspiring
more or less from heat, and giving off perhaps fifty times as great
a volume of aqueous vapor as of CO2, very ample artificial venti-
lation is needed when no other means of ventilation is available.
Gas Warfare. It would be out of place to attempt to discuss the
nature and mode of action of the various substances used in gas
warfare; but a certain number of facts of physiological interest
in connection with respiration may be fitly referred to here.
The first serious gas attacks were made, as is well known, with
330
RESPIRATION
chlorine, discharged into the air in a good breeze as "drift gas''
from cylinders of liquefied gas. The liquefied gas quickly evapo-
rated, thus cooling a large body of air which rolled along the
ground, producing at the same time a mist if the air was nearly
saturated, and passing downwards into every trench. From ac-
counts given by officers and men at the time, I estimated that
along the lines attacked there was usually about .01 per cent of
chlorine in the air; but of course the percentage would vary. At
about this and higher concentrations, chlorine has an immediate
and severe irritant effect on the air passages, and a less severe
action on the eyes. Bronchitis follows if the exposure lasts for
more than a very short time, and some time later symptoms of
oedema of the lungs appear, owing to the action of the gas on the
alveolar walls. The symptoms are then similar to those which
follow exposure to nitrous fumes. The men suffering from this
condition were deeply cyanosed, with superficial veins about the
neck prominent, greatly increased depth and rate of breathing,
and a frequent, but usually fairly strong pulse. Intelligence was'
clouded, but the distress seemed very great.
On testing a drop of blood by diluting it to a yellow color,
saturating with coal gas and comparing the pink tint thus pro-
duced with the tint of normal blood similarly diluted, it was evi-
dent that there was no decomposition of the haemoglobin. The
cyanosis was therefore due to imperfect saturation of the blood
with oxygen. That the imperfect saturation was due, not to slow-
ing of the circulation, but to imperfect saturation in the lungs,
was shown at once by the effect of giving oxygen. This abolished
the cyanosis, cleared up the clouded intelligence, but had no great
effect on the breathing. On post mortem examination of fatal
cases it was found that the lungs were voluminous and greatly
congested. Large quantities of albuminous liquid could be
squeezed out through the cut bronchi, and there was much em-
physema.
The interpretation of the more dangerous symptoms seems
fairly clear. The cyanosis was due to the fact that the blood in
passing through the lungs was imperfectly oxygenated, owing
mainly to swelling and exudation, which hindered the diffusion
of oxygen inwards to the blood. On raising the alveolar oxygen
pressure when oxygen was given, the diffusion became much
faster and the blood was properly oxygenated. The hyperpnoea
remained, however, and was probably attributable to the fact
that though much air was entering the lungs, a great deal of it
RESPIRATION 33 1
only went into the emphysematous spaces where there was little
or no circulation, leaving the rest of the lung imperfectly venti-
lated, with an abnormal excess of COg in the alveoli which were
permeable to blood, and consequently an abnormal excess of
breathing.
Considering the depth of the cyanosis it was somewhat re-
markable that consciousness was not more impaired; but the ex-
cess of CO2 which accompanied the cyanosis would of course
facilitate the dissociation of oxyhaemoglobin in the tissue capil-
laries, and thus diminish the real anoxaemia. The distention of
superficial veins was an indication of the veno-pressor effect of
excess of COo combined with failure on the part of the heart to
respond normally to the large amount of blood returning to it
from the tissues. This failure was evidently due to the anoxaemic
condition of the blood supplied to the heart. The failure was pre-
sumably most marked in the left ventricle, which has far the most
. work to do, and the consequence would be a rise of blood pressure,
not only in the veins, but also in the right side of the heart and
the whole pulmonary circulation. The rise in pulmonary blood
pressure would of course tend to aggravate greatly the oedema of
the lungs, and would thus in itself be a very serious source of
danger. The ease with which oedema of the lungs follows on in-
creased venous blood pressure, even when there is no injury to the
lungs, has been shown experimentally by Knowlton and Star-
ling.25
The cause of the greatly increased flow of blood was simply
the fact that the arterial blood was in a venous condition, with
both a lowered oxygen pressure and raised CO2 pressure. The
perfectly normal effect of this, as pointed out in Chapter X, is to
cause dilation of capillaries and increased blood flow through the
tissues. Owing, however, to the pressor reaction of the vasomotor
center, the arterioles and probably also the venules in most parts
of the body except the central nervous system were contracted,
and in this way the blood pressure was maintained, so that the
^ pulse was of good strength.
It was first observed by Macaulay and Irvine of Johannesburg
I that in the treatment of cases of oedema of the lungs from
poisoning by nitrous fumes in mines, great benefit is often ob-
tained by free bleeding to the extent of about half a liter. From
the foregoing account it is clear that bleeding will reduce the
' venous and pulmonary blood pressure, and thus also reduce the
" Knowlton and Starling, Journ. of Physiol., XLIV, p. 206.
332
RESPIRATION
tendency to oedema of the lungs. The indication for bleeding is
evidently the distention of superficial veins. Bleeding was fre-
quently employed in the treatment of the chlorine cases, and with
great success. It is evident, however, that if there is no venous
distention, bleeding could not be expected to do anything but
harm.
A more radical treatment is the continuous administration of
air enriched with oxygen. Unfortunately the problem of con-
tinuous administration of oxygen had never been attacked before
the war, and no suitable apparatus was available for the early
chlorine cases. But in the later stages of the war many cases of
lung oedema were successfully treated continuously with oxygen
by means of a nasal tube or the apparatus described in Chapter
VII.
The next lung irritant gas used was phosgene (COClg). This
produces dangerous effects in considerably lower concentration
than chlorine, and its action is distinguished by the fact that it
has relatively less effect on the air passages and eyes and in the
end more on the alveolar walls. Thus a man exposed to a danger-
ous concentration of phosgene may notice but little irritant effect
at the time, or this effect may pass off rapidly, while the dangerous
effects on the alveoli only show themselves some hours later.
Phosgene was at first used as drift gas; but when drift gas was
abandoned as more or less ineffective against the protective
measures adopted, and also unmanageable owing to uncertain-
ties of wind, etc., phosgene was largely used in shells or bombs.
Various other substances with similar toxic properties were also
employed.
A change in the type of the symptoms accompanying lung
oedema was now noticed. The deep plum-colored cyanosis and
venous distention were usually absent, and bleeding was useless.
The cyanosis was still very marked, but was of a pale or "gray"
type. The breathing was also shallower, and the pulse feeble and
rapid. Many slighter cases were also observed in which no defi-
nite lung symptoms were observed, but only general malaise with
cyanosis and fainting on any muscular exertion.
In all these cases it seems evident that the rate of diffusion of
oxygen through the alveolar walls was diminished, but without
any marked interference with diffusion of CO2 outwards, so that
owing to the hyperpnoea from want of oxygen there would be a
deficiency of CO2 in the arterial blood. This is very intelligible
in view of the fact that on account of its greater solubility COy
RESPIRATION 333
diffuses outwards from the blood much more readily than oxygen
diffuses inwards (see Chapter VIII). The deficiency of CO2 in
the arterial blood would prevent or minimize the true hyperpnoea,
.md lessen the increase of circulation through the tissue capillaries
and the pressor excitation of the vasomotor center. But it would
increase the true tissue anoxaemia with a given degree of cyanosis.
Anoxaemia in the coronary circulation would also lead to the
enfeebled action of the heart, as shown by the very weak and
feeble pulse. The symptoms generally were those of a pure anox-
aemia with urgent danger of failure of the respiratory center in
;he manner already referred to in Chapter VI.
In these cases bleeding was of course useless. On the other
land injection into the blood of saline solution or, still better,
7um-saline, seemed likely to be of some use in view of the failing
)lood pressure. By far the most effective treatment, however, was
:he continuous administration of air enriched with oxygen, par-
icularly if this was begun early and before there was time for the
langerous effects which continued severe anoxaemia causes. By
his means the oxygen pressure in the alveolar air was sufficiently
•aised to permit of a nearly normal aeration of the arterial blood;
md the administration could be continued till the lung inflamma-
ion subsided.
The chronic after effects on the respiratory center of irritant
jases have already been referred to in former chapters.
CHAPTER XII
Effects of High Atmospheric Pressures.
The foundations of our scientific knowledge of the physiological
effects of high and low atmospheric pressures were laid broad
and firm by the investigations of Paul Bert, collected together in
his book, already so often referred to, ''La Pression Barome-
trique," published in 1878. It will be convenient to consider first
the effects of high atmospheric pressures.
Very high atmospheric pressures are met with in deep diving
and in engineering work under water or in water-logged strata.
Apart from laboratory experiments on animals, the highest
atmospheric pressures (up to ten atmospheres) have been met
with in deep diving. To understand the conditions under which
a diver is placed, it is necessary to understand the design of the
ordinary diving dress, which was introduced early last century by
Siebe, the founder of the well-known London firm of manu-
facturers of diving apparatus. The dress consists of a copper
helmet which screws on to a metal corselet, the latter being
clamped water-tight to a stout waterproof dress covering the
whole body except the hands, which project through elastic cuffs
(Figures 75 and J6). Air is supplied to the diver through a non-
return valve at the back of the helmet from a stout flexible pipe
strengthened with steel wire and connected with an air pump at
the surface. The air escapes through an adjustable spring valve
at the side of the helmet (Figure Tj). The arrangement is thus
such that the pressure of air in the helmet is at least equal to, and
can, by varying the resistance of the valve, be made greater than,
the water pressure at the outlet valve. For every 34 feet of fresh
water (or 33 feet or 10 meters of sea water) the pressure in-
creases by one atmosphere, or nearly 15 pounds per square inch.
At a depth of 33 feet of sea water the diver is therefore breathings
air at an excess pressure of one atmosphere, or a total pressure of
two atmospheres. It is absolutely necessary that he should breathe
compressed air, otherwise his breathing would be stopped in-
stantly by the pressure of the water upon the abdomen ; and at a
greater depth blood would probably pour from his nose and mouth
on account of the squeezing to which all parts of his body, except
his head in the helmet, would be subjected.
Figure 7 5-
Diving dress, fiont view, with air pipe and life line,
which are connected with the helmet behind.
Figure Td.
Diving dress, back view, showing attachment of air pipe
and life line with telephonic connection ; new pattern, with
legs laced up to prevent diver from being capsized and
accidentally blown up to surface, or hung in a helpless
position.
RESPIRATION 2^-
In order to enable the diver to sink and stand firmly on the
bottom, the dress is weighted with 40-pound leaden weights,
back and forward, as shown, with 16 pounds of lead on each
boot — about 112 pounds of lead in all. Besides the air pipe, the
diver is connected with the surface by a so-called life line, which
usually contains a telephone wire. He goes down by a rope at-
e RejuUior
Helmet
StclUn »/Oofltf V4/«
Figure 77-
and section of outlet valve.
tached to a heavy weight which has been lowered to the bottom
previously, and on reaching the bottom he takes with him a line
attached to this weight, so that he can always find the rope again.
As a diver enters the water, the superfluous air in his dress is
driven out through the outlet valve by the pressure of the water
round his legs and body. The water seems to grip him all round.
If the valve is freely open he feels his breathing somewhat
336 RESPIRATION
labored by the time he gets first under water. The reason of this is
that the pressure in his lungs is that of the water at the valve
outlet, whereas the pressure on his chest and abdomen is greater
by something like a foot of water. He is thus inspiring against
pressure, and if he has to breathe deeply, as during exertion, the
breathing is apt to become fatigued in the manner described in
Chapter III. With another foot of adverse pressure the fatigue is
very rapid. One of the first things which a diver has to learn is
to avoid the adverse pressure by regulating the spring on the
outlet valve, so that the breathing is always easy. The spring
regulates at the same time the amount of air in the dress, and
therefore the buoyancy of the diver. A practiced diver can thus
slip easily, and without exertion, up or down the rope. A pres-
sure gauge attached to the air pipe where it leaves the pump
indicates the depth of the diver at any moment.
The breathing is of course easiest when the dress is full of air
down to the level of the diaphragm, but when this is so the diver
is in danger of being "blown up" ; for if he is crawling on the
ground, it may easily happen that the air gets into the legs of
his dress. His head goes down so that the excess of air can-
not escape readily. He is then blown helplessly to the surface,
while his arms are fixed in an outstretched position (see Figure
78). His air pipe may be caught by a rope or other obstruction,
so that he is hung up in a helpless position with his legs upwards,
the excess of air being unable to escape at the valve since it is
downwards. In very deep diving there is considerable risk of
being blown up ; and to avoid this risk the arrangement for lacing
up the legs, shown in Figure "j^, was introduced (see also Fig-
ure 79).
In the Denayrouze apparatus, extensively used on the Conti-
nent, the air is pumped into a steel reservoir on the diver's back.
By means of a reducing valve his air is supplied from the reser-
voir according to his requirements. The arrangement is a beauti-
ful piece of mechanism, but an encumbrance which gives rise to
various inconveniences and dangers, one being that the depth of
the diver cannot be read off at the surface, and another that he
cannot regulate the pressure in his helmet.
For engineering work in preparing foundations, etc., on the
sea bottom, a diving bell is sometimes employed. This is a heavy
metal box, open below, and supplied with compressed air by a
pipe (Figure 80). It is lowered to the bottom with the workmen
sitting in it, and they can work dry on the bottom. The diving
Figure 78.
Diver in ordinary dress blown up. His head is down and his arms
©utstreched.
Figure 79.
Diver in laced-up dress purposely blown up. His head
is up and his arms free.
Figure 80.
Diving bell in use at National Harbour Works, Dover. Each bell
measures 17x10 feet by 6^ feet high, and weighs about 35 tons.
Figure 81.
Diagram showing use of caisson in making the foundations
RESPIRATION
337
bell in its crude original form was invented by Sturmius in the
sixteenth century, and further developed by Halley two centuries
later.
The caisson introduced about 1840 by the French engineer
Triger, for sinking colliery shafts through water-logged strata
near the surface, is a further development of the diving bell. It
is now largely used for carrying the foundations of the piers of
bridges, etc., through soft ground on the bottom of a river or the
sea. The caisson (see Figure 81) is the bottom section of the
steel pier, and resembles a diving bell except for the fact that it
communicates with surface through a tube occupying the center
of the future pier and kept full of compressed air. This tube
serves for access and for removal of excavated material. The men
excavate the soft bottom so as to allow the caisson to sink down
to a secure foundation, and the sections of the pier are added
from above and filled with concrete as the caisson sinks. Access
to the central tube is through an air lock on surface. The men
enter the air lock, close the door, and then let the air pressure
rise till they can open the door into the central tube ; and in coming
out the reverse process is used.
In tunneling operations in soft strata under water, the ad-
vancing tunnel is kept full of compressed air, so as to hinder the
penetration of water into the advancing end, as the steel rings
forming the permanent walls of the tunnel are successively put
in. The men thus work in an atmosphere of compressed air, to
which access is gained through one or more air locks. The tubes
and large tunnels under the Thames or deep in the water-logged
London clay, and under the Hudson and East Rivers at New
York, have been, or are being, constructed by this means. In the
sinking of colliery shafts through water-logged strata the freez-
ing or cementation processes are now generally used, as, except
in strata fairly near the surface, the water pressures are too high
for the compressed-air process.
Various physiological disturbances are associated with ex-
posure to compressed air, and these must now be considered one by
one. As the pressure rises when a man goes below water, in a
diver's suit, or as compressed air enters an air lock through which
he is passing to a caisson or tunnel, the first trouble usually noticed
is a sense of pressure and pain in the ears. This is due to un-
balanced pressure on the memhrana tympani, owing to the fact
that the Eustachian duct does not open freely so as to equalize
the air pressure in the middle ear with the atmospheric pressure
338 RESPIRATION
outside. The passage is specially liable to be blocked if any
catarrh of the air passages is present; and if the warning pain is
disregarded the membrane may burst, though this is not a very
serious accident. In men accustomed to compressed air the Eus-
tachian tubes open easily, so that no inconvenience is felt, and a
diver goes quite easily within two minutes to a pressure of seven
atmospheres or more, while one who is not accustomed to com-
pressed air may have a long struggle with his Eustachian tubes
before he can reach an extra pressure of half an atmosphere. It
also happens occasionally that there is trouble with the frontal
sinuses. The same difficulties with the middle ear may, of course,
be met with by airmen during rapid descents, or even, to a minor
extent, in descending a deep mine shaft.
A man who has reached a pressure of six or seven atmospheres,
and is breathing pure air, is perfectly comfortable if he has es-
caped ear trouble. His voice is, however, altered by the com-
pressed air, and this is so marked that it is often difficult to make
out through the telephone what he is saying. At first sight it
might seem that an increased mechanical pressure of several
atmospheres would in itself be expected to have an appreciable
effect on a man or animal. It was commonly supposed, for ex-
ample, that the increased pressure on the skin must at first tend to
drive blood into the internal organs, producing congestion of the
brain, etc., with a converse effect on diminishing the atmospheric
pressure. The pressure is, however, transmitted instantly through-
out all the liquid and solid tissues of the body, so that this idea
was totally fallacious, and indeed ridiculous. As will be seen
below, many divers have lost their lives owing to well-meant in-
junctions to descend and ascend slowly. As regards other possible
effects of a few atmospheres of mechanical pressure, it should be
remembered that the intrinsic pressure of water is calculated to
be over 10,000 atmospheres. As the tissues are largely composed
of water, the addition to this of a few atmospheres of mechanical
pressure in the liquid or semi-liquid parts of the body cannot be
of much account.
As Paul Bert showed experimentally, the serious inconveni-
ences and dangers to which workers in compressed air are ex-
posed are due (apart from easily avoidable effects on the ears)
not to the mechanical pressure, but to the increased partial pres-
sures of the gases in the air breathed. If the air breathed is pure,
the only gases which come into consideration in this connection
are nitrogen and oxygen; but if the air is rendered impure by
RESPIRATION 339
respiration, as is commonly the case in diving, carbon dioxide
also comes into consideration. The case of this gas may be con-
sidered first, though Paul Bert did not himself allude to it in
connection with work in compressed air, as he was not practically
familiar with diving.
Owing to the difficulties frequently experienced by divers in
attempts to work at depths over about 12 fathoms a Committee,
including myself as the physiological member, was appointed by
the British Admiralty to investigate the whole subject of the
difficulties and dangers associated with deep diving.^ It appeared
that men who attempted to make any serious exertion when at
depths of over about 12 fathoms often became unconscious or
greatly exhausted. The symptoms pointed to excess of CO2, and,
on taking samples from the divers' helmets at about this depth,
we frequently found 2 or 3 per cent of COo. This occurred in spite
of an apparently abundant supply of air from the pumps, which
were working at a much faster rate than was sufficient to keep the
diver comfortable at a lesser depth. As explained in Chapter II,
the physiological effects or 3 per cent of CO2 at 1 1 fathoms, or a
total pressure of three atmospheres, is equal to that of 3 x 3 = 9
per cent at normal atmospheric pressure; so no wonder the divers
became unconscious. The pumps were often found to be leaking
badly through the piston rings, as many of them were old, and
no tests were then employed to detect this leakage. Apart from
this cause, however, the air supply was often insufficient.
It is evident that in order to keep down the pressure of COg
in the air of the helmet to a proper limit, the amount of air as
measured at surface by the strokes of the pump must be increased
in proportion to the increase in the total atmospheric pressure in
the helmet. The diver at 3 atmospheres pressure, requires, there-
fore, three times as much air, and so on in proportion to the
pressure. When this was attended to, and the piston rings kept
tight, no discomfort whatsoever was experienced at a depth of
even 35 fathoms. With a full air supply, hard exertion is actually
easier to a diver at some depth than near surface, on account of
the higher oxygen pressure, as explained in Chapter IX.
By far the most serious danger to divers and other workers in
compressed air is of a quite different character. From the earliest
days of diving and work in compressed air it had been observed
that soon after returning to atmospheric pressure the men fre-
^ Report of the Admiralty Committee on Deep Water Diving, Pari. Paper, C. N.,
1549. 1907-
340 RESPIRATION i
quently became ill, and sometimes died or became paralyzed, i
The risk of these attacks increased with the pressure and the
duration of exposure to it, but they never occurred except on
return to atmospheric pressure. Divers are exposed to the highest
pressures, and in divers the attacks were of the most dangerous
character. In the worst cases the diver began to feel faint a few
minutes after return to surface; soon he became unconscious
and his pulse disappeared; and in a few minutes he was dead.
In other cases his legs became paralyzed, and cases of "diver's
paralysis" used to be not uncommon in British hospitals. In the
slighter cases, very common among workers in caissons and tun-
nels under construction, there is severe pain, known to the work-
men as "bends," in one or other of the limbs, or in the body.
Another of the common slight symptoms is itching of the skin.
Various other nervous symptoms are also met with, the whole
complex being designated as "caisson disease" — a somewhat mis-
leading name.
Paul Bert investigated on animals the nature of compressed
air illness or "caisson disease," and found that it is due to libera-
tion in the blood and tissues of bubbles of gas consisting almost
entirely of nitrogen. In the rapidly fatal cases the heart becomes
filled with a mass of bubbles which stop the whole circulation..
In the cases of paralysis bubbles have obstructed the circulation^
and so caused necrosis of parts of the spinal cord; and it is evi-
dent that the bubbles may produce the most varied symptoms
according to the positions in which they are formed.
The cause of the bubble formation was evident. At the highi
pressure the blood in the lungs is exposed to greatly increased
partial pressures of nitrogen and oxygen, although, as shown in
Chapter II, there is no increased pressure of COa- As, in ac-
cordance with Henry's law, liquids take up in simple solution a
mass of any gas proportional to its partial pressure, the blood in
the lungs takes up in the compressed air an extra amount of nitro-
gen and oxygen proportional to the increased pressure. The extra
oxygen disappears at once when the blood reaches the tissues, but
the extra nitrogen does not disappear, and gradually saturates
the whole of the tissues till they are charged with nitrogen at the
partial pressure existing in the air breathed. When the external
atmosphere is reduced to normal, the internal partial pressure of
nitrogen is of course far above the atmospheric pressure. The
blood and tissues are therefore supersaturated with nitrogen and
bubbles begin to form. These bubbles consist primarily of nitro-
Figure 82.
Portion of goat's mesentery showing bubbles in blood vessels caused by
rapid decompression in i^ minutes from 100 lbs. pressure, after i J^ hours
exposure at this pressure.
RESPIRATION 3^1
gen, but of course take up a little oxygen and COo from the sur-
rounding blood and tissue liquids. If they are formed in the blood
they tend to block the circulation on account of the great resist-
ance which they cause. Figure 82 is from a photograph of blood
vessels in the mesentery of a goat killed by rapid decompression,
and shows abundant bubbles in the veins.
The bubbles are formed, not merely in the blood, but also in
the tissues outside it. We found that fat in particular is apt to be
very full of bubbles and thus become spongy. It had been found
by Vernon in connection with another investigation that gases
are much more soluble in oils than in water. In connection with
our investigations he determined the solubility of nitrogen in
body fats at blood temperature, and found that it is about six
times as great as in water. ^ The tendency of fatty substances to
act as a special reservoir of dissolved nitrogen is thus intelligible ;
and Boycott and Damant^ afterwards showed that fat animals,
other conditions being the same, are considerably more liable to
symptoms of caisson disease than spare animals. Not only ordi-
nary fat, but the myelin sheaths of nerve fibers, will form reser-
voirs of dissolved nitrogen ; and for this reason bubbles will tend
to be liberated in the white matter of the brain and spinal cord,
and inside the sheaths of large nerves. The "bends" and certain
other associated symptoms from which workers in compressed
air so frequently suffer are probably due to liberation of bubbles
from the gas dissolved in the myelin sheaths. It is difficult to un-
derstand otherwise the severe pain of "bends." Figure 83 shows
the positions of a large number of bubbles found in the white
matter at different parts of the spinal cord.
The increased amount of nitrogen dissolved in the blood at
high atmospheric pressures was demonstrated by Paul Bert by
blood-gas analyses ; and Hill and Greenwood^ not only confirmed
this, but showed that there is the same excess in the urine. Hill
and Macleod also observed directly the sudden appearance of
gas bubbles in the capillaries of the frog's web when the animal
was decompressed from a high atmospheric pressure.*^
As a preventive of the occurrence of caisson disease Paul Bert
recommended slow and gradual decompression; but his experi-
ments in this direction were not very successful, as he had not
* Vernon, Proc. Roy. Soc, LXXIX, B, p. z(i(i, 1907-
" Boycott and Damant, Journ. of Hygiene, VIII, p. 445. 1908.
*Hill and Greenwood, Proc. Roy. Soc, LXXIX, B, p. 21, 1907.
'Hill and Macleod, Journ. of Hygiene, III, p. 436, 1903-
342
RESPIRATION
2ud cervical.
3rd dorsal.
Figure 83.
Shows the distribution of extravascular bubbles in five regions of the spinal
cord of goat 3 (series IV). The animal died of oxygen poisoning during de-
compression after 3 hours' exposure at 81 lbs. in an atmosphere containing
36 per cent oxygen. The bubbles are practically confined to the white matter
and are there especially concentrated in the boundary zone where the circula-
tion is least good. Each diagram is a composite drawing showing all the bubbles
in 0.4 mm. length of cord. (After Boycott, Damant, and Haldane.)
RESPIRATION 343
completely realized the conditions. Slow and uniform decompres-
sion was, and still is, also enjoined by various government regu-
lationSj etc., in different countries, but with only very moderate
success; and deaths or paralyses from caisson disease remained
common if the extra pressure used was above about 1.5 atmos-
pheres. Workers in compressed air had soon discovered that the
pain of ''bends" can be relieved at once by returning into the com-
pressed air; and this became quite intelligible from Paul Bert's
experiment. He made some experiments on the curative effects
of recompression, but here again he was not very successful, as
he applied the remedy only in extreme cases. Medical recompres-
sion chambers for the treatment of compressed air illness were
first introduced by Sir Ernest Moir in connection with the con-
struction of the first East River tunnel at New York, and the
Blackwall Tunnel under the Thames, about 1890. They proved
strikingly successful when applied to the cases which occurred
with the comparatively slow decompression in the air lock. Pa-
ralyses and "bends" were relieved at once, even when they had
occurred a considerable time after leaving the tunnel. The pro-
vision of medical recompression chambers has now become a
necessary adjunct of all considerable engineering undertakings
at pressures of over about 1.5 atmospheres, and in extensive deep
diving operations. Figures 84 and 85 show one of the recompres-
sion chambers used in the British Navy. The trouble, however,
about the use of recompression chambers is that it is often very
difficult to get the patient out without the symptoms recurring.
The decompression may require many hours, or even days in bad
cases.
Paul Bert also tried another method of treatment — that of
administering pure oxygen to his animals. This must hasten the
diffusion outwards of nitrogen, while the oxygen itself is ab-
sorbed by the tissues. At first sight it might seem as if this plan
ought to be very successful, either in treatment or in the pre-
vention of bubble formation during decompression. The results,
however, were disappointing and from causes which will be made
evident below. There seems, however, to be some scope for oxy-
gen administration where there is great difficulty in getting a
patient out of a medical air lock, and where there is no fear of
oxygen poisoning — a condition which will be discussed presently.
When the Admiralty Committee had dealt with the troubles
traced to CO2, it was faced by the dangers of caisson disease,
which of course became much more important after it had been
344 RESPIRATION
rendered possible for divers to work at great depths without in-
convenience. The existing precautions against ''caisson disease"
were evidently quite insufficient. The divers were officially en-
joined to descend and come up at a slow and even rate of about
5 feet per minute, but many serious or fatal cases were occurring
in spite of this. The problem was to find a safe and reasonably
short method. Very slow methods are impractible on account of
changes of tides and weather. The whole physiological side of
compressed-air illness had therefore to be reconsidered.
The formation of bubbles depends, evidently, on the existence
of a state of supersaturation of the body fluids with nitrogen.
Nevertheless there was abundant evidence that when the excess
of atmospheric pressure does not exceed about ij4 atmospheres
there is complete immunity from symptoms due to bubbles, how-
ever long the exposure to the compressed air may have been, and
however rapid the decompression. Thus bubbles of nitrogen are
not liberated within the body unless the supersaturation corre-
sponds to more than a decompression from a total pressure of
2% atmospheres. Now the volume of nitrogen which would
tend to be liberated is the same when the total pressure is halved,
whether that pressure be high or low. Hence it seemed to me
probable that it would be just as safe to diminish the pressure
rapidly from 4 atmospheres to 2, or 6 atmospheres to 3, as from
2 atmospheres to I. If this were the case, a system of stage
decompression would be possible, and would enable the diver to
get rid of the excess of nitrogen through his lungs far more
rapidly than if he came up at an even rate. The duration of ex-
posure to a high pressure could also be shortened very consid-
erably, without shortening the period available for work on the
bottom.
The whole matter was put to the test in a long series of experi-
ments carried out on goats by Professor Boycott, Commander
Damant, and myself^ at the Lister Institute, London, in a large
steel chamber which was given for the purpose by the late Dr.
Ludwig Mond (see Figures S6 and 87). We found that after
very long exposure of a number of the animals at a total pressure
of 6 atmospheres sudden decompression to 2.6 atmospheres pro-
duced not the slightest ill eff"ect. This decompression is in the
proportion of 2.3 to I, and the drop of pressure was 3.4 atmos-
pheres. In a corresponding series where the drop of pressure was
"Boycott, Damant, and Haldane, Journ. of Hygiene, VIII, p. 242, 1908. The
Report of the Admiralty Committee contains a short abstract of the work.
Figure 84.
Outside of naval recompression chamber, showing man-
hole for access, and air lock for food.
Figure 85.
Inside of recompression chamber, showing bed for patient.
RESPIRATION 3^^
the same, but from 4.4 to i atmosphere, or in the proportion of
4.4 to I, only 20 per cent of the animals escaped symptoms, while
20 per cent died, 30 per cent had severe symptoms, and 30 per
cent had "bends," quite easily recognized in the animals by their
behavior and the manner in which they held the affected limb
(Figure 88). It seemed evident, therefore, that it is quite safe to
halve the absolute pressure rapidly. Before venturing on such
extensive rapid decompressions of divers under water we re-
peated the goat experiments on men in the steel chamber, Com-
mander Damant and Lieutenant Catto being the subjects. There
were no ill effects in a number of experiments, nor in subsequent
trials by them under water at sea; and rapid decompression to
half the absolute pressure is now the routine practice of divers,
and is not known to have ever resulted in harm.
We were still, however, only at the beginning of the inquiry.
It was evident that the whole danger lay in the last stages of the
decompression. "On ne paie qu'en sortant," as was remarked by
Pol and Watelle, who were the first to give a medical account of
the symptoms of caisson disease.''^ The problem was to get divers
completely clear of the compressed air without paying. This
problem had resolved itself into that of avoiding the critical
supersaturation with nitrogen in any part of the body at or before
the last stage of decompression.
Let us consider the process of saturation and desaturation more
closely. The blood passing through the lungs of a man breathing
compressed air will, in accordance with what has been explained
in Chapter IX as to the permeability of the lung epithelium to
gas, become instantly saturated to the full extent with nitrogen
at the existing partial pressure in the air. When this blood
reaches the systemic capillaries, most of the excess of nitrogen
will diffuse out and the blood will return for a fresh charge, this
process being repeated until at length the tissues are fully charged
with nitrogen at the same partial pressure as in the air. But the
blood supply to different parts of the body varies greatly, as we
have seen. The capacity of different parts of the body for dis-
solving nitrogen varies also. Thus the white matter of the central
nervous system has but a small blood supply and at the same time a
high capacity for storing nitrogen ; and the same remark applies to
fat. The gray matter, on the other hand, has an enormous blood
supply and no extra capacity for storing nitrogen. Other tissues,
^ Pol et Watelle, Ann. d' hygiene publique, (2), p. 241, 1854.
346 RESPIRATION
such as muscles, may or may not have a great blood supply, ac-
cording to the amount of work a man is doing. We can easily
see, therefore, that the time taken for different parts of the body
to become saturated with nitrogen will vary greatly.
Taking into consideration the amount of fatty material in the
body, we estimated that the whole body of a man weighing 70
kilos will take up about i liter of nitrogen for each atmosphere
of excess pressure — about 70 per cent more nitrogen than an
equal weight of blood would take up. Now the weight of blood in a
man is about 6.5 per cent of the body weight; hence the amount
of nitrogen held in solution in the body, when it is completely
1 70
saturated with nitrogen, will be about — — or 26 times as great
as the amount held in the blood alone. If, therefore, the composi-
tion of the body were the same at all parts, and the blood dis-
tributed itself evenly to all parts, the body would have received at
one complete round of the blood after sudden exposure to a high
pressure of air one twenty-sixth of the excess of nitrogen cor-
responding to complete saturation. The second round would
add one twenty-sixth of the remaining deficit in circulation, i.e.,
1/26 X 25/26 of the total excess. The third round would add
1/26 X (25/26 X 25/26), and so on. On following out this calcu-
lation, it will be seen that the body would be half saturated in
less than 20 rounds of the circulation, or about ten minutes, and
that saturation would be practically complete in an hour. The
progress of the saturation would follow the logarithmic curve
shown in Figure 89. Actually the rate of saturation will vary
widely in different parts of the body ; but for any particular part
the rate of saturation will follow a curve of this form, assuming
that the circulation rate is constant.
There is abundant evidence, both from human experience and
from experiments on animals, that liability to compressed-air
illness increases with duration of exposure. We found that in
goats the liability increased up to about 3 hours' exposure, but
did not increase further even with far longer exposure. In man,
on the other hand, limitation of exposure to 3 hours has been
found to diminish the liability distinctly, and we calculated from
the goat experiments, taking into account the greater rate of
circulation in the goat on account of its much smaller weight (see
Chapter X), that in man the liability would increase up to about
5 hours' exposure. We had therefore to allow for parts of the
body which would only become half saturated in about i J4 hours,
but for nothing slower than this.
Figure 88.
'Bends" of foreleg in a goat.
RESPIRATION
347
The longer any part of the body takes to saturate, the longer
will it also take to desaturate to the point at which it is safe to
reduce the pressure to normal. But if we know the pressure and
duration of exposure, we can now calculate a safe rate of further
decompression after the initial reduction of total pressure to half
no
12 3 4 5
Multiples of the time required to produce half-saturation.
Figure 89.
Curve showing the progress of saturation of any part of the body
with nitrogen after any given rise of pressure. The percentage
saturation can be read off on the curve, provided the duration of
exposure to the pressure, and the time required to produce half satu-
ration of the part in question, are both known. Thus a part which
half saturates in one hour would, as shown on the curve, be 30 per
cent saturated in half an hour, or 94 per cent saturated in 4 hours.
has been carried out : for we can calculate the rate at which nitro-
gen is being carried away from parts which saturate and de-
saturate quickly, or from those which do so slowly. We can thus
regulate the rate of decompression so that no part of the body
is at any time supersaturated to such an extent as to cause risk of
bubble formation. In this way tables were calculated for regu-
lating the rate of decompression of divers and other workers in
compressed air. For the sake of convenience the decompression
348
RESPIRATION
rate was calculated in stages, each of which represents a reduc-
tion in depth of lo feet, so that a diver is stopped by signal at every
ten feet of ascent.
Figure 90 represents what is happening during a dive to 28
fathoms, with the stay on the bottom limited to 14 minutes, and
75
^60
^
^
45
30
15
/o
15
50 35 40 45
20 25
Figure 90.
Diving to 168 feet by new method: Diver 14 minutes on the bottom and 46
minutes under water. The curves from above downward represent, respectively,
the variations in saturation of parts of the body which half saturate in 5, 10, 20,
40, and 75 minutes; the thick line representing the air pressure.
the new method carried out of rapid descent and ascent by stages.
It will be seen that when the diver reaches surface, the maximum
condition of supersaturation with nitrogen in any part of the body
corresponds to only 17J/2 pounds per .square inch (or 1.17 atmos-
pheres) of air pressure. This leaves a margin of safety. Figure 91
shows what happened by the old method, with the same time on
RESPIRATION
349
the bottom. It will be seen (i) that the dive took twice as long a
time, and (2) that when he reached surface the maximum super-
saturation was 36 lbs. (2.4 atmospheres), so that he would run a
75
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Figure 91.
Diving to i68 feet by old method: Diver 14 minutes on the bottom and 84
minutes under water. The curves from above downward represent, respectively,
the variations in saturation of parts of the body which half saturate in 5, 10, 20,
40, and 75 minutes; the thick line representing the air pressure.
most dangerous risk. It is evident from the figure that the slow
descent and most of the slow ascent were simply adding to the
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Figure 92.
Theoretical ascents of a diver after a prolonged stay at 213 feet of sea
water. Stage decompression in 309 minutes compared with uniform decom-
pressions in 309 minutes and in 10 hours. Continuous lines = stage decompres-
sion : interrupted lines = uniform decompression. Thick lines = air pressure :
thin lines = saturation with atmospheric nitrogen in parts of the body which
half saturate in 75 minutes.
350 RESPIRATION
danger. These figures show also in a clear way, the advantages oi
cutting down the duration of stay on the bottom. It appears from
Figure 90 that with the short stay on the bottom the more slowly
saturating parts of the body have not time to reach a dangerous
degree of saturation, though they might do so if similar dives
were repeated after short intervals on one day.
With a long exposure to a high air pressure the time required
for safe decompression, even by the stage method, becomes much
too long for ordinary diving work. Figure 92 shows, for instance,
that it would take nearly five hours by the stage method, and ten
hours with uniform decompression, for completely safe decom-
pression after a stay of some hours under a pressure of 35^^
fathoms of water, or an excess pressure of 6J4 atmospheres.
In the ordinary diving table, therefore, the stay on the bottom is
so limited that the diver can be decompressed safely in half an
hour. Nevertheless, it may happen that it is justifiable to stay
longer, or that a diver's air pipe is fouled by something on a wreck
and even that he cannot be liberated till the tide slackens or turns.
To meet such cases a supplementary table was drawn up. These
two tables are reproduced below.
Since the introduction iijto the British Navy twelve years ago
of the method of decompression embodied in the tables, with the
corresponding regulations as to air supply and testing of the
pumps, deep diving has been conducted with comfort and safety
to the divers, so that compressed-air illness has now practically
disappeared except in isolated cases where from one cause or
another the regulations have not been carried out. When a medi-
cal compressed-air chamber is available, it is justifiable to cut
down the time for the last wearisome stages of the decompression,
and so extend the time on the bottom. This has been cautiously
tried under Commander Damant's supervision, but the result was
that the divers began to suffer from *'bends." These could easily
be relieved in the chamber, but much loss of time and incon-
venience resulted, and the "bends" were apt to recur. It seemed
better to keep the chamber as a precaution against emergencies or
unforeseen accidents. I calculated the tables with great care on
the theoretical lines borne out by the experiments and in the
light of all the available evidence from human experience ; and it
appears that the times cannot be cut down without risk of trouble,
unless the divers are placed in the chamber as a matter of routin
after each dive.
If a diver develops serious symptoms of compressed-air illness,
RESPIRATION 351
{ and no compressed-air chamber is available, the best plan is to
screw on his helmet and drop him down under water till his
symptoms disappear. An unconscious man (who had developed
bad symptoms as a result of disregarding orders to stop at the
proper stages) soon answered the telephone when he was dropped
down in this way. The trouble, however, is to get the man up
again safely. A very cautious ascent is needed. When once bubbles
of any considerable size have formed it takes a considerable time
to get them redissolved.
The reason why a bubble in the blood or elsewhere in the body
tends to disappear, is that the partial pressure of nitrogen in the
bubble is greater than in the blood. The blood is saturated in the
lungs with nitrogen at a pressure of about 75 per cent of the
existing atmospheric pressure. In the venous blood, and there-
fore in the tissues, the pressure of oxygen, as shown in Chapter X,
is only about 6 per cent and of CO2 about 6.5 per cent of an
atmosphere. There is also a pressure of about 6 per cent of aqueous
vapor. As the bubble is at atmospheric pressure and the total gas
pressure in the surrounding tissues is only about 75 -|- 18.5 =
93.5 per cent of an atmosphere, its nitrogen pressure is above that
of the tissues by 6.5 per cent. It must therefore gradually go into
solution, and at high atmospheric pressures it will do so all the
sooner since the pressures of oxygen and COg do not increase pro-
portionally to the atmospheric pressure. If the bubbles are only
very small they will probably dissolve very rapidly on recompres-
sion; but if they are large, and particularly if they have been
formed at places where there is but little circulation, they will take
a long time to disappear. Great patience may therefore be needed
in treatment by recompression.
In the experiments made at sea under the direction of the
Admiralty Committee, the greatest depth at which trials were
made was 35 fathoms. At this depth Commander Damant and
Lieutenant Catto were perfectly comfortable, and in all the
numerous experimental dives which they made up to this depth
with stage decompression, no symptoms whatever of compressed-
air illness were observed. This depth was, however, greatly ex-
ceeded in the course pf operations for the recovery of a United
States submarine at Honolulu in 191 5. A diving crew had been
trained in the new methods at New York, and proceeded to Hono-
lulu to assist in getting hawsers in position round the submarine,
which was lying at a depth of 50 fathoms (corresponding to an
excess pressure of over 9 atmospheres or 135 pounds per square
352 RESPIRATION
inch). The operations were successful, and these remarkable
dives are described in a paper by Assistant Surgeon French,
U. S. N., who was one of the medical officers in immediate
charge.^
Eleven dives were made to depths of from 306 to 270 feet, the
time on the bottom being usually about 20 minutes. The stage
decompression, which was shortened as a recompression chamber
was always ready, occupied about no minutes. When everything
went according to plan, as turned out in eight of the dives, there
were no symptoms except in one case. One of the divers, however,
got foul at a depth of 250 feet and was delayed there about three
hours before he could be liberated. When he was freed he came
up beyond the proper stopping places, disregarding the telephoned
orders. Possibly he was partly stupified by the prolonged action
of the high pressure of oxygen. At forty feet from surface he
collapsed. This was about 40 minutes after starting the ascent.
He was then pulled up to surface, where he was still able to
say a few words before becoming unconscious. His dress was
quickly ripped off and he was hurried into the recompression
chamber along with the two doctors and the other diver who had
rescued him. By this time he was black in the face, his breathing
had ceased, and no pulse could be felt at the wrist, x^rtificial res-
piration was at once applied, and at the same time the pressure
was run up to 75 lbs. in 3j4 minutes, which ruptured both the
eardrums of one of the doctors. As 75 lbs. pressure was reached
the patient suddenly recovered and sat up, feeling all right again.
He was then gradually decompressed to 20 lbs. in about ij4
hours, but at this point severe pain developed, so that the pressure
had to be raised again. For the next five hours many attempts at
decompression below 20 pounds had to be given up. At last he
was very gradually decompressed in about 3 hours in spite of the
pain. Soon after being taken from the chamber he was in a very
precarious condition, with the pulse no longer palpable. In spite
of haematuria, almost complete suppression of urine, extreme
pain, and other threatening symptoms, he recovered gradually;
and when it was possible to examine his lungs he was found to
have double broncho-pneumonia, the result, presumably, of the
very high oxygen pressure, as will be explained below. In a few
weeks he had completely recovered.
This case shows clearly the efficacy of recompression even under
"French, U. S. Naval Medical Bulletin, p. 74, January, 19 16.
RESPIRATION 3^3
conditions of apparently the most desperate character. It would
have taken over four hours to bring him up at all safely by stage
decompression, and his blood was certainly full of bubbles before
he was got into the chamber.
The difficulty of safe decompression in the chamber is one that
has often been met with before in bad cases. It may be necessary
to keep a patient in the chamber for 24 hours or more.
In work in tunnels or caissons the pressures encountered are
not nearly so high as in diving work; but the durations of ex-
posure are usually a good deal longer. Hitherto the time given to
decompression in the air lock has hardly ever been sufficient to
prevent symptoms, though in recent years it has often been suffi-
cient to prevent almost entirely the very dangerous symptoms
produced by rapid decompression, which leaves most of the body
in a condition of supersaturation with nitrogen. On this account
most of the symptoms in tunnel workers, etc., consist of the
"bends,'' itching of the skin, etc., due to bubbles in the tissues
which saturate and desaturate very slowly. In divers, on the
contrary, the symptoms met with before stage decompression was
introduced were mostly of a far more serious character, and due
to wholesale formation of bubbles in the blood and in tissues which
saturate and desaturate fairly quickly. Death or more or less
permanent paralysis were therefore common. With shortened
stage decompression it is usually the less serious symptoms which
appear among divers, and if the stage decompression is shortened
these symptoms must be expected. It is unfortunate that stage
decompression cannot be introduced in some countries on account
of antiquated state regulations enjoining decompression at a
constant rate, or even decompression starting very slowly and
increasing in rate as atmospheric pressure is approached.
During decompression, or immediately after it, it is very de-
sirable that as much muscular work as possible should be carried
out, so as to increase the circulation, and therefore the rate of
desaturation, over all parts of the body, and particularly those
parts which, owing to muscular exertion during exposure to the
high pressure, may have become saturated to a greater extent
than would otherwise be the case. For this reason the naval divers
were enjoined to keep their arms and legs moving as much as
possible during the stoppages at each stage. Bornstein has more
recently brought forward evidence collected at the Elbe tunnel
works that muscular exertion just after decompression diminishes
greatly the liability to "bends."
354 RESPIRATION
It is probable that the bubbles first formed in supersaturated
blood and tissues are extremely small and comparatively harm-
less. One can observe the formation of these minute bubbles in
water which has stood in a pipe under pressure in contact with
air. When the tap is opened the water comes out milky with
minute bubbles, but no large bubbles are present. The smallness
of the bubbles leaves time to deal with cases of sudden decompres-
sion. Thus a diver who is blown up accidentally from a great
depth comes to no harm if he is sent down again at once or very
quickly got under high pressure in a recompression chamber. The
small bubbles already formed seem to go into resolution at once.
With any delay, however, the bubbles become larger and more
difficult to redissolve. In the diver referred to above bubbles had
evidently formed long before he reached surface and was recom-
pressed.
In the case of workers in tunnels and caissons it is practically
very difficult, and undesirable in various ways, to keep the men
very long in an air lock during decompression. Another plan
seems much better, and has been partially carried out in recent
years in tunnels under construction at New York.^ The very high
pressures needed to keep the advancing face secure are only
employed in a section close to the face, this section being separated
from the rest of the tunnel by a steel air dam. If the total air
pressure in the advanced section is not more than 1%. times that in
the rest of the tunnel, the men can come through the air lock with-
out any delay. Let us suppose that the excess pressure is 35 lbs.
at the face and 7.5 lbs. in the rest of the tunnel. The total atmos-
pheric pressure is thus 50 lbs. at the face and 22.5 lbs. in the rest
of the tunnel. It is evident, therefore, that the men who have been
working at the face can come straight through either air lock,
even after very long shifts, provided that they are kept for a
sufficient time (fully an hour) in the low-pressure part of the
tunnel before coming through the second lock. If there were ar-
rangements for washing, changing, and meals in the low-pressure
section, this hour could be profitably employed. A six-hour shift
could be worked at the face, with an interval for a meal in the
low-pressure section, and there would be no blocking of the air
locks. The men could also go home at once, without the risk of
symptoms developing later. A plan of this kind, modified to suit
the varying conditions at different undertakings, seems to afford
the best means of solving the difficulties with air locks ; but exist-
" Japp, Trans. Intern. Congress on Hygiene, Section IV, Washington, 19 12.
RESPIRATION 355
ing state regulations might need modification to enable the im-
provement to be introduced. In any case there is now no justifica-
tion for imperiling men's lives by methods of decompression which
are known to give imperfect protection.
At present the tendency of the supervising medical officers is
to shorten the periods of work at the face under high pressure;
and of course the period of decompression may then be shortened
also. While this may cover the physiological aspects of the prob-
lem, it is evidently very uneconomical as compared with the
method above suggested.
Not only may increased partial pressures of nitrogen and COo
cause trouble, but also increased pressure of oxygen. The poison-
ous action of oxygen at high partial pressure was discovered by
Paul Bert; and his numerous and very thorough experiments on
the subject are described in his famous book. There is a popular
belief, based on the supposed similarity between life and com-
bustion, that the breathing of oxygen at a high partial pressure
must quicken the processes of life, and Paul Bert's experiments
on the effects of a high partial pressure seem to have been begun
with the view of testing this belief. He found that when the partial
pressure of oxygen exceeds three or four atmospheres, very re-
markable tonic convulsions are produced in warm-blooded ani-
mals, and they soon die. More remarkable still, perhaps, their
body temperature falls in the compressed oxygen, and the con-
sumption of oxygen and production of CO2 are markedly di-
minished. The oxygen acts as a poison.
He then extended his observations to other forms of life besides
warm-blooded animals, and proved conclusively that for life in
every form, including the very lowest, oxygen at high pressure
is a poison. Plants, infusoria, and bacteria are killed just as
certainly as the higher animals. His experiments left no doubt that
it is the partial pressure of oxygen, and not mere mechanical
pressure, that matters. When air was used instead of pure oxygen,
the pressure required to produce fatal effects was nearly five times
as great as when pure oxygen was used, but the pressure of oxy-
gen was the same. He also found that oxygen pressures of less
than one atmosphere would kill or retard the growth of various
small organisms of different classes in the animal kingdom, and of
plants ; and he came to the conclusion that any increase over the
normal oxygen pressure of ordinary air is more or less detrimental
to living organisms directly exposed to it. He had discovered a
biological fact of the most far-reaching significance.
356 RESPIRATION
It is usually not till the oxygen pressure in the air reaches more
than three atmospheres that warm-blooded animals show marked
immediate symptoms of oxygen poisoning. This we can under-
stand. The extra oxygen taken up in the arterial blood is nearly
all in simple physical solution, as Paul Bert showed by blood-gas
analyses of the arterial blood. At three atmospheres of oxygen the
blood will only take up about seven volumes of oxygen in solution.
On the other hand, the blood commonly loses about as much oxy-
gen in its passage through the capillaries. It is also indicated
by the results of experiments described in Chapter X, that the
effect of the increased oxygen is to slow the circulation, so
that more oxygen than usual is lost. Hence the oxygen pres-
sure will probably be very little above normal in the tissues
or venous blood until the oxygen pressure in the arterial blood
is over three atmospheres. As was shown in Chapter VII, ani-
mals in which the haemoglobin has been thrown out of action
by CO or nitrite poisoning are still a little short of oxygen when
they are breathing oxygen at two atmospheres pressures. We can
therefore easily understand why so high an oxygen pressure as
three or four atmospheres is needed before the nervous system
and other tissues are markedly affected by the oxygen.
In his experiments on warm-blooded animals Paul Bert had,
however, overlooked one thing which his other experiments might
have led him to look for. Although the tissues generally in a
higher animal are protected from the high pressure of oxygen,
since they have round them that wonderfully constant internal
environment which protects them from so many variations in the
external environment, yet the cells lining the air passages and
lungs are exposed to the high oxygen. It was discovered by Lor-
rain Smith in 1899^^ that oxygen at a pressure quite insufficient
to affect the nervous system appreciably will, if time is given,
produce fatal inflammation of the lungs. The higher the pressure
of the oxygen, the sooner this appears. The lungs are filled with
exudation, so that they sink in the fixing fluid, a general oedema
similar to that in phosgene poisoning being produced. Probably
the animals only survive as long as they do in the compressed
oxygen because they get sufficient oxygen in spite of the oedema.
As Lorrain Smith showed, the oedema protects them against the
effects of very high oxygen pressure on the nervous system. At an
oxygen pressure of 180 per cent of an atmosphere (that to which
"Lorrain Smith, Journ. of Physiol., XXIV, p. 19, 1899.
RESPIRATION 357
the American diver referred to above was exposed for three
hours) one of the animals died from lung inflammation in 7 hours.
The higher the oxygen pressure the more rapidly was the fatal
inflammation produced. The lowest oxygen pressure at which fatal
pneumonia was observed was 73 per cent of an atmosphere, after
4 days' exposure. At 40 per cent no ill eff"ects were observed. It is
evident from these observations that when oxygen is used con-
tinuously for therapeutic purposes the percentage ought not to be
increased more than is really necessary. A lung that is already
inflamed may be extra sensitive to an unusually high oxygen
pressure. At an oxygen pressure corresponding to 57 fathoms of
water we found that out of seven goats one died in three hours
from pneumonia, while the others were also affected, but re-
covered on decompression. At an oxygen pressure corresponding
to 40 fathoms we could not detect in ourselves any subjective
symptoms during short exposures ; but quite probably such symp-
toms might appear after longer exposure, and the behavior,
described above, of the experienced American diver seems sug-
gestive of this.
Although oxygen at high pressure acts generally as a poison,
yet as shown in Chapter IX, the living swim bladder may contain
oxygen at a pressure of 100 atmospheres without harm to the
cells lining its walls. These cells are apparently ''acclimatized" to
the oxygen, just as the cells lining the stomach wall are acclima-
tized to hydrochloric acid. It is not improbable that the lungs are
capable of acquiring some degree of acclimatization or immunity
to the effects of a high pressure of oxygen ; but on this point there
are as yet no observations.
CHAPTER XIII
Effects of Low Atmospheric Pressures.
Very low atmospheric pressures are met with on mountains or
high plateaus and in ascents by balloons or aeroplanes to great
altitudes. Mountain sickness, one of the characteristic effects of
low atmospheric pressures, was known long before atmospheric
pressure and the composition of the atmosphere were understood.
It was commonly attributed to poisonous emanations. A good
account of earlier records of it is given by Paul Bert. His experi-
ments on animals and men showed clearly that the physiological
effects produced by low atmospheric pressure are simply the re-
sult of the diminished partial pressure of oxygen. The nature of
these effects and the manner in which they are produced have been
described generally in Chapters VI and VII in connection with
the symptoms and causes of anoxaemia. It remains, however, to
discuss the subject in detail.
Although Paul Bert's very important conclusion that the physi-
ological actions of oxygen and other gases depend on their partial
pressures has often been referred to in preceding chapters, no
very definite account has been given of his experiments. It will
be convenient to summarize them here, and at the same time refer
to certain points on which later investigation has thrown new
light.
By studying the conditions producing death in animals (chiefly
sparrows) confined in a closed vessel at varying atmospheric pres-
sures and with varying compositions of the initial air breathed,
Paul Bert proved that if the pressure of oxygen was not sufficiently
high to produce oxygen poisoning, death was due either to in-
creased pressure of CO2 or to diminished pressure of oxygen. At
ordinary barometric pressure, and with ordinary air inclosed in
the vessel, death occurred when the oxygen percentage fell to
about 3.5. At half the ordinary pressure 7.0 was the fatal oxygen
percentage, so that the partial pressure of oxygen was the same;
and so on down to pressures of a third or even a fourth of an
atmosphere. If the vessel was filled with air highly enriched with
oxygen and the pressure was reduced to a fourth, or even a tenth,
the result was the same as regards the fatal partial pressure of
Figure 93.
Paul Bert's apparatus for showing the effects of varying
low pressures of oxygen and CO2. The tap B is connected with
an air pump, and D with a bag of oxygen or nitrogen, while C
connects with a mercury manometer.
5r?iWi.ifiSi^HHW
1
«
Figure 94.
Paul Bert's twin steel chamber for studying in man the
effects of very low atmospheric pressures with respiration of
oxygen.
RESPIRATION 359
oxygen. On the other hand if the vessel was filled with the en-
riched air and left at ordinary barometric pressure, death oc-
curred when the percentage of CO2 reached about 26, although
the oxygen pressure was far above the danger point ; and similarly
if the vessel was filled with compressed air at a pressure not suffi-
cient to cause oxygen poisoning. The cause of death depended
simply on whether the partial pressure of 3.5 per cent of an
atmosphere of oxygen or 26 per cent of an atmosphere of COg
was reached first. The mere mechanical pressure had no influence.
When, however, the partial pressure of oxygen was raised to the
dangerous limits referred to in Chapter XII, death was due to
oxygen poisoning, or hastened by it ; and the results suggest that
increase of the circulation rate, owing to the presence of CO2, with
consequent increase of the partial pressure of oxygen in the tissues,
increased the poisonous action of the oxygen, though Paul Bert
was unaware of the action of CO2 on the circulation.
Figure 93 shows an apparatus used by Paul Bert for showing
that it is the diminished pressure of oxygen, and not simply the
diminished barometric pressure, that affects an animal. The fol-
lowing are the notes of an experiment on a sparrow.
"At 3.20 pressure reduced to 250 mm. in a few minutes. On
further reduction to 210 mm. the animal turned round and round,
fell down, and was at the point of death. I restored the normal
pressure by letting in air enriched with oxygen; the animal re-
covered immediately and appeared lively and well. The air in the
bell jar now contained 35 per cent of oxygen. At 3.30 pressure
reduced to 180 mm. when the animal again became very ill. Pres-
sure again restored to normal by letting in oxygen, when the ani-
mal recovered at once. The air now contained 77.2 per cent of
oxygen. On again reducing the pressure the animal did not fall
over till 100 mm. pressure was reached. Immediate recovery on
restoring the pressure by letting in oxygen. The air now contained
87.2 per cent of oxygen. On reducing the pressure to 100 mm. at
3.50 the animal did not seem at all in danger; but at 80 mm. it fell
over in a dying condition. It recovered at once on letting in oxy-
gen. The air now contained 91.8 per cent of oxygen, and at 4.05
the pressure was reduced to 75 mm., when the animal again be-
came very ill, so that there was only just time to open the taps and
let it recover." This experiment shows very clearly that in air
greatly enriched with oxygen the barometric pressure could be
reduced to about a third of what was possible in ordinary air.
It was evident that oxygen could be used to avert the very
36o
RESPIRATION
dangerous effects of the rarefied air in balloon ascents ; and Paul
Bert proceeded to test this on himself in a steel chamber which
he had procured. The arrangement is shown in Figure 94. In this
chamber he not only studied in himself and others the subjective
and other effects of low barometric pressure when ordinary air
was breathed, but also showed that by breathing oxygen all these
effects could be prevented in man, down to very low pressures.
Figure 95 is a diagram showing the variations of pressure in one
76 _
70 .
i
60 _
^^>.^^^p
RE55I0N5
\
\
\
\
1
V
f
^
/
/
PULSATIONS
~v
/
,0
\
/
U-
^^^
^^
N^
so
40
30
25 _
80.
70.
60,
50.
10-20
30
^0
50
20
30
40
50
II- iO
Figure 95.
Tracing showing Paul Bert's pulse rate during a decompression experiment
in his steel chamber. Upper line = barometric pressure in centimeters. Lower
line = pulse rate. At o the breathing of oxygen was begun and continued
till the end of the experiment.
of his experiments, and the striking effect on his pulse when he
began the continuous breathing of oxygen. The oxygen abolished
at once the various symptoms, of which an account was given in
Chapter VI.
I have frequently verified in steel chambers, and also when air
very poor in oxygen was being breathed, Paul Bert's statements
as to the effects of oxygen. He noted the sudden increase in ap-
parent brightness of light and loudness of sounds, the return of
powers of memory and of intellectual powers, etc. As illustrating
how even one who is perfectly familiar with the effects on vision
of rapid relief of anoxaemia may be deceived by the subjective
RESPIRATION 361
effect, I may mention a recent personal experience. Dr. Priestley
and I had gone to a barometric pressure of about 360 mm. in a
steel chamber to test a piece of apparatus ; and, being anxious to
test our Eustachian tubes, we opened the inlet tap full, so as to
raise the pressure to nearly normal within about a minute, as in a
iiose dive of about 18,000 feet. Our ears were all right, but I was
alarmed to see the filament of the electric lamp suddenly become
intensely bright, as if it were about to fuse ; and on hastily pushing
the door open at the end of the decompression I inquired what had
gone wrong with the voltage. The appearance was of course only
subjective. I had forgotten the increase of oxygen pressure, and
had only been thinking of the mechanical effect on the eardrums.
Nothing in subsequent investigation has shaken Paul Bert's
conclusions as to the effects of gases being dependent on their
partial pressures, though the scientific world has taken a long
time to assimilate his reasoning, s© that much of what has been
subsequently written on the subject of high and low atmospheric
pressures has been simply out of date. On a number of points,
however, later investigations have thrown new light. To take one
quite minor point first, the action of CO in air does not depend
upon its partial pressure, ^ince the higher the pressure of an
atmosphere containing CO is raised the more innocuous does the
CO become, from the causes already discussed in Chapters IV
and VI L But at a constant partial pressure of oxygen the physio-
logical action of CO depends upon its partial pressure. There may
be other apparent exceptions to Paul Bert's rule, but we may be
confident that they will also turn out to be only apparent.
In his experiments Paul Bert took into direct account only the
pressure of oxygen and other gases in the inspired air. But we
have already seen that what directly matters is the gas pressures
in the alveolar air. When the barometric pressure is lowered the
alveolar oxygen pressure falls at a greater proportional rate than
the oxygen pressure of the inspired air. This is because, even
though the breathing is increased, which would in itself tend to
keep up the alveolar oxygen pressure, and may nearly prevent
the alveolar CO2 percentage from rising, the percentage of
aqueous vapor is constantly rising. At a barometric pressure of
47 mm. no air at all would enter the lungs, since the pressure of
aqueous vapor would be 47 mm., and the liquids of the body would
from this cause alone be just about their boiling point; as a matter
of fact they would boil at a higher pressure, as they contain much
free CO2. At a pressure of 100 mm. in an atmosphere of pure
362 RESPIRATION
oxygen, the alveolar air in situ would contain 47 per cent of HgO ;
probably about 20 per cent of COo; and 33 per cent of oxygen,
with a partial pressure of about 4.3 per cent of an atmosphere or
33 mm. of mercury. This pressure of oxygen is only one twenty-
third of that in dry oxygen at atmospheric pressure, though the
oxygen pressure in the inspired oxygen is only reduced to a little
over a seventh.
It is thus somewhat remarkable that until extremely low baro-
metric pressures, such as under 100 mm., were reached, the deaths
of the animals from want of oxygen should have coincided so
closely with a threshold oxygen pressure in the inspired air. The
probable explanation of this has already been referred to in
Chapter VI. With fall of barometric pressure the rate of dif-
fusion in a gas increases rapidly, since the mean free path of
each molecule before it strikes another molecule is increased. As
a consequence, the oxygen molecules in the neighborhood of the
alveolar epithelium reach it more rapidly, so that when there is
scarcity of oxygen the blood can be more readily saturated to the
existing mean oxygen pressure in the alveoli, or to whatever
higher oxygen pressure can be produced by active secretion. The
excessive fall in alveolar oxygen pressure at low barometric pres-
sures is thus partially compensated.
An experiment which Paul Bert describes (p. 749 of his book)
would seem to confirm this explanation. A bird was placed in the
apparatus (Figure 93) and the pressure reduced to 220 mm., at
which the animal had severe symptoms of anoxaemia. The pres-
sure was then raised to normal, not with air, but with nitrogen.
The animal died almost at once, though the partial pressure of
oxygen was 6 per cent, and the alveolar oxygen pressure must have
been raised, owing to the greatly diminished proportion of aque-
ous vapor in the alveolar air at normal barometric pressure.
The importance of the CO2 present in the air was not noticed
by Paul Bert. In all his experiments where the oxygen pressure
of the inspired air fell to about 3.5 per cent before death there
was also a considerable proportion of CO2 in the inspired air.
This CO2 must have stimulated the respiration greatly, in the
manner already explained so fully, thus diminishing the fall in
alveolar oxygen pressure. The presence of COo tends to diminish
the percentage saturation of the haemoglobin in the arterial blood,
owing to the Bohr effect already referred to at length in Chapters
IV and VII, but there is the counterbalancing advantage that the
haemoglobin holds on less tightly to oxygen in the systemic
RESPIRATION 363
I
^xapillaries. The excess of CO2 has, however, another quite dis-
I tinct effect in counterbalancing the effects of the low alveolar oxy-
gen pressure : for the circulation can increase, owing to the stimu-
,, lus of anoxaemia, without the counteracting effect due to the
production of alkalosis through deficiency of CO2. In this way the
oxygen pressure in the systemic capillaries is kept considerably
^ higher than if there were no excess of CO2 in the inspired air.
Other things being equal, the presence in the inspired air of
a moderate proportion of CO2 diminishes the effects of oxygen
deficiency, as can easily be shown experimentally. The CO2, by
increasing the breathing, raises the percentage of oxygen in the
alveolar air; and a very small excess in the alveolar CO2 pressure
is sufficient to produce a large effect on the breathing. There is
consequently a considerable increase in the alveolar oxygen pres-
sure. That, however, the effects of CO2 in relieving anoxaemia
are not simply due to the increased oxygenation of the blood can
be shown most strikingly in CO poisoning. A given percentage
of CO is less poisonous when administered to an animal breathing
human expired air. As this does not raise the alveolar oxygen
pressure, the effect cannot be due to increased oxygenation of the
arterial blood, and must be put down to increase in the circulation
rate, and consequent better supply of oxygen to the tissues. Lor-
rain Smith and I found that excess of CO2 has no effect in stimu-
lating oxygen secretion by the lungs.
Although Paul Bert had in reality proved quite conclusively
that the physiological effects of low atmospheric pressures depend
on the lowering of the oxygen pressure, the theory was promi-
nently brought forward by Mosso twenty years later that these
effects are due primarily to excessive loss of CO2 from the body,
'or "acapnia." Mosso imagined that as a physical consequence of
the low atmospheric pressure more CO2 than usual is washed out
of the blood in the lungs, and that this is the cause of mountain
sickness. ••■ His physical chemistry was completely at fault. If the
volume of air breathed did not alter, the partial pressure of CO2
in the alveolar air would remain the same, and no more CO2 would
be given off at low than at ordinary atmospheric pressure. Actu-
ally, however, there is an excessive loss of COo at low atmospheric
pressure, and this is due to the increased breathing caused by the
anoxaemia. Moreover we can, for the reasons already explained,
mitigate the anoxaemia by adding a suitable proportion of CO2
^ Mosso, Life of Man on the High Alps (translation), London, 1898.
364 RESPIRATION
to the inspired air. Acapnia may thus be looked on as a contribu-
tary cause of the symptoms, so that at first sight there seems to be
some experimental support for Mosso's theory. The acapnia^
although most important, is, however, only a secondary result of
the lowered oxygen pressure. This aspect of the matter has become
clear only recently through the work of Kellas, Kennaway, and
myself (see Chapter VI), and independently along closely similar
lines by that of Yandell Henderson and Haggard.^
Mosso held to his acapnia theory till the time of his death, and
it was quite in vain that I myself endeavored to persuade him that
Paul Bert was right. "Acapnia'' became for a time to many
physiologists the same sort of ignis fatuus as "reduced alkaline
reserve" has been in recent years. In 1906, however, Zuntz and
his colleagues placed the main facts in true perspective in an ac-
count of investigations carried out at high altitudes in the Alps.*
We must now consider acclimatization to high altitudes and
anoxaemia caused in other ways. Paul Bert in his book (pp. 336^
1 105) describes and discusses acclimatization, though he had not
himself studied it experimentally. The evidence pointing to the
fact of acclimatization was clear. He suggested that the tissues
become gradually accustomed to a smaller supply of oxygen in
the blood, and perhaps become more economical in their use of
oxygen. He also, however, suggests that the oxygen capacity of
the blood may become increased at high altitudes; and this he
afterwards verified by actual examination of blood taken from
animals living at high altitudes.^
■^In 1892 Viault showed that the number of red corpscles per
unit volume of blood is increased at high altitudes, and Miintz
that the percentage of iron is increased. Various subsequent ob-
servers established clearly the fact that in animals and persons
living at high altitudes there is an increase in both the percentage
of haemoglobin and the number of blood corpuscles in the blood.
By far the most complete and accurate series of observations on
the increase in haemoglobin was that carried out in connection
with the Pike's Peak Expedition by Miss FitzGerald on persons
living permanently at different altitudes in the Rocky Mountains
and elsewhere in America. Figure 96. shows graphically the
average results obtained at different altitudes.
It will be seen from this figure that on an average the per-
* Haggard and Henderson, Journ. Biol. Chem., XLIII, p. 15, 1920.
'Zuntz, Loewy, Miiller, and Caspari, HbhenkUma und Bergwanderungenj 1906.
*Paul Bert, Comptes rendtis, XCIV, p. 805, 1882.
RESPIRATION
365
centage of haemoglobin varies inversely with the barometric
pressure, and that even quite small diminutions in barometric pres-
sure are effective in causing a rise in the haemoglobin percentage.
In different individuals, however, the effects on the haemoglobin
percentage of a given diminution in barometric pressure vary
%
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Figure 96.
Average haemoglobin percentages in persons living
permanently at different altitudes (FitzGerald).
considerably. Thus among the persons acclimatized on the
summit of Pike's Peak (barom. 453 mm.) the rise in haemoglobin
percentage varied from 13 to 53 per cent of the normal. The rate
at which the haemoglobin percentage rises when a person goes to
a high altitude varies also. In some persons the rise is very slow ;
and in consequence of this some observers have failed to detect
any rise on going for a short time to a high altitude.
As the average rise in haemoglobin percentage is appreciable
with only small increases of altitude, one would expect to find
that with increase of atmospheric pressure above normal the
haemoglobin percentage would fall below the normal value at
sea level. That this is actually the case was shown for dogs and a
I monkey by A. Bornstein, who kept the animals under atmospheric
I pressure of about three atmospheres or 2,280 mm. in the Elbe
I tunnel at Hamburg during its construction.^ She found that the
I ''Adele Bornstein, Pfluger's Archiv., 138, p. 609, 191 1.
366 RESPIRATION
haemoglobin percentage and number of red corpuscles fell about
20 per cent, and that there was no fall in the case of animals kept
in the tunnel at a place where the atmospheric pressure was not
increased. It appears, therefore, that the haemoglobin percentage
is regulated generally in relation to the oxygen pressure in the
arterial blood, and rises or falls according as this pressure is
diminished or increased.
It is easy to see what the physiological advantage will be,' other
things being equal, of a rise in the haemoglobin percentage. As
the blood passes through the systemic capillaries, its oxygen pres-
sure will fall more slowly than usual. Hence although the arterial
oxygen pressure is considerably below normal, the venous oxygen
pressure will be much more nearly normal, so that the lowering
of the oxygen pressure in the tissues is diminshed. There may be
much more of available oxygen in the arterial blood at a high
altitude than at sea level, but this in itself avails nothing, since it
is the pressure, and not the quantity, of oxygen in the blood that
counts. To explain the beneficial effects of increased haemoglobin
percentage at high altitudes and in other conditions where chronic
arterial anoxaemia exists we must consider the effects of the
increased haemoglobin on the oxygen pressure in the tissues. At
the same time we must bear in mind the influence of increased
haemoglobin percentage in diminishing the COg pressure, and
therefore the hydrogen ion concentration, in the tissues ; and this
brings us to a second factor in acclimatization.
— :^ In recent years, it has gradually been shown more and more
clearly that at high altitudes the volume of air breathed is in-
creased and remains so after acclimatization. This was already
more or less evident from the measurements by Zuntz and his
colleagues of the volume of air breathed and respiratory exchange
at high altitudes, and, as mentioned in Chapter VI, was rendered
quite clear by the experiments of Boycott, Ogier Ward, and
myself on the alveolar air at low atmospheric pressures. We drew
the conclusion that the blood, apart from the CO2 contained in it,
becomes less alkaline at low atmospheric pressures, so that less
COo is needed to excite the respiratory center. This diminution in
the ''fixed'* alkalinity of the blood was already known through
titrations. Barcroft then found on the Peak of Teneriffe that in
spite of the lowered pressure of COg in the arterial blood, the
dissociation curve of the oxyhaemoglobin of the blood in presence
of the alveolar COg pressure remains sensibly normal. This also
pointed in the same direction. The phenomena did not, however,
RESPIRATION 367
correspond with those accompanying excess of lactic acid in the
blood, and Ryffel was unable to find any such excess in the blood
or urine. Accordingly the conclusion was drawn by my colleagues
and myself after careful observations during the Pike's Peak
Expedition, that the diminution in available alkali in the blood
must be due to a lowering in the level of concentration to which
the kidneys regulate the fixed alkali in the blood. We thought
that the anoxaemia must influence the kidneys specifically in this
direction.
The Anglo-American Pike's Peak Expedition® was planned
with the special object of studying acclimatization to the oxygen
deficiency of the air at high altitudes. We selected Pike's Peak
(14,100 feet) because it was possible, not only to get apparatus
and supplies to the summit easily by the cogwheel railway, but also
to live there without the disturbing effects of cold and hardship.
We were thus enabled to watch in ourselves the progress, which
was very striking, of acclimatization, and to observe the effects of
the rarefied air on the numerous unacclimatized persons who came
up. V .
It is evident that a simple increase in the breathing must
greatly diminish the arterial anoxaemia at high altitudes : for not
only will the alveolar oxygen pressure be increased, but in conse-
quence of excessive removal of CO2, the haemoglobin passing
through the lungs will combine more readily with oxygen, in
accordance with the discovery, already often alluded to, of Bohr
and his pupils. It might thus appear as if a simple increase in
breathing were the natural adaptive response to the anoxaemia
of high altitudes and other conditions. But, as already pointed
out, such a response is, except for a very short period, or to a very
limited extent, prevented, owing to the effect of the lowered COg
pressure in diminishing the breathing; and an increased circula-
tion rate (which would also tend to diminish the fall of oxygen
pressure in the tissues) is also prevented in the same way. More-
over the increase in percentage saturation of the haemoglobin in
the tissues is in any case of only limited advantage, since, owing
to the lowered CO2 pressure, the haemoglobin holds on more
tightly to the oxygen. Nevertheless there will be some increase in
breathing and circulation rate; and this will represent a com-
promise between the effects of want of oxygen and of deficiency
" Douglas, Haldane, Henderson, and Schneider, Phil. Trans. Roy. Soc, B,
203, 1913. y
/
368
RESPIRATION
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Figure 97.
Pressure of CO2 and oxygen in alveolar air of three members of the Pike's
Peak Expedition at about sea level (Oxford and New Haven), at Colorado
Springs (6,000 feet), and on Pike's Peak (14,100 feet). Thick line = alveolar
CO3 pressure, and thin line = alveolar oxygen pressure. Interrupted lines =
normal alveolar CO2 and oxygen pressures at sea level.
RESPIRATION 369
of C02- It is during this condition that mountain sickness is pro-
duced.
In the course of a day or two, or of several days, the mountain
sickness passes off if the altitude is not too great ; but the breathing
is only slightly increased further, as we found on Pike's Peak
(Figure 97) by analyses of the alveolar air. Further light on
acclimatization was afterwards thrown by Hasselbalch and Lind-
hard*^ in a series of observations during which they remained for
a number of days in a steel chamber at reduced pressure. They
found by direct measurement that after acclimatization the hydro-
gen ion concentration of the blood is approximately normal, thus
confirming Barcroft's conclusions from observations of the dis-
sociation curve of the oxyhaemoglobin of the blood. They also
found that the excretion of ammonia in the urine is distinctly
diminished; and this led them to the conclusion that the very
slight acidosis which presumably causes the increased breathing
is due to diminished formation of ammonia in the body.
In a still more recent investigation^ by Kellas, Kennaway, and
myself, we found that on exposure to a considerable diminution
of atmospheric pressure there is at once a very marked decrease
in the excretion of both acid and ammonia by the kidneys. The
urine may become actually alkaline to litmus. These observations
threw a new and quite clear light on the increased breathing at
high altitudes. It became evident that the increased breathing is
primarily due simply to the stimulus of anoxaemia. This increased
breathing not only raises the alveolar oxygen pressure, but also
washes out an abnormal proportion of CO2 and thus produces a
condition of slight alkalosis, to which the perfectly normal re-
sponse is a diminution of ammonia formation and in the acidity
of the urine, as explained in Chapter VIII. This response tends to
continue until the normal reaction of the blood is restored, owing
to reduction in the "available alkali" in the body. There is no
acidosis at any stage of the process ; the supposed acidosis is only
the compensation of an alkalosis. Nevertheless the process of
compensation is never quite complete. If it were so the excretion of
ammonia would return to its normal value on acclimatization,
whereas actually there is still, as shown by Hasselbalch and
Lindhard's observations, a slight but distinct diminution in am-
monia excretion. Moreover if the compensation were complete
'Hasselbalch and Lindhard, Biockem. Zeitschr., 68, pp. 265 and 295, 1915;
and 74, pp. I and 48, 19 16.
* Haldane, Kellas, and Kennaway, Journ. of Physiol., LIII, p. 181, 19 19.
370 RESPIRATION ^
there would be no extra breathing caused by the immediate effect
of the anoxaemia. Actually there is still a slight amount of extra
breathing from this cause, since on raising the alveolar oxygen
pressure there is an immediate, though comparatively slight, rise
in the alveolar CO2 pressure, as we found on Pike's Peak when a
mixture rich in oxygen was breathed in place of ordinary air.
The evident reason why the compensation does not become more
complete is that if it were made more complete the normal com-
position of the blood would be very seriously altered; and such
alterations tend to be resisted. The compensation thus represents a
compromise.
A similar interpretation of the apparent slight acidosis of high
altitudes was reached on independent grounds by Yandell Hender-
son, and published shortly before our paper appeared.^ As already
mentioned in Chapter VIII, he and Haggard made the very
important discovery that with prolonged and very excessive
ventilation of the lungs (thus producing great alkalosis) the
available alkali or "alkaline reserve" of the blood diminishes
greatly. A similar diminution occurs at high altitudes, and Hen-
derson attributed it to the increased breathing produced by the
anoxaemia, and was thus the first to identify its true nature as a
compensatory response to the alkalosis produced by the increased
breathing.
^ It is evident that the compensatory change in the available
alkali of the blood and whole body tends to make increased breath-
ing possible with a minimum stimulus from actual anoxaemia.
The anoxaemia tends, therefore, to be relieved. In other words a
process tending to acclimatization has occurred. It will be noted
that the phenomena have been interpreted on what is usually
, called a teleological basis, though no conscious adaptation of
means to end is implied, but only a tendency of the living body to
maintain its normal standards. The justification for this mode of
interpretation, and the demonstration that it constitutes the neces-
sary scientific basis of physiology, will be postponed to the next
chapter.
In connection with the Pike's Peak expedition Miss FitzGerald
carried out a large series of investigations of the alveolar air of
persons living permanently, and therefore fully acclimatized, in
towns and villages at different altitudes in or near the Rocky
Mountains. At a later date further observations were made at
'Yandell Henderson, Science, May 8, 19 19; and Haggard and Henderson,
Journ. Biol. Chem., XLIII, p. 15, 1920.
RESPIRATION
371
lower altitudes in South Carolina. ^^ The average results are
shown in Figure 98. The results for men and women are given
separately, as men have a higher average alveolar CO2 pressure
than women, as mentioned in Chapter II. It will be seen that
within the limits of atmospheric pressure investigated, the aver-
Cas pressure AlUhidle.
mm of 800 750 700 650 600 550 500 450 400 550 300 2SO 200 '" ^*'-
eOO 750 700 650 6O0 550 500 4SO 4O0 3SO 300 250 200
Atmospheric pressure in mm. of mercury.
Figure 98.
Alveolar gas pressures in relation to barometric pressure or altitude.
age alveolar CO2 and oxygen pressures fall proportionally to
the atmospheric pressure. To judge from these results the al-
veolar oxygen pressure at the height of 24,600 feet reached by the
" FitzGerald, Phil. Trans. Roy. Soc, B, 203, p. 35 1 ; and Proc. Roy. Soc, B,
88, p. 248.
372 RESPIRATION
Duke of Abbruzzi's expedition would only be about 31 mm., and
the CO2 pressure about 21 mm. The figures, according to a form-
ula of Henderson,-'^^ would be oxygen 38 mm., and CO2 15 mm.
Acclimatization would be a very incomplete process if it de-
pended solely on the increased breathing observed at high alti-
tudes. In spite of increased breathing and coincident increased
saturation of the arterial blood owing to the alkalosis produced,
there is at first very distinct cyanosis when persons first go to a
high altitude. On Pike's Peak this was very striking, though in
different persons the degree of cyanosis varied greatly. The fact
that there was so much cyanosis although the mean alveolar oxy-
gen pressure was about 50 mm. — sufficient in presence of the
lowered alveolar CO2 pressure to saturate the haemoglobin of
average human blood to 85 per cent or more — is now explicable
by the fact that, as explained in Chapter VII, the oxygen pressure
of the mixed arterial blood is very appreciably below that of
the mixed alveolar air, and particularly at lowered atmospheric
pressure. The cyanosis disappears, however, after a day or two,
or sometimes longer, of mountain sickness; and in persons who
have reached the high altitude by gradual stages, as in the Him-
alayas, there may, apparently, be little or no cyanosis, and certainly
no mountain sickness. Among the party of four Europeans with
the Duke of the Abbruzzi, who gradually reached a height of
24,600 feet in the Himalayas, there were no signs of mountain
sickness or. undue exhaustion at any stage. In the account of the
expedition the conclusion was even drawn that ''rarefaTction "bl
the air, nnd^r ordinary conditions of high mountains^ to the
limitsL-raar.hed hy fpan at th<^ present dM^jSi barometric pressure
of 12.28 inches or 312 mm.) does not produce mountain sick.-
Iiess."^^ Mountain sickness, and its accompaniments were con-
sidered to be "in reality phenomena of fatigue." The writer of
this account was not aware of the fact that mountain sickness is
easily produced in unacclimatized persons without any fatigue,
and occurs quite readily in persons sitting in a steel chamber or
going by train to a high altitude.
We may contrast the experience of the Duke of Abbruzzi's
party with that of Hasselbalch and Lindhard in their steel
chamber. ^^ They started altogether unacclimatized, from the sea-
level air pressure of Copenhagen, and only reduced the pressure
" Y. Henderson, Journ. Biol. Chem., XLIII, p. 29, 1920.
Filipo de Filippi, Karakouram and Western Himalaya, London, 19 12.
"Hasselbalch and Lindhard, Biochem. Zeitschr., 8, p. 295, 19 15.
RESPIRATION
373
to 520 mm., corresponding to a height of 1 1,000 feet; but after a
few hours they became so seriously affected by mountain sickness,
with alarming cyanosis, intolerable headache, and feelings of
asphyxia during the night, that they had to raise the pressure to
584 mm. (about 7,000 feet). Those ascending Pike's Peak started
from a height of about 6,000 feet and were thus partially acclima-
tized ; otherwise their symptoms would doubtless have been more
marked than they actually were.
In Chapter IX the quantitative evidence has already been given
that at high altitudes after acclimatization the lungs actively
secrete oxygen inwards even during rest, and that were it not so
the immunity from symptoms of mountain sickness among ac-
climatized persons would be totally unintelligible. It only remains
to discuss here some special points with regard to oxygen secre-
tion.
The fact that some time is needed before oxygen secretion is
effectively established at a high altitude, accords exactly with the
fact that it takes a man some time to get his lungs and other parts
of his body into good physiological training for heavy muscular
exertion. As was pointed out in Chapter IX there is now very
clear evidence that in persons who are in good training oxygen
secretion by the lungs plays a very important part, whereas in
persons not in training any secretion evoked by muscular work is
so feeble as to be quite ineffective. Both at high altitudes and in
training for muscular exertion the power of secretion develops
with use; and development occurs in exactly the same manner
with the exercise of all other physiological functions. At high
altitudes the stimulus to secretion originates in consequence of the
imperfectly saturated condition of the arterial blood; and al-
though after acclimatization is established the saturation of the
arterial blood with oxygen becomes less incomplete, yet part of
the incompleteness must remain; otherwise there would be no
stimulus to oxygen secretion. In this connection it should be noted
that the arterial oxygen pressure given by the carbon monoxide
method is the average oxygen pressure of the blood leaving the
alveoli, and not the oxygen pressure of the mixed arterial blood.
The latter value is undoubtedly a good deal lower for the reason
already explained.
It has for long been well known to mountaineers that persons
who^re in good physical training for hard work are far less
susceptible to mountain sickness and the other characteristic effects
of high altitudes than those who are not in training. This fact is
374 RESPIRATION
the origin of the common and quite erroneous opinion that
mountain sickness is due simply to exhaustion and has nothing to
do with barometric pressure. It now seems probable that in so
far as acclimatization is due simply to increased power of oxygen
secretion good physical training in heavy exertion will do as
much as continued exposure to the high altitude. As we have
already seen, however, acclimatization consists not merely in
increased power of oxygen secretion, but also in increased haemo-
globin percentage and diminution in the available alkali in the
blood and tissues so as to permit of increased breathing without
the development of alkalosis. It takes time to bring about these
changes, and they are not brought about by training for muscular
work. The increased haemoglobin, though it was the first acclima-
tization change to be discovered, is probably of relatively minor
importance, inasmuch as recovery from mountain sickness and
related conditions commonly occur before there is any noticeable
change in the haemoglobin percentage. The diminution in avail-
able alkali seems to be much more important, but the process is
evidently a rather slow one. This is readily intelligible when one
considers the amount of alkali that has, apparently, to be got rid
of, partly by excretion through the kidneys, and partly through
suspension of formation of ammonia inside the body. Possibly
this part of acclimatization might be greatly hastened by the
administration of ammonium chloride, the striking effects of
which on the blood reaction were described in Chapter VIII.
The question of acclimatization has assumed new interest, owing
to the recent great extension of the use of aeroplanes at high
altitudes. The great advantage of good physical training seems
evident in this connection. At the same time it also seems evident
that only a limited amount of acclimatization can be produced
either by physical training or by intermittent exposures in aero-
planes to low atmospheric pressure. The limitation was distinctly
evident in the experiments, mentioned in Chapter IX, on the
degree of acclimatization produced by intermittent exposures at
low pressures.
We must now discuss the symptoms of balloonists and other
airmen at very great altitudes, and the means of averting these
symptoms. Enormous heights can easily be reached by balloons;
and quite recently, in consequence of the great improvements
during the war in the construction of aeroplanes and their engines,
a height nearly as great as those reached in balloons has been
reached in aeroplanes. The limitation in the heights to which men
RESPIRATION 375
have hitherto been able to go is due entirely to the physiological
effects of the reduced oxygen pressure and the quite evident im-
perfections of the apparatus used for overcoming these effects.
Hot-air balloons were devised by the brothers Montgolfier, and
first used at Paris in 1783. Shortly afterwards the well-known
French physicist Charles invented the hydrogen balloon and made
the first ascent in 1785, reaching a height of 13,000 feet. Higher
ascents were soon after made, and in 1804 another Frenchman,
Robertson, reached about 26,000 feet and was greatly affected.
In the same year Gay-Lussac went to about 23,000 feet, but only
noticed slight effects. It seemed pretty evident that the limit of
safety was about 25,000 feet, but until 1875 ^^ balloonist seems to
have been actually killed by asphyxiation due to the rarefied air.
In 1862 the well-known meteorologist Glaisher and the bal-
loonist Coxwell made a famous very high ascent from Wolver-
hampton; and Glaisher's account of the symptoms observed was
very full and valuable. ^^ In 48 minutes they had reached a height
at which the barometer stood at 10.8 inches (274 mm.). Glaisher
found that after this he could no longer read his thermometer or
even his watch. His last reading of the barometer was 9.75 inches
(248 mm.), which he estimated as corresponding to 29,000 feet.^^
He then found that his arms and legs were paralyzed, and then
his neck also, so that he could not hold up his head. He could still
vaguely see Coxwell, who had climbed up to free the rope of the
valve, this having got tangled, owing to rotation of the balloon.
He tried to speak, but could not, and then suddenly he became
blind. He says, "I was still completely conscious, and my brain
was as active as in writing these lines." Then suddenly he lost all
consciousness and appears to have been unconscious for about
seven minutes, during which Coxwell had fortunately succeeded in
stopping the ascent of the balloon and bringing it down again for
a considerable distance. During Glaisher's return to consciousness
he first heard the words "temperature" and ^'observation," but
without seeing anything. Then he began to see his instruments
vaguely, and then other objects, and finally was able to take up
his pencil and continue his observations. The barometer was then
11^ inches (292 mm.). Coxwell had never lost consciousness.
He climbed down with great difficulty. Seeing Glaisher's condition
he tried to pull the valve rope, but found that his own arms were
now paralyzed. He then, with great presence of mind, got hold
"Glaisher, Travels in the Air, London, 1871.
" It is somewhat doubtful whether the aneroid barometer was correct.
376 RESPIRATION
of the rope with his teeth, and so succeeded in opening the valve
and turning the balloon downwards. By his presence of mind
and determination he saved both Glaisher's life and his own.
The next very high ascent was made by the three French sci-
entists Croce-Spinelli, Sivel, and Tissandier in 1875, and re-
sulted in the death of the two former. This tragic occurrence
revealed in a very clear manner the insidiousness of the onset of
dangerous anoxaemia, and the absolute necessity for taking the
most efficient means of guarding against it at very high altitudes.
Croce-Spinelli and Sivel had tried the effects of oxygen in Paul
Bert's steel chamber, as well as during a previous ascent to about
25,000 feet. They were thus familiar with its effects. The balloon
was therefore provided with bags of oxygen. Paul Bert, who was
away from Paris at the time, had, however, written to them that
the bags provided were too small to last for more than a short
period. There was not time, however, to get larger ones, and for
this reason they decided not to begin using the oxygen till they
felt themselves really in need of it. They reached a height of
about 24,600 feet with the barometer at 300 mm. and the balloon
no longer rising. At this point Sivel asked both his companions
whether they would go higher, and on receiving their assent cut
the strings of three bags of sand used as ballast. Figure 99 repre-
sents the appearance of the car of the balloon at this point. In
Tissandier's notebook there was the entry "1.25, T = — 10°,
B = 300. Sivel throws ballast. Sivel throws ballast." The writing
was scarcely legible, and the repetition of the words was charac-
teristic of the symptoms of anoxaemia. The balloon then rose
rapidly. Tissandier relates that he tried to take up the mouthpiece
of the oxygen tube, but his arms would not move. Nevertheless
he had no sense of the danger, but felt happy that they were
rising. He saw the barometer passing 290 and then 280 and wished
to call out that they were at 8,000 meters, but his voice was
paralyzed, and immediately afterwards he lost consciousness and
did not wake up till about forty minutes later.
The balloon was then descending rapidly and he noted that
the barometer was at 315. His companions were still unconscious.
He let go some ballast, and shortly afterwards Croce-Spinelli
woke up and let go more, including the aspirator. He then became
unconscious again. The balloon must have gone up, and he did
not wake up again till an hour and a quarter later. The balloon
was then at about 20,000 feet and falling very rapidly. Both Sivel
and Croce-Spinelli were dead. Tissandier had great difficulty in
Figure 99.
Sivel, Tissandier, and Croce-Spinelli in the car of
the Zenith, Sivel preparing to cut the strings of the
ballast bags at 300 mm. barometric pressure. Croce-
Spinelli with the bubbling arrangement for breathing
oxygen in his hand. Tissandier reading the barometer.
The oxygen bags are seen above the car, and the re-
versible aspirator fixed to the basket work.
RESPIRATION
377
letting go the anchor and landing safely, but succeeded. Figure
lOO indicates diagrammatically the course of the balloon. The
maximum height was given by an automatic recorder.
8000
0 Paris
CKoicot/rovx
Figure lOo.
Diagram of the voyage of the Zenith, April 15, 1875.
It was clear that all three had been paralyzed before they tried
to breathe the oxygen. Doubtless they were all convinced that
they felt all right and in full possession of all their faculties. The
feeling of self-confidence seems always to be present in conditions
of gradually advancing anoxaemia. I have experienced it myself,
not only in steel chambers, but also in experimental CO poisoning;
and the conviction that one is fully competent is still present in
spite of the knowledge that this conviction may be a gross illusion.
A man who is grossly intoxicated by alcohol has just the same
378 RESPIRATION
insane confidence that he is all right. At very high altitudes in
balloons or aeroplanes it is imperative that oxygen should be
breathed continuously.
For about twenty years after the accident just described no
further very high ascents in balloons seem to have been attempted.
The next high ascents were made in Germany, starting with an
ascent by Berson and Gross to 26,000 feet in 1894. Berson alone
then reached a height of 30,000 feet; and finally in 1 901 Berson
and Siiring reached about 36,000 feet (11,000 meters), with a
barometric pressure of 180 mm. In all these ascents oxygen was
used, without which they would have been quite impossible; but
at the end of the last ascent both Berson and Siiring became un-
conscious, though fortunately not before the former had pulled
the valve rope and thus turned the balloon downwards. Berson
had the cooperation of the Austrian physiologist, von Schrotter,
and the latter in his book describes not only the ascents, but
various preliminary experiments in a steel chamber and experi-
mental ascents in which he made physiological observations. Von
Schrotter had thoroughly grasped Paul Bert's work and was not
misled by the mistaken opposition of some physiologists to the
oxygen theory. ^^
Berson and Siiring used steel oxygen cylinders from which a
constant stream of oxygen came to them through a tube which
they could hold in the mouth. The cylinders were a great improve-
ment on the bags used by Croce-Spinelli and his companions, but
in other respects the arrangement was very imperfect, as von
Schrotter pointed out. With any increase of breathing the volume
of oxygen supplied became insufficient, so that only a mixture of
air and oxygen was breathed, the air being taken in through the
nose or by opening the mouth. Moreover it required constant
attention to inspire through the mouth, even if the supply of
oxygen was adequate. It was no wonder, therefore, that first
Siiring and then Berson was overcome.
In one of the ascents by Berson and von Schrotter liquid air
was tried for the first time. It failed, partly because there was
no proper means of gasifying as much of the liquid as they re-
quired, and partly because the oxygen percentage in the gasified
liquid air was not high enough. Cailletet had, however, already
indicated a method of controlling the gasification, and this method
in an improved form was extensively used by the Germans during
"Von Schrotter, Der Sauerstojf in der Prophylaxie und Therapie der Luft-
dtuckerkrankungen, 1906.
RESPIRATION 379
; the war — for instance in the very high flights needed for bombing
London. It is of course necessary to use liquid oxygen. Simple
liquid air would evidently be quite useless ; but if ordinary liquid
air is allowed to evaporate for a sufficient time the nitrogen dis-
tills ofi", leaving a residue very rich in oxygen. It was this residue
j that was employed by von Schrotter and Berson.
;i To improve upon the simple tube hitherto used, von Schrotter
\ strongly recommended the use of a face piece, and figures the
! first form used. The face piece covers both mouth and nose, and
j the oxygen passes into it through a tube in a constant stream.
\ This arrangement was introduced for aeroplanes before the war,
and is now extensively used. The airman can inspire or expire
air freely, but always receives a certain amount of oxygen, and has
not to think of his breathing. The amount of oxygen, whether from
a steel cylinder or from a Dewar flask of liquid oxygen, can be
adjusted according to the height, but it is simpler to arrange for
a constant supply which is sufficient, or more than sufficient, up
to a certain height. About half the oxygen is wasted, as it reaches
the face piece during expiration. This waste can be prevented by
an arrangement similar to that already described (Figure 49) in
connection with the administration of oxygen to patients. Priest-
ley and I found in steel-chamber experiments that with this ar-
rangement about I liter. a minute (measured at sea-level pressure)
was sufficient up to a height of 28,000 feet during rest ; but at least
2 liters were needed for such exertions as an aeroplane observer
or pilot has to make. With the light steel cylinders or large Dewar
flasks now in use the waste of oxygen with the ordinary arrange-
ment of mask does not greatly matter, however.
A height as great as Berson and Siiring reached in a balloon
has quite recently (March, 1920) been reported as reached in an
aeroplane by Major Schroeder of the American Army Air Service,
who, however, also became unconscious, and had a very narrow
escape. How it was that the oxygen supply became insufficient in
this remarkable ascent has not yet been reported.
The heights hitherto attained represent by no means the limit
which Paul Bert's experiments on animals indicated when pure
oxygen is breathed. All that is shown by them is that the oxygen
supply was insufficient. At 36,000 feet a man breathing pure
oxygen would be quite unaff'ected by the altitude. The barometric
pressure is about 180 mm. In the alveolar air there would be a
pressure of 47 mm. of aqueous vapor and 40 mm. of CO2. Hence
(by diff"erence) there would be 93 mm. of oxygen pressure ; and in
380 RESPIRATION
the rarefied air this would certainly suffice to saturate the arterial |
blood to the same extent as at sea level. At 140 mm. of barometric l
pressure there would still be at least 53 mm. of alveolar oxygen ;
pressure; and it is probable that marked symptoms of oxygen
shortage would only begin to appear at pressures below this. At I
100 mm, they would become urgent in unacclimatized persons.
At 80 mm. Paul Bert's animals were at the point of death.
It is difficult to see how the addition of CO2 to the inspired
oxygen could be of any service, although at moderate diminutions ,
of pressure CO2 is of considerable service, as already pointed !
out. When pure oxygen is breathed it is impossible to raise the '
alveolar CO2 pressure without lowering the alveolar oxygen pres- j
sure; and at very low barometric pressures every millimeter of I
alveolar oxygen pressure counts. Moreover rise of alveolar CO2 !
pressure would, on account of the Bohr effect, tend of itself to ■
diminish the percentage saturation of the arterial blood with
oxygen and thus counteract any advantage gained by increased
rate of circulation. Aggazotti has shown^'' that when animals are
placed in oxygen containing a considerable percentage of CO2
they are capable of withstanding extremely low pressures; but
the same was found by Paul Bert when the atmosphere was one
of pure oxygen. Aggazotti himself reached the very low pressure
of 120 mm. in a steel chamber while breathing oxygen with CO2
added.
To make it safe to go much above 30,000 feet it would be
necessary to have an apparatus which made it certain that the
wearer always breathed pure oxygen, or at any rate oxygen not
mixed with any other gas than CO2. An ordinary mine-rescue
apparatus with the usual constant oxygen supply of about 2 liters
per minute (measured at ordinary atmospheric pressure) would
secure this result with a very moderate expenditure of oxygen.
Care would, however, be necessary to insure that both the purifier
and the oxygen supply worked properly at the low temperature
and pressure met with at very high altitudes. With a larger con-
sumption of oxygen an apparatus could be made to work safely
without a purifier. If it were required to go much above 40,000
feet, and to a barometric pressure below 130 mm., it would be
necessary to inclose the airman in an air-tight dress, somewhat
similar to a diving dress, but capable of resisting an internal pres-
sure of say 130 mm. of mercury. This dress would be so arranged
"Aggazotti, ArcA. Hal. de Biologie, XLVI, 1905.
RESPIRATION 381
, that even in a complete vacuum the contained oxygen would still
have a pressure of 130 mm. There would then be no physiological
limit to the height attainable.
The problem of going to very high altitudes with an oxygen
apparatus is similar to that of using a self-contained breathing
apparatus in mine air which is either intensely poisonous from
the presence of CO or HgS, or contains little or no oxygen.
This problem has been solved successfully, so that teams of
miners have worked daily for weeks or months at places a long
I distance from where there was any oxygen in the air. The same
• care as is needed and actually taken in the case of the mining
, apparatus is even more necessary in the case of airmen at great
I altitudes, but, owing to prevailing ignorance, has not yet been
: applied. At 36,000 feet, for instance, with the barometric pres-
sure at a quarter the normal, an airman breathing pure oxygen
would be much nearer danger if, owing to some accident, he took
several breaths of the surrounding air, than a miner using a self-
contained breathing apparatus would be if he took several breaths
i of an atmosphere of fire damp. The miner would have in his
lungs to start with a pressure of 700 mm. of oxygen, whereas the
j airman would have only about 90 mm. To the airman at very
\ high altitudes it is therefore specially necessary to have an ap-
\ paratus which is perfect in its action and is used with all the
precautions which our existing physiological knowledge shows
to be necessary.
CHAPTER XIV
General Conclusions.
On looking back at the results reached in successive chapters of
this book certain points of general physiological significance
emerge. The present chapter will be devoted to their discussion.
— 1^ It is evident that within the limits of health the breathing
represents the lung ventilation required to keep the reaction
and the pressure of oxygen in the blood supplying the re-
spiratory center constant within certain narrow limits, and that
the breathing - increases or diminishes in accordance with the
quantity of air needed to produce this effect. The "chemical" and
"nervous" stimuli acting on the respiratory center co5perate in
bringing about the constancy. The circulation is, in the main,
similarly regulated so as to maintain a normal reaction and
oxygen pressure in each of the various organs, although other
factors may also determine the local circulation rate to some
extent.
The quantity of respired air required to keep the arterial blood
normal varies with the very variable consumption of oxygen and
output of carbonic acid by the whole of the living tissues. In
different individual parts of the body the variations in consump-
tion of oxygen and output of carbonic acid are still more striking;
and meeting these variations there are equally striking variations
in the local circulation rates.
What is regulated by the breathing and circulation is not pri-
marily the consumption of oxygen and formation of carbonic acid,
but the partial pressures, or diffusion pressures, of these sub-
stances. If their diffusion pressures become more than slightly
abnormal the result is, not a mere slowing or quickening of physio-
logical activity, but totally abnormal activity and abnormal change
in structure. What is immediately effected is the maintenance of
these pressures. The supply of oxygen and removal of carbonic
acid are such as to keep them approximately steady. We have also
seen that it is simply as an acid that carbonic acid is of physio-
logical importance, so that in reality a normal reaction, or normal
diffusion pressure of hydrogen and hydroxyl ions, and not merely
a normal diffusion pressure of carbonic acid, is maintained.
RESPIRATION 383
After Harvey's discovery of the circulation and Lavoisier's
discoveries with regard to respiratory exchange and animal heat
many physiologists looked upon circulation and breathing as
processes which primarily determine and regulate tissue activity.
We can trace this, for instance, in the physiological ideas of
Descartes and Liebig, and in ideas still to some extent prevalent
as to the causes of respiratory exchange, secretion, and growth.
Closer examination has shown that breathing and circulation are
responses to tissue activity, and do not primarily determine it.
Another tendency has been to regard the nervous system as the
primary autonomous regulator of breathing and circulation. The
evidence brought forward above has shown, however, that the
regulative influence of the nervous system is not autonomous,
but dependent on conditions of environment determined mainly
by varying tissue activity.
In his **Le9ons sur les phenomenes de la vie" (p. 121) Claude
Bernard drew the conclusion that **all the vital mechanisms,
varied as they are, have only one object, that of preserving con-
stant the conditions of life in the internal environment" (the
blood). No more pregnant sentence was ever framed by a physi-
ologist, and the long series of investigations described in the
present book may be regarded as an attempt to follow out in
regard to blood reaction and oxygen supply the line which
Bernard indicated. Physiological activities can in one sense be
summed up in the ''preservation of the conditions of life in the
internal environment," with consequent maintenance of normal
structure. In another sense, however, physiological activity is
constantly disturbing the internal environment. What is actually
maintained is a dynamic balance between the disturbing and
restorative activities. The order displayed in this dynamic balance
is the order of biology.
In view more particularly of Paul Bert's experimental demon-
stration that the physiological action of gases dissolved in the
blood depends on the pressures which they exert in the surround-
ing atmosphere — that is to say on their vapor pressures — we may
conclude that it is the diffusion pressures of substances dissolved
in the blood that correspond to Bernard's "conditions of life." This
definition includes temperature : for diffusion pressure, other
things being equal, varies as the absolute terAperature and indeed
gives us our measure of temperature, since the expansion of gases
or liquids, by which we measure temperature, depends on increase
of diffusion pressure.
384 RESPIRATION
It is a familiar fact that, apart from the contained gases, the
composition of blood plasma is extremely constant. The varied
experiments initiated by Ringer and carried forward by many
other observers indicate directly the physiological importance of
the various salts or their ions which are present in blood plasma,
and render intelligifele the exactitude with which their concentra-
tions are regulated by the kidneys. The facts collected in the pres-
ent book show that also as regards hydrogen and hydroxyl ions
and free oxygen the composition of the blood plasma in contact
with any particular part of the tissues is, and must be, very con-
stant, and is kept so by regulation of breathing, circulation, kidney
excretion, and other physiological activities. Thus oxygen and
hydrogen and hydroxyl ions take their place in a strict quantita-
tive sense beside the salts, proteins, sugar, etc., which help to
make up Bernard's "conditions of life."
We also now know that what is called the osmotic pressure of
blood plasma is so constant that the existing methods of measur-
ing it by depression of freezing point or vapor pressure are too
coarse for the detection of such differences as are constantly oc-
curring during life and evoking the ordinary physiological re-
sponses of the kidneys and other organs. Osmotic pressure de-
pends, however, as already mentioned (Chapter VI 11)- on the
difference between the diffusion pressure of a solvent in a solution
and in the pure solvent. It is thus in reality the diffusion pressure
of water in the blood that is maintained so constant. The diffusion
pressure of water can thus be placed in the same category as that
of other substances among Bernard's "conditions of life." The
experiments of Priestley and myself-'^ on the excretion of water
by the kidneys show that the regulation by the kidneys of the
diffusion pressure of water in the blood is comparable in its ex-
treme delicacy to the regulation of blood reaction.
As a general rule salts, water, and various other substances
present in blood plasma are to only a very small extent used up
by or given off from the tissues. Hence in the case of most
tissues it would require only a very slow circulation to keep the
concentrations of these substances constant in the blood, pro-
vided that the temperature was constant. If, however, the circu-
lation were much slower than it is, and if this were rendered
possible by the provision in the blood of much greater capacity
for carrying oxygen and CO2 as easily dissociable compounds,
* Haldane and Priestley, Journ. of Physiol., L, p. 296, 1916; Priestley, Ibid.,
L. p. 304. 1916.
RESPIRATION 385
the even regulation of temperature in the body would apparently
become impossible, and in other ways the physiological inter-
connection between different parts of the body would be less close
and rapid.
Although water and salts are by ordinary measurements neither
absorbed by nor given off from most living tissues, it is evident
that this only means that passage of them into the tissues is bal-
anced by passage outwards. A liquid, like a gas, consists of mole-
cules in rapid movement and diffusing in all directions. We can-
not follow the movements of individual molecules, and can only
detect gain or loss when either the relative proportions of different
kinds of molecules alter, or the total number increases or dimin-
ishes. When as many molecules or ions of any one substance
are passing in as are passing out there appears to be neither ab-
sorption nor giving off of the substance. Nevertheless there is
continuous molecular or ionic exchange, and the blood is in con-
stant and active physiological connection with the surrounding
tissues. As is shown by the immediate effects of altering the
diffusion pressure of salts, water, or other blood constituents, the
exchange of molecules continues during life, whether a tissue is
"active" or "resting." In reality there is constant physiological
activity, and the conventional sharp distinction between conditions
of rest and activity is extremely misleading.
From the standpoint of physical chemistry life depends upon
the maintenance of a balance of molecular exchanges between the
tissue elements and their environments. If the balance is disturbed,
so that, for instance, too many or too few water molecules or
potassium, calcium, or sodium ions are passing from the blood
to the tissues or vice versa, life is imperiled. The case is exactly
similar with oxygen molecules, or with hydrogen and hydroxyl
ions. If the oxygen diffusion pressure in the plasma falls so low
that the proportion of oxygen molecules passing in is abnormally
low as compared with that passing out there is physiological dis-
turbance ; and similarly, as shown in Chapter XII, when too much
oxygen is passing inwards.
Hitherto the supply of oxygen has not been regarded from this
standpoint. It has been generally assumed that the oxygen mole-
cules are all passing in one direction and that an irreversible re-
action occurs in the living tissues by which oxygen is fixed so that
no free oxygen molecules are returned to the environment. The
facts indit:ating the great importance of a certain definite dif-
fusion pressure of oxygen in the immediate environment of the
386 RESPIRATION
tissue elements are inconsistent with this view. The experimental
evidence shows that we must place the diffusion pressures of oxy-
gen and carbonic acid in exactly the same category as the diffusion
pressures of water, salts, and other dissolved constituents of blood
plasma. This means that oxygen molecules are constantly passing
both outwards and inwards, although in ordinary tissues more
are passing inwards. It is only in oxygen-secreting tissues that we
find that on one side of the secreting membrane oxygen molecules
are passing more readily outwards, and only, so far as yet known,
in the green parts of plants and in the presence of light that free
oxygen is on all sides passing more readily outwards from living
tissue elements than inwards. But even in green plants, as Paul
Bert showed, a considerable diffusion pressure of oxygen is neces-
sary for life.
We can thus compare living structures to dissociable chemical
molecules and particularly molecules which, like haemoglobin,
form molecular compounds only capable of existing in so far as
rate of loss is balanced by rate of gain. We must, however, assume
that the dissociation and association are taking place simultane-
ously in many different directions, corresponding to the many
different substances present in the blood plasma and necessary
for life. We have also to remember that although the individual
tissue elements are all in connection, direct or indirect, with the
blood plasma, they are also in connection with one another, and
that this implies additional conditions of stability in connection
with which molecular or ionic gains and losses are balanced
against one another.
It is clear that the stability in respect of one kind of molecular
gain or loss determines the stability in respect of others. Thus a
small deficiency of oxygen molecules, or a small excess of hydro-
gen ions, in the blood plasma, disturbs the equilibrium of the
receptor elements in the respiratory center and leads to the extra
molecular discharges which show themselves in increased activity
of the center. Disturbances in other directions of the composition
of the blood plasma have similar results, though the receptors
are specially sensitive to changes in reaction or deficiency in oxy-
gen pressure. We can interpret similarly the mode of action of
various stimuli acting on living tissues, including what, for want
of more intimate knowledge, we call mechanical stimuli. Hence we
are led to the conception of a living organism as the seat of a vast
system of mutually dependent reversible chemical reactions. For
irreversible chemical reactions physiology has but little use.
RESPIRATION 387
The mechanistic interpretation of life fails to take account of
the mutual dependence throughout a living organism of these
reactions. When we remove any part of the organism from its
physiological connection with its environment including the other
parts, we at the same time necessarily alter its reactions and the
stability of its living structure. Hence we cannot investigate an
organism as we investigate the parts of a machine by taking them
apart and ascertaining the properties and structure of each sepa-
rate part. The same criticism applies to what may be called the
"hormone" theory of the interconnection between the parts of an
organism. On this theory the interconnection is brought about
through the existence of special chemical messengers, or "hor-
mones," produced in minute quantities by each organ, and bring-
ing about specific excitatory effects, resulting in coordinated
action. The hormone theory, like the mechanistic theory, tacitly
assumes that, apart from the influence of hormones, and of the
central nervous system, each part of an organism leads an inde-
pendent existence. The truth is that every substance which enters
into the life processes of any part of an organism is as much a
hormone as any other such substance. Water, for instance, is the
most abundant constituent of the body, and a very minute excess
in the diffusion pressure of water in the blood excites very striking
reaction in the kidneys. This minute excess seems, therefore, to
act as a hormone, just as a minute deficiency in alkalinity or in
oxygen pressure acts as a hormone to the respiratory center.
Since, however, water, hydrogen and hydroxyl ions, and oxygen
are influencing the body continuously, the conception of them as
hormones, acting only occasionally, is quite misleading. The
physiological interconnection between different parts of the body
is continuously in existence and far more intimate than is assumed
by either the ordinary mechanistic theory or the hormone theory.
In the case of chemical compounds which we ordinarily regard
as being stable in their existing environment, and not in a constant
state of association and dissociation, it is well known that the
particular nature of one of the atomic linkings may make a great
difference to the others. Thus the general properties of an or-
ganic compound may be greatly changed when a hydrogen atom
is replaced by a chlorine atom or a methyl radicle. We have also
seen in Chapter IV how in oxyhaemoglobin the affinity of the
haemochromogen part of the molecule for oxygen is affected by
changes in environment affecting primarily another part of the
molecule. From the point of view of our present chemical knowl-
388 RESPIRATION
edge there is thus nothing new in principle in the fact, character-
istic of physiological reactions, that any particular reaction is de-
pendent upon the whole life of an organism. Nevertheless it is just
here that we strike the dividing line between the physical sciences
and biology.
A physiological reaction, when we examine it closely, is always
found to depend on a vast number of conditions of structure and
environment. It is true that under "normal conditions" the same
stimulus will produce the same reaction again and again; but
when we inquire what normal conditions represent we find some-
thing which is indefinitely complex from the physical and chemi-
cal standpoint. We have only to alter slightly the diffusion pres-
sure of one or other of the many substances, only partially known,
in the blood plasma, in order to obtain a quite different reaction.
For instance a given fall in the diffusion pressure of oxygen fails
to excite the respiratory center if the hydrogen ion concentration
of the blood is very slightly below normal; and if the calcium
ion concentration were a little above or below normal there would
doubtless also be an abnormal result. The presence of a trace of
ether or morphia, or probably of numerous other substances,
affects the center in a similar manner. The excitability of a tissue
to any given physical or chemical stimulus may thus vary in-
definitely under slightly different conditions.
If we attempt to investigate physiological phenomena from the
standpoint merely of physics or chemistry, we are thus at once
landed in confusion. In investigating ordinary physical or chemi-
cal phenomena, we can examine one by one the parts or units
we are dealing with and ascertain their properties, so that from
the empirical knowledge thus gained we can predict what will
result when they act on one another. In other words we can give
physical and chemical explanations of their mutual action. But
when we attempt to do this as regards the actions on one another
of the parts of an organism, or of the organism and its environ-
ment, we are met by the difficulty that we cannot ascertain the
structures and properties of any of the separate parts, since their
structures and properties actually depend on the existing physio-
logical relations of the parts and environment to one another. The
relativity of the phenomena confronts us at every turn in the
attempt to reach physical and chemical explanations of physio-
logical reactions.
Up to a certain point we can, it is true, understand living organ-
isms mechanically. We can, for instance, weigh and measure them
RESPIRATION 389
and their parts, and investigate their mechanical and chemical
properties. This enables us to predict certain points in their be-
havior, as shown, for instance, in Chapters IV and V. But when we
look more closely it becomes quite evident that the knowledge
we gain from mere physical and chemical examination hardly
touches any fundamental physiological problem. We cannot es-
cape from the relativity of the phenomena we are dealing with.
The only way of real advance in biology lies in taking as our
starting point, not the separated parts of an organism and its
environment, but the whole organism in its actual relation to
environment, and defining the parts and activities in this whole in
terms implying their existing relationships to the other parts and
activities. We can do this in virtue of the fundamental fact, which
is the foundation of biological science, that the structural details,
activities, and environment of organisms tend to be maintained.
This maintenance is perfectly evident amid all the vicissitudes of
a living organism and the constant apparent exchange of material
between organism and environment. It is as if an organism al-
ways remembered its proper structure and activities ; and in repro-
duction organic "memory," as Hering figuratively called it,^ is
transmitted from generation to generation in a manner for which
facts hitherto observed in the inorganic world seem to present no
analogy. We can discover and define more and more clearly by
investigation these abiding details of structure and activity, dis-
tinguishing accidental appearances from what is really main-
tained; and this process of progressive definition is the work of
the biological sciences.
If we look back on the general outcome of the investigations
summarized in this book, it is evident that the progress made has
consisted in distinguishing underlying identity of activity amid
superficial appearances which at first sight present confusion. In
the second and third chapters it was shown that behind the ir-
regularities of ordinary breathing the mean pressure of CO2 in
the alveolar air is maintained steady within narrow limits for
each individual; and in a later chapter it was more definitely
shown that this implies a similar steadiness in the CO2 pressure of
the respiratory center. In Chapter VIII this conclusion is widened
by the evidence that CO2 pressure is only important as an index
of blood reaction, and that it is blood reaction, and not mere pres-
sure of CO2, that is kept so constant by the breathing. In Chap-
' E. Hering, Memory as a Generalized Function of Organized Matter (1870).
English Translation, Chicago, 19 13.
390 RESPIRATION
ters VI, VII, and IX it is shown that there is similar maintenance i
of the pressure of oxygen in the blood, and in Chapter X evidence
is collected that the circulation is so regulated as to keep both the
oxygen pressure and the reaction very nearly steady in each part
of the body. Chapter XIII deals with the manner in which the
body adapts itself to an abnormal atmosphere in accordance with
the principles laid down in preceding chapters.
It is thus with the dominant fact that in various definite re-
spects the internal environment of the living body tends to be
maintained very steady that the investigations brought together
in the preceding chapters have mainly dealt. This dominant fact
is what makes a scientific treatment possible in actual practice,
and furnishes us with principles by means of which we can predict
physiological responses and at the same time gain a practical con-
trol of the living body, such as is required in medicine and sur-
gery.
When we find that a certain characteristic structure and internal
environment exists within a living organism, we have discovered
what at first sight appears to be a fact capable of definition, though
not of explanation, in physical and chemical terms. Thus the
"normal" diffusion pressures of substances present in the blood
are simply diffusion pressures which we can measure and define,
one by one, in ordinary physical and chemical terms. But when
something occurs which tends to alter one of the diffusion pres-
sures, or to disturb the structure, we realize more fully the real
nature of what is maintained in a living organism : for the altera-
tion is not entirely prevented, but met by active readjustment of
such a character that what we easily recognize as organic identity
is maintained. If, for instance, the oxygen pressure in the air
inspired is lowered, a quantitatively corresponding lowering in
the oxygen pressure of the blood passing through the tissues is
prevented by increased breathing, oxygen secretion by the alveolar
epithelium, and rise in the haemoglobin percentage. At the same
time other disturbances which would naturally result from these
changes are met by diminution in the "available" alkali in the
blood, increase in blood volume, and so on. A widespread re-
adjustment of physiological activities and of blood composition
has thus occurred, but with the result that the more fundamental
diffusion pressures of oxygen, hydrogen and hydroxyl ions, etc.,
have altered only very little, and in this slight alteration they have
held together as a whole. The oxygen pressure, for instance, is
not restored at the expense of hydrogen-ion pressure or excessive
RESPIRATION 391
work of the heart or lungs. What is maintained in the tissue en-
vironment is oxygen pressure in its organic relations. The rela-
tivity to one another of the phenomena of life stands out clear in
this maintenance of organic identity.
In the course of biological investigation we meet on all hands
with similar examples of maintenance and reestablishment of
organic identity; and the existence of this actively-maintained
identity is the scientific basis of practical medicine and surgery.
But for the fact that functional as well as structural compensation
is constantly occurring, not only under ordinary physiological
conditions, but also in cases of injury by disease or accident, and
that by observation and experiment we can learn to understand,
predict, and aid it, physicians and surgeons would be absolutely
helpless. Neither scientific biology nor scientific medicine could
be based on the ordinary working hypotheses of physics and chem-
istry, since these hypotheses furnish no sufficient means of under-
standing and predicting biological phenomena. Biologists, physi-
cians, and surgeons are not, and never will be, simply chemists
and physicists.
In physiology we are always dealing with responses to immedi-
ate stimuli ; but the responses are evidently determined in relation
to the maintenance of organic identity. They are organic responses,
and are simply rendered unintelligible when by the common con-
fusion in thought running through so much of the present teaching
of physiology they are represented as examples of mechanical
determination. Such expressions as the "mechanism" of respira-
tion, or secretion, or of maintenance of the internal environment
generally, are examples of this confusion. On closer examination
all the assumed mechanical reactions turn out to be expressions of
the organic maintenance which is the subject matter of the bio-
logical sciences.
Biology must take as its fundamental working hypothesis the
assumption that the organic identity of a living organism actively
maintains itself in the midst of changing external appearances.
This identity is not physical identity nor identity of form or
chemical composition, but something which we can perceive and
trace by exact quantitative investigation just as readily and ex-
actly as we perceive and trace physical identity in what we inter-
pret as the inorganic world. The science which traces this organic
identity is biology. Anatomy or morphology traces it as regards
structure, and physiology as regards activity. But since organic
structure is only the outcome or expression of ordered activity,
392 RESPIRATION
and organic activity only the activity which expresses itself in
organic structure, the two branches of biology are in reality one,
and we may look forward to a time when the present wholly
artificial and sterilizing separation of them will disappear along
with the disappearance of the mechanistic theory to which the
separation is due.
The true scientific procedure of biology is different from that
of the physical sciences. In physics and chemistry the procedure
employed is to ascertain the properties of the separate units of
matter and energy with which it is assumed that these sciences
deal. Thus from the properties and movements of the parts of a
material system such as a machine we can predict its behavior
and can design and control machinery. From the properties and
movements of the molecules in a given quantity of gas we can
predict its behavior. From the properties of the atoms of carbon
and other elements we can predict the existence and many of the
properties of carbonaceous and other compounds. But we cannot
predict in this way the behavior of a living organism. The re-
lationships, for instance, into which the carbon atoms as inter-
preted by chemistry enter within living organisms show them-
selves to be too complex and changeable, so that, apart from the
biological method of treatment, we should be totally at a loss. In
the physical sciences we are looking at collections of units, each of
which is looked at from the outside. In biology we are looking at
each unit from the inside, and biological results affbrd abundant
justification for this method of looking at them.
It may appear at first sight as if the biological method were
unscientific, and the claim may be made that it ought to be, and
ultimately must be, possible to advance in biology by the method
of the physical sciences. This claim must now be examined care-
fully.
The reason why the physical or chemical method of treatment
is so unsatisfactory in biology is that in connection with living
organisms the properties of the parts show peculiarities which we
do not meet with in what we distinguish as the inorganic world.
Let us take the case of nitrogen atoms. When nitrogen is pres-
ent as a gas at an ordinary temperature the properties of its mole-
cules seem to be very simple for all practical purposes. The mole-
cules simply repel one another when they meet, or when they
encounter molecules of other gases; and the kinetic theory of
gases, based on this simple assumption, enables us to predict with
the greatest accuracy the behavior at ordinary temperatures and
RESPIRATION 393
pressures of a mass of gaseous nitrogen or of a mixture of nitrogen
with another gas. But if we raise the temperature sufficiently, and
hydrogen or oxygen is present, the nitrogen combines with it, form-
ing ammonia or oxides of nitrogen. The properties of nitrogen
have thus shown themselves to be more complex than the simple
kinetic theory of gases assumed. But from the atomic theory as ap-
plied in chemistr]^, and the theory of valencies, we can still predict
more or less successfully the composition of the compounds formed
by the nitrogen. Most of their special properties have to be ascer-
tained by experiment ; but once ascertained they can be used for
the purpose of predicting how these compounds will behave un-
der quite new conditions. It is exactly the same when we come to
the complex proteins and other organic nitrogenous compounds
which can be separated from the bodies of organisms. So long as
they are separated from living organisms we can investigate
them just as we investigate other chemical compounds, and they
present no real obstacle to such investigation.
The obstacle appears whenever the assumed chemical mole-
cules are participating in the life of an organism. Their proper-
ties seem then to become fluid and dependent from moment to
moment on the position of each molecule relatively to multitudes
of other molecules of the most diverse kinds. We consequently
cannot trace the individual molecules, and cannot tell whether or
how they are in combination with other molecules. They seem to
develop a quite indefinite potentiality of exhibiting unsuspected
properties.
Now this fact shows us clearly that the simple atoms and mole-
cules of physics and chemistry are only a sensuous illusion : for,
behind the supposed simplicity, indefinite potentialities are hid-
den and actually show themselves in connection with the phenom-
ena of life. The properties and activities of what we call atotns
or molecules are in reality a function of their relations to
other atoms and molecules ; and this fact, which is not at once evi-
dent in what we call the inorganic world, becomes perfectly evi-
dent in biological phenomena. Organic individuality is something
very evident to our perception, and has thus the same claim to
reality as inorganic structure; but, from a purely physical and
chemical point of view, living structure and activity constitute not
merely a molecular flux like that of a river or a flame, but an
altogether undefinable flux — undefinable because we cannot define
the molecular changes. It is biological and not physical or chemi-
cal structure and activity which biological investigation enables
394 RESPIRATION
us to define more and more accurately and fully. Only when an
organism is dead do we seem to have before us a physical and
chemical complex.
Those who insist that physiological activity must in reality be
physical and chemical change have to answer a previous ques-
tion as to the justification for the assumption of physical and
chemical reality. The molecules, atoms, and electrons of the
physical sciences seem real enough so long as we confine ourselves
to the superficial aspect of reality which is dealt with by the
physical sciences; but it is the same reality that is dealt with by
biology, and we reach a different interpretation of it through the
study of biological phenomena. In this interpretation the self-
existent individuality of atoms and molecules fades away in rela-
tivity.
The modern world has become so accustomed to the material-
istic assumption which identifies the mechanical interpretation of
reality with actual reality that in spite of the existence of biology,
psychology, ethics, religion, and philosophy it is difficult at pre?
ent to obtain even a hearing for the view that physical reality rep-
resents no more than superficial sensuous appearance. By the help
of various makeshift hypotheses such as those of vitalism or
animism, the real philosophical problem as to the ultimate validity
of the physical interpretation of reality has been evaded for the
time. But these evasions cannot satisfy us, and the problem comes
up in a clear-cut and definite form in connection with the relation
of biology to physics and chemistry. The facts dealt with in the
latter sciences present us with one interpretation of "reality," or
"nature," and those dealt with by the former present us with a
different one.
Which of the two interpretations corresponds more closely to
actual reality? There appears to me to be no doubt that the biolog-
ical interpretation does. The progress of the physical sciences
has taught us that the gases, liquids, and solids which to super-
ficial examination appeared to be continuous and inert substances
are not only discrete but made up of molecules in continuous
relative movement, and, in the case at least of solids and liquids,
continuously affecting one another's movements and properties.
We now know also that atoms themselves are systems of still more
elementary units moving relatively to one another at enormous
velocities, and that in chemical combination, and even in solution
or what we call simple mechanical interaction, these systems are
modified, as shown, by electrical phenomena. The chemist can
RESPIRATION 395
determine with great apparent accuracy the proportions of hydro-
chloric acid and water in an aqueous solution. In actual fact there
may be practically no hydrochloric acid molecules present and far
fewer simple molecules of water than would appear from the
analysis, since the molecules are partly ionized and partly com-
bined with one another in various forms. Consequently the re-
sults of the analysis represent only a ''practical" convention, how-
ever useful this convention may be. In reality the properties
of both the conventional hydrochloric acid and the conven-
tional water depend on the particular conditions existing in the
solution. But the inquiry can be, and has been, pushed still further.
At first sight it seems as if, in whatever way the molecules of
water and hydrochloric acid may be split up or combined, the
mass present is something independent of changeable relations.
But here, again, the progress of physical science has indicated
that even the mass of what is present depends upon relative move-
ment, and finally that absolute movement in empty space is a
conception to which no experimentally verifiable meaning can be
attached.
We only deceive ourselves when we imagine that in physical
and chemical investigation we are free of relativity. Behind
all the superficial appearances of a ''real" physical world, rela-
tivity finally appears ; but in biological phenomena the relativity
is always evident and prominent, and precludes the possibility of
even a conventional physical and chemical interpretation of
the observed facts. In frankly accepting relativity, and framing
her interpretations on a principle based upon it, biology comes a
step nearer to actual reality than the physical sciences.
It has come to be popularly believed that if we knew enough
of the physics and chemistry of what occurs in a living organism
biological interpretation could be reduced to physical and chemi-
cal interpretation. Though the attempts to give physical and
chemical interpretations of biological phenomena have never been
successful, and their failure in detail is becoming more and more
evident with the progress of both physiological and physical in-
vestigation, labored endeavors are still made to teach physiology
and represent the growing body of physiological knowledge in
physical and chemical terms. The investigations described in the
present book illustrate the fruitlessness of these attempts. In the
phenomena connected with breathing we are everywhere dealing
with organic regulation — in other words with the manifestations
amid superficial changes which at first sight puzzle and confuse
396 RESPIRATION
us, of organic identity. It is the same in connection with the phe-
nomena of circulation, excretion, absorption, and other physio-
logical activities. I wish to claim very definitely that in dealing
with biological phenomena and putting her questions to Nature,
biology must use her own working hypothesis, and not those of the
physical sciences.
The organic regulation which we find everywhere in a living
organism does not represent something imposed from without on
the processes occurring in the organism, but is simply a natural
expression of the reality which is present. It is Nature we are
studying in biology, not a special "vital force" or other super-
natural influence. But the biologist must be free to interpret
Nature in his own way ; and it is Nature as Hippocrates saw her,
and not as Democritus saw her, that he sees and cannot help
seeing. Organic regulation, maintenance, and reproduction are
nothing but the expression of this biological Nature.
The universal acceptance among biologists of the doctrine of
evolution has often been assumed to carry with it the corollary that
life has arisen out of inorganic conditions ; and in this way a short
cut has been made to the conclusion that biology must in ultimate
analysis be nothing but physics and chemistry. This reasoning
cannot be justified. Even in the simplest forms of life it is still
unmistakably life that we are dealing with ; and if we succeed in
tracing life to yet simpler forms we shall still find life, so that the
"inorganic conditions'* into which we have traced life will ap-
pear to be something very different from inorganic conditions
as we now represent them to ourselves.
We can see, and particularly clearly in the case of higher or-
ganisms, that the life of each organism is an association of the
lives of more elementary organisms, each of which shows its full
being only in the life of the whole, but is also more or less capable
of independent existence. It is by the separation and subsequent
full development of these more elementary organisms that re-
production is brought about. The life of a higher organism has
been said to be the "sum" of the lives of its constituent cells. Such
an expression is, however, misleading: for a cell apart from its
particular place in the living body, or the particular environment
which exists there, behaves very differently from the same cell
in its proper place. It thus cannot be physiologically defined apart
from its place in the whole organism. The organism as a whole is
no less real because it includes in its life the lives of individual
cells, and each cell, as shown very clearly in connection with the
RESPIRATION
397
facts first discovered by Mendel with regard to reproduction, in-
cludes the lives of still more elementary centers of life. The same
reasoning applies, of course, to communities of what appear at
first to be quite separate organisms. An organism separated from
its kind is an artificial abstraction, just as is an organism separated
in other ways from its environment.
Although such processes as respiration, circulation, secretion,
absorption, and various forms of nervous activity, occur inde-
pendently of consciousness, many bodily activities are accompa-
nied by consciousness. Muscular exertion, for instance, is for the
most part consciously determined, and as muscular activity de-
termines breathing, and in other ways the breathing is determined
by conscious activity and under direct conscious control, it is
necessary to refer to the relation of conscious to unconscious
bodily activity.
We can interpret unconscious physiological activity from the
biological standpoint which has hitherto served us in the interpre-
tation of breathing, circulation, etc. ; but it is different with con-
scious activity. In perception we are aware of what we interpret
as ''objective reality," and voluntary actions are quite evidently
determined by this awareness. The awareness signifies that in
perception, as distinguished from a simple physiological reaction,
the reaction is not simply definable as occurring at a certain
moment or within a certain definite time, but involves also past
and future times, as well as surrounding space. When I see my
pen now, I see it as a material structure which has existed and
will continue to exist. I also see it as being in relation to many
other things not at the moment visible in the physiological sense.
The light in which I see it is not merely that of an electric lamp
but of all my other experience. When I write with the pen the
movements of my muscles are determined by the actual presence
to me of innumerable past, present, and anticipated future events
in both my own individual history and that of mankind. The past
events are not simply past and done with, like events interpreted
physically or biologically, but they, and not their mere effects,
are still present and active. What I have experienced before, what,
for instance, I have read of Hippocrates, or Johannes Miiller, or
Claude Bernard, or Paul Bert, is still taking on fresh meanings in
my mind and directly determining my action now. The same is
true of all I have absorbed of the common spiritual heritage and
anticipations for the future of my country or of mankind. Actual
memory is no mere organic memory. I am living and acting in a
398 RESPIRATION
spiritual world for which separation, not merely in space, but
also in time, has none of the meaning which it possesses for the
world interpreted physically or biologically. Along the years
and across the oceans action and reaction are direct in this spirit-
ual world.
It is evident that in conscious activity we are face to face with
facts that neither physical nor biological hypotheses are capable
of interpreting. Yet conscious activity manifests itself in connec-
tion with the same beings that seem also to live and breathe as
mere organisms, or to consist of nitrogen, hydrogen, oxygen,
carbon, and other atoms leading a wild and undefinable dance.
In presence of the evidence of life we cannot rest satisfied with the
physical and chemical interpretation of these beings; but simi-
larly in the presence of conscious activity we cannot rest satisfied
with the biological interpretation. Biological phenomena show
us that the physical interpretation of the universe is only an im-
perfect preliminary interpretation for which all that can be said
is that it is of essential practical use in the absence of fuller
knowledge. But the facts relating to perception and volition show
us that the biological interpretation is also no more than a prac-
tical makeshift. As mathematicians, physicists, chemists, biolo-
gists, we are only "practical" men, though we often take our
practical working hypotheses for representations of actual re-
ality. We do so by unconsciously neglecting for the time a great
part of the facts to be explained — in particular the facts that our
world not only includes living organisms, but is a known world
and a world of spiritual values. In reality our sciences are only
making use of abstractions of a limited practical value. ^
In conscious activity the self-conserving and species-conserving
organic activities of living organisms take on a new and far wider
interpretation. Mere organic self-conservation appears now as
conservation of a system of consciously realized interests; and
social interests assume a commanding position as compared with
individual interests. In so far as bodily interests are carried out
consciously, therefore, the physiological interpretation of them
recedes into the background; and this is still more true of the
physical and chemical interpretation.
In the preceding chapters, I have attempted to justify the
physiological interpretation of unconscious bodily activities by
pointing out how breathing, circulation, etc., are manifestations
' A fuller discussion of this point of view will be found in my book "Mech-
anism, Life and Personality," New Edition, 1921.
RESPIRATION 399
of the maintenance of organic identity. Up to a certain point one
can apply the same reasoning to conscious activities by showing
how exquisitely dependent they are from moment to moment on
the integrity of normal ''conditions of life" in the internal en-
vironment, and how they play their part in maintaining this in-
tegrity in accordance with Claude Bernard's conception. But such
treatment of them is wholly insufficient, since they evidently par-
ticipate in that spiritual world to which reference has already
been made. Hence they cannot be described in terms of the work-
ing hypotheses of biology, and attempts to describe them ade-
quately in such terms are merely childish. A fortiori they cannot
be described in physical terms.
Perception and volition are often referred to as processes occur-
ring in the cerebral hemispheres as a result of physical impulses
communicated along sensory nerves from outside. For certain
limited practical purposes this is a useful view to take of them.
But, as already pointed out, perception and volition as such are
not capable of description as events occurring at a certain time and
place, since from their very nature they include other times and
places, and may be said to be creative of time and space. The
working conception under which we attempt to describe them as
events occurring here and now is totally inadequate; and in so
far as we express them in terms of this conception we reduce them
to mere abstractions. By a process of abstraction we can observe
in ourselves and interpret as mere physiological or even physical
events our perceptions and voluntary actions. These observations
constitute an important part of our existing practical knowledge,
but they belong to physics or physiology, and not to psychology,
since in making them we deliberately leave out of account all that
is characteristic of conscious activity.
To those who argue that all our conscious activities are depend-
ent on physical conditions, the reply is that "physical conditions"
are in ultimate analysis only imperfect abstractions. If once we re-
gard them as anything more, we are plunged into all the difficul-
ties which modern philosophy since Descartes has been continu-
ously and successfully grappling with. The universe is a spiritual
universe, and not a dualistic universe of matter and mind.
This book is concerned with physiology and not psychology.
I have claimed for physiology its rightful practical sphere in
distinction from that of physics and chemistry. But we have
reached a limit to the sphere of physiology when we come to deal
with conscious activity.
APPENDIX
This appendix contains a description and discussion of several special
methods of blood examination associated with my name, together with
modifications introduced by myself and others since the methods were
originally described. Methods of gas analysis are not included, since
these are collected in my book "Methods of Air Analysis."
Until a few years ago the gases present in the easily dissociable and
free state in blood were universally determined by means of the mercurial
vacuum pump, which had been gradually perfected by Lothar Meyer,
Ludwig, Pfliiger, and others, while Leonard Hill had considerably
simplified it for ordinary uses. It required, however, an inconveniently
large amount of blood and was also not very accurate, since even when
large volumes of blood were used errors due to gas adhering to the glass
could not be avoided. The presence of these errors was clearly shown by
the fact that the amount of nitrogen apparently obtained from the blood
was not only variable, but much greater than the amount which the blood
was capable of dissolving. The excess of nitrogen could be calculated as
due to contamination with air from the pump; but this correction was
not very satisfactory, since gas must also be left in the pump at the end
of the operation of pumping. The discovery which I made in 1897, that
oxygen or CO can be liberated quantitatively from oxyhaemoglobin or
CO haemoglobin by ferricyanide,^ made it possible to dispense with the
blood pump and greatly simplify blood-gas determination and increase
its accuracy. With the new method Lorrain Smith and I found also that
the oxygen capacity of blood varies exactly as its coloring power, so that
the oxygen capacity can be determined colorimetrically. The methods
now to be described are based partly on the ferricyanide reaction and
partly on the colorimetry of blood.
A. Determination of Oxygen Capacity of Blood Haemoglobin
by Ferricyanide
The following method of determining very accurately the oxygen
capacity of the haemoglobin in blood or a solution of haemoglobin was
first fully described in 1900.- Although the oxygen capacity can be de-
termined with much smaller quantities of blood by the apparatus de-
scribed below, it seems useful to describe also the earlier method, as it
^ Haldane, Journ. of Physiol., XXII, p. 298, 1898.
' Haldane, Journ. of Physiol., XXV, p. 295, 1900.
RESPIRATION
401
can be carried out with very simple apparatus, easily put together in any
laboratory, and suitable not only for exact research, but for use by
students. The chemical facts on which the method is based have already
been referred to in Chapter IV.
The apparatus is shown in Figure 10 1 and the process is as follows.
Twenty cc. of the oxalated or defibrinated blood thoroughly saturated
with air by rotating it in a large flask, are measured out from a pipette
into the bottle A, which has a capacity of about 120 cc.
V^^
Figure 10 1.
Apparatus for determining the oxygen capacity of haemo-
globin in blood.
As it is important to avoid blowing expired air into the bottle, the
last drops of blood are expelled from the pipette by closing the top and
warming the bulb with the hand. In filling the pipette, care must also be
taken that the corpuscles have not had time to begin to subside in the
vessel from which the pipette is filled. Thirty cc. are then added of a
solution prepared by diluting ordinary strong ammonia solution, (sp.
402 RESPIRATION
gr. 0.88) with distilled water to 1/2 50th, and the mixture shaken. The
ammonia solution prevents COg from coming off and also lakes the
blood. Unless the blood is laked, the ferricyanide cannot act on the
haemoglobin, since the corpuscle walls are impermeable to ferricyanide.
About 4 cc. of a saturated solution of potassium ferricyanide are then
poured into the small tube B (the length of which should slightly exceed
the size of the bottle) and placed upright in A. The rubber stopper, which
is provided, as shown, with a bent glass tube connected with the burette
by stout rubber tubing of about i mm. bore, is then firmly inserted,
and the bottle placed in the vessel of water C, the temperature of
which should be as nearly as possible that of the room and of the
liquid in the bottle. If the stopper is not heavy enough to sink the bottle,
the latter should be weighted. By opening to the outside the three-way
tap (or a T tube and clip) on the burette, and raising the leveling tube,
which is held by a spring clamp, the water in the burette is brought to
a level close to the top. The tap or T tube is then closed to the outside,
and the reading of the burette (which should be graduated to .05 cc, and
read to .01 cc.) taken after careful leveling, as soon as the temperature
has become constant, as shown by the constancy of the reading. Mean-
while the water gauge (which has a bore of about 2 mm.) attached to the
temperature and pressure-control tube is accurately adjusted to a defi-
nite mark. This is easily accomplished by sliding the rubber backwards
or forwards on the narrow glass tube D. The control tube is an ordinary
test tube containing some mercury to sink it.
As soon as the reading of the burette is constant, the bottle is tilted so
as to upset B, and is shaken as long as the gas is evolved. During this
operation B should be repeatedly emptied, as otherwise the oxygen dis-
solved in its liquid might not be completely given off. When the evolution
of gas has ceased, the bottle is replaced in the water. If, as is probable,
the very sensitive pressure gauge indicates an alteration in the tempera-
ture of the water, cold water from a tap, or else warmed water, is added
till the original temperature has been reestablished, and the reading of
the burette noted as soon as it is constant. The bottle is again shaken,
etc., to make sure that the result is constant ; and usually about fifteen
minutes will be needed to complete the operations. The temperature of
the water in the jacket of the burette^ and the reading of the barometer
are now taken, and the oxygen evolved is reduced to its dry volume at 0°
and 760 mm. A table can be used for the reduction, and one is given in
Methods of Air Analysis.
* The jacketing of the burette may be omitted, in which case the thermometer
should be suspended with its bulb close to the upper part of the burette.
RESPIRATION 403
To calculate the oxygen evolved from 100 cc. of blood, allowance must
be made for the fact that a 20 cc. pipette does not deliver 20 cc. of blood,
but only about 19.6 cc. The actual amount of shortage can easily be
determined by weighing. A further slight correction is needed on ac-
count of the fact that the air in the bottle at the end of the operation is
richer in oxygen than at the beginning, so that, as oxygen is about a
third more soluble than air, slightly more gas will be in solution. With a
bottle of 120 cc. capacity and 20 per cent of oxygen in the blood, the air
in the bottle will evidently contain about 26 per cent of oxygen, so that,
assuming that the coefficients of absorption of oxygen and nitrogen in
the 54 cc. of liquid in the bottle are nearly the same as in water, the
correction will amount at 15° to .03 cc. in the reading of the burette, if
the oxygen capacity is normal, or 0.75 per cent of the oxygen given off.
In order to make quite sure that no oxyhaemoglobin remains in the
solution owing to a reshrinkage of corpuscles on adding the ferricyanide,
and consequent escape of some of the oxyhaemoglobin from the action
of the ferricyanide, the liquid in the bottle can afterwards be examined
as follows. Part of it is diluted with 0.8 per cent salt solution, shaken up
in a test tube with expired air so as to render the solution just acid, and
examined spectroscopically. Any trace of oxyhaemoglobin left in incom-
pletely laked corpuscles is shown by the presence of the characteristic
absorption bands. These are completely absent if only methaemoglobin
is present, as ought to be the case. If they are present the result will be
too low, and the experiment must be repeated with saponin added.
If the blood is saturated with CO instead of oxygen the reaction is
slower, but gives precisely the same result. The correction for physically
dissolved gas is, however, scarcely appreciable, as CO is very little more
soluble than air. If the blood has begun to decompose, owing to bacterial
action, the result will of course be too low, and this can easily be detected,
because of the fact that each successive reading of the burette will be
lower, owing to the disappearance of oxygen.* There is no appreciable
error, owing to the tension of ammonia vapor in the air ; and the method
is one of extreme accuracy and certainty. Different determinations ought
not to differ by more than i /200th of the quantity measured. On com-
paring the results with those from the pump, after allowance in the case
of the pump for oxygen in simple solution in the blood, or adhering to
* Under certain abnormal conditions even fresh mammalian blood, as Douglas
iJourn. of Physiol., p. 453, 1910) has shown, may in presence of the ferricyanide
absorb an appreciable amount of oxygen before a determination is complete : in
which case the quicker method described below is greatly preferable. An appreciable
absorption can also be detected in normal fresh human blood left for an hour or
two in the apparatus.
404 RESPIRATION
the glass in the pump, I obtained the following results, using a large-
sized Bohr pump with every precaution.
VOLUMES OF OXYGEN PER
100 VOLUMES
OF BLOOD
By blood
■pumf
By ferricyanicie
method
Defibrinated ox blood
24.38
-
24.43
24.3 s
Oxalated
20.36
20.47
20.57
22.20
Oxalated
22.40
Average
[22.33
22.38
22.39
B. Determination of Oxygen Capacity of Blood Haemoglobin
by Haemoglobinometer
Colorimetric methods of estimating the relative concentrations of
haemoglobin in blood have been used for long; and in 1878 the late
Sir William Gowers introduced his well-known and extremely con-
venient "haemoglobinometer" for clinical purposes.^ In this apparatus
there are two tubes A and B (Figure 102) of equal diameter; A is
sealed and contains picrocarmine jelly of such strength and composition
that when 20 cubic millimeters of normal human blood are diluted with
water in the tube B to the mark 100, the tints of the liquid in the two
tubes are the same. If the blood contains abnormally little or much
haemoglobin, the quantity of water required to produce the tint of the
standard picrocarmine solution will be correspondingly less or more,
so that the percentage of the normal proportion of haemoglobin can be
read off on the tube. The diameter of the tubes and strength of the
picrocarmine or haemoglobin solution are so chosen that any variation
from the normal strength can be perceived with the maximum of readi-
ness. A solution much stronger or weaker would not be suitable. The
design is thus not only extremely convenient, but also thoroughly cor-
rect in principle.
When it was discovered that the coloring power and oxygen capacity
of haemoglobin are strictly proportional to one another it became evident
•Gowers, Trans. Clinical Soc, XII, p. 64, 1878.
RESPIRATION
405
that the Gowers haemoglobinometer could be made a very exact instru-
ment for determining the oxygen capacity of blood, and could also be
improved in other respects. I introduced the necessary improvements in
1901.^ For the picrocarmine solution there is substituted a i per cent
solution of blood with an oxygen capacity of 18.5 cc. per 100 cc. of blood,
since the average of a number of normal men showed that this is the
average oxygen capacity for men. To make this solution keep its coloring
Figure 102.
Gowers-Haldane Haemoglobinometer
A — Glass tube containing blood solution of standard tint.
B — Graduated tube.
C — Rubber stand for tubes A and B.
D — Capillary pipette and suction tube ; wires for cleaning
the pipette are supplied.
E — Bottle with pipette stopper.
F — Glass tube holding 6 lancets.
G — Tube and cap for fixing over ordinary gas burners.
power it is saturated with CO, and sealed up with only CO, and no oxy-
gen, in the empty space above the blood solution. Hoppe Seyler had
already found that a strong solution of CO haemoglobin retains its
coloring power. This is also true for a dilute solution ; and the standard
haemoglobinometer tubes filled and sealed twenty years ago have re-
mained absolutely unaltered in color.
" Haldane, Journ. of Physiol., XXVI, p. 497, 1901. The instrument is made
by Hawksley, Wigmore Street, London, W.
406 RESPIRATION
One defect of the picrocarmine tubes arose from the fact that the picro-
carmine is not completely stable, so that after a time its color alters. But
even the original standard was somewhat indefinite, depending as it
did on the particular percentage of haemoglobin in the sample of normal
blood with which it was standardized. Another defect depended on the
fact that the colors of the blood and picrocarmine solution are not the
same spectrally. In consequence of this a color match with one quality
of light is no longer a match with a different quality of light. Thus in
ordinary artificial light the reading of the instrument is quite different
from that in average daylight ; and in different qualities of daylight, and
with different observers, the match differs. The same defect exists in
various later forms of haemoglobinometer, where colored glass or colored
paper is used as a standard. By using CO haemoglobin as the standard
solution, and saturating the blood under examination with CO or coal
gas these defects are avoided.
To avoid errors due to inequality in the diameters of the tubes, each
tube has first of all two marks placed on it — ^the first at the level when
.2 cc. of water are introduced into a dry tube, and the second at the
level given by 2 cc. The distance between these two marks must corre-
spond exactly in the standard tube and measuring tube and this must be
borne in mind if either tube gets broken and has to be replaced. The
20 cubic millimeter pipette is also standardized by weighing on a deli-
cate balance.
To make a determination, some water is first introduced into the
measuring tube. Twenty cmm. of blood from a prick in the finger or
ear are then measured into this water from the dry pipette. The blood
sinks, and the pipette is rinsed out with some of the water standing above
the blood. Some coal gas or CO is then run into the upper part of the
measuring tube through narrow rubber or glass tubing, and the top of
the tube promptly closed with the finger. With the thumb of the same
hand on the lower end of the tube the latter is then inverted several
times so as to saturate the haemoglobin completely with CO, but without
warming the contents of the tube. The finger can then be slid off the
open end of the tube without the slightest loss of liquid. More water
is now added by means of the dropping pipette until the tints appear
equal. When this point is reached the level is read off after a short inter-
val to allow liquid to run down. Another drop is introduced, and then
another, until the tints appear unequal again; and the mean of the
readings giving equality is taken as showing the required percentage.
This indicates the oxygen capacity of the haemoglobin in percentages of
18.5 cc. of oxygen capacity per 100 cc. of blood.
In judging of equality in tint the tubes are held up before a window
RESPIRATION 407
or an opal shade covering a gas flame or electric lamp. At every observa-
tion the tubes are transposed. This is essential since it will be found
that in all probability the tint of one tube will appear deeper when it is
held on one side than when on the opposite side. If, for instance, the
tubes are nearly equal in depth of color they will appear equal when one
tube is on the right or left side, but not vice versa. A slight inequality
of this kind is rather a help to accuracy, as probably only one reading
will give equality on both sides. With careful work any error in a de-
termination should not exceed 0.5 per cent. The method is thus one of
great accuracy.
It is often loosely assumed that colorimetric estimations are uncertain.
This is certainly not the case if they are properly carried out, with ap-
preciation of the precautions needed to avoid the errors referred to
above, of physiological origin. Another common misconception is that a
uniform colored surface is necessary, and that, as a tube does not give
this, a method such as that just described must be inaccurate. The
surfaces need not be uniform, provided they are similar to one another,
as in the case of two similar tubes.
The correctness of a Gowers-Haldane haemoglobinometer can be
checked at any time by the ferricyanide method described under A or
C. Another check on the correctness of the standard solution is that it
must have practically the same pink tint as fresh blood saturated with
CO. If there has been any defect in filling, the standard tube will appear
yellower. With a proper standard tube one can tell at once by the
absence or presence of yellow color whether a patient's blood is free from
methaemoglobin or other abnormal blood pigments.
For ordinary clinical work it is convenient to work ordinarily with a
picrocarmine standard tube, and only occasionally ascertain the correc-
tion necessary with this standard. The correction can easily be made by
comparing the results for the same person and time with the two tubes.
C. Determination of Oxygen and Carbon Dioxide in Blood by
Ferricyanide and Acid
As mentioned in Chapter IV, a method, based on the use of ferri-
cyanide, was described in a paper by Mr. Barcroft and myself in 1902.'^
The principle of this method is that, without permitting any previous
contact of the blood with air, the oxygen of a small measured volume of
blood is liberated by ferricyanide in a closed vessel, and the pressure
produced by the liberation measured without any alteration being allowed
in the volume of gas in the vessel. The CO2 is then similarly liberated by
^ Barcroft and Haldane, Journ. of Physiol., XXVIII, p. 232, 1902.
408 RESPIRATION
acid, and its pressure measured. When certain corrections are made,
is then possible to estimate either the total oxygen and total CO2, or the
combined oxygen and combined CO2 in the blood. The gas is measured
by the increase of pressure at constant volume, and not by the increase
of volume at constant pressure. Theoretically, either method is correct,
in accordance with Boyle's Law ; but as Barcroft required a method for
dealing with very small quantities of blood, and a very delicate pressure-
gauge was needed in any case, it seemed simpler to graduate the pres-
sure gauge in millimeters, and keep the gas at constant volume, retain-
ing, however, the control vessel, as in the original form of apparatus.
I therefore designed the apparatus as it was originally figured in our
paper, and the tests we made gave very satisfactory results so far as
they went.
One defect of the apparatus described in the previous section is that
a considerable time is needed to reach temperature equilibrium and to
shake out all the extra free oxygen from the blood solution. The latter
defect would apply still more to an apparatus in which CO2 had to be
shaken out. In the new apparatus the volume of liquid was therefore
greatly diminished, and the relative volume of air to blood solution
greatly increased; and this was also rendered advisable owing to the
fact that nearly as much CO2 remains in solution in the liquid as is
present in an equal volume of air. The increased volume of air had,
however, the disadvantages, first that the pressure of ammonia in the
air introduced an appreciable source of error, and secondly that much
more care was needed as to temperature equilibrium in the blood vessel
and control vessel. A further source of error was slight variation in
capillarity at different levels in the gauges of the blood vessel and
control vessel. In spite of all improvements in this apparatus and the
methods of using it, there appears to be a range of error with it of at
least 2 per cent of the quantity measured, even when the error due to
ammonia vapor is completely eliminated.
The apparatus was rendered much more convenient, though also less
easy to make or repair, by Brodie.^ It was also simplified by Barcroft;
who named his modification the "differential" apparatus.^ Barcroft con-
nects the gauges of the blood vessel and control vessel, so that there is
only one manometer instead of two, and estimates the gas given off from
the readings of this compound gauge. With this construction the ap-
paratus works at neither constant volume nor constant pressure, so that
the gas given off cannot be correctly deduced from the mere readings of
the gauges. He therefore calibrates the apparatus empirically with the
'Brodie, Journ. of Physiol., XXXIX, p. 391, 1910.
' Described fully in Barcroft's book, The Respiratory Functions of the Blood.
i
RESPIRATION
409
help of the oxygen liberated from a titrated solution of hydrogen perox-
ide. But this is a rather serious complication, and even if the calibration is
correctly made it can only apply correctly at a certain barometric pressure
and would not be quite valid over the variations of barometric pressure
ordinarily met with. I cannot, therefore, regard this plan as satisfactory
for some kinds of exact work. On the other hand this objection
does not apply where the empirical calibration is not needed, as in
determinations of the percentage saturation of haemoglobin with oxy-
gen— for instance in investigating dissociation curves of oxyhaemo-
globin. Barcroft has also devised a small model, for which only o.i cc.
of blood is required.
A very different form of the ferricyanide method has recently been
introduced by Yandell Henderson and Smith.^^^ The blood (i cc.) is
introduced (under ammonia solution without contact with air, just as
in the Barcroft-Haldane method) into the bottom of a diffusion tube
of about 12 cc. capacity. This tube is provided with a 3-way tap at the
bottom end and a thin rubber stopper at the top, and is graduated for a
short distance from the top. A fine hypodermic needle is then thrust
through the rubber to equalize the pressure inside and outside of the
tube, the needle withdrawn, and the blood and ammonia solution mixed
so as to lake the blood. Ferricyanide solution is then injected through the
stopper, and the tube rotated for five minutes so that the whole excess
of free oxygen diffuses out into the air of the tube. The tube is then
inverted and the stopper removed under water so that the pressure inside
and outside the tube is equalized. The volume of gas in the tube is read
off ; and finally nearly the whole of this gas is drawn into a Haldane gas-
analysis apparatus, and the oxygen percentage determined. From the
increased oxygen percentage of this gas as compared with air, and the
volume of gas in the tube, the oxygen given off by the blood can easily
be calculated. The CO2 in the blood is estimated similarly; and both
oxygen and CO2 can be estimated in the same sample of blood. This
method seems to be about as accurate as the Barcroft-Haldane method,
and to be easier for those familiar with accurate gas analysis. It appears
to be specially suitable for comparisons of the arterial and venous blood
in animals ; and evidently any CO in blood can be estimated conveniently
by this method, which also has the advantage that corrections for physical
solution of gases are greatly reduced.
Still another method is to use the Van Slyke vacuum apparatus in
connection with ferricyanide. ^^ This, however, involves the various
"Yandell Henderson and Smith, Journ. of Biol. Chem., XXXIII, p. 39, 19 18.
"Van Slyke, Journ. of Biol. Chem., XXX, p. 347, 1917 ; and XXXIII, p. 127.
1918.
410 RESPIRATION
sources of error connected with the use of a vacuum pump, or necessitates
analysis of the gas obtained from the blood.
Until recently we have used at Oxford the Brodie modification of the
Barcroft-Haldane apparatus. As, however, the range of error with this
apparatus has been about 2 per cent, I have quite recently devised a
new apparatus, with a view especially to more accurate determinations
of the oxygen in human arterial blood, and of dissociation curves. ^2
With this apparatus it is possible to reach an accuracy as great as with
the original ferricyanide apparatus — i.e., to within 0.5 per cent of the
oxygen capacity of the blood. This new apparatus will therefore be de-
scribed in full. On account of the present difficulty and expense in getting
glass apparatus made, it was designed so that it could if necessary be
put together in a laboratory from easily obtainable parts, just as in the
case of the original apparatus.
When blood from a blood vessel is used, a glass syringe with solid
glass piston is employed for obtaining the sample. This method was first
applied to human arteries by Hiirter, and developed by Stadie and others.
Professor Meakins, with whom I have been associated in work on human
blood gases, employs the following procedure. A very small quantity of
finely powdered potassium oxalate is introduced into the bottom of the
syringe. The piston is then introduced and a little liquid paraffin drawn
in, and as much as possible expelled again with the syringe pointing
upwards so as not to expel the oxalate. After disinfection of the skin the
needle (previously sterilized) is introduced into the radial artery or other
vessel, and about 5 cc. or more of blood withdrawn, a compress and
bandage being afterwards applied over the place for an hour if the
vessel was an artery. The needle is then removed and washed, and the
blood transferred (with the syringe pointing upwards) through a rubber
connection into a graduated pipette holding more than 2 cc. From this
pipette an exactly measured quantity of about 2 cc. is introduced beneath
the sodium carbonate or ammonia solution in the blood-gas flask. At the
end of the operation about 0.5 cc. remains in the pipette, so that none
of the blood has come in contact with air.
The apparatus is shown in Figure 103. In principle it is similar to that
shown in Figure loi, but designed for small quantities of blood and for
determining COg. The blood is received in one of the small flasks shown,
while the other is for temperature control. Each has a capacity of about
20 cc. The procedure differs according as it is desired to determine the
oxygen or the CO2 of the blood. In the former case the first step is to
measure 2 cc. of a i per cent solution of dried sodium carbonate into
one of the two small flasks (about 20 cc. capacity) shown and add a
" Haldane, Journ. of Pathol, and BacterioL, XXIII, p. 443, 1920.
RESPIRATION
411
small quantity of saponin on the point of a penknife. Exactly 2 cc, or at
any rate an exactly determined volume, of the blood is then measured
out from the pipette into the flask beneath the sodium carbonate solution.
The flask is then firmly corked and completely immersed beyond the
cork in the bath alongside the other (control) flask until the temperature
Figure 103.
Apparatus for blood-gas analysis.
of the air in the flask becomes completely steady. The flasks are con-
nected, as shown, by means of thick-walled rubber tubing of about 2 mm.
bore with the two gauges and gas burette fixed on the wooden stand. The
glass connections, taps, and gauges are also of 2 mm. bore, and so ar-
ranged that the connections of the two flasks are of equal volume. The
burette itself consists of an ordinary i cc. dropping pipette divided to
.01 cc, and therefore capable of being read to .002 cc. The correctness
of the graduation can easily be tested by weighing the water delivered by
it. The taps are at first left open to air, but are turned after a few
minutes so that the flasks communicate only with the gauges and burette ;
and the leveling tubes are previously adjusted so that the gauge levels
412 RESPIRATION
are at the zero marks and the burette level is at a convenient distance
below zero. The gauges are then carefully observed, and the water in
the bath is occasionally stirred by blowing air through it. It will be
found that when both the gauges are exactly adjusted they do not keep
even when left to themselves until at least ten minutes after the blood
flask has been placed in the bath. The alterations are compensated by
means of the leveling tubes; and when the gauges have come steady,
or only move together, the burette is read off exactly. The confining
liquid is distilled water containing a small quantity of bile-salts which
make the readings more certain and sensitive.
The blood flask is now agitated for two or three minutes in order
that the blood may take up all the gas it is capable of taking. At the
same time it is laked by the saponin. In the process of agitation the flask
is never removed from the bath. It is held by the neck with forceps or
something else interposed to shield it from the warmth of the fingers.
The gauges are now again adjusted, and, after they are quite steady,
which should be the case almost at once, the burette is again read off. The
difference between the two readings gives the gas absorbed by the blood
from the air. From this we can calculate the volume of oxygen absorbed
by the haemoglobin.
The first step in the calculation is to reduce the gas absorbed to its
dry volume at o° and 760 mm. and calculate its volume per 100 cc. of
blood. For this purpose the barometer is read and the temperature given
by a thermometer (not shown in the figure) fixed on the front of the
stand, with the bulb close to the upper part of the burette. It is evident
that what is required is not the temperature of the bath or connections,
but that of the burette. The reduction is easily made with the help of a
table with factors for correction, such as that at page 60 (second edi-
tion) of my book on Methods of Air Analysis.
We have now to calculate how much of the gas absorbed has simply
gone into physical solution. Blood in the living body is saturated with
nitrogen at the partial pressure of the nitrogen in the alveolar air.
Allowing for the aqueous vapor present, this partial pressure is about
75 per cent of the existing atmospheric pressure. The coefficient of ab-
sorption of nitrogen in blood at 38° C is .011, according to Bohr's de-
termination. Hence at ordinary atmospheric pressure there will be .83 cc.
of nitrogen (at 0° and 760 mm.) in solution in 100 cc. of blood. The
blood in the flask will become saturated at about 15° with nitrogen at a
partial pressure of about 78 per cent of an atmosphere ; and, as the co-
efficient of absorption is .016, about 1.25 cc. of nitrogen will be in
solution per 100 cc. of blood saturated with air at 15°. Thus 100 cc. of
blood will take up .42 cc. of extra nitrogen on saturation.
RESPIRATION 413
To calculate how much extra oxygen the blood will take up in simple
solution, we must know the partial pressure of oxygen at which the blood
taken from the living body is saturated, and this can be deduced pretty
accurately from the percentage saturation of the haemoglobin and the
dissociation curve of oxyhaemoglobin in human blood. Now it was found
by Meakins and Davies^^ that the haemoglobin of normal human arterial
blood is about 95 per cent saturated, which corresponds to an oxygen
pressure of 11 per cent of an atmosphere, or 84 mm. The coefficient of
absorption of oxygen in blood at 38° is .022. Hence there will be .24 cc.
of oxygen in simple solution in 100 cc. of arterial blood. At 15° the co-
efficient of absorption is .031 and at ordinary atmospheric pressures the
partial pressure of oxygen in the bottle will be 20.5 per cent of an
atmosphere. Hence .63 cc. of oxygen will be in solution in 100 cc. of
blood saturated with air at 15°, and the extra oxygen taken up in solu-
tion will be .39 cc. Thus the total extra gas taken up in solution will be
.42 + .39 = .81 cc. in 100 cc. of blood, and only the balance of the
proportion actually taken up in the blood flask will go to saturate the
haemoglobin. Hence if the temperature of the water bath is 15° the
allowance for gas in simple solution will be .81 cc.
If the bath is above or below 15° this allowance will be a little less or
greater, and a calculation shows that for each degree above or below 15°,
between the temperatures of 20° and 10°, the allowance will have to be
diminished or increased by .038 cc.
An example will make the calculation of the percentage saturation of
the haemoglobin clear. Let us suppose that 2.15 cc. of arterial blood have
been delivered into the flask and the constant reading of the burette
after temperature equilibrium had been obtained was .072 cc, and after
agitating the blood .030. Thus 0.042 cc. of gas had been absorbed from
2.15 cc. of blood, or 1.95 cc. from 100 cc. The temperature was 14° and
the barometer 755 mm. Hence the factor for reduction to dry gas at 0°
and 760 mm. was 0.930. Therefore the dry gas at standard pressure and
temperature was 1.81 cc. The temperature of the bath was 13°. Hence
.81 + .08 = .89 cc. went into physical solution, so that 0.92 cc. of oxygen
was absorbed by the haemoglobin.
To determine the percentage saturation of the haemoglobin it is
necessary to know the total oxygen capacity of the haemoglobin ; and this
can now be determined directly. To the tube passing through the stopper
of the blood flask there is attached a loop of wire into which a small
tube of thin glass can be inserted. In the tube is placed .25 cc. of satu-
rated ferricyanide solution and the flask closed and reinserted in the
water bath till temperature equilibrium is reached. The burette is again
"Meakins and Davies, Journ. of Pathol, and Bacter., XXIII, p. 451, 1920.
414 RESPIRATION
read off, and the flask turned up so as to let the ferricyanide flow into
the blood solution. Before doing this, however, the blood solution should
be observed to make sure that it is perfectly laked and transparent;
otherwise more saponin must be added. The flask is now agitated as
long as gas continues to come off as shown by the movements of the
gauge. This will take three or four minutes. The burette is again read
off, which gives the volume of oxygen given off. This is reduced to dry
volume at 0° and 760 mm. and per 100 cc. of blood.
Let us suppose that the oxygen capacity of the haemoglobin in the
above example was 17.4 cc. per 100 cc. of blood. The percentage satura-
tion of the haemoglobin in the arterial blood was therefore
17.40 — .92
100 X z=: 94.7.
17.40
It is easier to determine the oxygen capacity by means of a Gowers-
Haldane haemoglobinometer, in which 100 per cent corresponds
to an oxygen capacity of 18.5. For this purpose a sample of the
blood drawn from the artery is used for the determination. In the above
example the oxygen capacity of 17.4 corresponds to 94 per cent on the
haemoglobinometer scale, and the range of error in carefully made
haemoglobinometer determinations is only about 0.5 per cent. The ac-
curacy of both mathods is strikingly shown by the fact that in 36 determi-
nations by Meakins and Davies of the oxygen capacity of blood from
patients and healthy persons the maximum difference between the re-
sults by the haemoglobinometer and by the new method was under i per
cent of the oxygen capacity.^*
A haemoglobinometer can, of course, be exactly standardized by the
method just described. If the haemoglobinometer is used, it is unneces-
sary to use saponin or ferricyanide in determining the percentage satura-
tion of the haemoglobin in the sample of blood. The total available
oxygen in the sample of arterial blood is the oxygen combined with
haemoglobin plus the dissolved oxygen. This was, in the above example,
16.48 +.24 1=16.72 cc. per 100 cc. of blood.
If, instead of being normal arterial blood, the sample was venous
blood, or arterial blood of abnormally low saturation with oxygen, the
calculation must be slightly modified, since less oxygen in simple solu-
tion is present in the sample. Thus if the blood turned out to be only
half saturated with oxygen the partial pressure of oxygen in the sample
would only be about 4 per cent of an atmosphere. Hence there would
only be .09 cc. of dissolved oxygen present, instead of .24 cc. This would
increase the correction at 15° for dissolved gas from .81 to .96 cc. — a
difference which, however, affects the result but little. Ordinary varia-
" Meakins and Davies, Journ. of Pathol, and Bacter., XXIII, p. 454. 1920.
RESPIRATION 415
tions of barometric pressure do not sensibly affect the correction, but at
high altitudes the correction must evidently be diminished in the pro-
portion of about 0.1 cc. for every 100 mm. of diminution in atmospheric
pressure.
If the blood is taken, not from the living body, but from a saturating
vessel, the gases dissolved physically must be calculated on the same
principle, allowing for their pressures in the vessel. ^^
The method just described has been tested for accuracy in several
ways. In the first place it has been found that when blood fully saturated
with air at room temperature is placed under the sodium carbonate
solution in the ordinary way and then agitated after the gauges have
become steady, there is no sensible variation in the reading of the burette
afterwards. The constancy of the reading can be relied on to .002 cc.
with careful work. Hence the percentage saturation can be relied on to
0.5 per cent, or the oxygen capacity per 100 cc. of blood to o.i cc, if the
measuring pipettes are properly calibrated. This is as good a result as
could be obtained with 20 cc. of blood by means of the original ferri-
cyanide apparatus. The present method is therefore as exact as the
original one for determining the oxygen capacity of blood, but is quicker
and more convenient. By using sodium carbonate instead of ammonia
solution the errors due to diminution of the vapor pressures of ammonia
and water on mixing the blood with the solution are eliminated, while
the use of saponin, first introduced by C. G. Douglas, produces the laking
of the blood which is necessary in order to allow the ferricyanide to
act on the oxyhaemoglobin. The fact that, as has been found by Meakins
and Davies, haemoglobinometer estimations coincide within i per cent
with the results by this method furnishes further confirmatory evidence.
The new apparatus gives sharper results than the constant volume
method which Barcroft and I described in 1902. This is, I think, partly
due to the larger volume (2 cc.) of blood employed; partly to the fact
that the disturbance due to the use of ammonia solution is avoided and a
sharper index of temperature equilibrium is given by the two gauges
of the present apparatus ; and partly because the gauge levels are always
at the same place, whereas in the constant-volume apparatus the gauge
levels shift to places wide apart, so that small errors due to varying
capillarity of the gauge tubes are apt to tell. It is thus difficult, with the
constant-volume apparatus, to avoid errors within 2 per cent on either
side of the actual percentage saturation.
^^ In the paper by Barcroft and myself where we first described the constant
volume blood-gas apparatus, the correction for gas in simple solution was un-
fortunately given incorrectly; and this doubtless accounts for the somewhat
distorted forms of the dissociation curves of oxyhaemoglobin in Barcroft's earlier
experiments on this subject.
41 6 RESPIRATION
When it is desired to determine the COg content of the blood the
procedure must be modified, as sodium carbonate cannot be used, and
2 cc. of blood would give too much COg for the capacity of the burette,
apart from other causes of error. Therefore only about i cc. of blood
should be taken. This is delivered under 1.5 cc. of a solution of 4 parts
of ordinary strong ammonia solution (sp. gr. .88) to a liter of boiled
distilled water, and a trace of saponin added. To avoid the presence of
any carbonate in the ammonia the strong solution is first shaken up with
some unslaked lime and allowed to settle. The stock of dilute solution
is kept tightly corked. As soon as the ammonia solution is placed in the
flask, the latter is kept tightly corked until the blood is added, otherwise
a considerable amount of CO2 may diffuse in and cause error. The blood
is shaken up to lake it, and .25 cc. of ferricyanide afterwards added to
liberate the oxygen, since if this were not done some oxygen might be
liberated by the acid. After all the liberated oxygen has been shaken off,
the small glass tube containing .25 cc. of 20 per cent solution of tartaric
acid is inserted and the burette read off after the gauges are steady. The
tartaric acid solution is then spilt into the blood solution and the flask
agitated under water till the CO2 has completely ceased to come off, as
shown by the gauge. The burette is then adjusted and read off and the
volume of gas given off reduced to its dry volume at 0° and 760 mm.
and calculated per 100 cc. of blood. Part of the COg however, remains
dissolved in the liquid in the flask, and must be allowed for. This liquid
is exactly the same as in the case of determination of COg by means of
the constant- volume apparatus described by Barcroft and myself, so the
correction is made in a similar manner. At a temperature of 13° the
coefficient of absorption of CO2 in this liquid was found to be i.oo. Hence
if we know the total volume of the flask as compared with the volume
of gas in it when the liquid is also present, and the temperature of the
bath is 13°, the total CO2 liberated from the blood will be to the amount
shown by the burette as the total capacity of the flask to the volume of
gas in it when the liquid is also present. The capacity of the flask to the
cork is about 20 cc. Let us suppose that as determined by weighing with
the cork in place it is 20.5 cc, including the capacity of a piece of glass
tubing of about 4 mm. bore and two inches long which passes through
the cork. The volume of liquid in the flask is 3.0 cc. Hence if the tempera-
ture of the bath is 13° the total volume of CO2 liberated is obtained by
20. tj
multiplying the corrected volume actually read off by — — or adding
175
17 per cent. If the temperature is above or below 13° a fortieth must be
subtracted from or added to this addition, since the solubility of CO2
diminishes by about a fortieth for each degree above 13°, and increases
RESPIRATION 417
similarly for each degree below 13°. The glass tubing passing through
the cork is 4 mm. in bore in order to give room for the COg given ofif
without its coming in contact appreciably with the rubber connecting
tubing. For determining COg in blood it is better to use an ordinary
cork than a rubber stopper in the blood flask, as the rubber leads to a
slow absorption of COg.
A further negative correction is required for any CO2 present in the
solutions used, or absorbed from the air in the flask ; also for the small
error in the opposite direction owing to disappearance of ammonia
vapor from the air of the flask. The joint correction, which ought to be
very small, and may be either positive or negative, can be ascertained
by a blank experiment in which boiled distilled water in place of blood
is used in the flask. Or if the capacities of the two bottles are nearly
equal the blank experiment may be performed in one flask along with the
blood experiment in the other. In this way the correction is eliminated.
As shown by this method by Meakins and Davies, arterial blood gives
slightly more CO2 than defibrinated blood at the same partial pressure
of CO2, as found in the experiments of Christiansen, Douglas, and
myself. ^^
The following example illustrates the mode of calculation. The volume
of CO2 given off from i.oo cc. of human arterial blood was 0.482 cc. as
read from the burette. Reduced to dry gas at 0° and 760, and calcu-
lated per 100 cc. of blood, this was 45.9 cc. The correction at 13° for the
CO2 left in solution was 16.5 per cent, but as the temperature of the bath
was 15° the proper correction was 15.3 per cent. Hence the CO2 con-
tained in 100 cc. of blood was 52.9 cc. A blank control experiment was
made simultaneously in the other flask, so there was no further correction.
In any cases where both the oxygen and CO2 in a sample of blood are
required, it is better and quicker to make the determinations simul-
taneously in two different apparatus.
For the proper working of the apparatus it is essential that all the
joints, including the cork, should be absolutely tight. There is no
difficulty about this if the rubber tubing used is smooth and clean. To
test for tightness the burette should be read after the gauges are steady.
Positive or negative pressure is then produced for some time in the
apparatus by raising or lowering the leveling tubes. On readjusting the
gauges, the reading should be exactly the same as before, if the apparatus
is tight. If a leak exists it can soon be localized by putting pressure on
one part after another of the connections.
The apparatus can be put together without very much trouble, and if
" Christiansen, Douglas, and Haldane, Journ. of Physiol., XLVIII, p, 272,
1914.
41 8 RESPIRATION
three-way taps are not available T tubes may be substituted. Messrs.
Siebe Gorman & Co., 187 Westminster Bridge Road, London S. E.,
supply it.
D. Colorimetric Determination of Percentage Saturation of
Haemoglobin with CO
This very convenient method is used in determining the oxygen pres-
sure of arterial blood, the total haemoglobin in the body, or the blood vol-
ume, as well as for investigations as to the properties of CO haemoglobin
and the phenomena of CO poisoning. It depends on the fact that a dilute
solution of CO haemoglobin has a pink color, quite different from the
yellow color of similarly diluted oxyhaemoglobin.
I originally used this color difference as an easy and delicate means
of recognizing the presence of CO in blood and roughly estimating the
saturation with CO; and I then thought that as it is impossible to
recognize by the difference of tint a difference of less than about 5 per
cent in the percentage saturation of haemoglobin with CO, the method
was at best a rough one. Various recent writers have fallen into the same
error. Further experience showed that with proper precautions the
method gives results of great accuracy. The following description is
taken almost verbatim from the account of the method given in 191 2 by
Douglas and myself in our paper on oxygen secretion. ^"^
A solution of normal human blood (or blood from the animal experi-
mented on) is prepared of such strength as to correspond to about 0.5
per cent of the proportion of haemoglobin in standard human blood of
100 per cent strength by the Gowers-Haldane haemoglobinometer scale.
Two test tubes of equal bore of about 0.6 inch are selected, and into
each of these 5 cc. of the blood solution are measured with a pipette.
From a o.i per cent solution of carmine in ammoniacal distilled water
(this solution being kept in the dark in a cupboard) a dilute solution of
carmine in distilled water with a strength of tint about equal to or rather
greater than that of the blood solution is then prepared in a measuring
cylinder. The requisite amount of dilution (about one-twentieth of the
o.i per cent solution if the latter has been recently prepared) can easily
be estimated by the eye, and can be obtained at once, when experiments
are made daily, by diluting to a definite extent. A burette is filled with
the carmine solution, and another burette with water. The blood solution
in one of the test tubes is then saturated with CO by allowing coal gas to
run through the free part of the test tube, quickly closing the tube with
the thumb, and shaking the blood solution with the gas for a few seconds.
" Douglas and Haldane, Journ. of Physiol., XLIV, p. 305, 19 12.
RESPIRATION 419
When looked at against the sky, the solution will now have a deep
purplish-pink tint, as compared with the brownish yellow of the normal
blood solution. The carmine is now added from the burette to the normal*
blood solution until its tint is about equal in quality to that of the satu-
rated blood solution. It will then probably be found that the depth of
tint is too great in the tube containing the carmine. Water is then added
from the other burette until the depth of tint is equal, and if necessary
more carmine, until complete equality of both tint and depth of color is
obtained. In judging of this, the test tubes should be held up against the
sky, and it is absolutely necessary to change them repeatedly from side
to side ; otherwise gross error is certain. It will nearly always be found
that the right-hand tube appears a little yellower or pinker than the left-
hand one ; and a little deeper or less deep in color. This difference is in
reality a great help to accuracy. A point is first reached when the tubes
appear equal in tint or depth when held in one position, but unequal in
the other, and the end point when the difference is the same on one side,
whichever tube is on that side, can be estimated with great delicacy.
The additions of carmine (or water) are continued until this point is
passed ; and if two successive additions both show equality, the mean of
the two readings is taken as correct.
To the carmine solution in the measuring cylinder a proportion of
water is now added equal to what had to be added from the water
burette to the carmine required to reach the end point of the titration.
The carmine solution is then ready for use. It will probably be found
that about 6 cc. of carmine are needed to reach the end point. The
amount required varies, however, according to the condition of the
strong carmine solution and the quality of the daylight. The carmine
solution is not stable, and it gradually becomes less deep in color, and
redder in tint than when first prepared. Hence the quantity of carmine
solution needed increases from month to month, and the extent to which
it has to be diluted for use diminishes. If the dilute solution is left for a
day or two exposed to light it becomes very markedly redder and more
dilute.
The titration of a blood sample is carried out as follows. One or two
drops of blood are needed, and are at once diluted with water. Half of
the dilute solution is poured into one of the two test tubes (always the
same one as that used for the saturated blood in standardizing the
carmine), and 5 cc. of the normal blood solution are measured with a
pipette into the other. Water is then allowed to drip from a tap into the
solution of the blood under examination until its depth of tint is about
equal to that of the normal solution. Carmine solution is now added to
the normal blood solution from the burette until the tints are equal,
420 RESPIRATION
more water being also added to the other tube if necessary. The solution I
under examination is then saturated with coal gas and the addition to
the normal blood solution of carmine is continued until the tints are
again equal. To illustrate the method of calculating the result we may
suppose that in the first result equality of tint was observed with 1.2 and
1.3 cc. of carmine, mean 1.25, and that in the second 6.4 and 6.8 cc. gave
equality, mean 6.6; the percentage saturation X is then given by the
result of the following proportion sum :
6.6 . 1.25
; 7T * ; ' : 100 : -X"
5 + 6.6 5 + 1.25
or, more simply,
6.25 6.6
100 X X = 35.1 per cent.
1.25 11.6
It is clear that the more carmine has already been added to the
normal blood solution the less effect on its tint will any further addition
have. Hence in approaching the point of equality only o.i cc. is added at
a time if not more than 2 cc. have already been added, whereas after
already adding 6 cc. it is useless to add less than about 0.4 cc. at a time.
The titration is repeated with the other half of the blood solution
for further safety, and it will be found that apart from accidents the
two results will nearly always agree within i per cent of the total satu-
ration. This accuracy is very surprising at first sight, since colorimetric
determinations have in general a rather bad reputation among chemists.
The carmine titration is also no ordinary colorimetric titration, but one
in which the quality, and not the density, of tint is estimated. We believe
that the bad results commonly obtained with "colorimeters" are due to
the two solutions being in some fixed position determined by the apparatus
used. An error of 10 per cent or more may easily occur from this cause.
Far more accurate results can be obtained with two ordinary test tubes
repeatedly transposed, as above described, than with complicated and
expensive colorimeters.
It will be found that the amount of carmine giving equality varies dis-
tinctly for different individuals. The proportional difference is, however,
the same at the two stages of the titration, so that the percentage result
obtained is the same. For the same individual the amount of carmine
needed varies, also, with different qualities of daylight, and is usually
less towards evening. This does not affect the percentage result, however,
provided that the two stages of the titration are completed by the same
light.
All these differences are due to the facts that the two solutions are
not spectrally identical; nor is the daylight at different times of day;
nor are the retinae of different persons equally sensitive to differences
RESPIRATION
421
in any particular part of the spectrum; nor, finally, is any part of the
retina of one individual constant in its excitability for either white
light or colored light; the excitability of any one part being dependent
on side light falling on neighboring parts of the retina. The numerous
colorimeters, haemoglobinometers, etc., in which these sources of error
cannot be eliminated, are liable to very gross error, and appear to be
responsible for the discredit under which colorimetric methods suffer.
With ordinary artificial light the differences in tint between the various
solutions become almost invisible. The dimmest daylight is better than
ordinary artificial light. With blue spectacles, however, the differences
become very evident, and fairly good results can be obtained in the
titration if the carmine is made of the proper strength (very much
stronger) to suit the light. Daylight is, however, far better.
It is essential to accuracy with the carmine method that the carmine
solution should accurately match the standard blood solution in defth of
color. If the two do not correspond, it is easy enough to get a result:
for when the solution in one test tube is too deep in color it is only
necessary to incline the other in order to make its depth of tint appear
equal. The calculation of the percentage saturation becomes fallacious,
however, as is easily seen. One source of slight error in the titrations is
that a carmine solution which, when made up, exactly matches the blood
solution in depth, may, towards evening, be rather too strong, owing to
change in the light. This change can, however, be detected and rectified
very quickly, and attention would automatically be called to it by the
fact that considerably less carmine than before would suffice to produce
the tint of fully saturated blood solution.
A further source of possible fallacy depends on the liability of blood
solution to decomposition. It is essential that the blood should be fresh,
and diluted with clean water in a perfectly clean vessel. Solution which
has been kept more than a few hours is useless. It may show no methae-
moglobin band, and appear to be unaltered; but on saturating it with
CO it will probably no longer give the full pink color of undecomposed
haemoglobin, and its depth of color will also be found to be less than
before. It is thus mixed with colored decomposition products which make
it useless for titration. The tint on saturation with CO affords a far more
delicate index than spectroscopic examination of the freedom of a blood
solution from pigments other than haemoglobin.
When blood saturated, or partly saturated, with CO is diluted with
water, a small part of the CO must necessarily go into solution in the
water, as some dissociation of the CO haemoglobin occurs. To demon-
strate this it is only necessary to saturate some blood with coal gas and
dilute some of it to 0.5 per cent with water. It will be seen at once that
422 RESPIRATION
the diluted blood is distinctly less pink than some of the same solution re-
saturated with coal gas ; and on titration the blood which has been simply
diluted will be found to be not more than 88 or 89 per cent saturated.
The percentage dissociation can be calculated if we know the partial
pressure of CO corresponding to various percentage saturations of the
haemoglobin at room temperature, and also the coefficient of solubility
of CO.
In the case of human blood, half-saturation occurs at room tempera-
ture in presence of air with about .05 per cent of CO. Hence with 50 per
cent saturation of a blood solution saturated with air the partial pressure
of CO will be .05 per cent of an atmosphere. Now 100 cc. of water (and
presumably also of a very dilute blood solution) dissolves about 2.5 cc.
of CO from an atmosphere of pure CO at room temperature (i5°C.), so
that at a partial pressure of .05 per cent it will dissolve 2.5 x .0005 =
.00125 cc. of CO, whereas 100 cc. of 0.5 per cent blood solution can take
up in chemical combination .0925 cc. of CO. Hence the proportion of the
haemoglobin dissociated is .00125 in .0925, or 1.35 per cent, so that if
50 per cent saturation were found by titration to be present we should
require to add 1.35 per cent to obtain the true result. By a similar
calculation we find that if the blood were found by titration to be 89
per cent saturated, we should have to add on 11 per cent in order to
obtain the true result, which would thus be 100 per cent. When human
blood is fully saturated with coal gas, the result actually found by titra-
tion, after dilution of the blood to 0.5 per cent, is 89 per cent, provided
the light is not bright. Hence the calculation agrees with the actual result.
In the brighter light of the middle of the day the result is, however, 2 or
3 per cent lower, even with a north light ; and on going outside so as to
increase the light, and avoid the absorption of actinic rays by window
glass, the result is still lower. This effect is due, as was pointed out by
Haldane and Lorrain Smith, to the action of actinic rays in dissociating
CO haemoglobin. The varying effect of light renders the carmine titration
with very high saturations of the blood with CO somewhat uncertain.
With low saturations, such as we have usually worked with, any error due
to this cause is trifling. We have at all times avoided bright light as far
as possible, and where it was necessary, as in the case of dissociation
curves, to titrate with high saturations of the blood, up to 80 or even
85 per cent, we have done the titrations by evening light. As an alterna-
tive, we might have used narrower test tubes and a greater concentration
of the blood solution, so as to diminish the correction for dissociation ;
but it is easier to judge the tints accurately when ordinary test tubes are
employed, and comparatively few determinations were needed with very
high saturations.
I
RESPIRATION 433
The following scalfe of corrections was used for human blood.
Observed percentage
saturation
Correction
added,
10 percent
0.15
20
30
0.35
0.6
40
0.9
50
60
1.35
2.0
70
80
89
3.1
5.4
II.O
For mouse blood the corrections used were 50 per cent higher, since
the partial pressure of CO required to produce a given saturation of the
blood with CO is about 50 per cent higher for mice than for men.
As already mentioned, the results of duplicate or triplicate titrations
of the same sample of blood agree very closely, the variation in the per-
centage saturation found hardly exceeding i per cent or 0.5 per cent
from the mean. When, as in determinations of arterial oxygen pressure,
two samples not differing much in percentage saturation are compared
successively with the same standard blood solution, the difference in their
percentage saturations with CO can be determined with corresponding
accuracy; for any errors due to imperfect preparation of the standard
solutions, or to the allowance for dissociation, will affect both results
equally. To determine the absolute range of the latter errors we made a
number of analyses of definite mixtures of normal blood with the same
blood saturated with coal gas. The coal gas contained about 7 per cent
of CO, and allowance was made for the small amount of CO present in
simple solution in the saturated blood.
The ox blood used for these mixtures was measured out from a pipette,
the blood being kept constantly stirred to prevent sedimentation of the
corpuscles. This method, though fairly accurate, is liable to slight
errors on account of variations in the quantity of blood which is left
adhering to the pipette. The following percentage saturations were ob-
tained on different occasions. The same carmine solution was used by
both observers.
In series (2) and (3) the mixtures were made with blood laked by
dilution to half, and were unknown to the observer. In (i) and (4) the
mixtures were made with whole blood, and were known to one observer.
In (4) each observer made up his own carmine solution.
424
RESPIRATION
It will be seen that the maximum error was 2.0 per cent, this including
any error in making the blood mixtures and standardizing the carmine
solutions. With double determinations the error was considerably less.
Found
( I ) Calculated
Found
(3) <
Calculated
(C. G. D.)
33.7
(33.9 (J. S. H.)
20.3
20.9
(34.0 (C. G. D.)
33-9
50.8
32.1
49.2
(76.0 (J. S. H.)
67.7
68.1
75.8
(76.8 (C.G.D.)
(75.2 (J. S. H.)
(4)
Found 1
(2) Calculated
Found (/. S. H.) Calculated
{C.G.D.-)
U.S.H.) .
25.4 .
26.8
II.2
10.3
11.4
33-9
338
25.2
26.0
27.1
50.8
52.3
50.5
51.9
52.5
^7^7
68.3
80.8
79-9
81.4
E. Determination of Blood Volume in Man during Life by CO
Since CO is not oxidized or otherwise destroyed in the living body,
and since it forms a relatively very stable molecular compound with
haemoglobin, but with no other substance in the body, it is evident that
if we administer to an animal a known amount of CO, and then de-
termine the percentage saturation of the haemoglobin with CO and the
total CO capacity of a given volume of blood, we can determine the CO
capacity of the total blood in the body, and hence deduce also the blood
volume. The blood volume during life was first determined in this way
by Grehant and Quinquaud,^^ who used dogs for the purpose and em-
ployed the blood pump for the blood-gas analyses. In 1900 Lorrain
Smith and I introduced a much simpler method, easily applicable to
man;i^ and this method has been extensively used for physiological,
clinical, and pathological work, as mentioned in Chapter X.
The apparatus required for administering the CO to a man is shown
diagramatically in Figure 104. The subject breathes through a glass
mouthpiece A, the nose being clipped or held. The mouthpiece communi-
cates by ^-inch rubber tubing with a bladder or india-rubber bag B of
"Grehant and Quinquaud, Journ. de I'anat. et de la physiol., p. 564, 1882.
" Haldane and Lorrain Smith, Journ. of Physiol., XXV, p. 331, 1900.
RESPIRATION
425
at least 2 liters capacity. Between the bag and mouthpiece there is inter-
posed a cylindrical metal vessel containing moist granulated soda lime
or other suitable absorbent to absorb COg. The end of this vessel may be
made to screw on and off, with an air-tight rubber washer; or may be
made in two pieces, the outer of which slides over the inner, as shown
in the figure, the junction being made air tight with plasticine. The soda
Figure 104.
Apparatus for determining blood volume in man.
lime is kept in position by two circular pieces of wire gauze, one of which
is pushed into the end of the inner vessel, and the other into the end of
the outer vessel. Good soda lime can be made by stirring fresh slaked
lime in powder with a strong solution of caustic soda till the mixture
granulates, and then sifting off the fine powder and coarse lumps by
means of two sieves. Granulated caustic soda will also answer. There
should be no appreciable resistance to breathing, and one tin of soda
lime should last for several experiments. When the soda lime is spent it
ceases to heat, and the breathing begins to become increased, owing to
un absorbed CO 2.
The narrow graduated cylinder D is filled under water with CO, of
which a stock, prepared from formic and pure sulphuric acids, can be
kept in a large bottle. Just before the experiment, some of the CO is, by
turning the water tap E, driven out through the test tube and 3-way tap
F to the outside. In this way all the air is expelled up to the 3-way tap.
The water tap is then closed, and afterwards the 3-way tap. Oxygen from
a steel cylinder is now turned on through the tube C to displace CO
426 RESPIRATION
from the tubing, which is then connected with the bag as shown in the
figure, and the bag filled pretty full with oxygen. Meanwhile the height
of the water in the cylinder is accurately read off, and the temperature
of the cylinder and barometric pressure noted.
The subject of the experiment now begins to breathe from the bag,
oxygen being supplied as required. The water tap is now slightly
opened, and the tap F turned so as to let CO as well as oxygen pass. The
required volume of CO is in this way very gradually driven in from the
measuring cylinder, about 20 cc. being passed in per minute. After the
CO has been passed in, the water tap is turned off, and the 3 -way tap
turned so as to shut off the CO. The CO is absorbed from the bag very
rapidly and completely. The oxygen supply is continued for at least ten
minutes, after which the subject is allowed to absorb most of the oxygen
in the bag. About 15 minutes after the last of the CO has been given, a
drop or two of blood is taken and diluted for analysis by the carmine
method described above. At the same time the oxygen capacity of the
blood is determined in the ordinary way by the Gowers-Haldane haemo-
globinometer. For further certainty it is well to make both determina-
tions in duplicate.
As a little air always gets mixed with the CO, a sample of the CO in
the cylinder should be taken for analysis. It is usually sufficient to
determine the CO2 (of which none should be present) and oxygen. From
the latter the proportion of air can be deduced.
Let us suppose that 150 cc. of CO were given, the temperature 12°,
and the barometer 765 mm. ; also that there was 0.82 per cent of oxygen
in the CO, corresponding to 3.9 per cent of air. 150 cc. of gas saturated
with moisture would correspond to 142.5 cc. of dry gas at 0° and 760 mm.
But as 3.9 per cent of this was air, only 137 cc. of CO were administered.
Let us also suppose that the percentage oxygen capacity of the subject's
blood was 18.1 (98 per cent by the haemoglobinometer) , and the per-
centage saturation with CO was 19.5. The total oxygen capacity or CO
capacity must have been 137 x =703 cc. ; the blood volume 703 x
19.5
100
— — =3880 cc. If the subject's weight was 60 kilos this corresponds to
18. 1
6.5 liters of blood to 100 kilos of body weight; and this result is usually
expressed as a blood volume of 6.5 per cent of the body weight.
In the original description of our method, we directed that the blood
sample should be taken within two or three minutes of the cessation of
administration of CO, as we assumed that by that time the CO would
be evenly distributed in the blood all over the body. The results from
samples taken three minutes after the first sample confirmed this as-
RESPIRATION 427
sumption. When, however, Douglas and Boycott made a number of de-
terminations with a much larger bag which necessitated continuation of
the breathing for a considerable time after the CO had been given, they
obtained higher average results for the blood volume in man than
Lorrain Smith and I had got. Douglas and I therefore reinvestigated the
question as to how long the CO requires to distribute itself equally, and
found that when the samples were taken only two or three minutes after
cessation of the administration of CO the percentage saturations of the
blood were from 10 to 25 per cent higher than 15 minutes later. After
10 to 15 minutes, however, the saturation remained constant if the
subject continued to breathe from the bag. Our original experiments gave,
therefore, results for the blood volume which were too low — ^probably by
about 25 per cent. The average blood volume in man by the CO method
is about 6.5 to 7 per cent of the body weight, and the total oxygen capacity
of the haemoglobin about i.i to 1.3 liters per 100 kilos of body weight.
It is probable that, as regards most of the circulating blood, mixture
with any added substance such as CO takes place very rapidly. In some
parts of the body, however, the circulation is so slow that a considerable
time is required for mixture.
Douglas,2o and also Boycott and Douglas^^ applied the above de-
scribed CO method to animals, and took the opportunity of comparing the
results with those obtained by the older colorimetric method of Welcker,
which can only be applied after death. The series by Douglas showed an.
average difference of — 3 per cent, and that of Boycott and Douglas of
+5-5 P^r cent with the CO method as compared with the Welcker method.
It is evident, therefore, that no substance except haemoglobin combines
wth CO. It must be remembered, however, that many of the muscles
contain some haemoglobin, and that by both methods this small fraction
of the total haemoglobin is estimated as if it belonged to the blood.
In using the CO method for human experiments it is necessary to
adjust the volume of CO administered to the patient's weight and prob-
able oxygen capacity, so that the percentage saturation of his haemo-
globin is not likely to rise above about 20; otherwise slight headache
may result. For persons of ordinary weight about 150 cc. of CO would
be suitable ; but in cases of pernicious anaemia or anaemia from loss of
blood, and in children or persons of low weight, far less CO should be
given. On the other hand in cases of polycythaema it may be necessary
to give 300 cc. or more in order to obtain a percentage saturation suffi-
cient for a satisfactory titration of the blood. As CO only leaves the
blood slowly when the percentage saturation is low, it is hardly neces-
sary, except in very exact experiments, to keep the patient breathing
from the bag after all the CO has been absorbed.
'"C. G. Douglas, Journ. Physiol., XXXIII, p. 493» 1906, and XL, p. 472, 1910.
"A. E. Boycott and C, G. Douglas, Journ. Path, and Bact., XIII, p. 256, 1909,
and A. E. Boycott, same Journal, XVI, p. 485, 191 1.
72 3
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