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PAPERS AND ADDRESSES

BY
WILLIAM HENRY WELCH

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PAPERS AND ADDRESSES

BY

WILLIAM HENRY WELCH

l> V

IN THREE VOLUMES

Vol. I
PATHOLOGY

PREVENTIVE MEDICINE

BALTIMORE '

THE JOHNS HOPKINS PRESS
MDCCCCXX

BALTIUORE, HD., V. B. A.

//'/
V.I

IN HONOR OF

WILLIAM HENRY WELCH

UPON

THE SEVENTIETH ANNIVERSARY OF HIS BIRTH

THIS COLLECTED EDITION

OF HIS PAPERS AND ADDRESSES IS PUBLISHED

AS A TOKEN OF AFFECTION, GRATITUDE AND ESTEEM

BY HIS ASSOCIATES AND PUPILS

EDITORIAL NOTE

On the eighth of last April Dr. Welch attained his seventieth
birthday. To many of his friends it seemed that such an
occasion ought not to pass without some manifestation of
affection and admiration on the part of the medical profession
of America to one who has long stood as its leader, and that
a worthy expression would be the preservation in suitable form
of the chief contributions from his pen.

Dr. Welch's writings are scattered through a great variety
of publications, many of which are more or less inaccessible.
It was accordingly decided to bring together and to publish
the more important of his numerous papers and addresses of
the past forty-two years, publications which reveal the great
part he has played in the development of medical science and
medical education.

With the permission of Dr. Welch, the editor, in his student
days, had collected these papers and addresses with a view to
republication. When it became evident that the work would
be interrupted by the war the appended Bibliography was
published. On his return from France after the Armistice the
editor was invited by the Publication Committee to undertake,
under its supervision, the editing of these volumes.

The collected material covers a period during which there
have been great advances in medicine, especially through the
impetus following the development of cellular pathology, the
discovery and study of pathogenic microorganisms, and the
more widespread adoption of experimental methods. It will
be noted that a number of the papers, and especially addresses
and discussions, are from stenographic reports. Some of
these have been revised and given appropriate titles, but no
attempt has been made in these or other articles to alter the
subject matter so as to bring it up to the later state of knowl-
edge. In view of the fact that these publications have appeared

in England, Germany, and America during a period covering
lU'arly a lialf century, the orthograpliy is not consistent through-
out the volumes.

The volumes include studies in i)athology, preventive medi-
cine, bacteriology, medical education, tlie relation of medicine
to other sciences, and the history of medicine in the United
States and elsewhere. Papers on similar subjects, although
scattered over a number of years, have been placed together
chronologically in groups.

In behalf of the Publication Committee the editor desires to
thank the editors and publishers of books and periodicals for
their hearty cooperation in consenting to the use of articles
appearing in these volumes. Especial thanks are due to
Sir Clifford Allbutt of Cambridge, England; Dr. Frederic S.
Dennis, New York; the Macmillan Company, London; Lea and
Febiger, Philadelphia; to the editors of the Bulletin of The
Johns Hopkins Hospital, the Transactions of the Association
of American Physicians, the Journal of the American Medical
Association, the Bulletin of the Medical and Chirurgical
Faculty of Maryland, the Maryland Medical Journal, the Jour-
nal of Experimental Medicine, Science, and numerous other
publications ; and to Mr. Max Broedel, who has redrawn some of
the illustrations.

It is largely through the active interest and advice of

Dr. "William Stewart Halsted and Dr. Henry M. Hurd in every

phase of the publication that this tribute to Dr. Welch has come

to pass. A great debt of appreciation is due to Dr. Simon

Flexner for his preparation of the Introduction. To Lieut. Col.

Fielding H. Garrison, M. C, U. S. Army, Dr. "William Sydney

Thayer, Dr. William G. IMaeCallum, Dr. John Howland, Dr. Lew-

ellys F. Barker, Dr. J. "^Vhitridge Williams, Dr. Ralph B. Seem,

Miss Minnie Blogg, The Johns Hopkins Press, Mr. Nathan

Billstein of the Lord Baltimore Press, and many other friends

of the author who have given valuable assistance the editor

expresses his indebtedness.

Walter C. Burket.
December 1920.

TABLE OF CONTENTS

PAGE

Introduction si

PATHOLOGY

Zur Pathologie des Lungenodems 3

Theory of Pulmonary Oedema 36

The Behaviour of the Red Blood-Corpuscles when Shaken with Indiffer-
ent Substances 42

The Structure of White Tlirombi 47

Hemorrhagic Infarction 66

Experimental Study of Haemorrhagic Infarction of the Small Intestine

in the Dog 77

Thrombosis 110

Embolism 193

Venous Thrombosis in Cardiac Disease 259

Miliary Aneurism of a Branch of the Gastric Artery 285

Duplicature of Arch of Aorta with Aneurism 286

Sudden Deaths from Cardiac Disease 288

An Experimental Study of Glomerulo-Nephritis 293

The Cartwright Lectures. On the General Pathology of Fever 303

Hyperthermy in Man 367

Adaptation in Pathological Processes 370

Hydrophobia 395

Cirrhosis Hepatis Anthracotica 408

The Pathological Effects of Alcohol 413

Osteo-Fibromyoma of the Uterus 432

Medullary Form of Sarcoma of the Sternum, with Metastases in the

Lymphatic Glands 434

Diffuse Infiltrating Carcinoma of the Stomach 440

Syringo-Cystoma 444

Chronic Jaundice with Xanthoma Multiplex 447

Chronic Peritonitis with Complete Obstruction, Caused by Numerous
Constrictions of a Previously Undescribed Character, Throughout

the Intestine 449

Idiopathic Phlegmonous Gastritis 457

ix

X TABLE OF CONTENTS

PAOE

The Effusion of Cliyle and of Chyle-Like Milky, Fatty, and Oily Fluids

into the Serous Cavities 458

Catheterization of the Ureters in the Male 4G0

Primary Echinococcus Cysts of the Pleura 4(51

ilalaria 4G3

So-Called Parasitic Bodies in Epithelioma 532

The Parasite of Cancer . . . ; 534

Exhibition of Animal Parasites 536

Intestinal and Hepatic Actinomycosis, Associated with Leukaemia. . . . 541

PREVENTIVE MEDICINE

Modes of Infection 549

Considerations Concerning Some External Sources of Infection in

Their Bearinfj on Preventive Medicine 567

Sanitation in Relation to the Poor 588

Asiatic Cholera in its Relations to Sanitary Reforms 599

The Relation of Sewage Disposal to Public Health GOT

Relations of Laboratories to Public Health G15

Duties of a Hospital to the Public Health G"21

Opening Remarks by the President of the Section on Pathology and

Bacteriology of Tuberculosis 629

What May be Expected from More Effective Application of Preventive

Pleasures Against Tuberculosis 632

Considerations Relating to the Control of Tuberculosis 637

The Significance of the Great Frequency of Tuberculous Infection in

Early Life for Prevention of the Disease G40

Control of Bovine Tuberculosis G51

Child Welfare G55

Institute of Hygiene 660

The School of Hygiene and Public Health at the Johns Hopkins

University 669

Remarks at Opening of Medical Conference of Red Ctoss Societies. . . . 672
Scope of the Proposed Health Activities of the League of Red Cross

Societies 674

WILLIAM HENRY WELCH

A BIOGRAPHICAL SKETCH

My Dear Associates :

On this memorable and beautifiil occasion I have the cherished honor of
having been chosen to perform, as it were, the duties of chronicler, in order
that we may all be led to review in our minds the successive steps by which
our great leader and master rose to such high distinction and wrought the
miracle of giving to medicine a new birth in this country; and in order,
also, that our successors, lighting their lamps at the shrine of Pathology
and studying the treasures which these precious volumes enclose, may catch
a gleam of what manner of man he was who produced them, and who by the
vigor of his living example and the charm of a rare personality, as well as
by the power of his spoken and written word, in the short span of a lifetime
raised medicine in the United States from a beneficent art to an expanding
science.

William Henry Welch was born in Norfolk, Connecticut, April 8, 1850.
He was the son of William and Emeline (Collin) Welch. His father was
a practising physician, as were four of his father's brothers. Moreover, a
great grandfather and grandfather were also physicians. When about one
year of age, WilHam Henry's mother died ; thereafter he was taken care of
and brought up by his paternal grandmother, who resided with the father.
A contemporary describes the youth as a great favorite in the village, inter-
ested in all kinds of sports and athletic exercises. During the Civil War, the
youthful William became captain of a company of zouaves, who, dressed
in regulation costume and provided with guns, drilled regularly on the
village green. When about twelve years old, William was sent to a nearby
boarding school at Winchester Centre, conducted by the Eeverend Ira W.
Pettibone, an uncle by marriage. Here he prepared for Yale College which
he entered in 1866, in his sixteenth year, and from which he was graduated
in 1870, with the A. B. degree, standing third in his class. During his
college period he impressed his teachers and classmates with the possession
of the gifts which afterwards distinguished him in so large a measure. After
graduation and before entering upon his medical studies, Welch taught
school for one year at Norwich, New York.

Thus it was in his twenty-first year that Welch matriculated at the College
of Physicians and Surgeons, in New York City. But this first venture into
2 xi

xii INTRODUCTION

medicine was very brief. An almost prophetic vision into the future gave
him pause ajid led to his return to New Haven for a year of study in chem-
istry, which field even at that early date he perceived to hold great future
possibilities for the study of medicine. This intermediate year was spent
jointly at the Sheffield Scientific School and at the Yale Medical School.
In the former, Welch came under the influence of Professor Oscar H. Allen
who strongly stimulated his interest in science in general and in chemistry
in particular. This rather unconventional and solitary personality, who was
not only chemist, but geologist, mineralogist and botanist as well, proved
to be an inspiring teacher. At the Yale Medical School the professor of chem-
istry was George Frederic Barker, afterwards professor of physics at the Uni-
versity of Pennsylvania and a member of the National Academy of Sciences,
who was deeply interested at the time in organic chemistry and thus turned
his pupil's attention to the writings of Kekule which were just then exerting
a dominant influence on chemical thought. Within the year the student was
mastering the concepts of Kekule in the original German. The breadth of
interest of the two able teachers under whom Welch had the good fortune
to come during tliis preparatorj' year, may well have exercised a directive if
latent influence on the gifted and impressionable pupil which at a somewhat
distant day was to assert itself in the determination to break with the tra-
ditional and alluring career of private and consultative practice, and to
embark upon the hazardous one of pathologj'. This decision was not, however,
arrived at immediately or even at the outset of his medical work, but came
later as part of a widening knowledge and an enlarging experience.

It was fated also that the two men who, each in his own although dift'erent
way, were to influence the rise of pathology in the United States, should
first come together in the chemical laboratory of the SheSield Scientific
School. T. Mitchell Prudden had gone through the School at about the time
when William 11. Welch passed through the College; but as in that day the
two sets of students — academic and scientific — rarely met and never mingled,
the two men were not brought into contact. When Welch entered the labora-
torj', Prudden was already there, filling a kind of voluntary instructorship ;
and thus the two men whose paths were to cross and recross in the many
subsequent years of sympathy, perfect understanding and common endeavor,
first discovered in each other, albeit still in embn'o as it were, that devotion
to science and its ideals which as the years lengthened was to prove secure
against the many and insistent allurements and pecuniary rewards of medical
practice.

The year of chemical study over, Welch returned definitely to his medical
studies. It will aid us a little later in the understanding of the change about
to be wrought in the pursuit of pathology — in the making of advances in

INTEODUCTION xiii

which the then unsuspecting medical student was to play so large a part — if
we pause to sketch in broad outline the kind of educational discipline offered
the medical student at the College of Physicians and Surgeons, a leading
institution, in the period embraced by the years 1873 to 1875.

In 1872, when Welch entered, the College of Physicians and Surgeons
had been in operation for sixty-five years and led all its competitors in the
number of its students and in teaching facilities. The CoUege occupied a
building of its own on Twenty-third Street, regarded as commodious, and
was a part of Columbia University. The term of instruction had been
extended from four to five months, and three instead of two sessions of
attendance upon lectures were required for graduation. The precarious
supply of material for dissection and for instruction in operative surgery
and the method of obtaining it had been superseded and made fairly adequate
by legal enactment. The courses in anatomy and to a less degree those in
medical chemistry comprised the entire provision for objective or practical
teaching, aside from the out-patient clinic at the College and the clinical
lectures given at the New York and BeUevTie Hospitals and the Almshouse.
A voluntary course of lectures on pathological anatomy with demonstration
of organs removed at autopsy was offered during the summer session by
Francis Delafield.

While the preceptorial system was still in vogue and the medical student
was still expected to obtain the main part of his clinical training during the
long interval between sessions, in the office and on the rounds of his preceptor,
the few outstanding students could hope to enter Bellevue Hospital for an
interneship, which might begin even six months before graduation. But
the didactic lecture, of which the instruction still chiefl}' consisted, was
expected to fill the mind of the student with the medical lore of the day,
while it served also to impress his imagination with the vigorous personality
and high authority of the eminent teachers under whom he sat, in a manner
now whoUy foreign to the spirit of medical teaching.

But to the able, energetic and ambitious student the plan, imperfect as
it was as an educational discipline, admitted of a choice of subject and
disposition of effort not contemplated in the system. And thus we find Welch
in the early period of his medical studies enticed away from the lecture halls
into the more alluring atmosphere of the dissecting room and very soon
serving as prosector to the professors of anatomy.

With the curriculum as indicated, it is obvious that no opportunity existed
to acquire thorough training in any subject, aside possibly from the grosser
aspects of human anatomy. The provision for pathologj' was extremely
meagre. Although a chair of physiology and pathology, filled by Alonzo
Clark, had been created in 1847, in the early seventies of the last century.

xiv INTRODUCTION

pathology had not become an independent subject of teachinij, but was
attiithed to tlie chair of medicine, still, as it happened, under Doctor
Clark, who had been transferred to the professorship of pathology and
clinual medicine.

There is no reason to suppose that Clark treated pathology otherwise
than by lectures, with perhaps at most the occasional use of specimens from
the deadhouse. On the other hand, Francis Delafield, who had become
adjunct professor of pathologj' and clinical medicine, was already studying
assiduously with the microscope the pathological changes in the kidneys in
Bright's disease and still other morbid processes, as viewed indeed from the
standpoint of the new cellular pathology just struggling into the light. But
of opportunity for the student himself to acquire even the rudiments of the
teclinique of the microscopic study of the organs and tissues in health and
disease, there was none. It was not, therefore, just at this juncture in
Welch's history that his interest in pathology asserted itself.

A compelling circumstance was, however, imminent. Among the prizes
offered to students was one provided by Doctor Seguin, then the professor
of diseases of the nervous system, for the best report of his clinical and
didactic lectures. It consisted of a Varick microscope fitted with superior
French triplex lenses. This prize was won by Welch, and it proved indeed
to be the spark which ignited the tinder of his latent interest in pathology
and caused it to burst into flame. Fortunately Welch now entered in October,
1874, upon his intemeship at Bellevue Hospital, where this strongly aroused
impulse was to find an abundant field for expression. He now also came
more directly under Delafield's influence, and was thrown with the elder
Janeway. Much of his time was spent in the deadhouse performing autopsies,
first on his own and then on many other cases ; and it is a remarkable tribute
to his technical skill and acumen of observation, as well as felicity of
description, that Delafield invited him to use his special book for recording
the protocols of the postmortem examinations, and that he was made a
curator of the Wood Museum attached to the Hospital.

Although it was perhaps not clearly perceptible at the time, it now
appears that the circumstances surrpunding and thus acting upon the sensi-
tive imagination of Welch, the student, were favorable to his development;
for notwithstanding the poverty of material resources and of laboratory
facilities of the era, he had the good fortune to come under the influence in
the medical college of not a few men of remarkable mental vigor and attain-
ments. Besides those already mentioned, there were on the faculty of the
College in his day Dalton and Curtis in physiology, St. John and Chandler
in chemistry, Edward Curtis in materia medica, Markoe in surgerj-. Sands
and Sabine in anatomy and McLane in obstetrics; weekly clinical lectures

INTEODUCTION ;xv

■were given by Willard Parker and T. Gaillard Thomas, the prestige of whose
strong personalities and eminent careers in surgery and in obstetrics and
gynecology respectively must have been potent forces. He was thrown as
prosector into close association with Sabine and with the demonstrators of
anatomy, John Curtis and McBurney. It was especially at the suggestion of
Sabine that Welch wrote his graduating thesis upon goitre, which received the
first prize, and in the preparation of which he familiarized himself with
medical literature and bibliography at the New York Hospital Library.
At Bellevue Hospital his contacts with Delafield and with Janeway became
numerous and close, the forerunner, as it chanced, of a relationship destined
to become even more intimate and significant at a somewhat later period.

Moreover, the era in which the young student found himself was one of
fundamental flux of belief brought about by the new cellular pathology and
the discoveries of Pasteur just impending. Into this whirlpool of shifting
ideas, which were to move in the next succeeding years with ever-increasing
speed, Welch with his eager, open and responsive mind was thrown. That
his imagination was powerfully stirred by the intellectual ferment of the
time may be assumed. One circumstance is, however, quite clear : at this stage
pathology as an independent career had not been seriously before his mind,
nor was it so to present itself until a whole new set of experiences had been
passed through.

The year and a half's interneship over, Welch is about to take ship for what
proved to be for him and us a great adventure. In April, 1876, in company
with his friend and fellow townsman, Dr. Frederic S. Dennis, he sailed
on the Cunarder "Bothnia" for Liverpool. From Liverpool he went to
London where he spent a few days, crossed tlie channel from Harwich to
Rotterdam and made his way leisurely along the flowering Dutch and Belgian
fields as the spring was passing into the mild early summer months, toward
Strassburg, the first stopping place on the long but important road which
was about to fascinate his view.

Welch's European experience begins with Waldeyer, the Director of the
Anatomical Institute in Strassburg, with whom he studied normal histology.
This subject was of course taken up on account of its fundamental importance
as a basis for pathological histology. But it is significant that the interest
in chemistry, also as a foundation subject, which carried Welch to New Haven
on the very threshold of entrance to his medical studies, had remained alive ;
hence part of his time was spent in Hoppe-Seyler's laboratory, under the
master himself and his assistant Baumann, in working through the former's
well-known textbook in physiological chemistry. In addition, time was
found to attend von Recklinghausen's autopsies and demonstration course,
although at this period no further courses were taken with this master of

xvi INTEODUCTION

pathology and for the reason that Welch concluded that until a grounding
in normal histology was secured, it would not be profitable to pursue patho-
logical histology.

The summer semester at an end, Welch left Strassburg for Leipzig, the
summer vacation being spent with a friend in a pedestrian tour in Switzer-
land and northern Italy. It is of interest to inquire just what was the lure
of Leipzig. Obviously Waldeyer was the attraction in Strassburg; now
it was Heubner and Wagner who drew the student to Leipzig. At that
time Heubner had not entered the field of pediatrics in which he afterwards
became celebrated, but he was working rather in the field of neurology ; and,
indeed, it was his important book on the diseases of the blood vessels of the
brain,' which Welch had read, that determined the choice. If we undertake
to penetrate further into the source of Heubner's attraction for Welch, we
are led back to the days at the College of Physicians and Surgeons in New
York and the lectures of Seguin which had exerted a strong influence on
Welch, so that if we had then inquired whither he was tending in medical
specialization we should liave discovered that he was looking to diseases of
the nervous system as the field for practice, while pathology remained his
main interest and subject of training in Germany, although he could not
then anticipate its pursuit as a means of livelihood on his return to America.

Circumstances were, however, to defeat this consciously worked out pro-
gram. In due course Welch subscribed for Heubner's course, only to find
very quickly that the latter was not then interested in teaching; soon the
course began to languish and the students to absent themselves, and it was
not long until Welch was looking elsewhere to fill his time. Wagner, who
later succeeded Wunderlich in the chair of internal medicine, was at the time
professor of pathological anatomy. Welch found Wagners courses and the
opportunities afforded for independent work by his institute admirably
adapted for his own purpose. Here he attended autopsies and obtained speci-
mens of tissue for microscopic examination. At first the blocks were given as
a favor ; but later Wagner's interest having become aroused he would person-
ally select the specimens for examination and for report. In tliis manner
Welch occupied his mornings ; the afternoons were, however, still free. He
attended Wagner's polyclinic, which kept him in touch with practical
medicine.

At this period Ludwig's laboratory was the centre of attraction for the
talented men in Germany and also for many foreigners especially interested
in physiology. Welch decided to offer himself and was accepted by Ludwig.
That tlie choice was a propitious one is shown by the group of men at tliat
time working with Ludwig and with whom Welch was now associated. The

' Heubner. Die luetlsche Erkrankungen der Hirnarterien, Leipzig. 1874.

^ IXTEODUCTION xvii

first assistant was the gifted and inspiring Kronecker with whom Welch
formed an enduring friendship. Among foreign students was Pawlow, and
Drechsel and Flechsig were in charge of the chemical and the histological
divisions of Ludwig's laboratory. Welch was set by Ludwig to study the
ganglia and nerves of the auricular septum of the frog's heart with the
gold chloride impregnation method, in the course of which he actually
brought into view the ganglionic cells with T-shaped fibres which Ranvier
described in detail somewhat later. The semester closed and the usual
"Abschied" supper was given by Kronecker. Of course Welch was invited
and there was characteristically exhibited a model of the ganglion cell with
fibres both entering and leaving it — a novel and as we now know a histo-
logically highly important event.

The first year of Welch's European study was now over. It had been
spent in preparing himself in normal histology, physiological chemistry,
pathological anatomy and physiologj' ; and it may be asked to what purpose
and for what ultimate end ? The answer is, in order to be ready to study
with "Virchow, whose institute he had visited during a short stay in Berlin.
This expectation was indeed the force back of the concentration on normal
histolog)', the reason for embracing eagerly a histological problem from
Ludwig, the motive in following Wagner's autopsy and microscopic courses ;
and, after all, the wish was to be frustrated and Welch's activities were to be
directed along a wholly new direction and into fresh channels.

The new impulse came from Ludwig who did not share the enthusiasm,
at least in the overwhelming degree then current, for the cellular pathology
of the period. Perhaps this response was the less heart}' because he did not
have the strong sense, as so many seemed to have, of a great innovation, but
rather viewed Virchow's doctrines as the extension, perhaps even the consum-
mation, of the earlier conceptions and discoveries of Schwann, Schleiden,
Eemak and Eeichert; or possibly it was his physiological bias or even a
subtler appreciation of the impending influence of the study of function on
the growth of pathology, which led him to induce Welch to alter his plans and
to offer himself to the brilhant young pathologist Cohnheim to whom he
undertook to write urging him to receive Welch and to furnish him with
a rewarding (lohnendes) theme.

This choice proved highly fortunate. As one reviews Welch's own pub-
lished work, his immediate influence on his students, or the more general
effect which his career has had on medical education, it is now quite obvious
that his intellectual temper was of the order called dynamic, and his vigorous
responses were to concepts built on facts of function far more than of form
and structure. The summer semester of 1877 with Cohnheim in Breslau
was perhaps the most delightful and satisfying of all the time Welch spent

xviii INTEODUCTION

abroad; and fortunately we possess a pen picture of him at that particular
time, drawn in clear and sympathetic lines.

Salomonsen, afterwards professor of pathology at Copenhagen and the
present Nestor of medicine in Denmark, had also come to Breslau for the
summer semester. The two foreign students, the first foreigners who studied
with Cohnheim, were at once thrown together; there existed, indeed, that
subtle quality in the temperaments of the two men that quickly made for
close association and then intimate friendship — a rare relation which neither
distance nor fleeting years have severed. Salomonsen states that the two
men who most influenced his own life were Carl Weigert and William H.
Welch. He goes on to enlarge and say that he and Welch had many points
of contact : both were sons of physicians, both on return to their own coun-
tries hoped to become pathologists to mimicipal hospitals, and both regarded
it as a matter of course that anyone wishing to enter on the career of
pathologist should aspire to work under Colmheim.

The two foreigners were proud of the distinction — what two eager young
men would not be? — of being the only foreigners in the laboratory among
such present or prospective stars as Weigert, Ehrlich, Lassar, Lichtheim,
Albert Neisser, Senftleben and 0. Rosenbach. They were always together —
from early morning to late afternoon — and they were taken up cordially
by their German colleagues of whose intimate circle they made a part. I
venture to quote a particularly appropriate paragraph from Salomonsen:

" That by accident I should have found so gifted a man and investigator
as Welch in Breslau, I at that time as well as later, regarded as the greatest
good luck. Cohnheim knew well how to appreciate Welch, and he recom-
mended him for the professorship of pathology at the Johns Hopkins Uni-
versity where Welch exerted a profound influence on the development of
medical education in the United States, and where the present generation
of American pathologists calls him master."

It was in this remarkable atmosphere that Welch spent a precious semester.
The work of the laboratory was pretty sharply divided between the autopsies
conducted mostly by Weigert, and the experimental investigations in which
Cohnheim shone ever brighter and brighter. The particular problem which
Cohnheim assigned to Welch was the ascertaining of the origin of acute
general oedema of the lungs. This is perhaps not the place to go into
minutiae of that splendidly conceived and executed piece of experimental
work. It was in many ways fortunate that Cohnheim was too preoccupied
at the time reflecting on his theory of tumors and in the preparation of his
textbook on general pathology to do more than propose the problem which
Welch developed largely according to his own notions of logical sequence.
Cohnheim, indeed, was greatly surprised when contrary to his preconception

INTEODUCTION xix

of the process, Welch found the factors involved in it to be mechanical.
The masterly paper describing this piece of work as it appears in Virchows
Archil' was written out by Welch in German and printed quite as he prepared
it. Cohnheim seems not to have altered essentially the composition, the
mode of presentation or the conclusions arrived at. Unfortunately for future
controversy Cohnheim misconstrued the implications of Welch's experiments
and in his epochal Lectures on General Pathologj' he substituted for the
term disproportion (Missverhdltniss) employed by Welch to express the
disharmony (often caused by spasm) in action of the two cardiac ventricles,
the term paralysis (Ldhmung) , which implies only one form of disharmony.

The by-products of this semester on Welch's development were as impor-
tant as the direct influences. Salomonsen's studies on tuberculosis of the
eye initiated him into the experimental side of the tuberculosis problem.
Salomonsen relates an incident showing the great impression made upon
the two foreign students by the first example of generalized tuberculosis in
the guinea pig which they observed. Their enthusiasm evoked hearty laugh-
ter from Cohnheim. It was, moreover, the period of Heidenhain's early brilli-
ant work, of the rich harvest of Cohn, the botanist; and to cap the climax, the
occasion of Koch's visit to Breslau to lay before Cohnheim and Cohn the
facts of his studies on anthrax, in the demonstration of which all the workers
in Cohnheim's laboratory were permitted to share. Finally, Weigert with
Ehrlich was just applying the aniline dyes to the staining of tissue elements
and bacteria and had recently completed his study of smallpox, in the course
of which he demonstrated by staining methods the masses of micrococci
within the pustules. Ehrlich also, although not yet graduated, was literally
dabbling in the aniline stains and it was a common event to see him with
hands covered up to the wrists with dyes of many colors. The close friend-
ship of Welch with Weigert and Ehrlich dates from this period.

It is significant that the spirit of the Institute was favorable to the new
bacteriology and that Cohnheim and his associates were all looking to the
new science to unlock doors still concealing the origin of the diseases called
infectious — an attitude striking in its difference from the skeptical and
rather disdainful one of the Virchow school of pathology. Thus on leaving
Breslau, Cohnheim sent Welch to Vienna by way of Prague, in order that he
might visit Klebs who was engaged in the study of acute endocarditis from
the microbiological side. There he spent several stimulating days, during
which Ellebs showed him through his excellent museum and demonstrated his
preparations showing microorganisms (micrococci) in the ulcerative lesions
of acute endocarditis. The impression which Klebs made upon Welch was
very strong; and in the light of present knowledge, the aecuracy and presci-

II INTEODUCTION

ence of Klebs' work, well in advance of his period, not only on endocarditis
but on diphtheria and experimental syphilis as well, have become clearly
apparent.

The next stop in the educational journey was made at Vienna which was
still a kind of Mecca for foreign medical students of all nationalities. The
immediate objective was a place in Strieker's laboratory, in order to continue
his studies in experimental pathology. As an index of the high feelings
prevailing at the time it may be mentioned that once Strieker learned that
Welch had been with the heterodox Cohnheim who taught that the pus cell
was merely an emigrated leukocyte, he was not inclined to receive him as
a worker in his laboratory. One piirpose of the visit to Vienna was to study
embryology under Schenck, but the choice was not fortunate and Schenck was
soon forsaken. It is interesting to note that Welch and Prudden found
themselves together in Vienna in their search for an opportunity to study
embryology.

On the whole, the chief lure of Vienna for the pathologist was its almost
inexhaustible store of pathological anatomical material. The reign of
Eokitansky was over, and his successor was Heschl, the discoverer of the
methyl-violet reaction for amyloid, but a far less significant personality.
The greater attraction was the young Chiari who was teaching and working
with the vigor which afterwards became so notable and carried him by way of
Prague to Strassburg to succeed the eminent von Eecklinghausen. To him
Welch went, but not to spend his entire time. There survived in his mind,
it appears, a residue of distrust that pathology would after all afford him a
career in America, or was it the love still for the more immediately practical
aspects of medicine which led him to enter upon courses on the skin under
Hebra, on neurology and psychiatry under Meynert, on the eye, and other
special subjects? But Vienna meant for Welch much more than gross
pathology and the medical specialties. The great city with its splendid
museums of art, its grand opera and its vivid life introduced features of
another order into his experience, feeding that general culture in literature,
history, and the fine arts which came to distinguish him quite as much as
his many-sided medical attainments. Welch remained in Vienna until the
Christmas holidays, when he turned his steps for a second time toward
Strassburg, spending a few days en route in Wiirzburg with Rindfleisch and
his assistant Ziegler.

The second pilgrimage to Strassburg was the carrying out of a plan formed
by Welch at the outset of his European study. He recognized in von Eeck-
linghausen the outstanding representative of the Virchow school of patholo-
gists, and his attendance upon the autopsies at the Pathological Institute,
while he was a pupil of Waldeyer, had stimulated his zeal to work directly

INTRODUCTION xxi

under the master. This desire could not be at once appeased, for as we have
seen, Welch lacked the preparation in normal histology which he regarded
as essential. But now that this requisite was supplied and the work with
Ludwig and with Cohnheim had provided a fair foundation for further
building, Welch offered himself to von Eecklinghausen and was accepted.
As another indication of the commotion which Cohnheim's investigations
were making in the placid waters of Virchowian pathology, it may be cited
that once von Eecklinghausen learned Welch was fresh from the laboratory
of that heretical pathologist, he chose as a theme for his special study the
inflammation of the cornea of the frog induced by various caustic chemicals.
The essential point of difference involved in the contentions of the Virchow
and the Cohnheim schools related to the origin of the pus cell. Was it derived
by multiplication from the fixed tissue cells, or was it a leukoc3i;e emigrated
from the blood ? The controversy has long been settled in favor of the latter,
or Cohnheim view; but in January, 1878, and for many years thereafter it
raged with vigor and even bitterness. The cornea was selected because of
its condition of non-vascularity. The novel experimental procedure employed
at von Eecklinghausen's suggestion by Welch was the excision of the cornea
after the injury and immersion in the aqueous humor of the frog or bullock,
and observation continued over long hours under the microscope. That
cells moved toward the injured spot in the non-vascular specimen was shown
beyond peradventure and even that they divided ; what was simpler, therefore,
than to conclude that migration is not dependent on the presence of the
blood, and hence pus cells are not translated leukocytes? This inference,
however, was not drawn by Welch, who recognized that the reasoning is
fallacious. The full explanation of the observed phenomena waited on later
studies and even on recent discoveries. We now know that connective tissue
cells, among which the corneal corpuscles and the ceUs of Descemef s mem-
brane are classed, are motile ; and as cells endowed with movement they are
attracted by certain stimuli called " chemical," such for example as arise in
tissue constituents acted on by chemicals and in other ways. Moreover, as
we now know, these fixed tissue cells readily multiply in vitro, and thus we
arrive at the conclusion that the chemically altered spot in the cornea attracts
towards itself neighboring uninjured, motile corneal and other cells, that
these cells aggregate about the site of the injury and even multiply there, and
thus give what may be called a spurious appearance of a collection of pus
cells. For it should be remembered that we are dealing with a period in which
tissues were not yet being stained with certain nuclear and other dyes that
bring into view brilliant and subtle distinctions of cellular structure;
but that the " inflamed " cornea was merely silvered in order that the cell

xxii INTRODUCTION

outlines might become perceptible, and, if desired, was subsequently stained
with haematoxylin to show the nuclei.

This practice of putting to the test new discoveries and contentions even
under somewhat hostile circumstances was not a poor discipline for the
future teacher of pathology in the United States. The experience may
indeed be regarded as having brought into play under favoring circumstances
a critical faculty inclined perhaps to leniency, while it held up as it were to
the mirror of his perceptions in a somewhat summary fashion the facts of the
ultimate and ineradicable residue of personal bias in all men, no matter how
great. In the long future years during which Welch dispensed knowledge
and, what is rarer, wisdom at The Johns Hopkins University and elsewhere,
he came as near as it is perhaps possible for a mere mortal to come, in escaping
the blemish of preconception and prejudice and in preserving and presenting
the ideal of the open though balanced mind.

But it would be wrong to infer that there was not also a constructive side
to this period with von Eecklinghausen. The pathologist was great in
attainments, and stimulating as a teacher. He engaged Welch in discussion
of many topics in pathology which were current at the time. One of these
related to the origin of tumors, regarding which von Eecklinghausen was
endeavoring to formulate his views along Unes which have since become more
familiar. He inchned to the conception that a kind of fertilization, whether
by conjugation or otherwise, took place among the cells, leading to the uncon-
strained multiplication characteristic of cancer and other tumors, in conse-
quence of which irregularities of division arose that were the striking obvious
signs of the cellular abnormality. Welch always retained an admiration for
von Eecklinghausen as a great pathological anatomist.

The first European adventure was now approaching its conclusion and
was to receive a suitable ending by a first visit to Paris and a second to
London. It is far simpler and more satisfying perhaps to leave to the
imagination the picture of Welch in the great and beautiful French city
with its wealth of present interests and of historic backgrounds everywhere
insistent. The fact may, however, be mentioned that time was found during
the two or three weeks of his stay to hear Eanvier, whom he admired greatly
and whose book on histology had been his guide, and to visit the main
hospitals. In London he heard Lister lecture at Kings College Hospital,
and shared in the prevailing excitement which arose from Lister's daring
surgical exploit of opening the knee joint. The next was the final act, namely
taking ship at Liverpool for the United States.

The arrival in New York in the spring of 1878 brought forward a question
which could be permitted to remain in the baekgroixnd in Europe, but now

INTEODUCTION xxiii

must be answered. Undoubtedly Welch possessed wares garnered at home
and abroad — but to what market were they to be taken ? That the practice
of medicine would be a necessary corollary to any other ambition he might
indulge, seemed never to have been doubted by him. Where else were the
necessary pecuniary rewards to come from? There seemed no alternative
but to decide immediately whether he should choose ISTew York or Norfolk
as a field of operations. In Norfolk his father was still busily, if not very
remuneratively, engaged in coimtry practice, in the course of which he
dispensed much kindness and, according to tradition, worldly wisdom with
his medicines. It strikes one now as very odd that Welch should have hesi-
tated at this juncture in his choice of New York or of IJorfolk. The anomaly
can best perhaps be explained by taking into account his remarkable modesty.
It seems almost impossible of belief that one so gifted and innately so force-
ful should not be aware in some, degree of the part which nature had cast
for him. But whatever pangs of indecision he may have suffered were about
to be allayed by destiny in the form of Doctor Goldthwaite.

Success in attaining interneships in hospital or appointments to the
medical services of the Army and Navy was stiU determined by the results
of competitive examination. To meet this situation the private " quiz " had
arisen and operated about the medical schools and upon the aspiring medical
students. The practice has now been generally discredited and discontinued ;
but in 1878 and for many years afterwards the " quiz " if successful was
a reputable and a relatively highly remunerative affair. The " quiz " masters
adapted the cramming process to the peculiarities and foibles of the indi-
vidual examiners, which they sedulously set themselves to learn. It is now
obvious that on joining Goldthwaite's " quiz " Welch never regarded the
undertaking as more than a stop-gap. It should not now surprise us to learn
that the combination of Goldthwaite and Welch proved irresistible and soon
outdistanced all competitors ; it could choose the most promising students and
its product gained the prize interneships. Welch endured the " quiz " three
years, after which and while it was at the height of its popularity he with-
drew. The reason is sufficiently apparent now, but then with the system in-
trenched as it were, it required insight and force to convict it of its salient
defect, namely that of being a bad method, viewed from the standpoint
of educational discipline.

The " quiz " was, after all, merely an incident, the main import of which
was that it ensured the necessary income, while leaving much of Welch's
time for more engrossing pursuits. As a matter of fact, Welch had offered
himself for practice and occupied at this period rooms with his friend Dennis
at 21 East Twenty-first Street, adjacent to the office of his old teacher, Alonzo

xxiv INTRODUCTION

Clark, who would refer occasional patients to the young men. The volume
of Welch's practice never became embarrassing, so that he was still free to
follow his major bent, which was to teach pathology.

The outlook for pathology in New York in 1878 was not bright. The
extent and the nature of the teaching had not changed materially since Welch
was a student in the medical college. New York was as much cut off from
the strong currents moving in Germany and France along the three main lines
of pathology — pathological anatomy, experimental pathology and bacteri-
o\ogy — as if Europe and America were not connected by a common intel-
lectual bond. Welch was, indeed, destined to play the principal part in break-
ing the barrier of American isolation, but at this time when he was offered
by Dr. Francis Delafield the lectures on pathology during the summer
semester at the College of Physicians and Surgeons, he declined the oppor-
tunity, because it carried with it no chance to set up a laboratory, which was
the one essential of Welch's aspiration. But what was denied him at the
College of Physicians and Surgeons, was about to be put before him at
Bellevue Hospital Medical College. This rival institution proposed to build
two small rooms over a hallway, which, added to another room, Welch could
turn into a laboratory.

The invitation was accepted at once, and Welch made his first break \vith
the established traditions in New York. For this was the heyday of schism
in medical schools and feelings ran high among the several faculties, and
the position of his alma mater, the " P. and S.," in the medical hierarchy of
the time was regarded as supreme. Certain of Welch's friends were not happy
over his choice and even considered that he had made " the mistake of his
life." Perhaps there were disadvantages of a kind in a Bellevue connection
as contrasted with the far greater prominence of the " P. and S." establish-
ment, but whatever they may have been in general, they were more than
compensated for by the laboratory and its proximity to the deadhouse at
Bellevue. The new pathological laboratory became at once an influential
factor in the medical educational system of New York, and students came
there to Welch from all three medical schools.

The leaven worked rapidly, for very soon the College of Physicians and
Surgeons awoke to the growing demands of pathology. A part of the
faculty had not ceased to view Welch's defection regretfully, and now that
the Alumni Association proposed to set up, under Delafield's general direc-
tion, a pathological laboratory, its direct conduct was offered to Welch.
The invitation was not accepted, but in declining it Welch characteristically,
as we should now say, put in another strong stroke for pathology, as the

INTEODUCTION xxv

following letter, which also explains his sense of obligation to the Bellevne
College, illustrates:

" New York, October 9, 1878.
" Mt dear Doctor Peddden :

" A few days ago Professor Delafield told me of the following scheme which
the Twenty-third Street Medical College has on foot. A laboratory for
histology and pathology is to be established in connection with the college,
by means of a fund given for the purpose by the alumni. It is to be taken
hold of in an earnest wa}% for the laboratory is to bold the same relation
to the college as the dissecting room does; that is, each student will be
obliged during some part of his course to work there before he can take his
degree. Doctor Delafield proposed that I should go in as his first assistant
and have charge of the histological department, and assist him as much as
necessary in the pathological part. The salary was to be five hundred dollars
for the first year, and I believe more subsequently. I was naturally delighted
with the offer and thought it to be Just what I wanted, an opportunity to
work in the direction where I had studied most. Upon speaking of the
matter, before coming to a decision, with some of the professors at Bellevue,
I find that they are reluctant to have me leave there, and even represent it
as not the square thing for me to go at present. The latter motive especially
has influenced me to stay, as I do not believe it pays to do anything unfair.
I feel as if I were relinquishing a great opportunity and do not see any equiva-
lent for it at present at Bellevue, but as there is a feehng there that it would
not be right for me to leave, I am going to stay and have so told Doctor Dela-
field. He asked me if I knew anyone who would be competent for the posi-
tion, saying there are a great many in New York who think they are, but few
who really are.

" I immediately suggested your name and he at once seemed pleased, and
deputed me to hunt you up by a letter and communicate the proposal to you.
I really think the offer an advantageous one, in fact presenting an oppor-
tunity better than any other I know for one with the tastes and resolution
which you have formed. I do not know anyone who could do greater Justice
to the work there than yourself, and it seems to me to present great possi-
bihties for the future. Personally I should like to have you here in New
York, for I fear I am going to rust out unless I have someone to talk witli
and help me on concerning the subject in which we are both interested.

" I do not know whether this letter will even reach you. Will you at least
drop me a postal card when you receive it, for if I do not hear from you in
a day or two, I am going to resort to further means of hunting you up. I
should also like to know how you decide."

With Prudden's installation at the College of Physicians and Surgeons,
pathology had come to be recognized as a subject of independent merit and
proportions, to be taught practically, by two of the leading medical schools
of the country. Prudden was a pupil of Arnold of Heidelberg, under whom
he had mastered a precise and deUcate pathological histological technique;
and later at Vienna, in part alongside Welch, he had imbibed the essence of

zxs-i INTRODUCTION

the teaching of morbid axiatomy. Thus and at last in the persons of Welch
and Pnidden, American pathology had come to be united with the best
sources of its inspiration abroad; and from now on the main task was to
widen and diversify this stream in the accomplishment of which purpose
Welch's career stands forth preeminent.

Welch was now fairly launched on a career in pathology, but his struggles
were not all over. The serious question all along was the economic one.
Pathology was not a remunerative profession at the time. The fees from
students taking the course were small, the occasional windfall from a private
autopsy was precarious. There were, of course, the fees for the examination
of specimens for physicians and surgeons, and the possibility existed then as
now of turning this practice into considerable income. But Welch shrank
from an enterprise which would consume his time and yield no corresponding
scientific return. After the abandonment of the " quiz " a way out was found
in that he became first, assistant demonstrator and later demonstrator of
anatomy at Bellevue, both paid positions; and then he ofi'ered himself for
practice. That his neighbor and teacher, Alonzo Clark, sent him patients,
we have seen ; it remains, however, to add that the now elderly gentleman
formed the habit of referring his surgical cases to Welch.

This was also the period of Welch's association with the elder Flint,
then at the zenith of his prominent career as teacher and consultant. He
was professor of medicine and the leading spirit at the Bellevue College,
and a great social and professional figure in New York. Flint was engaged
at the time in bringing out a new edition of his Practice of Medicine and
asked Welch to revise the sections on pathology. Welch " jumped at the
chance " and was given a free hand, except for two or three topics which were
reserved for his son, Austin Flint, Jr. Anyone today reading Flint's
Practice of Medicine will recognize the superior merit of the introductory
chapters on general pathology and the sections on the pathology of the
special diseases there given, the whole amounting to a textbook on pathology.

It was Flint's habit to precede his lectures on " practice " with a sketch of
the pathology of the subject to be presented. Pretty soon these preliminary
lectures were turned over to Welch, who lost apparently no opportunity
to increase the prestige of pathology in the curriculum. Thus he introduced
the class autopsy, which he held once a week in a room filled with students.
Notwithstanding these clear indications of Welch's unmistakable bent
and trend, Flint assumed all along that Welch would become a consultant
and succeed him in the professorship of medicine. Indeed, he took steps
by having the faculty elect Welch to the clinical professorship of medicine
to make his succession certain. Welch on learning of this action brought
about its revocation, first because of the injustice which he considered done

INTEODUCTIOjST xxvii

to the then incumbent of the clinical professorship, and next because of
his great interest in pathology.

Looking backward it can be perceived that these many shifts and activities
were incidental to the laboratory of pathology. First the " quiz," second the
demonstratorship in anatomy, third practice — each in turn supplied the
necessary income in money to cover living expenses. Each in turn was fol-
lowed with energ}' and success, and abandoned as soon as the needed income
was available from a source less exacting of the precious time to devote to
autopsies and laboratory, or freer from considerations violating fundamental
beliefs in sound educational method. Pretty soon his skill in performing
autopsies and his eagerness for pathological material brought to Welch privi-
leges from the Babies' Hospital and also from the coroner, with whom Welch
stipulated that he was not to testify in court. It is of passing interest to
note that none of these were paid positions, but that at this time a small
stipend came to Welch from the registrarship of the Woman's Hospital,
which position he then held, and where he made the autopsies and studied
the specimens, mainly ovarian tumors, removed at operations.

Half a dozen years had passed since his return from the European studies,
and Welch had intrenched himself deeply in the medical life of New York.
He was the outstanding pathologist and representative of the new pathology,
and there came to him to study or to work, the alert and ambitious among
the medical students and young practitioners of the day. These years had
contained not a little that was pleasant, but much also that was discouraging
to one who possessed a deeper feeling for and a wider outlook on medical
education. It is true that improvements were creeping into the medical
curriculum ; the annual sessions at this time were indeed extended from five
to seven months and more emphasis was being placed on the laboratory and
less on the purely didactic form of instruction; but progress was painfully
slow and medical teaching lagged sadly behind that of continental schools.
However, a turn in medical affairs was impending which was to transform
within a few years the entire educational structure.

The Johns Hopkins Hospital was approaching completion and the thoughts
of President Oilman and the boards of trustees of The Jolins Hopkins Uni-
versity and Hospital were turning toward the establishment of the medical
school provided for in the splendid gift of Johns Hopkins. A leader to
guide the new enterprise was sought, and it is quite clear from Salomonsen's
statement that President Oilman asked Cohnheim's advice, and doubtless the
advice of others at home and abroad. Welch seems to have been the unani-
mous first choice. Dr. John S. Billings, so intimately associated with the
planning of the Hospital, visited Welch at Bellevue, doubtless in this con-
nection, and Welch was invited to become professor of pathology in the
3

xxviii INTEODUCTIOX

University and pathologist to the Hospital. The great opportunity for which
he had waited and labored and toward which his dearest aspirations turned
had now come to Welch.

There was no doubt in Welch's mind that the Baltimore venture was
full of promise and should be embraced. In the meantime, however, his
position in New York had become so important, it is not surprising that a
strong effort should be made to retain him. At first Welch's friends failed
to see how anyone could exchange the professional opportunities of New
York for those of provincial Baltimore. The incidents of the transition from
the " P. and S." to Bellevue College were recalled in this almost grotesque
adventure. But there was no doubting Welch's seriousness, and hence steps
were taken at once to thwart his plans. The fear of losing Welch was the
immediate incentive which brought the Carnegie Laboratory into being.
Doctor Dennis, an intimate friend and admirer of Welch, obtained a sum
of $50,000 from Mr. Carnegie for the erection of the laboratory. But there
is reason to believe that Doctor Dennis had in mind, besides the purpose of
anchoring Welch to New York, the setting up of the laborator}' as an integral
part of the medical educational system of the United States.

But the Carnegie Laboratory was, after all, a building only, with such
simple and necessary equipment as was demanded by the work of the period
in pathological anatomy and in bacteriolog}', just at its beginnings in the
United States. There was no provision made for a paid staff, and there were
no funds for daily running expenses. Just what might have happened had
these essentials been provided, it is impossible to say, for imdoubtedly with
the erection of the Carnegie Laboratorj- the outlook for pathology in New
York had suddenly brightened. But the vista opened before Welch's eyes
at Baltimore was extremely fascinating, and strong as now may have been
the motive to remain in New York, the imprecedented position which The
Johns Hopkins University, at the zenith of its great reputation, had attained
in fostering science, was a lure not to be resisted. Everything about the
opportunity at Baltimore attracted Welch, who wished above all to be free
to develop pathology in a manner approaching that which he had come to
know in Germany; and fortunately for the history of medical progress in the
United States, he j-ielded to manifest destiny, although in doing so he was
breaking with old and devoted friendships and turning his back on a posi-
tion in New York never yet attained by a devotee of a laboratory branch of
medical science.

In the six years which had elapsed since Welch had returned from his
first period of foreign study, the center of interest had begun to shift from
the purely cellular pathology of Virchow to that of the microbiology of
Pasteur and Koch, in which the bacteria appear as the direct incitants of

INTRODUCTION xxix

disease. Here at last, it seemed, were to be discovered the agencies whose
actions are the immediate excitants of those organic and cellular changes or
lesions constituting the visible reactions of the tissues to the injurious in-
fluences taking place in the course of the phenomenal process designated
disease. This new direction of development was highly sympathetic to
Welch who had been a spectator at Breslau, at the prologue to this swiftly
moving drama, when Koch visited Cohn and Cohnheim in order to exhibit
his anthrax cultures. Welch desired first-hand knowledge of and experience
in the new field, and as The Johns Hopkins Hospital was still in process of
construction, we find him setting out again, in the summer of 1884, for
Germany.

The new goal was Koch in Berlin. But an interview with him at the
Beiclisgesundheitsamt led Welch on Koch's advice to go to Mrmich for the
autumn to study under Frobenius in Bollinger's laboratory, preparatory to
work under the master at a later date. It appears that Koch was soon to leave
the Gesvndheitsamt to be established in the Hygienic Institute under uni-
versity auspices, near the Alexanderplatz. Frobenius proved a slavish
teacher of Koch's technique, which he communicated to his pupils along with
such comments as he had gleaned from conversations with Koch. Still, it was
a beginning in the new field, and the relatively unfavorable conditions led
again, as once before at Leipzig, to connections of great future importance.
Here Welch made the acquaintance of Hans Buchner and also of Escherich,
Lehmann, Neumann, Celli and others who had come to follow the first course
in bacteriology given in a university. Especially with Celli, who had already
begim his studies of the malarial parasite, he formed an intimate and endur-
ing friendship. Welch followed at this time Kitt's demonstrations in animal
pathology in the veterinary school and worked in von Pettenkofer's institute
of hygiene with the master himself and his assistant, Eenk. All was grist
that came to Welch's mill for in after years the former experience was to
bear fruit in his important studies on the swine diseases and the close interest
in Theobald Smith's work, and the latter to contribute to that comprehensive
grasp of the subject of hygiene now being embodied in the new school of
public health at Baltimore, his latest and highly remarkable creation.

Welch did not go at onc-e from Munich to Berlin but acting still under
Koch's direction went in Januar}- to Gottingen to work under Fliigge, who
was professor of hygiene and much closer to Koch and being advised by
him. This period was in every way advantageous, as Fliigge was a far more
inspiring and systematic teacher than Frobenius, and his influence proved
lasting and valuable. Here again he became acquainted with fellow students
gathered in Gottingen for tlie same purpose, who afterward became dis-
tinguished bacteriologists, such as MacFadyen, Nicolaier and Wyssokowitch.

XXX INTRODUCTION

The final touch in Welch's preparation in the new bacteriology was ad-
ministered by Koch himself — a vivid teacher — who himself conducted the
courses, which he had previously organized for militar}- doctors and which had
such far-reaching consequences. Fortune again threw Welch and Prudden
together, for the latter who had taken over the laboratory at the College of
Physicians and Surgeons established by the Alumni Association, was now
in Berlin also seeking training in the new science of bacteriology. The course,
which was of a few weeks' duration, consisted essentially in the practice of
'solating bacterial species by means of Koch's solid culture technique or
by passage of them through the animal body, in order to effect separation of
virulent from other varieties, and in the consideration of form, staining
reactions and physiological and pathogenic propensities. The climax of the
course was the study of the bacillus inducing Asiatic cholera. At this period
not a little apprehension existed that Europe might again be visited by that
scourge. The disease had raged in India and Eg}-pt and the year before
had gained a foothold in Europe in certain Mediterranean ports — hence the
desirability of mobilizing a small army of trained bacteriologists to combat
that plague should it threaten' in earnest. Koch himself was deeply im-
pressed with the danger; indeed so appalling did he consider the calamity
of an epidemic outbreak of cholera in Europe that he did not trust himself
to bring with him to Berlin cultures of the bacillus isolated in India or
Egypt, but preferred to destroy them lest by inadvertence they should gain
access to food or water. Now, however, that cholera actually existed on
European soil and danger of its spread was imminent, the circumstances
not only justified but compelled instruction in its bacteriological detection,
and for this purpose he went to Toulon to secure anew fresh cultures.

But Koch admonished his piipils not to carry away from the laboratory
living cultures of the cholera bacillus. This piece of sound advice, following
the end of the course at a Kneipe held in honor of the Geheimrath led to
an amusing incident. The next morning Welch and Prudden met acci-
dentally at an early hour on one of the bridges spanning the Spree, each,
as it seems, seeking secrecy. It developed that each had gone to an apothe-
cary's shop and purchased concentrated sulphuric acid (or was it a saturated
solution of corrosive sublimate?), which they had poured over the surface
of tube cultures of the cholera bacillus originally intended to be taken with
them to America and that they now proceeded to drop into the Spree. They
expected, of course, to see the tubes sink immediately out of sight, instead
of which they had the momentary disquieting experience of observing them
bobbing up and down as they slowly floated down stream. The guilty pair
hurried away, just, it is said, as a large Schutzmann appeared on the scene.

INTEODUCTION xxxi

An impression of Koch and the influence of his instruction at the time
is given by Prudden:

" Thus the course in the study of bacteria, of one month's duration, in
Koch's laboratory was brought to an end, and the writer cannot refrain from
remarking that the calm, judicial mind of Doctor Koch — the master worker
in his field — his marvelous skill and patience as an experimenter, his wide
range of knowledge and his modest, unassuming presentation of his views
are all calculated to inspire confidence in the results of his own work, to
stimulate his students to personal exertion in this field, and to lend certainty
to the already wide-spread hope that ere long through the resources of science
we shall be able to cope successfully with those most terrible and fatal enemies
of the human race — the acute infectious diseases." '

Welch arrived in Baltimore in September, 1885, and there found Council-
man at work in pathology. He immediately joined Welch and together they
set up a laboratory in a couple of rooms on the top floor of the biological
laboratory, offered them by Newell Martin. The two-storied building at
the Hospital, designed as a deadhouse, was hurriedly completed and con-
verted into a pathological laboratory. This arrangement was intended
merely as a stop-gap in the emergency and until the buildings for the medical
school, then expected soon to be organized and constructed, could be provided.
As it happened, the consummation of the medical school project was long
delayed and the small quarters intended merely for a deadhouse and its
essential adjuncts, became the permanent home of the pathological depart-
ment, as well as indeed the actual physical foundation on which were later
erected two additional stories to house temporarily the departments of
anatomy and pharmacology of the medical school. When in a few years those
two departments secured elsewhere other and more adequate quarters, the
pathological department spread through all the vacated space, which, in
view of its expanding activities, was sorely needed.

The history of the pathological department of The Johns Hopkins Uni-
versity and Hospital, that was to play so profound a part in the educational
progress of the United States, dates from 1886 at which time Welch began
to exert the influence which peculiarly distinguishes his career from that
of his predecessors in this country and elsewhere. Hitherto there had been
abroad departments or institutes of pathology by which was usually meant
pathological anatomy and histology, and sometimes experimental pathology
or bacteriology. Welch's receptive and constructive mind responded power-
fully to the training he received in these several branches of science, so
that he became master not of one branch only, but of all. Thus it came about

' Prudden, T. M., on Koch's method of studying bacteria. Report to the Con-
necticut State Board of Health for 1885, pages 225-226.

xxxii INTRODUCTION

that in setting up the pathological department in Baltimore he inevitably,
and doubtless unconsciously, employed all these resources of knowledge and
progress, and in so doing inaugurated a new era. Hereafter pathology, at
least in the United States, could hope to develop symmetrically, utilizing for
its advancement the materials and methods not of one branch of the science
merely but of all branches, main and collateral, which being directed toward
it might sullice to render a pathological phenomenon more comprehensible
or afford the solution of a problem in medicine otherwise elusive.

The purpose when Welch was called to Baltimore was to proceed immedi-
ately witli the selection not only of the staff for The Johns Hopkins Hospital
but of tlie faculty of the medical school as well. Unforeseen economic con-
ditions postponed the realization of the latter design; but as the hospital's
resources had not been reduced by the unhappy accident which crippled the
finances of the University, a clinical faculty was brought together. Welch's
part in the choosing in 1888 and 1889 of Doctors Osier, Halsted, and Kelly
was conspicuous and decisive, just as later with the opening of the medical
school in 1893 it was his acquaintance with their work and his unerring
judgment of them as men which added to the distinguished trio Doctors
Mall, Howell, and Abel in the completion of the first major faculty of The
Johns Hopkins Medical School. But Welch did not await the opening of the
hospital or the consummation of the plan for a medical school to start active
teaching and to get under way problems of research. Work was begun in an
informal manner with medical graduates and advanced students in biology,
and the quality of the material and the effects of Welch's influence can be
gathered from the list of names of the first group to assemble under him.
In it were Councilman, Mall, Nuttall, Abbott, and Bolton. Before long this
informal plan was superseded by systematic courses in pathology, including
pathological histology and bacteriology, and university lectures. These were
not permitted, however, to degenerate merely into short, superficial series
of demonstrations, lectures and exercises ; but they always carried with them
the freshness of the unexpected from the wide variety of activities going on
in the laboratory and also the incentive to individual endeavor when any new
point arose exciting to someone's curiosity.

With the founding of the medical school along the lines now familiar
but none the less at that time novel to the point of revolution, the break with
the past was complete and the aspiration which for so long kept Welch a
student and a teacher was to be realized, and in full measure. Henceforth
medical education in the United States was to be on a basis equalling at least
the best continental model. The faculty of the medical school was to lose its
local and provincial character and to be representative of the most ]iotent
forces in the country, while the young men and women seeking to enter

INTRODUCTION xxxiii

medicine were to possess a foundation training in physical, chemical and
biological science and to be equipped so as to follow in the original tongues
the greater scientific medical literatures of the French and the Germans.
This was revolution indeed; but like all of Welch's reforming acts it was
a programme of construction not of destruction. Welch's career stands
forth supreme as a force for advancement, whether in research, education,
hospital organization or public health ; but one searches in vain his writings
or the records of his public utterances for evidence of vehemence or denun-
ciation. His was too understanding and sympathetic a spirit to judge men
and things harshly for faults and shortcomings, the origins of which were
sunk deeply into a past whose circumstances were so unlike those of the
present. He made use rather of the gentler art of persuasion by exposition
and example, leavening now here and now there, until the cumulative power
of the intellectual and social ferment induced became so great as to be
irresistible, and the whole mass was moved forward.

From the outset Welch was the central figure and guiding genius of the
medical group. The pathological laboratory became an active centre of
research and teaching. Welch's life quickly became filled to overflowing.
He conducted investigations of his own, launched others on productive
themes, and saw to it that the invaluable pathological specimens from the
surgeons and gynecologists were made use of to advance knowledge and
train a generation of special pathologists in those important fields. He
lectured on special and general subjects in pathology and bacteriology in
a manner so learned and fascinating as to produce impressions not only
immediately stimulating to his auditors in high degree but of enduring
permanence. The suggestiveness of these lectures led frequently to new
undertakings in research. Moreover, the autopsies he performed, his demon-
strations of gross pathological specimens and his teachings at the microscope
stand out as unsurpassable models. He entered also into the medical
activities of Baltimore and of the State of Maryland, and became a great
influence for betterment in private and public medicine. He was, of course,
the first dean of the medical school and guided the policy of the new institu-
tion into the productive channels that have so eminently distinguished it.
His many talents were therefore called into constant play, and heavily over-
taxed as they must often have been there was never indication of exhaustion.
When occasion arose he was always ready, eager and able for a new advance,
as witness his leading part in the recent development of the full-time
system, so-called, in the clinical branches of medical teaching, in establishing
a model school of public health and hygiene, and in serving on scientific
and philanthropic boards possessing great wealth, for promoting scientific

xxxiv INTRODUCTION

discovery and for carrying the benefits of medical knowledge to the furthest
parts of the world.

The achievements of Welch as an investigator, teacher and reformer in
medicine are so many and varied that it is not possible to do justice to them
in detail in a mere sketch. This is particularly true of that part of his career
covered by the Baltimore and Johns Hopkins period. These three noble
volumes of his collected papers and addresses are the best expression of his
many-sided activities. i\jid j'et precious as they are, they afford no real
insight into Welch's almost flawless personality, the depth of his friendship
and wealth of his kindness, his faculty of intense application and devotion
to the work in hand whether in laboratory or in public interest, his com-
manding influence and guiding spirit over the work of his associates and
many pupils, the stimulating wholesomeness of his public activities, and
his rarely unselfish and tolerant nature which led him to shower liis great
gifts prodigally and far and wide. The recipient of almost every honor
in the gift of his colleagues, he fortunately, in time, saw the return of his
labors, increased manj'-fold, enriching science through progress made in
education, in deeds performed and discoveries by the men and institutions
over whose destinies he had presided. And lastly these volumes fail to
show us still another side of Welch's accomplishments as remarkable almost
as those of the science we so love to laud in him. I refer to his culture outside
the realm of medicine in the field of literature, in which he possesses an
almost unerring taste for the best in poetry and prose, and in the domain
of the fine arts. His mind is indeed stored with the beautiful creations of
other men's minds from ancient times to our own day. It is to all these
remarkable qualities, innate and acquired, united in one man, that we owe
that thrice rare personality William Henry Welch, master in medicine and
beloved of men.

Simon Flexxeb.

PATHOLOGY

ZUR PATHOLOGIE 1>ES LTJNGENODEMS '
(Aus dem pathologischen Institut in Breslau)

Obwolil das LuDgenodem der hiiufigste pathologische Befimd am Sections-
tische ist, so ist es doch niemals der Gegenstand einer experimentellen
Untersuchungsreihe gewesen, und seit Laennec's Beschreibimgen ' ist
unseren Kenntnissen iiber diesen haTifigen imd wichtigen pathologischen
Zustand iiberhaupt Weniges hinzugefiigt worden. Seit der Zeit, in welcher
ein Verhiiltniss zwischen erhohtem Blutdruck in den Capillaren und ver-
niehrter Ausscheidung aus denselben verniuthet worden ist, hat man ange-
nommen, dass das Hauptmoment beim Zustandekommen von Lungenodem
in einer gesteigerten Spannung der Limgencapillaren zu suchen sei. Da
aber die Betrachtungen, welche dieses Moment zu vriirdigen versucht haben,
zum grossten Theile ohne Beriicksichtiguug der Eigenthiimlichkeiten des
Lungenkreislaufs oder unter irrthiinilichen Voraussetzungen iiber denselben
gemacht worden sind, so habe ich nach dem Vorschlag des Herm Prof.
C 0 h n h e i m eine Eeihe von Versuchen an Kaninchen und Hunden im
Breslauer pathologischen Institute angestellt, welche den Zweek hatten mit
Eiicksicht auf die neueren Forschungen iiber den Pulmonalkreislauf unsere
Kenntnisse von den Ursachen des Lungenodems zu erweitern. Meinem
hochverehrten Lehrer spreche ich hiermit fiir seine freuudliche und thatige
Hiilfe meinen herzlichsten Dank aus.

Xach der gangbaren Anschauung ist das Lungenodem die Folge entweder
einer Hydramie oder einer Hyperamie. arterieller oder venoser.

Was das hydramische Oedem betrifft, so haben die Versuche von C o h n -
h e i m und L i c h t h e i m ' ergeben, dass das Lungenodem nach Inf undi-
rung grosser Mengen von Kochsalzlosung zwar bei Kaninchen kein seltenes
Ereigniss ist, doch nicht constant eintritt, und bei Hunden selten beobachtet
wird. Daraus diirfen wir schliessen, die hydramische Plethora allein,
obwohl ein begiinstigendes Moment, ist nicht im Stande Limgenodem zu
erzeugen, sondem das Zustandekommen desselben erfordert noch einen
zweiten Factor. Ueber diesen letzteren werden wir spiiter zu handeln haben.

In den systematischen Lehrbiichern der Medicin werden Lungenhyper-
amie und Lungenodem gewohulich in demselben Capitel und ungetrennt

»Arch. f. path. Anat. u. Physiol, u. f. klin. Med., Berl., 1878, LXXII, 375-412.
'Laennec, De I'auscultation mediate. T. II. Paris. 1819.
' Virchows Archiv Bd. 69. S. 106.

3

4 ZUR PATHOLOGIE DES LUNGENODEMS

behandelt. Damach kann jede Hyperamie, seien ihre Natur und ihre
Ursachcn wplche sie wollen, wenn sie hochgradig genug ist, Lungenodem
zur Folge haben. Des Naheren glaube ich die gegenwiirtigen Anschauungen
am richtigsten darzulegen, wenn ich die Ansichten iiber Hyperamie und
Oedem der Lunge wiedergebe, welche in dem Lehrbuch von N i e m e y e r '
und dcm Handbuch der Medicin von v. Ziemssen' enthalten sind.

Die Hyperamie der Lunge wird in Flujdon und in Blutstockung oder
passive Hyperamie getheilt.

Als Ursachen einer Fluxion werden von x^iemeyer angef iibrt :

1. Gesteigerte Herzaction,

2. Directe Eeize, wie Einathmen heisser oder mit reizeuden Substanzen
vermischter Luft,

3. CoUaterale Hyperamie,

4. A^erdiiDDung der Luft in den Alveolen (verengerte Glottis). Diesen
Ursachen f iigt Hertz hinzu :

5. Wirkimg des kalten Trunks bei erhitztem Korper und Abkiihlimg der
Korperperipherie,

6. Eutziindliehe Zustande.

Als Ursachen eiuer Blutstockung werden erwahnt :

1. Storung des Abflusses des Blutes aus den Pulmonalvenen, namentlich
Stenose und Insufficienz der Mitralis (seltener Klappenaffectionen der
Aorta),

2. Jede geschwachte Herzaction.

Bevor wir envagen, inwieweit diese verschiedenen Momente fahig sind,
Limgenodem zu verursachen, werde ich zuerst'an die folgenden wohlbekann-
ten Charaktere, welche dasselbe darbietet, erinnem. Gewohnlich tritt das
Lungenodem plotzlich auf und kann fast ebenso rasch verschwinden, wie
es entstanden ist; es ergreift beide Lungen; es erscheint bei den verschieden-
artigsten Krankheiten und ist ein constanter Begleiter von keiner; es tritt
oftmals bei der Agonie auf, eine Begleiterscheinung eher als eine Ursache
des Todes; die mikroskopische Untersuchung einer odematosen Lunge
zcigt die hochgradigste Piillung der Capillaren und zahlreiche ausgetretene
rothe Blutkorperchen. Von dem aciit auftretenden allgemeinen
Lungenodem, wovon hier ausschliesslich die Eede ist, muss dagegen das
serose Transsudat unterschieden werden, welches sich haufig in der Nahe
entziindeter Lungentheile befindet und gewohnlich als ein collaterales Oedem
bezeichnet wird.

Wenden wir uns also zunachst zu einer Kritik der verschiedenen, oben
angcgebenen Ursachen des Lungenodems !

•Niemeyer, Lehrb. d. spec. Path. u. Therap. Bd. 1. Berlin, 1S74.
'Hertz, Anamie Hyperamie und Oedem der Lungen. v. Ziemssen's
Handb. der spec. Path. u. Therap. Bd. 5. Leipzig. 1S74.

ZUR PATHOLOGIE DES LUNGENODEMS 5

1. Gesteigerte Herzaction. Wenn wit aus den Verhaltnissen
im grossen Kreislaiif einen Schluss auf den Lungenkreislauf ziehen diirfen,
dann ist es von vomherein sehr unwahrscheinlieh, dass vermehrte Blutzu-
fuhr (Fluxion) zu einer Lunge, welche sich nicht in entziindlichem Zustande
befindet, und aus deren Venen der Abfluss nicht gehindert ist, zu Oedem
fiihren soUte. Zu anderen Korpertheilen kann der arterielle Zufiuss be-
trachtlich vermehrt werden, zum Beispiel durch Erweiterung der zufiihren-
den Arterien oder durch Yerengerung oder Verlegung anderer Gefassgebiete,
ohne dass eine vermehrte Abscheidung aus den Capillaren folgt.' Es soil aber
nach Henle,' Niemeyer, Hertz u. A. ein besonderer Grand existiren,
aus welchem bei gesteigerter Herzaction das Blut sich in den Lungen haufen
soil. Dieser von vielen Seiten behauptete Grund ist der, dass die Lungen-
capillaren weniger resistent gegen vermehrten Bludruck seien, als die
Capillaren anderer Organe. Dass in dieser Beziehung ein absoluter Unter-
schied existirt, ist kaiun zu leugnen, aber Druck und Widerstande im Pul-
monalkreislauf sind um Vieles geringer als im Aortensystem, und es ist kein
Grund anzunelimen, dass im Verhaltnisse zu d i e s e m Drueke und zu
d i 8 s e n Widerstanden die LungencapiUaren weniger resistent sind, als
andere Capillaren. In diesem Gebiete aber, auf welchem uns die meisten
Factoren unbekannt sind, ist es gefahrlich zu speculiren und gliicklicher-
weise konnen wir auch ohne alle Speculationen auskommen. Bei jeder
compensirten hochgradigen ilitralstenose muss der Druck in der Puhno-
nalarterie hoher sein, als ihn ein nicht hypertrophisches Herz in einer Lunge,
in der keine Hindernisse fiir den Abfluss des Blutes existiren, zu Stande
bringen kann, und doch giebt es in diesem Stadium keine Anzeiehen, dass
die „Eesistenz der Capillaren" iiberwunden ist. Dass liier keine allmahlieh
sich entwickelnde Yermehrung der Widerstandsfiiliigkeit der Capillaren in
Betracht zu ziehen ist, beweist der Umstand, dass nach einem kiinstlich
angelegten Aorten- oder Mitralisfehler der Blutdruck in der Arteria carotis
sich nicht andert.* Die Yersuche von L i c h t h e i m ° liber Unterbindung
einer Lungenarterie sowohl, v,-ie die Yersuche iiber Unterbindung der
Lungenvenen, welche unten berichtet werden sollen, deuten eher auf eine
relativ grossere als auf eine relativ kleinere Besistenz der LungencapiUaren
im Yergleich mit denen anderer Organe bin. Weder physiologische noch
pathologische Beobachtungen sprechen dafiir, dass erhohte Herzkraft allein,
ohne Hinzutreten anderer Momente, in den Lungen leichter als in den
iibrigen Korpertheilen Oedem erzeugen konne.

"Emminghaus, Arbeiten aus. d. phys. Anstalt zu Leipzig. 1873. S. 68.
' Handbuch d. rationellen Pathologie. Bd. II. S. 421. Braunschweig, 1847.
' C o h n h e i m . Vorlesungen iiber allgemeine Pathologie. S. 38. Berlin, 1877.
•Lichtheim, Die Storungen des Lungenkreislaufs und ihr Einfluss auf den
Blutdruck. Breslau, 1876.

G ZUE PATHOLOGIE DES LUNGENODEMS

2. DirecteReize. Diese konnen, insofem sie nicht durch Stoning
der Athmungsvorgange oder durch ihre Wirkung auf andere Organe todten,
als Entziindungserreger fiir die Lufhvege und die Lungen betrachtet
werden." L a s s a r " beobachtete Lungenodem als eine inconstante Be-
gleiterscheinung des Todes in Erstickungsfiillen, welche ausnahmsweise der
Einathmung von Saurediimpfen folgen. Die Seltenheit, mit welcher Lungen-
odem nach der Einwirkung von directen Eeizen auf die Lunge erscheint,
niacht es wahrscheinlich, dass es nicht der unmittelbare Effect des Eeizes
sei, sondem denselben TJrsprung hat, wie dasjcnige Oedem, welches bei den
verschiedensten Todesarten entsteht, und fiir welches ich nnten versuchen
werde, eine Erklarung zn geben.

3. Collaterale Hyperaniie. Gerade bei der Lunge hat das
sogenannte collaterale Oedem eine grosse Kolle gespielt. Wenn die Circula-
tion in einem Lungenlappen oder einer ganzen Lunge gehemmt wird, dann
entwickelt sich in den freien Theilen eine compensatorische Hyperamie,
welche der gangbaren Anschauung zufolge zum Oedem fiihren kann. Als
die Folge soleher coUateralen Fluxion fasst Virchow"^ das Lungenodem
auf, welches er durch Injection von Oel in die Venen erzeugte. Die Ver-
suche von L i c h t h e i m " haben uns schon gelehrt, dass, wenn Aeste der
Lungenarterie bis zu drei Yiertel der Arterienbahn verlegt werden, der
Dnick in der Arteria carotis keine wesentliche Veranderung erleidet, und
der Druck in den oflen gebliebenen Arterien der Lvmge eine gewisse Steige-
rung zeigt, welche im Verhiiltnisse zu dem normalen niedrigen Werthe
desselben steht. Als Folge aber dieser selten in so hohem Grade beim
Menschen zu beobachtenden coUateralen Hyperamie hat er niemals Lungen-
odem gesehen, und auch ich war nicht im Stande ein coUaterales Oedem zu
erzeugen. Dass in den Fallen, in welchen ein allgemeines acutes Oedem
nach embolischer Yerstopfung einer Lungenarterie entsteht, dieses auf
anderen Momenten als der coUateralen Hj'peramie beruht, beweisen die eben
erwahnten Versuche und audi die Inconstanz seines Auftretens unter diesen
Umstiinden. Der hiiufige Befund von Lungenembolien, welche ohne jegUche
symptomatische oder anatomische Folgeerscheinimg entstanden sind, ist
jedem erfahrenen Pathologen bekannt.

Wenn aber das sogenannte collaterale Oedem sich nicht auf die compen-
satorische Hyperamie zuriickfiihren lasst, woher kommt es sonst? Llit
jeneni N'amon werden zwei verschiedene Zustande bezeichnet, einmal das
aUgemeine acut auftretende Oedem, welches bei Ivrankheiten entsteht, die

"B. Heidenhain, Dieses Archlv. Bd. 70. S. 441.
" Zeitschrift fiir phys. Chemie. Bd. I. Hft. 3.
" Spec. Path. u. Therap. Bd. I. S. 191. Erlangen, 1S54.
" Op. cit.

ZUE PATHOLOGIE DES LUJ^GEXODEMS 7

eine Hemmimg der Circulation in einem Theile der Lunge verursachen,
fiir's zweite die locale serose Durchfeuehtung des Lungengewebes in der
Nahe von entziindlichen Heerden, Xeubildungen u. s. w. Der erstere
Zustand, glaube ich, ist denselben noch zu besprechenden Ursachen zuzu-
sclireiben, wie das allgemeine Lungenodem iiberhaupt, der letztere dagegen
als ein entziindliches Oedem aufzufassen. Schwer in Einklang zu bringen
mit der Hypothese, dass das locale collaterale Oedem die Folge bios einer
compensatorischen Blutdrucksteigerung sei, ist der Umstand, dass die Ver-
breitung desselben oftmals in keinem Yerhaltnisse zu der Grosse der Gefiiss-
verengerung steht. Einerseits sieht man haufig um kleine lobulare Pneu-
monien, kleine embolisehe Infarcte u. s. w. eine verhaltnissmassis' grosse
odematose Zone, andererseits kann man dieselbe giinzlich vermissen bei
Krankheiten, -welche grosse Abschnitte des Lungenparenchyms fiir die Cir-
culation unwegsam machen. Wenn einnial eine entziindliche Gefassverander-
ung existirt, dann kann bekanntlich vermehrte Blutzufuhr zu gesteigerter
Transsudation in dem betreffenden Theile fiihren," und deshalb diirfen wir
nielit einer collateralen Hj-peramie jeden Einfluss absprechen, das Haupt-
moment aber ist die vorhergehende Gefasswandveranderung."

4. Verdiinnung der Luft in den Alveolen. Vor 30
Jahren stellte Mendelssohn'" eine merkmirdige Theorie auf, nach
welcher das Wesen der Lungenhyperamie iiberhaupt in einer Luftverdiin-
nimg in gewissen Lungenpartien zu suehen sei. Er ging von der falschen
Hypothese aus, dass die Yeranderungen der Lunge nach Vagusdurchschnei-
dung auf einer Verdiinnung der Luft in den Alveolen beruhen. „Diese Luft
verhalt sich zur Schleimhaut der Lunge wie die unter einem trockenen
Schropfkopf /•' " Die Versuche von 0. Frey " in Betreff der Yerengerung der
Trachea sprechen nicht dafiir, dass eine bedeutende Lungenhyperamie durch
Hindemisse, welche den Eintritt der Luft in die Luftwege beeintrachtigen,
entstehe. Eine Yerengerung der Glottis als eine Ursache des Lungenodems
zu betrachten, entbehrt jedenfalls der experimentellen und der klinischen
Grundlage.

5. Wirkung des kalten Trunks und Erkaltung des
K 6 r p e r s, oder allgemeiner ausgedriickt, Widerstande im grossen

"Gianuzzl, Berichte d. konigl. sachsischen Gesellschaft der Wissenschaften,
1866. Cohnheim u. Lich theim, 1. c. S. 139.

"Colinlieim, Vorles. uber allg. Pathologie. S. 261, 416. 419.

"Mendelssohn, Der Mechanismus der Respiration und Circulation, oder
das explicirte Wesen der Lungenhyperamie. Berlin, 1845.

" Arch. f. phys. Heilk. 1845. S. 277.

"* Die pathologischen Lungenveranderungen nach Lahmung der Nervi vagi.
Leipzig, 1877.

8 ZUR PATHOLOGIE DES LUNGENODEMS

Kreislaufe im AUgemeineii. Eine Erkliirung fiir die Entstehung der
Lungenliyperiimie in Folge der Wirkung der Kiilte auf den Magen oder auf
die Hautoberflache hat man in der Thatsache zu finden geglaubt, dass nach
Yerengerungausgedehnter Gefassgebiete (Baucheingeweide, Haut) der Blut-
druck in anderen Theilen des Aortensystems steigt." Die Versuehe von
L i c h t li e i m aber liaben uachgewiesen, dass die Spannnng im kleineu
Kreislauf in hohem Grade von Druckveriinderungen des grossen Kreislaufs
unabhiingig ist. In Uebereinstimmung damit fiude ich, dass beim Hunde
der Pulmonaldruck ohne wesentliche Veriindenmg bleibt, wenn den einzigen
offenen Weg fiir das Blut aus dem liuken Ventrikel in den Korperkreislauf
die eine Arteria carotis oder die eine Subclavia bildet. Der Druck in der
Carotis kann in Folge von Hindernissen in der Circulation zu mehr als dem
Doppelten seiner normales Hohe gebraclit werden, ohne dass der Pulmonal-
duck steigt. In Hinblick auf diese Thatsache diirfen wir nicht eine
Lungenh)-perdmie in Folge von Erkaltung unmittelbar von einer collateralen
Blutdrncksteigerung herleiten. Die Erkaltung fiir eine Ursache von Hy-
drops pulmouum zu halten, entbehrt iibrigens der kliuischen Berechtigung,
und in den seltenen Fallen, in welchen ein Zusammenhang vorhanden zu
sein scheint, sind sicher andere Momente im Spiele.

6. EntziindlicheZustitnde. Das locale collaterale Lungenodem
hat C o h n h e i m schon mit Eecht als ein entziindliches angesprochen.
Wirft man nun die Frage auf, ob es ein primiires, idiopathisches, entziind-
liches Lungenodem giebt, so liegt kein Grund vor, ein allgemeines Lungen-
odem entziindlicher N"atur anzunehmen. Das erste Stadium freilich der
Vaguspneumonie und das der crouposen Pnoumonie haben eine grosse Ver-
wandtschaft mit localem Lungenodem." Wenu wir aber in diesen Fallen
von einem entziindlichen Limgenodem sprechen diirfen, so ist damit nur
genieint, dass in Folge einer entziindlichen Veranderung der Gefasswande
ein Zustand entsteht, welcher die grosste Aehnhclikeit mit dem Zustande
der Lungen bei gewohnlichem Lungenodem besitzt. Dass aber das Stauungs-
und das entziindliche Oedem nicht zu identificiren sind, beweisen, von allem
Andem abgesehen, die Untersuchuugen von L a s s a r ^ iiber die BeschafEen-
heit der Lymphe bei- der Entziindung.

Blutstockung. Je skeptiseher uns unsere Erfalirungen iiber das
Zustandekommen von Wassersucht im grossen Kreislaufe hinsichtlich der

"Hermann und Ganz, Pfliiger's Arcliiv fiir Phys. 1870. S. 8.

"Friedlander, Untersuchuugen iiber die Lungenentzundungen. Berlin,
1873.

Unverricht, Studien iiber die Lungenentziindung. Inaug.-Diss. Breslau,
1877.

•■Virchows Archiv Bd. G9. S. 516.

ZUR PATHOLOGIE DES LUNGENODEMS 9

Moglichkeit der Entstehung des Lungenodems durch fluxionare Hyperamie
machen, mit desto grosserer Sicherheit werden wir von der Blutstauung
Oder venosen Hyperamie einen derartigen Effect erwarten. Weder die
anatomische Structur noch die physiologischen Eigenschaften der Lungen-
capillaren, so weit sie uns bekannt, geben uns Grund anzunehmen, dass sie
nieht, wie andere Capillareii, eine betriichtliche Behinderung des Veiien-
abflusses mit seroser Ausschwitzung beantworten.

Als Ursachen der Blutstockung in der Lunge werden angefiihrt : Storung
des Abflusses des Blutes aus den Pulmoualvenen und geschwaclite Herz-
action.

1. Storung des Abflusses aus den Lungenvenen. Als
ein tj-pisches Paradigma von beliindertem Abflusse aus den Lungenvenen
konnen wir beispielsweise eine Mitralstenose betrachten. Wie allgemein
bekannt, kann eine betrachtliche Verengerung des Mitralorificium eine Zeit
lang existiren ohne nennenswerthe Storungen von Seiten des Gefasssystems.
Dieser Zustand wird das Stadium der Compensation genannt. Wahrend
desselben stromt durch jeden Querschnitt der gesammten Gefassbahn
dieselbe Menge Blut in der Zeiteinheit wie unter normalen Verhaltnissen.
Es fliesst deshalb in der Zeiteinheit von den Lungenvenen durch das veren-
gerte Orificium dieselbe Menge Blut in das linke Herz wie vorher durch da^
normal weite Ostium. Wegen der vermehrten Widerstande muss der rechte
Ventrikel mit grosserer Kraft arbeiten. In Folge des erschwerten Abflusses
und der vermehrten Geschwindigkeit, welche das rechte Herz der ausge-
triebenen Blutmasse ertheilt, muss der Seitendruck in alien Theilen des
Pulmonalgefasssystems steigen. Dass unter diesen Umstanden Lungen-
odem niemals eintritt, fiihrt v. D u s c h zu der Bemerkung " : ., Dass das
Lungenodem nicht oder docli nicht vorzugsweise durch die Drueksteigerung
in den Lungenvenen hervorgebracht wird, geht daraus hervor, dass in den
Fallen hochster Drueksteigerung bei geniigender Compensation em relativ
giinstiger Zustand fiir den Kranken hergestellt wird." 1st v. D u s c h
berechtigt anzunehmen, dass der Druck in den Lungenvenen am grossten
in dem Stadium der Compensation ist? Die Beantwortung dieser Frage ist
mit grossen Schwierigkeiten verbunden. v. D u s c h geht von aer Voraus-
setzung aus, dass die Menge Blut, welche ein Ventrikel in der Zeiteinheit
empfangt, allein von dem Drucke in den unmittelbar vor demselben geleg-
enen Venen abhiingt, und, da diese Biutmenge am grossten wahrend der
Compensation ist, so schliesst er, dass der Venendruck dann am hochsten
sein muss. Die Geschwindigkeit aljer, mit welcher das Blut aus den Venen
in den entsprechenden Vorliof einfliesst, hangt nicht allein von dem Drucke
ab, sondern von einer Kraft, welche der Summe der Widerstandshohe

" Lehrbuch der Herzkrankheiten. S. 96. Leipzig, 1868.
4

10 ZUR PATHOLOGIE DES LUNGENODEMS

(Seitendruck) und der Geschwindigkeitshohe in den betreffenden Venen
gleicht. In den Kiirpcrartcrien ist der Worth der Gesch\nndigkeitshohe im
Vergleich mit der Widerstandshohc so klein, dass er bei Druckmessungen
vernachliissigt wird, aber in den Venen, wo die Widerstande so gering sind,
ist derselbe fiir die Fortlx-wegung des Blutes nicht ausser Acbt zu lassen.
Im Stadium der gestorten Compensation ist die bewegende Kraft des rechten
Ventrikels vermindert ; dem entsprechend ist die Spannung in der Lungen-
arterie geringer geworden, aber die Gei?animtmenge Blut, welche die Lungen
cnthalten, kann unverandert bleiben oder sogar vermehrt werden. Ent-
sprechend der verminderten Spannung in den Arterien der Lunge vertheilt
sieh das Blut anders ; die Lungenvcnen entbalten mehr, die Arterien weniger
als vorher. Jetzt gilt es die schwierige Frage zu erortern, ob diese Vermeh-
rung des Inhalts der Lungenvenen eine Drueksteigerung in denselben zu
Stande bringt. Setzen wir die Geschwindigkeitshohe in den Lungen-
venen =G, die Widerstandshohe = W, so haben -nir die bewegende Kraft in
denselben K = W-fG. Sollte die Sunune W-l-G den Werth erreichen,
welchen sie wiihrend des Compensationsstadiums hat, so wiirde bei gleich-
bleibenden Widerstanden der linke Yentrikel die normale Menge Blut
erhalten, und, vorausgesetzt dass seine Kraft unbeeintrachtigt ist, fortbc-
wegen. Deshalb kann der Seitendruck W im hoehsten Falle um eine Grosse
steigen, welche G wahrend der Compensationsperiode gleichkommt. Der
Werth von G ist uns unbekannt. Yolkmann" berechnet den AVerth
der Geschwindigkeitshohe im Anfange der Aorta zu 8,2 Mm, auf die
Hohe einer Blutsaule bezogen. Selbst wenn wir annelmien, dass der
Gesanimtquerschnitt der Lungenvenen nur die Halfte dessen der Aorta ist,
so wird doch die Grosse von G weniger als H ilm. Quecksilber betragen.
Setzen wir ferner voraus, dass die Geschwindigkeitshohe wahrend des Com-
pensationsstadiums um das Mehrfache gesteigert sei, so wird doch immer
der Werth von G so klein bleiben, dass die Maximalgrenze einer vermuth-
lichen Druckerhohung bei gestorter Compensation zu niedrig ausfallen muss,
um — im Hinblick auf die unten zu berichtenden Versuche iiber Pulmonal-
druck beim Zustandekommen von Limgenodem — die Entstehung desselben
bei ungeniigender Compensation den mechanischen Hindernissen iind der
wegen venninderter Kraft des rechten Ventrikels geiinderten Vertheilung
des Blutes allein zuschreiben zu diirfen.

Jedenfalls steht so viel fest, dass ein betrachtliches Hinderniss fiir den
Abfiuss des Blutes aus den Lungenvenen existireu kann, ohne dass dadurch,
so lange dieses Hinderniss durch vermehrte Arbeit des rechten Ventrikels
ausgeglichen wird, die Entstehung von Lungenodem herbeigefiihrt wird.

" Die Hamodynamik. S. 214. Leipzig, 1850.

ZUK PATHOLOGIE DES LUNGEXODEMS 11

Wir kommen zu der letzten der oben angefiihrten Ursachen des Lungen-
odems.

2. Geschwachte Herzactio n."* Dieses Moment scheint der
Scliwerpunkt der Sache zu sein. Die anderen angeblichen Ursachen haben
sieh nicht als causae effieientes erwiesen und konnten im besten Falls nur
von beschrankter Bedeutung sein ini Vergleiche mit diesem anscheinend
allgemein wirksamen Factor. Selbst in den Fallen, wo andere Verander-
ungen im Spiele sind, hat man sieh doch auf Herzschwache als einen mit-
wirkenden Factor berufen, weil in der That in der Mehrzahl der FaUe von
allgemeinem Lungenodem die Thatigkeit des Herzens herabgesetzt ist.
Wenn wir aber annehmen, dass eine allgemeine Herzschwache wirklich
Lungenodem herbeizufiihren vermag, so ist das entstehende Oedem nicht
die Folge einer Drucksteigerung in den Capillaren und Venen, mit anderen
Worten kein Stauimgsodem. Es ist unmbglich, dass durch Herzschwache
der Druck in den Lungenvenen die Hohe erreichen soil, welche bei unver-
minderter Herzkraft in den Lungenarterien herrscht. Da aber nach Unter-
bindimg der Venen der einen Lunge, diese Venen wie blinde Anhangsel der
entsprechenden Arterie zu betrachten sind, so muss der Druck in diesen
derselbe sein, wie in der Arterie (oder annahernd derselbe, indem keine
wesentliche Erleichterung seitens der Bronchialvenen stattfindet, wie, von
anatomischen Griinden abgesehen, das Auftreten von vollstandiger, hamor-
rhagischer Infarcirung der betreffenden Lunge beweist) und doch entsteht
unter diesen Umstiinden niemals Oedem." Da in dem analogen Falle im
Korperkreislauf, wo sammtliche von einer Extremitiit abfiihrenden Venen
zugebvmden werden, Oedem entsteht, so miissen wir den LungencapiUaren
im Verhaltnisse zimi Drucke im Pulmonalkreislauf eine grossere relative
Impermeabilitat zurechnen, als den Capillaren anderer Organe.

Ist aber die Folge der Herzschwache Lungenodem? Die nothwendige
Folge ist es unbedingt nicht. Eine Sj'ncope kann noch so lange dauern
imd fiihrt niemals zum Hydrops pulmonum. Durch Vagusreizung konnen
wir die bewegende Kraft des Herzens vernichten, so dass die Spannung in
den Gefiissen der des ruhenden Blutes gleich wird und es entstehen nicht
die geringsten Zeichen eines Lungenodems. In den allerseltensten Fallen
iiberhaupt ist der Tod die Folge eines plotzlichen Erloschens der Herzkraft ;
diese sinkt viehuehr allmahlich von ihrer normalen Grosse bis auf NuU,
und doch sterben nicht alle Menschen an Lungenodem. Aber, erwidert

" Was ich hier iiber Herzschwache zu sagen habe, bezieht sieh ausschliesslich
auf die gewbhnliche Auffassung dieses Zustandes. scil. eine gleichzeitige und
gleichmassige Schwachung beider Herzhalften. Eine Schwachung, bei welcher
die Kraft des einen Ventrlkels verhaltnissmassig weniger herabgesetzt wird,
als die des anderen, lasse ich vorlauiig ausser Betracht.

-' C 0 h n h e i m , Op. cit. S. 419.

12 ZUR PATHOLOGIE DES LUNGENODEMS

man, wenn Lungenodem eintreten soil, muss die Herzschwache lange dauem !
Als eine derartige in der That nicht seltene Folge der Ilcrzsfliwache, welche
Tage und Wochen lang, besondcrs bei caeheuhtisuhen und fieberliaften Krank-
heiten, gedauert hat, wird das sogenannte hypostatische Oedem vielseitig
aufgefasst. Eiu ITauptmerknial aber des allgemeineu Lungenodems ist eben
sein acutes Auftreten, welches fiir eine plotzlich eintretende Ursache spricht,
und in vielen Fallen ist dean Lungenodem keine langdauernde Herz-
sehwache vorhergegangen. Die Beobachtung am llenschen berechtigt uns
deshalb zu dem Schlusse, dass eine Erniedrigung der Ilerzkraft an und fiir
sich kein Oedem erzeugt, das Experiment wird uns lehren, dass eine Schwach-
ung des rechten Ventrikels in gewissem Sinne sogar ein ungiinstiges Moment
fiir das Zustandekommen von Lungenodem ist.

Ich halx; im Yorhergelienden die gangbaren Anschauungea iiber die
TJrsachen von Lungenodem einer Kritik unterzogen, und wir kommen nun-
mehr zu dem Schlusse, dass keine uns eine geniigende Erklarung darbietet.
Obwohl die meisten der oben em'iihnten Bedingungen auf falschen tlieo-
retischen Voraussetzungen begriindet worden sind, bin ich denselben doch
so wenig wie moglich von theoretischen Gesichtspunkten und so viel wie
moglich von Seiten der Beobachtung und des Versuches entgegengetreten.
Sollen wir nun aber von alien mechanischen Momenten absehen und die
Ursachen des allgemeinen Lungenodems in anderen Bedingungen suchen?
Es scheint allerdings, als ob nach unseren bislierigen Betrachtungen dem
Lungenodem eine ganz aparte Stellimg im Vergleich mit den Wassersuchten
anderer Korpertheile einzuriiumen sei. Bei dieser Lage der Sache konnen
wir nur durcli das Experiment einer Losung des complicirten Problems
etwas naher zu treten hoflfen.

Die erste zu beantwortende Frage ist: Giebt es iiberhaupt ein Stauungs-
odem in der Lunge? Denn eigentlich haden wir bis jetzt keinen Grund
gefunden, die Existenz desselben beim Menschen anzunehmen.

Eine Stauung in der Lunge konnen wir zu Stande bringen durcli Hinder-
nisse in den Lungenvenen, in dem liuken Vorhofe, in dem linken Veutrikel
und in der Aorta.

Die Versuche wurden an Kaninchen und an Hunden gemacht. Iliuide
bieten den Vortheil, dass an ihnen der Druck in der Pulmonalarterie leicht
zu messen ist. Bei Kaninchen entsteht andererseits Lungenodem leichter
als bei Hunden. Bei beiden Thieren giebt die Aorta zuerst den Truncus
anonymus ab, von welchem die linke Carotis, die rechte Subclavia und die
rechte Carotis ihren Ursprung zu nehmen pflegen. Der zweite Hauptast
der Aorta ist die linke Subclavia.

Weim man einem Kaninchen den Aortenbogen zwischen dem Truncus
anonymus und der linken Subclavia unterbindet, so wird das Thier an den

ZUK PATHOLOGIE DES LUNGENODEMS 13

hinteren und der linken vorderen Extremitat gelahmt und leidet wegen
Lahmung des Zwerchfells und der Musculi intercostales an starker Dyspnoe.
Nach ^ — 1 Stunde stirbt es, ohne dass besondere Veranderungen an den
Lungen zu bemerken sind. Mit Hiilfe der kiinstlichen Athmung, welche
in fast alien diesen Versuchen benutzt wurde, lebt das Thier langer, jedoch
gleichfalls ohne dass die Lungen nach dem Tode etwas Bemerkenswerthes
darbieten. Wenn gleichzeitig die eine Carotis communis durch eine end-
fetandige Manometercaniile verlegt wird, so steigt der Druck in derselben um
50 bis 100 pCt. iiber seine normale Hohe. In dieseni Falle, wo bios die
andere Carotis und die rechte Subclavia offen sind, habe ich gewohnlich kein
Lungenodem nach dem Tode gefunden; gelegentlieh jedoch, besonders bei
jungen Kaninchen, erfolgt ein massiges Oedem. Erst wenn der
Aortenbogen zwischen Truncus anonym us und linke
Subclavia und zwei Aeste des Truncus anonymus
geschlossen werden, d. h. wenn die einzige Abfluss-
rohre aus der Aorta (die Kranzarterien ausgenommen) die eine
Carotis oder die rechte Subclavia bildet, entsteht
ganz regelmassig Lungenodem. Das Thier wird gleich nach
der Unterbindung luiruhig, in 1 — 2 Minuten bekommt es Krampfe und
stirbt unter den bekannten Erstickungserscheinungen. Wenn man, wie C.
Friedlander" schon gethan hat, die Aorta zwischen dem Herzen und
dem Truncus anonymus zuklemmt oder luiterbindet, so stirbt das Thier
nach einigen Seeunden mit heftigen Krampfen, und die Untersuehung der
Lungen gleich nach dem Tode zeigt starkes Oedem. Die Lungen werden
grosser und blutreicher als normal gefunden, und aus der Trachea und den
Bronchien fliesst eine schaumige, wassrige Fliissigkeit von gelblichem oder
gelblich-rothlichem Farbenton aus. Wenn man die Trachea zuerst offnet,
ohne die Lungen zu beriiliren, findet man nicht selten gar keine serose
Fliissigkeit in derselben; doch geniigt, wenn Oedem vorhanden ist, ein
leichter Druck auf die Lungen, um das serose Ttanssudat herauszupressen.
Die Unterbindung der oben genannten Arterien bietet keine Schwierig-
keiten. Der Hautschnitt, welcher vorher gemacht worden ist, um die
Trachealcaniile einzusetzen, wird in der Mittellinie bis zu 3 — 4 Cm. unter-
halb des oberen Sternalrandes verlangert. Obwohl es moglich ist, die Aorta
und die Aeste des Truncus anonymus mit gekriimmten Haken von oberhalb
des Sternums her zu erreichen, wird doch die Operation um Vieles erliehtert,
wenn man die Crista an dem oberen Theile des Sternimis abschneidet und
das Sternum in der Ausdehnung von 1 — 2 Cm. mit starker Scheere spaltet.
Dies geht ohne Blutung vor sich, wenn der Schnitt in der Mittellinie gefiihrt

^ Op. eit.

14 ZUR PATHOLOGIE DES LUNGENODEMS

wird. Will man die Aorta dicht am Herzen unterbinden, so muss man das
Sternum weiter spaUen und den oberen Theil des Herzbeutels eroffnen.
Mit einiger Sorgfalt kann man sehr gut das Brustbein bis zum Ansatz des
Zwercbfells in der Mittellinie spalten, obne dass eine von beiden Pleura-
hohlen geoffnet wird. Nacbdem die im vorderen ]\Iediastinimi gelegene
Driisen- und Fettmasse, welche den Aortenbogen und seine Aeste bedeckt,
mittelst Pincetten zerrissen worden ist, liegen diese frei zu Tage.

Versuch, welche den Zweck batten zu untersucben, um wie viel es notbig
sei die aufsteigende Aorta zu verengern, um Oedem zu erzeugen, ergaben,
dass das Lumen der Aorta fast zu Verschluss verengert werden muss, ehe
Lungenodem eintritt.

Bei diesen Yersucben machte icb die interessante Beobachtung, dass bei
Kaninehen Yerengerung des aufsteigenden Aortenbogens bis zu einem
gewissen Grade eine Drucksteigerung jenseits (peripber) derverengten Stelle
bewirkt. Um die Arterie, ohne Zerrung der anliegenden Gebilde, zu veren-
gen, wurde ein G r a e f e ' sches Ligaturstabchen benutzt, welcbes Yer-
kleinerung des Gefasslumens in jedem beliebigen Grade bis zur voU-
standigen Yerschliessung erlaubt. Als ein Beispiel fur das interessante
Yerhalten des Carotisdruckes nacli Yerengerung der aufsteigenden Aorta,
fiihre icb das Folgende aus einem Versuehsprotokoll an.

Yersueh 1. Grosses Kaninehen. Tracheotomie. Kiinstliche Ath-
mung. Quecksilbermanometer in Yerbindung mit rechter Carotis. Druck
sebwankt zwischen 100 und 115 ilm. Brustbein in der Jlittellinie gespal-
ten, Aortenbogen freigelegt, Herzbeutel geoffnet. Starker Faden um die
Aorta zwischen Herz und Truncus anonraius gelegt und an dem
G r a e f e ' scben Ligaturstabchen befestigt. Durcli Zuschraubung wird die
Aorta allmahlich verengert, wodurch der Druck in der Carotis von 100 bis
zu 140 Mm. steigt. Bei weiterer Yerengerung bleibt der Druck einige Zeit
auf dieser Hohe und dann, nachdem die Yerkleinerung des Gefiissquer-
schnitts einen gewissen Grad iiberschritten hat, fiingt er an allmahlich zu
sinken. Eine Wioderholung des Yersuches giebt dasselbe Resultat. Ge-
wohnlich aber nach Wiedereroffmmg des Gefasslumens steigt der Druck
etwas iiber seinen friiheren Werth (auf 130 — 140) und sinkt dann wieder bis
zu einem Punkte zwischen 100 — 115. Als der Faden noch fester zuge-
schniirt wird. so dass das Gefasslumen fast ganz verschlossen ist, bekonimt
das Thier Kriimpfe; der Knoten um die Aorta wird gleicb losgemacht, so
dass die Arterie ihre normale Weite wieder erhiilt. Wahrend der Er-
stickungskrampfe steigt der Druck l)is zu 180 und zeigt die bekannten
rhythniisehen Scliwankungen. Nach den Kriimpfen ist das Thier beweg-
ungslos und xinerrcgbar, athmet nicbt selbstiindig, Druck 120. Jetzt bei
jeder Yerengerung der Aorta sinkt der Druck pari passu in der Carotis,
\md obwohl das Thier sicb etwa-s erholt, so dass es selbstiindig atlmiet und
die Hornbaut etwas erregbar wird, bringt doch eine Aortenverengening
nicht mehr eine Drucksteigerung in der Carotis zu Stande. Das Thier wird

ZUR PATHOLOGIE DES LUNGEXODEMS 15

getodtet durch Einspritzung von Curare ia die Vena jugularis ext., um
eine plotzliche Herzlahmung wahrend massiger Yerengermig der Aorta zu
erzeugen. Die Obduction ergiebt kein Lungenodem.

Diese Dmcksteigerung nach Verengenmg der Strombalm aus dem linkea
Ventrikel ist wahrscheinlich derselben Natur vrie diejenige, welche S.
Mayer" nach Unterbindung der Hirnarterien beobachtet hat, imd einer
Eeizung der vasomotorischen Centren durch Hirnanamie zuzuschreiben.
Man konnte auch an eine Reizung des linken Ventrikels denken, durch
■vrelche derselbe zu grosserer Arbeit erregt wird, als um die vermehrten
Widerstande zu iiberwinden nothig sei. Dafiir spricht vielleicht der
Umstand, dass nach Herstellung der normalen Gefassweite der Druck iiber
seine normale Hohe steigt (in einem Falle von 100 bis zu 160). Es ist
von Interesse zu bemerken, dass in dem obigen Yersuche, nachdem die
allgemeine Erregbarkeit vernichtet worden, die Drucksteigerung ausblieb
welches Verhalten vielleicht einer gleichzeitigen Unerregbarkeit der vasomo-
torischen Centren zugeschrieben werden kann. Bei verschiedenen Kaninchen
fallt die Druckerhohung sehr ungleichmassig aus ; bei Hunden hal)e ich sie
liberhaupt nicht beobachtet.

Was lehren diese Yersuche iiber die Entstehung von Lungenodem ? Sollen
wir annehmen, dass ein Widerstand fiir den Abfluss des Blutes aus der
Aorta, welcher den Carotisdruck mn das Zweifache erhoht, keine Stauung
in der Lunge verursacht, oder dass die Stauung nicht ausreicht, um Oedem
zu Stande zu bringen ? Diese Fragen sind zu beantworten nur durch Mes-
sung des Pulmonaldruckes wahrend Yersehliessung der Aorta oder ihrer
Aeste. Zu diesem Zwecke wurden Yersuche an Hunden angestellt.

Liehtheim hat gefunden, dass nach Unterbindung der Brustaorta
dicht iiber dem Zwerchfell bei midurchschnittenem Halsmarke der Druck
in der Lungenarterie unverandert bleibt, wahrend der Carotisdruck bekannt-
lich bedeutend steigt. Meine Yersuche haben seine Resultiite nicht nur
bestatigt, sondern sogar ergeben, dass der Druck in beiden Arteriensystemen
in noch hoherem Grade von einander unabhangig ist, als aus jenen Yer-
suchen hervorgeht.

Das Yerfahren bei Messimg des Lungenarteriendruckes war im "Wesent-
lichen dasselbe, welches Liehtheim benutzte, auf dessen Beschreibung
ich verweise."" Ich legte aber das Fenster in der linken Thoraxhiilfte hoher
als er, nehmlich zwischen erster und vierter oder zweiter und fiinfter Rippe,
weil von einem solchen Fenster sowohl die Aorta in ihrer sanzen Liinffe
bis zum Zwerchfell wie deren Aeste ohne grosse Schwierigkeit zuganglich
sind. ilan kann von derselben ThoraxofiEnung, welche fiir Druekmessung

"Wiener Sitzungsberichte. LXXIII. Abth. III. S. 85.
" Op. cit S. 26.

16 ZUR PATHOLOGIE DES LUNGENODEMS

in dem zum unteren Lappen gehenden Aste der linken Lungenarterie dient,
den Truncus anonynius oder seine drei Aeste, die linke Subclavia und den
Aortenbogen an irgcnd einer beliebigen Stclle zuklenimcn oder unter-
binden. Wenn man diese Gefasse ohne Oeffnung einer Pleurahohle
erreifhen will, dann ist dasselbe Verfahren wie bei Kaninehen anwendbar,
i. e. Spaltung des Bnistbeins in der Mittellinie. Wegen der grbsseren Tiefe
des vorderen Mediastinums bei Hunden ist es empfehlenswerth, nach Eroff-
nung des Thorax in der Mittellinie die Arteriae mammariae gleich zu unter-
bindcn, weil sie bei Blosslegiing der grossen Arterienstamme leicht verletzt
werden konnen. Mit Ausnahme einiger Controlversuche waxen sammt-
liehe Vorsuche an curarisirten Huiiden angestellt, die durch kiinstliche
Athmung am Leben erhalten wnrden. Bei alien Versuchen warden die
Arterien nach dem Tode von dem linken Ventrikel oder Anfangstheile
der Aorta aus mit einer Aufschwemmung von chromsaurem Blei aiisgespritzt.
Dieses Verfahren ist unbedingt nbthig, erstens um zu beweisen, dass die
Arterien an den Unterbindungsstellen festverschlossen sind und zweitens um
festzustellen, ob andere Wege, als man glaubt, offen geblieben sind. Die
Aorta besonders muss sehr fest zugebimden werden. In seltenen Fallen
nimmt die rechte Subclavia von dem Aortenbogen selbst, hinter der linken
Subclavia, ihren Ursprung.

Obwohl L i e h t h e i m nachgewiesen hatte, dass Oeffnung einer Pleura-
hohle keinen Einfluss aui den Pulmonal- oder Carotisdruck ausiibt, machte
ich doch zuerst die Versuche ohne Pneumotliorax, aber die Ergebnisse
waren dieselben wie bei offenem Thorax.

Um die Grenze zu finden, bei welcher die Hindernisse fiir den Ausfluss
des Blutes aus dem linken Ventrikel hinreichend gross sind, um Lungen-
bdem zu Folge zu haben, wurden zuerst die Aorta peripher von der linken
Subclavia, dann gleichzeitig die linke Subclavia selbst und endlich die
Aeste des Truncus anonymus unterbuuden. In einer nicht unbedeutenden
Anzahl von Versuchen ist es mir nicht gelungen Luugenbdem bei Himden
zu erzielen, ehe jeder Ausfluss aus dem Aortenbogen abgeschlossen worden
war. Entweder muss der Aortenbogen zwischen dem Herzen und der
Ursprungsstelle des Truncus anonymus, oder gleichzeitig alle vorher abge-
gebenen Aeste verschlossen werden.

V e r s u c h 2. Mittelgrosser, curarisirter Hund. Arterien, ohne,
Verletzung der Pleura, in der folgenden Reihe verlegt. Endstandige Hg.-
Manometercaniile in linker Carotis communis, Unterbindung der linken
Subclavia nahe an ihrem Ursprung. der Aorta dicht jenseits der letzteren,
der reehten Carotis comnnuiis und der rechten Subclavia dicht peripher
von der Art. vertebralis. Der Carotisdruck steigt von 80 bis zu 220 ]\Im.
Die Pulse sind von Zeit zu Zeit durch T r a u b e ' sche Wellen unterbrochen.
Erst nach einer Stimde ist der Carotisdruck bis ungefahr Null gesunken. Die

ZUR PATHOLOGIE DES LUNGEXODEMS 17

Section ergiebt kein Lungenodem. Einspritzung mit chromsaurem Blei
zeigt, dass die Art. vertebralis destra der einzige offene Weg fiir das Blut
aus der Aorta gewesen ist.

V e r s u c h 3. Mittelgrosser, curarisirter Hund mit Hg.-Manometer
in Verbindung mit linker Carotis irnd mit dem unteren Aste der linken
Limgenarterie. Carotisdruck 80 — 90. Lungenarteriendruck 18 Mm.
Unterbindung der linken Subclavia nahe an ihrer Ursprungsstelle. Druck
in beiden Arterien nnverandert. Unterbindimg der Aorta dicht jenseits
der linken Subclavia. Carotisdruck steigt von 80 bis zu 160 Mm. Lungen-
arteriendruck bleibt unverandert. (Vago-sjTnpathici durchschnitten um
die grossen Druckschwankungen zu beseitigen.) Unterbindung des Truncus
anonj-mus dicht an seiner IJrsprungsstelle. Der Druck in der Lungen-
arterie steigt von 18 Mm. bis zu 60 Mm. Hg. Xach 5 Minuten sinkt er
allmahlich zu 16 Mm. Section ergiebt starke Stauung und Oedem beider
Lungen.

In diesem Falle erreichte der Pulmonalisdruck nach Unterbindung der
Aorta und seiner Aeste eine Hohe, welclie ungefahr das 3^ fache seines
urspriinglichen Werthes betragt. Nach Unterbindung der Aorta allein
dicht peripher von der Art. subclavia sinistra entsteht entweder keine
Veranderujig in dem Drucke der Lungenarterie oder er steigt im hochsten
Falle 4 — 5 Mm. Quecksilber. Diese kleinen Druckverandenmgen werden
natiirlicli am besten an einem Sodamanometer studirt. In einem Versuche,
in welchem die einzig ofFen gebliebene Arterie rechte Subclavia war, stieg
der Pulmonalisdruck von 180 (seiner urspriinglichen Hohe) bis zu 230
Mm. Soda (bios 4 Mm. Hg.). In einem anderen Versuche, in welchem
mit Ausnahme der linken Subclavia jeder Abfluss aus dem Aortenbogen
verschlossen worden war, stieg der Pulmonaldruck von 170 Mm. Soda bis
zu 230 Mm. (35J pCt.), wahrend der mit einem endstandigen Manometer
gemessene Druck in der Carotis von 60 bis zu 230 Mm. Quecksilber
(300 pCt.) gestiegen war.

Diese erstaunliche Immunitat des Pulmonalkreislaufs gegen Druek-
verandeningen im Korperkreislauf giebt uns die Antwort auf die oben aufge-
worfene Frage. Das Ausbleiben von Lungenodem bei solchen Hindemissen,
welche den Carotidendruck zwei- bis vierfach erhohen konnen, ist kein
Beweis, dass eine Stauung in der Lunge kein Oedem zu Folge hat, da solche
colossale Widerstande existiren konnen, ohne dass eine irgend betrachtliche
Steigerung des Druekes im kleinen Kreislauf statthat; es be-(veist im besten
Falle bios, was wir schon von der Beobachtung am Menschen wussten, dass
ein gewisser Grad von Lungenstauung vorhanden sein kann, ohne Oedem
herbeizufiihren. Lungenodem entsteht bei Kaninchen, wenn die eine Carotis
oder die eine Subclavia die einzige Ausflussrohre bildet, und bei Hunden,
wenn der Abfluss noch mehr erschwert ^vird. und erst bei solcher Einen-
gung der Gefassbahnen erleidet der Pulmonaldruck eine bedeutende
Steigerung !

18 ZUR PATHOLOGIE DES LUNGENODEMS

DasErgebnissderVersuchebetreffsUnterbindung
der grossen Ar ter iens tiimme ist also, dass durch
dieselbe Lungenodem und zw?r ein S t a u ungso dem
erzeugt werden kann, dass aber eine bedeutende
Stauung in der Lunge in Folge von Wilderstanden
im grossen Kreislaufe erste dann entsteht, wenn
diese eine Hohe erreicht haben, von welcher beim
Menschen kaum die Rede sein kann.

Diese Stauung ist, wie jede Stauung, dadurch bedingt, dass mehr FlUssig-
keit zufliesst als abfliessen kann. Die Krafte, welche das Blut noch in's
rechte Herz treiben, nachdem die bewegende Kraft des linken Ventrikels
zum grossten Theile oder ganzlich aufgehoben worden ist, sind die hohere
arterielle Spannung, der Gefiisstonus und moglicberweise eine saugende
Wirkung des rechten Ventrikels. Dass der Gefiisstonus von Einfluss bei
dieseni Vorgange ist, beweisen die Versuche von G o 1 1 z ," und die Beo-
bachtung von B e z o 1 d und Gscheidlen," welche fanden, dass nach
Absperrung des Blutabflusses aus dem linken Ventrikel der venose und der
arterielle Druck sich langsamer ausgleichen, wenn der Gefasstonus durch
Durchschneiduug des Halsmarkes herabgesetzt wird. Als ich bei einem
Hunde die Aorta dicht hinter der linken Subclavia zuklemmte, sank der
Druck gleichzeitig in der Arteria femoralis (von 100 bis zu "30 Hg.) und
in der Vena femoralis (von 30 bis zu 15 Soda), wahrend er sowohl in der
Vena jugularis externa (von 5 bis zu 25 Soda), wie in der Carotis communis
(von 100 bis zu 150) stieg. Dagegen nach Zuklemmung der Aorta zwischen
linkem Ventrikel und Truncus anonymus stieg der Druck in der Vena
jugularis und der Vena femoralis (in der ersteren von 0 — 5 bis zu 50 Soda,
in der letzteren nicht genau messbar wegen ungeniigender Lange der llano-
meterrohre). Ob bei Zuklemmung hinter der linken Subclavia die Vermeh-
rung des Zuflusses zum Herzen durch die obere Hohlvene die Verminderung
desselben durch die untere Hohlvene deckt, muss ich dahingestellt lassen,
dafiir aber spricht die Ilnveranderliclikeit des Pulmonaldruckes. Bei Ver-
schluss der Aorta ascendens andererseits ist die Drucksteigerung in den
Korpervenen am wahrscheinlichsten der Stauung im kleinen Kreislauf
zuzuschreiben.

Von besonderem Interesse ware es zu constatiren, in welcher Weise das
Zustandekommen von Lungenodem bei Unterbindung der Arterien durch
die Herzkraft beeiuflusst sei. In Anblick der geliiuiigen Anschauimgen iiber
die Bedeutung von Herzschwache als eine TJrsache von Lungenodem, konnte

" Virchow's Archiv Bd. 28, S. 428. 1864.

'° Unterauchungen aus dem physiol. Laboratorium in Wiirzburg. 1867. Hft. 2.

ZUK PATHOLOGIE DES LUNGENODEMS 19

man vielleicht geneigt sein zu glauben, dass eine Verminderung der Herz-
kraft die Entstehung von Lungenodem bei diesen Experimenten begiiagstigt
hatte." Andererseits ware aber zu erwagen, ob nicht vielmehr eine grosse
Schwache des rechten Ventrikels ein Hinderniss fiir das Zustandekommen
derjenigen Drucksteigening in der Lunge sein muss, welche fiir die Entste-
hung von Oedem nothig ist. Oefter als erwiinscht war die Gelegenheit
vorhanden, die Probe auf diese Ueberlegung zu maehen. Bei Hunden,
denen entweder zu viel Curare eingespritzt war, oder bei welchen die Opera-
tion mit offener Pleurahohle lange gedauert hatte, wurde oftmals die
Herzkraft so niedig (oder, wie von einigen Beobachtungen walirseheinlicher
ist, der rechte Yentrikel so unerregbar), dass TJnterbindimg des Aorten-
bogens und aller seiner Aeste kein Oedem mehr erzeugte. Dem entspreehend
stieg der Druck in der Pulmonalarterie weniger als in den Fallen, wo Oedem
eintritt.

V e r s u c h 4. Bei einem tief curarisirten kleinen Hunde war 2 Stun-
den nach Anfang der Operation der Carotisdruck bis zu 30 Mm. Hg.
gesunkcn, als die Arterien in der folgenden Reilie unterbunden wurden :
Truncus anonjTuus zwischen linker Carotis imd rechter Subclavia, linke
Subclavia vorAbgabe eines Astes, und die Aorta dicht binter der linken
Subolavia. Da eine Manometercaniile in der linken Carotis steckt, so ist
der grosse Kreislauf jetzt vollkommen unterbrochen. Die linke Carotis
zeigt zuerst hohen Druck mit colossalen Schwankungen. Durch die Systole
wird der Druck bis zu 340 Mm. Hg. getrieben, wahrend der langdauernden
Diastole sinkt er auf 40 Mm. Dabef ist ein ausgesprochener Pulsus bige-
minus vorhanden. Nach diesen grossen Schwankungen tritt eine Periode
eine von hohem Drucke, schnellem Pulse und kleinen Schwankungen
(Mitteldruck 250 — 260 Mm.). Diese zwei Arten von Perioden alterniren
in Je 10 Minuten. Xach einer halben Stunde, wahrend welcber die kiinst-
liche Athmung erhalten worden ist, ist der Druck bis auf 50 'Mm. gesunken.

Nach Unterbindung der Arterien bleibt der Pulmonaldruck andertbalb
Minuten unverandert, dann fiingt er an zu steigen und im Laufe von 3 — 4
Minuten erreicht er eine Hohe von 35 Mm. Hg., von welcber er bald wieder
auf 18 Mm. sinkt. Es entstand kein Oedem.

Obwohl ein Druck von 35 Mm. Hg. in der Pulmonalarterie nach den
Messungen von Lichtheim und von mir immerhin ein hoher genannt
werden muss, ist er doch nicht zu vergleichen mit dem Drucke, welcber in
den Versuchen zu Stande kam, wo das Herz bei der Gefassunterbindung
kraftig war imd Lungenodem entstand (cfr. Vers. 3). Das Ausbleiben von
Lungenodem in diesen Fallen, wo die sonstigen Bedingungen vorhanden

"Wie es kaum nothig zu betonen ist. wird hier nur von einer allgemeinen
Herzschwache geredet; eine auf den linken Ventrikel beschrankte Schwachung
wiirde selbstverstandlich die Entstehung von Lungenodem im gegebenen Falle
erleichtern.

20 ZUE PATHOLOGIE DES LUNGENODEMS

sind, ist kaum anders zu erklaren als dadurch, dass die Kraft des rechten
Ventrikels zu gering ist, um die nothigv; Blutmasse in die Lungen hinein-
zuscliafifon. Es kann auch sein, dass die Stromkraft uiid der Gefasstonus
gleichzeitig so herabgesetzt sind, dass keine geniigendo Blutmasse in die
Venen und in's rechte Herz hineinfliesst. Ich mochte aber bezweifeln, dass
eine fiir die Entstehung von Lungenodem hinreichende Blutmasse nicht
zur Verfiigung des rechten Ventrikels stehe, da in einem ahnlichen Ver-
suche, in welchem der Druck in der Arteria pulmonalis durch die Unter-
bindung wenig beeinflusst war, der Druck in der Vena jugularis von 0 — 10
bis zu 60 Mm. Soda stieg.

In gleichem Sinne spricht ein versuch an einem Kaninchen bei welchem
gleich nach Unterbindung der Aorta zwischen Trimeus anonymus und
linker Subclavia und des Truncus anonymus zwischen linker und rechter
Carotis der Carotisdruck von 100 Mm. bis zu 40 Mm. Hg. sank, anstatt,
wie gewohnlich, um das Zweibis Dreifache zu steigen. Dieser ist der ein-
zige Falls aus zahlreichen Versuchen, bei welchem die Unterbindung der
Aorta und ihrer Aeste an einem Kaninchen nicht starkes Lungenodem hervor-
rief, und wir haben den besten Beweis durch das Verhalten das Carotisdrucks,
dass die plotzliche Untcrbrechuug des Blutstroms eine Herzliihmung
bewirkte. Hier war ein holier Druck vorhanden, als die Arterien unter-
bunden wurden, so dass wir das Ausbleiben von Lungenodem in diesem
Falle ausschliesslich der geschwiichten KJraft des rechten Ventrikels zuschrei-
ben miissen, wahrend die Stromkraft und der Gefasstonus zur Zeit der
Unterbindung normal waren. Uebrigens sei hier erwahnt, dass dies der
einzige Fall war, wo eine plotzliche Herzlahmung die Folge der Unterbin-
dung der Aorta war.

Das Verhalten des Herzens nach Unt-erbrechung des Kreislaufs durch
Verschliessung der grossen Arterien ist nicht ohne Interesse. Es fahrt
nehmlich bei erhaltener kiinstlicher Athmung oftmals eine Zeit lang fort
luit hohem Drucke zu pulsiren. Nachdem der grosse Kreislauf Stillstand
gebracht worden ist, kann man mit einer eudstandigen Manometercaniile
in der linken Carotis und einem Sodamanometer in einem Aste der Arteria
pulmonalis den Druck in diesen Gefassen messen, wiilirend das Herz die vor
ihm stehende Blutsaule noch kraftig bin und her treibt. Die Arterien
werden wie in Versuch 4 zugebunden. Wie aus diesem Versuch ersichtlich
ist, bleibt der Druck eine Zeit lang hoch ; bei Ilunden kann er sogar noch
eine halbe bis eine Stunde eine betrachtliche Hohe behaupten. Um sicher
zu sein, dass aller Blutxufluss ausgeschlossen sei, habe ich nach einiger
Zeit die beiden llohlvenen unterbunden, ohne das Versuehsresultat dadurch
zu veriindern. Der Puis zeigt die oft erwahnten, grossen, rhythmischen,

ZUR PATHOLOGIE DES LUNGENODEMS 21

periodischen Schwankungen, der Druck sinkt sehr allmahlich und nicht
ganz regelmassig, sondern erhebt sich von Zeit zu Zeit.

Eine interessante Frage ist, ob unter diesen Verhaltnissen der Coro-
narkreifilauf noch existirt. Als Beweise fiir seine Existenz erwahne ich da.s
Folgende. Ich habe mehrmals beobachtet, dass, wenn die kiinstliche Ath-
mung imterbrochen wird, nach 3 — 1 Minuten der Druck anfangt zu sinken
und zwar rascher sinkt als bei Fortsetzung derselben. Nach Herstellung
■der kiinstlichen Athmung steigt er wieder, aber diese Steigerung fangt nicht
gleich nach Beginn der Athmung an. In einem Versuche an einem Hunde,
nachdem der Carotisdruck von 170 bis zu 80 bei sistenter kiinstlicher Respi-
ration gesunken war, hat er seine friihere Hohe nach Herstellung der
kiinstlichen Athmung -svieder erreicht. Bei einem Kaninehen, an dem
der grosse Kreislauf unterbrochen war, habe ich beobachtet, dass nacli
Einstellung der kiinstlichen Athmujig das Blut im Vorhofe und der Goro-
nararterien allmahlich dunkel wurde, und dass die Athmung die rothe
Farbe wieder hervorrief. Man konnte vielleicht glauben, dass das I'lissver-
haltniss zwischen der Blutmenge und dem Gefiissrauminhalt unter diesen
Umstanden so gross sei, dass der Blutdruck liberhaupt nicht auf Null
sinken wirrde, das ist aber nicht der Fall.

Ein Saugethierherz, welches so machtig imter dem Reize des hohen
Blutdrucks fiir eine halbe bis eine Stunde pulsirt, bei welchem die Kraft
der Systole durch Druckmesser ermittelt werden kann, bei welchem cen-
trales Nervensystem und Gefasstonus ausser Wirkung gesetzt sind, und bei
dem der Coronarkreislauf noch existirt, ware kein unwiirdiger Gegenstand
fiir weitere TJntersuchungen. Die Dauer iind die einzelnen Phasen des
Phanomens sind variabel, aber die Bedingungen derselben habe ich nicht
weiter verfolgt. Hunde sind am besten fiir die Beobachtung derselben
geeignet. Bei Kaninehen scheint es am vortheilliaftesten, die Gefasse in
der folgenden Reihe zu unterbinden, die Aorta zwischen Truncus anony-
mus und linker Subclavia, die untere Hohlvene im Thorax, der Truncus
anonymus dicht peripher von linker Subclavia (Hg.-Manometer in linker
Subclavia). Wenn man bei einem Kaninehen die aufsteigende Aorta
zubindet, pulsirt der. linke Ventrikel gewohnlich nicht lange fort und das
Herz steht weit mit Blut ausgedehnt still. Nicht selten habe ich kleine
Blutungen unter dem Visceralblatt des Pericards nach Unterbindung der
Aorta beobachtet.

Da wir bisher nur die Erzeugung von Lungenodem durch Stromhinder-
nisse im grossen Kreislauf besprochen haben, so bleibt noch iibrig, die Ent-
stehung desselben in Folge von vermehrten Widerstanden im kleinen Kreis-
lauf selbst und im linken Abschnitte des Herzens zu betrachten.

22 ZUR TATHOLOGIE DES LUNGENODEMS

Um die Lungenvenen zu unterbinden macht man ein Fenster im Thorax,
wie fiir Druckmessung an der Lungenarterie. Beim Kaninchen sind
gewohnlich zwei Yenenaste, beim Hunde drei der liuken Lunge, deren
Unterbindung keine sonderliche Schwierigkeit bietet. Beim Kaninchen ist
es rathsam, olme kiinstliche Athmmig zu operiren, da die Lunge dann
zusammengefallen ist, aber man muss sich in Acht nehmen, bei der Umle-
gung eines Fadens um den unteren Venenast, nicht die Pleura der rechten
Seite zu verletzen, weil dies die Anwendung der kiinstlichen Athmung
sogleich unabweislich macht. Die Venenaste zu dem oberen und dem
mittleren Lappen der rechten Lunge sind leicht zu erreichen, aber der Ast
zu dem unteren Lappen und besonders der zu dem zimgenformigen hinter
der unteren Hohlvene liegenden Lappen sind uur mit grosser Schwierig-
keit zu fassen, so dass ich, wenn es darauf ankam sammtliche Lungenvenen
zu unterbinden, es vorgezogen habe, die Wurzel der rechten Lunge entweder
im Ganzen oder in ilirem unteren Theile en masse zuzubinden, wodurch
natiirlieh in dem betrefienden Theile der arterielle Zuiluss abgeschlossen
wird, was nach den Untersuchungen von L i c h t h e i m die Blutmasse in
den freien Theilen vermehren muss. Sowohl wenn man seine Wurzel en
masse unterbinden will, als wenn man seine Vene sucht, ist es nothig diesen
zimgenformigen Lappen hinter der Vena cava herauszuziehen und eine
Art von Ligamentimi, welches sein Pleurafortsatz bildet, mit den Fingern
sorgfaltig zn zerreissen, was sich ohne Blutung ausfiihren lasst.

Wie sehon erwiilint. bedingt die Yerschliessung siimnitlicher Venen der
einen Lunge kein Oedem. Das Thier lebt mehrere Stuuden nach der Opera-
tion und nach dem Tode findet man die betreffende Lunffe vollstandig
hamorrhagisch infarcirt. Im Gegensatz zu dem Auftreten von Lungen-
odem braucht es eine verhaltnissmassig geraume Zeit, ehe diese Infarcirung
zu Stande kommt, wahrend das Oedem gleich erscheint, wenn der Blutab-
fluss hinreichend gehemmt wird. Wenn ausser den Venen der linken Lunge,
die Venen, welche von dem oberen und dem mittleren rechten Lappen
kommen, zugebunden werden, bleibt auch das Lungenodem aus. In der
That muss man den Abflussweg aus den Lungen-
venen fast vollstandig verlegen, ehe es zur serosen
Ausschwitzungkommt. So lange ein Ast zweiter Ordnung offen
bleibt, ist das Hinderniss noch nicht gross genug. Kaninchen und Hunde
verhalten sich in dieser Beziehungr unsefahr gleich.

Versuch 5. Mittelgrosser curarisiter Hund. Hg.-Manometer in
Verbindung mit linker Carotis. Druck 60 — 70. Soda-Manometer im
unteren Aste der linken Lungenarterie. Druck 120. Xach Unterbindimg
des Hilus der rechten Limge bleibt der Carotisdruck unverandert, wiihrend
der Pulmonaldruck bis zu 300 steigt. Gleich danach werden die Venen der

ZUE PATHOLOGIE DES LUNGENODEMS 23

linken Lunge, mit Ausnalime eines kleinen Astes der unteren Vene, unter-
bunden. Der Carotisdruck sinkt auf 40 Mm., wo er 5 — 6 Minuten unver-
andert bleibt, und sinkt dann welter. Ein Hg.-Manometer, welcher anstatt
des zu niedrigen Soda-Manometers in Verbindung mit demselben Aste der
Lungenarterie gesetzt worden ist, zeigt eine Druckhohe von 55 Mm. Hg. in
Folge der Venenunterbindung. Die Obduction ergiebt sehr starke Stauung
und Oedem der linken Lunge ; rechte Herzhalf te ausgedehnt, linke fast leer.
Einspritzung von chromsaurem Blei in den linken Vorhof zeigt, dass alle
die Gefasse, wie oben angegeben, fest verschlossen sind und dass nur ein
kleiner Ast des linken unteren Yenenstammes offen bleibt.

LTnterbindung sammtlicher Lungenvenen, so dass aller Abfluss aus
denselben so plotzlich wie moglich aufhort, ist weniger giinstig fiir das
Zustandekommen von Lungenodem, als wenn, wie in dem eben beschriebenen
Versuche, ein sehr geringes Ausfiiessen in den linken Ventrikel ermoglicht
wird. Nach Verschliessung sammtlicher Lungenvenen stirbt das Thier
ausserst rasch und das Herz pulsirt nachher nur kurze Zeit. Bei vier Ver-
suchen an Kaninchen verursachte die Unterbindung der Lungenvenen (i. e.
der Wurzel der rechten Lunge und sammtlicher Venen der linken) zweimal
Limgenodem.

V e r s u c h 6. Starkes Kaninchen. Tracheotomie. Druck in rechter
Carotis 100 — 115 Mm. Hg. Faden um die beiden Venen der linken Lunge
gelegt. Kiinstliche Athmung. Unterbindung der ganzen Wurzel der
rechten Lunge. Carotisdruck bleibt unverandert. Gleich nachlier die
beiden linken Lungenvenen zugebunden. Caroti-sdruck sinlvt gleich auf Null.
In 10 Secunden nach voUendeter Unterbindimg wird das Thier unruhig,
in 20 Secunden bekommt es heftige Krampfe und in 45 Secunden ist es
todt. Die sofortige Obduction ergiebt deutliches, aber nicht starkes Oedem
der linken Lunge. Beide Limgen hyperamisch, die rechte dunkelroth, die
linke hellroth. Eechte Herzhalfte stark ausgedehnt, linker Ventrikel leer,
zusammengezogen. Korpervenen gestaut.

Verengerung der Venenbahn der Lunge scheint den
Carotisdruck ebensowenig herabzusetzen wie die Verschliessung ent-
sprechender Abschnitte der Lungenarterien. Man kann die Lungenvenen
wenigstens bis zu drei Viertel ihrer Capacitat verschliessen, ohne dass der
Carotisdruck wesentlich beeinflusst wird, aber nach TJeberschreitung einer
gewissen Grenze fangt der Druck im Aortensystem an zu sinken.

Der Druck in der Pulmonalarterie steigt weniger nach Unterbindung
von Aesten der Lungenvenen als nach Verschliessung entsprechender
Arterien.

V e r s u c h 7. Grosser, curarisirter Hund. Druck in linker Carotis
100 — 120 Mm., im unteren Aste der Art. pulmonalis sinistra 20 Mm. Hg.
Zubindung der drei linken Lungenvenen bewirkt Veranderung weder im
Carotis- noch im Pulmonalisdruck. Unterbindung der Venen, welche von
dem oberen und dem mittleren rechten Lappen herkonunen, hat keinen

24 ZUR PATHOLOGIE DES LUNGENODEMS

Einfluss auf den Carotisdruck, aber der Druck in der Art. pulmonalis steigt
4 Mm. Es bleibt jetzt bios die Vene offen, allerdings eine grosse, welche von
dem reehten uiiteren Lappen herkommt. Die Wurzel der reehten Lunge
wird en masse fest zugebunden. Der Druck in der Carotis sinkt gleich fast
auf Null; der Pulmonalisdruck steigt fiir einen Augenblick raach, sinkt
dann plotzlich und das Herz stelit still und lost keine Contraction mehr aus.
Die Obduction zeigt beide Lungen blutreich, aber kein Oedem. Einspritzung
mit chromsaurem Blei ergiebt, dass bei der Unterbindung der Lungenwurzel
nur der Venenstamm des reehten unteren Lappens offen geblieben war.

Der plotzliche Herzstillstand, welcher der Zubindung der reehten Lungen-
wurzel in diesem Falle folgte, erklart zur Geniige das Ausbleiben von Lun-
genodem. Wie schon oben er^viihnt, tritt oft unmittelbar nach Unterbindung
der Venen der einen Lunge und der Wurzel der anderen, wenn nicht eine
vollstandige Paralyse, so doch eine deutliche Schwachung des Herzens ein.
Eine Parese des reehten Ventrikels aber, wie wir sie bei Unterbindung der
Aorta schon gefunden haben, ist ein ungiinstiger Zustand im BetreflP des
Zustandekommens von Lungenodem, obwohl sie einen betriichtliehen Grad
erreichen mu^s, ehe die Entstehung des Lungenodems verhindert wird.

Ist die Herzlahmung, welche in einigen Fallen beobachtet wurde, die
Folge des plotzlichen Verschlu&ses des Ausfliessens aus den Lungenvenen,
wobei der Coronarkreislauf zum Stillstand gebracht wird (im Gcgensatz
zur Unterbindung der Aorta, S. 23), oder die Folge der langdauemden und
tiefeingreifenden Operation? Die Eroffnung beider Pleurahohlen, die
unvermeidliche Storung und Zerrung der dem Herzen anliegenden Gebilde,
die Beriihrung und Verschiebung des Herzens selbst bei Zubindung der
tiefiiogenden unteren und hinteren Venen der reehten Lunge oder der Lun-
genwurzel, und die lange Dauer der Operation beim Lufteintritt in die
Pleurahohlen sind alles Momente, welche wohl die Herzkraft bedeutend
herabsetzen konnen. Beutner'" hat darauf aufmerksam gemacht. dass
bei offener Pleuraliohle die rechte Herzkraft sich bedeutender abschwacht
als die linke, dass die erstere im Sinken begriffen sein kann, wiihrend die
letztere noch steigt. Eine mogliche Erkliirung findet er darin, ,, dass das
linke Herz sich weniger leicht abkiihlt wegen seiner dickeren Muskelmasse ".
Fiir uns liegen die Verhaltnisse, wie wir sehen werden, gerade umgekehrt:
Schwachung des linken Ventrikels bei so wenig wie miiglich beeintriichtigter
Kraft des reehten Ventrikels ist es, welche die Entstehung von Lungenodem
begiinstigt. Desshalb sind die bei Unterbindung der Lungenvenen noth-
wendigen Eingriffe fiir unseren Zweck djrect entgegeuwirkeuder Natur. Die
Versuche von B e z o 1 d " iiber Zuklemmung der Kranzarterien erlauben uns

" Ueber die Strom- und Druckkrafte des Blutes in der Arteria und Vena pul-
monalis. Zeitschrift fiir rat. Med. N. F. Bd. 2, S. 119. 1852.
" Untersuch. aus d. physiol. Laborat. in Wiirzburg. 1867. Hft. 2.

ZUE PATHOLOGIE DES LUNGENODEMS 25

auch nicht dem Auihoren des Coronarkreislaufs alien Einfluss abzusprechen,
um so mehr da beim Einfliessen einer sehr kleinen Blutmenge Lungenodem
leichter zu Stande kommt, als bei vollstandiger Abspeming der Blutzufuhr
vom linken Ventrikel.

Das fiir unseren Zweck wichtigste Ergebniss der
Versuche iiber Einsetzung von Hindernissen in den
Abfluss des Blutes aus den Lungenvenen in den
linken Ventrikel ist, dass dadurch zwar Lungenodem
erzeugt werden kann, dass aber diese Hindernisse
enorm, ja dass fast sammtliche Lungen ven enas te
verlegt werden miissen, ehe Oedeni entsteht, und
dass erst bei diesen colossalen Wi derstande n der
Druck in der Pulmonalarterie eine bedeutende
Steigerung erleidet.

Demjenigen, der mit TTntersuchungen iiber den Lungenkreislauf nicht
niiher vertraut ist, kann es vielleicht auffallen, dass ich mir Schliisse iiber
den Dnick in den Luugenvenen aus Messungen in der Luiigenarterie erlaubt
habe. Alle Forscher " aber, welehe Druckmessungen in den Lungengefassen
angestellt haben, stimmen darin tiberein, dass die Widerstande in den
Lungencapillaren so klein sind, dass Druekerhohung in den Lungenvenen
von einer gleichsinnigen Veranderung in der Lungenarterie begleitet ist.
Die Untersuchungen von Lichtheim haben es wahrscheinlich gemacht,
dass der Tonus der Lungengefasse ausserst gering ist. B e u t n e r fand bei
einer Katze 9 Mm. Hg. als Maximalwerth der Diilerenz der Druckkrafte in
der Arterie und in der Vene am Vorhofe. Wir aber sind bei imseren Unter-
suchimgen lun so mehr berechtigt, von dem Druckwerthe in der Lungenar-
terie einen Schluss auf die relative Spannung in der Vene zu ziehen, als es
sich um ganz grobe Abweichungen von der Norm handelt.

Weniger well es von principieller Bedeutung ist, als um alle Wege zu
untersuchen, auf welchen mechanische Hindernisse den Abfluss des Blutes
aus der Lunge hemmen konnen, habe ich bei Kaninchen durch Abbindung
des grossten Theiles des linken Vorhofes und durch Zuklemmung des linken
Ventrikels Lungenodem zu Stande gebracht. Es ist erstaunlich, ein vvie
grosser Abschnitt des Vorhofes oder des Ventrikels verlegt werden muss,
nicht, nur ehe Lungenodem eintritt, sondern auch ehe der Carotisdruck zu
sinken anfangt. Ich mochte sagen, dass wenigstens drei Viertel der
Capacitat des linken Ventrikels ausgeschaltet werden miissen, um Lungen-
odem zu verursaclien. Die Zuklemmung geschah mit stark fedemden, breiten
Charriere'schen Klemmpincetten. In einem Versuche lebte das Thier eine

"Beutner.G. Colin, Badoud, Hofmokl, Lichtheim.
5

26 ZUR PATHOLOGIE DES LUNGENODEMS

halbe Stuiido, iiaclidcm wenigstens die Halfte des linken Ventrikels zuge-
klenimt war uiid starb mit Erstickungserscheinmigen ohne Lungenodem.
Die erste Wirkung einer partiellen Zuklemmung besteht darin, durch Herz-
reizung (oder duroli Hirnananiie?) den Druck in der Art. carotis zu erholien,
welclier audi nach Abnalmie der Klemnipincetten lioch bleibt. In einem
Versuche habe ich beobachtet, dass, gleich nachdem der grosste Theil des
linken Ventrikels zugeklemmt wurde, das Thier in einen tetanischen Zustand
gerieth. Dasselbe wurde bewusstlos iind blieb unerregbar bis zuni Tode,
welcher (durch Drucksinkung erkennbar) nach ungefahr 15 Minuten ohne
Krampfe oder Dyspnoe, aber niit starkem Lungenodem, eintrat.

Nachdem wir die Bedingungen ermittelt haben, unter welchen ein
mechanisches Oedem der Lunge an Kaninchen und Hunden experimentell
lierbeizuf iihren ist, so entsteht die Frage : welches Liclit werfen die vorliegen-
den Beobachtungen auf die Ursachen des Limgenodems helm Menschen?
Es liegen gewiss die Bedingungen des Lungenodems, welches ich durch
mechanische Momente zu Stande gebracht habe, sehr weit entfemt von den-
jenigen, welche in der grossten Mehrzahl der Falle von acutem, allgemeinem
Hydrops pulmonum beim Menschen herrschen, und iiber die Entstehung des
letzteren konnen die Ergebnisse der oben erwahnten Versuche anscheinend
wenig Positives aussagen. Und doch liegt, meiner Meinung nach, in ihnen
der Schliissel zur Losung des Problems, das uns beschaftigt.

Das Oedem, welches ich kiinstlich erzielt habe, ist ein Stauungsodem und
tritt erst dann ein, wenn der Druck im Lungenkreislauf bedeutend erhoht
ist. Das mikroskopische Bild dieses Oedems stimmt in alien seinen wesent-
lichen Charakteren mit dem des allgemeinen Lungenodems deim Jlenschen
iiberein. Bei beiden sieht man hochgradige Fiillung der Lungencapillaren
und zalilreiche ausgetretene rothe Blutkorperchen. Diese Uebereinstimmung
bestiirkt an sich die ohne geniigende Griinde gewohulich angenommene An-
sicht, dass das Lungenodem ein Stauungisodem sei. Indess haben die
obigen Versuche die geliiufigen Erkliirungen dieses Oedems entkriiftigt. Von
denselben giebt es eigentlich nur zwei, welche Anspruch auf Wahrschein-
lichkeit machen konnen und in Einklang mit klinischen Erfahrungen zu
stehen scheinen. Dies sind die beiden oben angegebenen Ursachen der
venosen Stauung, Storung des Abflusses des Blutes aus den Pulmonalvenen
durch Klappenfehler des linken Ventrikels und geschwachte Herzaction.
Es fohlt, meiner Ansicht nach, ohnehin niclit an Griinden, um die Unzu-
langlichkeit beider Momente fiir die Erklarung des Zustandekommens des
Oedema pulmonum nachzuweisen ; jedenfalls lassen die Ergebnisse des Ex-
periments ihre Unhallharkeit klar zu Tage treten. Eine „ Storung des
Abflusses des Blutes aus den Pulmonalvenen " durch mechanische Hinder-

ZUE PATHOLOGIE DES LUNGENODEMS 27

nisse verursacht erst dann Oedem der Lunge, wenn dadurch fast sammtliche
Veneuaste verlegt worden sind. Von solchen Hindernissen im grossen oder
im kleinen Kreislauf kann beim Menschen kaiim die Rede sein ; wenigstens
miissen wir diesem Momenta eine allgemeine Bedeutung bei der Losung
unseres Problems absprechen. Geschwachte Action des ganzen Herzens
erzeugt nicht nur an und f iir sich kein Oedem, sondern, wenn selbst die son-
stigen Bedingungen vorhanden sind, kann sie das Auftreten desselben
hintanlialten.

Giebt es denn keine andere Ursache fiir Lungenstauung, welehe wir als
die Bedingung \on Lvuigenodem betrachten konnen, ohne mit den bekannten
Eigenschaften der Pulmonalcirculation und den klinischen Beobaclitungen in
Widerspruch zu treten? Oder soUen wir etwa auf die Wirkung mechan-
ischer Momente verzichten und imsere Zuilucht zu der Annahme einer
unbekannten Gef iisswandveranderung nehmen ? Zu solch einem Schritt wird
sich, denke ich, schwerlich jemand entschliessen, so lange nicht alle mechan-
isehen ErklarungsmoglielLkeiten erschopft sind. Eine solche aber scheint
mir jedes Missverhaltniss zwischen der Kraft des linken und der des rechten
Ventrikels zu sein, wobei der erstere nur einen Bruchtheil der Blutmenge
in der Zeiteinheit heraustreiben kann, welehe der letztere in die Lungenar-
terie hineinschafft, d. h. eine linksseitige Lahmung des
Herzens.

Wenn ich das Wort Missverhaltniss gebrauehe, so denke ich selbstverstand-
lich nicht an den absoluten Unterschied zwischen der Kraft des rechten und
der des linken Ventrikels. Diese Kraft steht bekanntlich in directem
Verhaltnisse mit der Widerstandshohe am Anfang des grossen resp. des
kleinen Kreislaiifs. Die Triebkraft des linken Ventrikels kann bedeutend
vermindert werden, wahrend die des rechten unverandert bleibt oder sogar
erhbht wird, ohne dass ein Missverhaltniss zwischen denselben sich ausbildet,
vorausgesetzt, dass die Widerstande im gleichen Sinne und in demselben
Verhaltnisse sich andern. Ein solch relatives Missverhaltniss
zwischen der arbeitskraft des linken Ventrikels und der des rechten bedeutet
dagegen, dass bei gleichbleibenden Widerstanden das
linke Herz nicht dieselbe Blutmenge in der Zeit-
einheit hinau szu t r e ibe n vermag, wie das rechte.

Gesetzt den Fall, der linke Ventrikel wird gelahmt, der rechte arbeitet mit
unverminderter Kraft fort und empfangt nicht weniger Blut als vorher, was
muss geschehen ? Das Blut muss sich in den Lungengef assen haufen, bis der
beharrliche Zustand, der bei jedem Kreislaufe eine Nothwendigkeit ist,
eintritt. Dieser kommt erst dann zu Stande, wenn die Widerstandshohe in
der Lungenarterie so gross geworden ist, dass der rechte Ventrikel nur
dieselbe Menge Blut in der Zeiteinheit hineintreiben kann, wie aus den

28 ZUK PATHOLOGIE DES LUNGENODEMS

Lungenvenen herausfliesst. Es ist klar, dass je schwacher der linke Ventrikel
einerseits und je starker der rechte andererseits, desto grosser die Druekhohe
in dem Lungenkreislauf ausf alien wrd, bei welcher der beharrliche Zustand
entsteht.

Ob diese Druekerhohung in einem gegebenen Falle Lungenodem verur-
sachen wird, ja ob sie iiberhaupt dazu hinreicht, ist von vornherein nicht mit
Bestimmtheit zu sagen. Es bedarf keiner Erorterung, dass die dynamischen
Momente andere sind als bei mechanischen Hindemissen fiir den Abfluss des
Blutes aus den Lungenvenen, wo ejne geringe Drueksteigenmg geniigt,
um erhebliche Widerstiinde zu iiberwinden. Selbst weun ich keine
experimentellen Beweise dafiir beibringen konnte, dass eine linksseitige
Herzschwachung ausreicht lun Lxmgenodem zu erzeugen, so glaube ich doeh
in Ansicht der ^langelhaftigkeit anderer Theorien, dass es nicht unniitz
ware auf diese H3'pothese aufmerksam zu maehen, welehe uns wenigstens
eine sehr plausible Erklarung der Entstehung von Lungenodem, ini Wider-
spruch weder mit den bekannten Eigenschaften der Pubnonalcirculation
noch mit der klinischen Beobachtung, darbietet. Selbstverstandlich aber
muss die H}'pothese eine ganz andere Stellung gewinnen, wenn es sich
beweisen liesse, dass eine linksseitige Herzschwachung an und fiir sich geniigt
um Lungenodem zu Stande zu bringen, imd deshalb schien es geboten,
dieselbe einer experimentellen Priifimg zu imterwerfeu.

Durch welehe Mittel aber ist es moglich eine einseitige Herzlahmung zu
erzeugen? Unter den verschiedenen Herzgiften hat keines, so viel mlr
bekannt, die Eigenschaft allein oder hauptsiichlich auf den einen Ventrikel
zu wirken. Die Kalisalze, Jodsalze, Kohlenoxyd, Strychnin konnen alle als
eine inconstante Folge ihrer giftigen Wirkung Lungenodem herbeifiihren.
Aber wegen der Inconstanz dieser Erscheinung und wegeu der Schwierig-
keit einen Beweis zu liefern, dass in einem gegebenen Falle der eine Ven-
trikel starker afficirt sei als der andere, musste ich bald vom Experimen-
tiren mit den Herzgiften absehen. Wenn nach dem Tode der rechte Ven-
trikel sich zusammenzieht, wahrend der linke stillsteht, os ist dieses kein
Beweis, dass der letztere gelahmt gewesen ist, da bekanntlich bei alien abster-
benden Herzen das rechte Herz seine Contractionsfahigkeit liinger bewahrt
als das linke, und Du Bois Eeymond gezeigt hat, dass der kraftigere
Muskel seine Eeizbarkeit rascher einbiisst als der weniger reizbare.

Auch die locale Einwirkung schiidlicher Stoffe auf die Aussenfliiche des
liuken Ventrikels erwies sich als fiir unseren Zweck vollig imgeniigend.
Ich versuchte durch Aufstreuen von Kalisalzen, durch Aufgiessen von
Chloroform, durch Eis, durch Hitze die Kraft des linken Ventrikels zu
beeintrachtigen. Er zeigte aber eine erstaunliehe Widerstandsfiihigkeit. Es
gelang mir in den meisten Fallen nur eine starkere Action des Herzens und

ZUE PATHOLOGIE DES LUNGENODEMS 29

erhcihten Carotisdruck zu erzielen, und wenn einmal der linke Ventrikel
stillstand, so wurde der rechte auch ruliig.

Endlich erreichte ich das ervriinsclite Ziel durch Quetschung der Waaid
des linken Ventrikels. Fiir diesen Zweck sind die Finger das beste Instru-
ment, Pincetten u. s. w. zerreissen die Muskelwand zu leicht. Ich habe den
Eingriff bios am Kaninchenlierzen gemacht, da das Herz des Hunds zu
starkwandig und kraftig ist. Der linke Ventrikel wird z-mschen den
Daumen und einen oder zwei Finger genommen, so dass so viel wie moglich
seiner Muskelwand inclusive des Septum ventriculorum gefasst wird, ohne
den rechten Ventrikel zu beeintrachtigen, und dann stark zusammenge-
driickt. Es erfordert; eine niclit geringe Kraft um den Ventrikel wirklich
zu lahmen. Ein Hg.-Manometer muss in Verbindung mit einer Carotis
stehen, damit man die Kraft des linken Ventrikels beurtheilen kann. Durch
diese Methode habe ich in vielen Fallen den linken Ventrikel entweder zum
Stillstand gebracht, oder mehr oder weniger vollstandig gelalunt, wahrend
der rechte noch einige Zeit stark pulsirt. In vielen Fallen aber hatte der
Eingriff andere Wirkungen. Nicht selten stand das ganze Herz plotzlich
still, selbst nachdem ein verhiiltnissmassig geringer Druck auf dasselbe ausge-
iibt worden war; oft wurden beide Ventrikel gleichmiissig und gleichzeitig
geschwacht. War endlich die Quetschung nicht stark oder nicht ausgedehnt
genug ausfallen, so wirkte hiiutig der Eingriff als ein Reiz fiir den Herz-
muskel.

Obwohl ein einziger Fall von unzweideutiger Lahmung des linken Ven-
trikels bei Fortarbeiten des rechten geniigt hiitte, um die Moglichkeit dieses
Zustandes zu beweisen und die Folgen desselben zu beobachten, suchte ich
doch durch ein grosseres Beobachtungsmaterial die daraus gezogenen
Schliisse ausser allem Zweifel zu setzen. Dabei wurden viele Thiere nutzlos
geopfert : doch ist es mir gelungen in einer grossen Anzahl von Versuehen
eine deutliclie allein oder hauptsachlich auf den linken Ventrikel beschriinkte
Lahmung zu erzielen, und ich kann mit Bestimmtheit behaupten, dass bei
einer gewissen Kraft des rechten Ventrikels eine hinreichend hochgradige
Schwachung des linken Lungenodem herbeifiihrt.

V e r s u eh 8. Mittelgrosses Kaninchen. Kiinstliche Athmung.
Quecksilberdruck in rechter Carotis 100—120 Mm. Thorax in der Mittel-
linie geoffnet und das Herz durch Eroffnung des Pericards blossgelegt. Der
linke Ventrikel wird zwischen den Fingem stark znsammengedriickt. Der-
selbe steht in Contraction absolut still und lost keine erkennbare Pulsation
mehr aus. Der Carotisdruck sinkt auf 20 ilm. Der rechte Ventrikel, der
zuerst stillstand, fangt nach einigen Secunden an wieder zu pulsiren und
zieht sich 3 Minuten lang anscheinend kraftig und in regelmassigem Ehyth-
mus zusammen. Die beiden Vorhofe pulsiren ungefahr dreimal so schnell
als der Ventrikel. Die Arteria pulmonalis und die beiden Vorhofe werden

30 ZUR PATHOLOGIE DES LUNGENODEMS

stark, der rechte Ventrikel massig ausgedehnt. Nach 2 — 3 Minuten bekommt
das Thier Krampfe und stirbt. Die Obductioa ergiebt sehr starkes Oedem
beider Luiigen.

V e r s u c h 9. Grosses Kaninchen. Kiinstliclie Athmunfj. Druck in
linker Carotis 90 Mm. Hg. Eroffnung des Thorax in der Mittellinie und
des Herzbeutels. Der linke Ventrikel inclusive des Septums wird mit den
Fingem stark comprimirt. Carotisdruck sinkt auf 30. Der linke Ventrikel
pulsirt einige Secunden mit diesem geringen Drucke und dann erholt er sich
allmahlicli. Nach wiederholter Quetschung sinkt der Dnick yrieder auf 30
und allmahlich noch tiefer. Im Gegensatz zu dem linken Ventrikel arbeitet
der rechte 3 — i Minuten anscheinend ungeschwacht fort, wahrend welcher
Zeit sich das Blut in der Lungenarterie, den beiden Vorhofen, dem recliteii
Ventrikel und den Korpervenen deutlich staut. Der Carotisdruck sinkt bis
Null und nach 5 ilinuten wird die kiinstliche Athmung sistirt. Das Thier
stirbt ohne Krampfe. Die Section ergiebt starkes Lungenodem. Es linden
sich kleine Blutungen in der gequetschten ^luskelwand des linken Ventrikels
und kleine Fibrinauflagerunsren auf seiner Innenflache.

Versuch 10. Kleines Kaninchen. Kiinstliche Athmung. Druck in
linker Carotis 90—100 Mm. Hg. Der ganze linke Ventrikel wird zwischeu
zwei auf den Branchen einer Pincette "befesti.ijten Korkplatte comprimirt.
Der Carotisdruck sinkt ziemlich rasch bis Null. Der rechte Ventrikel
pulsirt 1-J — 2 Minuten fort \ind dann stirbt das Thier unter Erstickungser-
scheinungen. Nachdem der rechte Ventrikel zu pulsiren aufgehorthat,
schlagen wie gewohnlich die Vorhofe noch weiter, am langsten'der rechte.
Die Section ergiebt Oedem beider Lungen. Die Pulmonalarterie und rechte
Herzhalfte sind stark ausgedelmt, die Korpervenen gestaut.

In einigen Fallen •mirde der linke Ventrikel durch die Quetschung
vollkommen zum Stillstande gebracht, in anderen pulsirte er noch mit
schwachem Drucke fort, in alien aber, bei welchen Lungenodem entstand.
schlug der rechte Ventrikel noch einige Zeit rhythmisch und anscheinend
mit ungeschwachter Kraft fort. Natiirlich aber geniigt der Augenschein
nicht und es war zur Controlle unbedingt nothig, den rechten Ventrikel
gleichfalls zu liihmen und zwar sowohl ohne Beeintrachtigung des linken
wie auch mit gleichzeitiger Liihmung desselben.

Man kann den rechten Ventrikel in derselben Weise wie den linken zur
Liihmung bringen, nur wird dies durch die Diinnwandigkeit desselben
erleichtert. Ich babe eine deutliche Lahmung des rechten Ventrikels sowohl
ohne gleichzeitige Beeintrachtigung des linken, wie auch mit Quetschung des
letzteren, mehrmals erzeugt, und nie Lungenodem in Folge
davon beobachtet. Einen Versuch will ich als Beispiel anfiihren.

Versuch 11. Mittelgrosses Kaninchen. Kiinstliche Athmung.
Quecksilberdruck in rechter Carotis 100 Mm. Eroffnung des Thorax in der
Mittellinie und des Pericards. Eecliter Ventrikel zwrschen den Fingem
zusamm(<ngepresst. Der Carotisdruck sinkt bis 30, aber nach einer Minute
ist er wieder auf 100 — 110 Mm. gestiegen. Der rechte Ventrikel wird wieder
gequetscht, Caroti.sdruck 20. Der rechte Ventrikel ist deutlich geliihmt und

ZUE PATHOLOGIE DES LUNGEXODEMS 31

wird mit Blut ausgedehnt, in viel starkerem Grade staut sich das Blut in dem
rechteu Vorhofe. Der linke Ventrikel pulsirt fort und bietet einen auffallen-
den Contrast zum rechten, welcher nach kurzer Zeit bios -mirmformige und
dann vibrirende Bewegungen macht. Nach ungefahr 2| Jilinuten stirbt das
Thier mit Krampfen. Bei der Section zeigen sich der linke Ventrikel und die
Arterien blutleer, dagegen die Venen strotzend gefiillt. Es ist kein Lungen-
odem vorhanden.

In B er ii c ks ich tigung der Ergebnisse dieser Ver-
suche diirfen wir ohne Bedenken linksseitige Herz-
paralyse als eine Causa efficiens von Lungenodem
betrachten. Theoretische Ueberlegungen lassen es kaum anders
erwarten. Wenn der reehte Ventrikel fortfahrt Blut in die Lungengefasse
hineinzupumpen, wahrend der linke nur einen Bruehtheil davon forttreiben
kann, wenn der Untersehied zwischen den Kraften der beiden Ventrikel
einen gewissen Grenzwerth iiberschritten hat, dann muss, scheint mir, der
Druck in den Lungencapillaren so hoch steigen, dass Lungenodem die Folge
wird. Der Einwand, dass die verminderte Kraft des linken Ventrikels die
Stromkraft im grossen Kreislauf so herabsetzt, dass keine fiir diese Druck-
steigerung hinreichende Blutmenge in den rechten Ventrikel einfliesst, ist
am besten durch das Ergebniss des Versuches beantwortet. Dariiber wie die
Stromgeschwindigkeit sich dal>ei verhalt, auch liber die absolute Hohe des
fiir das Zustandekommen von Lungenodem nothigen Kraftunterschiedes der
beiden Ventrikel habe ich keine experimentellen Data, und theoretische
Betrachtungen iiber diese Punkte hatten keinen Werth.

Diese durch das Experiment gestiitzte Hypothese bietet meiner Meinung
nach die beste Erklarung der Eigenthiimlichkeiten des Auftretens von
Lungenodem beim Menschen.

Die grossere Schnelligkeit, mit welcher Oedem sich in der Lunge ent-
wickelt als in anderen Korpertlieilen, findet seine Erklanmg in der absolut
grosseren Durchlassigkeit der Lungencapillaren, oder, besser ausgedriickt,
in der grosseren Differenz zwischen dem Seitendruck in den Gef iissen und den
Widerstiinden, welche der durchdringenden Fliissigkeit entgegenstehen.
Einerseits bedingen die Ursachen von Lungenodem einen fiir den Pulmonal-
kreislauf verhaltnissmassig hohen Seitendruck, andererseits finden die
Lungencapillaren nur eine schwache Stiitze an dem Lungengewebe. Wenn
man bedenkt, dass unter normalen Verhaltnissen die Spannung in den
Lungengefiissen sehr gering ist, dass sie zu einem erstaunlichen Grade gegen
Druckveranderungen im grossen Kreislauf geschiitzt sind, dass selbst bedeu-
tende Storungen im Limgenkreislauf mit geringen Druckanderungen aus-
geglichen werden konnen, so begreift man, dass sie gegeniiber den physiolo-
gischen und vielen pathologischen Verhaltnissen einer grosseren Starke nicht
bediirfen. Wegen der giinstigen Abdvmstungsbedingungen in der Lunge

32 ZUR PATHOLOGIE DES LUNGENODEMS

und wegen des durcli liistologische Untersuchuxigen wahrscheinlich gemach-
tcn reichlichen Ljniphabflusses aus derselben, ware es iiberdies leicht
erklarlich, dass eine bei leichten Dnicksteigeningen moglicherweise ein-
tretende vermehrte Ausscheidung aus den Lungencapillaren ohne storende
Erscheinimgen ablaufen konnte. Wenn aber eine plotzliche und hochgradige
Drucksteigerung in den Lungencapillaren eintritt, fiir welcbe die obigen
Versuche Beispiele darbieten, dann verratJien die Capillaren ihre absolut
geringere Widerstandsfahigkeit dadurch, dass Lungenodem in der Zeit von
einer oder zwei Minuten imd noch schneller entstehen kann. Es ist eben
dieses stiirmische Auftreten, welches eine grosse Anzahl der Fiille von Oedema
pulmonum beim ilenschen charakterisirt. Seine Erkliirung liegt auf der
Hand, wenn wir die Ursache desselben in einer plotzlicben Schwachung des
linken Ventrikels suchen. Mit anderen Erklarungsweisen scheint es mir
dagegen nicht leicht diesen Charakter des Lungenodenis in ELnklang zu
bringen.

Ein weiteres jMerkmal des Lungenodenis ist die Inconstanz seiner Ent-
stehung bei anscheinend gleichen Bedingungen. Wenn Lungenodem bei der
Todesagonie wegen der allgemeinen Herzschwache entstiinde, wenn die
eollaterale Hyperamie Oedem der einen Limge bei Hepatisation der anderen
herbeifiihrte, wenn bei einer Mitralstenose das mechanische Hindemiss des
Blutabflusses oder bei Morbus Brightii die Hydramie die Ursache des Oedems
bildete, warum erscheint es dann in dem einen Falle und bleibt in dem
anderen aus, obwohl in beiden diese Bedingungen anscheinend in gleichem
Grade vorhanden sind ? Diese unter den obigen Voraussetzungen so rathsel-
hafte Inconstanz ist wohl erklarlich, wenn wir Jene Zustiinde als begiin-
stigende Momente (Dispositio ad morbum) betrachten, aber eine vor-
wiegende Schwache des linken Ventrikels als die
nachste L^rsache annehmen. Wenn bei der Agonie zum Beispiel die beiden
Herzhalften beim Absterben gleichen Schritt halten, so entsteht kein Lun-
genodem, wenn aber der linke Ventrikel vorauseilt und rascher gelahmt wird,
als der rechte, dann kann es zu Stande kommen. Daljei wird natiirlich nicht
gesagt, dass der rechte Ventrikel nicht gleichzeitig audi schwaclier werde ;
er ist sogar wahrscheinlich in den meisten Fallen von Lungenodem ge-
schwacht. Diese Schwache aber begiinstigt an und fiir sich nicht das Auf-
treten von Lungenodem. Gewiss freilich verliert der linke Ventrikel sein
■mmderbares Anpassungsvermogen an wechselnde Widerstande, verander-
liclien Fiillungsdruck und was auch sonst fiir regulatorische Einrichtigungen
der Herzkraft im Spiel sein mogen, nicht eher vollstiindig, als bis die Leist-
vmgsfahigkeit des g a n z e n Herzens angegriffen worden ist. So entsteht das
Lungenodem, welches in Verlauf von Herz-, Lungen-, Nierenkrankheiten
u. s. w. auftritt erst dann, wenn die Gesamratthiitigkeit des Herzens herabge-

ZUK PATHOLOGIE DES LUNGENODEMS 33

setzt ist, \iiid deshalb ist man zu der irrthiimlichen Jleinung gekommen, dass
allgemeine Herzschwache allein eine Causa efficiens des Hydrops pulmo-
num sei.

Hier mochte ich einem Einwand begegnen, welcher sieh folgendermaassen
ausdriicken liesse. Wenn zum Beispiel bei einer uncompensirten Mitral-
stenose der rechte Ventrikel den vorhandenen Widerstanden nicht gewach-
sen ist, vie kann man annehmen, dass bei nocb grSsseren Hindemissen seine
Kraft ausreichen ■vrerde, mn die f iir die Entstebung von Liongenodem nothige
Druckhohe zu Stande zu bringen? Aber eben diese vermehrten Wider-
stande sind ein Eeiz fiir das recbte Herz : wahrscbeinlicb ist der Haupt-
regulator der Herzkraft in den vor ihm liegenden Widerstanden gelegen,
und obwohl der rechte Ventrikel, wahrseheinlich selbst in normalem
Zustande, nicht auf die Dauer die Druckhohe behaupten konnte, welche fiir
die Entstebung von Lungenodem nothig ist, reagirt er doch, selbst in
geschwachtem Zustande, fiir eine kurze Zeit auf die plotzlich vermehrten
Widerstande mit dem nothigen Kraftaufwand. Das rasche Zuriicktreten von
Lungenodem in vielen Fallen ist vielleicht ebenso sehr auf die ungeniigende
Kraft des rechten Yentrikels die Stauung langer zu behaupten, wie auf
Herstellung der Kraft des linken Herzens zu beziehen. Dass es eine minim'ale
Grenze giebt, unter welcher die Kraft des rechten Ventrikels nicht mehr
fahig ist, ein Stauungsodem zu erzeugen, betrachte ich aJs sehr wahrschein-
lich, aber es sind keine Anhaltspunkte vorhanden, um zu bestimmen, wo
diese Grenze liegt. Und vielleicht ist es mehr verminderte Erregbarkeit. als
verminderte Kraft des rechten Ventrikels, welche der Entstebung von
Lungenodem hinderlich wird. Da aber das Oedem, welches ohne vorherge-
hende bedeutende allgemeine Herzschwache — wie gelegentlich bei Krank-
heiten der Kreislaufsorgane, sowie bei Gebirnkrankheiten, besonders trau-
matischer Natur — plotzlich auftritt, das starkste und von den bedrohlich-
sten suffocatorischen Erscheinungen begleitet ist. wahrend dasjenige der
Todesagonie oftmals so gering ausfallt, dass man zweifelt, ob es iiberhaupt
den Namen verdient, so konnen wir schliessen, dass es fiir den Grad des
Lungenodems nicht gleichgiiltig ist. ob eine betrachtliche allgemeine Herz-
schwache vorhergegangen ist oder nicht.

Wenn ich eine ILnksseitige Herzparalyse als die Causa proxima des acuten
allgemeinen Lungenodems in Anspruch nehme, so meine ich nicht, dass
anderen Momenten, als Herzfehlern, Hydramie etc., aller Einiiuss abzu-
sprechen ist, sondern nur, dass diese allein uns keine befriedigende
Erklarung der Entstehving des Oedema pulmonum geben.

In der Entstehungsweise und in den Erscheinungen von Lungenodem
beim Menschen ist nichts, was, so viel ich sehe, gegen die auseinanderge-
setzte Hypothese spricht, wahrend vieles seine vollkommene Erklarung

34 ZUR PATHOLOGIE DES LUNGENODEMS

dadurch fiiidet. Ob divs Yorhandensein des vorausgesetzten Zustandes dea
Herzens am Menschen zu beweisen sei, scheint mir zweifelhaft. Das von
klinischer Seite " hervorgehobene Symptom des acuten allgemeinen Lungen-
odems, starker Herzsehlag bei schwachem Pulse, scheint eine Stiitze fiir
unsere Auffassung darzubieten, doch moehte ieh nicht zu vieles Gewicht
darauf legen, da auch eine Lungenstauung aus irgend welcher anderen
Ursache den rechten Ventrikel secundiir zu starkerer Arbeit veranlassen
konnte. Da es nur in untergeordnetem Grade auf die absolute Kraft-
leistimg des linken oder des rechten Ventrikels, vielmehr vorzugsweise auf
das Verhiiltniss zwischen beiden ankommt, so mag es schwierig sein, diese
relative Verschiedenheit klinisch zu constatiren, indess trotzdem wird sich
vielleicht die Aufmerksamkeit der Kliniker in Zukunft auf diesen Punkt
richten.

Das mikroskopische Bild des allgemeinen Lungenodems lasst sich mit
wenigen Worten zusammenfassen. Erzeugt man kiinstlich Lungenodem,
zum Beispiel durch Unterbindung der aufsteigenden Aorta, und nimmt, ohne
die Lvingen beriihrt zu haben, etwas von der Oedemfliissigkeit sorgfaltig mit
einer Pipette aus der Trachea heraus, so finden sich darin folgende korper-
liche Elemente: zahlreiche rothe Blutkorperchen, Bronchialepithelien,
sparsame Lxmgenepithelien und freie Kornchen von demselben Aussehen,
wie diejenigen in den Lungenepitlielzellen, selten weisse Blutkorperchen.
Die als Lungenepithelien angesprochenen Zellen sind platt, zwei- bis viermal
so gross als weisse Blutkorperchen, grob granulirt, rund oder oval, enthalten
jede einen blaschenformigen, ovalen Kern, selten deren zwei, und kommen
meistens vereinzelt vor. Im Verhaltnisse zu der Menge der rothen Blut-
korperchen ist jedenfalls die Anzahl aller iibrigen Elemente verschwindend
klein.

Schnitte aus der menschlichen odematosen Lunge zeigen die prachtvollste
natiirliche Injection der Capillaren. In diesen liegen oft die Blutkorperchen
zu zweien oder dreien in einem Querschnitt, wahrend gewohnlich, selbst in
hyperamischen Lungen, bios ein einziges Blutkorperchen in einem Quer-
schnitt Platz findet. Die Capillaren sind mit anderen Worten zwei- bis drei-
fach liber ilire nomiale Weite ausgedehnt. Ausserhalb der Gefasse finden
sich viele rothe Blutkorperchen in den Alveolen und den Interstitien.

Die oben als Lungenepithel erwahnten Zellen findet man in grosser Menge
an Schnitten aus der f rischen Lunge. Aber, wie schon Friedlander
hervorgehoben hat, sind sie eden so zahlreich und mit demselben Aussehen
an Schnitten jeder frischen Lunge zu sehen imd bieten deshalb nichts fiir

"^ L e b e r t , Handbuch d. pract. Medicin.

ZUE PATHOLOGIE DES LTJNGENODEMS 35

Lungenodem Charakteristisches. Der Befund derselben in der Tracheal-
fliissigkeit macht es wahrscheinlich, dass die serose Ausschwitzung die
Epithelien in derselben Weise ablest, wie dies eine indifEerente Zusatzfliissig-
keit bei der mikroskopischen Untersuchung thut. Ini frischen Zustand ist
fiir diese Zellen das am meisten Charakteristische ihr komig-er Inhalt. Der-
selbe besteht aus Komchen von ziemlich starkem Glanz, welche oftmals
dicht um den Kem gebauft liegen. Zwischen dem komigen Inhalt und der
einfachen Zellcontoiir befindet sich ein blasser Hof, welcher sich nacli Wasser-
zusatz aufblaht. Die Kornchen sind theils eiweissartiger, theils fettiger
Natur. Nach Zusatz von Essigsaure werden die Zellen blasser, aber ein
bedeutender Theil der Kornchen bleiben noch. An Schnitten von in Alkohol
geharteten Praparaten sind die Epithelzellen schwer als solche zu erkennen,
weil ihr komiger Inhalt meistens versehwunden ist, und die Kerne nicht
leicht von den Capillarkemen zu unterscheiden sind.

THEORY OF PULMONARY OEDEMA'

I am glad to comply with your kind invitation to say something concern-
ing the theory of the causation of certain forms of pulmonarj- oedema which
I advanced 25 years ago on the basis of an experimental research under-
taken at the suggestion and under the supervision of my honored teacher.
Professor Cohnheim, in his laboratory in Breslau. This research was the
first experimental study of tlie subject, and Professor Sahli, one of the lead-
ing critics of the theory, has been good enough to say that " even the oppo-
nents of the theory need not hesitate to give it praise of having for the
first time directed, ujx)n the firm foundation of pathological exjieriment,
the pathologj' of pulmonarv' oedema into straight and serviceable paths."

Permit me to recall some of the leading results and conclusions of my
investigation, published in " Virchow's Archiv," in March, 1878. These
related to acute general oedema of the lungs, from which the inflammatory
forms of oedema were separated. The various hypotheses current at that
time, concerning the causation of pulmonary oedema, were subjected to a
critical analysis, based in part upon experimental work, and all were rejected

^ The following is an introductory note by S. J. Melczer which states the
reason for including a letter from Dr. Welch in Meltzer's publication on
Oedema in 1904: "Welch's Theory of Pulmonary Edema. — In discussing the
various forms of edema in the first edition of his brilliant lectures on general
pathology, Cohnheim remarked that there is one form of edema, a most
important one, for which he could as yet offer no adequate explanation; this
is pulmonary edema. But soon after, pulmonary edema was elucidated by a
theory which still occupies a commanding position in general patholog>-. The
theory was based upon an extensive series of experiments carried out in
the laboratory of Cohnheim by an investigator who is now our foremost
pathologist in this country — I refer to Dr. William H. Welch, of Johns Hop-
kins University. It is just twenty-five years since the theory was advanced.
In the course of this quarter of a century the theory was tested experimentally,
discussed and criticized by Sahli, Grossmann, and Lowit. It seemed to me
that it would be highly instructive to hear the originator of this theory present
and discuss it again in his concise way. Professor Welch complied with my
request, for which 1 wish here to express my gratitude. Permit me to read
to you the remarks written down by Prof. Welch on his theory of pulmonary
edema."

In: Edema, a Consideration of the Physiologic and Pathologic Factors Con-
cerned in its Formation, by S. J. Meltzer, New York.

Am. Med., Phila., 1904, VIII, 195-196.

3G

THEORY OF PULMOXAEY OEDEMA 37

as unsupported or directly opposed by established facts. Although some
of these hj^iothetic causes of pulmonary oedema, such as active hyperaemia,
enfeebled action of the entire heart, and passive hyperaemia due to mitral
and aortic valvular disease, continue to be prominently mentioned in some
textbooks, I consider that the criticism passed upon them is still valid, and
that no satisfactory additional evidence in their support has been furnished.

ily investigations were directed mainly toward a solution of the question
whether acute general pulmonarv' oedema belongs to the group of the so-called
mechanical oedemas, referable to passive hyperaemia, or to that other group,
of more obscure caui:ation, which includes the hydraemic or cachectic oedemas,
and which was at that time, and is still, often attributed to changes in tlie
vascular walls. Even 25 years ago it was recognized by Cohnheim that
other than mechanical factors are concerned in the oedemas due to venous
congestion, and especially that these are not the direct result of rise of
of intracapillary pressure, but for the purposes of my research it was not
deemed necessary to consider how passive hyperaemia induced oedema. The
essential thing was to determine whether or not acute general oedema of the
lungs belongs to this latter category.

Acute general oedema of the lungs is characterized by several features,
which seem to give it a position quite apart from oedemas of other parts of
the body. Among these distinctive features may be mentioned the often
rapid or sudden onset of the affection, sometimes its quick disappearance,
its occurrence as an occasional complication of a great variety of acute
and of chronic diseases, although a constant accompaniment of none, and
its frequency as a terminal or even agonal event. Whatever be the explana-
tion adopted, it must take cognizance of these and other peculiar characters
of pulmonary oedema. In view of these characters, and of previous work
by himself and Lichtheim, relating to the pulmonary circulation. Professor
Cohnheim, when I began my experiments, considered it improbable that
oedema of the lungs would be shown to be a " StauungscBdem " or conges-
tive oedema.

I endeavored in the first place to determine whether it is possible to pro-
duce, experimentally, oedema of the lungs by obstruction to the outflow of
blood from the pulmonary veins. The previous experiments of Cohnheim
and Lichtheim had already demonstrated that very great increase of the
blood-pressure in the aorta may occur with relatively little effect upon the
pressure in the pulmonary vessels, and also that the right ventricle is capable
of overcoming enormous obstacles in the pulmonarj' circulation without
material lowering of the aortic pressure. My experiments confirmed and
extended these results. I succeeded, however, in producing oedema of the
lungs, both by ligation of the aorta and its branches, and by ligation of pul-

38 THEORY OF PULMONARY OEDEMA

monary veins; but the degree of obstruction to the circulation in the aorta
or in the pulmonary veins necessary to bring about this result, was found
to be t^o enormous that it is scarcely conceivable that it could, under any
circumstances, occur in human beings.

The experiments thus far, while proving the possibility of the occurrence
of pulmonary oedema in consequence of passive hyperaemia, not only shed no
light upon the conditions actually concerned in the production of this
affection in human beings, but, on the other hand, tended to discredit the
causative factors which had previously been based upon this assumption.

The possible ways in which venous hyperaemia of the lungs might be
induced were not, however, exliausted by experiments mentioned. There
occurred to me as a possible mechanical explanation of pulmonary oedema,
a condition which I described in the following words: "A disproportion
between the working power of the left ventricle and of the right ventricle
of such character that, the resistance remaining the same, the left heart is
unable to expel in a unit of time the same quantity of blood as the right
heart." I lay some stress upon this mode of statement of my theory, and
emphasized it by the type in my article. It is triie that I mentioned and
examined experimentally only paralysis of the left ventricle as a cause of
this incongruity between the two sides of the heart, but it is evident, as was
iiioiitioned by Cohnheim soon afterward, that spasm of the left ventricle
might bring about the same result.

The experimental test of this hypothesis is a matter of great difficulty.
I sought in vain for some poison which would act in the desired way upon
the left ventricle. Although several poisons occasionally produced oedema
of the lungs, none did so constantly, and I was unable to demonstrate in
this way an isolated, paralyzing effect on the left ventricle. I succeeded,
however, in paralyzing the left ventricle of rabbits by the coarse procedure
of squeezing it between the fingers, and I observed in many instances after
this manipulation, continued, apparently forcible action of the right ven-
tricle with diminished force of the left ventricle, as indicated by the pres-
sure in the carotid artery. Under these circumstances well-marked pul-
monary oedema resulted. It is this experiment upon the rabbit which con-
stituted the experimental basis of the theory of pulmonary oedema advanced
in my article on the subject.

I considered briefly the nature of the forces which might be operative in
supplying the right ventricle with tlie requisite amount of blood for the
production of pulmonary oedema after lessened output from the left ven-
tricle, and to this aspect of the subject Sigmund Mayer, shortly after my
publication, devoted especial attention.

THEORY OF PULMOXARY OEDEMA 39

I was not unmindful of the fact that this theory, if applicable to human
beings, must conform to clinical and anatomical observations, and I endeav-
ored to point out that it not only was not contradicted by such observations,
but that it furnished a better exi^lanation than any other hypothesis, known
at that time, of man}' cases of acute general pulmonary oedema in man.

Of the fate of this theory during the quarter of a century since its pub-
lication it is impossible for me to speak in detail in this necessarily brief
communication, but there are a few points upon which I should like to
touch. The theory has obtained wide, although by no means universal
acceptance, in German and Russian publications, being unreservedly adopted,
for example, by such eminent clinicians as Striimpell and Eichhorst. It
seems to be little kno^vn and has been but little discussed by American, En-
glish and French writers. The experimental results have been abundantly
confirmed and extended, although not all are agreed in their interpretation.

Grossmann, in an interesting experimental study of pvilmonary oedema due
to poisoning by muscarin, believes that he has demonstrated that this form
of oedema is due to spasm of the left ventricle with resulting venous hyper-
aemia of the lungs, and that the same condition of the left ventricle is present
in many cases of human pulmonary oedema. This opinion is not, as Gross-
mann seems to suppose, opposed to the fundamental conception underlying
my theory — namely, a disproportion between the action of the two ventricles
in the sense that the left ventricle propels in a unit of time only a fraction of
the quantity of blood expelled by the right ventricle into the pulmonary
artery. It seems to me, however, more probable that an enfeebled action of
the left ventricle, rather than a spasmodic action, is likely to be the cause of
this disproportion under the conditions in which pulmonarj' oedema ordi-
narily occurs.

The most important criticism to which my theory of pulmonary oedema has
been subjected, is by Sahli, in a valuable paper published in 1885. The
strongest points in his argument against the theory are that the radial pulse
in cases of pulmonary oedema to which my explanation might be applied,
does not indicate paralysis of the left ventricle, and that the anatomical con-
dition is not one of hyperaemia. Both of these possible objections had
occurred to me, and Sahli is in error in stating that my theorj- was promul-
gated without consideration on my part whether the pathological-anatomical
condition of human oedematous lungs is one of hyperaemia.

I stated in my article that it seemed to me doubtful whether clinical
methods could determine whether the assumed relative disproportion between
the work of the two ventricles existed or not. In my judgment, Sahli is
mistaken in supposing that the paralysis of the left ventricle must be almost
complete in order that the degree of passive hyperaemia requisite for the

40 THEORY OF TULMONARY OEDEMA

production of pulmonary oedema should ensue. As is well known, it is
absolutely essential for tlie integrity of the circulation and the continuance
of life, tliat each ventricle should pump into its artery the same quantity
of blood in a given time. This is the central fact of the circulation, and is
secured under normal conditions by regulatory mechanisms of the most
perfect order. The disturbance implied by interference with this mechanism
is profound, and hence, in accordance with my theory, pulmonary oedema
is practically unknown in previously healthy persons. Let, however, this
mechanism be so disturbed that at each systole, the right ventricle throws
even a little more blood into the pulmonary artery than does the left ventricle
into tiie aorta ; then it will not be long before there is a large excess of blood
in the pulmonary vessels. What is in the first instance essential is not the
absolute force of either the right or of the left ventricle, but rather the
relation between these. Hence I do not consider that the condition of the
peripheral pulse affords satisfactory indication whether the heart is dis-
turbed in the sense required by my theory.

The difficulty or impracticability of upsetting, in the case of healthy
animals, the remarkable mechanism which coordinates the relative force
of the two ventricles by an experimental procedure which stops short of a
high degree of paralysis of the left ventricle, is doubtless what might be
expected under these conditions, but it is reasonable to suppose that in those
severe affections of human beings which are associated with general pul-
monary oedema, this coordinating mechanism may he disturbed far more
readily and without extreme grade of paralysis of the left ventricle. , The
experiment upon the rabbit, already cited in support of the theory, must
be considered as only a crude and imperfect reproduction of the condition
assumed to underlie the onset of pulmonary oedema in man.

Sahli contends that the pallor of many oedematous lungs proves that the
oedema is not of a congestive type. He seems to have made no microscopical
examination of such lungs. I describe in my article the microscopical char-
acters of general pulmonary oedema in human beings, and there, it seems
to me, show conclusively that the oedema is one usually associated with venouo
hvperaemia. Certainly the enormous distention of the capillaries, the large
number of corpuscles in tlie serous transudate and the richness in albumin
of this transudate, are features of congestive rather than of hydraemic or
cachectic oedema. The color of dropsical tissues is an unsafe guide for
judging their blood-contents, and, while in my experience, lungs which are
the seat of general oedema, often enough show to the naked eye the evidences
of hyperaemia, I have often been surprised to find, even in the paler lungs,
by microscopical examination, marked hyperaemia and diapedesis of red
corpuscles. Renant and others have made similar observations.

THEORY OF PULMONARY OEDEMA 41

Lowit, in an experimental research published in 1893, reached the con-
clusion that congestive oedema of the lungs is the result of obstructed outflow
of blood from the pulmonary veins associated with increased inflow of blood
into the pulmonary artery. It is only through a misconception of my theory
of disproportionate action of the two ventricles, that Lowit should find any
conflict between his conclusion and the essence of this theory. Lowit's main
contention, however, tliat rise of pressure in the pulmonary artery attends
obstructed outflow from the pulmonary veins only when the supply of blood
to the pulmonary artery is increased, is opposed by the results not only of
his predecessors, but also of Grossmann and other experimenters. I agree
also with Grossmann, in opposition to Lowit, that increased supply of blood
to the pulmonary artery is not essential for the production of congestive
oedema of the lungs, although it is a self-evident corollary of my theory, as
was pointed out in my article, that given the requisite disproportion between
the action of the two ventricles, the higher the pressure in the pulmonary
artery, the more favorable are the conditions for the production of pul-
monary oedema.

Incomprehensible to me, as indeed it has been to others, and entirely with-
out experimental support, is the opinion expressed in a criticism of my theory
by Jiirgensen, that paralysis of the right ventricle leads to pulmonary
hyperaemia and oedema of the lungs.

It is hardly necessar}' to state that such factors as changes in osmotic pres-
sure, alterations in the capillary endothelium, interference with the absorp-
tion of lymph, which have become prominent in the later discussions of the
causation of oedema may be utilized in the explanations of pulmonary
oedema, as of congestive oedema elsewhere, but I find great difficulty in con-
ceiving any of these factors alone to be the primary cause of acute general
oedema of the lungs.

In one respect I am in agreement with Sahli; namely, that a larger
number of cases of pulmonary oedema are referable to inflammatory changes
in the vascular walls than is generally supposed. My opinion is based upon
the results of the systematic bacteriological examinations which are made at
all autopsies at the Johns Hopkins Hospital. Not only in irregular and
localized oedemas, but also in not a few extensive and even general pulmonary
oedemas, plate cultures from the lungs show numerous colonies of bacteria,
most frequently streptococci and lanceolate micrococci, so numerous that
they must have been in active growth in the lungs.

THE BEHAVIOUR OF THE RED BLOOD-CORPUSCLES WHEN
SHAKEN WITH INDIFFERENT SUBSTANCES'

While the action of chemical reagents upon the red blood-corpuscles has
been often studied, comparatively little attention has been given to the
changes produced in the corpuscles by agents whicli act mechanically. As
regards the effect of forcible compression of the red blood-corpuscles,
Vintschgau observed that by pressing the cover-glass upon a drop of blood,
sharp-bordered fragments of the red blood-corpuscles are produced. Another
possible mode of acting mechanically upon the red blood-corpuscles and the
one vvliich we have adopted is to shake the blood with finely and coarsely
granular insoluble substances. Although we at first undertook these experi-
ments with reference to their bearing upon another theme, it was found that
the'results of these provisional experiments were not so simple or so easily
obtained as had been anticipated, so that they seem to merit a separate
communication.

Rollett' has already adopted the procedure of shaking the blood with
insoluble substances, but from a chemical not from a mechanical point of
view. He observed that by shaking the blood with certain insoluble sub-
stances oxyhaemoglobin is reduced to haemoglobin. RoUett supposed that
after long-continued shaking some blood-corpuscles must be destroyed inas-
much as the red colour of the blood cannot be restored by shaking with air.

We at first adopted the simple method of shaking the blood in a test tube
with iron-filings for ten to fifteen minutes. Although tliis seemed to cause
a diminution in the number of red blood-corpuscles the results were not
sufficiently clear and unmistakable, especially when undiluted blood was
used. It is not necessary to mention here all of the other methods which
were attempted, for all difficulties were overcome as soon as it became
possible to shake the blood as long as it was wished. Through the kindness
of Mr. Carl H. Schultz there was placed at our disposal in his manufactory
of mineral waters a machine for shaking bottles. This machine, which
could be kept in motion tlie whole day, possessed an apparatus on which
several bottles could be fastened parallel to each otlier and shaken to and fro
longitudinally. There were 180 excursions a minute, the length of each
excursion was 39 cm., the velocity was therefore 1.17 M. per second. We

'S. J. Meltzer and W. H. Welch.
J. Physiol., Lond., 1884-85, V, 255-260.
'Rollett: Sitzgber. d. Wiener Akad. Math.-naturwis. CI. LII, Abth. 2.

42

BEHAVIOUR OF RED BLOOD-CORPUSCLES 43

were thus enabled to shake tlie blood not only hours but days and weeks at a
time. By shaking different bottles at the same time and under the same
conditions it was possible to study the action of different substances as well
as the action of the same substance according to the coarseness of its particles.

When it was not oiir object to observe the effect of varying the ratio
between the quantity of the substance and that of the blood, we took 15 c.c.
each of the substance and of the blood, either undiluted or diluted witli
physiological salt solution (0.6^). Bottles holding 100 c.c. were always
employed, so that there was a column of air over the fluid to be shaken (in
contrast with Rollett's experiments with exclusion of air). The fresh
defibrinated blood of the ox was used. This is especially mentioned because
according to Rollett the blood of different species of animals is reduced with
varying, degrees of rapidity.

In general it may be said that after shaking the blood for a considerable
time with granular insoluble substances a period is reached when the blood
attains the maximum degree of darkness in colour and all the red blood-
corpuscles have disappeared.

Furthermore, the blood-corpuscles disappear the sooner; (a) the greater
the specific gravity of tlie substance used, (b) the finer the particles of the
substance, (c) the larger the quantity of the substance in proportion to that
of the blood, and {d) the smaller the number of blood-corpuscles contained
in the fluid, that is more rapidly in diluted blood than in undiluted blood.

The blood was shaken with fragments of pumice-stone, sand, iron, lead,
copper, brass and quicksilver. Iron and brass were employed in varying
degrees of fineness of the particles.' We also used with success lead-shot
about 2 mm. in diameter. The longest time necessary for the disappearance
of the red blood-corpuscles — nearly three days — was required by lead-shot
on account of the coarseness of the particles, and by pumice-stone on
account of the low specific gravity. The shortest time — -7 to 8 hours — was
required by quicksilver on account of its weight and the fineness of the
particles into which it can be divided. Rollett * asserts that the reduction
of oxyhaemoglobin takes place with silver much more slowly than with iron,
and that quicksilver and platinum are without reducing power. For our

'Rollett in Hermann's Handb. d. Phys. Bd. IV, 1, p. 55, sas's: "Oxyhaemo-
globin yields Its loosely combined oxygen to reducing substances iron

filings (Rollett), still better Ferrum hydrarg. reduct. (Ludwig and A. Schmidt)
and is changed to reduced haemoglobin." The original article of Ludwig and
Schmidt was not accessible to us. It is possible that the greater efficacy of
ferrum reductum is due to the greater fineness of its particles. We found also
in our experiments that reduced iron is more effective than iron filings. This
was not, however, the case when the finest powder obtained by straining the
substance was used.

' Rollett, loc. cit.

44 BEHAVIOUE OF KED BLOOD-CORPUSCLES

puqiosp, however, we have found quicksilver the most effective of all agents,
so that in our further experiments we have used it exclusively.

In order to study the transitional stages before the complete disappear-
ance of the red blood-corpuscles we have sliaken for different periods of
time — one hour, two hours, three hours, etc. — several bottles each containing
15 c.c. of blood and 15 c.c. of mercury. With the naked eye one can clearly
follow the gradual change in colour. At the end of an hour the blood appears
much darker in colour than the unshaken specimen. From hour to hour
the shaken blood becomes darker and darker in colour, until at the end of
about 7 hours it becomes absolutely black, and from that time on no further
change can be observed. Microscopically no distinct change can be seen
until the third hour. From that time on the red blood-corpuscles disappear
more and more, those which remain seem to become somewhat paler while
the intervening flxiid becomes less clear and transparent. The diminution
in number of the red blood-corpuscles continues for several hours, not, how-
ever with uniformity. The largest number of corpuscles disappear somewhat
suddenly between tlie 5th and 6th hour. Up to this time the diminution is
relatively small. The few corpuscles which remain after the main loss
often resist destruction for a long time.

There can be no doubt that the cause of the disappearance of the red
blood-corpuscles is a mechanical one. The reduction of haemoglobin which
follows shaking the blood for a short time was interpreted by Eollett as a
mechanical effect, although this view rested on a less firm basis than in our
experiments, for he failed to obtain this reduction by the heaviest metals.
In our experiments we have found that the result depended not upon the
chemical constitution of the substances employed but upon their quantity,
their specific gravity, and the fineness of their particles, all purely mechanical
conditions.

In what way, however, the blood-corpuscles disappear and just what be-
comes of them we could not positively determine. It was to be expected
that the blood-corpuscles by being shaken with finely divided indifferent
substances either would be broken into fragments, as by pressure upon the
cover-glass, or would lose their haemoglobin and be converted into stromata
or shadows. We have diligently sought both for fragments and for shadows
of the blood-corpuscles, but we have not been able to discover either, although
in the course of our experiments, reagents were found capable of demonstrat-
ing the most invisible shadows. Tlie destruction of the red blood-corpuscles
under these circumstances appears therefore to be molecular and tolerably
sudden. A certain commotion of the haemoglobin in the blood-corpuscles
appears to precede their complete destruction. It has already been men-
tioned that before their disappearance the red blood-corpuscles lose some of
their colouring matter. To this fact is to be added the following noteworthy

SHAKEN WITH INDIFFERENT SUBSTANCES 45

observation. If the blood be shaken with any of the substances mentioned
for a period so short that no visible change in the blood has occurred, and
then the blood be allowed to stand at rest, it will be found that at tlie end
of 15 to 18 hours nearly all the red blood-corpuscles have completely lost
their colouring matter, while the corpuscles in the control-specimen are still
wholly intact. A shaking therefore of only short duration suffices to render
less firm the combination between stroma and haemoglobin. It is perhaps
only tliis loosening of the combination between haemoglobin and stroma and
not the expidsion of the haemoglobin which is accomplished by the shaking.
The complete separation of the haemoglobin from the corpuscle and its
solution in the surrounding fluid occurs afterward. Continued shaking
hastens but little, it may be, the separation of the haemoglobin from the
blood-corpuscles; it causes apparently a molecular destruction of the blood-
corpuscles before the haemoglobin has left them.

It may also be noted that all blood-corpuscles do not possess equal power
of resistance (cohesion?). Mention has already been made of Rollett's
observation that the reduction of haemoglobin takes place with varying
rapidity in the blood of different species of animals. In our experiments it
was found that the greater number of red blood-corpuscles disappeared at
about the same time, while a small fraction disappeared either earlier or
later, ilay not this be interpreted as in favour of a greater or less cohesive
power in certain corpuscles in contrast with the average cohesive power of
the majority of corpuscles? A similar supposition is made with reference
to those corpuscles which resist for a long time the action of water.

We have also studied the effect produced by shaking with quick-silver
blood to which various reagents have been added. The addition of con-
centrated solutions of common salt, sulphate of magnesium, sulphate of
sodium, sulphate of zinc, acetate of lead and sugar has no appreciable in-
fluence upon the result as above described. On the other hand after the
addition to the blood of solutions of pyrogallic acid, tannin, alcohol, chlorate
of potash, nitrate of silver, and sulphate of copper, the red blood-corpuscles
are unaffected by shaking, no matter how long this be continued. It is not
necessary to describe here the action upon tlie red blood-corpuscles of the
various reagents in the latter group. This has already been described by
various investigators. We used strong alcohol, pyrogallic acid in 20^ solu-
tion, tannin and sulphate of copper in 10^, chlorate of potash in 6.25^
(1:16 the maximum of its solubility at the ordinary temperature) and
nitrate of silver in 3^ solution. Two parts of the solution were added to one
part of tlie blood. As regards the formation of shadows, the blood-corpuscles
are affected but little by the first three reagents and not at all by the last
three. No matter how long the shaking be continued, the blood-corpuscles
remain unaffected by it. The experiments were frequently repeated, always

46 BEHAVIOUR OF RED BLOOD-CORPUSCLES

with a control-specimen, and always with the same result. With some of
these reagents (chlorate of potash, pyrogallic acid and nitrate of silver) we
have shaken the blood over two weeks. The blood-corpuscles appeared as
intact at the end as at the beginning of the experiment. It is hardly
necessary to add that under tliese circmnatances solution of the haemoglobin
does not occur upon allowing the blood to stand after it has been shaken.

As no change was produced by shaking the blood for two weeks it did not
seem necessary to continue the procedure any longer. The effect of these
reagents does not seem to be merely an increase in the cohesion of the red
blood-corpuscles. In fact sugar and sulphate of sodiimi are credited with
the power of hardening the red blood-corpuscles," and in our experiments
these substances were without influence. The reagents of the active group
must produce some change in the constitution of the red blood-corpuscles
which renders them wholly insusceptible to such mechanical influences as
we employed. The different substances of this group have as approximately
common properties, (a) the power of coagulating albimien, and (b) the
power of changing haemoglobin into meta-haemoglobin. We content our-
selves merely with reference to these points, as the subject is not sufficiently
matured to warrant fuller consideration.

In the endeavor to discover shadows of the red blood-corpuscles in the
shaken blood we found tlie reagents customarily recommended little adapted
for this purpose. These reagents themselves transform blood-corpuscles into
shadows, and moreover tliey are of little service when the shadows are very
pale and the fluid turbid. While the idea previously seems to have been to
demonstrate the shadows by means of colouring agents (eosin, vesuvin, etc.),
we have found tliat other reagents are more suitable. It would seem that
all reagents which cause a coagulation of albumen are adapted to render
visible tlie palest stromata. We have used successfully for this purpose
picric acid (saturated solution), pyrogallic acid (20;?^), bichromate of pot-
ash (2^) tannin (10;^), sulphate of copper (10;^), nitrate of silver (3^),
chlorate of potash (1: 16) and diluted mineral acids. The stromata appear
after the addition of these reagents in a few seconds as pale rings, except in
the case of chlorate of potash, which makes them appear as bluish-wliite
round discs. The clearest outlines are produced by picric acid, pyrogallic
acid, chlorate of potai?h and nitrate of silver. The first two reagents are,
however, not adapted for the study of normal blood, as they, like most of
the other reagents, cause more or less separation of haemoglobin. On the
other hand, nitrate of silver and chlorate of potash are admirable reagents
for the purpose in view. If two parts of the reagent (of the before men-
tioned concentration) be mixed with one part of blood, then the shadows
come plainly to view while the intact corpuscles remain unchanged.

Moh. Miiller: Hand. d. Physiol. Figuera, Ann. d. Cliim. u. Phys. XL.

THE STRUCTURE OF WHITE THROMBI'

A year ago, upon an occasion similar to this, you had the pleasure of
listening to Dr. J. Collins Warren's address upon the healing of arteries
after ligature. As his researches were directed especially toward the later
stages of the changes which follow injury of the bloodvessels, it will, perhaps,
not be acceptable if I call your attention to the histological structure of those
plugs which often constitute the earliest alteration following such injurj'.

While all that pertains to the subject of thrombosis is of importance,
recent investigations have lent special interest to the study of the minute
structure and the mode of formation of white thrombi.

Since Virchow's memorable publications ' upon the subject of thrombosis,
it has been generally believed that a thrombus is essentially a blood coagu-
lum, and differs from an ordinary post-mortem clot only in the arrangement
and the relative proportion of the constituent histological elements. The
most important of the ditferences noted by Virchow are the characteristic
lamination of thrombi, and their greater richness in white blood-corpuscles,
and in granular material. These differences were believed to be sufficiently
explained by the slow formation of thrombi from the circulating blood, in
contrast with the rapid coagulation of blood at rest, and by secondary changes
in the thrombus.

During the two decades following the publication of Virchow's researches
on this subject, more attention was paid to the causes, to the effects, and
to the metamorphoses of thrombi, more particularly to their so-called organi-
zation, than to the intimate structure of recently formed thrombi. Zahn's
investigations of thrombosis, published in 1875, marked an epoch in the
history of our subject.' Zahn had been preceded by Mantegazza,' who, in
1869, called attention to the role played by white blood-corpuscles in the
formation of white thrombi, but the observations of the latter author had
remained comparatively unknovra.

Zahn emphasized the most important differences existing between thrombi
formed from the blood in repose, the so-called red thrombi, and those

' Delivered before the Pathological Society of Philadelphia, April 28, 1SS7.

Tr. Path. See, Phila., 1885-7, XIII, 281-300.
'Virchow: Gesammelte Abhandlungen. Frankfurt a. M., 1856.
'Zahn: Virchow's Archiv, 1875, Bd. 62, p. 81.
'Mantegazza: Gaz. med. Lombarda, 1869.

47

48 STEUCTUEE OF WHITE THROMBI

developed from circulating blood, viz., tlie white and the mixed thrombi.
AVhereas the former do not differ from an ordinary coagulum of blood, the
latter, according to Zahn, originate from clumps of white corpuscles. Zahn
observed miscroscopically in the mesenteric vessels of the living frog, the
first formation of white thrombi out of white blood-corpuscles which accu-
mulated in vessels at places which had been subjected to various injuries.
The white corpuscles thus accumulated, if they were not detached by the
circulation, rapidly disintegrated into a mass of granular material which
Zahn considered to be granular fibrin. According to the widely accepted
views of Zahn, therefore, a white thrombus at its inception consists essentially
of white blood-corpuscles, which, after a short time, break up into a mass
of granules identical with fibrin in their reactions.

The observations of Mantegazza and of Zahn were confirmed, in 1876,
by Pitres," who made corresponding observations of the living circulation in
warm-blooded animals, whereas Zahn studied the circulation only in frogs.
Pitres, however, did not, like Zahn, identify the granular material resulting
from the disintegration of white blood-corpuscles with fibrin.

The role thus assigned to the white corpuscles in the formation of white
thrombi certainly seemed to be at variance with A'irchow's view that all
thrombi are coagula. A reconciliation, however, was effected between the
new obsen-ations and the old doctrine, chiefly through the investigations of
Weigert.' This pathologist, adopting the views of A. Schmidt as to the part
taken by the white corpuscles in the spontaneous coagulation of the blood,
assigned to tliese corpuscles essentially the same role in white thrombi.
The coagulation necrosis of leucocytes in thrombi is a process differing,
according to Weigert, morphologically, but not in essence, from the dissolu-
tion of white corpuscles and the formation of fibrillated fibrin in the
ordinary coagulation of the blood. White thrombi, therefore, continued to
be regarded as in the main genuine coagula.

The first opposition to the views of Zahn came from Haycm,' who. in
1878, attempted to prove that the coagulation of fibrin is a function of the
small bodies, called by him htematoblasts, and subsequently, by Bizzozero,
blood plates, the name now generally adopted. Osier, who was among the
first to observe the existence of human thrombi composed almost exclusively
of blood plates (or plaques, as he, accepting the suggestion of Kemp, prefers

'Pitres: Arch, de Phys. norm, et path., 1876, p. 230.

"Weigert: Virchow's Archiv, Bd. TO, 1S77, and Bd. 79, ISSO. Fortschritte d.
Medicin, 1S83.

'Hayem: Recherches sur I'.^natomie norm, et path, du Sang. Paris, 1878.
Comptes Rendus de I'Acad. d. Sc, 1882, 18 Juli.

STRUCTURE OF WHITE THROMBI 49

to call them), has presented fully in the last series of Cartwright Lectures,
the existing state of our knowledge concerning these bodies.' In 1882,
Hayem published his observations on the structure of thrombi. He found
that the thrombi which are formed in wounds of arteries are made up of
blood plates.

A few months later Bizzozero' described, with much detail, both the
fibrin-forming properties of the blood plates, and their presence as the
essential and primary constituent of white thrombi, in these respects con-
firming the opinions of Hayem. Bizzozero was the first to study the forma-
tion of thrombi from blood plates in the living circulation, usuing for this
purpose the mesentery of warm-blooded animals.

In the following year, Hlava," working under Weigert's direction, was
unable to confirm the views of Hayem, and of Bizzozero, and upheld the
doctrine of Zahn and of Weigert, that white thrombi, in their earliest forma-
tion, consist mainly of leucocytes, which subsequently undergo coagulation
necrosis.

Lubnitzky," working under the direction of Langhans, pubhshed, in 1885,
an interesting article, in which she claimed that the thrombi which are
formed in arterial wounds, and which are the chief agent of nature in
checking hemorrhage from this source, are composed primarily of blood
plates. The blood plates, when thus accumulated, are, according to
Lubnitzky, either identical with fibrin, or are quickly transformed into
this substance.

The most thorough study hitherto made of tlie share taken by the blood
plates in the formation of thrombi we owe to Eberth and Schimmelbusch. "
These authors consider that sufficient proof of the existence of blood plates
in the normal circulation is afforded by the observation of the plates in the
circulating blood of the mesenteric vessels of dogs and rabbits examined
under physiological salt solution, with high magnifying powers. In opposi-
tion to Hayem and to Bizzozero, they deny that the plates have any share in
the coagulation of fibrin, which they regard rather as a kind of crystalli-
zation in the plasma. The plates, when removed from the natural conditions
of their existence, rapidly undergo a metamorphosis, called by Eberth and
Schimmelbusch viscous metamorphosis, and characterized especially by the

'Osier: On Certain Problems in the Physiology of the Blood Corpuscles.
The Medical News, April 3, 10, 17, 18S6.

"Bizzozero: Virchow's Archiv, 1882, Bd. 90, p. 261.

"Hlava: Arch. f. exp. Path. u. Pharm., 1883, Bd. 17, p. 392.

'» Lubnitzky: Arch. f. exp. Path. u. Pharm., 1885, Bd. 19, p. 185.

'^ Eberth u. Schimmelbusch: Virchow's Archiv, 1885, Bd. 101; 1886, Bd. 103,
Bd. 105.

60 STRUCTURE OF WHITE THROMBI

sticking of the plates to each other and to foreign substances. Under normal
conditions the plates circulate with the red corpuscles in the axial blood
current, but they make their appearance in the plasmatic zone when the
rapidity of the circulation is diminished. A moderate slowing of the blood
current is attended by the formation of the so-called border zones, or accumu-
lation of white corpuscles in the plasmatic current, whereas a greater
diminution of the velocity of the stream is characterized by fewer leucocytes,
and more plates in the peripheral current. Other irregularities of the
circulation, such as the little eddies produced by obstacles or projections in
the stream, or by dilatations of its bed, may likewise throw the plates from
the a.xis into the peripherj' of the stream. Mere slowing of the circulation
is not attended by the formation of thrombi. In order to observe this
formation, Eberth and Schimmelbusch subjected the living mesenteric
vessels, chiefly of dogs, to various mechanical and chemical injuries. They
then observed under the microscope, in many, but not in all instances, the
accumulation of blood plates at the seat of injury. Here the plates became
adlierent to each other and to the wall of the vessel, in consequence of their
viscous metamorphosis, and thus formed plugs which were often subsequently
washed away, but which sometimes increased in size so as to obstruct com-
pletely the lumen of the vessel. Red and white corpuscles may be included
in the mass of plates, but their presence is purely accidental, and they are not
to be regarded as an essential constituent of the primarj' thrombus.

As the result of their microscopical observations of the formation of
thrombi in living bloodvessels of warm-blooded animals, Eberth and
Schimmelbusch, therefore, conclude that wliite thrombi are at first com-
posed essentially of blood plates, and that the chief factors in the causa-
tion of such thrombi are slowing of the circulation or other irregularities
in the current, and the viscous metamorphosis of the blood plates. This
metamorphosis may be the result of various influences, such as contact with
injured or diseased vascular walls and with foreign substances.

These conclusions as to the structure of white thrombi at their earliest
formation Eberth and Schimmelbusch confirmed by the microscopical
examination of sections of thrombi produced artificially by various injuries
to the vessels. In experimental thrombi produced by mechanical injury of
the vessels, as by wounds or by temporary ligation, they failed to find any
fibrillated fibrin, whereas, in thrombi formed around foreign bodies intro-
duced into the lumen of a bloodvessel, they observed some fibrin, situated
usually between masses of plates, although even here they think it probable
that fibrin is absent in the very earliest stages. They also detected fibrin,
but in less amount, in thrombi produced by cauterization of the vessel walls.

STEUCTURE OF WHITE THROMBI 51

While the investigations of Eberth and Schimmelbusch confirm the view
of Hayem, Bizzozero, and Lubnitzkj' that white thrombi are made up pri-
marily of an accumulation of blood plates and not of leucocytes as Zahn had
led us to believe," they are opposed in one important particular to the con-
clusions of the latter group of authors. Tliey deny that the blood plates are in
any way concerned in the generation of fibrin or are transformed into a sub-
stance resembhng fibrin. They, therefore, deny that a white thrombus is
primarily a coagulum, as has hitherto been unquestionably believed. They
regard the process of thrombosis, here under consideration, as a conglutina-
tion of bodies preexistent in the blood and not as a coagulation.

The arguments brought forward by the preceding investigators in favor
of the existence of blood plates in large number in the normal circulation,
convincing as they may seem, are nevertheless opposed by several observers.
In view of the researches of Lowit," this must for the present be considered
as an open question.

Notwithstanding the brief period which has elapsed since the publication
of Eberth and Schimmelbusch's researches upon thrombosis, their con-
clusions have already met with considerable opposition. It was hardly to
be expected that such a radical overturning of accepted beliefs as these
recent investigations involve should pass unchallenged.

While there is general agreement of opinion as to the important par-
ticipation of blood plates in the composition of white thrombi, Eberth and
Schimmelbusch's conception of the process of thrombosis as a conglutination
of blood plates which have undergone a viscous metamorphosis is opposed
by Hanau" on the ground that thrombi never have a viscid consistence.
In support of the coagulative nature of the accumulation and metamorphoses
of blood plates in white thrombi Hanau finds that plates as weU as fibrin
are transformed into hyaline, that a rim of hyaline forms around masses

" Since the delivery of this address Eberth and Schimmelbusch have pub-
lished the results of their repetition of Zahn's experiments on the mesenteric
vessels of frogs, and they find that fusiform corpuscles, which they consider to
correspond to the mammalian blood plates, are the main constituents of white
thrombi artificially produced in these animals. Vide Virchow's Archiv, Bd.
108, 18S7. Lowit, on the other hand, regards these fusiform corpuscles as a
variety of the white corpuscles and not as the analogues of blood plates, and
he confiirms the original statements of Zahn regarding the rormation of
white thrombi in frogs. Archiv f. exp. Path. u. Pharm., Bd. 23, 1887.

"Lowit: Beitrage z. Lehre von d. Blutgerinnung, Sitzb. d. k. Akad. d. Wiss.
Wien, Bd. 89, Abth. Ill, u. Bd. 90, Abth. Ill, and Tageblatt d. 59ter Versaml
Deutscher Naturforscher u. Aertze in Berlin, p. 306, 1886.

'■■Hanau: Fortschritte der Medicin, No. 3, 1887.

52 STRUCTUEE OF WHITE THROMBI

of plates, and tliat fibrin and plates often take the place one of the other
in iliroinbi.

Weigert " protests even more vigorously against the effort of Eberth and
Schiinmelbusch to remove a large class of thrombi from the category of
coagnla. He has made a careful examination of human white thrombi,
and points out especially their richness in fibrillated fibrin, which he
demonstrates by a new staining process, and the abundance of leucocytes.
He is unable to identify these anatomical thrombi with the experimental
thrombi of Eberth and Schimmelbusch, and argues that until some reconcili-
ation is effected between the two we should continue to base our conception
of the nature of thrombi upon the study of the anatomical thrombi. Eberth
and Schimmelbusch reply that their studies have been directed to the very
earliest stages of the process of thrombosis, whereas the thrombi examined
by Weigert belonged to subsequent metamorphoses."

It is apparent from the foregoing review of recent investigations con-
cerning the nature and structure of thrombi that unanimity of opinion
on this subject has not been reached. There is general agreement that the
blood plates play an important role in the early formation of many thrombi.
Further investigations are needed to determine whether or not the plates
are present in the perfectly normal circulation. For a proper understanding
of the process of thrombosis it is important to determine whether or not
the blood plates when accumulated to form a thrombus, are products of
coagulation or subsequently undergo any metamorphosis which can be called
coagiilation. To determine this the gross characters of the plate thrombi,
such as their color and consistence, will serve as important criteria, as has
been pointed out by Weigert. It is, of course, of capital importance to learn
whether the experimental white thrombi differ in their nature from human
thrombi as seems to be intimated by Weigert. Before far-reaching con-
elusions can be drawn it is necessary to demonstrate the identity of the
experimental and of the anatomical process of thrombosis. The micro-
scopical study of human thrombi certainly seems opposed to the opinion that
fibrin and leucocytes are unessential constituents of white thrombi. So
constant and so abundant are these elements in post-mortem white thrombi
that pathological anatomists will not readily admit that their presence is

"Weigert: Tageblatt der 59ter Versamml. Deutscher Naturforscher u. Aerzte
In Berlin, p. 306, 1886.

"Schimmelbusch: Tageblatt d. 59ter Versamml. Deutscher Naturforscher in
Berlin, p. 306, 18S6. Eberth u. Schimmelbusch, Fortschritte der Medicin. No. 6,
1887. The paper of Lbwit, on thrombosis, who is opposed in many important par-
ticulars to Eberth and Schimmelbusch, appeared after the delivery of this
address. Arch. f. exp. Path. u. Pharmak. Bd. 22, 1887.

STRUCTURE OF WHITE THROMBI 53

accidental or unessential to our conception of the nature of the thrombotic
process.

In ^-iew of the fundamental importance of the question last touched upon,
I have undertaken some investigations, first, as to the structure of human
white thrombi ; and second, as to the structure of thrombi produced experi-
mentally in animals by mechanical injury of the bloodvessels. In the
study of experimental thrombi I have directed my attention, in the first
place, to their constitution at their earliest formation, and especially to the
presence or absence of fibrin and of leucocytes at this period. It has seemed
to me that a control with reference to the latter point of observations of
Hayem, Bizzozero, Lubnitzky, and especially of Eberth and Schimmel-
busch, notwithstanding the carefulness of these observations, might not be
imwelcome. I have also studied the structure of experimental thrombi in
their later stages. It is undoubtedly upon this point that our knowledge is
the least complete, and it is to be expected that when this gap is filled up
there will be less divergence of opinion as to the relation between the experi-
mental and the human thrombi.

There will be found on exhibition under the microscopes sections of
human marantic thrombi formed in various infectious and waiting diseases.
Among others specimens are present from a case of widespread thrombosis
following parturition. In this case there were fresh thrombi in the femoral
and iliac veins, the inferior vena cava, the branches of the pulmonary
artery, and the cerebral sinuses. The constituent elements of these thrombi
are fibrillated fibrin, hyaline substance, red blood-corpuscles, leucocytes,
fragmented nuclei, and granular material, of which a considerable part can
be recognized as blood plates. The proportion of each of these elements in
the composition of thrombi varies much in different cases, and it will be
well to consider the share taken by each in the formation of thrombi.

There have been various opinions as to the nature of the granular material
found in thrombi. Thus it has been regarded as produced by the breaking
up of fibrillated fibrin (Yirchow), as molecular or granular fibrin deposited
as such from the blood — a view advocated by the majority of the older
(Mandl, Addison) and by many recent authors — as granular fibrin formed
by the necrosis of white corpuscles (Zahn) , as the result of simple disintegra-
tion of white corpuscles (Pitres). At present, however, there can be no
doubt that most of what has been called in thrombi granular fibrin, or the
products of disintegration of leucocytes, consists of more or less altered blood
plates. The acquisition of this knowledge is an important advance in
pathology, whatever may be thought of the nature of the plates.

Blood plates seem to be a constant constituent of fresh marantic thrombi.
The plates are often present in such thrombi in as recognizable form and

54 STRUCTURE OF WHITE THROMBI

arranfrement as in recent experimental thrombi. I have found thrombi,
particularly some endocardial vegetations and parietal arterial thrombi,
whith at first glance appear to be composed of nothing but plates; but
careful examination in such cases has always revealed the presence also of
fibrillated fibrin and leucocytes. In the majority of cases, however, the part
of the tlirombus composed of plates is less extensive then that made up of
fibrin and leucocytes. Frequently the plates are arranged in massed between
which lie the fibrin and leucocytes. Such masses of plates, which are more
frequently situated in the interior of the thrombus than adjacent to the
vessel-wall, are often enveloped in a rim of dense material resembling fibrin.
In sections stained with haematoxylin and eosin the areas occupied by the
plates can often be recognized with a low power by the various manner in
which the different constituents of the thrombus stain.

All of the granular material in thrombi cannot be demonstrated to be
composed of plates, but it is probable that most of this formless granular
matter is the result of the disintegration and metamorphosis of the plates.
That some of the granules are produced by the disintegration of leucocytes
is probable, for it is not difficult to demonstrate the destruction of leucocytes
in many thrombi. I believe also that a granular precipitate in thrombi
is sometimes caused by the hardening agents.

As regards fibrin, I can confirm the recent statements of Weigert as to
the abundance and the constant presence of tliis substance in all marantic
thrombi, except in softened foci where it is absent. Some thrombi are com-
posed almost wholly of fibrin. The fibrin may assume various forms, such
as the form of a delicate network, or of coarse interlacing or parallel bands,
or of irregular masses, or of the so-called canalized fibrin. In sufficiently
thin sections, such as can be made from specimens imbedded in paraffine,
there is generally no difficulty in demonstrating in thrombi a rich network
of fibrin even without the aid of Weigert's special stain for this purpose.
Leaving out of question, therefore, the nature of the blood plates, there can
be no doubt that human thrombi, as we meet them at autopsies, are genuine
coagula, save in the foci of so-called puriform softening.

Hyaline material appears to be formed both out of fibrin and out of
blood plates. Thrombi composed wholly of hyaline I have found in the
liver of a cat in which a few drops of croton-oil had been injected, in
hemorrhagic infarctions of the lungs, and in corroding ulcers of the duo-
denum and of the stomach. Hyaline is an inconstant constituent of thrombi,
but its presence is not rare.

The aceiunulation of leucocytes in human wliite tlirombi is so well known
that tliere would be no necessity of emphasizing it here, were it not that the
recent study of experimental thrombi has led to a revision of the doctrine

STEUCTUEE OF WHITE THROMBI 55

that white thrombi are composed primarily of masses of white blood-
corpuscles. While it is true, as has already been mentioned, that there are
thrombi which are composed almost entirely of plates, or of fibrin, or of
hyaline, or of these substances in combination, this is the exception, and in
the vast majority of fresh thrombi leucocj'tes are present in large number.
In inflammatorj- thrombi leucocytes may be so abundant as to obscure all
other constituents. Usuallj' the leucocytes in marantic thrombi are not
scattered uniformly throughout the thrombus, but are massed together in
clumps ; these clumps of leucocytes, unlike the clumps of plates, are generally
pervaded by a network of fibrin.

It is not at all infrequent to find in old thrombi leucocj'tes and even
masses of them which are devoid of nuclei. In imdergoing this necrosis
the nuclei of the white blood-corpuscles may be broken up into fragments
which can be recognized as small irregular particles which assume a nuclear
staining, but this nuclear fragmentation does not seem to be the rule. Gen-
erally the necrotic leucocj'tes can be recognized simply by their form, without
any trace of nuclei.

Eed corpuscles are present in variable numbers in marantic thrombi.
They cannot be regarded as an essential constituent of the thrombus. I find
in many marantic thrombi the so-called shadows of the red blood-corpuscles,
which can be easily overlooked imless especial attention be given to search-
ing for them.

In properly prepared sections it is not rare to find colonies of micrococci
even in thrombi not connected with pyjemic processes, especially in marantic
thrombi from cases of typhoid fever or other infectious diseases.

From the foregoing summary of the histological characters of human white
thrombi, it is apparent that any satisfactory explanation of the process of
thrombosis must account for the presence of blood plates, of fibrin, and of
leucocytes, for these are essential constituents of thrombi. The valuable
investigations by Eberth and Schimmelbusch of experimental thrombi have
led them to regard the blood plates as the sole primary elements in these
plugs. Further investigations are needed to determine the role played by
fibrin and white blood-corpuscles in the formation of experimental thrombi.

My experiments upon the production of thrombi have been made mostly
on dogs. The vessels selected have been the femoral artery, the femoral vein,
and the jugular vein, in the majority of cases the femoral vessels. Various
methods were employed to produce thrombi, such as the application of
caustics, the introduction of foreign bodies, and various mechanical injuries.
I have given the most attention to the thrombi resulting from mechanical
injuries, for it is admitted by Eberth and Schimmelbusch that the thrombi
following the application of caustics, and those formed around foreign sub-

66 STRUCTURE OF WHITE THROMBI

stances, contain, in an early stage, if not at tlieir beginning, fibrin as well as
blood plates. These autliors assert that "coagulation is a process which
plays only a modest role in the circulating blood, whereas here the most
prominent and frequent phenomenon is conglutination, which, indeed, is
solely concerned in the practically most important form of thrombosis, viz.,
that following simple mechanical injury of the vessel-waU, in whatever way
this may have been produced." "

The follo-R-ing two modes of producing mechanically thrombi have given
good results. One metliod is to tie a stout ligature tightly and suddenly
around the vessel and at once cut the ligature loose. In this way the intima
and a part of tlie media are usually torn. It is only when great force is used
that the vessel is ruptured. The ligature leaves a whitish ring around tlie
vessel at the seat of its application. If, as often happens, the walls of the
vessel remain stuck together after removal of the ligature, tlien moulding
the vessel slightly between the fingers will restore the lumen, which now
presents a fusiform dilatation at the seat of injur)'. The adventitia in tliis
situation often becomes infiltrated with blood.

Another method which I have employed, is to push into a branch of the
femoral artery or femoral vein one of the hooked instruments or gouges em-
ployed by dentists and called excavators, and tlien, after pressing the hooked
extremity forward into the main trunk to scrape the inner wall of the vessel
to any extent desired. The stem of the instrument, if necessars', can be filed
down so as to render its introduction easier. After the withdrawal of the
instrument the opened branch of the vessel is secured by two ligatures. Of
the various shapes which the working extremities of these instruments
possess, those with a small cup-shai^ed gouge bent at right angles to the
handle (spoon excavator) I have found particularly suitable.

The animals experimented upon have been tied down and anfesUietized,
usually with morphine and chloral, or morphine and ether, or morphine
alone.

It is important, when the vessel is removed from the body, that four
ligatures should be applied, two above and two below the seat of injury,
and that any collateral branches included between the pairs of ligatures
should also be tied. These ligatures should be applied with as little dis-
turbance of the vessel as possible. If the vessel be cut out without the
preliminary application of ligatures, the contents of the vessel are partly
discharged, and in this way the thrombus may be lost or its position changed.

Various hardening fluids were employed, such as corrosive sulilimate,
alcohol, iliiller's fluid, picric acid, osmic acid, and Flemming's solution.

" Eberth and Schimmelbusch. Virchow's Archiv, Bd. 105, p. 459.

STRUCTURE OF WHITE THROMBI 57

Of these, warm saturated solutions of corrosive sublimate are decidedly
the best. This fluid preserves the blood plates and other elements almost
perfectly and admits satisfactory subsequent staining of the specimens.

The procedure adopted in hardening in corrosive sublimate is the fol-
lowing: A clear, saturated aqueous solution containing some undissolved
sublimate at the bottom is heated to 40° C, and in this is suspended the
specimen to be hardened. After a few minutes I have usually cut away
the ligatures at the ends of the vessel, as there is now no danger of the
escape of the contents. The vessel containing the sublimate solution and
specimen is kept in a thermostat at a temperature of 40° for one to two
hours. The specimen is then washed in water having a temperature of
40° and afterward placed in a mixture of half alcohol and half water, and
kept in this mixture at a temperature of 40° for a number of hours, often
over night. This prolonged washing is to remove crystals which other-
wise are present in large number. Even after this treatment sometimes
peculiar crystals are present, which, however, do not materially interfere
with the study of the sections. The addition of a little iodine to the
washing fluid, as suggested to me by Prof. Gaule, assists in removing the
crjstaJs. From the fifty per cent alcohol the specimen is transferred to
strong, and finally to absolute alcohol. I have made use almost exclu-
sively of paraffine as an imbedding medium, as much thinner sections
can be obtained in this way than by imbedding in celloidine. Satisfactory
results can be obtained by staining the specimens en masse in hsematoxylin
and in eosin, but, as a rule, the sections have been stained after causing
them to adhere to the slide. When serial sections were desired, they were
cut in the form of ribbons. Gaule's method of making the sections adhere
to the slide by placing upon each section laid dr}' upon the slide a drop
or two of forty or fifty per cent alcohol, and after ten minutes putting
the slides in a thermostat at a temperature of 40° and keeping them there
for two hours, is the simplest and best with which I am acquainted. After
this treatment the sections are so firmly adherent that all the manipulations
of staining and preparing the sections for mounting can be carried on with-
out fear of their detachment. In sections stained with haematoxylin and
eosin the plates have a violet tint, and when in masses can be readily recog-
nized with a low power.

I wish first to direct your attention to the macroscopic and the micro-
scopic appearances of fresh experimental plate thrombi. Such a thrombus
may be convieniently produced by tying forcibly a coarse string around
the femoral artery of a dog and then at once cutting the string loose in the
manner already described. After the time desired for the production of
the thrombus has elapsed, the injured part of the artery inclosed between
7

68 STRUCTURE OF WHITE THROMBI

two pairs of ligatures is to bo removed and the artery is to be carefully slit
up with a pair of delicate scissors.

Let us examine an artery treated in this way which contains a thrombus
formed within five minutes. There will be fovmd, closely adherent to the
torn inner wall of the vessel, a parietal thrombus which at this period does
not usually extend in a longitudinal direction much beyond the ring of
lacerated tissue. The thrombus can be readily distinguished by its color
from the blood which envelops it and wliich can be washed away with salt
solution. The thrombus projects irregularly into the lumen of the vessel,
the projecting part being made up usually of round or irregular masses
which are connected together.

The thrombus has a homogeneous, grayish, translucent appearance, com-
parable to particles of boiled sago, and resembling, therefore, the color of
the Malpighian bodies in a waxj' spleen. When bits of the thrombus are
pressed into thin layers between the slide and the cover-glass they present
a bluish transparency almost glass-like. The epithet hyaline can be appro-
priately applied to the naked-eye appearance of the thrombus.

The consistence of the thrombus is soft, the weight of the cover-glass
suflBcing to make bits of the thrombus spread out into thin layers. In
attempting to tease apart portions of the thrombus, it is found that this
does not break up into little granules, as would be the case if the blood
plates which compose it had undergone no changes and were simply in
apposition to each other; but, on the other hand, the thrombus possesses
considerable cohesion, and in breaking it into fragments with teasing needles
fine sticky threads can be drawn out a short distance which break apart, or,
if the tension be removed, retract. Portions of the thrombus pressed be-
tween the fingers present a sticky, gelatinous consistence. In view of
Hanau's objection, already mentioned, to Eberth and Schimmelbusch's
designation of the change by which the plates adhere to each other as a
viscous metamorphosis, it is to be emphasized that fresh plate thrombi have a
somewhat viscid consistence, which becomes more marked in the course
of an hour after the removal of the thrombus. I cannot, therefore, accept
Hanau's objection, so far as this point is concerned, as valid.

If parts of the fresh thrombus be teased in physiological salt solution
or in Bizzozero's methyl-violet salt solution, or in Hayem's solution, tliere
will be seen masses of blood plates and a large number of free plates floating
in the liquid. The plates appear as pale, well differentiated, round or some-
what irregular bodies varying in size, the average being about one-quart«r
the diameter of a red blood-corpuscle. Masses of plates resemble colonies
of large micrococci. They can be made to assume feeble tints with a variety
of coloring agents, but I have not been able to give them, in their fresh

STEUCTUEE OF WHITE THEOMBI 59

state, a sharp, elective staining. In water the plates become paler and some-
what swollen ; in very dilute acetic acid they become darker in color and more
distinct, in strong acetic acid they disappear from view.

By tapping with a needle upon the cover-glass it can be seen that the
individuals composing the masses of plates adhere to each other. Such
masses may be readily flattened out and compressed. The plates, espe-
cially when in masses, may be drawn out lengthwise by currents of fluid
or by pressure. The remarkable viscidity of the plates can be demonstrated
by placing a bit of filter paper at the edge of the cover-glass and thus causing
currents in the fluid which fail to draw along even the isolated plates.

In order to see the regular and characteristic appearance of the fresh
plates when arranged in masses, it is necessary that they should not be
subjected to any pressure. When masses of plates are compressed even
by the weight of the cover-glass they often appear to be made up wholly
or in part of pale lines instead of coarse granules. This appearance of
lines or threads seems to be due to an elongation and coalescence of the
plates. These lines are often arranged with considerable regularity. They
might be mistaken for threads of fibrin. A similar appearance of threads
produced by coalescence of the plates is sometimes seen in hardened speci-
mens where the threads are often varicose. Whether this appearance is
due to the action of the hardening agent or to some other influence, such
as the force of the circulating blood, must be left unsettled.

Although the plates make up the great mass of the thrombus leuco-
cytes are present even at this early stage (during the first five minutes), and
rapidly increase in number, so that at the end of half an hour the throm-
bus usually contains them in abundance. My investigations have not led
me to assign so insignificant a role to the leucocytes in experimental
thrombi as is done by Eberth and Schimmelbusch. I agree with these
authors in finding that thrombi produced mechanically in the manner
mentioned consist in their inception essentially of blood plates. At the
end of five minutes the leucocytes may be so scanty as not to attract atten-
tion. Usually, however, by this time clumps of leucocytes as well as scat-
tered leucocytes are present here and there in the thrombus, and, as already
mentioned, their number continues to increa,«e. I have found them at the
end of six hours, in mechanical thrombi, as numerous as in many human
marantic thrombi. It is true that much diversity exists as regards the
number of leucocytes even in thrombi of the same age, still it is the rule
that white corpuscles, while they do not collect so rapidly or in such num-
ber as the blood plates, do accumulate and form a constituent part of
experimental mechanical thrombi. In order to study the situation of the
leucocytes sections of hardened specimens are necessary, but portions of

60 STRUCTITKE OF WHITE THKO.MBL

fresh tlironibi teased apart, and treated witli dilute acetic acid are favorable
for ascertaining their number.

In searcliiug for fibrin in fresh thrombi, it is inijiortant not to mistake
for fibrin tlie threads produced by compression of the clumps of j)lates
in the manner already mentioned. If these flattened-out masses of plates
be washed with water, or, better still, with dilute Lugol's solution, there
may be produced an appearance of interlacing and of parallel threads,
which bear considerable resemblance to fibrin, but which are paler and
which do not project beyond the margins of the clumps. Unmistakable
fibrin in the form of fibrils, however, is to be found in experimental
mechanical thrombi, but, so far as my observations go, not in the earliest
stage of their formation. I have found fibrin in thrombi at the end of
five minutes; frequently at the end of fifteen minutes, and usually at the
end of half an hour. Fibrin is often found in so much larger amount
in the fresh thrombi than in sections of the hardened thrombi that it is
probable that it is formed in part after the removal of the vessel. As will
be mentioned subsequently, fibrin can be demonstrated, also, in the hardened
specimens, although not in the youngest thrombi. I am not able, therefore,
to agree with Eberth and Schimmelbusch in denying altogether the presence
of fibrillated fibrin in experimental thrombi produced by mechanical injury of
the vessel, although our observations are in accord regarding the youngest
thrombi.

I have dwelt thus at length upon the appearances of the fresh experi-
mental thrombi because I have been unalile to find any description of these
appearances. With the exception of a brief allusion by Lubnitzky to sec-
tions of frozen thrombi, all the previous observations seem to have beeu
made either u])on the mode of formation of these tlirombi in the living
circulation or upon sections of hardened specimens. As has been suggested
by W'eigert, and as is apparent from the foregoing description, a knowledge
of the gross appearances of the plate thrombi is important in forming a
judgment as to their nature. Sections are, of course, necessary to enable
us to study more carefully the constituents of the thrombi and particularly
their arrangement.

As already mentioned, I have made use cliiefly of corrosive sublimate
as a hardening agent, of paraffine as an imbedding medium, and of hsema-
toxylin and eosin as staining agents." In sections prepared in this way
the plates can be seen with a distinctness and uniformity in shape that
leave nothing to be desired. I am led to believe that most of the appearances

" Since the delivery of this address I have also made use of Weigert's new
method of staining fibrin on specimens hardened in alcohol.

STRUCTURE OF WHITE THROMBI 61

whifli have b«?n described as changes in the plates occurring during the first
half hour (Lubnitzky and others), are due to imperfect methods of harden-
ing. Eberth and Schimmelbusch recognize this fact in their preparations.

Plate thrombi can be recognized in sections as well as in the fresh state
by their peculiar translucence'. I can only confirm the statments of Eberth
and Schimmelbusch as to the composition of the experimental thrombi in
their earliest formation. They are made up of blood plates. To the torn
and partly detached internal elestic lamella as well as to the lacerated media
masses of plates are attached, which extend into the lumen of the vessel.
Upon sections clumps of plates often appear to lie free in the lumen sur-
rounded by blood, but subsequent sections show the connection of these
clumps with others or with parts of the vascular wall. The thrombus often
forms a complete ring around the torn inner wall of the vessel. Xot every
injured part of the internal wall of the vessel is covered with a thrombus.
One is often surprised to find such parts, even when severely lacerated,
entirely free from thrombi or with only a thin layer of plates, recognized
with a high magnifying power. The mass of plates composing the thrombus
does not always appear uniform, but often, especially in older thrombi, there
are lighted and darker portions, due apparently to greater density in the
number of plates in some places than in others.

An appearance mentioned by Hanau is of interest, namely, the pres-
ence of a dark band around the margin of masses or islands of plates. Simi-
lar dense lines can often be seen running irregularly through sections of
the tlironibus. These denser bands have been interpreted as hyaline or as
fibrin. It is not easy to determine their exact nature. They look Like fibrin
in many cases, but it is possible that they are produced by coalescence of the
plates as the result of pressure or traction from the circulating blood in a
manner similar to the lines which can be artificially produced in masses of
fresh plates by pressure in the manner already described. Plates are not
confined to the interior of the vessel, but when the internal elastic lamella
and the media have been ruptured they often find their way in masses into
the layers of the torn media or even into the adventitia. It is interestino-
to note the absence of any transition, as a rule, between the thrombus and the
blood. The plates are just as dense usually at the margin of the thrombus
as in the interior, and immediately adjacent to the peripheral plates come
the red blood-corpuscles where the blood was still circulating before the ves-
sel was removed.

Leucocytes are not generally present in large cumber in thrombi during
the first five minutes of their formation. If serial sections be examined,
here and there clumps of white corpuscles can be found even at this early
stage. There are often more white corpuscles mingled with the plate masses

62 STRUCTURE OF WHITE THROMBI

in the coats of the vessel than in the thrombus proper. Leucocytes, scanty
at first, continue to accumulate in larger and larger number, until they
form a prominent part of the thrombus. I have found them in great abun-
dance at the end of half an hour, although sometimes at this period their
number is small. The leucocytes are generally arranged in clumps between
masses of plates, although some are usually scattered in among the plates. It
is probable that the clumps of leucocytes are deposited in that form directly
from the circulating blood. There is reason to believe that the leucocytes
may also wander into the thrombus, for in sublimate specimens elongated
nuclei, such as are seen in undoubtedly wandering white corpuscles in the
wall of the vessel, can also he occasionally detected in the masses of plates.
Moreover, the number of leucocytes within these masses increases with time.
In successfully prepared sections the protoplasm can be seen around the
nuclei of the white corpuscles, so that I do not agree with Lubnitzky that
this has become merged with the plates. Sometimes the leucocytes are sur-
rounded with a clear zone as if they lay in little spaces within the mass of
plates, but this appearance is probably due to the action of the hardening
fluid. Both uninuclear and multinuclear white corpuscles are present, but
the latter predominate, and in the later stages many of the nuclei often
appear much broken up.

Although I have not seen any appearances which indicate that the white
corpuscles disintegrate into granules, still non-nucleated white corpuscles
can sometimes be detected, so that a necrosis or death of these corpuscles
may take place within the thrombus. This does not seem, however, to be
a common or extensive process.

As has already been stated, fibrillated fibrin is present in experimental
thrombi produced by mechanical injury of the vessel. It is not, however,
found in the youngest tlirombi, and the date of its appearance varies in
different cases. I have found it in hardened specimens at the end of five
minutes, but this is exceptional. It is not uncommon to find it at the end
of fifteen minutes. I exhibit under the microscope sections of a tlirombuj>
of one-half hour's duration, in which there is a considerable amount of dis-
tinct fibrillat<?d fibrin. The amount of fibrin increases with tlie age of the
thrombus, and in thrombi of twenty-four hours' duration fibrin makes up
usually a large part of the thrombus.

The fibrin appears in islands and bands between the masses of plates, and
often extends in coarse fibres into tlie surrounding blood. The net-work is
usually coarse, but fine threads are also present. After a time the clumps of
white and of red corpuscles included in the thrombus are pervaded by a net-
work of fibrin, whereas, this is absent in the dense clumps of plates. I have
the impression that there is, in general, a relation between the number of

STEUCTURE OF WHITE THROMBI 63

leucocytes and the amount of fibrin, although the former appear in con-
siderable quantity before tlie latter.

Inasmuch as in older thrombi (twenty-four to forty-eight hours) fibrin
and leucocytes compose a large part of the thrombus, whereas, at its incep-
tion the thrombus is made up almost entirely of blood plates, one is tempted
to believe that the plates may be transformed into fibrin, but of this trans-
formation I can bring no positive proof. The plate-masses, after a time,
lose their regular granular appearance and appear darker in color and more
homogeneous, but typical plates may be foimd in large number in thrombi
forty-eight hours old.

It is apparent from the foregoing description, that experimental thrombi
acquire with time all of the characteristics of human thrombi. The sus-
picion which has been raised that they represent a distinct class of thrombi,
from the study of which we can draw no conclusion as to the formation of
human thrombi, is unjustifiable. It is another question whether we are to
suppose that all human white thrombi are formed in tlie manner described.
Although I have not succeeded in producing permanent leucoc)-tic thrombi
experimentally, still there is every reason to believe that some human
thrombi are composed from the beginning essentially of leucocytes. In
observations which I have made recently for another purpose, of the living
circulation in the mesentery of dogs, I have observed the formation of
small parietal thrombi composed of white corpuscles, but these have in-
variably been washed away after a short time.

We may, it seems to me, think of the mode of formation of the experimental
thrombi, which we have studied, and doubtless also of many human thrombi
as follows : Given suitable conditions, such as alteration of the vessel wall,
slowing and irregularity of the circulation, the first constituents of the
thrombus to accumulate are tlie blood plates. But although the plates
collect at first in larger number and more rapidly, the leucocj-tes do not long
remain absent, and in the course of time they are present in such quantity
that they must be considered an essental constituent of the completed
thrombus. At first the conditions for the coagulation of fibrin are not
present, but with the increasing accumulation of leucocytes these conditions
appear and fibrillated fibrin is deposited. It is in harmony with the current
ideas concerning the cause of the coagulation of fibrin, to suppose tliat at
first the fibria ferment is absent, and that this is subsequently furnished
by the leucocytes. The absence of fibrin in the early thrombi composed
wholly of plates, is an argument additional to the evidence brought forward
by Lowit and others, that the plates do not furnish the fibrin ferment. It is
apparently only after the leucocytes have been included for a time in the
thrombus that they die or imdergo some alteration in their constitution

64 STRUCTURE OF WHITE THROMBI

wliK h leads to the formation of the fibrin fcriuput. The final result is a plug
composed of plates, leucocytes, and fibrin, and included red blood-corpu-scles.

It seems to me an error to base our conception of the nature of a thrombus
e-xclusively upon the constitution of tlic tlirombus in its inception. While
admitting tliat tlie tlirombus is at first composed wholly of blood plates, we
do not, as a matter of fact, meet with humaji tlirombi in this early stage, or
at least, only under exceptional circiuustances. Our ideas as to the constitu-
tion of tlirombi are based upon the examinations of the completed plugs
which contain fibrin and leucocytes as well as plat«s. The study of the
experimental thrombi enables us to form a clearer conception of the mode
of formation of the thrombus, but does not nec-essitate any radical change in
our ideas as to what constitutes a thrombus.

The question as to whether a thrombus is a coagulum or not, is, of course,
open to discussion only regarding the plate thrombi in tlieir earliest forma-
tion. Whether or not we are to regajd the plate thrombi before fibrin has
made its appearance as coagula, is a question which is not likely to be settled
until we acquire more definite information as to tlie origin and nature of
tlie blood plates. There is nothing in the gross appearances of these plate
tJirombi which would prevent us from considering them as soft, gelatinous
coagula. Wooldridge, Lowit, and others believe that tlie plates are allied to
fibrin but are not identical with it. I purposely avoid entering into any
discussion here as to tlieir existence in the normal circidation, for this is a
point which must still be regarded as sub judice, and which is not likely to
be settled by tlie experimental study of thrombi.

The attempt of Eberth and Schimmelbusch to draw a sharp distinction
between thrombi formed by conglutination and thrombi formed by coagula-
tion, seems to me unwarranted. In the first place the process which they
designate as conglutination may be, so far as we at present know, a form of
coagulation. In the second place, whatever we may think as to the nature of
the process of conglutination, the preceding investigations have demon-
strated tile transformation of conglutionation thrombi into imdoubted coagu-
lation thrombi.

As regards the relation lietween clianges in the walls of the vessels and
thrombosis, I liave reached the same conclusion as tliat expressed by vou
Recklinghausen, Eberth and Schimmelbusch, and others, that Cohnheim's
views on this point were too exclusive. It is possible to produce experi-
mentally severe injury of the internal coats of bloodvessels without any
resulting thrombus. Among many positive results I have also in my notes
the records of not a few negative results which have followed injury of tlie
walls of the vessels by caustics, by forcible application of rough clamps, by
scraping the interior of tJie vessel, etc. As is urged by these writers as well

STRUCTURE OF WHITE THROMBI 65

as by Weigert and others, slowing of the circulation and irregularities of
the circulation produced by abnormalities in the lumen of the bloodvessels,
are factors no less important in the production of tJirombi than alterations
in the vessel walls.

There is much which speaks for the correctness of tlie view advocated by
Kohler, Hanau, and others, that some thrombi are caused by fermentative
clianges in the blood. Cases such as tlie one already mentioned, of extensive
thrombosis of a large number of the bloodvessels tlirougliout tlie body, are
most naturally interpreted as examples of fermentation thrombosis.

HEMORRHAGIC INFARCTION '

Of the various aspects of the subject of hemorrhagic infarction, I have
selected for my contribution to this discussion that which relates to the
mechanism by which the hemorrhage is produced in the infarction.

Together with Dr. F. P. Mall, Fellow in Pathology of the Johns Hopkins
University, I have undertaken some experiments in order, if possible, to be
able to form an independent and positive judgment as to some of the
unsettled questions which pertain to hemorrhagic infarction. It seemed to
me hardly worth while to present to an audience of this character, merely a
critical review of the many opinions which have been and are held as to the
mode of production of hemorrhagic infarction.

Before communicating the results of our experiments, I will call your
attention to the history of opinion concerning the nature of hemorrhagic
infarction, in order that we may understand the present aspect of the subject.

The first clear anatomical description of hemorrhagic infarction was given
by Laennec,' in 1819, under the name of pulmonary apoplexy. He seems
to have regarded the condition as analogous to cerebral hemorrhage, but he
expressed no positive opinion as to the causation.

After Laennec, BouiUaud,' CruveiUiier,* and several other noted the
presence of coagula in the arteries and veins adjacent to hemorrhagic infarc-
tions, but, in accordance with the pathological views of that time, they
interpreted these coagula as evidence of phlebitis. This gave origin to the
doctrine, advocated especially by Bochdalek,' that hemorrhagic infarctions
are inflammatorj' in their nature and due to a primary capillary phlebitis.

Rokitansky, in the first edition of his " Pathological Anatomy," also
attributed the origin of hemorrhagic infarction to capillary thrombosis, but,
in conformity with the humoral pathology of the Vienna school, he regarded
this thrombosis of the capillaries as referable not to inflammation but to a
change in the constitution of the blood.'

' Delivered before the Associatiou of American Physicians, Army Medical
Museum, Washington, D. C, June 2, 18S7.

Tr. Ass. Am. Physicians, Phila., 1887, II, 121-132.

'Laennec: De I'Auscultation Mediate, t. II, p. 41. Paris, 1819.

•Bouillaud: Arch, gen., 1826, t. XII, p. 392.

•Cruveilhier: Anat. Path., livr. III.

•Bochdalek: Prager Vierteljahrsschrift, 1846, Bd. IX.

•Rokitansky: Handb. d. Path. Anat., Bd. II, p. 680 et seq., Wien, 1844. Bd.
I, p. 243, Wien, 1846.

66

HEMORRHAGIC INFARCTION 67

Virchow,' by his memorable articles on thrombosis and embolism, pub-
lished between 18-16 and 1856, overthrew phlebitis from the dominant role
in pathologj' which it had assumed through the teachings of Cruveilhier, and
he introduced and established upon a firm basis the doctrine of embolism.
He did not, however, reach any positive conclusion as to the nature and
mode of production of hemorrhagic infarction. In his earlier writings he
was inclined to regard the ante-mortem coagula occluding arteries leading
to pulmonar}' hemorrhagic infarctions as secondary to the infarction and
not concerned in its causation. This view was based chiefly upon his fail-
ure to produce hemorrhagic infarction experimentally by injecting into the
blood emboli which lodged in branches of the pulmonary artery.

Virchow subsequently became doubtful as to the secondary nature of the
plugs occluding the arteries leading to infarctions by the observation of
cases of hemorrhagic infarction of the intestine in connection with embolism
of the superior mesenteric arterj'. In an article published in 1853, reporting
a case of embolism of the superior mesenteric artery, he suggested as pos-
sibilities most of the explanations which have since been advanced to account
for the apparently paradoxical phenomenon that the occlusion of an artery
is followed by hyperjemia and hemorrhage in the region supplied by this
artery. He laid especial emphasis upon changes in the vascular wall as the
result of prolonged ischsemia and upon increased pressure in the collateral
vessels. He also dwelt upon irregularities in the circulation leading to
stasis in some of the open vessels of the district whose artery is occluded.
In another connection, when treating of ischsmia, Virchow calls attention
to the possibility of a regurgitant flow of blood from the veins when the cor-
responding arteries are obstructed.' Virchow's chief motive in adducing
changes in the walls of the bloodvessels as an essential factor in the causation
of hemorrhagic infarction is the apparent impossibility of explaining the
occurrence of the hemorrhage on purely mechanical grounds.

Notwithstanding the cautious manner in wliich Virchow expressed hiui-
self upon the relation between embolism and hemorrhagic infarction, it has
been accepted by nearly all subsequent writers that obstruction of an artery
may lead to hemorrhagic infarction in the region supplied by that artery,
provided suitable conditions in the collateral circulation exist

'Virchow: Gesammelte Abhandlungen, 1856.

•Virchow: Handb. d. spec. Path. u. Ther., Bd. I, p. 127. Erlangen, 1857.
It is true, as pointed out by Mogling (Ziegler u. Nauwerck's Beitrage z.
Path. Anat., Bd. I, p. 145. Jena, 1886), that Virchow does not apply this factor
to the explanation of the production of hemorrhagic infarction, but it is
apparent that the reasoning which he employs to explain venous regurgitation
in partial anaemia applies to the condition present when hemorrhagic infarc-
tion follows arterial obstruction.

68 iiEMoinnrAnic ixfahctiox

The first to apply directly to the explanation of hemorrhagic infarction
a rcgiirgitaiit flow of blood tlirough tlie vein* of the district the artery of
wliich is obstructed, was B. Cohn,' in 185G. This view, liowever, he sub-
sequently abandoned " on the ground of experiments, which, nearly twenty
years afterward, were repeated by Litten. Cohn found that not only do
hyporaemia and liemorrhagic infarction occur when both artery and vein of
a part are tied, but the hyperaE?mia is more intense tlian when tlie artery
alone is ligated. Moreover, when all connection of a part witli the circu-
lation, except through the vein, is cut off, no hemorrhage follows. Cohn,
in his later work, regarded most hemorrahgic infarctions as referable essen-
tially to capillary obstruction, and, as a rule, not capable of production
merely by occlusion of a main artery. He did not separate infarction,
particularly renal and pulmonary infarctions, clearly from inflammation,
an error into which Panum also fell."

Regurgitation of venous blood was accepted by Beckmann " as the
explanation of hemorrhagic infarction of the intestine following embolism
of the superior mesenteric artery. He refers to the statments upon this
point of Virchow and of Cohn, and says that it is difficult to conceive that
the blood which produces the uniform hemorrhagic extravasation over
nearly the whole extent of the small intestine can come from the distant
arterial anastomoses. To Beckmann belongs the credit of pointing out
that most of the infarctions of the kidney are from the beginning pale and
unattended with much hemorrhage."

Blessig," in an experimental work on changes in the kidney following
ligation of the renal artery, performed under Virchow's direction, came
to the conclusion that obstruction of an artery is followed by hemorrhagic
infarction only when the corresponding vein is likewise occluded. It is
noteworthy that he observed hemorrhagic extravasation in the kidney after
ligation of both renal arterj- and vein.

An epoch in the history of our subjects is marked by the publication,
in 1872, of Cohnheim's " Investigations Concerning the Embolic Pro-
cesses."" Cohnheim studied microscopically, in the tongue of curarized
frogs, the process of formation of hemorrhagic infarctions produced by
artificial emboli which, after introduction into the aorta, lodged in branches

' B. Cohn: De Embolia ejusque sequelis. Diss., 1856.

" B. Cohn: Klinik d. embolischen gefasskrankh. Berlin, 18G0.

^ Panum; Virchow's Archiv, 1S62, Bd. 25, p. 433.

"Beckmann: Virchow's Archiv, 1858, Bd. 13, p. 504.

" Ibid., op. cit., 1861, Bd. 20, p. 219.

"Blessig: Virchow's Archiv, 1859, Bd. 16, p. 120.

"Cohnheim: Untersuchungen iiber die embolischen Processe. Berlin, 1872.

HEMOREHAGIC INFAECTION 6'J

of the lingual arteries. He reached the conclusions that the blood which
produces the infarction is derived by regurgitant flow from the veins, that
the hemorrhage occurs by diapedesis, and that the diapedesis is the result
of some molecular alteration in the vascular walls deprived of their normal
circulation. The hemorrhage occurs some time after the embolic occlusion
of the artery. In this article Cohnheim also considers the peculiarities
of the circulation io the organs which are most frequently the seat of
infarction, and thereby laid down his doctrine of terminal arteries (endar-
terien) — that is, arteries the branches of which do not anastomose with
each other.

Although Cohnheim made no attempt to reconcile his views -with the
opposing conclusions reached experimentally by Cohn and Blessig, never-
theless the authorit}' of his name, the clear and admirable presentation
of his experiments, the inherent reasonableness of his views, and the fact
that they were deduced from actual observation under the microscope,
combined to win general acceptance for Cohnheim's explanation of hemorr-
hagic infarction.

This explanation, however, did not long remain unchallenged, for in the
year following Cohnheim's publication, Zielonko," who worked under von
Recklinghausen's direction, reached a different conclusion as to the causation
of liemorrhages following arterial obstruction. Zielonko's observations were
upon the web of the frog's foot. The main points in Zielonko's conclusions
which interest us, are that the blood which produces the hemorrhages after
obstruction of an artery, comes from the collateral vessels and not by a
reflux from the veins, and that the hemorrhage is at least quite as much
the result of stasis in the capillaries, and consequently increased pressure,
as of changes in the vascular walls. A regurgitant flow of blood in the
veins may occur, but this does not extend so far back as the capillaries, and
has no share in the formation of the stases.

Similar results were obtained by Kossuchin," who worked under Afanas-
siew's direction, and published his article in 1876. He repeated Cohn-
heim's experiments upon the frog's tongue. He was unable to observe
reflux of blood from the veins into the capillaries belonging to the obstructed
arteries, and he attributes the hyperjemia of the district whose artery is
occluded chiefly to collateral fluxion. Hemorrhages occur by diapedesis
only in the peripherj' of the embolized area and in tlie surrounding zone
of collateral hyperemia; at a later period, when necrosis sets in, hemor-
rhages occur throughout the embolized area, and are due probably to necrosis

"Zielonko: Virchow's Archiv, 1873, Bd. 57, p. 436.
"Kossuchin: Virchow's Archiv, 1876, Bd. 67, p. 449.

70 HEMORRHAGIC INFARCTION

of the vessel walls. The early hemorrhages occur especially from capillaries
in the condition of stasis, or adjacent to such stases, and are probably
referable to increased blood pressure.

The careful observations of Zielonko and Kossuchin seem to have had
little or no influence in preventing the general acceptance of Cohnheim's
teachings. On the other hand, the more pointed attack of Litten " upon
Cohnheim's doctrine has had greater influence upon tlie current views con-
cerning the production of hemorrhagic infarction. Litten concludes that
the hypersemia and hemorrhage which follow ligation of the renal artery
cannot be due to a regurgitant flow of blood in the renal vein, because
the same or an even greater hyperemia follows when both artery and
vein are ligated, and no such result occurs if all connection of the kidney
with the circulation, save through the renal vein, be cut off. The only
possible source for the increased supply of blood is the collateral circulation.
Similar experiments were made upon the lung and the spleen. Litten's
experiments upon this point are essentially a repetition of those performed
twenty years previously, with the same results, by Cohn. Of Cohn's mani-
fold experiments upon the kidney, spleen, and intestine, to disprove the
agency of regurgitation of venous blood in the causation of hemorrhagic
infarction, Litten seems to have been ignorant, for they are not mentioned
in his article. Litten also denies the efficacy of a second factor, which Vir-
chow and Colinheim had adduced to explain the occurrence of hemorrhagic
infarction, namely, changes in the walls of the vessels produced by pro-
longed ischaemia. This denial is based first upon the fact that hyperaemia
and diapedesis begin in a very short time after ligation of the renal
artery, and, secondly, upon the absence of any hemorrhage which can pos-
sibly be attributed to changes in the vascular walls, in cases when the cir-
culation has been reestablished in the kidney of the rabbit after its cessation
for three or four hours. The same conclusions had been previously drawn
by Kossuchin from experiments of the same nature made upon frogs.

Von Recklinghausen," in an admirable chapter upon thrombosis and embol-
ism, has called attention to a new factor in the causation of hemorrhagic
infarction, namely, hyaline thrombosis of the capillaries. He has observed
hyaline thrombi in the capillaries in all hemorrhagic infarctions of the
lung examined in recent years, as well as in hemorrhagic infarctions of the
spleen. The obstruction to the circulation produced by these thrombi

"Litten: Zeitschrift f. klin. Med., Bd. 1, p. 131.

"Von Recklinghausen: Handb. d. Allg. Path. d. Kreislaufs u. d. Ernahrung,
p. 160. Stuttgart, 1883.

HEMOKEHAGIC INFAECTION 71

causes, he believes, a rise in pressure and hemorrhage. The blood enters
from the collateral channels.

This review of the history of opinion concerning hemorrhagic infarction
makes it evident that there is still much to explain in the causation of this
condition, and that there is abundant opportunity for further experimental
work.

The experiments of Dr. Mall and myself relate to hemorrhagic infarction
of the intestine, and were performed almost wholly upon dogs. The intes-
tine offers many advantages for the experimental study of hemorrhagic
infarction. It is easy to produce infarction in this situation, whereas it is
difficult to produce hemorrhagic infarction of the lung artificially. The
circulation of blood in the spleen is of so peculiar a nature that this organ
is less adapted to our purpose than the intestine. Infarction of the kidney
in man is usually a white infarction, with only a margin of estravasated
blood. As is well known, occlusion of the superior mesenteric artery in
man is followed by hemorrhagic infarction extending throughout nearly
the whole length of the small intestine, and even into the upper part of
the large intestine.

In the mesentery the condition of the circulation can be modified in
many ways. The branches of the superior mesenteric artery anastomose
freely, forming in the dog only one row of arches, from the summits of
which branches are given off which enter the walls of the intestine. It is
possible to convert any one of these main arteries into a terminal artery.
The collateral circulation can be limited to any extent desired. The intes-
tine offers the advantage that it is easy to look over its whole extent and
determine the exact situation and character of an infarction.

Of importance is the high pressure in the veins leading from the intestine.
The blood pressure in the mesenteric and portal veins is higher than in
any portion of the venous system. We have found the pressure in the
superior mesenteric vein equal to from 30 to 50 mm. of mercury. If regurgi-
tation of blood from the veins is a factor in the production of hemorrhagic
infarction, it should be apparent here.

If the superior mesenteric artery be ligated near its origin, there follows
an intense hemorrhagic infarction which begins about five or six hours
after the ligation, and increases in intensity until it reaches its maximum
about seven or eight hours after the obstruction was produced. If the ani-
mal be now killed, it is foimd that the hemorrhagic infarction begins
abruptly with a sharp line of demarcation in the lower part of the duodenum.
It reaches its greatest intensity within an inch or two of its beginning, and
extends throughout the whole length of the small intestine into the colon,
where it gradually diminishes in intensity, but stiU ends somewhat abruptly.

72 HEMOHRHAGrC INFARCTION

Tlie Iiyiipra'mia and heniorrliajre begin in the mucous membrane, and are
more intense there than in any of the other coats. The mucous membrane
is of a dark red, almost black color. The submucous coat also becomes infil-
trated witii bl(X)d, but the nuiscuhir coat is much prone to hemorrhage. The
lumen of the intestine contains much dark blood mixed with mucus. Upon
microscopical examination the capillaries and veins, particularly of the
mucosa, are engorged with blood, and there is extravasation of blood into
the tissues.

The first point whicli we wished to settle is the source of the blood which
causes the hypera^mia and hemorrhage after ligation of the superior mes-
enteric artery. This blood must come either from the collateral arterial
and capillary anastomoses or by a regurgitant flow from the veins. The
collateral anastomosis above is with the pancreatico-duodenal artery, that
below with the inferior mesenteric artery.

In order to determine whether a regurgitant flow of blood from the veins
is the source, we ligated the superior mesenteric vein coincidently with
ligation of the artery, and found that the infarction, instead of diminishing
in intensity, became more marked, and was established at an earlier period.
The same results were obtained by ligation of the superior and inferior
mesenteric veins, and by ligation of the portal vein at the same time, with
that of the superior mesenteric artery. It seemed, therefore, certain that
a regurgitant flow of blood from the veins is not the cause of the infarction.
In order to remove all doubt, we isolated the intestine from all its connec-
tions with the circulation, except through the superior mesenteric vein.
And, although we convinced ourselves that no thrombosis had occurred in
this vein, there resulted no hypenemia or hemorrhage in the intestine. We
have repeated this experiment with a loop of intestine, and always with
the same result, death of the part, but no hemorrhagic infarction. It will
be remembered that the pressure in the veins is high, so that if a regurgitant
flow of blood in the veins is a factor, it should certainly be manifest here.

In order to determine to what extent the collateral circulation may be
cut off, and still hemorrhagic infarction follow, we ligated the superior
mesenteric artery, coeliac axis, and jwrtal vein, and in another series of
experiments, in addition to the ligation of these vessels, we ligated the
duodenum and the ileum, not far from the ileoco'cal valve. Under these
circumstances the collateral anastomosis must be slight, and yet hemorrhagic
infarction occurred. The collateral anastomoses, however, without being
completely cut ofF, may be so reduced that they do not suffice for the pro-
duction of hemorrhagic infarction. Thus, if the vessels (including the
subintestinal plexus) and the intestine bo so tied that the blood can enter
only through the vessels in the intestinal wall at the lower end of the loop,

HEMORRHAGIC INFARCTION 73

it is found, if the loop be a long one, tliat hemorrhage makes iis appearance
only in the lower end, and, after extending a short distance, ceases, to be
replaced first by patches of hemorrhages, and then by simple anaemic necrosis.

We wished to determine another point, of some theoretical interest at
least, namely, whether the blood which produces hemorrhagic infarction
must enter from the collateral channels. For this purpose we Ugated all
of the vascular communications of the intestine, with the exception of the
main artery and the main vein, and then tied the intestine above and below,
so that the included intestine was supplied only by the main arterj-, and the
blood returned by the main vein. Under these circumstances no infarction
results. We then placed a rubber clamp around the artery, and gradually
tightened it, so that the blood circulated with less and less force. We carried
the compression so far that the pulsations disappeared in the branches of
the artery, although the blood still continued to flow, as was demonstrated
by cutting one of the branches. By thus obstructing the circulation in the
main arterj', while all collateral anastomoses were cut off, we succeeded in
producing hemorrhagic infarction of the included part of the intestine.
This experiment sheds some light upon the condition of the circulation dur-
ing the production of hemorrhagic infarction.

We wished t« measure the blood pressure in a part in which hemorrhagic
infarction is taking place. To accomplish this we inserted a canula, con-
nected with a mercury manometer, into a branch of the superior mesenteric
artery. Immediately after ligation of the superior mesenteric artery, the
pressure fell from 130 mm. to about 30 mm., and remained at about this
point during the whole time the infarction was taking place. We may, there-
fore, conclude that the arterial tension in a part where hemorrhagic infarc-
tion is occurring, is very low. As is apparent from, the historical review which
has been given, it was important for us to determine whether changes in
the walls of the blood vessels are a factor in tlie production of hemorrhagic
infarction. The only change of which one can think in this connection is
that caused by insufficient nutrition, in consequence of deficient supply of
arterial blood. We shut out for variable periods of time parts of the intes-
tine from the circulation, either by tying tightly rubber tubing around
an intestinal loop with the corresponding mesenterj', or, after ligating the
intestine and all its vessels, except the main artery, by compressing this
artery by means of a fiat rubber clamp. After about three hours peristalsis
ceases, and cannot be reproduced by stimulation of the intestine. If then,
or even at a later period, the ligature or clamp be removed, the blood at
once shoots in with great rapidity, and the arteries, veins, and capillaries,
which were previously shut out from the circulation, become distended with
blood. As a rule, during the period of ligation, no thrombosis has occurred
8

74 HEMOHHUAGIC INFAIUTION

in the vessels. In no instance in wliieh the veins were free from thrombi,
were we able to produce a hemorrhatric infarction in this way. Even if,
after the circulation has been reestablished, the superior mesenteric artery
be lifrated, we could not observe that the hemorrhagic infarction appeared
earlier, or was more intense in a part of the intestine which had been pre-
viously deprived of its circulation for three or four hour.*, than in the
remainder of the small intestine. Our experiments upon this point were
manifold, and afforded no evidence in favor of the view that hemorrhagic
infarction is in any way dependent upon alterations in the vascular walls.

In view of the observations made by Cohnheim upon the frog's tongue,
we regarded it as of great importance to devise some means of studying the
circulation in the mesentery under the conditions in which hemorrhagic
infarction occurs. Our observations upon this point are not yet completed.
One of the methods which we adopted was a modification of that of Eberth
and Schimmelbuseh.*' We employed an electric light submerged in the
salt solution, and placed beneath the stage of the microscope in order to
illumine the object. We also obtained fairly satisfactory results by simply
drawing the mesentery out over a glass plate, and keeping it irrigated with
warm physiological salt solution.

Immediately after occlusion of the superior mesenteric artery the circu-
lation ceases in the veins, arteries, and capillaries of the mesenterv-. In a
very short time the circulation returns and has the following characters.
The arteries contain a much smaller quantity of blood than normal, and
they appear contracted. The blood flows in the arteries with considerable,
although much diminished, rapidity and without distinct pulsation. The
movement of blood in the veins and capillaries is sluggish and irregular.
In some of the veins the direction of the current is normal ; in others it is
backward, but we were not able to trace the regurgitant flow into the capil-
laries. In many of the veins and capillaries there is entire cessation of the
current. Frequently the circulation becomes reestablished in vessels where
it had previously ceased, and in other vessels stasis occurs. The distinction
between axial and plasmatic current is obliterated. Gradually the veins
become more and more distended with blood, and these as well as many of
the capillaries become filled with homogeneous red cylinders of blood. .Some-
times the red corpuscles become clumped together, and such clumps can be
seen moving in the veins. We also noticed frequently clumps of white
corpuscles in the circulation. The extravasations of blood took place chiefly
from the small and medium sized veins, but also from the capillaries, and at
least, in part, by the process of diapedesis. Tlie microscopical appearances

" Eberth u. Schlmmelbusch. Virchow's Archiv, Bd. 103, p. 57.

HEMORRHAGIC IXFARCTIOX 75

in the veins and capillaries resembled those seen in passive congestion
resulting from venous obstruction, and yet we were unable to discover
coagula in the larger veins.

I have now presented to you the most important results of the experi-
ments which we have thus far performed. I have not regarded this as an
appropriate occasion to describe in detail the methods employed, or to
weary you with the minutiae of indi\'idual experiments. These, together
with the results of other experiments bearing upon this question, we hope
to publish in more complete form elsewhere.

Our experiments justify the following conclusions :

1. Tlie blood which produces hemorrhagic infarction comes from the col-
lateral circulation and not by reflux from the veins.

2. The blood pressure is very low in the region where hemorrhagic infarc-
tion is taking place in consequence of the occlusion of the main artery.

3. If the force of the arterial and capillary circulation sinks below a
certain point, no hemorrhagic infarction occurs.

4. There is no evidence that changes in the vascular walls are concerned
in the production of hemorrhagic infarction.

5. Where hemorrhagic infarction, resulting from arterial obstruction, is
taking place, the large and small veins are distended with blood, and the
arteries contain less blood than normal. The circulation is sluggish and
irregular in the veins and capillaries, in many of which stasis and probably
physical alterations in the red corpuscles occur.

6. The hemorrhage occurs by diapedesis.

It would appear that hemorrhagic infarction, occurring under the con-
ditions described, is the result simply of mechanical alterations of the cir-
culation, although it is not easy to give an entirely satisfactory mechanical
explanation of all of the phenomena. We should remember that our know-
ledge of the dynamics of the circulation of the blood is still imperfect. We
have to do with a circulation influenced by complicated physiological condi-
tions, and with a fluid containing solid particles of complicated physical
properties.

The distention of the veins may be explained by the insufficient force
with which the blood is propelled through them. This force is so feeble
that the blood corpuscles cannot be pushed through them as rapidly as they
are sent in from the arteries and capillaries. The red corpuscles thujs
accumulating in the veins generally block them up, and there are appearances
which speak for some physical alteration in the red corpuscles when thus
massed together. When many of the veins and capillaries are thus plugged
with stationary or feebly propelled colunms of red corpuscles, it is con-

76 HEMORRHAGIC INFAKCTIO^f

ceivable that a pressure far below the normal may suffice to pu.sli tlie red
eorpuseles through the vasnular walls, inasmuch as their progress in the
normal direction is impeded. That the character of the tissue surrounding
the vessels is an important factor is evident from the more rapid occurrence
and greater degree of the hemorrhage in the lax mucous than in th" dense
muscular coat of the intestine.

The conclusions which we have drawn from our experiments apply strictly
only to infarction of the intestine. There is, apparently, no reason why
the same inferences do not apply to hemorrhagic infarctions in other situa-
tions. Still the conditions should be investigated separately for each organ
of the body subject to hemorrhagic infarction.

EXPERIMENTAL STUDY OF HAEJIOREHAGIC INFARCTION OF
THE SMALL INTESTINE IN THE DOG '

The experiments described in this paper were undertaken to determine
the circulatory conditions and the source of the blood in the production of
haemorrhagic infarction, the time of onset of the infarction, as well as other
pertinent factors. In order to subject this question to experimentation it
is necessary to make tests upon an organ in which haemorrhagic infarction
invariably follows occlusion of its main artery. Furthermore it is necessary
tliat the vascular system of the organ be accessible throughout its whole
extent. Both these requirements are present in the small intestine of
the dog.

Anatomy and Physiology.

The arteries of the small intestine are arranged in such a manner that the
pressure in the arterioles of the different parts of the intestine is practically
the same. This condition of things exists in the whole small intestine, as it
is supplied with a single arterial trunk. Soon after the superior mesenteric
artery leaves the aorta it passes over the duodenum and forms a semicircular
curve between the two layers of the mesentery. From this curved vessel the
branches to the intestine arise — first a branch to the duodenum and then
branches of different sizes to the rest of the small intestine. The smallest
of these branches pass directly to the niesenteric border of the intestine,
while the larger divide several times and the ultimate twigs of all anastomo.se
to form a single series of mesenteric arches. From these arches branches
arise about every half centimeter, pass alternately to opposite sides of the
intestine and penetrate the muscle-wall near the mesenteric attachment, to
be distributed as a rich plexus (Heller's) in the submucosa. Before these
branches (long arteries) pass through the submucosa they give rise to two
or three twigs which anastomose with like branches from their neighbors,
and thus form an arterial plexus just outside of the intestine. From this
arterial plexus many small branches arise and penetrate the muscular coats
at right angles to he distributed to the submucosa of the mesenteric side of
the intestine. The arrangement is such that before the arteries reach the
villi there are three distinct sets of arterial anastomoses ; the arches, the
extraintestinal plexus and Hellers plexus of the submncosa.

» William H. Welch and Franklin P. Mall. This paper, written in 1887, has not
previously been publiEhed.

77

78 EXPERIMENTAL STUDY OF

A study of tlie vessels of tlic intestine su<i:<rest< tlie following:

1. Since but one artery supplies the intestine, the circulation through the
intestine depends entirely upon the pressure at the beginning of the superior
mesenteric artery.

2. Since all the terminal branches of the superior mesenteric artery are
about equally distant from their origin, it is probable that with a given
pressure and rapidity, equal parts of the intestine are supplied with equal
quantities of blood.'

3. The fact that the artery divides into some fifteen branches, and these in
tuni into several smaller branches, each of which has an independent muscu-
lar coat, makes it possible that a simple contraction of the circular muscle
coat at any point can mitigate the flow of the blood to the intestine supplied
by the arterial branch. This statement applies to the smallest arterioles.

4. The rich anastomosis in the submucosa aids materially to equalize the
flow through the mucosa when the capillary resistance in the mucosa is
increased or diminished, due to contraction or relaxation of the muscularis
mucosae or Bruecke's muscle.^

Our experiments were performed in a systematic maimer to determine the
following question: (1) Through what channels, under what pressure and
other circulator)' conditions, and at what time does the blood enter the
vessels to produce haemorrhagic infarction? (2) These factors having been
determined can we produce haemorrhagic infarction of the intestine by other
methods than ligation or complete occlusion of the main arterial branches ?
(;>) In case this is possible in the living animal can it be accomplished also
in the isolated intestine when nourished by artificial circulation?

'A more careful statement would probably be about this: If we consider the
Intestine to be divided Into equal parts, a to z. a will receive m amount of blood;
J, „, — n: c, m — 2n.- and j. vi — 25n. being much less than half of m. This state-
ment is more nearly correct for I, as one passes from the duodenum down to the
caecum the vessels gradually become larger and longer. 2. Injections of the
intestine first fill the vessels of the duodenum and then those lower down the gut
until the caecum is reached. 3. During digestion fat absorption seems to take
place more in the upper part of the intestine and diminishes as the caecum is
approached. 4. Haemorrhagic infarction after ligation of the superior mesen-
teric artery is as a rule more intense in the duodenum than elsewhere. But
since the diameter of the intestine becomes less and less as the caecum is
approehed, it is reasonable to suppose that a given length of intestine in the
duodenum must obtain more blood than the same length nearer the caecum, so
ultimately it may be provided that a villus from the ileum obtains as much
blood as one from the duodenum.

'For a more detailed account of the blood-vessels of the dog's intestine see
Mall: Blut. u. Lymphwege im Diinndarm d. Hundes. Abhandl. d. K. K. Ges.
d. Wiss.. Bd XIV, 1887, Leipzig.

HAEMORRHAGIC IXFARCTION

79

LiGATDRE OF THE SUPERIOR MESENTERIC ArTERY.'

Immediately after ligating the superior mesenteric artery the muscular
walls of the intestine contract and become anaemic. This condition con-
tinues for some three to four hours, when the intestinal walls gradually
relax and the mucous inembrance becomes first hyperaemic and then in-
farcted, the process extending from the middle of the duodenum downward.
The infarction is complete at the end of six to eight hours ; after this time
its intensity is not generally increased &s the excess of blood now leaves the
tissues and enters the lumen of the intestine. The various experiments
upon which the above statements are made are given in Table I.

TABLE I
Condition of the Intestine after the Supebiob Mesenteric Artery had been

LiGATED FOB 3 10 21 HOUES

Experi-
ment

Duration

of the

Condition of tlie intestine

Remarks

experiment

1

3hrs.

Muscle walls pale, mucosa hy-
peraemic.

2

4 "

Somewhat more hvperaemic than
No. 1.

3

5 "

Hyperaemia of mucosa, more in-
tense than No. 2.

4

0 "

Mucosa of parts supplied by the

The artery ligated was one of

artery hyperaemic.

the large branches of the
superior mesenteric.

5

5 "

Infarction of the entire mucosa.

6

6 "

11 ti ti a tt

7

7 "

11 tt tt tt tt

8

7 "

Infarction more intense than
No. 7.

9

12 "

Complete infarction of the in-

There was much blood within

testine.

the lumen of the intestine.

10

21 "

Cat. The infarction is mottled

Considerable blood within the

and not complete.

lymphatic channels.

11

18 "

Intestine dilated and flabby;

Intestine filled with gas and

mucosa very haemorrhagic.

blood.

In all the experiments either the hyperaemia or the infarction begins
abruptly in the middle of the duodenum, marked by the junction of the
superior mesenteric arterj' and the pancreaticoduodenal artery, gradually
becomes somewhat less intense as the caecum is approached and ends very

* In all the experiments the animals were anaesthetized with ether or ether
and morphia combined.

80 EXPERIMENTAL STUDY OF

abruptly in the middle of the large intestine opposite the junction of the
superior and inferior mesenteric arteries. Not only is the infarction some-
what more marked in the upper part of the intestine than in the lower, but
it also begins earlier and becomes more intense in the villi than in the
intestinal glands (crypts), the rapidity and intensity of the infarction thus
corresponding in both instances with the physiological activity of these
parts when viewed from the standpoint of absorption.

After the infarction is complete the muscular walls of the intestine
gradually become flabbj' the process beginning in the duodenum, then
gradually extending to the caecum. The intestine dilates, putrefaction
takes place within the lumen and gas is formed which gradually distends
the walls and discolors the haemorrhagic mucous membrane. Even in
extreme states of relaxation the muscular walls are not necessarily dead,
for they often respond to strong irritants.

What has been determined from the foregoing experiments regarding the
time required in the production of an infarction can also be determined
from a single experiment. After ligature of the superior mesenteric artery
the intestine is to be examined from hour to hour, at each time removing
a piece of it in order to examine the mucosa as well as for comparison.
Immediately after ligating the superior mesenteric artery the intestinal
contractions become verj* active and continue for several hours. During the
. third hour the contractions diminish greatly, the veins begin to dilate and
the intestine takes on a bluish tinge. During the fourth hour the intestine
is motionless and the blueness increases. This stage is followed by hyperae-
mia and then still greater hj'peraemia and infarction. The same result is
obtained if the intestine is observed by the method of Sanders Ezn and van
Braam Houckgeest, as well as by the method of artificial circulation through
tlie isolated, but living, intestine.

It was noted in the foregoing experiments that the boundaries of the
infarcted region are sharply defined by the distribution of the branches of
the artery ligated. To test this question in detail a special set of experi-
ments was made.

LiGATDRE OF BRANCHES OF THE SUPERIOR MESENTERIC ArTERY.

The experiments given in Table I show that the anastomoses with the
inferior mesenteric and the pancreatico-duodenal arteries are not sufficiently
large to reestablish the circulation through the intestine after the main
trunk of the artery has been ligated. It now remains to determine to what
extent the anastomoses between the mesenteric arches can reestablish the
circulation when a main branch of the superior mesenteric artery has been
tied. Furthermore it is desirable to determine to what extent the arterial

HAEMORRHAGIC INFARCTION

81

plexus in the submucosa can re-establish the circulation through the mucosa
after all the extra-intestinal arteries have been cut off. To answer this sec-
ond question the experiments given in Table II were made (Fig. 1).

TABLE II

LiIGATDBE OF THE MAIN BRANCHES OF THE SUPERIOB MESEXTEBIC AETEBIES AS
WELL AS OF THE TEBillXAX TWIGS TO THE INTESTINE

Experi-
ment

Vessels ligated

Length of 1

the loop of

intestine

cut otf

Duration

of the

experiment

Results

12

Mesenteric branch and arches

as shown in Fig. 1, o. a', a".

13 era.

5 hrs.

Mucosa opposite branch
ligated, haemorrhagic.

13

Same as No. 12 with an addi-
tional ligature of the intes-
tine at a'.

13 •' ,

5 '•

Mucosa opposite branch
ligated extremely hy-
peraemic.

14

As No. 1-2

P tl

5 "

Mucosa not changed.

16

5 long intestinal arteries on
either side.

..-

4 "

Mucosa hyperaemic.

IG

4 long intestinal arteries on
either side.

2 "

7 "

■'

17

4 long intestinal arteries on
either side.

2 "

4 "

Mucosa not changed.

18

3 long intestinal arteries on
either side.

1.5 "

7 "

Mucosa hyperaemic.

19

3 long intestinal arteries on
either side.

1.5 "

4 "

Mucosa not changed.

20

2 long intestinal arteries an
either side.

1 "

7 "

Mucosa hyperaemic.

21

2 long intestinal arteries on
either side.

^^

7 "

tf (t

22

2 long intestinal arteries on
either side.

1 "

7 "

Mucosa not changed.

23

2 long intestinal arteries on
either side.

4 "

24

1 long intestinal artery on
either side.

.5 "

4 "

« tt it

25

6 long intestinal arteries on
one side.

3 "

4 "

26

5 long intestinal arteries on
one side.

2.5 •■

4 "

H W .i

27

4 long intestinal arteries on
one side.

2 .•

4 "

(< it tt

28

3 long inteftinal arteries on
one side.

1.0 "

4 "

t( it tt

29

2 long intestinal arteries on
one side.

1 "

4 "

it it it

30

1 long intestinal artery on
one side.

.5 ■'

4 "

tt tt tt

Where the ligated extra-intestinal arteries belonged to the arches it was
found that the plexus of the submucosa is sufficiently large to reestablish
the circulation through the mucosa in a loop of intestine 5 cm. long but not

82

EXPEIMMEXTAL STUDY OF

large enough for a loop 13 cm. long. If only the long intestinal arteries are

ligatod it is found tliat in case they are ligated on hoth sides of the intestine
this suliniucous plexus can l)arely reestablish the circulation in a section of
intestine 1 cm. long, while if the same vessels are ligated only on one side
of the intestine the lateral anastomoses as well as those of tlie submucosa from
the opposite side can easily reestablish the circulation through a loop 3 cm.
long, and probably much longer. These two groups of experiments indicate
tlie presence of the additional set of anastomoses (subintestinal plexus) be-
tween the mesenteric arches and tlie submucous plexus.

In order to determine more exactly the length of the intestine which can
be nourished through the submucous plexus and mesenteric arches respec-
tively the experiments, given in Tal)le III, were made. The idea underlying

TABLE III

LiGATl'RE OF THE BRANCHES OF THE SUPERIOR MESENTERIC ARTERT INCLUDING THE

Duodenum, with or without Ligature of all of the Mesenteric Arches

Length

Experi-
ment

Vessels ligated

of the
intestine
experi-
mented
upon

Duration

of the

experiment

Results

31

All the mesenteric
branches and arches
ligated as shown in
Fig. 1, with ligature
of the duodenum.

128 cm.

5 hrs.

The mucosa supplied by the
artery x" is infarcted, that
by ihe next artery x' less
infarcted and that by the
third artery i' is liyperae-
mic. The remainder of the
mucosa is anaemic.

32

Mesenteric branches
and the duodenum
including its arch
ligated as shown in
Fig. 2.

145 "

G ■'

The mucosa supplied by tlie
first branch is unchanged,
that supplied by the second
branch is infarcted, and the
rest of the mucosa is anae-
mic.

33

Same as No. 32

120 "

18 -

The mucosa of the part sup-
plied by the first branch is
hyperaemic, that of the
second and third branches
(12 cm. long) haemorrhagic,
the remainder (90 cm.) is
necrotic.

experiment 31 is to determine the change in the mucosa after ligature of all
the arteries entering the intestine with the exception of the submucous plexus
near the caecum, as shown by the diagrammatic Fig. 1. The result in this
experiment is so definite that it at once gives us a key to the origin of the
infarcted blood, at the same time refuting completely the Cohnheim doctrine
of venous regurgitation.

HAEMORRHAGIC IXFARCTION 83

Had a venous regurgitation taken place in this experiment, then the whole
mucosa of the intestine would have Ijeen equally infarcted. The sharp zone
marked by the degree of hyperaemia in the mucous membrane shows that the
origin of tlie blood is not from the veins, as the veins have not been interfered
with in any portion of the intestines. The zone of infarction begins sharply
opposite the ligature of the last mesenteric arch, and extends equally through-
out the mucosa supplied by this branch, A'^. The mucosa supplied by the
next branch, X„, is verj' hyperaemic, while that of the third branch, A'3 is
slightly hyperaemic. The rest of the intestine is anaemic.

The only suitable explanation of this experiment is that a sufficient quan-
tity of blood entered the artery A'l through the submucous plexus to produce
the infarction of the mucosa, the blood being equally distributed because the
pressure as well as the quantity of blood was equalized by the arterial branch
Xi communicating freely with all parts of the infarcted region. The second
zone received its flow from tlie first zone, and the third from the
second. From the fourth zone onward there is anaemia as the heart-beat
was not strong enough to overcome the increased resistance of more than
tliree dilatations in the arterial bed, produced by the operation. There-
fore, a certain quantity of blood is required for normal circulation, less
quantity produces haemorrhagic infarction, still less hyperaemia, while
finally when the quantity is very small anaemia and necrosis follow.

While experiment 31 determines the relative extent of the circulation
through the mucosa with the blood entering the submucous plexus, experi-
ments 33 and 33 (Fig. 2) determine it with the blood entering through the
mesenteric arches. In these two experiments the vascular system of the
intestine is reduced to series of mesenteric arches communicating on one
end only with the main trunk of the artery. The experiment shows that the
first arch carried a sufficient quantitv' of blood to the mucosa (20 cm. long)
of the first system to re-establish the circulation through it. The second
system, however, is haemorrliagic ; the remaining systems anaemic and
necrotic. In experiment 33 the first communicating arch is a very tiny
vessel, and the first zone of mucosa is not haemorrhagic but hyperaemic,
the second and third zones are haemorrhagic and the remainder of the
intestine is anaemic and necrotic. So, therefore, these experiments show
that a slight diminution of blood supply produces hyperaemia, less blood
supply haemorrhagic infarction, still less hj-peraemia, and finally if the
quantity is greatly diminished anaemia and necrosis of the intestine.

Combination Experiments Made to Show the Source of the Blood in
Haemorrhagic Infarction.

If it is true that the blood required to produce an haemorrhagic infarction
of the intestine after ligature of the artery enters through the collateral

84 EXPERIMENTAL STUDY OF

arterial branches and is not obtained through venous regurgitation, then
ligature of the vein with the artery must increase the intensity of the infarc-
tion rather than diminish it. In the infarction which follows ligature of the
artery the blood has still a free outlet into the vein, while if this channel is
also obstructed the infarction must be intensified. The experiments of Cohn,
of Litten, as well as our own, support this view. As the smaller branches of
the mesenteric vessels are approached the veins become relatively larger and
larger ajid therefore the ligature of a peripheral vein with its artery does
not intensify the infarction so much as the ligature of a larger vein with its
artery. These statements which are drawn in a general way from the experi-
ments to follow point towards the mechanical explanation of haemorrhagic
infarction. Experiment 34 is a repetition of 33 with the exception that the
accompanying veins are ligated with the arteries. In this experiment the
infarction and hyperaemia of the mucosa are but slightly intensified by the
ligature of the veins in addition to the arteries. In case the anastomoses are
smaller, as they are in 36 and 37, including the veins in the ligature intensi-
fies the infarction.

The same is true in experiments 41 and 42, as well as all the experiments
given (Table VII) in which the main large veins were ligated with the
artery. This result is to be explained by the ratio between the sectional
area of the arteries and veins not occluded in the experiment. Fig. 4 is the
scheme of Experiment 34 (Fig. 3). The average sectional area of artery a
is 0.28 square millimeters; of a' 0.032. The area of the vein v' 0.152. In
general the area of the vein is five times tliat of the accompanying artery. In
case the veins are ligated as indicated in Fig. 4, it is found that the capil-
laries of the mucosa of c' and c" remain normal ; those of c' become
hyperaemic, and those of c* and c' become haemorrhagic. If the anastomos-
ing arteries are considered to have rigid walls the relative quantity of blood
entering these capillaries of these different systems would be for c, 1/1 ; c',

1/9; c^, 1/9- ; r', l/9^ In reality, however the dilatation of the

anastomosing arteries increases this quantity considerably. On the other
hand the sectional area of the veins being at least five times that of the accom-
panying arteries they can with case carrv- off the diminislied quantity of
blood from the region becoming infarctcd and in no way favor stagnation.
The result is different when the area of the veins more nearly reaches that
of the arteries, as in the case of the submucous plexus and in the very large
veins. Here, occlusion of the veins with the arteries intensifies the degree
of the infarction.

All the necessary experiments to produce the different degrees of an
infarction can be performed to advantage on small loops of intestine as
given in Fig. 6 and Table V. The sectional area of the veins of the sub-

HAEMORRHAGIC INFARCTION

85

mucosa approaches nearlj' that of the arteries, so this factor can also be
included to advantage in making the different experiments. The experi-
ments together point toward the cause of the infarction in the showing of
the normal circulation.

Given the proper degree of stagnation, the greater the capillary blood
pressure the more rapidly is the infarction produced and the greater is its
intensity. In case the artery only is obstructed, the stagnation of circulation
and the blood pressure must be pretty definite in relation to production of
haemorrhagic infarction, for a slight increase or diminution of these two
factors is followed by only hyperaemia (and occasionally oedema) on the
one hand, or anaemic necrosis on the other, as the experiments of Tables III
and IV illustrate.

TABLE IV

Combination Experiments Similab to those Given in Table III with the Veins
Included with the Abtebies

Experi-
ment I

34

33

36

SS

Vessels ligated

Both mesenteric ar-
teries and veins li-
gated as shown in
Fig. 3.

All of the arteries and
veins including tlie
duodenum and ileum
ligated with the ex-
ception of one large
arterial branch and
its vein to the middle
of the intestine li-
gated. Only through
this artery could
blood reach the in-
testine.

Arteries and veins with
the exception of a
small central twig, as
indicated in Fig. 5,
Ko. 36, ligated.

Single arterial bro.ncIi
and mesenteric arches
with veins ligated.
Fig. 5, Xo. 37.

Experiment like No. 36
excepting that the
length of the loop of
intestine ia shorter.
Fig. 5, No. 38.

Length of
loops

operated
upon

Duration

of the

experiment

120 era.

16

7 hra.

7 "

7 "

7 "

Result

Mucosa of first and second
systems apparently normal ;
third system hyperaemic;
fourtli, fifth and sixth,
haemorrhagic; seventh hy-
peraemic, and so on, see
Fig. 3.

The part of the intestine sup-
plied by tlie patent artery
and vein were apparently
normal; the mucosa on
eitlier side of this was hv-
peraemic; the remaining
intestine botli above and
below haemorrhagic, the
upper part being more in-
tense than tlie lower.

Mucosa supplied by the open
artery and vein normal, witli
hyperaemia on one side and
infarction and hyperaemia
on the other.

Infarction, although not in-
tense throughout the entire
mucosa of the experimental
region.

Mucosa unchanged.

86

EXPERIMEXTAL STUDY OF

TABLE V

Experiments i ton L(K)rs of Intestine from 5 to 6 cm. Long to Test the Effect

OF Ligating Different Vessei.s itox the Mrcous Memhrane of the

Intestine. The Duration of the Experiment.s is in all

Instances Six Hours

Experi-
ment

VeBeels ligated

Results

39

Both venous and arterial arclies and in-
testine on both ends ligated. Fig. G, a.

Mucosa unchanged.

40

Artery and both arterial and venous
arches. Fig. 6. h.

"

41

The same with the intestine on one end
ligated. Fig. 6, c.

Mucosa hyperaemic.

42

Arterv and veins and arches with intestine

Complete infarction more in-

on one end ligated. Fig. 6, d.

tense near intestinal liga-
ture.

43

The same as above with the main artery
open. Fig. 6, e.

Same as above.

44

Arterv and vein and arches ligated. Fig.

Complete infarction of the

6,/.

mucosa, being sharply
marked above and below.

45

The same with the artery open. Fig. 6, g.

The infarction is not as in-
tense as the above (Xo. 44).

46

All the veins and arteries with the excep-

Extreme infarction of the in-

tion of the main arterv ligated. Fig.
6, h.
All the arteries and veins with the excep-

testine.

47

The intestine is necrotic.

tion of the main vein ligated. Fig. G, /.

anaemic and flabby.

Another instructive combination in tying the arteries is given in the
experiments of Table VI. They may be considered as experiments within

TABLE VI
Experiments Within Experiments

Experi-
ment

48

49

50

Vessels litrated

Duration

of the

'experiment

Two main branches and pe-
ripheral arches of both
arteries and veins ligated.
The same experiment was
then performed on smaller
vessels in tlie middle of the
first, as shown in Fig. 7.

Ligature of the superior
mesenteric artery with ad-
ditional ligature of four of
its main branches side by
side. Fig. 8.

Ligature of the superior
mesenteric artery as well
as all of its main branches.

4i hrs.

Results

Infarction of the entire mucosa
being more intense opposite
the second experiment than
elsewhere (see Fig. 7).

Infarction of the mucosa of the
whole small intestine with the
exception of 50 cm. near the
caecum. The infarcted zone
extends into tlie part supplied
by the secondary ves.sels which
have been ligated.

Infarction of the intestine at its
upper as well as its lower end.
The middle anaemic zone is
considerably longer than in
Experiment 49.

HAEMOBRHAGIC INFARCTION 87

experiments. In case the inclosed experiment does not cover a great area,
as shown in Fig. T, b, the infarction in it is intensified. In case the inclosed
experiment is of such an extent that by itself it will cause intense infarction,
placing it within another experiment, x, results in diminution of the infarc-
tion. In Experiment 49, the second group of arteries ligated. Fig. 8, x'-
supplied nearly 100 cm. of intestine, about enough to produce an infarction
in its middle 50 cm., judging by Experiment 32, Fig. 2. Tying the main
artery in addition reverses the result upon the loop supplied by the arteries
marked x^. What should be normal upon the periphery, beyond a, is now
haemorrhagic and what should have been haemorrhagic, between a and a,
is anaemic.

After making these experiments upon the loops of the intestine to deter-
mine the origin of tlie blood in haemorrhagic infarction it is easier now to
consider in an intelligible way the results after ligature of the coarser vessels
of the intestine. These experiments are given in Table Til ; they can be
compared to advantage with those given in Table I. In Experiments 51 to
56 the inferior mesenteric artery as well as other anastomoses in some cases,
were left open, and these vessels account sufficiently for the blood required to
produce the infarction. In 57, however, all possible circulation through the
arteries was eliminated, only the portal vein having been left open ; no infarc-
tion followed. In case the veins alone are ligated there is no infarction of
the intestine, provided the anastomoses are sufficiently large to carry off the
blood. As the veins through which the venous blood may escape are ligated
the intestine gradually becomes more and more infarcted, as shown in
Experiments 62, 63 and 64.

Under certain conditions which can happen only in an experiment, infarc-
tion of the intestine may be caused by venous regurgitation. In Experi-
ment 65 the entire root of the mesenterv' with the exception of the inferior
mesenteric vein was ligated, the ligature, of course, including the duodenum
and colon. The exj>eriment is similar to No. 56. The extreme infarction
which followed must have been caused by the blood which entered the portal
system through the inferior mesenteric artery and vein. In this experiment
the portal pressure was soon raised to the arterial and an infarction fol-
lowed, for we have here the favorable condition ; that is, stagnation and
pressure. No. 66 is a similar experiment on a smaller scale (Fig. 9). The
arteries and veins of two neighboring loops were ligated in such a manner
that in one loop. Fig. 9, A, there was high arterial pressure with the veins
ligated, while in the other loop, B, high venous pressure with the artery
ligated. In both loops an intense infarction followed. When the artery of
the loop B is cut open at E, Fig. 9, the condition in this loop is very similar
to that in the intestine after simple ligature of the superior mesenteric

88

EXPERIMENTAL STUDY OF

TABLE VH

LlOATUBE OF DlFFEBENT LABGE ABTEBIES AND VEINS OF THE ABDOMINAL ViSCEBA

Experi-
ment

Duration

Vossels liffated

of the

Results

experiment

51

Superior mesenteric artery and

lOhrs.

Infarction throughout entire

vein and inferior mesenteric

small intestine.

vein.

52

Superior mesenteric artery and

5 "

Extreme infarction tliroughout

portal vein.

the small intestine; duode-
num and stomach hyper-
aemic.

53

Coeliac a\i8, superior mesen-

6 "

Extreme infarctiim of tlie

teric artery and portal vein.

small intestine.

54

The same as above

6 "
6 "

The same as above.

55

Coeliac axis, superior mesen-

Infarction of tlie entire intes-

teric artery, portal vein and

tine.

duodenum including mesen-

teric arch.

56

Coeliac axis, superior mesen-

3 "

Infarction of intestine.

teric artery, portal vein and

stomach and spleen. Fatty

duodenum and ileum.

metamorphosis of liver.

57

Whole root of mesentery witli
the exception of portal vein.

10 "

No liaemorrhajjic infarction.

58

Superior mesenteric vein.

48 "

No infarction.

59

Superior mesenteric and pan-
creaticoduodenal veins.

21 "

,.

60

All the veins of a loop 15 era.

12 days.

The anastomosing vein dilated

long with the exception of one

and varicose.

arcli.

61

The same as Experiment 60

4 "

Coagulative necrosis and
iiaemorrhagic infarction of
loop.

62

Superior and inferior mesen-

2i hrs.

Mucosa hyperaemic and in-

teric veins.

farcted.

63

Superior mesenteric, inferior

Ihr.

Extreme infarction of whole

mesenteric and pancreatico-

small intestine.

duodenal veins.

64

Portal vein

i "

Intestine hyperaemic.
Extreme degree of infarction.

65

Root of mesentery with the ex-

3 hrs.

ception of the inferior mesen-

teric.

C6

The vessels and intestine of two

4 "

The loop B became blue first.

intestinal loops ligated as in-

and then loop A. The intes-

dicated in Fig. 0. The circu-

tine of both loops was inter-

lation was forced to take the

nally haemorrhagic.

direction of the arrows.

67

The same as above

4 "
4 ••

The same as above.

68

The same as above only that the

First the loop A became hy-

artery was cut open at E

peraemic, then the loop li.

(Kig. 9).

At the end of four hours the
loop A was very haemor-
rhagic; the loop />" was less
so.

69

The same as above

4 "

The same as above.

HAEMORRHAGIC INFARCTION

89

artery, with the difference that the direction of the circulation is reversed.
Under these conditions, haemorrhagic infarction foUows (68 and 69).

We have here again absence of the pulse wave, retarded circulation and
capillary pressure, factors which are essential in the production of an infarc-
tion, provided there is no obstruction in the outflow of blood.

LiGATCRE OF ElTHER ARTERIES, VeIXS OR BoTH, AT THE SaME TiME

Reducing the Blood Pre.ssure in One of Them to Zero.

The results obtained by ligating the different vessels in the study of
haemorrhagic infarction are in general confirmatory of those obtained by
Cohn some forty years ago. In order to gain a deeper insight of this ques-
tion it is necessary not only to study the vessels from without but also from
within.

The first experiments we performed to study the bhood pressure in the
intestine during the production of an infarction are given in Table VIII.

TABLE VIII

ExPEEiMEXTS Made to Produce Haemorrhagic Infabction of a Loop of Intestine
AT THE Same Time Opening Eithbie the Artery, the Vein ob Both

Experi-
ment

70
71
72

73

74
75

76

77

78
79

Vessels ligated

Artery and mesenteric
arches.

Artery, vein and mesen-
teric arcliea.

The same

Artery and arches . . . .
Artery, vein and arches

Artery, vein, mesen-
teric arches and in-
testine on one side.

The same

Vessels
opened

Lenirth

of the

loop of

intestine

Durntion

of the

experiment

Artery.

8 cm.

4hr3.

None.

8 •'

4 "

Artery
and"

8 "

4 "

vein.
None.

12 "

10 "(?)

tt

12 "

10 "(?)

Vein.

12 "

10 "(?)

Artery.

12 "

10 "(?)

None.

10 "

5 "

Artery.

10 "

5 "

Vein.

10 "

5 "

Results

Mucosa not clianged.

Mucosa hyperaemic.

Mucosa slightly hy-
peraemic.

Mucosa haemor-
rhagic.
The same.

Mucosa very liaemor-
rhagic.

Mucosa oedematons
and s ome what
haemorrhagic.

Mucosa haemor-
rhagic.

The same.

In these experiments the pressure in either the artery or the vein was re-
duced to zero by simply opening a branch of either of them after ligature of
the main trunk.

90 EXPERIMENTAL STUDY OF

It is fair to assume that when an arterial or venous branch is cut open
and constantly observed, to see that it is bleeding freely and does not become
plugjred with clots, the pressure within it will fall nearly to zero. As the
average pressure in the vena porta is usually 6 mm. Hg., reducing the pressure
to zero after the artery has been ligated should have little effect upon the
production of tlie infarction as is proved to be the case. On the other hand,
reducing the arterial pressure to zero, as in Experiments 70, 76 and 78, no
infarction should follow, but in some of these experiments the intestine
became more haemorrhage than it would have been had the artery not been
opened. The result in these three experiments is not uniform; in 70, in
which the vein was not operated upon, the intestine did not even become
hyperaemie, while in 76 and 78 in which the veins were also ligated tlie
intestine became haemorrhagic. In Experiments 75 and 76, which were
done under like conditions upon the same animal, the veins were not opened
until the loops had become very hyperaemie. due to the ligatures which had
been applied. Opening the vein (75) relieved this hyperaemia at once,
while opening the artery (76) made no perceptible effect upon it. In tliis
point of difference may be the key to the cause of the intensified infarction
after ligature of both artery and vein with the arterial pressure reduced to
zero. To test this question a step further. Experiments 77, 78 and 79 were
made under like conditions upon the same animal. In Experiment 78 the
blood flowed from the cut end of the artery at the rate of 3.5 c. c. per hour,
and out of the cut vein at the rate of 43 c. c. per hour, confirming what was
observed regarding the hyperaemia in Experiments 75 and 76. The blood
which produces tlie infarction in the above experiments can enter the loops
only through the submucous arterial plexus. And it is very remarkable that
under these conditions it appears easier for blood to pass over from the sub-
mucous arterial plexus through the capillaries than simply backwards and
out of the opened artery. Other factors, as constriction of the artery due to
contraction of its muscular coats when the blood pressure is low, or as
muscular contractions of the walls of the intestine, may play a role in tins
remarkable experiment. Under certain conditions the contractions of the
muscular coats of the intestine accelerates the circulation througli its wall
to such a marked degree that the venous pressure may exceed the arterial.'
This condition is also observed in Experiment 82. Until the nonnal circu-
lation through the intestine is more tlioroughly understood it will remain
difficult to explain Experiment* 76 and IS.

'Mall: Johns Hopkins Hospital Reports, I, p. 54.

HAEMORRHAGIC INFARCTION

91

Blood Pressure in the Arteries and Veins of the Intestine During

THE Production of an Haemorrhagic Infarction After

Ligature of the Superior Mesenteric Artery.

The experiments given in Table VIII indicate that it is essential to record
the pressure in the distal end of the superior mesenteric artery after the
main branch has been ligated, during the production of an infarction. In
the experiments recorded in Table IX cannulae were introduced into a

TABLE IX

Blood Prkssure in the Distal Ends of the Sufebior Mesenteric Artekt and
Vein after Ligation of One or Both of these Vessels

Vessel ligated

Blood pressure in mm. Hg.

Duration

of

experiment

Experi-
ment

Before

ligature

After
ligature

Result

Artery

Vein

Artery

Vein

80

Superior
mesenteric
artery.

128

29

••

5 hre.

Infarction of the entire
mucosa.

81

Artery and
vein.

131

7

30

8

4 "

The same.

82

Artery, vein
and pancre-
aticoduo-
denal.

60

25

?

Extreme infarction. In
the first part of tlie
experiment the pres-
sure in the artery and
vein is given for every
10 m inutes. After tlie
first hour it was more
irregular.

branch of the superior mesenteric artery and vein, pointing centrally. Then
the main trunks were ligated. The pressures were recorded upon the moving
drum and the cannulae and intestines observed during the entire experiment.
After ligature of the artery tlie intestine became very irritable and pale
and remained so into the third hour. Then it gradually became quiet and
hyperaemic the infarction taking place during the fourth and fifth hours.
Immediately after ligature of the artery the pressure in both the artery and
vein fell to its lowest point. In the course of five minutes, however, the
pressure gradually rose and remained stationary during the whole experi-
ment. In Experiments 80 and 81 the arterial pressure feU to about one-
fourth the normal after ligature of the artery. In 82 the venous outflow
was completely obstructed so the pressure in the artery gradually rose, but
the venous pressure rose more rapidly and at one time exceeded the arterial.
The infarction followed very rapidly. These few experiments, together with

92

EXPERIMENTAL STUDY OF

many others, show that a considerable blood pressure is present in the pe-
ripheral end of the artery after its ligation, while haemorrhagic infarction is
taking place, and Experiments 80 and 81 fix this pressure at one-fourth the
normal.

Pkoduction of Haemorrhagic Infarction of the Intestine by Partly

Occluding the Superior Mesenteric Artery Afteii all

THE Anastomoses Have Been Ligated.

In case the initial cause of the infarction which follows ligature of the
superior mesenteric artery is simply reduction of the arterial pressure, then
infarction should always result when the arterial pressure is reduced by
other means than by tj'ing the main artery. This view is suljstantiated by
the experiments recorded in Table X.

TABLE X

Experiments in which the Arterial Pressure was Reduced by Clamping the

Main Trunk of the Superior Mesenteric Arteby after Ligature of

ALL OF ITS Arterial Anastomoses Incht)ing the Intestine

Above and Below

Experi-
ment

Vessel clamped

Degrree of clamping

Duration

of
clampiag

Result

83

84
85

Superior mesenteric

artery.
Artery to loop of

intestine.

Arterial pressure re-
duced to k 30 mm.

Until pulse nearly
disappeared.

Until pulse disap-
peared.

3 hrs.
6 "
6 "
6 "
6 "
8 "

8 "

Mucosa very hyper-

aemic.
Mucosa hyperaemic.

Mucosa hyperaemic

and infarcted.
Mucosa hyperaemic.

Infarction.

Extreme haemor-
rhagic infarction.

The same.

86

All arterial anasto-
moses tied and
clamp on superior
mesenteric artery.

The same

87
88

89

tt «
tt tt

In making the experiments the main artery and vein were isolated and
all of the remaining tissues at the root of the mesentery, including the duo-
denum and colon, were ligated. By this method the blood entered the
intestine through the main stem of the artery only. The same precautions
were employed when experimenting upon a loop of intestine. In this experi-
ment it is necessary to clamp the main trunk of the arterj' in such a manner
that no kinking is possible to obstruct the circulation entirely. This was

HAEMOEEHAGIC INFAECTION 93

accomplished by a double-screw clamp encircling the artery with a thick-
walled rubber tube 4 mm. in diameter and 10 cm. long on either side of it.
In screwing down the clamp most of the force was spent in compressing the
rubber tube, thus making the clamp firm. The length of the rubber tube
kept the clamp in place. By this method of constricting, the artery lies in
a firnj slot which cannot kink it.

The degree of constriction of the artery was regulated in Experiment 83
by measuring the pressure in the distal end of the artery. The clots which
formed in the cannula were, liowever, very troublesome, so another method
of determining the proper reduction of arterial pressure was employed. In
all of the experiments in which the superior mesenteric artery was ligated
it was observed that there was no detectable pulse wave in the arteries of the
mesentery. The same was true in Experiment 83. So in most of the experi-
ments given in the table, the main artery was compressed until the pulse
wave in the distal branches had just disappeared. A small branch was then
cut open and it was found that the blood oozed out of it drop by drop, as it
did from the one cut in Experiment 83. By this method not only was the
pressure of the artery quickly reduced, but the pulse wave was also arrested.

The result of Experiments 84, 85 and 86 was not as satisfactory as was
expected beforehand, but in 87, 88 and 89 the infarction was in every respect
as intense as could be obtained by ligature of the main trunk with the
anastomoses open. Furthermore there was a great quantity of blood within
the lumen of the intestine of Experiments 88 and 89.

These experiments, as all others, indicate that in the production of an
haemorrhagic infarction the rapidity of the circulation through the capil-
laries is greatly diminished. In infarctions following partial occlusion of
the artery, the circulation is suiEeiently slow to produce infarction when the
arterial pressure is reduced to one-fourth the normal, which is also just the
point at which the perceptible pulse wave is lost.

Experiments Made to Test the Effect of Ischaemia Upon
Haemorehagic Infaecation.

It is observed in the foregoing experiments that a very definite period of
time elapses after ligature of the superior mesenteric artery, or its branches,
before the beginning of haemorrhagic infarction. After diapedesis is well
started the further progress of the infarction is fairly rapid. These facts
induced Virchow to suspect that capillary necrosis is caused by the
ischaemia, tlius favoring the escape of blood into the tissues. This idea in
turn served as a basis for Cohnheim's theory, who in addition accounted for
the necessary blood through venous regurgitation. The experiments which

94

p:xrKRT:\iK\TAii study of

follow contradict the idea that capillary necrosis plays any role whatever in
the production of hapmorrhajjic infarction.

Table XI ^ives a group of experiments in which either the whole intestine
or one of its loops was deprived entirely of arterial blood for from 30 minutes
to 3 hours, after which the circulation was reestablished.

TABLE XI

ESPEBIMENTS IN WHICH THE ISCHAEMIC I.NTESTIXE WAS FOLLOWED BY RE-
ESTABLISHllEM OF THE CiRCCLATION

Experi-
ment

First operation

Duration.

Second
operation

Duration

Result

90

91

Ischaemia of a loop of
intestine.

The same

i hr.

i "
2J hrs.
2.i "
3 '■
3 "
3 "

3 "

Circulation
reestab-
lished.

The same.

i* ti
it ti

it a
it ti

it It

20 hrs.

20 "
8 "
3 "
3 '■
3 "
3 "

2 "

Intestine appar-
ently normal.

The same.

92
93
94

Ischaemia of entire in-
testine.

Ischaemia of a loop of
intestine.

Tlie same

a it

Mucosa slightly hy-

peraemic.
Mucosa apparently

normal.
The same.

it ti
ti it

95
96

97

The same. The vein
was not closed.

Ischaemia of entire in-
testine. The superior
mesenteric vein left
open.

Loop of intestine
ischaemic. Main vein
was left open.

In making these experiments all possible anastomoses, including those
through the intestinal walls were first ligated, after which the main artery
and vein was compressed by tying it between two blocks of rubber. In every
experiment a small arterial twig of the mesenten,- was opened immediately
aft^r clamping the main artery, and before as well as after the renewal of the
clamp, in order to determine the condition of the circulation in the experi-
mental loop. In all cases it was found that the method is satisfactory, for
in no instance were we troubled with clot-formation either in the artery or
the vein. It was also found that after several hours of ischaemia the intes-
tine was quiet and would barely respond to irritants. Under this condition
reestablishing the circulation was followed by a gush of blood through the
arteries over into th» veins, the intestine at the same time becoming very
hyperaemic.

HAEMORRHAGIC INFARCTION

95

In no instance, however, did haemorrhagic infarction follow. In Experi-
ments 95, 96 and 97 the vein was not included in the clamp in order to give
the " venous reflux " every possible chance in the production of the infarc-
tion. Yet the result here was also negative.

In the second group of experiments. Table XII, a loop of intestine was

TABLE XII

ISCHAEMIA OF THE INTESTINE FOLLOWED BY ReESTABLISHMENT OF THE ClBCULATIOX
AND LiIGATUBE OF THE SUPBBIOB MeSENTEBIC ABTEBY

EKperl-
ment

First operation

Duration

Second
operation

Duration

Result

98

Ischaeraia of loop of

2i hrs.

Superior

12 hrs.

Loop no more in-

intestine.

mesenteric
ligated.

farcted than the
rest of the mucosa.

99

The same

3 "

The same. .

5 "

The same.

100

tt ..

3 "

«

5 "

ti t.

101

Ischaemia of loop and
vein cut open.

3 "

tt ((

15 "

Mucosa of loop less
infarcted than rest
of intestine.

102

Ischaemia of loop of

3 "

The same

4 "

Loop more infarcted

intestine.

and por-
tal vein
ligated.

than mucosa of
immediate neigh-
borhood, but not
as much as that
of duodenum.

103

Ischaeraia of loop of

2i "

Ligature

8i "

Mucosa with the

intestine with an ad-

removed

exception of loop

ditional ligature

from loop.

extremely haemor-

around the superior

rhagic.

mesenteric artery.

first made ischaemic for a number of hours, after which the circulation was
reestablished in order to exclude the possibility of clot-formation within the
vessels of the experimental loop. As soon as this possibilit)' was excluded the
superior mesenteric artery was ligated. In this group of experiments a loop
of the intestine was ischaemic some hours longer than the rest of the intestine,
and therefore if ischaemia is favorable to the production of an infarction
that in the loop should be increased. With the exception of 102, this was not
the case.

In fact, there seemed to be a tendency for the experimental loop to be less
infarcted than the remaining intestine. It may be of some value to add a
note regarding Experiment 102. After the clamp was removed from the
vessels of the experimental loop the intestine became very hyperaemic.
Ligature of the superior mesenteric artery was followed by anemia and

96

EXPEEIMFA'TAL STUDY OF

violent contraction of the whole intestine with the exception of the loop.
Next, the portal vein was ligated and then the intestine became much bluer
than the loop.

In the third group of experiments the proper vessels were clamped for a
sufficient length of time to produce an infarction after which the circulation
was reestablished. The test in these experiments is to determine whether
an " ischaemia," xtnder which an infarction does follow, favors increased
infarction in ca-^e the blood pressure is increased. The result was again
decidedly negative. When the damp was removed from the main artery its
branches began to pulsate, and the blue intestine became pink as the blood
shot through its veins. It appears as if the infarction is at once washed
out instead of becoming increased, and in the course of from 10 to 20 hours
the condition of the intestine is nearly normal in appearance.

TABLE XIII

Vessels Clamped a Stjfficientlt Long Time to Produce ax Ixfarctiox after
WHICH Reestablishing the Cihcclation Washed it Out

Experi-
ment

Vetiele clamped

Duration

Condition
of loop

Time
between
removing
the clamp
and
ending
the ex-
periment

Result

104

105
100

107

Artery of large loop
clamped.

Superior meBentcric

artery.
Superior mesentericand

panort'atitoduodcnal

arteries.
Arterv and arches of

loop 35 em. long.
Arteries and veins of

large loop.
Artery and vein to loop

20 cm. long.
Artery, vein and mesen-
teric arcliee to large

loop.
Artery and vein of loop

20 em. long.
Vein and mesenteric

arches of loop 20 cm.

long.

4 hrs.

6i "
4 "

5i "
4 "
5J "
4 "

51 "
61 "

Loop very hy-
peraemic.

The same . . .

20 hrB.

20 hrs.

10 •'
17 "
10 ■'

20 ■<

10 "
10 "

Hyperaemic spots
in mucosa of
loop.

Infarction.

Slight infarction.

Mucosa sliglitly

hyperaemic.
The same.

108

109
110

Mucosa normal.

Mucosa necrotic

HI

and of brownish-
red color.
Mucosa but

112

slightly tinged.
Mucosa somewhat

more colored
tlian that in im-
mediate neigh-
borhood.

HAEMOERHAGIC INFARCTION

97

The Production of Haemokritacsic Infarction in the Isolated
Intestine with Artificial Circl'lation.

The experiments made upon the intestine witliin the livino; animal
indicate that the cause of haemorrhagic infarction after ligature of the
superior mesenteric artery is not to he found in the necrosis of the capillaries
nor in venous regurgitation, but in physical conditions within the blood
stream itself, due to a slowing of the circuJation with absence of an arterial
pulse wave.

In case this if true, artificial circulation through the isolated intestine
with whipped blood under a low but constant pressure will result in haemor-
rhagic infarction, provided that an important factor does not lie in the
difference between whipped and normal blood. The experiments given in
Table XIV show that with the circulation in tlie isolated intestine similar to

TABLE XIV

expebimen'ts in which artificial circulation was carried on through the

Isolated Intestine with Whipped Blood Diluted with Normal

Saune Solution at 37° C.

Experi-
ment

Arterial
pressure

Venous
pressure

Duration

of ex-
periment

Note

Result

113

0-120

0-30

1 hr.

Hyperaemia.

Loop with rythmic con-

114

66

0-40

35 min.

Rytlimic contractions

of a large loop while

tractions hyperaemic;

venous pressure was

rest of intestine

high.

haemorrhagic.

115

0-93

0-50

1 hr.

Vermicular contrac-
tions active.

Haemorrhagic infarc-
tion.

116

mo

V

20 min.

No blood came from the
vein.

The same.

117

15

8

4i hrs.

Intestine handled a
great deal.

Spotted infarction.

118

10-80

10

5* "

The same

Hyperaemia.
No infarction.

119

65

4

4J "

Vermicular contrac-

tions active.

120

27

7

4i "

Infarction.

121

40-65

4

5 ••

Parallel experiments.
Neither specimen dis
turbed.

Hyperaemia. Intestine
contracted.

122

20-35
65

1
1

5 "

41 "

The same

Infarction.

123

Parallel experiments

Hyperaemia.

on two specimens

which had been pre-

served upon ice for

48 hours.

124

20

1

4A "

The same

Infarction.

98 EXPERlMKNTAIi STUDY OF

tliat in the intestine after ligature of the superior mesenteric artery, haemor-
rhagic infarction takes place very rapidly.

It has been found that the muscular walls of the intestine show great
activity in the isolated intestine for a number of hours after its removal
from the body, provided it is nourished with blood through its arteries and
is kept at normal body temperature. The short time which elap.ses (this
need not exceed five minutes) while the intestine is being removed from the
animal to the warm chamber does not seem to affect this, for in experiments
iiuide in this way the activity of the contraction of the muscular walls is as
vigorous as when the artificial circulation is established before the normal
is broken.

In performing the operation the only precaution necessar}' is to ligate
the duodenum and colon with their mesenteric arches and then cut out the
whole intestine vrith an abundance of the root of the mesentery. The can-
nulae and the rest are easily apjilied. In all of the experiments the whipped
blood from the same animal diluted a number of times with normal saline
solution was used. The pure blood appears to be much too thick for this
experiment, as it is difficult to inject it through the capillaries (Exp. 116).
In case a large quantity of blood was needed, that which flowed from the vein
was whipped and again injected into the artery.

Microscopic Examinatiox of the Mesenteric Circulation'. Rate of

Venous Outflow.

In Experiments 113-118 the vessels of the mesentery were constantly
examined with the low power of the microscope, and similar microscopical
examinations were made of the mesenteric circulation after ligature of the
superior mesenteric artery in the living animal. Examinations of this sort
proved to be difficult for obvious reasons, yet the impressions obtained from
continuous study of the same specimen during consecutive hours are fairly
definite.

Our apparatus consisted of a microscope illuminated by electric light and
completely immersed in the saline solution of the warm bath in which the
intestine and mesentery were floated. It wa.s necessary to be careful in
liandling the mesentery for any stretching of it interfered materially with
the circulation. Either hyperaemia or infarction followed in everj- case.

In the.se experiments the arteries are at first contracted, but they soon
dilate as the blood shoots through them. At first the red corpuscles barely
touch one another as they flow through the capillaries, but as they reach the
smaller veins there is a tendency for them to accumulate in clumps which are
then broken up and carried on into the larger veins. This clumping is
observed only here and there, being rapidly broken up by the advancing

HAEMORRHAGIC INFARCTION 99

columu of blood, but it gradually appears in more and more of the veins, and
in some it becomes permajient, producing an evident oljstacle to the forward
movement of the blood. These clumps and columns of red blood corpuscles
in the veins may be pushed along by the current or they may move to and fro
or eventually become stationary. Similar phenomena of distention with
red blood corpuscles, to and fro movement of the same and eventual stasis
can also be observed somewhat later in the capillaries. An interesting
appearance, often observed in tlie veins and capillaries, is that of interrupted
columns of compacted red blood corpuscles with intervening clear spaces
wliich are sometimes clumps of white corpuscles, sometimes of platelets,
sometimes only clear plasma.

Coincident with this partial blocking of the veins and capillaries, red
blood corpuscles begin to pass through the walls of these vessels by diape-
desis ; and after a time the haemorrhage becomes so great that it is difficult
to observe the conditions within the vessels. The venous outflow is dimin-
ished immediately or shortly after the beginning of the experiment, it then
rises, but later on it continuously falls to a minimum.

Fig. 10 gives the pressure curve and the venous outflow of Experiment 118.
After the experiment was well under way the blood elements were easily
seen in the arterioles, capillaries and small veins. The branching of the
artery appeared to be the cause of an equal distribution of the corpuscles
within the capillaries. Frequently the red discs stuck together, but these
clumps were shattered as the stream of blood broke to enter the branches of
the artery. Throughout the capillaries the red corpuscles were well sepa-
rated, but as they entered the small veins the corpuscles again began to form
into clumps. These clumps of corpuscles were nearly always headed by
hyaline masses apparently composed of blood platelets. So long as a clump
of blood corpuscles met no obstacles on its way to a larger vein nothing
happened, but as soon as a clump met another clump as the venous bed
became smaller, a complete obliteration of a main branch followed. Fre-
quently pictures, as shown in Fig. 11, were seen — columns of blood headed
by hyaline masses would come against, but not enter, a venous stream, b,
which remained unbroken. It seemed as if the force back of the column, a,
was not strong enough to drive it into the main current, b, which was very
rapid. Increasing the arterial pressure forced column, c, to enter the main
stream but it was extremely difficult to dislodge the column, a. After
raising the arterial pressure several times to TO mm. Hg. the column,
a, began to vibrate, then to advance slowly and finally it shot into the main
stream. After the experiment had continued for two hours nearly all the
veins were blocked, but raising the arterial pressure removed the obstruction.
During the fourth and fifth hours (Fig. 10) obstruction due to the forma-

100 EXPERIMENTAL STUDY OF

tion of clumps in the veins, took place a second time. Earh time this condi-
tion accompanied low arterial pressure, and it was followed by a diminished
venous outflow and an intense hvperaemia of the intestine.

In Experiment 119 the arterial and venous pressure were kept constant
during its entire duration, but the venous outflow varied greatly, as shown
in Fig. 12. The intestine was handled very little in observing the capillary
circulation with the microscope.

Tliroughout the experiment there was but slight tendency for the cor-
puscles to form in clumps and no infarction followed. During the third
hour there was a marked dilatation of the veins and an increased outflow of
blood. At this time the lymphatic channels of the mesentery carried off a
great deal of lymph in whiih there was a considerable number of red blood
corpuscles.

The record of Experiment 120 is given in Fig. 13. The high arterial
pressure at the beginning and again at the end of the experiment need not be
taken into consideration for the intervening four liours can be considered
alone. Again we had the curve of the venous outflow, which towards the end
of the experiment gradually fell nearly to zero. At this time the infarction
of the mucosa was complete and the second rise of arterial pressure caused it
to intensify greatly.

Experiments 121 and 122 were made upon the intestine of dogs of the
same size and under like conditions at the same time, differing only in that
the arterial pressure in one was high and in the other low. Fig. 14 gives the
curves of Experiment 121. The outflow curve is the usual one. There was
no infarction of the mucosa, it was only hyperaemic.

The arterial pressure of Experiment 122 was changed several times in
order to reduce the venous outflow to the lowest possible amount. During
the whole experiment 500 c. c. of blood entered the artery and but 116 c. c\
came from the vein. The rest was used in the production of the infarction
which followed.

The whipped blood and the intestines used in making Experiments 123 and
124 were first placed in the ice box for 48 hours, then placed in the wann
chamber and artificial circulation carried on through one of them at 65 mm.
and the other at 20 mm. Hg. The outflow curve of 123 is given in Fig. 15;
no blood came from tlie vein in 124. In these two experiments the conditions
were entirely mechanical as the intestine as well as the blood was dead. With
the low pressure infarction followed, while with the high pressure the mucosa
was only hyperaemic at the end of the experiment.

Conditions fob Production of Haemokrhagic Infarction
The experiment.* given in Table XI \' prove that haemorrhagic infarction
is produced in the isolated intestine under conditions similar to those under

HAEMORKHAGIC INFARCTION 101

which it occurs within the living body. ^loreover whipped blood appears to
hasten the infarction. The amount of blood which flows from the veins when
the pressure is constant, sometimes after a transitory diminution, increases
during the first hour of the experiment then gradually diminishes. The first
or the first and second variations of the venous outflow seems to run parallel
with the activity of the contractions of the muscular walls of the intestine.
Similar curves have been demonstrated by Mosso in other organs either alive
or dead through which circulation is carried on with whipped blood or with
blood serum.

The cause of the final diminution of the venous outflow, while the intes-
tinal mucosa is becoming hyperaemic and infarcted, is to be sought within
the blood current due to the absence of a pulse wave as already demon-
strated by von Frey. You Frey made the discovery that if artificial circula-
tion is carried on through an organ with an intermittent pressure imitating
the normal pulse, the venous outflow equals the arterial inflow. When, how-
ever, the arterial pressure is constant the venous outflow diminishes, due
partly to contraction of the capillary walls and partly to a remarkable clog-
ging of the capillaries with red blood corpuscles, as we have found in our
experiments. According to von Frey a red corpuscle is first caught at the
junction of two capillaries, partly obstructs their lumina, thus acting as a
filter which catches up more red corpuscles which finally cause complete
obstruction. A pulsating arterial pressure will easily dislodge the first cor-
puscle and thus keep the capillary stream open.

In our experiments we found that the first obstruction began by clumps
of corpuscles lodging in small veins, but we were unable to determine whether
these are first formed in the capillaries, as described by von Frey, then In-
come dislodged, to be carried on into the smaller veins and in turn obstruct
them. In the intestine the sectional area of the capillaries is 300 times that
of the main artery; in the smallest veins it falls to ITO, and in the main
vein to 4. The moving column of blood must divide at least 50 million times
during a small fraction of a second in passing from the main arteries to
the capillaries. This rapid divison and subdivision of the column appears
to be sufficient to keep the corpuscles within the arterial stream from sticking
together. But when the capillaries are reached we have a stream which is
composed of a single row of corpuscles which can no longer be divided, and
also a relatively slow circulation. Everv'thing is favorable for them to cling
to the capillary walls at their points of division as described by von Frey.
If the clumps here formed are dislodged the_v must at once enter a venous
bed, which is but half as large as the capillarj- bed and which further on
diminishes in section area very rapidly, the speed of the circulation at the
same time increasing in the inverse ratio of the area of the venous bed. The
clumps already started in the capillaries are carried to the small veins and

102 EXPERIMENTAL STUDY OF

Boon obstrui't them, and this in turn favors further obstruction of the capil-
laries, as well as of the neifrlilxiriiip veins for a greater quantity of blood
must now pass tiirough them. Finally the rapidity of the capillary circula-
tion is greatly diminished and the arterial blood pressure is now extended in
greater part than before to the capillaric-;.

It is evident from the preceding description that the phenomena observed
under these peculiar circulatory conditions are in large part dependent upon
the ])hysical properties of the blood especially upon its viscosity and the pres-
ence and physical characters of suspended particles which readily stick
together; and differ in important respects from those which would occur
under similar conditions with a thin homogeneous fluid. The pressure
gradient from the arteries to the veins in the ischaemic area is so low that
the red blood corpuscles cannot fully overcome the resistance in the veins
and ciipillarics. They accumulate in these situations and probably undergo
some physical change by which they become adherent to one another and to
the vascular wall. The absence of the normal pulse-waves prevents the
breaking up of these masses of corpuscles, the long pulse-waves sometimes
observed, having little or no effect in distintegrating the masses. In this
way numerous small veins and capillaries become blocked, with the resulting
rise of intracapillary pressure and diminution of outflow of blood through
the veins.

The diapedesis is due to stagnation of the blood, and to blood pressure.
Without a certain height of pressure there is no diapedesis ; and with a given
retardation and stasis of blood-current, the higher the intracapillary and
intravenous pressure the greater the amount of the diapedesis. The matter
which needs explanation is that the diapedesis may occur with lower than
normal arterial pressure, and through vessels walls apparently unaltered.
This we attribute to the fact that the red corpuscles, in consequence of the
slow circulation and absence of pulse-wave, have opportunity to become
engaged in the narrow paths followed by the lymph as it passes between the
endothelial cells. Diapedesis is a slow process, and the channels for it are
much smaller than the diameter of red corpuscles. Unless the red cor-
puscles can get started on the path between the endothelial cells, they cannot
traverse it; and unless the circulation is very much slowed and the outer
plasmatic current obliterated there is no opportunity for the corpuscles to
become engaged between the endothelial cells, provided, that is, the vascular
wall is normal. With greatly retarded circulation there is this ojiportunity
and when the way in front is blocked by compact masses of red corpuscles,
and sometimes by actual agglutinative thrombi, the only path open for the
corpuscles is that folh)Wcd by the lymph between the endothelial cells. This,
then, becomes the direction of the least resistance for their movement.

HAEMORRHAGIC INFARCTION

103

Fig 1, — Diagram of the Superior Mesenteric Artery and Small Intestine to
illustrate Experiment 31. Ligatures were applied at the points marked X. The
degree of shading of the intestine indicates the intensity of the infarction of the
mucosa. The numbers opposite the convex border give the length in centimeters
of the infarcted zones. The letters a. a' and a" refer to Experiment 12.

25 cm

E.xperiTnenl 32

Fig. 2. — Diagram to illustrate Experiment ?,2. X. point of ligatures of the
arteries and intestine. The infarction is marked by the shaded area.

104

K.XI'KKIMHNTAL STUDY OF

35cm

Fig. 3. — Diagram to illustrate Experiment 34. X. point of ligatures of the
arteries and intestine. The zone of mucosa 3 cm. long is oedematous, the zone
10 cm. long is infarcted and so on.

X

w

l-C

Normal Hyperaemic Infarcted

Experiment S'l
Fig. 4.— Scheme of vessels of Experiment 34. A. artery; v. vein: c. capillary.

HAEMORRHAGIC INFARCTION

105

Experiment 36 Exp. 37 Exp. 3 3

Fio. 5. — Diagram of Experiments 36, 37, and 38. X, point of ligature.

E)cp.39 y^ Exp. 40

Exp. 41 pi

f

1

p; ^ ,1

Exp. 42 1^ Exp. 4 3

Exp. 4 5

Exp. 44

Exp. 46

Exp. 47

Fig. 6. — Diagram of Experiments 39 to 47. The artery is solid and the vein
outlined; A', point of ligature; the shading indicates the intensity of the
hyperaemia or the infarction of the mucosa.

10

106

HAEMORRHAGIC INFARCTION

Experiment 48

Fig. 7. — Diagram of Experiment 48.

Experiment 49
Fig. 8. — Diagram of ExperimeDt 49.

Experiments 66, 68 and 69.

Fin. 9. — Diagram of Experiment 66. X, points of ligature; arrow shows direc-
tion of tiie circulation. The solid vessel represents the artery and the outlined
vessel the vein. B. point artery was opened in Experiments 68 and 69.

mm. pressin-e and
C.C. ouiflow

Artery

outflc

Vein

lock

Experiment 118
Fiii. 10. — Curve of Experiment 118. The brolsen line represents the arterial
pressure; the dotted line the venous pressure; the unbroken line the average
outflow in c. c. for 5 minutes reduced 5 times.

Experiment 118

Fio. 11. — Tracing of a small vein partly blocked with clumped red corpuscles
or agglutinative thrombi from Experiment 118.

108

EXPERIMENTAL STUDY OF

mm. pr«««ur« and

TO
60
50
^0
30 ■
20
10
0 ■

12

.Artery

OulHow

Vein
o' clock

12 3 4

Experiment 119

FiQ. 12. — Curve of Experiment 119. The outflow curve is reduced 12 times.

mm. pressure and
c.c. outflow

Artery

.Outflow

Veiri

^ 5 o'clock

Experiment 120
Fio. 13. — Curve of Experiment 120. The outflow curve is reduced 10 times.

HAEMOKRIIAGTC INFAECTION

109

mm pressure and
c*. ouiflow

90
80 ]

10
60 4
50
40
30

20 •
10
0

Outflow

Artery

Velr

12 1 Z 3 4 5 o'clock

Experiment 121
Fig. 14. — Curve of Elxperiment 121. The outflow curve is reduced 6 times.

mm. pressure and
cc. outflow

70 T

60

50 ■

40

30

20

10

-. Artery

T

, Ooinow

Vein
oVlock

Experiment 123
Pig. 15. — Ourve of Experiment 123. The outflow curre is reduced 6 times.

THROMBOSIS'

Definition. — A thrombus is usually defined as a blood-coa^ulum, formed
in the heart or vessels during life. This definition applies to most cases;
but, in order to meet the objections of those who do not concede that all
thrombi are genuine coagula, and to give due prominence to the participation
of blood-platolcts and corpuscles, a thrombus may be more broadly defined
as a solid mass or plug formed in the living heart or vessels from constituents
of blood. Thrombosis is the act or process of formation of a thrombus, or
the condition characterised by its presence.

Structure of Thkombi. — The formed elements which may enter into
the composition of fresh thrombi are blood-platelets, fibrin, leucocytes, and
red corpuscles. These elements may be present in varying number, propor-
tion, and arrangement, whence there results great diversity in the appearance
and stnicture of different thrombi.

The two main anatomical groujis of thrombi are the red and the white
thrombi. j\Iany of the mixed thrombi may be regarded as a variety of the
white thrombus. In addition there are thrombi of relatively minor impor-
tance composed wholly or chiefiy of leucocytes, of fibrillated fibrin or of
hyaline material.

Red Thrombi. — These are formed from stagnating blood, and in the recent
stvite do not differ in appearance iiiul st.rui-ture from clot.s formed in shed
blood. They are made up of fibrillated iil)rin and of red and white corpuscles
in the same proportions as in the circulating blood, or the white corpuscles
may be somewhat in excess. If any part of such a red thrombus be exposed
to circulating blood, white material, consisting of platelets with fibrin and
leucocytes, is deposited upon it. This deposit may aid in distinguishing
the thrombus from a ]iost-niortem clot.

While and Mixed Thrombi. — Most thrombi are formed from the circulat-
ing blood, and are white, or of a mixed red and white colour. The white
or gray colour is due to the jircseiicc of plat^^let.-;, fibrin, and leucocyte's, occur-
ring singly, or, more frequently, in combination. The admixture with red
corpuscles is not an essential character of tiie thrombus, although it may
be sufTicient to give it a ]ire(lominaiitly red colour.

Fresh white human thrombi, when examined microscopically, are seen
to l>e composed of a granular material, usually in islands or strands of vary-

»In: Syat. Med. (AUbutt). Macmillan Co., Lond., 1899. VII, 155-285.
110

THROMBOSIS 111

ing shape and size, around and between whieh are fibrin and leucocytes with
a larger or smaller number of entangled red corpuscles. The granular mat-
ter, to which the older observers attached comparatively little importance,
and which they interpreted as granular or molecular fibrin or the detritus of
white corpuscles, is now known to be an essential constituent of the white
thrombus, and is composed chiefly of altered blood-platelets. Intact polynu-
clear leucocytes are usually numerous in the margins of and between the
masses of platelets, and may be scattered among the individual platelets.
Not less important is the fibrillated fibrin, which is generally present in
large amount. It is particularly dense in the borders of the platelet-masses,
and stretches between them in anastomosing strands, or as a finer network
containing red and white corpuscles. Within the accumulations of platelets
in fresh thrombi fibrin is often absent, or is in small amount. These various
constituents of the thrombus often present a definite architectural arrange-
ment, and soon undergo metamorphoses which will be described subsequently.

Thrombi of the kind just described, and as we find them at autopsies on
human bein'gs, are completed products, and it is difficult, indeed generally
impossible, from their examination to come to any conclusion as to the
exact manner of their formation ; particularly as regards the sequence and
relative importance of their different constituents. So long as the knowledge
of the structure of thrombi was limited to that derived from the study of
these completed plugs, the coagulation of fibrin was generally believed to be
the primary and essential step in their formation ; although Virchow pointed
out the greater richness in white corpuscles as a feature distinguishing them
from postmortem clots.

Zahn, in 1872, was the first to make a systematic experimental study,
mainly in frogs, of the mode of formation of thrombi. He came to the con-
clusion that the process is initiated by the accumulation of white corpuscles
which, by their disintegration, give rise to granular detritus. This is
quickly followed by the appearance of fibrin, which was readily accounted for
by Weigert on the basis of Alexander Schmidt's well-known suggestion of
the origin of fibrin ferment from disintegrated leucocytes. Zahn's views,
anticipated in part by ilantegazza in 1869, and confirmed by Pitres in 1876,
gained prompt and vride acceptance.

Continued experimental study of the subject, however, especially upon
mammals, led to opposition to Zahn's conclusions, and favoured the opinion,
now generally accepted, that the ordinary white thrombus starts as an accu-
mulation not of leucocytes but of blood-platelets. The investigators chiefly
concerned in the establishment of this doctrine are Osier (1881-82), Hayem
(1883), Bizzozero (1882), Lubnitzky (1885), and Eberth and Schimmel-
busch (1885-86).

]]2 THROMBOSIS

Tliprc is 1)0 diflficulty in producing thrombi experimentally by injury,
either mechanical or cheniic'al, to the vessel-wall; or by the introduction of
foreign bodies into the circulation. If the early formation of such a thrombus
be observed under the microscope in the living mesenteric vessels of a dog, as
was done by Ebcrth and Schininielbusch, it is seen that the first step consists
in tlie accumulation of blood-platelets at the seat of injurj-. These plates, in
consequence of their viscous metamorphosis, at once become adherent to
each other and to the wall of the vessel, and thus form plugs which may
be subsequently washed away into the circulation, but which sometimes so
increase in size as to obstruct the lumen of the vessel completely. Red and
white corpuscles may be included in the mass of platelets ; but their presence
at this stage is purely accidental; they are not to be regarded as essential
constituents of the thrombus in its inception.

The microscopial examination of young experimental thrombi confirms
the results of these direct observations, and affords information as to their
further development. To obtain a clear idea of this development, thrombi
should be examined at intervals of minutes from their beginning to those
half an hour old or older. I reported tlie results of such an experimental
study in 1887. The material composing the youngest thrombi formed from
the circulating blood appears macroscopically as a soft, homogeneous, gray,
translucent substance of viscid consistence. Microscopically it is made up
chiefly of platelets, which are seen as pale, round, or somewhat irregular
bodies, varying in size but averaging about one-quarter the diameter of a
red corpuscle.

Leucocytes, which may be present in small number at the beginning,
rapidly increase in number, and within the first fifteen minutes to half an
hour they are usually in such abundance that at this stage of its formation
they must be considered an essential constituent of the thrombus. They
tend to collect at the margins of the platelet-masses and between them.
These leucocytes are nearly all polynucleiir, and usually present no evidence
of necrosis or disintegration.

With the accumulation of leucocytes, fibrillated fibrin, wliich at first was
absent, makers its appearance; being, as pointed out by Ilanau, especially
well marked and dense in the margins of the masses of platelets. Within
these masses it is usually absent. The rapidity with wliich leucocytes and
fibrin are added to the masses of platelets varies much in different cases. At
the end of half an hour the thrombus may be composed of platelets, leuco-
cytes, and fibrin with entangled red corpuscles, in essentially the same pro-
portions and with the same arrangement as in the human thrombi already
described ; or even after several hours it may still consist almost wholly of
platelets.

THROMBOSIS 113

The prevailing view is that platelets exist in normal blood, where they
circulate with the red corpuscles in tlie ajcial current. In accordance with
this view, many observers, following Eberth and Schimmelbuseh, explain
the beginning of a white thrombus by the accumulation of pre-existing
platelets upon a foreign body, or, in consequence of slowing or other irregu-
larities of the blood-flow, on the damaged inner wall of the heart or vessels.
Contact with the abnomial surface sets up an immediate viscous metamor-
phosis of the platelets whereby they adhere to each other and to the foreign
body or vascular wall. Eberth and Schimmelbuseh designate this process
as conglutination, and distinguish it sharply from coagulation, which they
regard as a later event in the development of the thrombus.

Those who hold with Lowit, tliat platelets do not exist in normal blood,
believe that tliey are produced at the moment of formation of the thrombus,
as the result of injury to the blood ; and many who believe tliat they are in
normal blood not as independent elements, but as derivatives from leuco-
cytes or red corpuscles, consider it probable that those in tlie tlirombus are
formed, at least in part, in consequence of such injury. Although there axe
observations which suggest that platelets may be derived from leucocytes,
tliere is no evidence tliat tJie masses of platelets fomid in incipient thrombi
come from leucocytes previously attracted to the spot.

Strong evidence has been recently presented, by Arnold, F. Miiller, and
Detemiann, in favour of the origin of platelets from red corpuscles. Wlassow,
working in Ziegler's laboratory, finds that the wliite thrombus is formed
primarily by the destruction of red corpuscles, and is composed at the very
beginning of shadows of red corpuscles, corpuscular fragments both with
and without haemoglobin, granular material and platelets of nucleo-proteid
substance; all derived from disintegrating red corpuscles. A similar view
is entertained by Mosso, Klebs, Arnold, Ziegler, and F. Miiller.

The accumulation of leucoc}i;es in tlie young thrombus may be explained
partly by mechanical causes, — tJie most evident being the projecting, irregu-
lar, sticky substaoce of tlie platelet masses associated with slowing and eddies
of the blood-stream, — and partly by chemiotactic influences.

Whatever difiiculties there may be, in accounting for the fibrin, relate to
tlie general subject of coagulation of the blood (see Professor Foster's article
in Allbutt's " System of Medicine," VI, p. 403) rather than to the special
conditions of the thrombus. As to the participation of platelets in the pro-
duction of fibrin, opinion is divided; and upon this point tlie study of
thrombi has not afforded conclusive evidence one way or the other. The
iLsual absence of fibrin- within the platelet masses for a considerable time
after tlieir fomiation may be tliought to speak against the generation of
fibrin-ferment by the platelets. But if, as is probable, the platelets contain

Ill TUUOMHOSIS

nucleo-proteid, it would be reaiwnable to suppose, in accordaiuc with cur-
rent pliysiolofjiL-al ideas, that they can yield one of the fibrin factors; and it
may be that iu these compact masses there is not enough fibrinogen famished
by "the plasma to generate an appreciable amount of fibrin. The character-
istic dense ring of fibrin immediately suouiid the platelet masses, where there
is abundant fibrinogen, could be interpreted in favour of the liberation of
fibrin-ferment by the collectcxl platelets. By the time, however, that the
fibrin appears, leucocytes have also accumulated in the same situation; and
they, eitiier alone or together with the platelets, may be the source of the
ferment; although, as already stated, the leucocytes in young thrombi gener-
ally show apparently intact nuclei and cytoplasm.

Does tlie recognition of the described mode of development of a white
thrombus necessitate a radical break, .«uch as that made by Eberth and Schim-
mclbusch, vrith the old and still common conception that a thrombus is
essentially a blood coagulum? This question applies only to the first stage
of formation of a white thrombus, for the completed thrombus is undoubtely
a coagulum. It is, however, of both scientific and practical interest to inquire
whether coagulative phenomena usher in the process of thrombosis or are
merely secondary. A decisive answer to this question cannot be given until
we are better informed than at present concerning the chemistry and
morphology of coagulative processes, and the source and properties of the
granular material constituting the youngest tlirombi. The possibility that
this material is already coagulated; and falls into tlie category of the coagu-
lative necroses, has been suggested by Weigert ; but without any proof of this
view. There is greater probability that the accumulation and metamorphoses
of the so-called platelets in beginning tlirombi represent a preparation for
coagulation or a first step in the process. As Hammerstcn has pointed out,
two chemical phases are to be distinguished in the process of coagulation ;
namely, the fomiation of fibrin ferment from it* zymogen, and the transfor-
mation of fibrinogen into fibrin under the influence of tJiis ferment. Morph-
ological phases may also be distinguished, and the platelet stage of thrombus
formation may be interpreted as the first morphological phase of coagulation
in circulating blood. According to Whu-^sow a similar mori)hological phase
may be recognised in the clotting produced by whipping shed blood. It would
lead too far afield to enter here into a discussion of the arguments in favor
of this view; but much in its support is found in recent chemical and mor-
phological studies of extravascular and intravascular coagulation, and of the
anatomical and cliemical characters of blood platelets.' It does not appear,

• This recent work has been critically reviewed by Uowlt in Lubarsch-Ostertag's
Ergebnlsse. 1897.

THROMBOSIS 115

therefore, that we are called uix)n at present to make any such radical
revision of the traditional conception of white thrombi as coagula, as haa
been advocated of late years by some writers.

Leucocytic Thrombi. — As has already been explained, leucocytes, although
they do not usher in the process of ordinary thrombosis, make their appear-
ance at an early stiige, and other accumulate in such numbers as to consti-
tute a large part of the thrombus. My studies of experimental ;uid human
tlirombi have led me to assign to them a more important part in tlie con-
struction of wliite thrombi than that indicated by Eberth and Schimmel-
busch. Whether the regular mural white thrombi ever arise as a collection
of leucocytes, in the manner described by Zalin, is uncertain. Such a mode
of development, if it occurs, is, I think, exceptional. Intravascular plugs,
however, occur, which are made up wholly or predominantly of polynuclear
leucocytes. These are foiuid mainly in small vessels in acutely inflamed
regions, where they are to be regarded as inflammatory and probably chemi-
otactic in origin. Leucocytic ma.sses may also be found after death in small
vessels in leucocythtemia, and in diseases with marked leucouytosis ; but it is
probable that these axe not genuine obstructing plugs.

Purely Fibrinous Thrombi. — As will be described subsequently, fibrin
usually increases in amount with the age of the thrombus. The masses of
platelets may be replaced by fibrin, and leucocytes may degenerate; so that
many old, unorganised thrombi consist of practically nothing but dense
fibrin, in places hyaline. I do not, however, desire now to call especial
attention to these old, metamorphosed thrombi.

One sometimes finds in inflamed areas, less frequently under other
circumstances, the vessels, particularly those of small size, partly or com-
pletely filled with fibrillated fibrin, presenting such an arrangement and
configuration as to indicate coagulation during life. Neither leucocytes
nor platelets need take part in the formation of these plugs of pure fibrin,
although sometimes they are present. K. Zenker has well described the
microscopical appearances in these cases. Whorls or brush-like clumps of
fibrin may spring at intervals from the wall of the vessel, where they are
attached especially to necrotic endothelium or to points devoid of endothe-
lium. The fibrin may be disposed regularly, often in stellate figures, around
definite centres in which, perhaps, a necrotic cell or fragment, endothelial or
leucocytic, or a clump of platelets can be demonstrated. The fibrin is often
notably coarse. The affec^ted vessels are not usually filled completely with
fibrin, and they can be artificially injected. In croupous pneumonia such
fibrinous masses are regularly present, both in capillaries and larger vessels
of the hepatised area. These purely fibrinous coagula are of anatomical
rather than clinical interest.

116 THROMBOSIS

Hyaline Thrombi. — These are of more interest and importance than the
purely fibrinous and loucocytic tlirombi just desctribed. The presence of hya-
line material in old white thrombi will be spoken of subsequently. To von
Recklinghausen we especially owe the recognition of hyaline thrombi as a
distinct class. Tlicy are found especially in the capillaries, but may occur
also in the smaller arteries and veins. The capillaries are filled with a
refractive, homogeneous, translucent, colourless or faintly yellow material,
which stains well with Weigcrt's fibrin dye. The same material may partly
or completely fill the smaller arteries and veins. Balls, as well as cylindrical
masses, of this hyaline substance may be found, especially in the cerebral
vessels.

This hyaline thrombosis has been observed in a variety of conditions,
partly general, partly local. It occurs especially in infective and toxic
diseases. Kriege found extensive hyaline thrombosis in the small vessels
after freezing the rabbit's ear. Yon Recklinghausen had previously attrib-
uted to this cause spontaneous gangrene of both feet occurring in an old
woman who had suffered repeatedly from slight frost-bites; and he likewise
found the same hyaline vascular plugs in cases of mortification following
experimental ergotism. Capillary hyaline thromboses are common in the
lungs in pneumonia, and in hsemorrhage infarcts. In general infective and
toxic states they may be present in the liver, the lungs, and, above all, in the
kidneys.

The most striking examples of this form of thrombosis, with which I
am acquainted, are encountered in the renal capillaries, chiefly of the glo-
meruli, of swine dead of hog-cholera; or of animals infected with the hog-
cholera bacillus. In extreme cases there is complete anuria; and it may be
impossible to force more than a minimal amount of injecting fluid into
the renal vessels. Sections stained with Weigert's fibrin-stain look as if
the capillaries had been injected with Berlin blue. Ribbert found similar
hyaline thrombi in the kidneys of rabbits inoculated with S. pyogenes
aureus. I have repeatedly found them in various experimental infections,
and in human infections. They occur in eclampsia. Bacteria are not neces-
sarily present, so that toxins are probably the underlying causative factor,
and for this there is experimental evidence.

Klebs and others have thought that the hyaline material is derived from
coalesced and altered red corpuscles. Red corpuscles may in fact be so
crowded together, and apparently coalesced, as to appear as nearly homo-
geneous yellowish cylinders (globular stasis). The genuine hyaline thrombi
have the staining reactions of fibrin, and are often continuous with ordinarv-
fibrillated fibrin in larger vessels. Transitions between fibrillated fibrin
and the hyaline material can sometimes be seen : but it is often impossible

THROMBOSIS 117

by any staining to resolve the latter into a fibrinous network. If the recent
views previously mentioned concerning the origin of platelets from red cor-
puscles and the participation of these corpuscles in the process of coagula-
tion be accepted, there would be no difficulty in adopting Klebs's hypothesis
as to the origin of hyaline thrombi from red corpuscles. Von Reckling-
hausen and Kriege find evidence that the hyaline substance is derived from
leucocytes.

Growth, JIetamorpiioses, akd Organisation of Thrombi. — Thrombi
in their growth assume various characters to which special epithets are
applied. A thrombus formed from the circulating blood is at first parietal
or mural, but by continued growth it may fill the vessel and become an
occluding or obstructing thrombus. A primitive or autochthonous thrombus,
caused by local conditions, may be the starting-point of a continued or
propagated thrombus, extending in the course of the thrombosed vessel and
perhaps into communicating vessels. A secondary or encapsulating throm-
bus is one which starts from an embolus of thrombotic material. A con-
tinued thrombus is also often spoken of as secondary. Thrombi are, with
rare exceptions, adherent, at least in places, to the wall of the ves.sel or
the heart. Mural thrombi appear more or less flattened against the vessel
wall, or they may project in a globular or polypoid form into the lumen.
Their free surface is generally rough. Loose thrombi in the heart are called
ball-thrombi.

The thrombus grows in length chiefly in the direction of the current of
blood; but it may grow in the opposite direction. The intact and growing
end of the thrombus is a flattened blunt cone usually not adherent to the
wall of the vessel; it is sometimes compared in shape to a serpent's head.
A venous thrombus extends in the direction of the circulating blood, not only
35 far as the next branch, but frequently a greater or less distance beyond
it, in the form of a mural thrombus. A thrombus is at first soft in consis-
tence and moist; but by contraction and extrusion of fluid it becomes more
compact, firmer, drier, and more granular in texture.

Mural thrombi, especially small ones, such as fresh vegetations on the car-
diac valves, may occur without any definite arrangement of the constituent
elements. Such thrombi may consist almost wholly of platelets ; but it is
most exceptional not to find at least some admixture with leucocytes and
fibrin coagulated intra vitam.

The larger white and mixed thrombi often present a typical architecture.
The stratified structure has long been known and emphasised. More recently
Zahn has directed especial attention to the rib-Hke markings on the free

UK THROMBOSIS

Kurliids,' 1111(1 Awlioir to tlie internal arc liitfitiiro of white and mixed
tliromlii. MieroFcopical sections of these thrombi often show an exquisitely
(raiiecular structure due to irrejrularly contoured, anastomosing; columns aJid
lanu'lI.T, of var\iii^ size and shape, which sprinc; at intervals from the wall
of the vessel and extend, usually in an oblique or twisting direction, toward
the free surface of the thrfinihus. upon whicli their extremities from the
network of whitish lines or the transverse ribs noted by Zahn. If the throm-
bus be detached from the inner wall of the vessel, similar projecting lines and
dots can be seen on its attached surface and often on the inner lining of
the vessel. This trabecular framework of the thrombus is composed of
masses of platelets with cortical layers of fibrin and leucocytes, as already
described. The wliole arrangement is aptly compared by Aschoff to branch-
ing coral stems. The spaces between the trabecute contain blood which
during life may be fluid or may have coagulated ; or they may contain only
fibrin and leucocytes, or an indefinite mixture of platelets, fibrin and red
and white corpuscles. Between the lamell.-e and columns bands of fibrin
with or without platelets, often stretch loosely and in a curved manner, the
concavity of the curve looking toward the axis of the vessel. Aschoff explains
the coral-like architecture and the ribbed surface of the thrombus partly
by the oscillatory or wave-like motion of the flowing blood, which, as pre-
viously suggested by Zahn, may account for the ribs, and partly by slight
irregularities of surface level normally present in the inner lining of vessels.
Zahn finds an analog)' between the ribs of a thrombus and the ripple-marks
in sand at the edge of the sea, or at the bottom of flowing streams. Before
Zahn, Wickham Legg, in 1878, described the surface of a cardiac thrombus
as " marked by lines resembling the impressions made by the waves on a
sandy shore."

The usual explanation of the red and white stratification of mixed thrombi
is that tlie thrombus is deposited in successive layers, of which the red are
formed rapidly and the white more slowly. There are manifest difficulties
in such an ex})lanation. It is more probable that the red layers are cruor
clots formed from blood brouglit to a standstill. Blood entering crevices,
spaces, and clefts resulting from the irregular mode of growth of the throm-
bus, or from its contraction, or from the blood-stream, often with increase
of pressure in consequence of the thrombotic barrier, undermining ami split-
ting the white substance, at first soft and later brittle, of the thrombus, may
readily stagnate and clot. Indications of such a splitting of the thrombus

' A number of writers before Zahn observed the markings on the surfaces of
thrombi. Uristowe in 1855 spoke of the " peculiar ribbed appearance " of the
surface of cardiac thrombi (Trans. Path. Soc. London, VII, p. 141).

THROMBOSIS 119

by the circulating blood are often seen in horizontal white lamellae covering
red layers and present within them : these lamella* are apparently split off
from the general framework and bent in the direction of the blood-current.
The typical architecture of the thrombus may not appear, or may be
obscured or destroyed by displacement of its parts through the blood-stream,
especially when tliis is forcible : hence it is often missed in arterial thrombi.
White thrombi are, as a rule, microscopically mixed thrombi ; and in colour
there is every transition from tliese to thrombi so red that careful examina-
tion is required for tlie detection of tlie white substance.

In long propagated venous thrombi smaller white thrombus-masses often
alteniate in a longitudinal direction with longer red ones. The explanation
of this is that a priniarj' white thrombus is formed, often starting from a
valvular pocket. This becomes an occluding thrombus, and the column of
blood reaching to the nearest branch, or to the confluence of two important
veins, is brought to a standstill, and forms a red, obstructing thrombus. At
the extremity of this, where the blood enters from the branch, another white
occluding thrombus may be formed, to be followed again by a red thrombus,
and so on. Thrombi are sometimes described as red in consequence of failure
to detect the small white autochthonous part of the thrombus. In fact the
term mixed thrombus is applied to three different appearances of thrombi :
(a) an intimate mixture of gray and red substances; (6) stratification in
successive gray and red layers, and (c) red propagated clot-s consecutive to
autochthonous white or mixed thrombi.

In old thrombi various metamorphoses have occurred which obscure or
obliterate the typical structure and architecture of the younger ones. The
masses of platelets, although they may persist a long time, become finely
granular, sometimes almost or quite homogeneous in texture. They are
invaded by fibrin, especially along the edges of spaces and clefts which
appear. Notwithstanding these profound changes a certain configuration
and a differentiation in staining properties often enable us to recognise the
sites of the original columns and lamellaj of platelets. The leucocytes, often
at an early date, undergo fatty degeneration and necrosis, their nuclei dis-
appearing both by karyolysis and karyorrhexis. The leucocytic detritus adds
to the granular material of the thrombus. The red corpuscles are decolour-
ised and fragmented. The haemoglobin is in part dissolved and, after organi-
sation begins, is partly transformed into amorphous and crv'stalline ha?ma-
toidin. These pigmentarv- transformations impart a brownish red colour to
red and mixed thrombi. Fibrin increases in amount and becomes coarse and
dense. The part of the thrombus adjacent to the vessel-wall is often con-
verted into compact concentric layers of fibrin at a period when masses of
platelets are well preserved nearer the lumen. The hyaline material, which

120 TRRONfROSIS

is very frequently found in layers and clumps in old thrombi, may be derived
both from fibrin and from platelets ; perhaps also from red corpuscles and
leucocytes. It may stain well by Weigert's fibrin-stain, or only faintly, or
not at all. Small spiK.es and canals, often containing nucleated cells, may
be present in the homogenous fibrin or hyaline substance (canalised fibrin
of Langhans) .

Of special importance are the liquefactive softenings which may occur
in old thrombi. These are distinguished as simple or bland, septic or puru-
lent, and putrid softenings.

The simple softenings occur in bland thrombi, being especially common
in globular cardiac thrombi which, when old, regularly contain in their
interior an opaque whitish or reddish thick fluid. This in old days was mis-
tiiken for pus, and hence the name purifomi softening (purulent cysts).
The liquid or pulpy material is the result of granular disintegration and
liquefaction of the solid constituents of the thrombus, and consists of necro-
tic fatty leucocytes, albuminous and fatty granules, blood pigment and
altered red corpuscles; the varj-ing red tint of the fluid depending upon
the number of red corpuscles originally present in the thrombus. Occasion-
ally acicular crystals of fatty acid are present. This form of softening is
probably due to the action of some ferment; it occurs in ordinary bland
thrombi, and is distinguished from the infective forms. It is not generally
supjKJsed that micro-organisms are in any way concerned in the process :
bacteria, however, have been found of late years repeatedly in these thrombi ;
and it may be that they are not so absolutely unconcerned in simple throm-
botic softening as is generally thought to be the case.

There is no question as to the participation of bacteria in the other forms
of softening. Septic or purulent softening, met witli most frequently in
infective thrombo-phlebitis, is a true suppuration; being the result of the
accumulation of polynuclear leucocytes with fermentative liquefaction of
tlie thrombus. The leucocytes are attracted in part from the blood of the
thrombosed vessel and in part from the vasa vasorum and surrounding
capillaries and veins. Pyogenetic bacteria, most frequently streptococci,
are present in the thrombus and the walls of the vessel. Putrid softening
is due to the invasion of putrefactive bacteria. Here the tlirombus is of a
dirty brown or green colour, and of foul odour.

The.se various softenings often lead to the separation of tlirombotic frag-
ments to be tnuisported by the circulation as emboli, — bland, septic, or
putrid according to the nature of the process.

White thrombi in veins, far less frequently in arteries, may undergo calci-
fication, forming phleboliths or arteriolitlis. They are generally approxi-
mately spherical, and lie loosely or slightly adherent in the lumen. They

THROMBOSIS 121

are found most frequently in the veins around the prostate and bladder of
men, in tlie plexus pampiniformes of women, and in tlie spleen.

One of the most interesting adaptive pathological processes is the so-
called organisation of thrombi, which is the substitution for the thrombus
of vascularised connective tissue. The thrombus itself takes no active part
in the process, but behaves as a foreign body. It is gradually disintegrated
and absorbed, largely through the acti\ities of phagocytes. The new tissue
springs from the wall of the vessel or tlie heart; the tissue-forming cells
being derived both from the endothelium and from other fixed cells in the
wall. Xew vessels spring from the vasa vasorum. Lacunar spaces in the
thrombus, or between the tlirombus and tlie vascular wall, may become lined
witli endotheliimi, and also serve as channels for the circulating blood. These
new vessels may establish communication with the lumen of the tlirombosed
vessel above or below the thrombus, or on both sides. The new tissue, which
at first is rich in cells, becomes fibrous, and contracts. The result may be
a solid fibrous plug, or a cavernous structure with large blood-spaces ; or, by
disappearance of tlie septa, a restoration of the lumen, with perhaps a few
fibrous threads or bands stretching across it, as in the normal cerebral venous
sinuses.

There are great diversities in indindual cases as to the rapidity of onset
and the course of the organising process; these differences depending upon
various circumstances, the most important of which are the location of the
thrombus, the condition of the wall of the vessel or heart, the general state
of the patient, and the presence or absence of infection. In favourable
cases the process may be well under way within a week. The wall of the
vessel, or of the heart, may be so diseased as to be incapable of furnishing
any new tissue ; as is usually the case in aneurysmal sacs, and often in varices
and in cardiac disease. The presence of pyogenetic bacteria prevents or
delays the process of organisation. The process is a proliferative angeiitis.
It is this angeiitis which leads to the closure of a vessel after ligation. If
the ligature be applied aseptically, and without injury to the internal coats,
usually no thrombus is formed, or only a very small one. The formation
of a thrombus is of no assistance in securing obliteration of a ligated vessel,
in fact it impedes the development of the obliterating endarteritis.

The causes of organisation of thrombi are probably to be sought partly in
the influence exerted by the thrombus as a foreign body, and partly in slow-
incr or cessation of the blood-current and lowerir.rr of the tension of the
vessel-wall (Thoma, Beneke). Whether, in addition, growth of cells may be
determined by chemical substances derived from the tlirombus is uncertain.

Etiology. — The recognition of the three classes of causes assigned for
thrombosis, namely, alterations in the blood, mechanical disturbances of the
11

122 THROMBOSIS

cinulatioii and lri>ioiis of llie vascular or cardiac wall, is not of recent date.
The (lyscra^tic theory is the oldest. John Hunter introduced and Cruveil-
hier elaborated the conception of primary phlebitis with consecutive plugging
of tlie vein ; and Baillie, Laennec, Davy and others emphasised stasis as a
cause of intravascular clotting. Virchow's niuuc, however, is the one
especially associated with mechanical explanations of thrombosis. Tlie
experiments of Briicke. sliowinj,' tlie importiince of integrity of tlie vascular
wall in ia'cping the blood fluid, led to general recognition of the part taken
by alterations of this wall in the etiology of thrombosis.

While it is generally agreed that slowing and other irregularities of the
circulation, contact of the blood with abnormal surface.*, and changes in the
composition of the blood are concerned, singly or in combination, in the
causation of tlironibosis, there is much difference of opinion as to the rela-
tive importance of each of tliese factors, and as to the part of each as a proxi-
mate, as a remote, or as an accessory cause. ^

Slowing and Oilier Irregularities of the Circulation. — Diminished velocity
of the blood-current is not by itself an efficient cause of thrombosis. The
circulation may lx> at a low ebb for a long time without the occurrence of
thrombi. A stationary' colunm of blood included in an artery or vein between
two carefully applied aseptic ligatures within tlie living body may remain
fluid for weeks (Glenard, Baumgarten). Slow circulation, however, in
combination with lesions of the cardiac or vascular wall, or witli the presence
of micro-organisms or other changes in the blood, is an iinport;uit predis-
posing cause of thrombosis, and frequently detennines the localisation of
the thrombus. This is evident from the relative infrequency of thrombi upon
diseased patches of tlie inner coat of large arteries in contrast with their
frequency upon similar ])atclies in the small arteries and in the veins; and
in general from the predilection of thrombi for those part* of the cireulatorj-
cliannels in which the blood-flow is normally, or as the result of disease, slow.
Extensive injun," to the walls of arteries may be experimentally produced
without resulting t.hromlK)sis.

Ebcrth and Schimmelbuseh find that under normal conditions the platelets
circulate with the red corpuscles in the axial blood-current, but make their
ap}>ear<mce in the outer still zone when the rapidity of the circulation is
sufficiently diminished. ^loderate slowing is attended by the accumulation
of white corpuscles in tliis zone, while a furtlier slackening of the stream is
cliaracterised by fewer leucocytes and more platelets in the peripheral layer.
Mere slowing of the circulation, however, does not suffice to form thrombi ;
there must be some abnormality of the inner lining of the vessel-wall, with
which the platelets are brought into contact, in order to induce the viscous
metamorphosis of these bodies essential in tlie fonnation of plugs. Hence

THROMBOSIS 123

Eberth and Schimmclbusch conclude that it is only by the combination of
slo\(ring of the circulation with changes in the inner lining that the formation
of white thrombi can be explained.

Von Eecklingliausen attaches more importance to a whirling or eddying
motion (Wirbelbeweguug) than to mere slowness of the circulation. He
has pointed out tliat eddies are produced when the blood enters normally or
pathologically dilated channels from smaller ones, or passes into a cul-de-sac,
or over obstructions; and he has considered in an interesting way the special
conditions causing this motion and its influence upon the production of
thrombi. This irregularity of the blood-current will be referred to again in
considering the localisation of v-enous thrombi (p. 138). Von Reckling-
hausen's observations make a valuable contribution to our knowledge of the
mec-hanical distiirbances of the circulation which favour the development
of thrombi.

Thrombi attributed to slowing of tlie blood-current, often combined with
eddying motion of the blood, are called stagnation-thrombi. Of these two
groups are distinguished: (a) those due to local circulatory- disturbances,
as from interruption or narrowing of the lumen of vessels by ligation or
compression, or from circumscribed dilatations, as aneurj'sms or varices; and
(&) marantic thrombi resulting from weakened heart's action, with conse-
quent feebleness of the general circulation. Virchow gave the name " ma-
rantic thrombi " to all or nearly all thrombi complicating or following
anaemic and cachectic states, general infective diseases — as enteric fever,
typhus fever, and the like, and certain constitutional diseases. He con-
sidered a condition of marasmus, or great prostration, to be the common
underlying factor. As we shall see subsequently, there are serious objections
to this explanation of these thromboses, which indeed constitute the class of
chief medical interest. The designation "marantic thromboses" for this
group is still, however, in common use. Although it is proper in these groups
of thrombi to emphasise the mechanical disturbances of the circulation as an
important accessory factor, it is evident, from what has been said, that the
class of stagnation-thrombi cannot be maintained in the strict sense origin-
ally advocated by Virchow. Other factors, especially lesions of the walls of
the heart or vessels, enter decisively into their causation.

Contact of the Blood with Abnormal Surfaces. Lesions of the Cardiac and
Vascular ^YaTls. — It is universally recognised that the influence of the endo-
tiielial hning of the vascular channels in maintaining the fluid state of the
blood is of the first importance. This influence appears to be partly physical
and partly chemical. The smooth, non-adhesive character of the inner sur-
face of tiie heart and vessels is the physical property wliich comes primarily
into consideration. Whereas the introduction of such foreign bodies as

124 THROMBOSIS

threads, or bristles with rough surface, into the circulation is an efficient
cause of thrombosis, perfectly smooth, indifferent bodies, as small glass balls,
may be introduced without causing any coagulation (Zahn). Freund has
shown that blood collected with proper precautions in vessels lined with oil
or vaseline remains fluid for a long time. Mere contact with a foreign
surface, tlierefore, does not suffice to induce clotting; tlie result depends
upon the cliaracter of this surface. Freund concludes that the essential
thing is that tlie surface shall Ix; such as to permit adhesion to occur between
it and the corpuscles, particularly the red corpuscles; the normal lining of
the blood-vessels being characterised by the absence of this adhesive property.
Witliout adopting Freund's theory of coagulation, which does not here
concern us, we can apply, with much satisfaction in the explanation of many
thrombi, his observations concerning the importance of adhesive surfaces in
causing coagulation. There should also be taken into consideration the
damage known to be inflicted by adhasive contact with abnormal surfaces
upon platelets or red corpuscles; if these be regarded as the source of the
granular material and platelets in thrombi.

Changes, therefore, which impair or destroy the smooth, non-adhesive
surface of the normal inner lining of the vessels play an important part in
the etiology of thrombosis; and thrombi thus caused may be called adhesion-
tlirombi. The efficiency of tliese lesions in causing thrombi is increased if,
by projection into the lumen, they obstruct the blood-flow; or by their rough,
irregular surface set up an eddying motion of the blood.

Although we have very little definite information about any chemical
activities of the normal vascular endothelium concerned in the preservation
of the fluidity of the circulating ijlood, there is endence that lesions of the
intima, through chemical as well as pliysical influences, may incite throm-
bosis. That necrotic endothelial and intimal cells may liberate fibrin-
ferment is in accordance with both physiological and pathological observa-
tions relating to the origin of tliis ferment from dead or disintegrated proto-
plasm in general. Eeference has already been made to observations of Zenker
indicating the coagulative influence of necrotic endothelium, and of the
intima deprived of endothelium.

Strong support for a belief in the participation of chemical substances in
the causation of certain thrombi due to intimal lesions is to be foimd in con-
trasting the effwts of mere traumatism with those of traumatism combined
with infection of the intima. This has been especially brought out in the
experimental studies of valvular lesions of the heart. Aseptic laceration
of the cardiac valves generally leads to but slight production of thrombi
upon the injured surfaces; whereas the same traumatic lesions, combined
with the lodgment and growtli of pyogeuetic bacteria, are usually attended

THEOMBOSIS 125

by the formation of considerable thrombotic vegetations. The differences in
the result can hardly be explained by differences in tlie physical characters of
the lesions in the two cases; but we have no definite knowledge concerning the
nature and mode of action of the chemical bacterial products concerned in
causing tlie tJirombi. We may draw the concluiiion that lesions of the intima,
apart from their more manifest characters, may possess certain specific
properties especially favourable to the production of thrombi.

The most important of the structural changes of tlie vascular and cardiac
walls which cause thrombosis are those due to inflammation, atheroma, calci-
fication, necrosis, other degenerations, tumours, compression, and injury.
Here again may be emphasised the importance of retardation and other
irregularities of the circulation in rendering these various lesions effective
causes of thrombosis. The aorta, for example, may be the seat of most
extensive deforming endarteritis, with irregular projecting calcific plates and
ragged atheromatous ulcers, without a trace of thrombotic deposit. The
forcible pulsating current prevents the adhesion and accuniuhilion of the
formed elements consituting the beginning thrombus, or quickly washes
them away. The presence in some instances of white mural thrombi in the
aorta upon an intima apparently but slightly damaged indicates the impor-
tance of certain specific, although little understood, characters of intimal
lesions in association with changes in the blood.

Foreign bodies, which have penetrated the blood-channels and set up
thrombosis, have been obsen-ed repeatedly in human beings, especially in
the heart and abdominal veins. Such accidents have followed swallowing
fish-bones, needles, nails, bits of wire and the like. A blood-clot or thrombus
in a vessel, or projecting into the lumen from a wound of the vessel, may
itself be looked upon as a foreign body, and lead to further extension of the
thrombus. There seems to be a certain self-propagating power in a throm-
bus. Similar effects are produced by the entrance of large parasites, such
as distomata, by the invasion of tumour-masses, and by the penetration of
parenchvTnatous cells into the circulatory channels (p. 228).

Infective Thrombi. Thromho-Phlebitis. — Phlebitis, as a cause of throm-
bosis, has reacquired witliin the last few years so much importance that it
is here singled out from otlier lesions of the vascular wall for special
consideration.

In the first half of the present century, mainly through the influence of
John Hunter and of Cruveilhier, thrombosis was by many regarded only
as an expression of inflammation of the inner lining of the vessels. The
material composing the thrombus was considered to be, at least in part,
an exudate of coagulable lymph from the inflamed vascular wall. Virchow,
by his monumental work on thrombosis and embolism, dating from 1846,

126 THROMBOSIS

reversed this onier of thinjjs, aiu] made, for the jrreat majority of cases,
the tlirombus the primary and essential j)henomenon, and the inflammation
of tlie wall, if present, a merely secondary effect. Phlebitis disappeared,
as a chapter, from works on internal medicine, and thrombosis took its place.
Within recent years, and again chiefly through the work of French investi-
gators, tlie pendulum has swung l)ack, and phlebitis has once more come to
tlie front as a common and important cause of thrombosis, and resumed an
important place iu many systematic treatises on medicine. This rehabili-
tation of phlebitis is due mainly to bacteriological investigations of throm-
bosed vessels, especially of the so-called marantic thrombi of infective and
cachectic diseases.

The distinction between bland thrombi and infective thrombi is an old
and important one. The thrombi in septic and suppurative phlebitis, con-
cerned especially in pyemic processes and surgical affections were for a
long time the chief, indeed almost the only recognised representatives of
the class of infective thrombi. There has been a gradual extension of the
domain of infective thrombosis, until now many thrombi, previously classi-
fied as bland, are considered to be of infective origin. This is notably true
of a large number of thrombi, formerly and still often called marantic, com-
plicating many infective diseases, wasting and cachectic conditions, and
ansemia. In 1887 Weigert stated that by means of his fibrin-stain he had
found unsuspected micro-organisms in marantic thrombi with surprising
frequency ; and since then there have been numerous similar observations, as
well as not a few negative ones. In France the studies of Comil and his
pupils, especially Widal, and of Yaquez have had the greatest influence in
developing the doctrine of the mycotic origin of this class of thrombi, and
particularly that of primary phlebitis as the cause of these thromboses. It
should not be forgotten that Paget, in 186G, contended for the primarily
phlebitic nature of thrombosis in gout.

Phlegmasia alba dolens of the puerperium is the prototype of this class
of thromboses. In the articles on various infective diseases, particularly
enteric fever (see Allbutt's " System of Medicine," I, p. BIT) and influenza
(Allbutt's " System of Medicine," I, p. 683), attention has been called to the
occurrence of thrombosis as a complication or sequel. Similar thromboses
occur in pneumonia, typhus, acute rheumatism, erj-sipolas, cholera, scarlatina,
variola, tuberculosis, syphilis — in fact with greater or less frequency in
nearly all acute and chronic infections. likewise in chlorosis, gout, leu-
kannia, senile debility, and chronic wasting and cachectic diseases, particu-
larly cancer, thrombosis is a recognised complication. The more important
associations of thrombosis with these various diseases will be considered more
in detail subsequently (p. 149).

THROMBOSIS 127

These various thromboses, occurring; very rarely as primarj' affections,
usually secondary to infective or constitutional diseases, compose the great
majority of those of medical, as distinguished from surgical interest. Clini-
cally and anatomically they undoubtedly have much in common. Is there
any common etiological point of view from which they may be regarded?
Virchow thought so in calling them marantic thrombi, and attributing their
causation to enfeebled circulation. The same causative factor still remains
the underlying one with those who, like Cohnheim, interpolate nutritive
changes in the endothelium between the slow circulation and the beginning
of the thrombus.

Impaired circulation cannot serve as a common etiological shelter for
this whole class of thromboses. There is no definite and constant relationship
between the condition of the circulation and the occurrence of these thrombi.
While many appear during great debility, others of the same nature, and
often in the same disease, occur when the heart's action is not notably weak.
Thrombosis may ensue early in influenza. It is oftener a sequel than an
accompaniment of enteric fever. On the other hand, the circulation may
be extremely feeble for days without the appearance of thrombosis.

Manv of these so-called marantic thrombi are unquestionably of infective
origin. Vaquez, in his monograph on phlebitis of the extremities, published
in 1894, has brought together the results of the observations of others, and
especially those of his own and Widal's investigations, which demonstrate
that bacteria are often present in these thrombi and in the adjacent vascu-
lar wall. Since the appearance of Vaquez' monograph there have been a
number of confirmatory observations. Widal emphasises the importance of
searching for bacteria in fresh thrombi, and in the autochthonous part of
the thrombus and the adjacent wall of the vessel. The largest contingent
of positive results has been furnished by the examination of puerperal
thrombi — many of which indeed are examples of septic thrombo-phlebitis,
and of the marantic thrombi of chronic pulmonary tuberculosis ; but bacteria
have also been found in thrombi complicating or following typhoid fever,
influenza, pneumonia, cancer, and other infective and cachectic conditions.

In relatively few instances has the specific micro-organism of the primary
disease, as the typhoid or the tubercle bacillus, for example, been present in
the thrombus; more frequently secondary invaders, especially streptococci
and other pyogenetic bacteria, have been detected : so that the thrombosis is
considered to be oftener the result of some secondary infection than of the
primary one. Colon bacilli have been found in typhoidal and other thrombi ;
but as these bacteria are found so commonly in the blood and organs after
death from all sorts of causes, no great importance can be attached to their
mere demonstration without some further evidence of their pathogenetic

128 THROMBOSIS

activity. As might be expected, streptococci are the bacteria found most
frequently in puerperal thromboses. Singer believes that gonorrhoea! infec-
tion is also a possible factor.

Not only in thrombi of infective diseases but also in cachectic thromboses
have bacteria, and here again most frequently pyogenetic forms, been demon-
strated. Nor is this surprising when we consider the frequency of secondary
infections in chronic diseases, especially as a terminal event; as has been
clearly brought out in the analyses, by Flexner, of the autopsies at the Johns
Hopkins Hospital, where bacteriological examination is a routine procedure
at the post-mortem table. Many of these infections are unsuspected during
life.

The supposition that in all of these cases the bacteria are accidentally or
secondarily present, and in no way concerned in tlie causation of the thrombi,
is extremely improbable. They are often in such number, in such arrange-
ment and associated with such lesions, that they must have multiplied in the
thrombus and in the vessel wall.

The problem whether the bacteria have led to thrombosis by first invading
the vascular wall and setting up inflammation is not solved by the mere
demonstration of their presence. Certainly, in some instances, this sequence
of events is plainly indicated by the microscopical appearances ; but in many
it is impossible to decide to what extent inflammatory changes in the wall
antedated the thrombus, for the latter, especially when infected by bacteria,
induces a secondarj' angeiitis. Opportunities to study very recent infective
marantic thrombi with reference to this point are not common.

In a case, which I examined, of multiple venous thrombosis complicating
leucocythaemia, there was a primary mycotic endophlebitis with secondary
thrombosis. There was a secondary streptococcus infection. In the intima
of the thrombosed vessels were numerous scattered foci in which large num-
bers of streptococci were present. In these areas there was necrosis of
endothelial and other intimal cells, with proliferation of surrounding cells
and many pohTiuclear leucocytes. These foci formed little whitish eleva-
tions capped with platelets, fibrin, and leucocytes ; the whole presenting an
appearance similar to that of endocardial vegetations. There was marked
nuclear fragmentation both in the infected intima and in the thrombus.
Fresh mixed throml)i, containing fewer streptococci, were connected with
these phlebitic vegetations. Although the vasa vasorum were hypertemic,
and were the seat of a moderate migration of leucocytes, streptococci were
absent from the adventitia ; and the appearances spoke decidly for the direct
penetration of the streptococci from the circulating blood into the intima. I
have examined three other similar cases. A similar form of mycotic endo-
phlebitis has been described by Vaquez (endophlebite vegetante). In other

THROMBOSIS 129

cases the intima is more diffusely inflamed. After a short time there is no
distinct line of demarcation between the thrombus and the intima, and all
of the coats of the vessel are more or less inflamed.

Although the bacteria found in the intima may gain access from without
through the vasa vasorum, or the lymphatics, it is probable that in the class
of cases here under consideration they more frequently enter directly from
the blood circulating in the main channel. There may be very extensive
bacterial inflammation of the venous wall, even with bulging of the intima
into the lumen, without any thrombosis.

We do not possess sufficiently numerous and careful bacteriological exami-
nations of the thrombi of infective and wasting diseases to enable us to say
in what proportion of cases they contain micro-organisms. It is certain
that in many instances such examinations have yielded negative results. It
is quite possible that in some of these negative cases bacteria, originally
present, have died out; but although by some authors much use is made
of this explanation, it is not in general a satisfactory one. Many of the
examinations were of thrombi sulBciently recent to exclude this possibility.

To explain these non-bacterial cases, the French writers assume the exis-
tence of a primary toxic endophlebitis, the toxins being either of bacterial
origin or derived from other sources. Ponfick, many years ago, called atten-
tion to the occurrence of degenerations of the vascular endothelium in
infective diseases ; and there can be no doubt of the frequency of both degen-
erative and inflammatory changes of the intima in toxic and infective
conditions.

A lesion which I have seen in the intima of veins (less frequently of
arteries) in tv'phoid fever, diphtheria, variola, and other infective diseases,
is a nodular, sometimes a more diiiuse, accumulation of lymphoid and
endothelioid cells beneath the endothelium. These cells, as well as the
covering endothelium, may undergo necrosis; indeed the appearances some-
times suggest primary necrosis with secondary accumulation of wandering
cells and prohferation of fixed cells. These foci are not unlike the so-called
lymphomatous nodules found in the liver in typhoid and other infections.
They may unquestionably be the starting-point of thrombi, as has been
ehown by Mallory in his study of the vascular lesions in typhoid fever.
Although this form of endophlebitis or endarteritis resembles that demon-
strably caused by the actual presence of bacteria in the intima, bacteria are
often absent, even in the fresh lesions; so that it is reasonable to suppose
that the affection may be caused by toxins. I think that this toxic endan-
geiitis is of importance in the causation of thrombosis complicating infective
and cachectic states.

VM) TFIROMBOSIS

There are, however, instances of so-called marantic thrombosis where no
visible alteration of the intinia can be made out at the site of the thrombus,
or only the slitrht fatty il(';^onrration of the endothelium which is such an
extremely common condition that it does not afford a satisfactor}' explanation.

It is obvious that bacteria are likely to find especially favourable oppor-
tunities to gain lodgment, and toxic substances to do injury, in situations
where the blood-current is slow and thrown into eddies; but the localisation
in these situations of thromboses complicating infective and chronic diseases
has perhaps been unduly emphasised. These thromboses may occur else-
where, even in the aorta and larger arteries. Pre-existing diseases of the
veins, especially chronic endophlebitis and varicosities, are conditions predis-
posing to infective and cachectic thromboses.

While we are justified in assigning a far more prominent place to the
agency of micro-organisms and to primarj' phlebitis in the etiology of
thrombosis than, until recent years, has been customary since Yirchow's fun-
damental investigations, recent attempts to refer all thromboses, formerly
called marantic, to the direct invasions of microorganisms and to phlebitis
go beyond demonstrated facts. We have not at present any satisfactory
bacteriological and anatomical substratum for so wide a generalisation.
The whole field, although difficult, is an inviting and fruitful one for fur-
ther investigation. The clinical arguments in favour of the phlebitic origin
of thromlwsis will be considered below (p. 1T2).

What has been said regarding the relation of phlebitis to thrombosis
complicating infective and constitutional diseases applies also to that of
arteritis to the similar arterial thromboses which, although less common
than the venous, are more frequent than w.is formerly supposed ; this will ap-
pear when we take up the association of thrombosis with particular diseases
(p. 149).

It is of course understood that the preceding remarks on tlie relation of
phlebitis and arteritis to thrombosis relate only to the medical thromboses,
and not to the septic and suppurative thrombophlebitides of the surgeon,
of the l)actcrial origin of which there is no question ; although these latter
may be concerned in diseases, such as suppurative pylephlebitis, which are
in the province of the physician.

Chemical Changes in the Blood. Ferment-Thrombi. — The old ideas of
chemical changes in the blood as causes of intravascular clotting, embodied
in such terms as acre coagulatorium, hyperinosis, inopexia. are now of his-
torical interest only. There appears to be no definite and constant relation
between the amount of fibrin obtainable from the blood, or the rapidity of
its coagulation in the test tube, and the occurrence of thrombosis in human
beings. Peripheral thrombosis is a less common complication of pneu-

THROMBOSIS 131

monia and acute articular rheumatism, which are characterised by high
fibrin-content of the blood, than of enteric fever and certain cachectic
states in which the fibrin-content is approximately normal or reduced.

In dogs whose blood was rendered incoagulable by injection of " pep-
tone " (albumose) Schimmelbusch produced platelet-thrombi experimen-
tally. On the other hand, Sahli with Eguet observed no collection of
platelets or formation of thrombi around hog's bristles or silk threads
inserted into the jugular veins of rabbits having incoagulable blood from
injection of leech extract; although control experiments regularly gave
positive results. These latter experiments show that chemical cliauges in
the blood may influence the process of thrombosis.

The main support of the belief entertained by some that the liberation of
fibrin-ferment in the general blood-stream is an import-ant cause of human
thrombosis, is based on the results of experiments which demonstrate that
the injection of various substances into the circulation may cause intravas-
cular clottings. The most important of the substances which have been
observed to produce this effect are laky blood (Naunyn), biliary salts
(Ranke), ether (Xaunyn, Hanau), fresh defibrinated blood (Kohler),
emulsions or extracts from cells, especially lymphoid cells (Groth, Woold-
ridge), transfusion of blood (Landois, Ponfick), and snake-venom (C. J.
Martin, art. " Snake-poison and Snake-bite," vol. iii. p. 819). The coagu-
lating effect of laky blood is attributable to the stromata of red corpuscles
rather than to dissolved haemoglobin (Wooldridge). The coagulating prin-
ciple here, as well as of the various tissue-extracts, is believed to be a nucleo-
proteid which, by combination with calcium, forms the fibrin-ferment. It
is to the presence of this ferment or the subsequent liberation of the ferment
that the dangerous intravascular clots following the injection of defibrinated
blood or the transfusion of foreign blood are due. The coagulative effect of
snake-venom under certain conditions is referred by Halliburton to pro-
teoses free from phosphorus, and therefore not nucleo-proteids. The action
of snake-venom upon coagulation is probably analogous to that of various
toxic albumoses, bacterial and vegetable. They are in general to be ranked
among anti-coagulating substances; but the result varies vriih the dose,
the manner of injection, and other circumstances. Wooldridge has shown
that thromboses are particularly prone to occur in the territory of the portal
system after the injection of various substances favouring coagulation.
Fibrin-ferment may be used up in the process of intravascular clotting, so
that after this has taken place the remaining blood may be incoagulable.

Interesting as these experimental results are to the physiologist, and
with reference to the theories of the coagulation of blood, it is difficult to
utilise them in any satisfactorj' way in the explanation of ordinarj- human

132 THROMBOSIS

thrombosis. Most of the experimenters make no statement as to the micro-
scopical structure of the intravascular clots, which are described generally
as soft, dark red mai^ses; and they seem to identify them witli ordinary
human thrombi, being apparently not familiar with the researches on the
peculiar constitution of the latter. Some of the substances used for the
experiments cause precipitates in the blood, and many are very destructive
to the red corpuscles. Hanau, however, has shown that masses of platelets
may be present in these clots.

Conditions analogous to those set up in these experiments may occur in
human beings ; but they are, so far as we know, most exceptional. Especially
do we lack satisfactorj- observations, in cases of thrombosis in human beings,
of increase of fibrin-feniient in the blood. Considerable quantities of
fibrin-ferment, more than are likely to be liberated under any probable cir-
cumstances in man, can be injected into the circulation without causing
coagulation. Still it is possible that the mechanism by which this excess of
fibrin-ferment is neutralised and coagulation prevented may be paralysed
under certain conditions. There are certain instances of rapidly-formed
red thrombi in vessels with apparently normal walls which, in the absence
of other explanation, it would be very convenient to refer to fermenUntoxi-
cation. Kohler and Hanau consider that many thrombi, especially those
complicating infective and cachectic states, are best explained by supposing
a liberation of fibrin-ferment in the blood, and they call them, therefore,
ferment-thrombi.

Hayem designates as thrombi from precipitation (thromboses par pre-
cipitation) many which otliers call ferment-thrombi; especially those fol-
lowing injection of various destructive substances into the circulation, and
tliose caused by burns and freezing.

Silbennann and others assert tliat thrombosis, particularly multiple
capillary tlirombosis, plays an important part in axtensive superficial burns,
and in poisoning with various substances destructive to the blood corpuscles,
such as anilin, potassium chlorate, arsenic, phosphorus, sublimate, carbon-
ous oxide, illuminating gas. These views need further confirmation before
they can be accepted, as several observers have obtained only negative results
in searching for tlirombi in tlie same class of cases.

Notwithstanding the lack of a substantial basis of demonstrated facts for
the opinion that human tlirombosis is often caused by liberation of fibrin-
ferment in tlie general blood-stream, it would be quite unreasonable to sup-
pose that chemical changes of the blood are without influence upon the
occurrence of thrombosis in man. Indeed, in infective and toxic conditions
such changes are doubtless tlie underlying factors. Both tlie circulatory
disturbances and the alterations in the vascular wall to which we attribute

THROMBOSIS 133

the production of thrombi are tlie result of damage done to the heart and
vessels by bacterial and otlier toxins. More than tliis, there is good reason
to believe tliat alterations in the formed elements of tlie blood, caused directly
or indirectly by toxic substances, are of great significance in the etiology of
thrombosis. The platelets are in all probability cell-derivatives ; and we
may well suppose that damage inflicted upon leucocytes and red corpuscles
may favour their production, and that, in consequence of abnormal com-
position of the plasma, the platelets themselves may more readily undergo
viscous metamorphosis, and form plugs. In view of recent observations in
favour of the origin of platelets from red corpuscles, the studies of EhrUch,
Maragliano, von Limbeck, and otliers, concerning degenerations and in-
creased vidnerability of these corpuscles in various diseases, are of interest
;svith reference to thrombosis; but it must be confessed that we cannot at
present make more than a hypothetical application of these results to the
explanation of certain forms of thrombosis. To discuss here further the
hj'potheses upon this subject would be barren of any useful result.

Increase of Blood-Platelets. — In view of the essential part taken by blood-
platelets in the formation of thrombi, it is important to inquire whether
thrombosis can be brought into any relation with a pathological increase of
these elements. Some obsen'ations of the existence of such a relationship
are highly suggestive.

Especial difficulties are encountered in the efforts to enumerate tlie plate-
lets on account of their small size and their viscid consistence, which causes
them to clump together. Brodie and Eussell give, as the norm, one platelet
to 8.5 red corpuscles; or about 635,000 per cubic millimetre. Tliis estimate
is considerably higher tlian that obtained by others, probably, however, by
less accurate methods. Van Emden gives as the average for human beings
in health 245,000 ; which corresponds fairly well with the figures of Hayem,
Cadet, Afanassiew, Muir, Fusari, and Determann, but is lower than those
of Laker and Prus.

There is considerable divergence of statement as to the niunber of platelets
in different diseases. This nimiber is markedly increased in chlorosis
(Muir), of which thrombosis is a well-recognized complication. The plate-
lets are increased in post-hfpmorrhagic anjemia (Hayem), which is one of
the remoter causes of thrombosis. There is evidence that hemorrhage after
childbirth, and in the course of various diseases, favours the occurrence of
thrombosis. Several observers have found the platelets reduced in number
in pernicious anaemia, which, unlike chlorosis, is rarely, if ever, complicated
by thrombosis (Hayem, Birch-Hirschfeld, Beugnies-Corbeau). In purpura
haemorrhagica there is extreme diminution of platelets, sometimes amounting
to total absence (Denys, Hayem, Ehrlich, van Emden), which constitutes

134 THROMBOSIS

tlie only demonstrated morphological change of the blood in this disease.
In febrile infections there is often a correspondence between leucocytosis and
the number of platelets. Thus in influenza, pneumonia, erysipelas, menin-
gitis, and septic infections tlie number of plat^'lets is often increased, in
severe cases sometimes diminished; whereas in enteric fever and malaria it
is diminished (ITayem, Eeync, Tiirk, JIuir, van Emden). The disappear-
ance of leucocytosis is sometimes followed by increase of platelets. In view
of the greater frequency of thrombosis as a sequel than in the course of many
acute diseases, the recognition by Hayem of a platelet crisis (crise hemato-
blastique) is interesting. After the crisis or subsidence of certain infective
diseases Hayem observed a rapid and marked increase in the platelets. This
was noted after pnemnonia and enteric fever. Platelets are said to be often
increaesd toward the end of pregnancy and after delivery (Ilayeni, Cadet).
In various cachectic conditions, in tuberculosis, and, in general, in states of
bad nutrition, increase is the rule. Dr. Muir finds that in spleno-medullary
leucocytha?niia the platelets are notably increased, but not in the lympliatic
form (art. " Leucocythaemia," Allbutt's " System of Medicine," V, p. 640).
In chronic passive congestion, due to heart disease, the platelets are said to
be diminished (van Emden). An increase of platelets in various conditions
in which they are usually diminished can often be attributed to complications.
Upon the whole there is much in support of tJie view tliat increase of platelets
is an index of lowered resistence of tlie red corpuscles.

It is fair to say that some of tlie foregoing statements regarding the con-
dition of the platelets in various diseases need further confirmation, and
that in general the subject is difficult and has been insufficiently investigated.
Nevertheless we cannot fail to have our attention arrested by a parallelism,
in many instances, between disposition to thrombosis and increased number
of platelets ; although in others no .such relationship is apparent. It must
suffice to call attention to this parallelism, for we are ignorant of the under-
lying factors.

It hardly need be said that the mere increase of platelets is insufficient to
explain the occurrence of tlirombosis. We are brought back here, as else-
where, to disturbance of the circulation and changes in the vascular walls
as the determinants of the localisation of thrombi ; while we must recognise
changes in the chemistry and morpholog)- of tlie blood as important pre-
disposing causes.

IjOCALISAtion. — Thrombosis may occur in any part of the circulatory
system. We distinguish therefore arterial, venous, capillary, and cardiac
thrombi. Lymphatic vessels may likewise become plugged with fibrin,
leucocytes, or foreign material ; such as tubercle, cancer, or red corpuscles.

Arterial Thrombi. — The majority of arterial thromboses are caused by
Bome local injury or disc!i.<e of the arterial wall, or by the lodgment of an

THROMBOSIS 135

embolus. Especially important are the arterio-sclerotic thromboses of the
brain, heart, and extremities.

Here may be mentioned tlie varying relations of arterial tlirombosis to
gangrene of the extremities. Thrombosis of arteries, as well as of veins,
may be secondary- to varieties of gangrene which are not caused by primary
plugging of the arteries. Senile gangrene is caused eitlier by embolism,
which may lc<ul to tJironilwsis, or by arterio-sclerosis, usually associated
with tlirombosis. In various infective and chronic wasting diseases gan-
grene may result from primary arterial thrombosis of the class often called
marantic. Many of these thromboses are infective in origin; but we have
not sufficient information to warrant tJie assertion that all are caused by
micro-organisms.

Of especial interest is tlie relation of thrombosis to certain forms of
so-called " spontaneous " gangrene which may occur in middle life, or even
in the young, and are often preceded by definite symptoms indicative of
gradual occlusion of the arteries. Von Winiwarter concluded from his ex-
aminations of several cases that the primary disease is an obliterating en-
darteritis resulting in complete closure of tlie affected vessels. Zoege von
Manteuffel, however, finds that thrombosis participates, in an interesting
way, in tJie gradual occlusion of the arteries. According to liim, by the
deposition and organisation of successive layers of parietal tlirombi, the
arteries, which are usually the seat of a primary sclerosis, gradually become
filled with va.scularised connective tissue. Haga considers this endarteritis
thrombotica to be sj-philitic. Hoegerstedt and Nemser believe that, in
general, the deposition and organisation of parietal thrombi are common and
important processes in angio-sclerosis. Von Recklinghausen has described
hyaline thrombosis of small arteries in spontaneous and arterio-spastic
gangrene.

The action of infeciive agents in the causation of focal and diffuse diseases
of tlie arteries is receiving constantly increasing attention. The occurrence
of acute and chronic arteritis as a result of various infective diseases — as
enteric fever, typhus fever, acute articular rheumatism, variola, scarlatina,
pneumonia, endocarditis, septicemia, syphilis, tuberculosis, leprosy — is now
so well established that it is reasonable to believe that the arterial throm-
boses complicating or following these diseases are often referable to an
infective arteritis.

It cannot be doubted that not a few cases reported in literature as primary
arterial thrombosis are to lie attributed to embolism wliich was overlooked.
The possible sources of emboli for the aortic system can be usually controlled
much more readily than those for the pulmonary arteries; for the latter
sources embrace all the systemic veins. These veins may contain mural

136 THROMBOSIS

thrombi, or in places occluding thrombi, which give no signs of their pres-
ence. The possibility that an entire thrombus may be detached and trans-
ported by the blood-current, so that its original location cannot be deter-
mined, is also to be considered. But, after all has been said, it is carrying
scepticism tt> an unjustifiable extreme to refuse to admit the occurrence of
primary arterial tlirombosis in infective, cachectic, and anamic states, under
circumstances where the localisation cannot be attributed to arterio-sclerosis
or other pre-existing arterial disease. Mr. Jonathan Hutchinson has recently
reported observations of rapid thrombosis of arteries without obvious disease
of the walls.

The most frequent site of arterial thrombosis is in the extremities, and
far more frequently in the lower than the upper. Arterial thrombosis, unlike
venous, occurs on the right side as often as on the left. Otlier situations,
more or less common, are the cerebral, pulmonary, coronary of the heart,
mesenteric arteries, and the aorta and its primary branches.

Venous Thrombi. — These may result from local causes, such as trauma-
tism, compression, phlebitis, phlebo-sclerosis, varix (266), inflammation
or other lesion of surrounding parts, and connection of venous terminals
with septic or gangrenous foci.

Vascular thn^nboses due to general causes are, in the great majority of
cases, situated in veins ; and to this group the chief medical interest attaches.
In special characters of the venous circulation we must seek the explanation
of the greater effectiveness of these general causes in veins than in arteries.
The physiological peculiarities, partly general and partly local, which come
especially into consideration, are — the slower mean speed of the blood in
veins than in arteries; the low blood-pressure; the flow from smaller into
larger channels; the absence of pulsation; the presence of valves; fixation
of the venous wall in certain situation to fasciae and bone ; the existence in
some places of wide sinuses and ampullar dilatiitions; the agency of certain
subsidiary forces, such as muscular contraction and movements of the limbs,
in assisting the flow in the veins ; the composition of venous blood, particu-
larly the higher content of CO.,, and perhaps the functions of the capillaries
and small veins in the production and absorption of l}'mph. It is obvious,
without detailed explanation, that some at least of these special characters
must render the venous system nmch more favourable than tJie arterial to
the occurrence, luider the general conditions known to dispose to thrombosis,
of retardation of the blood-current; eddying motion of the blood, and
damage to the vascular wall from impoverished and insufficient blood-supply,
or prolonged contact with micro-organisms and toxic substances, the agency
of which in the etiology of thrombosis has already been considered.

The best evidence that these mechanical conditions determine the localisa-
tion of tlie majority of thrombi of infective, anaemic, and cachectic diseases

THROMBOSIS 137

is afforded by tlie marked preference of sucli thrombi for situations where
these conditions are in the liigliest degree operative. The tendency of
venous thrombi to start from valvular pockets has already been mentioned.
It is important to note that thrombi due to general causes, unlike those start-
ing from local septic foci, do not begin in the rootlets, but originate usually
in tlie main venous trunks of a member. The very large veins are unusual
primary seats of marantic thrombi. Beginning as a rule in a sinus or
medium-sized vein, the thrombus may grow centrally into largo veins ; as
from the femoral into the iliacs and vena cava, and peripherally into small
veins, not, however, generally reaching the smallest veins. The favourite
starting-point of so-called martuitic thromboses of the cerebral sinuses is in
the middle of tlie superior longitudinal sinus at the top of the cranial cavity,
whence the thrombus may extend fonvard, but tends especially to grow
toward tlie torcular Herophili, and into other sinuses and into the cerebral
veins. There is, however, no rigid rule in this matter. The plug may begin
in other sinuses, or even in the cerebral veins.

In extensive tliromboses, such as occur especially in veins of the tliigh
and leg, it is sometimes difficult to determine the point of origin of the
thrombus, and the exact manner of its propagation. Often, however, decisive
information can be gained by careful attention to features indicative of the
age of thrombi, as already described (p. 119). Thus the autochthonous
part of tlie thrombus is gray, or reddish gray, and firmly adherent; the con-
tinued part often red and more loosely attached, and the older parts fre-
quently softened or liquefied in the centre. By observation of such points as
these, the common assumption that a tlirombus, occupying continuously
botli large and small veins, began in the most distal veins and grew tlience
into the larger channels, can often be shown to be erroneous. An occluding
thrombus may lead to such disturbances of the circulation as to cause the
formation of discontinuous multiple thrombi on both tlie central and the
peripheral sides, and these may become connected by red or mixed thrombi.
In short, the modes of extension of thrombi are sometimes complicated, and
not readily unravelled.

The so-called law of Lancereaux was enunciated by him in 1862 as an
explanation of the common site of thrombi in tlie cerebral sinuses, and at the
summits rather than at the peripheries of tie extremities; his rule is as
follows : — " ilarantic thromboses are always formed at the level of the points
where the blood has the greatest tendency to stasis, that is, at the limit of
the action of the forces of cardiac propulsion and of thoracic aspiration."
There are serious physiological objections to the physical conceptions of tlie
circulation underlying this so-called law, which in any event cannot be
accepted in the exclusive form given to it by Lancereaux. Wertheimer has
12

138 THROMBOSIS

shown that the cfTect of tlioracic aspiration upon the venous circulation ex-
tends to remote parts of the saphenous vein by the side of tiie tendo Achillis.
As the collective sectional area of the veins steadily diminishes from the
capillaries to the heart, the average speed of the blood must be greater in
the large veins than in the small ones, if the circulation is to continue for
any length of time ; and this remains true even when the energj* of the blood-
current is feeble.

ilucli more satisfactory, it seems to me, is the explanation offered by von
Recklinghausen, of which mention has already been made (p. ri3). This
explanation places the chief emphasis upon the eddying movement (Wirbel-
bewegung) of the outer lines of flow of the blood-stream when there are
counter-currents, or when the blood with retarded flow passes from smaller
into larger channels or over obstructions, or especially into spaces relatively
too wide for the received volume of fluid. Especially favourable for the
appearance of this irregularity of the circulation are the ampullar dilata-
tions just above the insertion of the venous valves, the intracranial sinuses,
and the femoral vein near Poupart's ligament, which, in consequence of fixa-
tion to bone or fasciae, cannot readily adjust themselves to a lessened volume
of blood, and in which counter-currents are set up by the obtuse or right
angles at which blood is received from some of tlie tributary veins. The
trabeculae which cross the cerebral sinuses may be a contributor}- factor.
Similar irregularities of the blood-flow must occur with feeble circulation
in other situations, as in tlie pelvic venous plexuses, where wide channels
are intercalated between smaller ones, in tlie recesses of the heart, and in
aneurysms and varicose veins. Von Recklinghausen has pointed out that
the plexus-like arrangement, the entrance of small veins into large ones,
and the close apposition of artery and vein render branches of the reual veins
in the kidney susceptible to irregular blood-currents.

The greater frequency of venous thrombosis in the left leg than in the
right is attributable to the more diliicult return-flow from tlie former, in
consequence of the greater length and obliquity of the left common iliac vein
and its passage beneath the right common iliac arterj-. It has been suggested
that pressure upon this vein by a distended sigmoid flexure or rectimi may
likewise contribute to slowing of the blood-current upon this side. The pre-
ponderence of thromboses of the left axillan,- and branchial veins over those
of the right is attributed in a similar way by Parmentier; that is. to tlie
greater length and obliquitj- of the left innominate vein.

As has already been urged, these mechanical disturbances of the circulation
are not, by tliemselves alone, eflScient causes of thrombosis. They simply
make certain parts of the vascular system seats of election for thrombi. It
is quite possible to exaggerate tlieir function in the etiology of thrombosis.

THEOMBOSIS 139

The presence of micTO-organisms or other changes in the blood may induce
lesions of the vascular wall in any part of tlie circulator}' system; and
primary thrombi may be formed in situations apparently the most unpromis-
ing, so far as tlie circulatory conditions are concerned; as for instances in
the pulmonary veins and in tlie venag cavaj near the heart.

Capillary Thrombi. — The blood in the capillaries remains fluid, even
with extensive venous and arterial thrombosis, unless necrosis or gangrene
of tlie tissue ensue, in which case, as in infarctions, the capillaries are always
plugged. The interesting fibrinous and hyaline thromboses of the capillaries
have already been considered (pp. 115 and 116).

Cardiac Thrombi. — There is no stranger chapter in the history of path-
ology than tlie story of cardiac polypi, from the first observation of fibrinous
clots in the heart by Benivieni, in the fifteenth centurv', until the end of
tlie last century. It is full of warnings against the uncritical use of post-
mortem findings. The cardiac polyps of the old writers were, for the most
part, nothing more than ordinary colourless post-niorten clots. Xor has the
error of confounding tliese with genuine thrombi wholly disappeared from
medical literature even at tJie present day. These moist, pale, yellowish,
smooth, elastic, uniform, more or less translucent, fibrinous clots, softer or
firmer according to their content of serum, non-adherent though entangled
witli muscular columns and trabeculas, often showing moulds of the valves
or other projecting surfaces with, at least, some red cruor clot at their most
dependent parts — such clots, membranous, polvpoid, band-like, or filling the
right cavities of tJie heart and sending worm-like offshoots into the vessels,
should never be mistaken for the drier, opaque, gray or reddish gray, granu-
lar, more friable, ucaally much smaller, adlierent, often centrally softened
or stratified thrombi.

Although there is a common impression that these fibrinous clots are
found during the death agony, I know of no good reason for such a view.
It is much more probable that they are analogous to the buffy coat of clots in
shed blood, and are formed after death, when coagulation does not set in
until tlie red corpuscles have settled from the plasma. Liberation of fibrin-
ferment, fibrin-content of the blood, sedimentation-time of red corpuscles
and coagulation-time,* all variable elements, are the leading factors which

* By " fibrin-content " is meant the amount of fibrin yielded by the blood, and
is not of course to be understood as implying the pre-existence of fibrin in the
blood. The rapidity of coagulation is an element which is more or less inde-
pendent of the total yield of fibrin. Red corpuscles settle from plasma or from
serum with varying degrees of rapidity in different specimens of blood. Clots
also vary much as to their contraction and the separation of serum. Although
in using such an expression as " coagulability of the blood " these factors are
often confounded, it is important that they should be distinguished.

140 THROMBOSIS

determine tlie production of these colourless clots. Most striking examples
of colourless clots arc found after death from pneumonia and acute articular
rheumatism, where tiie fibrin-content is high, the sedimentation-time rapid,
and the coagulation-time slow. The whole doctrine of death from " heart-
clot " in these and other acute diseases is based, in my opinion, upon mis-
taken interpretation of fibrinous post-mortem clots.

The fresh vegetations of endocarditis are not generally included in the
consideration of cardiac thrombi. Still they are genuine thrombi, and there
is no more favourable situation for the study of the formation of mycotic
thrombi than the acutely inflamed heart-valve. The first step is the inva-
sion of bacteria, as a rule directly from the blood in the cardiac cavities, into
the endothelial and subendotlilial layers. The surrounding cells undergo
rapid necrosis with karyorrhe.xis ; and simultaneously are deposited upon
the damaged spot masses of conglutinatcd platelets followed by leucocytes
and fibrin, these masses forming the vegetations. Proliferation of the
subendothelial and adjacent cells quickly follows, polynuclear leucocytes
migrate into the area, and before long new vessels with organisation of the
thrombus make their appearance. A process essentially the same may
occur not only in the mural endocardium but also in arteries and veins
(vegetative arteritis, vegetative phlebitis, p. 128).

Putting aside these endocardial vegetations, it has been customary to
consider the conditions leading to cardiac thrombosis as essentially identical
with those of peripheral venous thrombsis, but there are differences. Cardiac
thrombi are found especially in association with chronic diseases of the heart,
lungs, arteries, and kidneys; in all of which, with the exception of pul-
monary tuberculosis, peripheral venous thrombosis is uncommon. On the
other hand, most of the acute infective diseases, as enteric fever, influenza,
pneumonia, which are so important in the etiology of venous thrombosis, are
in general of less relative importance in the causation of cardiac thrombosis,
although it may occur in these diseases. In cachectic states, especially
phthisis and cancer, the conditions as regards the incidence of cardiac and
of venous thrombi are more nearly identical, for here thrombi are often
enough foiuid in the jicart; particularly when there is well-marked fatty
degeneration. Cardiac tliromlxjsis stands in no such peculiar relation to
chlorosis and gout as does venous thrombosis, although its occurrence in
these diseases is not unknown. The great field for cardiac thrombi is
afforded by diseases of the valves and walls of the heart, and esi>ecially by
dilatation of one or more of its cavities with cardiac insufficiency (asystole
of the French school) ; conditions which, in spite of the great retardation
of the venous flow, are not often attended by peripheral venous tlirombosis,
unless in association with diseases known to dispose to the latter.

THROMBOSIS 141

The seats of election for cardiac thrombi are the auricular appendices and
the ventricular apices between the columnaB camcaa ; the particular situation
varying as the cause may ailect the whole heart, on only one side, or one
cavity. In cardiac insufficiency from general or local causes these recesses
and pockets must offer the best possible conditions for slowing of the blood-
current, and especially for the formation of eddies. That there is no actual
stasis of the blood is shown by the gray or reddish gray colour of the thrombi.

The familiar glohiilar thrombi (vegetations globuleuses, of Laennec)
are by far the connnouest form of cardiac thrombus. Varying in size usually
from a pea to a hazel-nut they may attain the size of a hen's egg. They are
usually multiple, and neighbouring ones are connected by an adherent sub-
trabecular thrombotic meshwork or membrane, of which they constitute
sessile or pedunculated spheroidal or ovoid projections. Their surface
may be smooth, or marked by delicate lines or ribs; and their interior is
usually converted into an opaque, gray, or brownish red grumous fluid,
so that the whole resembles a cyst with puriform contents. The liquefaction
is of the bland variety already described (p. 120). Although the projecting
covering of these cysts is often only a thin shell it rarely bursts. These
thrombi may, however, be the source of emboli. Hearts containing these
thrombi are often the seat of fatty degeneration. Usually no localised
mural disease is to be detected with the naked eye beneath these thrombi,
although the microscope generally shows degeneration or defect of the
endotheliiun. It is most exceptional for any trace of organisation to be
present in these globular thrombi.

Calcification of cardiac thrombi is a rare event. Delepine has described
very fully a cardiolith. and has collected reports of similar cases. Some
of these are probably phleboliths in or derived from varicose veins which
Wagner, Zahn, and Bostroem have described in the wall of the heart, par-
ticularly in the septum auriculorum.

Somewhat different as a rule are the viural thrombi found on areas of
circumscribed disease of the heart wall; as on infarction, fibroid patches,"
and gummata, and in partial aneurysm. These may be identical in appear-
ance with the ordinary globular cysts ; but often they are flat or polypoid,
stratified, and more intimately incorporated with the cardiac wall.

Cardiac thrombi may be in the shape of massive or of elongated polypoid
formations, occupying a large part of one of the cavities, and extending

'' It is interesting to note that in 1809, Allan Burns in his classical work on
" Diseases of the Heart," in recording his observations on angina pectoris with
calcification of the coronary arteries and polypi in the left ventricle, called
attention to the relations between disease of the coronary arteries and cardiac
thrombosis. He thus anticipated Weber and Deguy, and other recent writers,
who have emphasised the occurrence of cardiac thrombi in angio-sclerotic hearts.

142 THROMBOSIS

even through valvular orifices into adjacent cavities or vessels. One of the
cavities, usually a dilated auricle, may be nearly filled with a massive lami-
nated thrombus, as in a case reported by Osier which I examined. There is
much resemblance between the clot in these cases and that I'uuml in aneu-
rysms.

Apart from endocardial vc<;otations not much is known of infective
thrombi in the heart, although it is probable that they occur more fre-
quently than is suspected. In a child dead of scarlatina I found, in associa-
tion with streptococcal mitral endocarditis, softened thrombi containing
streptococci in the right auricular appendi.\. There are a few scattered
reports of the discovery of bacteria in cardiac thrombi. Particularly inter-
esting are tlie observations of Weichselbaum, of Birch-IIirschfeld, and of
Kotlar, of tubercle bacilli in white cardiac thrombi. Birch-llirschfeld
found in a case of extensive genito-urinary and chronic pulmonary tuber-
culosis a white organised thrombus in the a])pcn(lix of the right auricle
which contained many tubercle bacilli and numerous tubercles. In these
and similar cases there is difficulty in determining whether the bacteria are
the direct cause of the thrombosis, or are secondarv- invaders. Kotlar
interprets his case as the development of miliary tubercles in an organised
thrombus.

As there are unquestionable instances of finding emboli derived from
venous thrombi in the right heart, the possibility of a thrombus arising
secondarily from such an embolus in this situation may be admitted ; but I
know of no convincing example.

Ball-thrombi, loose in the left auricle, are rare forms of cardiac thrombi.
The first observation which I have found of such a thrombus was published
by William Wood in 1814, in Edinburgh. As in other typical cases, the
loose thrombus was in the left auricle and there was extreme mitral stenosis.
The patient, a girl 15 years old, had tlie regular symptoms of chronic val-
vular disease. Death was not sudden. Wood thus dcscrilies the appcarajices :
" The substance occupying the sinus venosus of the left auricle, when par-
ticularly examined, was found to be of a darkish red colour, in form com-
pletely sjjherical, measuring rather more than an inch and a half in diameter.
It felt firm, but elastic; the surface was everywhere smooth and polished,
but having a singularly clotted appearance. KoUing loosely in the auricle,
it had no connection with surrounding parts. When cut oyieu, after having
been kept for some days in diluted alcohol, it was found to consist of a sac.
one-eighth of an inch in thickness, formed of an immense number of firm,
smooth laminas which could be esisily separated from each other. Within
the cavity formed by this sac was contained a quantity of coagulated blood."
Adherent to the wall of the auricle near the mitral valve was a firm, oval

THROMBOSIS 143

thrombus on the free surface of which was a superficial concavity which
formed a " kind of socket for the loose ball to roll in." This last feature
is a unique observation.

In 1863, Dr. J. W. Ogle reported a typical instance of ball-thrombus in
the left auricle with extreme mitral stenosis, and accompanied the report
with an admirable drawing. In 1877 Dr. Wickham Legg reported likewise,
to the London Pathological Society, two cases of ball-thrombi in the left
auricle with mitral stenosis. He refers to Ogle's specimen which he
re-examined, and to a fourth specimen in the museum of St. Thomas's Hospi-
tal. One of his cases is unique in the presence of two ball-thrombi in the
left auricle. This patient was brought dead to the hospital, and presumably
died suddenly in the street. Yon Recklinghausen's brief description, in
1883, of two cases of ball-thrombi is quoted in the subsequent German
records on the subject as the first observation of this interesting form of
cardiac thrombus; although there were much fuller previous accounts of
at least four cases, with mention of a fifth, in Scotch and English records
extending back as far as 1814; those of Ogle and Legg being certainly very
accessible in the " Transactions of the London Pathological Society." Mac-
leod's case of loose thrombus in the right auricle is properly excluded by von
Recklinghausen from the class of ball-thrombi. If the conception of a ball-
thrombus be simply that of a loose tlirombus too large to pass through the
valvular orifice, then van der Byl's case, reported in 1858, should be included
in this class. He found in a case of sudden death " an irregular, shaggy-
looking mass sticking " in the extremely contracted mitral orifice. When
floated out in water this assumed a sac-like appearance, was about the size
of a pigeon's egg, and completed a broken thrombotic sac in tlie auricular
appendix. This embolus must have been freshly detached, and had not
assumed the typical spherical or ovoid shape of the ball-thrombus. There
have been later reports of ball-thrombi, by Hertz (two cases). Osier (two
cases), Arnold, von Ziemssen, Redtenbacher, Krumbholz, Rosenbach, Stange,
and Eichhorst (three cases mentioned without any details), making twenty,
without including Macleod's and van der Byl's cases.' Of these, fifteen are
reported with sufficient details for analysis. This form of thrombus, there-
fore, although rare, is not so much of a curiosity as has been generally
supposed.

' I have also not included Schmorl's case, mentioned by Stange, as it is evidently
identical with that of Krumbholz, nor Fiirbringer's case of numerous globular
thrombi, the largest the size of a cherry, in the right auricle, although he reports
it as belonging to the group of ball-thrombi. He is evidently under a misconcep-
tion of the nature of ball-thrombi. There was not the slightest reason why these
small bodies, many of them indeed minute, if they were really loose during life,
should not have travelled on with the blood-stream.

144 THROMBOSIS

Three characters, in my opinion, should enter into the definition of a
ball-tlironibus : (i.) entire absence of attachment and consequent free
mobility; (ii.) imprisonment in consquence of excess in the diameter of
the thrombus over that of the first narrowing in the circulatory passage
ahead of it; and (iii.) such consistence and shape that the thrombus must
not of necessity lodge as an embolus in this passage. The third point does
not prejudice the question of the possibility of ball-thrombus lodging as an
embolus; but it excludes from the group such detached, shaggy, irregular
masses (as in van der Byl's case) as must necessarily be caught at once as
emboli in the narrowed passage in front. According to this definition a
ball-thrombus might, theoretically at least, occur in any circumscribed or
sac-like dilatation of the circulatory system ; indeed von Recklinghausen
considers loose phleboliths and cardiac ball-thrombi as analogous.

All of the cardiac ball-thrombi — as thus defined — hitherto reported, were
in the dilated left auricle; and, with one exception, were associated with
mitral stenosis. In Stange's case there was aortic stenosis, with slight
insufficiency of the mitral valve without stenosis. The agency of mitral
stenosis in the production of ball-thrombi is not only that it prevents the
escape of detached thrombi which might pass the normal orifice, but also
that it favours the formation of thrombi in the left auricle, particularly in
the appendix ; and doubtless also, through the particular disturbance of the
circulation, aids in their detachment, increases the tendency to their rotary
motion, and prevents the complete emptying of the left auricle during
systole, thus rendering more difficult the lodgment and fixation in the val-
vular orifice of thrombotic masses which at first may be irregular in shape.

The thrombi have varied in size from that of a small walnut to that of a
hen's egg; in Wood's case the thrombus was over an inch and a half in
diameter, and in Ogle's the weight was more than four drachms. In ten the
shape was spherical; in four ovoid; in one (probably of recent separation)
a somewhat irregular flattened hemisphere. In six the surface was smooth
and polished; in six marked by granules, lines, ribs, or little depressions;
in two smooth and knobbed; and in one (Eedtenbacher's) beset with very
fine, gray, fibrinous villi. Nine were centrally softened ; four solid through-
out ; and for two there is no statement on this point. The colour was gray
or reddish gray; in Wood's "darkish red." In the majoritv' of cases it is
said there were adherent thrombi in the left auricle, usually the appendix;
and where this is not expressly stated tliey may have been present. In five
cases only was there a rough or projecting spot on the surface of the ball
indicative of the previous attachment; and in two this spot was not at all
smoothed off: so that the detachment was evidently very recent, possibly
indeed during the autopsy, as in one of tlie two loose balls in Legg's first

THROMBOSIS 145

case. Krumbholz says that the surface of his thrombus was covered with
endothelium. In none, however, was any distinct evidence of organisation
detected, for von Ziemssen's statement on this point is too indefinite to be
considered.

Ogle, in 1863, clearly recognised the mode of production of a ball-throm-
bus " by the constant and free agitation of a fragment of fibrinous coagulum
separated from some part of the endocardium, and uniformly increased by
fresh material at its circumference precipitated from the surrounding blood-
stream." Von Recklinghausen has given the fullest and most satisfactory
explanation of the spherical shape and smooth surface, in noting that at
least some ball-thrombi have a globular shape when first detached ; and that
irregular bodies, of tlie consistence of thrombi, rotating in a cavity and grow-
ing by successive accretions, assume a spherical shape by a process of mould-
ing, and not by the grinding or breaking off of corners and projections, as was
suggested by Hertz to accoimt for the smooth roundness of ball-thrombi.
In two or three instances where the ball-thrombus has consisted of a central
irregular nucleus enveloped in a concentrically laminated capsule, it has
been assumed that the former represents tlie original detached part, and the
Jatter successive accretions during free rotations in the auricle. While sug-
gestive of such an interpretation, this structure may, however, exist in still
adherent globular thrombi. It seems to me probable that most ball-thrombi
are smooth and at least approximately spherical when first detached. It is
difficult to say how much a thrombus may have grown after its separation.

In nearly all cases that the loose thrombus apparently came from the left
auricular appendix, where adherent thrombi were rarely missed when it is
expressly stated that they were searched for. In Wood's case the dark red
colour, central blood-clot, and polished surface suggest the possibility that
the loose body was a separated polypus resulting from haemorrhage in the
wall of the axiricle or from a varix : and this opinion is strengthened bv the
socket-like depression in the adherent thrombus, for it is not clear how such
a socket could be formed by a thrombus loose in the auricle ; but it miglit
have been the impression left by a polypus attached at some other point.

As regards the clinical significance ' of cardiac ball-thrombi, Wickham
Legg expressed the notion which would probably at first occur to most
persons. " A loose thrombus." he says, " in the left auricle would at any
time be ready to act as a ball-valve, and stop the circulation in the mitral
orifice " ; and in this opinion he was strengthened by the presumably sudden
death of his patient. Yon Recklinghausen, however, who at the time knew

' In order to complete without interruption the description of ball-thrombi I
introduce here their clinical significance, although the consideration ot the symp-
toms of thrombosis is taken up subsequently.

146 THROMBOSIS

only of his own two cases and the two of Hertz, in critising a similar opinion
expressed by tlie latter, brouj^ht forward several arguments opposed to tliis
notion. The main points of his argument are that instances of sudden death
are not infrequent in extreme mitral stenosis without ball-tlirombi; that
lodgment of the thrombus in tlie mitral orifice has not been observed, and,
even if it wore found lying loosely over the orifice at tlie autopsy, that tliis
would not indicate its position at tlie moment of death ; that the funnel of
the stonosed mitral orifice is elliptical in cross-section and shallow, so that
a rolling sphere of the consistence of a ball-thrombus could neither com-
pletely occlude it nor get wedged in it, nor, if the ball should enter the shallow
funnel, is there anything to hold it there, so that Uie next moment it would
roll out. To these points may be added Arnold's argument that the throm-
bus cannot be horizontally pressed by the auricular contractions against the
orifice; for during its systole the dilated auricle does not completely empty
itself of blood through the stenosed orifice.

The histories of the cases of cardiac ball-thrombus support in general the
position of von Recklinghausen. No symptoms were observed which may
not occur in mitral stenosis. Death was gradual in all except four. In
only one of these four cases of sudden death was tliere any conclusive evi-
dence that the thrombus was the cause. This was Dr. Osier's second patient
upon whom the autopsy was made in my lalwratoiy liy Dr. Flexuer. Tlie
patient, a woman aged 20, was seen in good condition a few hours before
deatli. At 4.30 a. m. she vras found by the nurse very cyanotic, she gave a
gasp or two, and died in a few moments. At the autopsy were found marked
hypertrophy and dilat^ition of the left auricle, right ventricle, and to a less
extent right auricle; without dilatation or hypertrophy of tlie left ventricle.
The segments of the mitral valve were thickened, adherent, and drawn down
by great shortening of the chordae tendine£e, so as to form the wall of a dis-
tinct funnel. There were no fresh vegetations and no oedema. The stenosis
was not extreme, the mitral orifice readily admitting the index finger. The
other valves and the coronarj- arteries were normal. An ovoid ball-thrombus,
resembling a thick chestnut, measuring 4x3.5x3 ctm., was found, upon
opening tlie heart, occupying with its smaller end and completely blocking
the funnel-shaped mitral orifice, from which it was readily removed by the
fingers. At one ix>le of the thrombus was an irregular, roughened .*pot
indicating a former attachment, probably to a thrombus in the apiiendix.
There can bo no reasonable doubt that the thrombus in tliis case was the
cause of the sudden de<ith. which is certainly not a common occurrence with
such moderate uncomplicated mitral stenosis at the age of this patient. In-
deed sudden death is less common in uncomplicated mitral stenosis tlian in
aortic valvular disease; as the former occurs often in young women, and is

THROMBOSIS 147

usually unassociated with disease of the coronary arteries. In the three
other instances of sudden death with ball-thrombus the ages were 21, 22,
and 39 years respectively. Only in one of tliese was the thrombus a perfect
sphere; so that it would appear tliat an oval thrombus is more likely to plug
the mitral orifice than a spherical one. This view is strengthened by the fact
that of the four observations of ovoid thrombi in tliree death was sudden.
In the light of our case it seems clear that a ball-thrombus may " act as a
ball-valve and stop the circulation in the mitral orifice," as suggested by
Legg; but it is certain that this is an exceptional occurrence.

Under the name of cardiac pedunculated polyps various formations have
been described. Some of these are ordinary unorganised or partly organised
polypoid thrombi, about which nothing more need be said ; but others are very
remarkable structures which occupy an entirely exceptional position, not only
among cardiac thrombi but among thrombi in general. In the older records
some of the latter were described as fibromatous or myxomatous polyps, —
two as haematoma; but in the later reports most have been recognised as
organised thrombi. They are often called true polyps in distinction from
the false polyps of the older writers.

The literature of the subject begins with Allan Burns in 1809. References
to many of the cases will be found in the papers of Hertz, zum Busch, and
Pawlowski. Among the noteworthy observations since Hertz are those of
Czapek, Voelcker, Bostroem, and Ewart and Rolleston. I have found
records of thirty-three ca.ses, at least twenty of which were well-characterised,
organised, pedunculated polyps. Twenty-five sprang from the wall of the
left auricle, usually the septxun ; four from the right auricle ; four from the
left ventricle.

The following are the more notable features of these curious formations : —
In many instances no cause whatever could be found for their occurrence.
The hearts containing them were often otherwise entirely normal, -with the
exception of changes manifestly secondary to the polyp, such as nodular
fibroid thickening of the mitral segments and dilatation and hypertrophy
of the left auricle and right ventricle. Unlike other cardiac thrombi they
are solitary formations, and often imassociated with ordinary thromliotic
deposits. The vast majority of these polyps spring from the septiim of the
left auricle near the fossa ovalis with short pedicle, sometimes narrow, some-
times broad. They are firm or gelatinous, elastic, ovoid or pear-sliaped
formations, in several instances hanging down into the left ventricle with a
constriction corresponding to the mitral orifice. The surface is usually
glistening, smooth, and covered by a distinct membrane which often resem-
bles the endocardium. It may present calcific, atheromatous, or pigmented
patches; and upon it may be irregular knobs and depressions. The colour

H8 THROMBOSIS

is described as yellowish, gray, dark red or brownish red ; tlie colour often
varying in different parts of the polyp. A prevailing dark red colour has
been observed in a large number of tlie cases. In distinction from nearly
all other cardiac thrombi, these polyps are more or less organised by con-
nective tissue and vessels; the organisation in some being little marked, in
others so far advanced that the structure resembles that of a fibroma or
myxoma. The central part is often luiorganised or less organised tJian the
base and periphery. In the incompletely organised forms the substance of
tlie polyp is composed of red corpuscles, fibrin, granular detritus, yellow
blood-pigment, leucocytes, and otlier cells between the blood-vessels and
fibrous septa. Laminated fibrin may be present in the peripheral layers.
Unless ordinary thrombi are likewise present, emlwli are usually missed.
A further distinction from the ordinary cardiac thrombi is that many of
tliese polyps, by encroaching upon the mitral orifice, are of as much clinical
as anatomical interest; tlie diagnosis during life in these cases being mitral
disease, usually stenosis.

We have no satisfactory explanation of these pedunculated polyps. The
ordinary causes of thrombosis are generally absent. Their commonest site
of origin, tlie septum of the left auricle near the oval fossa, is not a usual
situation for ordinary thrombi. They stand in no demonstrable relation to
patency of the foramen ovale or to circumscribed endocarditis in this situa-
tion.

Bostroeni has suggested that an explanation may be found in the existence
of varicose veins which have been observed repeatedly in tlie septum, usually
near the posterior quadrant of the foramen ovale. A difficulty vrith this
explanation is that nine out of ten of the varicosities observed by Wagner,
Zahn, Rindfleisck, and Bostroem were on the right side of the septum. In
one instance, however, Bostroem found in the left auricle a spherical, dark
red polyp, 13 iiini. in diameter, attached by a short, narrow stem to the septum
on the posterior lower margin of the completely closed foramen ovale. This
proved to be a varix containing a phlebolith. In another ca^e a similar
thrombosed varix had broken from its pedicle on tlie septum of the right
auricle, and was lodged as an embolus in a branch of the pulmonary artery.
He suggests this as a possible source of ball-tlirombi. Of still greater signifi-
cance is Bostrocm's demonstration in an old museum specimen, lalielled
"thrombosis of the right auricle (pedunculated cardiac polyp) peripherally
organised," of an enormous comjiletely thrombosed varix almost filling the
right auricle. In still another case he proved conclusively that a broad-
based, nearly spherical polyp, occupjnng a large part of the right auricle,
was a h.Tmorrliage in the wall of the auricle. Choisy and Xuhn long ago
interpreted the polyps, which they observed, as tlie result of lueniorrluige in
the septum of the left auricle.

THROMBOSIS 149

In the Ught of Bostroem's interesting investigations, more attention than
has been customary sliould be given to the possibility that pedunculated
polyps are the result of hannorrhage or are thrombosed varices. Most com-
petent investigators, however, have unhesitatingly pronounced the polyps
which they have examined to be organised thrombi. It would appear, there-
fore, that the nature of these formations is not always the same. At any
rate the great majority of the typical pedunculated polyps, to which the
preceding description applies, occupy a position quite apart from ordinary
cardiac thrombi. As already remarked, by no means all of the cases described
as true cardiac polyps belong to this peculiar group. Some, as in Krumm's
case, are ordinar}* partly organised thrombi attached to diseased patches of
the heart wall.

Association with Certain Diseases. — Thromboses may be divided, as
regards their clinical relations, into the following groups: (i.) those result-
ing from direct injury of vessels, including the penetration of foreign bodies ;
(ii.) referable to diseases of the vascular wall, as to angio-sclerosis, sj'phili-
tic arteritis, aneurysm, varix; (iii.) caused by lesions of neighbouring parts;
(iv.) thromboses of arteries and veins whose terminal branches end in
septic and gangrenous areas; (v.) complications or sequels of (a) infective
diseases, (6) cachectic and anaemic states, (c) cardiac disease, (d) certain
constitutional diseases; (vi.) idiopathic and primary infective thromboses.
Several of these groups, being mainly of surgical interest, will not be con-
sidered here. The thromboses embraced in the fifth and sixth groups are
of such special medical interest that it is proper in this article to give them
particular attention ; although it is manifestly impossible within reasonable
limits to take up all in detail. Some of them are noticed in other parts of
this work.

Enteric Fever. — Cardiac Thrombosis is a rare complication of enteric
fever. In 2000 fatal cases of enteric fever in Munich there were only eleven
instances of acute endocarditis (Holscher). Girode, Viti, Carbone, and
Vincent have found the typhoid bacillus in endocardial vegetations; and
vegetative endocarditis has been produced experimentally by intravascular
injections of pure cultures of the typhoid organism combined with injury
to the valves. More frequently the endocarditis has been due to secondary
infection. In rare instances in the course of enteric fever globular thrombi
are formed in the auricular appendages and ventricular apices; and these,
as well as the endocardial vegetations, may be the source of emboli.

Arterial thrombosis is a still rarer event, but, in consequence of its
gravity, an important one. Bettke, in 1-420 cases, found four of gangrene of
the extremities ; but in 2000 Munich autopsies no instance is recorded, a result
in contrast with fifty-nine of thrombosis of the femoral vein in the same

150 THROMBOSIS

eeries. Keen, in his admiralilc monofrrapli, has collec'ted and analysed
115 cases of gangrene associated with enteric fever, and due to plugging of
the arteries. In twenty-one cases arterial thrombosis was observed without
gangrene, the absence of which is much more common with thrombosis of
arteries of the upper extremity than of tlie lower. The earliest appearance
of the gangrene was on the fourteenth day; the latest in the seventh week.
In the great majority of cases the thrombus was seated in the arteries of
the extremities ; and in those of the lower far more frequently than of the
upper. In eight out of eleven cases of arterial thrombosis of the lower
extremities, collected by Barie, the posterior tibial artery was concerned. In
contrast with venous thrombosis the right side is the seat as often as the left.

Other arteries, as the pulmonary, the superior mesenteric, and the cerebral,
may become thrombosed. Four fatal cases of typhoidal thrombosis of the
middle cerebral artery, or its branches, have been reported (Huguenin,
Barberet and Chouet, Vulpian and Osier) ; and other cases have been
recorded in which the diagnosis of cerebral thrombosis was made from the
symptoms. In Osier's case, in which Dr. Flexner and I examined the brain,
the middle cerebral artery was open ; but the ascending parietal and parieto-
temporal arteries and their branches were occluded by adherent, firm, mixed
thrombi. The adjacent brain substance was studded with punctiform
haemorrhages, but not much softened. Typhoid bacilli were widely distrib-
uted in tlie body.

The arterial thrombosis may be secondary to embolism; but in the great
majority of cases it has been reported as autochthonous. In the older
records the thrombosis has been usually regarded as marantic; wherea-s the
tendency now is to refer it to an infective arteritis; a view which is prob-
able, although we have few conclusive observations in its support. Eattone
and Ilaushalter claim to have demonstrated the typhoid bacillus in the walls
of occluded arteries; and Gilbert and Lion, Crocq, and Boinet and Eamary
have produced an acute aortitis experimentally, by injuring the vessel wall
and then injecting typhoid bacilli into the circulation. The bacteriological
studies are too meagre and unsatisfacton- to warrant any definite statements
as to the specific cause of arterial thrombosis in enteric fever.

The far commoner venous thrombosis of enteric fever has been adequately
considered by Professor Dreschfeld in Allbutt's Syst. ^led., vol. i. p. 817;
and the points bearing on its causation have been presented under Etiology.
Richardson has called special attention to the '' marantic " thromboses of
intracranial veins complicating enteric fever.

Injiucnza. — Xearly all of our knowledge of thrombosis in influenza dat«s
from the pandemic of 1889-90, which led to the recognition of countless
complications, among which those of the circulatory system occupy a less

THROMBOSIS 151

prominent place than the respiratory and nervous. Arterial thrombosis,
although far from common, is still not an extra-ordinarily rare complication
or sequel of influenza. It is more common in this disease than in any other
acute infection. In a few instances it appeared as early as the third to the
fifth day, but in most during convalescence. Over forty cases of arterial
thrombosis or of gangrene accompanying or following influenza have been
rejwrted. References to many of tliese will be found in the monographs of
Leichtenstern and of Lasker; but their lists are far from complete. In a
partial collection of the cases I find that the popliteal arterj' was occluded in
six; the femoral in four; the iUacs, the axillar)-, the brachial, the pulmonary,
and the renal each in two; and the central artery of the retina (embolism be-
ing probably excluded) in one. The cerebral arteries were repeatedly invaded.
In several instances there were multiple thrombi. Sj-nmietrical gangrene
following bilateral plugging was observed in a number of cases. Gangrene
was observed in all the cases of occlusion of the arteries of the lower extremi-
ties, but not regularly with that of the upper.

It is difficult to say in how many cases the occlusion was due to embolism.
Endocarditis is a rare but recognised complication of influenza, and globu-
lar cardiac thrombi have also been observed. In the great majority of cases
it seems clear that there was primary arterial thrombosis.

Yetwus fhromhosis is a far commoner result of influenza; and has been
the subject of a special memoir by Chaudet, and of nmuerous articles in
the medical journals of all countries. Twenty-five cases are recorded in
Guttmann and Leyden's collective investigation, and many additional ones
are to be found in the vast literature on influenza. Dr. Goodhart, in his
article on " Influenza " (Allbutt's Syst. Med., vol. i. p. 683), notes the fre-
quency and the occasional diagnostic value of this complication, which may
appear during tlie course of the disease or weeks afterwards, and in mild as
well as severe cases. In the great majority of instances the femoral vein
was attacked; but tlie veins of the upper extremity were thrombosed more
frequently than in other acute infective diseases. Leichtenstern notes the
acute onset and course in some of the cases. There are records of throm-
bosis of the cerebral sinuses in influenza. Klebs and Kuskow describe
capillary thrombi in the lungs.

Few observers are satisfied with the explanation of either the arterial or
the venous thromboses of influenza as marantic. Leyden suggests as a cause
increase of blood-platelets from disintegration of leucocv-tes. Evidences of
such disintegration, or of masses of platelets in the blood, have been noted
by Klebs, Chiari, and Biiumler. Maragliano observed the onset of necro-
biotic changes of the red corpuscles in influenza almost immediately after
withdrawal of the blood. French writers for the most part attribute the

152 THROMBOSIS

thrombosis to infective arteritis or phlebitis (arterite grippale, phiebite
grippale). Rendu, however, in his case of arterial thrombosis rejects this
explanation ; as he found the walls of the thrombosed arteries entirely nor-
mal (nothing is said of a microscopical examination), and he attributes the
thrombosis to feeble circulation. In liis case there was also a thrombus with
softened centre in the left ventricle, and the occlusion of the artery may
have been due primarily to an embolus. Gerhardt attributes the gangrene
in his case to spasm of the arteries, considering it therefore analogous to
symmetrical or arterio-spastie gangrene. In support of the more probable
view that the thrombosis is the result of some change in the vascular wall,
directly referable to infection or intoxication, Kuskow observed with great
frequency degeneration, proliferation, and desquamation of the vascular
endothelium in influenza. In a fatal case of influenzal phlegmasia alba
dolens Laveran found streptococci in the blood. These organisms have often
been found in the blood and organs of those dead of influenza.

In a remarkable case of multiple thrombotic vegetations present in large
nimibers in the pulmonarj' artery, especially in the left main branch, and also
on the pulmonarj' valves (other valves normal), Flexner in my laboratory
foimd in the thrombus, chiefly enclosed within polynuclear leucoc}'tes, very
numerous, extremely delicate bacilli, which were identified as the influenzal
baciUi of Pfeiffer. This establishes the occurrence of an acute arteritis and
thrombosis due to the bacillus of influenza.

Pneumonia. — The sixteenth century error of mistaking for ante-mortem
coagula the firm, yellowish white cardiac clots, intimately intertwined with
the columnas carneae, and found after death from pneumonia more frequently
than from any other disease, has not wholly disappeared at the end of the
nineteenth century ; for coagulation of blood in the right heart is still occa-
sionally spoken of as a special danger in pneumonia. Genuine antc--mortem
thrombi in the cavities of the heart occur in pneumonia, but they are rare;
being much less common than in many diseases in which death from " heart-
clot " is not mentioned as a special danger. Acute valvular endocarditis is
a well-recognised complication of pneumonia. Mention has already been
made of coagula in pulmonary vessels directly connected with the inflamed
lung (p. 115).

Benedikt, Brunon, Rendu, Leyden, and Blagden have observed gangrene
of the extremities consecutive to arterial thrombosis in pneumonia. Blag-
den's patient was a woman 92 years old. In Leyden's case there was throm-
bosis of the lower end of the abdominal aorta. Gangrene of the extremities
in pneumonia may also be the result of embolism ; of this event Osier has
observed an instance.

THROMBOSIS 153

Venous thrombosis, although more frequent than arterial, is scarcely
mentioned in text-books as a complication or sequel of pneumonia. Few
cases have been reported. Da Costa, in a valuable article on the subject,
reports three personal observations, and has collected from the Literature
six additional ones, and two which are doubtful. In addition to these, I
have found reports of cases by Barbanceys (two cases), Lepine, Fabrics,
Yalette, !Mya (two cases), and Lee Dickinson (seven cases), making a total
of twenty-three cases of venous thrombosis in pneumonia. The femoral or
internal saphenous veins were those invaded, the affection being oftener on
the left than on the right side. There were at least three deaths from pul-
monary embolism consecutive to the thrombosis. The afEection, if one may
draw any conclusion from so small a number of cases, is more common in
women than in men. Of 367 cases of pneumonia, observed by Dickinson,
peripheral venous thrombosis occurred in seven, of which four were in young
women, two of these being chlorotic. In several instances of influenzal
thrombosis pneumonia had occurred. Laache ranks pneumonia next to
influenza and enteric fever as regards the frequency of occurrence of peri-
pheral thrombosis : but this event is far commoner in the last two diseases.
The affection occurs during convalescence, rather than in the course of
pneumonia ; and presents the same general characters as the phlegmasa alba
dolens of enteric fever. Da Costa verv' plausibly attributes it to a primary
infective phlebitis. Mya, in one of his cases, found pneumococci in large
numbers in tlie tlirombus.

Acute Articular Rheumatism. — There was a time when rheumatic phle-
bitis ranked in importance next to the puerperal form ; but it is now recog-
nised that most of the cases of thrombosis attributed by the older writers
to rheumatism had nothing to do with acute articular rheumatism. Schmitt
and Vaquez have sifted the reported cases, and they find that, while phlebitis
or venous thrombosis is to be recognised as a complication of genuine acute
rheumatism, it is a rare one. The infrequency of this event is noteworthy
in view of the fibrinous state of the blood and the frequency of acute endo-
carditis. Gatay has reported a doubtful case with negative result of the
bacteriological examination of the thrombus. Legroux reports an instance
of thrombosis of the brachial artery without gangrene in acute articular
rheumatism.

Appendicitis. — Mention may be made of the occurrence of thrombosis
with appendicitis, as this affection is of medical as well as surgical interest.
Besides the septic thrombo-phlebitis of the mesenteric and portal veins,
thrombosis of the iUac and femoral veins may occur on the left side as well
as on the right. The published reports indicate that this is more common
on the right side; but in the 131 cases of appendicitis in the service of my
13

ir.t THKOMBOSIS

coUea^e Professor Halsted, witli the iiotts of wliiih Dr. Bloodgood has
furnished me, there were four instances of peripheral venous thrombosis, all
of the left log: one bein<: liniiU'd to the calf. Three of these were in chronic
appendicitis, the operation being between tlie attacks. Myntcr, who lias also
observed thrombosis of tlie left femoral vein, attributes it to great prostra-
tion and weak circulation. It is interesting to note the analogy- of appen-
dicitic thromboses to pueri)cral thromboses, where we also have septic and
suppurative thrombi in veins immediately adjacent to the inflamed organ,
and less manifestly infective tIiromt)i in the veins of the lower extremities.
It is probable, however, that the latter thrombi in appendicitis, as well as
in the puerperal cases, are frequently caused by bacteria, and oftenest by
streptococci, w^hicli are concenied in both affections with great frequency.
In one of Mynter's cases sudden dcatli wa^ probably due to pulmonary embol-
ism following thrombosis of the femoral vein.

Other Acute Infective Diseases. — It would lead too far to continue a
detailed inquiry into the association of thromlx)sis with other acute infective
diseases. It must suffice to specify typhus fever, relapsing fever, dysentery,
erysipelas, suppurative tonsilliti.s, diphtheria, variola, scarlatina, measles,
Asiatic cholera. In many instaucei~ thrombosis, as associated with specific
infective diseases, has been due to a secondary septiciemia, streptococci being
the commonest secondarv* invaders. The disposition in or after typhus fever
to arterial as well as to venous thrombosis should be especially emphasised.
Thrombosis has been added to the growing list of complications of gonor-
rha'a (Martel, Perrin, and Monteux and Lop).

Tuberculosis. — The consideration of thrombosis directly referable to
tuberculous processes adjacent to vessels need not detain us. The occur-
rence of intimal tubercles, where the evidence is conclusive that tubercle
bacilli have penetrated the inner lining of vessels directly from the circula-
tion in the main channel, may be mentioned not only as a cause of thnmi-
bosis, but also as an interesting illustration of this mode of infection of the
vascular wall. Several instances of endocarditis caused by the tubercle
bacillus have been described, and mention has already been made of tubercu-
lous cardiac thrombi (p. 142). Jlichaelis and Blum have produced vegeta-
tive tulwrculous endocarditis experimentally, by injuring the valves in rab-
bits and then injecting tubercle bacilli into the ear veins. Particularly
demonstrative of infection taking place through the vascular enotlielium
are the rare instances of tuberculous foci in the aortic intima, without inva-
sion of the outer coats, and without tuberculosis of neighbouring ])art.s.
Two instances of this form of aortic tuberculosis have been observed in my
laboratorj', and described by Flexner and Blumcr. I have recently examined
a section, in the possession of Dr. Ciaylord, of a superficial tuberculous focus

THROMBOSIS 155

in the iiitima of the aorta with an exquisite platelet and fibrinous thrombus
containing tubercle bacilli attached to the nodule. A similar case has been
described by Stroebe. These rare instances are cited because they furnish
conclusive proof that bacteria may penetrate the inner lining of vessels from
the main ciiannel, even where the blood-current is forcible; and may set
up inflammation of the intima with secondary thrombosis. Ilektoen's inter-
esting observations of changes in the intima of vessels in tuberculous men-
ingitis furnish additional evidence along the same lines.

Arterial thrombosis, outside of the forms to which reference has just
been made, and which are of pathological rather than clinical interest, is a
rare event in tuberculosis. Most common are the instances of thrombosis
of the pulmonary artery or its main branches in phthisis. Dodwell mentions
an instance of thrombosis of both popliteal artery and vein. Vaquez, in
chronic pulmonary tuberculosis, describes an interesting case of thrombosis
of the left subclavian, axillary and brachial arteries with gangrene of the
arm : he found streptococci in the plug and in the wall of the vessel, includ-
ing the vasa vasorum, but no tubercle bacilli.

On the other hand, peripheral venous thrombosis in advanced phthisis is a
comparatively common and well-recognised ailment. In the great majority
of cases veins of the lower extremities, the left oft^ner than the right, have
been plugged ; but the thrombus may be in the inferior vena cava, or other
veins, or the cerebral sinuses. Dodwell, in his valuable paper on this sub-
ject, places the proportion of cases of phtliisis with this complication at
about 3 per cent. In about 1300 necropsies of phthisical patients at the
Brompton Hospital tiiere were twenty cases of thrombosis of veins of the
lower extremities (1.5 per cent).

The peripheral venous thromboses of advanced phthisis are visually cited
as typical examples of the marantic or cachectic form. Dodwell, however,
while recognising enfeebled circulation as a factor, is inchned to refer the
tJirombosis to some miknown change in the vascular wall set up by a compli-,
eating septiciemia. He emphasises the infrequency of venous thrombosis
with the acute and the very chronic forms of phthisis, and its relative fre-
quency with an intermediate type with remittent or continued fever. He
also noted association with intestinal and laryngeal ulceration in a larger
percentage of the thrombotic cases than the average. As is well known,
secondary septictemia^, usually streptococcal, are very common in phthisis.

There are several records of bacteriological examination of the peripheral
thrombi in phthisis, which show that they may be of mycotic origin. Vaquez
found tubercle bacilli, without other micro-organisms, in a thrombus of the
left profunda and femoral veins. They were present also in the wall im-
mediately beneath the endothelium, but were absent from the media and

156 THROMBOSIS

ndvontitia. Sabrazes and Mon<,'()ur in two instances found tul)('rcle l)acilli
both in the i)hig and in tlie wall of a thrombosed iliac vein: tliey were
associated with micrococci. More frequently micrococci, presumably py-
ogenetio, have been found, without tubercle bacilli, in the thrombi and
vascular walls: examples of this are recorded by Vaquez. Notwithstanding
these suggestive bacteriological findings it would be quite premature to con-
clude that all the periplieral venous thromboses of phthisis are referable to
direct infection of the venous wall by bacteria. In a rather old thrombus of
the iliac and femoral veins in phthisis I failed to find any micro-organisms,
either by culture or by microscopical examination.

llirtz has called attention to the occurrence of phlebitis in the initial
stage of phthisis. Some cases so reported have appeared to be chlorotic in
origin.

Cachectic States. — Of other marasmic or cachectic states, in which throm-
bosis is somewhat frequent, may be especially mentioned those resulting
from cancer, dysenter\% chronic diarrhnni, gastric dilatation, prolonged sup-
purations especially of Iwne, arnvniia from loss of blood, and syphilis. The
association of tlirombosis with syphilis has been recently discussed by Barbe.
Phthisis has just been considered. It is especially in the young and the very
old that these conditions are most likely to produce tlirombosis. Thromboses
of the cerebral sinuses, and of the renal and other veins, in marasmic infants,
particularly after diarrhoea, are well recognised. Peripheral venous throm-
bosis is more often associated with the waxy kidney than with other forms
of Bright's disease. The thrombi occasionally found in the renal veins in
chronic diffuse nephritis are probably due to local causes, and not to cachexia.

There is a French thesis by Rigollet on thrombosis in malaria, and Pitres,
Bitot, and Eegnier have likewise called attention to the subject. It is
doubtful whether there is any relation between malaria and thrombosis. In
over 'iOOO cases of malaria observed in Professor Osier's service at the Johns
Hopkins Hospital no instance of thrombosis wii.s found. (Personal com-
munication by Dr. Thayer.)

TrousiJeau attached some diagnostic significance to the occurrence of
thrombosis in cancer. There have been instances of latent cancer of the
stomach in which peri]iheral venous thrombosis was the first symptom to
attract attention, as indeed it W!u« in Trousseau himself who died of gastric
cancer. Gouget has reported a case of widespread venous thrombosis, of
eight months' duration, which wiis the only affection obserbed during life.
At the autop.sy a small cancer of the stomach was found. Dr. Osier has told
me of a personal observation of verj' extensive multiple tlirombosis associated
with cancer of the stomach.

The principal seats of cachectic thromboses arc tlie auricular appendages,
between the columiue carnese of the right heart, in the veins of the lower

THROMBOSIS 157

extremities, the cerebral sinuses, the pelvic veins, and the renal veins. Lanee-
reaiix has strongly urged that this form of tlirombosis never occurs in the
arteries. Doubtless in not a few reported cases embolism has not been
satisfactorily excluded ; but older observations of Charcot and von Reck-
linghausen, and several recent ones, leave no doubt of the occurrence of
genuine so-called marantic or cachectic thrombi in arteries, even in the
aorta.

While pre-existing vascular disease, particularly angio-sclerosis and vari-
cose veins, are predisposing conditions, these plugs are often seated upon
intimae vi^liich show very slight alteration. Indeed competent observers have
repeatedly described the vessel wall beneath marantic tlirombi as normal.
While secondary septic infections often participate in the causation of
cachectic thromboses, the view that all have this origin is at present un-
substantiated. It is clear that enfeebled circulation is of importance in
their causation; but, for reasons already stated, tliere must be some addi-
tional element, which, in many cases at least, cannot well be other than
changes in the composition of the blood. The nature of these changes is
not known. Possibly increase of platelets, or a special vulnerability of cells,
perhaps of the red corpuscles from which platelets are derived, may be
concerned.

Cardiac Incompetency. — I have already had occasion in this article to
speak repeatedly of the importance of feebleness of the general circulation
in the causation of tlirombosis. Thrombi in the heart itself have been con-
sidered (p. 139). In this respect attention is called to the occurrence of
peripheral venous thrombosis in chronic passive congestion due to cardiac
incompetency, chiefly from valvular disease. Especially noteworthy, in view
of the slow venous circulation and the frequency of cardiac thrombi in this
condition, is the infrequeney of peripheral thrombosis. Hanot and Kahn,
in reporting an instance of thrombosis of the right subclavian vein, say that
they were able to find in the French literature, which is exceptionally rich
in clinical contributions to the subject of thrombosis and plilebitis, only five
additional observations of peripheral venous thrombosis in cardiac disease.
I do not think that tliis complication is quite so rare as would appear from
this statement; for, without any systematic effort to collect cases, I have
found records of eighteen additional ones — Ramirez (two cases), Baldwin,
NicoUe, Hirschlaff (two cases), Robert, Ormerod, Mader, Huchard (two
cases), Cohn (three cases), Cheadle and Lees (three cases reported by Poyn-
ton) ; and I have observed two instances of femoral and iliac thrombosis
associated with mitral regurgitation.

The most notable fact concerning these twenty-six cases is that seventeen
were thromboses of veins of the neck or upper extremity or both, far more

158 THROMBOSIS

frequently of the left than the right side; and one of the innomiiiiite veins.
In one of Cheadle and Lees' cases the innominate, subclavian, axillary, and
iiitenial and external jugular veins upon both sides, the left inferior thyroid,
and tlie upper two-thirds of the superior vena cava were thronilwsed ; and
in another of their cases both internal jugulars and both innoniinates were
completely plugged, and there was a mural thrombus in the upper pait of
the su[)erior vena cava. It may be that femoral thrombosis is more common
in heart disease than would appear from these figures; it is less likely to be
reported than thrombosis of the neck and arms, and, on account of the
oedema attributable to cardiac insufTiciency, may more readily be overlooked
both at the bedside and the autopsy talile. When, however, we consider that
Bouchut places the ratio of thromboses of the upper extremity to those of
the lower at 1 to 50, the relatively large number of the former associated
with cardiac disease is certainly most striking. The clinical histories seem
to show that thrombosis is more likely to occur in the cases with tricuspid
regurgitation than in others; but it is certainly even then a very rare event.
In several cases there was some complication, especially pressure on the
veins and tuberciilosis. The explanation of the greater frequency of the
thrombosis on the left than the right side has already been given (p. 1158).

The relative freedom from peripheral venous thrombosis in cardiac dis-
ease, in spite of conditions of the circulation apparently favourable to such
an occurrence, may perhaps be attributable partly to the reduction in plate-
lets in this condition (which has been noted by van Emden), and partly to
the absence of von Recklinghausen's " Wirbelbewegung " (p. 138), an irregu-
larity of the circulation which occurs especially in vessels too wide in pro-
portion to the amount of blood which they receive. Hanot and Kahn refer
the thrombosis to a cachectic state developing in the last stages of cardiac
disease. Hucbard likewise attributes it to cardiac cachexia associated with
secondary infection. Cheadle and Lt-cs' three cases are referred by Poynton,
who reports them, to rheumatic infection. The bacteriological examination
was negative.

As will appear later (p. 244), there is evidence that arterial plugging
associated with mitral stenosis is due oftener to primary thrombosis than is
generally supposed.

Ulilorosi-'i. — The association of tbronilK>sis with clilorosis is of peculiar
interest. Professor Allbutt, in his article on " Clilorosis " ( AUbutt's " Sys-
tem of ^Medicine." V, p. 508), has .<ketclied the more essential features, but
has referred some points for consideration here.. In the older literature tliere
are reports of plugging of the veins in young women which undoubtedly per
tain to chlorosis. Thus William Sankey, in 1814. says: "I have met with
two cases in young women, not after parturition ; both were severe and well

THROMBOSIS 159

marked; both had obstructed menses." But Trousseau, with his pupiL
Werner, in 1860 was the first to draw distinct attention to this association.
References to the more important records, up to 18H8, will be found in tlie
recent article by Schweitzer, from EichJiorst's clinic.

Although tlirombosis is not a common complication of chlorosis, it is
sufficiently frequent to indicate a special tendency to its occurrence in this
disease ; a tendency calculated to arrest attention on account of the age and
the class of the patients, tlie obscure causation, and the unexpected and
calamitous termination wliich it may bring to a disease ordinarily involving
no danger to life. Some idea of the frequency of chlorotic thrombosis is
perhaps afforded by the statements that von Noorden observed 5 instances
in 230 chlorotics, and Eichhorst 4 in 243. The list of reported cases was
brought by Proby in 1889 to 21, by Bourdillon in 1892 to 32, and by Schweit-
zer in 1898 to 51. I have found reports of 30 additional cases not included
in these lists, and am indebted to Dr. W. S. Thayer for an unpublished
personal observation; making a total of 82. (References will be found at
the end of this article.) I have also seen 13 other cases mentioned, but with-
out sufficient detail for statistical analysis; and I have come across several
references to articles on the subject not accessible to me. Slavic and Italian
literature has not been searched, and the American to only a small extent.
I have no doubt that mention or reports of over 100 cases of thronibosLs
chlorotica could be gathered by thorough overhauling of medical books and
periodicals. Thirty-one of my cases are from French literature, twenty-five
German, eighteen English, three Scandinavian, two American, and one
Italian. It would, however, be quite imwarrantable from this literary in-
equality to infer any difference in the incidence of the affection according to
race or country.

The statistical study of these eighty-two cases brings out a nmnber of
interesting points, of which some only are directly pertinent to this article.
Thrombi in the heart are very rarely mentioned in the post-mortem reports.
There were only four instances of primary arterial thrombosis, two being of
the middle cerebral arteries (Vergely) ; one of the pulmonary (Rendu)
without thrombosis elsewhere, and one of the right axillary (Tuckwell) with
gangrene of the hand and recovery. Dr. Tuckwell reports his case as one of
embolism ; but it is usually included among the arterial thromboses, and
probably with as much or as little right as the others.

All the remaining 78 cases were venous tliromboses. There was throm-
bosis of the cerebral sinuses in 32 cases (39 per cent), 6 (19 per cent) of
these being associated with thrombosis of the lower extremities. In four
instances thrombi extended from the sinuses into the internal jugular veins.
Unquestionably sinus-thrombosis is represented by too high percentage

160 THROMBOSIS

fi{rwrps in my list, for tlie obvious reason that reports of an affection of such
gravity and such interest, especially to neurologists, are much more likely
to get into print tliaji those of ordinary femoral tlirombosis. Still the figures
are impressive, and indicate that sinus-thnmiljosis is not of great raritv in
chlorosis; to which malady a leading place among the causes of spontaneous
thrombosis of the cerebral veins and sinuses in women must be conceded.

In 51 of the 82 cases there was venous thrombosis of the extremities
(62.2 per cent — too low a percentage as already explained) ; 50 being of the
lower and three of the upper, of which only one was limited to the upper
extremity. Of the 50 cases of thrombosis of the lower extremities (which
are probably involved in at least 80 per cent of all chlorotic thromboses),
the process was bilateral in 46 per cent, and unilateral in 54 per cent —
34 per cent being left-sided and 20 per cent right-sided. The usual prefer-
ence of femoral thrombosis for the left side is shown by the beginning of the
affection in the left leg in 64 per cent of the thromboses of the lower ex-
tremities, in the right leg in 29 per cent, and on both sides simultaneously
in 7 per cent. There is in the list one case (Kockel's) with meagre historj-,
in which no mention is made of thrombi outside of the upper part of tlie
inferior vena cava; death ensued from pulmonary embolism. This I have
not included among the thromboses of the extremities.

So large a proportion of thromboses involving both lower extremities
merits emphasis as a characteristic of chlorotic thrombo.sis. So again the
repeated observations- of multiple and successive tliromboses, relapses and
recurrent attacks (it may be after weeks or after years), all point to the
peculiar and widespread tendency of thrombosis in some cases of chlorosis.
The most remarkable example of this is Huels' case, in which various large
veins of the extremities, trunk and neck became tlirombosed in quick succes-
sion, until finally only the jugular and right subclavian veins remained free.
The patient recovered. In five cases examined after death the inferior vena
cava was plugged ; and in a few of tliose who recovered the symptoms indi-
cated extension of the thrombus from the iliacs into this vein.

While tlie prognosis of chlorotic sinus-tlirombosis is extremelv bad, Bris-
towe and Buzzard each report an instance of recovery. Such a possibility
has been questioned, but I sec no reason to doubt it. Not very infrequently
after death in one or more of the intracranial sinuses thrombi are found which
had occasioned no recognisable symptoms during life, and no lesions of tlie
brain.

A fatal issue of luicomplicated thrombosis of the extremities is due almost
always to pulmonary embolism, which occurs oftenest in the second to the
fourth week after the onset, and usually after some movement of tlie body.
In my collection of cases there are thirteen instances of pulmonan- embolism

THROMBOSIS 161

(25 per cent of the fifty-two cases with venous thrombosis outside of the
cerebral sinuses) . All but two tenninated fatiilly. In some other cases there
were symptoms suggestive of embolism ; and doubtless emboli lodged in
smaller pulmonary arteries witliout giving any indication of their presence.
After making due allowance for the undoubtedly disproportionate repre-
sentation of embolism of the large pulmonary arteries in published records,
this catastrophe remains sufficiently frequent to impart a certain gravity to
the prognosis even of simple femoral tlirombosis in chlorosis.

There are almost as many hj-jxitheses of chlorotic tlirombosis as of
chlorosis itself. None of these introduces any factors which have not been
considered already under etiology. The principal causes which have been
assigned, eitlier singly or in combination, may be grouped as follows: (i.)
feeble circulation due to weakness of the heart, sometimes intensified by
congenital hj'poplasia of tlie blood-vessels (Virchow) ; (ii.) alteration of
the vascular endothelium, especially fatty degeneration (Eichhorst, Renaut) ;
(iii.) primary phlebitis of unknown causation (Vaquez) ; (iv.) increase of
platelets (Hanot and JIathieu, Buttersack) ; (v.) some fault in the com-
position of the blood, variously defined as lowered specific gravity, deficiency
of salts ( ?) (Renaut), presence of extractives derived from muscular activity
(Proby), increase of fibrin-ferment (Birch-Hirschfeld) ; (vi.) secondary
infection (Villard, Rendu, Oettiuger, von Xoorden).

It is not necessary here to discuss all these views in detail. The data for
estimating their value have for tlie most part already been presented in this
article. Such primary lesions of the vascular wall as have been noted in the
thrombosed veins have usually been trivial, and are common enough without
thrombosis. There is at present no bacteriological basis for the infective
supposition. Villard's much-quoted observation is unconvincing; in his
case a small piece of a peripheral thrombosed vein was excised and examined
by Nepveu for micro-organisms with negative result. Villard adds that
Bossano found micro-organisms in the blood, but gives no details ; and there
is no evidence that these micro-organisms may not have come from the skin.
Perhaps more weight should be attached to a few observations in which some
source of infection, such as furuncle, was present. Proby, Lowenberg, von
Noorden, and other observers have examined the thrombi and blood of
cldorotics without finding any micro-organisms. Nevertheless von Noorden
and others are favorably disposed to the infective hypothesis, on clinical
grounds. Sometimes the onset of chlorotic thrombosis is ushered in by a
chill or chiUy sensations ; usually there is fever, which may be well marked ;
and in general the symptoms are thought by some to indicate infection. It
does not seem to me imperative to interpret these symptoms as necessarily
indicative of infection by micro-organisms.

UVi THROMBOSIS

Tlioro are dillk-ultios witli all ol" the liyixjthe.sus \vhu:h have been sug-ge&ted.
I think that there may be some significance for the etiology of chlorotic
thrombosis in the increase of platelets noted by Hatiot aiul Mathieu, and by
Hayem; and determined more accurately by ^luir.' I shall also venture to
suggest that there may be some nutritive disturbance of the red corpuscles,
in consequence of wliicli they disintegrate more readily from slight causes,
and produce the granular material, chiefly platelets, which constitutes the
beginning white thrombus; and in support of this opinion I will call atten-
tion to Maragliano and Castellino's observations of the lowered resistance of
chlorotic red corpuscles. Another element which may enter into the causa-
tion is some little understood irregularity of the circulation, other than re-
tarded flow, which is manifested in the venous thrills and hums; and which
may in certain situations, where thrombi most frequently form (sinuses,
femoral vein), lead to the eddies showai by von Recklinghausen to be of
importance in the causation of thrombosis; although I confess that the
fullness of the veins in chlorosis does not support this suggestion.

Gout. — Since the publication of the classical paper on gouty phlebitis by
Paget in 18GG, followed by those of Prescott Hewett iuid Tuckwell, tliis
affection lias been well recognised (see art. on " Gout," Allbutt's " System
of Medicine," IV, p. 161). Its causation is unknown. Paget with much
reason regards the ailment as a primary^ phlebitis with secondary thrombosis ;
and in this he has been followed by most writers on the subject. Although
deposition of urates has been found in the sheaths of veins, there is no evi-
dence that gouty phlebitis is caused in this way. Sir W. Roberts, on p. 172
of the article just quoted, ingeniously suggests that the presence of scattered
crystals of sodiiun biurate in the blood may constitute foci around which
thrombi may be formed.

Idiopathic Thrombosis. — Paget says that the occurrence of phlebitis in
elderly persons without any evident external cause warrants the suspicion of
gout ; and that this is perhaps the most common form of idiopathic phlebitis.
There remain, however, rare instances of apparently spontaneous thromlw-
jihlebitis, occurring in previously hcaltliy individuals, which cannot be CJC-
plained in tliis way. Daguillon ha.s observed and collected a number of
such cases.

" Buttersack has recently described the presence in the blood of chlorotics of
cylindrical masses of platelets identical with the first form of Litten's blood-
cylinders. These he considers to bo aipillary platelet-thrombi, which have been
washed out by the circulating blood. While they may occur in other conditions,
Buttersack associates them especially with chlorosis. It remains to be determined
whether this cast-like arrangement of platelets is not the result of the mode of
preparation of the specimen of blood.

THROMBOSIS 163

Primary Infective Thrombosis. — -There are rare instances of arterial and
venous thrombosis, generally widespread, whicli present the cliaracters oJ"
an acute infective disease without anatomical lesions other than the thrombo-
phlebitis, or tlirombo-arteritis, and the changes consecutive to the vascular
obstruction and to the vascular or general infection. The thrombosis may
be referable to a primary infective angeiitis, or to a general infection wall
changes in the blood and circulatory disturbances. The former class of
cases may be considered analogous to mycotic endocarditis, the localisation
being in the vascular intima instead of in the endocardium. In the latter
group, which probably is not strictly separable from the former, the veins
or the arteries are plugged with thrombi, which are often extensive and
multiple. The venous is more common than the arterial form. Vessels
both of the extremities and of the viscera may be invaded. The affection
appears as an acute infective fever with the special localisation of the
process in the blood-vessels.

As belonging to the group of primary infective thrombo-phlebitides I
should interpret a case reported by Dowse. A woman, 43 years old, pre-
viously in good health, was suddenly seized with chills, fever, and great
prostration, accompanied by the rapid onset of severe pain and oedematoui?
swelling of the right leg. Death occurred after two and a half weeks. At
the autopsy the iliac, femoral, popliteal, and deeper veins were found to be
filled with mixed, adherent, predominantly red thrombus. The tissues
around the thrombosed vessels were suffused with blood.

Osier has reported an instance of the arterial form of primarv' infective
thrombosis. A man, aged 20, who had recovered from typhoid fever two
years previously, presented fever, rapid pulse, diarrhcea, and abdominal pain,
followed by gangrene of both legs extended to the middle of the thighs. He
died about two weeks from the beginning of the illness. At the autopsy was
found thrombosis of the femoral and iliac arteries, of the lower two inches
of the abdominal aorta, and of two large branches of the splenic artery. The
spleen was enlarged, and contained large infarcts, one the size of an orange,
which had given rise to peritonitis. There were infarcts also in the right
kidney. Nmnerous micrococci were found in the splenic infarct, and in the
exudate covering it. The heart, the intestine, the brain, and the lungs
showed no lesions.

Effects axd Symptoms. — The lesions and the symptoms produced by
thrombi are referable to the obstruction of the circulation caused by the plug,
and to the local and constitutional effects of irritative or toxic substances
which may be present in the thrombus or vascular wall. It is obvious that
these effects must vary with the functional importance of the part supplied
by the obstructed vessel ; with tlie rapidity, extent, and completeness of the

ICJ THROMBOSIS

obstruction ; witli the location of the plug in heart, artery, capillary, or vein ;
with the size of the vessel ; with the readiness of establishnieut of a collateral
circulation ; with the nature of the thrombus, and with associated local and
general morbid conditions. Thus tlie obstruction of each important vessel
produces its own anatomical and clinical picture. The thromboses of certain
vessels, as the intracranial sinuses, the portal vein, the femoral vein, are well
characterised, distinct alfcctions, which receive separate consideration in
medical books. But I know of no modem work which presents in a syste-
matic and t.liorough way the anatomical and clinical characters of occlusion
(if each of the important vessels of the body; although scattered tlirough
medical literature is a large and to a considerable extent unutilised casuistic
material for such monograpliic treatment. In this article, treating of the
subject as a whole, the more general considerations concerning the effects of
tlirombosis, with special reference to certain common and clinically important
localisations wliicli do not receive separate treatment elsewhere in this work,
will be presented. Widely different are the effects according as the throm-
bosis is cardiac, arterial, capillary, or venous.

Of Cardiac Thrombosis. — If the presence of globular cardiac thrombi
could be determined during hfe, it would be generally recognized as an
index of grave impairment of the heart's action. But, apart from furnish-
ing emboli, ordinary globular thrombi are not known to occasion any symp-
toms. There may be instances when during life cardiac thrombi may be
suspected as more probable sources of emboh, particularly of those causing
pulmonary infarction, rather than either endocardial vegetations or venous
or arterial thrombi; but beyond conjecture the diagnosis can hardly go.
Gerhardt attributed to the pressure of thrombosed auricular appendages
upon the pulmonary artery or aorta murmurs heard over the arterial orifices
of the heart; but other causes of such murmurs are commoner and better
recognised. The encroachment of massive thrombi and of pedunculated
polyps upon the orifices of the heart may occasion murmurs, thrills, and
symptoms indistinguishable from those of valvular disease. In three such
cases, involving the mitral orifice, von Ziemssen observed gangrene of the
feet, which he was inclined to refer to arterial thrombosis rather than to
embolism ; but this symptom has not the diagnostic value which he assigns
to it, for in other cases it was present only exceptionally, and it may occur
in ordinary mitral stenosis. Unless the orifices are encroached upon, the
mere presence even of large thrombi usually occasions little or no distur-
bance of the heart, or none which can be distinguished from that of asso-
ciated valvular or mural disease. The clinical features of ball-thrombi
have already been considered (pp. 145 and 14(i).

Of Arterial Thrombosis. — The effects of arterial thrombosis are so much
like those of embolism that it will be convenient to defer the detailed con-

THROMBOSIS 165

sideration of their manifestations in common to the article on embolism
(p. 201), and here to speak only of the more distinctive features and clinical
types of arterial thrombosis.

Whether the occlusion of an artery be by a thrombus or an embolus, the
result, apart from possibly infective properties of the plug, depends upon
the possibility of establishment of an adequate collateral circulation. If
the anastomoses are such as to permit the ready development of a collateral
circulation, an arterial branch may be plugged without any mechanical
effects. In the case of certain visceral arteries, as the terminal cerebral,
branches of the splenic, and of the renal, a collateral circulation sufficient
to nourish tlie part supplied by the occluded artery cannot be established,
even with a slowly-fonning thrombus. In some situations, however, arteries
whose abrupt obstruction by an embolus may cause the gravest lesions and
sjTuptoms, may be closed gradually by thrombus without serious conse-
quences. This has been observed in thrombosis of various arteries of the
extremities, neck, and trunk; as the femoral, the iUac, the carotids, the
mesenteric, the coeliac axis, a main division of the pulmonary artery, and
even the aorta. But in order to secure whatsoever advanbige may accrue
from its slower formation, the thrombus must find other conditions favour-
able for the development of a collateral circulation ; and often enough these
conditions, of which the most important are integrity of the arterial walls
and vigour of the general circulation, are absent. Furthermore, thrombosis
is often rapid in attack, and hence, whether the plug be a thrombus or au
embolus, the result is frequently the same.

In the differential diagnosis between arterial thrombosis and embolism
emphasis is properly laid in the former upon the more gradual appearance
of the symptoms of vascular occlusion and pre-existing arterial disease,
and upon sudden onset and the detection of some source for an embolus, par-
ticularly cardiac disease, in the latter (see " Diagnosis of Embolism," p.
221). But mistakes in diagnosis are sometimes unavoidable; for all the
clinical phenomena which attend the one may occasionally be associated with
the other form of arterial obstruction. Nor can the distinction always be
made, with the desired precision, at the autopsy, although generally this
is decisive. Hence cases are reported as arterial thrombosis which are doubt-
less emboUsm, and conversely.

Within recent years primarj- arterial thrombosis, occurring independently
of chronic diseases of the arteries, has been recognised as a more frequent
and important affection than had been generally supposed since the accep-
tance of Yirchow's doctrine of embolism. Of especial medical interest are
the primary arterial thromboses, arising oftener as a sequel during convales-
cence than as an accompaniment of various infective diseases, particularly

166 THROMBOSIS

of enteric fever and influenza. The associations and localisation of these
thromboses, as well as the prevailing view that tliey are infective and refer-
able to an acute arteritis, have already been considered.

Arterial Tlirombofis of the Extremities. — When, as is usual arteries of
the lower e-xtremitics arc affected, the first symptom is pain in the limb.
This is often severe and paroxysmal, and is increased by pressure at certain
points in the course of the vessel. The obliterated artery may be felt as a
hard, sensitive, pulseless cord; and below it pulsation may be feeble or cease
altogether. Before obliteration the pulsations may be of wider amplitude
than normal, in consequence of lack of arterial tone (Gendrin, Barie). The
leg, especially about tlie foot and ankle, becomes pale, cold, mottled with
blush-red spots, lunub and paretic. Witli loss of tactile sensation there is
often increased sensitiveness to painful imiiressions. There may be diminu-
tion or loss of muscular reaction to both galvanic and faradic currents.
There may be increased moisture of the skin, and some cedematous swell-
ing of the affected leg. Unless adequate collateral circulation be speedily
developed the termination is gangrene. While the extent of the gangrene
is in relation to the seat of the obstruction, it varies also according to the
collateral circulation ; so that with occlusion of the femoral or iliacs it may
affect only the foot or even a toe; or with closure of the popliteal or tibial
arteries it may extend as high as the point of obstruction. The gangrene
is usually dry : but if septic inflammation or closure (u* the veins occurs it is
likely to be moist. Recovery may follow with loss of the gangrenous part;
or death may result from exhaustion, from extension of the mortification,
from septica-niia and toxa:'mia.

The rarer arterial thrombosis of the upper extremities may likewise lead
to gangrene; but here the chances for restoration of the circulation through
the collaterals arc much better.

I have already referred to the relations of thrombosis to senile, spon-
taneous, and other forms of gangrene (p. 135). Heidenhain and Xaunyn
hold tliat arterio-sdcrotic thrombosis is the usual cause of diabetic gangrene;
but further investigations into the causes of this form of gangrene are
needed. Thrombosis of the abdominal aorta presents a group of symptoms
which will be described under Embolism (p. 243).

The complex of symptoms called by Charcot " intermittent claudication "
may be observed with thrombosis of arteries of the lower extremities, or of
the iliacs or abdominal aorta ; but it is more common with arterio-sclerosis.
The term "intermittent claudication" (boiterie) is used by French vet-
erinarians to describe similar symptoms in horses affected with thrombosis of
the iliac arteries, which is not a rare disease in these animals. In these
cases tlie lower extremities receive enough blood for their needs during

THROMBOSIS 167

repose, but not during active exercise. The slighter manifestations consist
only in some muscular weakness and numbness of the legs after exercise;
but in more severe cases, after walking a quarter of an hour or perhaps less,
occur great muscular weakness, numbness, and pains and cramps in the
legs, which may become cold, exsanguinated, sometimes cyanosed in the
peripher}-, and almost pulseless. All of these symptoms disappear after
repose, perhaps of but a few minutes' duration. Charcot's syndrome has
in a number of reported cases been a precursor of arterio-sclerotic gangrene,
but it may exist for years without this event. The phenomena are uni-
lateral or bilateral, according to the seat of the arterial obstruction. Spasm
of the arteries is evidently an important element in the pathogeny of inter-
mittent claudication.

Other evidences of inadequate collateral circulation with arterial throm-
bosis of the extremities may be muscular atrophy and so-called trophic dis-
turbances, which are generally the result of traumatism or of some infection
in the member whose natural resistance is lowered by the imperfect blood-
supfily.

Thrombosis of the visceral arteries may produce lesions and symptoms
identical with those following embolism, such as sudden death from throm-
bosis of the pulmonary arter)% of the coronaries of the heart, or of the
basilar: isclijemic cerebral softening, and infarctions of the lungs, heart,
spleen, kidnev's, retina, and intestine, with their attendant symptoms.

Thrombosis of the Pulmonary Artery. — It is especially to be noted that
thrombosis of the pulmonarj' arterv', both in its principal divisions and in
smaller branches, is often entirely latent, botli as regards resulting lesions in
the lungs and the symptoms. Thrombosis of the main trunk or primary
branches may, however, produce sudden or rapid death; or a sub-acute or
chronic affection characterised by dyspnoea, cyanosis, haemoptoic infarctions
and incompetency of the heart, as in a ease reported by Blachez.

Dr. Xewton Pitt believes that thrombosis of the pulmonary arteries is
far more frequent than is generally supposed, even going so far as to say
" that thrombosis in the pulmonarj- artery, so far from being very rare,
possibly occurs more frequently than in any other vein or artery in the body."
This opinion is based partly upon failure to find a source for an embolus;
in the right heart or systemic veins, and jiartly upon absence of folding,
fracture, or other appearances of the plug suggestive of an embolus, as well
as upon association with general conditions known to dispose to thrombosis.
A similar remonstrance against the current interpretation of so many plugs
in the pulmonan,- arteries as embolic in origin was made by Bristowe in 1869.
In my experience sclerosis and fatty degeneration of the intima of the pul-
monary vessels is not particularly uncommon ; and I also believe that pri-

168 THROMBOSIS

niary thrombosis of the pulmonary arteries, particularly of medium-sized
and smaller branches, is more frequent than is usually represented in text-
books. Still, for reasons to be considered under Embolism (p. 231), the
evidence seems to me in favour of the usually accepted opinion that the
majority of plugs found in the pulmonary artery and its main diNisions in
cases of sudden death are emboli.

Throjn basis of the Coronary Arteries of the Heart.' Cardiac infarction. —
Although the general subject of infarction from arterial occlusion is reserved
for the article on embolism, infarction of the heart is caused so much more
frequently by thrombosis than by embolism that it is more appropriately
considered here.

Thrombosis of the coronarj' arteries is in the great majority of cases an
incident of angio-sclerosis of the heart, an affection of great clinical impor-
tance. It may also result from acute or chronic endaortitis near the orifices
of these arteries, and possibly from acute inflammation of the coronary
arteries. Thrombotic vegetations, springing from the aortic valves, have
been known to block the mouth of one of the coronary arteries.

There has been much discussion concerning the existence of anastomoses
of the coronar\- arteries. It has been demonstrated that anastomoses exist
between the main trunks of these arteries, the most important being those
between the auriculo-ventricular branch of the left coronary and branches
of the right coronan' in the sulcus on the posterior surface of the heart,
forming a horizontal or equatorial auriculo-ventricular circle (Haller), and
those between the anterior and the posterior interventricular branches near
the apex of the heart, forming a vertical or meridional circle. There are
also anastomoses on the surface of the left auricle between branches of the
left coronary and those of the left bronchial artery. There are, however,
no anastomoses between the branches of the coronan,- arteries after they
have penetrated the myocardium, these intramuscular branches being anato-
mically terminal arteries.

These anastomoses do not usually suffice for the nutrition of the heart
after rapid occlusion cither of the main trunks or of intramuscular branches.
Thrombosis of one of the coronary arteries may be the cause of sudden death.
Barth reports the case of a robust young man, aged thirty, who died sud-
denly when in apparently the best of health. At tlie autopsy it was found
that the mouth of the right coronary artery was blocked by a thrombus, the
size of a pea to a bean, attached to a small atheromatous patch of the aorta,
close to the opening of the right coronary. By a singular fat^ility this first

• I regret not to have noticed that this subject had been presented by Sir R.
Douglas Powell in AUbutt's Syst. Med., V, p. 899. The paging cannot now be
altered.

THROMBOSIS 169

and only atheromatous patfli to be found anywhere in the otherwise per-
fectly healthy body had formed at the particular point where the small
thrombus springing from it stopped one of the streams feeding the very
fountain of life.

Porter has shown experimentally that the frequency of arrest of the
heart after closure of the coronary arteries is in proportion to the size of
the arter}' occluded ; and that when arrest occurs it is preceded by a fall of
aortic pressure and an increase of the diastolic intraventricular pressure.
This increased intracardiac pressure checks the flow of blood in the coronary
veins, and thus interferes with the eoronars' circulation in the entire heart.

There are, however, many recorded cases which demonstrate that the
main trunk of one of the two coronary arteries may be plugged by a throm-
bus without causing sudden death. In an instance reported by Dr. Percy
Kidd the patient suffered from extremely irregular and weak action of the
heart, shortness of breath, and paroxysms of dyspnoea; and gradually sank
from cardiac failure. The right coronary arter}', about three-quarters of
an inch from its origin, was blocked throughout by a firm, partly decolour-
ised, adherent thrombus. The left coronar}-, particularly its descending
braneli, was greatly narrowed by sclerosis. There were no infarctions or
tibroid patches in the heart. Chiari has reported an instance of thrombotic
occlusion of the main stem of the right coronary giving rise to an embolus
which lodged in the main trunk of the left coronary artery. Sudden death
was caused by the latter. In areas supplied by the right coronary were
ischa?mic infarctions showing reactive inflammation. These, as well as
the symptoms and the appearance of the thrombus, indicated that the main
trunk of the right coronar}' artery had been closed for at least several days
before death.

If the patient lives long enough, the usual, but not absolutely imperative,
anatomical result of thrombosis either of the main trunks or of intramuscular
branches of the coronary arteries, is infarction in the area supplied by the
occluded artery. As the descending or anterior interventricular branch of
the left coronar}' is by far the most frequent seat of sclerosis and conse-
quent thrombosis, the infarct is most commonly situated in the lower part of
the interventricular septum and of the anterior wall of the left ventricle.
The size of the infarct corresponds in general to that of the occluded artery ;
but, as a rule, the infarct occupies only a part, sometimes but a small part,
of the area previously supplied by the obstructed vessel. Unlike infarcts
in most other situations, those of the heart are not, as a rule, typically
wedge-shaped, but are often irregular in outline, and sometimes appear as
if several smaller areas of infarction had coalesced; indeed there may be
multiple, detached infarcts resulting from occlusion of a single artery.
14

170 THROMBOSIS

Both pale, anseinic infarcts and haemorrhagic infarcts occur in the heart,
but tlie former are the more common. Freeh, anaemic infarcts are swollen,
firm, of an opaque yellowish-wliitc colour, and often present in the margin
a zone of hvpera'niia and ha-iiiorrhage. Mieroseopieally, they are the seat
of typical coagulative necrosis ; the muscle fibres being devoid of nuclei, indis-
tinctly striated or homogeneous, and of brittle consistence. The term myo-
malacia cordis, introduced by Ziegler, is not a good designation of the most
fresh infarcts of the heart. The infarct usually reaches the endocardium,
which then presents a mural thrombus ; and it may extend to the pericardium
and cause a localised fibrinous pericarditis. A reactive intlammation leading
to the ingrowth of granulation tissue appears in the margin of the infarct,
which, in course of time, is absorbed and replaced by scar tissue, unless it
become infected and suppurate.

Cardiac infarction may be the cause of rupture of the heart, or of a parietal
aneurysm ; or may result simply in a fibroid patch. It is more common than
would appear from tiie meagre attention usually given to the subject in
te.xt-books, and is of much anatomical and clinical interest.

The symptoms a.ssociated with coronary thrombosis are those of the
angiosclerotic heart, so that it is hardly possible to make a positive diagnosis
of thrombotic occlusion of the coronary arteries. Irregular, often slow pulse,
sliortness of breath, precordial distress, angina pectoris, sudden death, all
these may occur from sclerosis of the coronary arteries, either with or with-
out thrombosis. Fibroid myocarditis is often present and directly referable
to arterial obstruction ; but the changes in the myocardium are probably of
nuuli less clinical importance than the underlying disease of the coronary
arteries. R. Marie has recently publislied a valuable monograph on infarc-
tion of the myocardium and its consequences, with a full consideration of
the previous literature and the addition of many new observations.

Thrombo.s-is of the mesentery arteries will be considered with embolism
of these arteries (p. 237).

Thrombosis of the cerebral vessels will be described in the part of this
work treating of diseases of the brain in the next volume of Allbutt's Syst.
Med.

Here may be mentioned the interesting observations of recent years con-
cerning the dependence of certain diseases of the spinal cord upon affections
of the blood-vessels of the cord, arterial thrombosis being an especially
important factor in many of these cases.

Capillan/ Thrornbosi.i. — In consequence of the abundant anastomoses,
it is only when all or nearly all of the capillaries of a part are thrombosed
that any mechanical effects result. Such extensive capillary thrombosis is
more frequently the result than tlie cause of necrosis of a part. According

THROMBOSIS 171

to von Recklinghausen, superficial, often extensive, necrosis of surfaces, as
of the skin iuid mucous membranes, may be caused l)y widespread hyaline
thrombosis of capillaries resulting from the energetic action of thermic,
chemical, and even mechanical agents. In frostbites and burns there may
be extensive local hyaline thrombosis of capillaries and small vessels. I
have already referred to my observations of anuria in swine, caused by exten-
sive hyaline thrombosis of the renal capillaries (p. 116). Although in
many cases I have seen similar hyaline thromboses in hiunan kidneys, tliey
were never so extensive as to seem likely to cause recognisable symptoms.
Several years ago I drew attention to tJie presence of hyaline thromboses
in capillaries and arterioles in the walls of some fresh gastric ulcers, and
since then I have been able to repeat tlie observation in three or four
instances.

Effects of Venous Thrombosis. — Thrombosis is so pre-eminently an affec-
tion of veins that chapters in text-books treating of the general subject usually
pay scant attention to it« occurrence in other part^ of the circulatory system.
In the veins thrombosis occupies the field of intravascular plugging almost
alone, for it is only in the portal system, and in the rare instances of
retrograde transport, that embolism enters into consideration; such extra-
ordinary occurrences as embolism of the azygos vein, resulting from throm-
bosis of the inferior vena cava, reported by Loschner, being mere pathological
curiosities.

The direct effects of venous thrombosis, as of arterial, are referable to the
mechanical obstacle to the circulation and to the properties of the throm-
bus. The mechanical effects result from inadequacy of the collateral circu-
lation. The free venous anastomoses in many parts of the body prevent
any disturbance of the circulation as a result of venous occlusion by simple
or benign thrombi. Such innocuous thromboses are particularly common
in the pelvic veins. In some situations veins, whose rapid occlusion may
cause serious lesions and symptoms, may be slowly plugged by a thrombus
without manifest harm. For example, it is not uncommon to find at autopsy
the main trunks of the renal veins completely thrombosed, without conse-
quent alteration of the kidney or corresponding symptoms during life;
although we know tliat ligation of these veins causes haemorrhagie infarction
of the kidney with albuminous, bloody urine.

Frequently, however, the contrast between the effects of ligation and those
of thrombosis of veins is in the other direction ; the thrombosis being followed
by venous congestion, and the ligation of the same veins being without evi-
dent disturbance of the circulation. The latter difference is not always
easy to explain ; but the factors to which we can often appeal with more or
less success, in attempting to account for the absence of sufficient collateral

lr■^ THROMBOSIS

circulation with venous thrombosis, are the extent of the occlusion, general
debility, feebleness of the cireulation in consequenne of coexistent anscmia,
infection, ciichexia or constitutional disorder, generally high venous pressure
and low arterial pressure, lack of muscular movement and perhaps of other
subsidiary forces aiding venous circulation, phlobosclerosis, inflammation or
some less evident affection of blood-vessels called upon for extra work, and
irritative or toxic properties of the thrombus. The importance of these, and
perhaps other accessory conditions, in explaining the passive congestion of
many venous thromboses in human beings is made evident, not only by the
inability to produce similar effects exi)erimentally by correspondingly slight
or moderate degrees of venous obstruction, but also by the varying efTects
of thrombotic processes with the same localisation and extent in different
persons and under difTcrcnt conditions. Thus femoral thrombosis may be
attended by absolutely no oedema or passive congestion, or may occasion
extreme degree of oedema and venous congestion.

The consequence of the passive hypenrmia caused by venous thrombosis
is local dropsy. This constitutes the characteristic symptom of uncompen-
sated venous obstruction by a thrombus a.s local necrosis does that of uncom-
pensated arterial thrombosis. In addition to the redema, there may be
diapedesis of red corpuscles, but this occurs to a perceptible degree only when
the obstruction to the venous flow is extreme, or the capillaries unusually
permeable. Such hiemorrhages are very rare in peripheral venous throm-
bosis, but are common with thrombosis of the portal and mesenteric veins,
the cerebral veins and sinuses, the splenic, the retinal, and some other vis-
ceral veins. Actual necrosis may likewise result from thrombosis of the
mesenteric, cerebral, and splenic veins; but, if it occurs at all with throm-
bosis of veins of the extremities, it is extraordinarily rare, and probably due
to complications.

In addition to these efTects, due directly to the blocking of the venous
circulation, even so-called IxMiign or simple thromboses often set up an
acute inflammation in the venous wall and .surrounding part; or, as already
explained, this inflammation may antedate the thrombosis. These chemical,
as distinguished from mechanical, effects consist chiefly in arterial hy{)er-
ccmia, iuflanmiatory wdema, pain, implication of nerves, and tx)nstitutional
symtoms, such as chills, fever, and quickened pulse. The occurrence of these
irritJitive or toxic efl'ect.s, even with the so-called marantic thromboses, is an
argument (in addition to those already considered) in favour of the infec-
tive nature of many of these plugs, and of their primarily phlebitic origin.
But while undoubtedly significant of such an intcri)rot,ition, it can hardly
be considered conclusive; for it is possible that cerfjiiii thrombi may possess
irritative properties not attributable to the presence of micro-organisms or

THROMBOSIS 173

their products, and that the phlebitis, as well as the periphlebitis, may
be secondary. However this may be, the old distinction between benign
and infective thrombi no longer appears so sharply marked as was once
supposed.

In rare instances the venous medical thromboses associated with anaemic,
infective, cachectic, and constitutional diseases are plainly septic, and give
rise to phlegmons, and perhaps pyaemia or septicemia. The suppurative
or septic thrombophlebitis, which with its attendant pyemia was in prs-anti-
septic days such a common and formidable wound complication, belongs to
the surgeon's domain, or, in puerperal sepsis, to the obstetrician's. (See
arts. " Pyaemia " and " Puerperal Septic Disease " in Allbutt's " System
of Medicine," I.) To the borderland of medicine and surgery belong cer-
tain septic thrombophlebitides of visceral veins, of which the most important
medical group, those of the portal system, has been considered by Professor
Chejme (Allbutfs "System of Medicine," I), and by Dr. Davidson in his
article on " Suppurative Hepatitis " (Allbutt's " System of Medicine," V,
p. 123 ) . Thrombosis of the umbilical vessels, which may occur either before
or after birtli, may be either simple or septic. The latter is an important
affection, the consideration of which belongs to treatises on diseases of
infants.

There is perhaps no pathological phenomenon which, on the face of it,
appears simpler of explanation tlian the local redema consequent upon venous
obstruction, but which, the more it is investigated, turns out to be, or at
least is made to appear to be, more complicated. The explanation which
naturally occurs to one, and which is often given, is that the oedema is due
simply to increased filtration of serum from the blood, in consequence of
the rise of intravenous and intracapillary pressure resulting from the obstruc-
tion to the venous circulation. It is certain that this simple explanation
does not suffice, at any rate for most venous thromboses, and tliat factors
other than the mere rise of blood-pressure in the veins and capillaries are
concerned; but as to the nature of these other factors there is great differ-
ence of opinion. The whole problem is wrapped up with that of the hypo-
theses of lymph-formation and lymph-absorption, so lively at the present day,
into the discussion of which it is impossible here to enter. Corresponding
to the two classes of these hypotheses, we have mechanical hypotheses and
vital or secretory hypotheses of the oedema of passive congestion. The
mechanical explanations are at least easier of comprehension. Cohnheim
attributed this form of oedema to increased venous and capillary pressure.
combined with increased permeability of the capillary wall due to malnu-

irt THROMBOSIS

trition." Starling and Cohnstein, with full knowledge of the later work,
to which they have made important contributions, are advocates of a similar
explanation.

Doubtless several factors, although not all necessarily operative in the
same case, are concerned in the causation of the oedema of venous thronilwsis.
Those which seem to me most apparent are the following: (i.) increased
intro-venous and intra-capillarv' pressure, with consequent increased transu-
dation of serum (not alone sutticient, for tying the femoral vein or inferior
vena cava generally causes no oedema) ; (ii.) increased permeability of the
capillar)' walls, which may be due to various causes, such as stretching from
larger content of blood, starvation and asphyxia of capillary endothelium
from lack of fresh supply of nutriment and oxygen, and injur}' from abnor-
mal composition of l)lood in anaMiiic, infective, cachectic, and constitutional
disease, or from inflammatory irritants; (iii.) diminished absorption of
lymph in consequence of lack of muscular movement, of imbibition of the
capillary walls with fluid, and especially of retarded capillar)' and venous
flow; (iv.) arterial dilatation from irritative or inflammatory influences
emanating from adjacent thrombosed veins, probably also from the asphyxi-
ated tissues, and acting either directly upon the arterial wall, or directly
upon vaso-motor nerves, or reflexly (here the conditions resemble those in
Banvier's well-known experiment of tying the inferior vena cava or femoral
vein, and producing vaso-motor paralysis by section of the sciatic nerve) ;
(v.) sometimes a waterj' condition of the blood rendering it easier of filtra-
tion. Experiments of Dr. Lazarus-Barlow indicate that changes in the
chemical composition of the tissues and tissue-fluids are also a factor in the
production of the oedema." The influence of hydrostatic pressure is evident
from the greater frequency of ccdema with thrombosis of the lower than of
the upper extremities, and from the effect of position ujwn the amount of
the (inlema. While these various factors can be conceived as essentially physi-
cal and chemical in their action, the living capillary wall upon which they
act, either directly or indirectly, is to he thought of as something different
from a dead animal or artificial membrane.

"■ Cohnheim is sometimes quoted as considering increased pressure a sufficient
explanation of mechanical oedema, althouph in his Allgemeine Pathologie, Bd. I,
p. 494, he expressly recognises as an additional factor " unknown influences on
the part of the living vessel-wall." As I had the opportunity, when working in
his laboratory on a problem concerning a?dema, to become familiar with his views
on this subject, I may be permitted to suy that he often spoke of increased per-
meability of the capillary wall as an essential factor in the explanation of the
(edema of passive congestion.

" To these changes, as the cause of alterations in osmotic pressure. Loeb
(PHiiger's Archiv, 1898, LXXI, p. 457) assigns the chief importance in the pro-
duction of oedema.

THROMBOSIS 1T5

Opposed to these mechanical explanations are the secretory hypotheses
of a'dema, of which Hamburger and Lazarus-Barlo'.v are leading exponents.
Of especial importance is the work of Lazanis-Barlow upon the oedema of
passive congestion. He finds all the physical explanations inadequate; and,
upon the basis of interesting experiments, he concludes that a principal
factor is increased secretion of lymph by the capillaries incited by starvation
of the tissues and accumulation of wa.ste metiibolic products. His " Manual
of General Pathology " may be consulted for a full presentation of his views
and a criticism of the mechanical hypotheses of ajdema.

The cedema of phlegmasia alba doleus is by no means all due to venous
congestion. Much, sometimes most of it, is an inflanmiatory oedema spread-
ing from the thrombosed veins. This is evident partly from the hard,
brawny, painful, at times warm character of the swelling (oedema calidum) ;
and partly from its location in the part of the extremity nearest the affected
veins. The cedematous swelling may begin above and extend downwards,
instead of in tlie usual direction from below upwards. The hydrarthrosis
often associated in moderate degree with phlegmasia is probably also refer-
able to an inflammatory serous exudate rather than to passive transudation
from venous obstruction. It occurs especially in the knee-joint.

Thrombosis of Veins of the Extremities. — Clinically the most familiar
form of venous thrombosis is that of the extremities ; the lower much
oftener than the upper. Its various sites and clinical associations have
already been considered (pp. 136 and 149). The affection may be entirely
latent; or may be recognised by a slight or moderate unilateral cedema with-
out general or other local sjTnptoms ; or may be in the form of well-marked
phlegmasia alba dolens; or rarely may assume a severely infective character,
with chills and high fever; or, exceptionally, may lead to phlegmon and
pyaemia or septicaemia. There is every transition between the extremes. The
latent and milder t^^pes occur especially with tul:)erculosis, cancer, and other
cachexia? ; the more severe manifestations with phlebitis of the puerperium,
infective diseases, and chlorosis ; but there are many exceptions to this rale.

In the more acute and well-characterised cases the general symptoms are
chieflv manifest at the onset; and consist in moderate elevation of tempera-
ture, rarely preceded by a distinct chill, oftener by chilly sensations and
quickened pulse. Increased frequency of the pulse may antedate the rise in
temperature, and the pulse may remain rapid ai'ter the temperature falls.
This disproportion between pulse and temperature is of diagnostic value
(Mahler, Wyder, Singer)," but it is not always present. These general

"Singer (Arch. f. Gynak , 1S98, LVI, p. 218) has made a careful study of the
pulse-curve in puerperal thrombosis. A step-like acceleration of the pulse-curve
often precedes other manifestations of thrombosis by several days.

1/6 THROMBOSIS

symptoms of the initial stage, which may persist for days, are often over-
looked ; or they are masked by an existing febrile disorder. They are
probably present in some degree, even in mild cases, oftener than the clinical
records show.

The characteristic symptoms are the local ones in the affected leg. Pain,
often paroxysmal, is usually the first to attract attention; but sometimes
it is the oedema. The pain may be severe. It is more or less generalised,
with especial tenderness in the groin, the inside of the thigh, the popliteal
space, and the calf. Oft^-n it is fir.^t noted and may remain localised in the
calf ; as is true of the (I'dcnia also. There may be sensations of numbness or
of " pins and needles." The cardinal symptom, oedema, sometimes descend-
ing sometimes ascending, gives rise to the firm, painful swelling of the limb,
covered witli tense, shiny, smooth, white or mottled skin, marked often by
dilated veins, whence comes the name milk-leg or white leg. The oedema in
typical phlegmasia alba dolens is hard and elasitc, pitting but little on pres-
sure. Occasionally the skin has a more livid, cyanotic hue, or it may be of a
brighter red. In the more acute cases the surface temperature is elevated ;
in others it is often lowered. Muscular movetnents are naturally restrained,
and it is said there may be actual paresis. The thrombosed vein, if accessible
to palpation, can often he felt as a hard, tender cord ; but it is best not to
attempt to gain this information, which in most cases is of little practical
importance. The sensation obtained from palpating the vein may be mis-
leading in consequence of the periphlebitis, or of the soft character of the
thrombus. Certainly, in view of the manifest danger of detaching an em-
bolus, only the gentlest manipulations are permissible. If the thrombosed
vein he superficial, it may sometimes be seen as a line of livid redness beneath
the skin. It is not always tender on palpation.

The great and usually the only danger from peripheral thrombosis is fatal
pulmonary embolism. It occurs oftenest between the second and fourth
weeks, but may occur earlier or later. The danger may be considered to be
past at the end of six weeks, if the local symptoms have subsided; although
there are exceptional instances of pulmonary embolism at a later period.
It is to Ije not«d that pulmonary embolism may result from latent and mild
forms of venous thrombosis as well as from those of the well-marked ex-
amples; it is, however, rare with the cachectic thromboses of tuberculosis
and cancer. Small pulmonary emboli usually caiise no lesions or s^-mptoms,
yet tliey may give rise to luemorrhagic infarction, or embolic pneumonia.

Nervous phenomena are sometimes so prominent as to have led to the
recognition of a neuralgic type of phlebitis (Graves, Trousseau, Quenu").
There may be even a mild peripheral neuritis associated with the venous
thrombosis. This is probably caused by the direct action of inflammatory

THROMBOSIS 177

irritants spreading from the inflamed veins ; but it has also been attributed
to thrombosis of small veins in the ners'e-trunks, to the bathing of the nerves
in the csdematous fluid, and to reflex irritation. Occasional sequels of
femoral thrombosis, for tlie most part very rare, are varicose veins, leg ulcers,
persistent chronic oedema, elephantiasis, muscular hypertrophy, muscular
atrophy, and club-foot.

There has been much discussion on the possibility of gangrene being
caused by thrombosis of the femoral or iliac veins. Cases have been reported
in which no other cause of the gangrene was found than venous thrombosis ;
but with peripheral venous thrombosis this is such an exceptional occurrence
that it seems clear tliat, when gangrene results, complicating factors — such
as arterial disease, pressure upon arteries, arterial spasm, great feebleness of
the circulation or septic inflammation — must be associated with venous
thrombosis. It is true that surgeons are familiar with gangrene after ligation
of tlie femoral vein, but here also the result is exceptional and attributable
to some complication. Bramie, upon anatomical grounds, attempted to
demonstrate that gangrene is to be expected after closure of the femoral vein
near Poupart's ligament, but the clinical evidence does not support tliis view.
Galliard has reported a case and has collected from the records others in
wliich gangrene had followed venous without arterial thrombosis.

The thromboses of the upper extremities are usually of shorter duration
and milder type than those of the lower ; unless referable to some persistent
cause, such as the pressure of a tumour. They are often accompanied by
some cervical oedema.

Thrombosis of the Inferior Vena Cava. — Since the days of Richard Lower
occlusion of the inferior vena cava has been tlie subject of much experi-
mental and clinical study. Tliere are reports of at least 140 cases of this
affection in human beings. The principal records are cited in the mono-
graphs of Vimont and Thomas, although the bibliography is by no means
complete. Thrombosis of this vein is rarely autochthonous. Usually it is
continued from the femoral or pelvic veins through the iliacs, or is due to
some abdominal disease, as the pressure of a tumour. It may occur without
any symptoms or without sjTuptoms suggestive of the diagnosis. The char-
acteristic symptoms are oedema of both lower extremities and of the abdom-
inal walls, and the development of a tj-pical collateral circulation. When
the renal veins are likewise occluded there may be albuminous, bloody urine ;
but with thrombosis of these veins this sjrmptom is oftener lacking than
present. The diagnosis rests especially upon the appearance of dilated
anastomosing veins coursing upwards from the groins and flanks over the
abdominal walls and lower part of the thorax. These tortuous, varicose veins,
sometimes as big as the little finger, make a very striking and characteristic

ns THROMBOSIS

picture. The superficial veins concerned in carrying on the collateral circu-
lation are the inferior and superior superficial epigastric, the long thoracic,
the superficial circumflex iliac, the external pudic, tiie lunilx)- vertebral
anastomotic trunk of Braune and numerous unnamed anastomotic veins.
The dirt>ction of the circulation is of course from below upward. In addition
there is a deep collateral circulation througli various visceral veins with
dilatation of the azygos veins. Sometimes the circulation is almost wholly
through the deep collaterals, and there may be little or no dilatation of the
visible superficial veins. In fact, in not a few cases, l>y the absence of
visible dilated collaterals, the diagnosis is rendered difficult or impossible.
Schlesinger has observed and collected a number of cases where the oedema
was in one leg only. This may be due to the previous establishment of a
collateral circulation on one side from a former iliac thrombosis, or to
unilateral iliac thrombosis with parietal thrombosis of the vena cava, or to
congenital duplication of the vena cava.

Thrombosis of the Renal Veins. — This affection is fairly common. It
may be an extension of a thrombotic process in the vena cava, or on the
other hand tlie latter may be secondary to renal thrombosis. Marantic
thrombosis of the renal veins is not unusual in infants with cerebral symi>-
toms, or exhausted by diarrhea. In adults thrombosis of the renal veins is
observed not very infrequently in chronic Bright's disease, particularly the
waxy kidney; and in malignant tumour of the kidney. The renal veins nink
among those predisposed to marantic thrombosis. I once made an autopsy
on a case of primary genito-urinary tuberculosis in which a caseous ma-ss
had broken into a renal vein which contained an adherent grayish-red
thrombus extending into the vena cava. Tubercle bacilli were present in
the caseous mass and the thrombus. There Wiis acute miliiiry tuberculosis.
The lesions and symptoms which one would expect to find with thromi)Osis
of the main trunk of the renal vein are oftener absent than present. The
various collateral veins, communicating through the capsule and along the
ureters with the lumbar, diaphragmatic, adrenal, spermatic, and other veins,
suffice for adequate return flow. Still a number of cases have l)een observed
with more or less ha-maturia and albuminuria which have been referred to
thrombosis of one or both renal veins, and genuine ha^morrhagic infarction
may occur.

Thrombosis of the Mesenteric T>i7i.s. — Thrombosis of veins in the intes-
tinal wall is often associated with ulcers and other morbid conditions in
the intestine. The thrombus may extend into the small mesenteric veins,
or the latter may be attacked independently. These small thrombi are
important chiefly as a source of infective emboli transported to the liver.

Thrombosis of the large mesenteric veins is less frequent thiui embolism
or thrombosis of the mesenteric arteries. I have reported an instance of

THROMBOSIS 179

this affection, and have found reports of 31 additional cases with pronounced
symptoms, and of a few cases without symptoms referable to the thrombus
and without intestinal lesion. The references will be found at the end of
this article. The superior mesenteric vein was thrombosed much oftener
tlian the inferior. In many cases with symptoms, the thrombosis was ascend-
ing and secondary to inflammation, ulceration or some other disease of tiie
intestine; in some instances it was descending from thrombosis of the portal
or splenic vein ; in a few it was secondary to enteric fever or some marasmic
or cachectic state; in one it was attributed to a calcific plate adjacent to the
vein, and in one it followed splenectomy. The symptoms are the same as
with occlusion of the mesenteric arteries (see art. " Embolism," p. 237), but
as a rule are even more violent in character and rapid in course. They are
as follows: sudden onset of very intense, colicky, not definitely localised
abdominal pain; distended, tender, tympanitic abdomen; vomiting, which
may be bloody ; obstipation or bloody diarrhcca ; and rapid collapse with cold
sweat and subnormal temperature. The diagnosis is likely to be acute ileus,
and laparatomy to be performed. Death generally occurs within two or
three days. Tlie symptoms may, however, be less violent, and tlie course less
rapid than those mentioned. At the autopsy are found hemorrhagic infarc-
tion and gangrene of the int&stine, haemorrhages in the mesentery, bloody
fluid in the peritoneal cavity, and sometimes, although not regularly, peri-
tonitis. The cases without symptoms have been usually tliromboses of slower
formation, but this does not appear to have been always the case.

In a case reported by Dr. Eolleston, the superior mesenteric vein was
filled with softened, canalised clot; and in addition the inferior mesenteric
vein, the internal and external iliac veins on both sides, and the splenic vein
were completely thromlwsed, and a partly occluding thrombus extended into
the portal vein. The thrombus in the superior mesenteric vein was regarded
as the oldest. There was old and recent inflammation of the intestine, but
no intestinal infarction.

Of interest is the relation of thrombosis of the mesenteric veins to portal
thrombosis. In several instances of the latter thrombosis of the mesenteric
veins occurred without hEeniorrhagic infarction of the intestine. Doubtless
the explanation is that a sufficient collateral circulation had been established
after the portal thrombosis to prevent the usual effects of a subsequent
mesenteric thrombosis. That this, however, is not always the case is shown
by the sudden or more gradual termination of some instances of portal
thrombosis with ha-morrhagic infarction of the intestine, in consequence of
the extension of the thrombus into mesenteric veins. This has occurred
especially in the more acute cases of portal thrombosis, but it may occur also
in tliose of several months' duration. Acute portal thrombosis may cause

180 THROMBOSIS

liacmorrliapc Lnfarctiou of tlie intestine without mesenteric tlirombosis; or
the infarction may be over a larger extent of intestine than corresponds to
the thronibosod mesenteric veins. On tlie other hand, tlie infarcted area may
be much smaller than that supplied by the thrombosed vein. The symptome
may be of slower development and of milder type when thrombosis of the
mesenteric veins is secondary to portal thrombosis than when it is primary.
The sequence of events in Fitz's case is interesting — globular thrombi in
the left ventricle, embolism and infarction of the spleen, secondary throm-
bosis of tlie splenic vein, extension of the thrombus into the superior mesen-
teric vein, ha^morrhagic infarction of the intestine terminating fatally.
There was no obstruction in the mesenteric arteries.

PyJcthrovihoitis. — The septic variety of thrombosis of the portal vein
(suppurative pylephlebitis) having been described (Allbutt's " System of
Medicine," I, p. 610, and V, p. 127), it remains to speak here of simple
portal thrombosis, oft«n called witlioiit much propriety adhesive pylepjde-
bitis. This is a well-characterised, although usually not readily-diagnosed
affection. It is caused most frequently by compression either of the intra-
hepatic branches of the portal vein in cirrhosis, syphilis, or tumours of the
liver; or of the main branches or trunk by fibrous periliepatitis, chronic peri-
tonitis, swollen lymph-glands, impacted gall-stones or tumours. Other
causes are diseases of the walls of the portal vein, either priman,' or propa-
gated from some neighbouring focus; extension of a thrombus from tlie
splenic or mesenteric veins; pancreatic disease; gastric cancer; ulcer, or
other gastric or intestinal disease ; infective and toxic diseases ; puerperal
eclampsia (Sclimorl) ; marasmus, and traumatism. Sclerosis and calcific-a-
tion of the wall of the portal vein deserve more attention as causes of portal
tlirombosis than they have usually received. To the 12 cases collected by
Spiegelberg and Borrman in which this was the cause, is to be added A. A.
Smith's case, in which I made the autopsy. There was extensive calcifica-
tion and thrombosis of both splenic and portal veins in a man about 60 years
old, who died of gastric haemorrhage. He had previously vomited blood on
several occasions. There was rapidly increasing ascites. Calcification of tlie
media of the portal vein may occur without marked affection of the intima.
Marantic portal thrombosis is very rare. and. according to Schiippel, occurs
chiefly as a tcnninal event without characteristic symptoms. Nonne, how-
ever, in reporting a case of marantic thrombosis from Erb's clinic, interprets
several previously reported instances with marked svTnptoms as belonging
to this variety. The thrombus may become organised and tlie vein converted
into a fibrous cord, as in a case reported by Osier.

The symptoms are those of portal obstruction — ascites, h.Tinatemesis and
enterorrhagia, splenic enlargement, dilatation of superficial abdominal veins.

THROMBOSIS 181

and progressive marasmus. The caprices of venous thrombosis are evident
here as elsewhere. Characteristic symptoms may be entirely lacking, or one
or more of the important symptoms may be absent. Ascites has been absent
or slight, especially in cases with abundant haemorrhages from the stomach
and bowels. In general, however, tlie rapid onset, the intensity of the evi-
dences of portal obstruction, and especially the quick return of ascites after
tapping are characteristic of obliterating portal thrombosis ; and by observa-
tion of these points a correct diagnosis has repeatedly been made. These
acute symptoms are of most diagnostic value when they appear in persons
previously in apparent health, as has been observed with phlebosclerotic
thrombosis; or in the course of some disease not itself a cause of obstruction
to the portal circulation. When, as in cirrhosis of the liver, the symptoms
ujifold themselves gradually, the diagnosis, is manifestly impossible, or at
best no more than mere conjecture.

I have added traumatism as a possible cause of portal thrombosis on the
basis of a diagnosis made by Dr. Delafield, while I was resident physician in
his service at Bellevue Hospital. A lad, who had received a severe blow on
the abdomen, was admitted with extreme ascites which had come on within
two weeks after the injury. He was repeatedly tapped, the clear fluid re-
accumiilating at first with great rapidity after each tapping, afterward
more slowly, until in the course of months there was complete recovery. In
the meantime enlarged veins made their appearance over the upper part of
the abdomen.

Jaundice is not a symptom of portal thrombosis, although repeatedly
observed as a complication. The channels for establishment of a collateral
circulation are the same as in cirrhosis of the liver, with the exclusion of
those which communicate with the portal vein itself, at or beyond the site of
occlusion.

Under certain exceptionally favourable conditions recovery may take place;
a satisfactory collateral circulation being established, with perhaps opening
of channels through the organised thrombus. The usually fatal termination
may be from haemorrhage or exhaustion, sometimes within a few weeks or
even days from the onset. I know of no instance, in man, of death within
a few hours after occlusion of the portal vein, such as occurs regularly,
with great fall of arterial blood-pressure, after ligating this vessel in rabbits
and dogs. As already mentioned, hsemorrhagic intestinal infarction may
be caused by portal thrombosis (pp. 179 and 180).

There has been much discussion on the occurrence of changes in the
liver which can be attributed directly to stoppage of the portal circulation.
In the majority of cases of portal thrombosis the liver has been the seat of
atrophic cirrhosis, but most modern authors have regarded the thrombosis

182 THROMBOSIS

as secondary to the cirrhosis. Dr. Samuel West, however, in 1878, took
strong ground in favour of the reverse being sometimes the case; and he
found support in the cxperinierital result^ of SoIowiefT. The later experi-
ments of Cohnlieim and Littcu have been widel}' accepted as indicating that
obstruction of the portal vein is without effect upon the hepatic structure
and functions. Bennant has recently gone over the entire experimental
and anatoniico-clinical evidence, and has reached the conclusion that stop-
page of the portal vein may lead to atrophic cirrliosis. The case which he
reports speaks strongly in favour of this view ; for only the right branch
of the portal vein was thrombosed, and the cirrhosis was limited to the
corresponding lobe of the liver. Nevertheless, eases of portal thrombosis,
some not of short duration, have been reported by Frerichs, Leyden, Alex-
ander, and others without any alteration in the liver; and I have observed
two such cases in which the symptoms of portal obstruction extended over
several months."

Thrombottiji of (he .Splenic Vem. — Primary thromlrosis of the splenic vein
and it^s radicles is rare. I have seen an instance of autochthonous thrombosis
secondary to calcification of the wall of the splenic vein. Thrombosis of
veins within the spleen, extending sometimes into the main trunk, is com-
mon with infarction, abscess, and certain other morbid processes in this
organ. Thrombosis of the main trunk may be caused by suppurative or
hffimorrhagic pancreatitis, or by cancer of the pancreas. As has already
been mentioned, thrombi may extend from the portal or mesenteric veins into
the splenic, as well as from the latter into the former. There is the possi-
bility of thrombosis secondary to retrograde embolism of the splenic vein.

Kcister has reported tlie rare complication of enteric fever with tlironibosis
of the radicles and main trunk of the splenic vein ; the evidence being conclu-
sive that the oldest part of the thrombus was in the spleen. The evidences
of occlusion of the main vein appeared at the beginning of convalescence.
The spleen was enormously swollen and the pulp of a diffuse reddish-black
colour. The capsule and surrounding tissues were suffused witli blood. As
there were thrombi in the small mesenteric veins near the ulcerated ileum,
there was a possibility of retrograde embolism; but Koster thinks it more
probable that the process originated within the spleen.

Thrombosis limited to the extra-splenic part of the vein may be com-
pletely or nearly compensated by the collateral venous circulation, so that
no changes or only a moderate passive congestion occur in the spleen.

"Chiari (Centralb. f. allg. Path. u. path. Anat. 1898, IX, p. 854) has recently
described endophlebitis, with thrombosis, of the radicles of the hepatic vein.
There were symptoms of portal obstruction.

THROMBOSIS 183

Thrombi occupying intraspleuie veins niay caiLee haemorrhagic infarc-
tion. Dr. Eolleston lias observed two instances of ansemic infarcts of the
spleen in association with thrombosis of the splenic vein. Litten probably
goes too far in attributing most genuine ha-morrhagic as distinguished from
pale infarcts of the spleen, to venous thrombosis rather tlian to arterial
embolism.

E.xtensive necrosis and hfemorrhagic infarction may be caused by torsion
of the pedicle of a movable spleen. A perhaps unique instance of this occur-
rence was observed in the Johns Hopkins Hospital, and has been described
by Osier.

Obliteration of the Superior Vena Cava. — Since the admirable studies by
Duchek (18.54) and by Oulmont (1856) of the causes and symptoms of
obliteration of the superior vena cava a considerable number of instances
of this condition have been reported. By far the most frequent cause is
the pressure of a mediastinal tumour, of swollen lymph-glands, or of an
aneurysm. Less common is the growtli of a cancer or other malignant
tumour into the lumen of tlie vein. Banti reports a curious case of general-
ised tuberculosis in which nearly the whole length of the superior vena cava
was completely filled by a neoplastic tuberculous mass projecting into the
right auricle. The outer walls of the vein were intact. The condition seems
to have been analogous to the tuberculous cardiac thrombi already described
(p. 142). Primary thrombosis of the superior vena cava is so rare as to
be a pathological curiosity. Poynton has reported an instance of thrombotic
occlusion of tlie upper two-thirds of the superior vena cava in association
with chronic and acute valvular endocarditis, and in a second case of val-
vular disease he found a mural thrombus in this vein. In both cases there
was tricuspid insufficiency (pp. 15T and 158). The characteristic symptoms
are a'dema and cyanosis of the upper half of the body — face, neck, arms and
thorax — and dilatation of deep and superficial veins, especially marked over
the anterior wall of the thorax and upper part of the abdomen. In a case
exJiibited by Dr. Osier to the Johns Hopkins Hospital iledical Society, the
anterior surface of the chest was covered with large, spongy bunches of enor-
mous varicose veins, in one of which a phlebolith could be felt. Other symp-
toms, which may be present, are cedema of conjunctival and buccal mucous
membranes, exophthalmos, watery secretion from the conjunctivae, nose-
bleeding, and such signs of venous congestion of the brain as headache,
vertigo, and ringing in the ears, especially on bending over. In the light
of the wliimsicalities of venous thrombosis it is hardly necessary to add
that the symptoms may be less marked, and may de\-iate from what might
naturally be expected.

181 THROMBOSIS

Tlirombo.'<is of (he Innominate, Subclavian, and Jugular ]'eiiut. — Tlie
more important literature of this subject is cited in the papers of Pohl,
HirschlafF, and Helen Baldwin. The occurrence of these thromboses in
cardiac disease, and from compression, has already been mentioned (pp. 157
and 158) ; other rare causes are infection, empyema, acute rheumatism, tuber-
culosis, marasmus, and traumatism. The symptoms are the usual ones of
venous congestion, oedematous swelling, pain in the regions from which the
veins convey blood, dilatation of collaterals, and in the case of the cervical
veins, recognition of the thrombosed vein by palpation, which, however,
should be done with great care.

Thrombosis of the pulmonary veins may be mentioned as a rare source of
embolism in the aortic system. It is usually secondary to some pulmonary
disease, as gangrene, malignant tumours, abscess, infarction, tuberculosis,
pneumonia. It has been observed with extensive emphysema of the lungs
(Schmale).

Thrombosis of the cerebral sinuses will be considered in connection with
diseases of the brain in the following volume. (Allbutt's Syst. Med.,
Vol. VIII.)

0. Wyss has described a remarkable instance of extensive haemorrhagic
myelitis caused by widespread hyaline and platelet thrombi in veins within
the spinal cord. The thrombosis was secondar}' to a glioma of the dorsal
cord. Rosin has likewise observed tlirombosis of veins extending the whole
length of the spinal cord, consecutive to a tumour of the cervical cord.

Multiple Thromboses. — Finally may be mentioned the cases in which
many veins in different parts of the body become thrombosed, as in Huels's
case of chlorotic thrombosis; and Osiers, of thrombosis secondary to cancer
of the stomach, already cited (pp. 160 and 156). Erlenmeyer has described
as "jumping thrombosis" (springende Thrombose), in distinction from
the ordinary creeping form, cases in which the process attacks first one vein
and then another, in a different region, until finally various veins in the
extremities, trunk, and brain may become plugged.

TuiivTMEN'T. — The treatment of thrombosis of the extremities is about
all that needs special consideration in this article. In view of the part played
by enfeebled circulation and secondary infections in the causation of throm-
bosis, prophylactic measures should be directed toward maintaining good
nutrition, strengthening the heart's action, and warding off secondary infec-
tion, so far as may be, or treating accessible foci of infection antiscptically.

In the absence of any available medicinal treatment known to have any
direct control over the process of thrombosis, the general indications for
treatment are to secure as speedily as possible an adequate collateral cir-
lulatioii, in order to ward off the danger of tissue-necrosis or gangrene from

THROMBOSIS 185

arterial thrombosis and the efTects of passive congestion from venous throm-
bosis; and, above all, in the case of venous thrombosis, to guard against
the detachment of emboli. These indications are best met by absolute rest,
suitable position and immobilisation of the thrombosed extremity, and
nourishing diet.

With venous thrombosis of a lower extremity the patient should lie on the
back with the limb elevated on an inclined plane, or in a trough well lined
with cotton wool. The limb should be kept warm by wrapping in cotton
wadding, and hot fomentations of lead-water and laudanum, or some simi-
lar preparation, may be applied. If the condition of the heart indicate it,
digitalis or other cardiac tonic may be given. At the height of the process
the pain may be so intense as to require the use of opium or some of it3
derivatives.

It is all-important to know what not to do. The patient should be cau-
tioned against moving tlie leg, especially against any sudden jerk. Palpa-
tion of the affected veins should be of the gentlest sort and is better omitted
altogether. All unnecessary movements and manipulations should be
avoided. Xothing is gained, and harm may be done by resorting, before
all danger of embolism is passed, to the old-fashioned treatment of rubbing
in mercurial or belladonna ointment. The length of time that the patient
should remain quiet in bed will vary according to the severity of the case.
Although the thrombotic process does not usually progress after the tenth
or twelfth day, it is a general rule that the patient should not be allowed
to walk in less than forty days. A large number of the deaths from pul-
monary embolism have occurred when the patient first walks, or goes to
stool, or takes a bath.

Light bandaging of the lower part of the leg assists the circulation ; but,
if applied at all, it should be with only minimal compression. After the
danger of embolism is passed, massage and bandaging may be employed
to advantage, or a long elastic stocking worn.

If gangrene result from arterial thrombosis, tlie time and site of opera-
tion should be determined upon surgical principles.

REFERENCES

The references are only to authors cited in the teTct, and are not intended to
be a complete bibliography of the subject. The references to authors cited under
different headings in the text will usually be found only under the first heading
in which the reference appears.

Stbucti-be of Thrombi

1. Arnold: Virchow's Archiv. 1897, I, p. 445.

2. Bizzozero: Virchow's Arch., 1882, XC, p. 261.

3. Determann: XVI. Congr. f. inn. Med., 1898, p. 237.

15

186 THROMBOSIS

4. Eberth and Schimmelbusch: Die Thrombose nach Versuchen u. Leichenbe-

funden. Stuttgart, 1888.

5. Hammersten: Ztschr. f. physlol. Chem., 1896-97, XXII. p. 333.

6. Hanau: Fortschr. d. Med., 1886, IV, p. 385.

7. Hayem: Compt. rend, de I'Acad. des sc, July 18, 1882.

8. Klebs; AUg. Path. Th. II. Jena, 1889.

9. Kriege: Virch. Arch., 1889, CXVI, p. 64.

10. Lowit: Arch. f. exp. Path. u. Pharm., 1887, XXIII. p. 1. and XXIV, p. 188.

11. Lubnitzky: Arch. f. exp. Path. u. Pharm., 1885, XIX, p. 185.

12. Mantegazza: Gazz. med. lombard.. 1869.

13. Mosso: Virch. Arch., 1887, CIX, p. 205.

14. MuIIer, Fr.: Ziegler's Beitr.. 1898, XXIII, p. 498.

15. Osier: Seguin's Arch, of Med., Feb., 1881.

16. Idem: Centralbl. f. med. Wiss.. July 29, 1882.

17. Idem: Cartwright Lectures, 1886.

18. Pitres: Arch. d. phys. norm, et path., 1876, p. 230.

19. von Recklinghausen: Handb. d. allg. Path. d. Kreislaufs u. d. Ernahrung.

Stuttgart, 1893.

20. Ribbert: Die path. Anat. u. d. Heil. d. durch Utaph. pyog. our. hervorgeruf.

Erkrank. Bonn, 1891.

21. Virchow: Gesammelte Abhandlungen. Frankf., 1856.

22. Weigert: Virchow's Archiv, 1877, LXX. p. 483, and 1880, LXXIX, p. 87.

23. Idem: Thrombose, in Eulenburg's Real-Encyclopadle.

24. Welch: The Structure of White Thrombi, Trans. Path. Soc. of Phila-

delphia, 1887, XIII.

25. Welch and Clement: Remarks on Hog Cholera and Swine Plague. Proc.

30th Annual Convention, U. S. Vet. Med. Assoc, etc., Chicago, 1893.

26. Wlassow: Ziegler's Beitriige, 1894, XV, p. 543.

27. Zahn: Virchow's Arch., 1875, LXII, p. 81.

28. Zenker, K.: Ziegler's Beitr., 1895, XVII, p. 448.

29. Ziegler: Lehrb. d. allg. Path. u. spec. path. Anat, 9te Aufl., Bd., I, p. 149.

Growth, Metamobphoses, and Oboanisatiox

30. Aschoff : Virch. Arch., 1892, CXXX, p. 93.

31. Beneke: Ziegler's Beitr., 1890, VII, p. 95.

32. Legg, Wlckham: Tr. Path. Soc. Lond., 1878, XXIX, p. 50.

33. Thoma: Lehrb. d. path. Anat., I, Stuttgart, 1894.

34. Zahn: Virchow- Festschrift Internat. Beitr., II, p. 199.

Etiology

35. Baillie, Matthew: Trans. Soc. Improvement Med. and Chir. Knowledge,

1793, I, p. 119.

36. Baumgarten: D. sogen. Organisation d. Thrombus, Leipz., 1877.

37. Beugnies-Corbeau: Gaz. mfd. de Lioge. 1890, p. 348.

38. Birch-Hirschfeld: Congr. inn. Med., 1892, p. 28.

39. Brodie and Russell: Journal of Physiol., 1897, Nos. 4-5.

40. Briicke: Brit and For. Med.-Chir. Rev., 1857, XIX, p. 183.

41. Cohnheim: Vorles. iib. allg. Path., Bd., I, Berl., 1882.

42. Cruveilhier: Anat path., Paris, 1829-42.

THROMBOSIS 187

43. Davy, John: Researches, Physiological and Anatomical, London, 1839.

44. Denys: Centralbl. f. allg. Path. u. path. Anat., 1893, IV, p. 174.

45. Eguet: Mitth. a. Klin. u. med. Inst. d. Schweiz, 1894, II, Htt. 4.

46. van Emden: Fortschr. d. Med., 1898, XVI, pp. 241 and 281.

47. Ehrlich and Lazarus: Die Anamie, 1. Abth. Wien, 1898.

48. Flexner: Journ. Exp. Med., 1896, I, p. 559.

49. Freund: Wien. med. Blatter, 1886, p. 296.

50. Idem: Wiener med. Jahrb., 1888, p. 259.

51. Glenard: Contrib. a I'etude des causes de la coag. spontan. du sang. Thfese.

Paris, 1875.

52. Groth: Ueb. d. Schlcksale farbloser Blutkoorperchen, etc. Inaug.-Diss.

Dorpat, 1884.

53. Halliburton: Journal of Physiol., 1893, XIII, p. 806; XV, p. 90, and (with

Picliering) XVIII, p. 285.

54. Hayem: Du sang et de ses alterations anatomiques. Paris, 1889.

55. Hayem: Wien. med. Zeit., 1897, Nos. 1719.

56. Hunter, John: Obs. on the Inflam. of the Intern. Coat of Veins, Trans.

Soc. Improvement Med. and Chir. Knowledge, 1793, I, p. 18.

57. Kiihler: Ueb. Thrombose u. Transfusion. Inaug.-Diss. Dorpat, 1877.

58. Laennec: De I'auscult. mediate, etc. Paris, 1819.

59. Landois: Die Transfusion d. Blutes. Leipz., 1875.

60. von Limbeck: Prag. med. Woch., 1890, XV, pp. 351, 365.

61. Mallory: Journ. of Exp. Medicine, 1898, III, p. 611.

62. Maragliano and Castellino: Ztschr. f. kl. Med., 1892, XXI, p. 415.

63. Martin, C. J.: Journal of Physiology, 1893, XV, p. 380.

64. Muir: Journal of Anatomy and Physiology, 1890-91, XXV.

65. Naunyn: Arch. f. exp. Path. u. Pharm., 1873, I, p. 1.

66. Paget: St. Barth. Hosp. Rep., 1866, II, p. 82.

67. Ponfick: Deutsche Klinik, 1867, Nos. 20-26.

68. Idem: Virch. Arch., 1874, LX, p. 153.

69. Idem: Virch. Arch., 1875, LXII, p. 273.

70. Ranke: D. Blutvertheilung u. d. Thatigkeitswechsel d. Organe. Leipz., 1891.

71. Sahll: Centralbl. f. inn. Med., 1894, p. 497.

72. Schimmelbusch: Ueb. Thrombose im gerinnungsunfahigen Blute. Inaug.-

Diss. Halle, 1886.

73. Silbermann: Virch. Arch., 1889, CXVII, p. 288.

74. Singer: Arch. f. Gyniik., LVI, p. 218.

75. Tiirk: Klin. Untersuch. iib. d. Verhalten d. Blutes bei Infectlonskrankh.

Wien, 1898.

76. Vaquez: De la thrombose cachectique. These. Paris, 1890.

77. Idem: De la phleblte, in Clin. med. de la Charite, Paris, 1894, p. 751.

78. Weigert: Fortschr. d. Med., 1887, V, p. 231.

79. Widal: Etude sur I'intection puerperale. These. Paris, 1889.

80. Wooldridge: On the Chemistry of the Blood and other Scientific Papers.

Arranged by Victor Horsley and Ernest Starling. Lond., 1893.

Localisation

81. Arnold: Ziegler's Beitr., 1890, VIII, p. 29.

82. Benivieni: De abditis nonnullis ac mirandis morborum et sanationum causis.

Florent, 1507.

188 THROMBOSIS

83. Blrch-Hlrschfeld: Deutsch. raed. Woch., 1892. p. 267.

84. Bostroem: Deutsch. Arch. f. kl. Med.. 1895. LV. p. 219.

85. Burns. Allan: Obs. on some of the most frequent and important diseases of

the heart. Edinb., 1809.

86. zum Busch: Ueb. d. Zusammensetzung d. Herzthromben. Inaug.-Olss.

Freiburg. 1. B.. 1891.

87. van der Uyl: Tr. Path. Soc. Lend., 1858. IX. p. 89.

88. Cholsy and Nuhn: Cited from No. 93.

89. Czapek: Prager med. Woch.. 1891. XVI. p. 458.

90. Deiepine: Tr. Path. Soc. Lend.. 1890, XLI, p. 43.

91. Ewart and Rolleston: Tr. Clin. Soc, Lond., 1897, XXX, p. 190.

92. Haga: Virch. Arch., 1898, CLII, p. 26.

93. Hertz: Deutsch. Arch. f. kl. Med., 1885, XXXVII, p. 74.

94. Hoegerstedt and Nemser: Ztschr. f. kl. Med., 1896, XXXI, p. 130.

95. Hutchinson. Jonathan: Arch, of Surg. Apr., 1898, p. 100,

96. Krumbholz: Arb. a. d. med. Klinik zu Leipzig, 1893, p. 328.

97. Krumm: Deutsch. Arch. f. kl. Med., 1895, LIV, p. 189.

98. Lancereaux: Trait6 d'anat. path, t., I, p. 604. Paris, 1875-77.

99. Kotlar: Prag. med. Woch., 1894, XIX, pp. 78 and 97.

100. Legg, Wickham: Tr. Path. Soc, Lond., 1878, XXIX, p. 49.

101. Macleod: Edinb. Med. Journ., Feb., 1883, p. 696.

102. Manteuffel, Zoege. von: Deutsch. Ztschr. f. Chir., 1898, XLVII, p. 461.

103. Ogle: Tr. Path. Soc Lond., 1S6S, XIV, p. 127.

104. Osier: Johns Hopkins Hospital. Rep., 1890, II, p. 56.

105. Idem: Montreal Med. Journ., 1897, XXV, p. 729.

106. Parmentler: Arch. g6n. de m6d.. July. 1889.

107. Pawlowski: Ztschr. f. kl. Med.. 1894. XXVI, p. 482.

108. von Recklinghausen: No. 19, and Deutsch. Arch. f. kl. Med., 1885, XXXVII,

p. 495.

109. Redtenbacher: Wien. kl. Woch., 1892, V, p. 688.

110. Rosenbach: Die Krankh. d. Herzens, Hft., I, p. 180. Wien u. Leipz.. 1893.

111. Stange: Arb. a. d. path. Inst. z. Gottingen, 1893, p. 232.

112. Voelcker: Tr. Path. Soc Lond., 1893, XLIV, p. 31.

113. Wagner: Arch. d. Heilk., 1861, II, p. 364.

114. Weichselbaum: Cited from No. 83.

115. Wertheimer: Arch, de physiol., 1S95, 5. S., VII, p. 107.

116. von Winiwarter: Arch. t. kl. Chir., 1878, XXIII.

117. Wood, William: The Edinburgh Med. and Surg. Journ., 1814, X, p. 50.

118. Zahn: Virch. Arch., 1889, CXV, p. 55.

119. v. Ziemssen: Congr. f. inn. Med., 1890, p. 281.

Association with Certain Diseases
Enteric Fever

120. Boinet and Romary: Arch. d. m6d. exp., 1897, IX, p. 902.

121. Carbone: Gaz. med. di Torino, 1891, No. 2:?.

122. Crocq: Arch. d. m^d. exp., 1894, VI, p. 5S3.

123. Gilbert and Lion: Bull. m6d., 1889, p. 1286.

124. Girode: Bull. mM., 1889, p. 1392.

125. Haushalter: Mercredi m6d., Sept. 20, 1893.

THROMBOSIS 189

126. Holscher: Miinch. med. Woch., 1891, pp. 43, 62.

127. Keen: Surgical Complications and Sequels of Typhoid Fever. Philadelphia,

1898. (Consult for other references to Arterial Thrombosis in Enteric
Fever. )

128. Rattone: Morgagni, 1887, XXIX, p. 577.

129. Vincent: Mercredi m6d., Feb. 17, 1S92.

130. Viti: Atti d. r. Accad. d. fisiocrit. di Siena, 1890, 4. S., II, p. 109.

In^uenza

131. Baumler: Congr. f. inn. Med., 1890, p. 305.

132. Chaudet: La phl6bite grippale. Paris, 1892.

133. Chiari: Prager med. Woch., 1890, p. 124.

134. Guttmann and Leyden: Die Influenza-Epidemie, 1889-90. Wiesbaden, 1892.

135. Klebs: Deutsch. med. Woch., 1890, p. 278.

136. Kuskow: Virch. Arch., CXXXIX, p. 406.

137. Lasker: Inaug.-Diss. Freiburg, 1897.

138 Leichtenstern: In NotUnagel's Spec. Path. u. Therap., Bd., IV, Th., II, Abth.,
I. Wien, 1896.

139. Leyden: Charite-Annalen, XVII, and XVIII.

140. Rendu: Bull. mSd., 1892, pp. 50, 296.

Pneumonia

141. Barbanceys: Etudes sur la coag. d. sang dans les veines. Th6se. Paris, 1870.

142. Blagden: St. Barth. Hosp. Journ., 1897-98, V, p. 122.

143. Da Costa: Philadelphia Med. Journ., 1898, II, p. 519.

144. Dickinson, Lee: Brit. Med. Journ., 1896, I, p. 149.

145. Fabrics: Sem. med., 1888, p. 144.

146. Laache: Deutsch. med. Woch., 1893, p. 785.

147. Leyden: Centralbl. f. in. Med., 1887, p. 25.

148. Osier: The principles and Practice of Medicine, p. 124. New York, 1898.

149. Traite de mSdecine, t. V, pp. 374, 432.

(For other references to arterial and venous thrombosis in pneumonia.)

Acute Articular Rheumatism

150. Gatay: Contrib. a I'fitude de la phlebite rhumatismale. These. Paris, 1895.

151. Legroux: Gaz. hebd. de mgd., 1884, p. 140.

152. Schmitt: De la phlebite rhumatismale. These. Paris, 1884.

Appendicitis

153. Mynter: Appendicitis and its Surgical Treatment, Philadelphia, 1897.

Tul>erculosis

154. Blumer: Amer. Journ. Med. Sc, 1898, II.

155. Dodwell: Am. Journ. Med. Sc, 1893, I, p. 641.

156. Flexner: Johns Hopkins Hosp. Bull., 1891, p. 120.

157. Hektoen: Journ. Exp. Med., 1896, p. 112.

158. Hirtz: Mercredi med., 1894, No. 40.

190 TnilOMBOSIS

159. Michaolis and Blum: Deutsche med. Woch., 1S98, p. 550.

160. Stroebe: Centralbl. f. allg. Path. u. path. Anat.. 1897, p. 998.

161. Sabrazes and Mongour: Rev. m6d. de Test. 1897, p. 306.

Cachectic States

162. Charcot: Union m^d., 1865, XXVI, p. 165.

163. Gouget: Bull, de la soc. anat, 1894. No. 13.

164. Pitres, Bitot, and Regnier: Cited from No. 77.

165. von Recklinghausen: No. 19.

166. Rigollet: De la phlebite paludeene. Th6se. Bordeaux, 1891.

Cardiac Incompetency

167. Baldwin, Helen: Journ. Am. Med. Assoc, 1897, August 21, p. 371.

168. Cohn: Klinik d. embol. Gefasskrankh. Berlin, 1860.

169. Cheadle and Lees: Lancet, 1898, II, p. 206 (reported by Poynton).

170. Hirschlaff: Inaug.-Diss. Berlin, 1893.

171. Huchard: Rev. gen. de clin. et de thgrap., 1897, XI, p. 787.

172. Kahn (and Hanot): Arch. g^n. de m6d., 1896. II, p. 469.

173. Mader: Jahrb. d. Wien. k.-k. Krankenanst, 1S95, 1897, IV, p. 252.

174. Nicolle: Normandie m§d., 1897, XII, p. 68.

175. Ormerod: Tr. Path. Soc. Lond., 1889, XL, p. 75.

176. Ramirez: Gaz. m6d. de Paris, 1867, No. 47, p. 716.

177. Robert: Bull, de la soc. anat., 1880, V, p. 314.

Chlorosis

178. Ball: Trans. Assoc. Amer. Physicians. 1889, IV, p. 52.

179. von Noorden: In Nothnagel's Spec. Path. u. Therap. Bd., VllI, Th., II.

Wien, 1897.

180. Schweitzer: Virchow's Arch., 1898, CLII, p. 337.

(The three preceding articles contain the principal references to
chlorotic thrombosis. The following Nos. 181 to 192 are the references
to cases not found in them.)

181. Audry: Lyon m6d., 1892 and 1893.

182. Dickinson, Lee: Tr. Clin. Soc. Lond., 1896, XXIX, p. 63.

183. Duckworth and Buzzard: Brit. Med. Journ., 1896, I, p. 149.

184. Gagnoni: Riforma med., 1897, XIII, p. 472.

185. Guinon: Bull, et m^m. soc. m6d. des hop. de Paris, 1896, XII. p. 297.

186. Gutheil: Inaug.-Diss. Freiburg, 1892.

187. Hayem: Bull. m6d., 1896, p. 261.

188. Powell, Douglas: Lancet, 1888, II, p. 1124.

189. Dr. Thayer's case was of a chlorotic young woman with thrombosis of left

femoral, iliac and uterine veins. Death from pulmonary embolism.

190. Vaquez: No. 77.

191. Vergely: Bull. m6d., 1SS9, p. 1175.

192. Villard: Assoc, franc, pour ravancement des sciences, 1891, 11, p. 791. Paris,

1S92.

193. Buttersack: Ztschr. f. kl. Med., 1897, XXXIII, p. 456.
193a. Sankey, W.: Ed. Med. and S. Journ., 1814, p. 401.

THROMBOSIS

191

Gouty, Idiopathic and Primary Infective Thro'm1>osis

194. Barbe: La France med., 1898. (Syphilis).

194a. Daguillon: Contrib. a I'etude clin. de la phl6bite primitive. Th6se. Paris,
1894.

195. Dowse: Lancet, 1879, II, p. 268.

196. Osier: TYans. Assoc. Amer. Physicians, 1887, II, p. 135.

197. Paget: No. 66.

198: Tuckwell: St. Barth. Hosp. Rep., 1874, X, p. 23.

Effects and Symptoms
Cardiac, Arterial, and Capillary Thrombosis

199. Barth: Deutsch. med. Woch., 1896, p. 269.

200. Blachez: Gaz. des hop., 1866, No. 13.

201. Bristowe: Tr. Path. Soc. Lond., 1870, XXI, p. 143.

202. Charcot: Compt. rend. soc. de biol., 1858, Paris, 1859, 2. S., V, pt. 2, p. 225.

203. Chiari: Prager med. Woch., 1897, Nos. 6, 7.

204. Gerhardt: Wiirzburg. med. Ztschr. Bd., IV, and V.

205. Heidenhain: Deutsch. med. Woch., 1891, p. 1087.

206. Kidd, Percy: Tr. Path. Soc. Lond., 1886, XXXVII, p. 197.

207. Marie, R. : L'infarctus du myocarde et ses consequences. Paris, 1897.

208. Naunyn: In Nothnagel's Spec. Path. u. Ther. Bd., VII, Th., VI, p. 216. Wien,

1898.

209. Pitt, Newton: Tr. Path. Soc. Lond., 1893, XLIV, p. 52.

210. Porter: Journ. Exp. Medicine, 1896, I, p. 46.

211. Welch: In Pepper's System of Medicine, II, p. 505.

212. von Ziemssen: No. 119.

Venous Thrombosis

213. Cohnheim: Vorles. iib. allg. Path. Bd., I, pp. 150, 492.

214. Cohnsteln: In Lubarsch-Ostertag's Ergebnisse, 1896, II, p. 563. Wiesbaden,

1897. (Consult for literature on theories of oedema.)

215. Galliard: Med. moderne, 1894, V, p. 861.
261. Hamburger: Virch. Arch., 1895, CXLI, p. 398.

217. Lazarus-Barlow: Phil. Trans. Roy. Soc, CLXXXV, B., 1894, p. 779.

218. Idem: A Manual of General Pathology. London, 1898.

219. Loschner: Prager med. Woch., 1888, No. 22.

220. Schlesinger: Deutsch. med. Woch., 1896, p. 460.

221. Starling: Lancet, 1896, I, p. 1407.

222. Thomas: Beitr. z. Difter.-Diagnostik zwischen Verschluss d. Pfortaders

u. d. unteren Hohlvenen, Bibliotheca medica, Cassell, 1895.

223. Vimont: Contrib. a I'etude des obliterations de la veime cave infer. Th6se.

Paris, 1890, p. 224.

224. Welch: Journ. of Exp. Med., 1896, I p. 35.

225. Koster: Deutsch. med. Woch., 1898, p. 325.

(This and the papers cited by K. contain references to 16 cases of
thrombosis of mesenteric veins. The additional cases with symptoms are
Nos. 226 to 239.)

192 THROMBOSIS

226. Barth: Bull. in«d., 1897, Oct. 27, p. 989.

227. Boucly: Th^se. Paris, 1894.

228. Burgess: Sheffield Med. .lourn., 1892-93, I, p. 317 (3 cases).

229. Dpiatour: Annals of Surgery. 1895, XXI, p. 24.

230. Fitz: Trans. Ass. Amer. Phys., 1887, II, p. 140.

231. Garmsen: Inaug.-Diss. Kiel, 1895.

232. Leech: Quart. Med. Journ., Sheffield, 1897-8, VI, p. 370.

233. Lilienthal: Matthew's Quart. Journ. Rectal, etc., Louisville, 1898, V, p. 158.

234. Lund: Hospitalstidende, Mar. 23, 1898.

235. M'Weeny: Lancet, Dec. 23, 1893.

236. Nordenfeldt: Hygiea, 1897, LIX, pt. 2, p. 228.

237. Smith: Dublin Journ. of Med. Sc, 1894. XCVII, p. 274.

238. Watson: Boston Med. and Surg. Journ., 1894, CXXXl, p. 556.

239. Westhoff : Inaug.-Diss. Kiel, 1895.

(Cases without symptoms are reported in Xos. 240-243.)

240. Cohn: Embolische Gefasskrankh.

241. Frerichs: Klinik d. Leberkrankh.

242. Rolleston: Trans. Path. Soc, London, 1892, XLIII, p. 49.

243. Spiegelberg: Virchow's Arch., CXLII, p. 547.

244. Baldwin, Helen: J. Amer. Med. Assoc, 1897, XXIX, p. 371.

245. Banti: Sperimentale, 1891, p. 408.

246. Bermant: Ueb. Pfortaderverschluss u. Leberschwund. Inaug.-Diss., 1897.

247. Borrmann: Deutsch. Arch. t. kl. Med., 1897, LIX, p. 283.

248. Conheim and Litten: Virch. Arch., 1876, LXVII, p. 153.

249. Duchek: Viertl. Jahrs. f, d. prakt. Heilk, 1854, XLI, p. 109.

250. Erlenmeyer: Deutsch. med. Woch. 1890, p. 781.

251. Hirschlaff: Inaug.-Diss., Berlin, 1893.

252. Litten: In Nothnagel's Spec. Path. u. Therap. Bd., VIII, Th., Ill, p. 41.

253. Nonne: Deutsch: Arch. f. kl. Med., 1885, XXXVII, p. 241.

254. Osier: Johns Hopkins Hosp. Bull.. 1891, II, p. 40.

255. Idem: Journ. Anat. and Physiol.. 1878, XXIX. p. 107.

256. Oulmont: Soc. med. d'observ., Paris, 1855, III, pp. 361, 468.

257. Pohl: Inaug.-Diss. Gottingen, 1887.

258. Rolleston: Trans. Path. Soc. London, 1892. XLIII. p. 49.

259. Rosin: Verhandl. d. XVI Congr. f. innere Medicin, 1898, p. 415.

260. Schiippel: In Ziemssen's Handb. d. spec. Path. u. Therap., Bd., VI II, I. 2,

p. 279.

261. Schmale: Ueber Thrombose d. Pulmonalvenen bei Emphysem. Inaug.-Diss.

Wurzburg, 1889.

262. Smith, A. A.: N. Y. Med. Journ., 1880, XXXI, p. 16.

263. Solowieff: Virch. Arch., 1875, LXII, p. 195.

264. West: Tr. Path. Soc. London, 1878, XXIX, p. 107.

265. Wyss, O.: Verhandl. d. XVI Congr. f. innere Medicin, 1898, p. 399.

266. Bennett, Wm. H.: The relations of thrombosis to varix (Lancet, 1898, II,

p. 973).

EMBOLISM '

Definition. — Embolism is the impaction in some part of the vascular
system of any undissolved iraterial brought there by the blood-curreut.
The transported material is an embolus. Embolism may occur likewise in
lymphatic vessels.

Historical Xote. — Rudolf Yirchow is the creator of the doctrine of
embolism. There is scarcely another patholopical doctrine, of equal magni-
tude, the establishment of which is so largely the work of a single man.
Xot but that there were foreshadowings of this conception before Yirchow,
notably by Bonetus and van Swieten in the seventeenth and eighteenth
centuries, and by Allibert and Frangois in the early part of the present cen-
tury. A few observers and experimenters, indeed, anticipated some of Vir-
chow's results. The wonder is that until Virchow-'s time the idea of embolism
remained so foreign to medical thought; so obvious and necessarj- a corollary
does it seem to be of the discovery of the circulation of the blood. Between
the years 1846 and 1856 Yirchow constructed the whole doctrine of embol-
ism upon the basis of anatomical, experimental and clinical investigations,
which for completeness, accuracy, and just discernment of the truth must
always remain a model of scientific research in medicine. These discoveries
introduced new chapters and necessitated a recasting of many old ones in
pathology. A number of important morbid conditions, among which pul-
monary embolism and cerebral embolism may be especially mentioned, were
now for the first time clearly recognised. Yirchow's studies of thrombosis
and his demonstration that not all intravascular, ante-mortem clots are
formed at the place where they are found, and that infarcts are not the
result of inflammation and capillary phlebitis, put an end to the false and
to us at present almost incomprehensible ideas then prevailing as to the
overshadowing importance of phlebitis in pathological processes. Especially
was the doctrine of metastasis, which in old days was one of the most
mystical in medicine, greatly expanded and at the same time placed upon an
intelligible and firm foundation.

The new fields opened by Yirchow have been industriously cultivated
by a multitude of workers. The additions to our knowledge have been many
and valuable, but they have related mainly to details, and can scarcely be
said to have led to new points of view. The works of Bernhard Cohn and

'In; Syst. Med. (AUbutt), ix)nd., 1899, VII, 228-285.
193

104 EMBOLISM

of Cohnheim may be signalised as among the most important of the con-
tributions since Virchow's early publications. Cohn's remarkable book,
published in 1860, is extraordinarily rich in anatomical, experimental, and
clinical facts, and it is well for any one who believes that he has a new obser-
vation or opinion concerning embolism to consult it before venturing on
publication ; a precaution which has evidently been often neglected by
writers on the subject.

Varieties of Emboli. — Substances of the most varied character, solid,
liquid or gaseous, may enter the circulation and be conveyed as emboli.
Unless some special epithet be used, an embolus is generally understood
to be a detached thrombus, or part of it, including under this designation
endocarditic vegetations. Other possible sorts of emboli are fragments of
diseased heart-valves, calcific masses, bits of tissue, tumour-cells, paren-
chymatous cells, animal or vegetable parasites, fat, air, pigment-granules
and foreign bodies. Emboli of air, of fat, and of parenchymatous cells
will be considered separately. An important classification, as regards
their effects, is into bland or aseptic emboli and toxic or septic emboli.

Sources of Emboli. — Emboli in the lungs come from the systemic
veins, the right heart or the pulmonary artery; those in branches of the
portal vein come from the radicles or trunk of this vein ; those in systemic
arteries from the pulmonary veins, the left heart, or some artery between
the heart and the location of the embolus. Sources of aberrant emboli,
resulting from unusual modes of transportation, will be considered subse-
quently (p. 196).

Various features in the structure and disposition of thrombi bearing
upon the detachment of emboli have been described in the preceding article.
Here may be especially recalled the continuation of an occluding venous
thrombus in the form of a partly obstructing thrombus beyond the entrance
of an important branch, and the occurrence of softening in the interior of
older thrombi ; phenomena evidently favourable to the detachment of frag-
ments. Globular thrombi in the right heart, particularly in the auricular
appendix, are a fruitful source of the emboli which cause pulmonary infarc-
tion in heart disease. Vegetations of the aortic and mitral valves, particu-
larly of the latter, furnish the great majority of emboli in the aortic system.
Thrombosis or embolism of an arterial trunk — as of the internal carotid,
splenic, femoral — is often followed by the conveyance of fragments of the
plug into branches of the artery. When the plug in the main trunk is an
embolus, this secondary embolism is described by Cohnheim as " recur-
rent"— an epithet which has also been applied to retrograde embolism, and,
therefore, to avoid confusion, had better not be used in either sense.

EMBOLISM 195

The detection of the source of an embolus is often unattended by any
difficulty; but sometimes it requires prolonged and painstaking search,
and occasionally even such a search is unrewarded. The greatest difficulties
are encountered when the source is in some peripheral venous thrombus
which has caused no symptoms and is unattended by lesions suggestive of
its location. An entire thrombus may be dislocated and transported as an
embolus.

Site of Deposit. — Emboli are carried along by the blood-current imtil
they are caught on some obstruction, or become lodged in a channel too
narrow to permit their further passage. It is evident that embolism can
scarcely occur except in the arterial system, pulmonary and systemic, and
in branches of the portal vein. The rare instances of embolism of systemic
veins wiU be considered under aberrant embolism (p. 196). An extremely
rare occurrence, of which several instances are recorded, is the blocking
of the tricuspid or mitral orifice by an embolus. The result is, of course,
sudden death. Very often an embolus is caught at an arterial bifurcation,
which it rides with a prolongation extending into each branch (riding
embolus). This may happen where the diameter of each branch is greater
than that of the embolus. It is not uncommon for several emboli to enter
successively the same branch of the pulmonary artery.

Any artery open to the circulating blood may receive an embolus of
appropriate size. The course followed by an embolus in its travels is
determined by purely mechanical factors, of which the most important
are the size, form, and weight of the plug; the direction, volume, and
energy of the carrying blood-stream ; the size of branches and the angles at
which they are given off; and the position of the body and its members.
In accord with these principles we find emboli in the lower lobes of the
lungs oftener than in the upper; and in the right lung oftener than in the
left, the right pulmonary artery being larger than the left. Emboli from
the left heart are more frequently carried into the abdominal aorta and its
branches than into the carotid or subclavian arteries. The left carotid,
arising directly from the aortic arch at its highest point, is in more direct
line with the aortic blood-stream than is the right carotid, and is there-
fore a commoner recipient of emboli. Tlie left common iliac artery is also
somewhat more directly in the line of the current in the abdominal aorta,
and, therefore, receives emboli somewhat more frequently than the right.

The order of frequency in which emboli are found in the different
arteries may be given about as follows: — pulmonary, renal, splenic, cere-
bral, iliac and the lower extremities, axillary and upper extremities, coeliac
axis vrith its hepatic and gastric branches, central artery of the retina,
superior mesenteric, inferior mesenteric, abdominal aorta, coronary of the

196 EMBOLISM

heart. There is, however, considerable difference of statement on this
point. As a matter of fact this list, like similar ones, does not inform
us of the frequency with which the different arteries of the body receive
emboli ; for it is evident that it is based almost entirely upon embolic
manifestations, and not upon the mere presence of emboli. Jf estimates
of frequency be based only on infective emboli, the order would be in
several respects different, the hepatic artery, for example, standing higher
in the list, and the cerebral lower — sufficient evidence that the customary
data for determining the frequency of embolism in different arteries relate
only to such emboli as leave behind some record of their presence. Infec-
tive emboli, however, do not inform us of the incidence of embolism in
different arteries; for these produce abscesses or other lesions in certain
special situations, and not in every place where they may lodge; a fact
which is brought out clearly in the experimental injections of bacteria
into the circulation of animals. It seems to me very probable that of
the systemic arteries, those going to the lower extremities must be more
frequent receptacles of emboU than either the splenic or the renal ; but
the smaller plugs in the former usually leave no readily demonstrable
record of their presence, whereas in the latter they always do.

Aberrant Embolism. — Certain exceptions to the general rules already
stated concerning the sources and direction of transportation of emboli
may be grouped under the heading of aberrant or atypical emlxjlism, the
latter epithet being the one employed by Scheven to designate paradoxical
embolism, and retrograde embolism.

Zaliu gave the name " paradoxical embolism," and his assistant Eostan
the name " crossed embolism," to the transportation of emboli derived from
veins into the systemic arteries without passing through the pulmonary
circulation. Cohnheim was the first to note the passage of venous emboli
through an open foramen ovale into the aortic system ; and since then there
have been enough observations of this so-called paradoxical embolism to
prove that, although not frequent, it is really of practical importance, and
not merely a curiosity. Zahn and Eostan found an open foramen ovale
in about one-fifth of their autopsies, which is a considerably smaller per-
centage than most pathologists, who have investigated the subject, have
found. An opening in the form of an oblique slit is certainly very often
present in the oval fossa (in 34 per cent of all cases according to Firket),
and it has been demonstrated by actual observation that, under certain
conditions, this form of opening suffices for the transit of emboli. In
three ca-ses an embolus was found by Zahn and Eostan actually engaged
in the opening, and two or three similar observations have been made by
others.

EMBOLISM 197

I have found records of twentj'-eight cases of paradoxical embolism,
and there is no reason to suppose that this list is complete. The evidence
ujxjn wliich the diagnosis is usually based is an open foramen ovale and
the presence in the systemic arteries of coarse emboli, for which the only
source to be found is on the venous side or in the right auricle. While
in some of the case? there may be room for scepticism as to the venous
origin of the arterial embolism, there can be none for Schmorl's observa-
tion, in a case of traumatic laceration of the liver, of plugs of hepatic
tissue in the left auricle and the main trunk of the renal artery, with an
open foramen ovale admitting a finger. Conditions favouring the occur-
rence of paradoxical embolism are, according to Zahn, increased pressure
in the right auricle and lowered pressure in the left. Under these cir-
cumstances the opening in the oval foramen is widened, and its walls
bulge toward the left auricle. Eostan and Hauser have seen thrombi
extending from the right auricle through the oval foramen into the left.

The best explanation of certain tumour metastases without pulmonary
implication is by paradoxical embolism. Here, however, there is some-
times another possibility; for, as Zahn has demonstrated, tumour cells
not of large size may pass through the pulmonarj' capillaries. Although
the lungs are an excellent filter, their capillaries are certainly so wide
that they may permit the transit of emboli too large to pass through
capillaries elsewhere in the body.

The first conclusive observation of retrograde transport of an embolus
in a human being was made by Heller, in 1870, who found, in a case of
primary cancer of the caecum and ileum, a loose plug of cancerous tissue
in a branch of an hepatic vein. The only metastatic growths were in the
mesenteric, retroperitoneal, and mediastinal lymphatic glands. Long before
Heller, however, the conception of retrograde transport of venous emboli
was familiar to pathologists ; especially in the discussions of the explana-
tion of metastatic hepatic abscesses in cases where the lungs are not
involved and the atrium of infection does not communicate with the portal
system. The experimental side of the subject was diligently cultivated.
The general trend of opinion among pathologists, however, was opposed to
the acceptance of the doctrine of retrograde transport, under conditions
occurring in human beings, until the publication of von Reckhnghausen's
article on the subject in 1885. He reported a convincing observation of
embolism of the renal veins with masses of sarcoma, derived from a primary
growth of the tibia, and also of retrograde embolism from the left auricle
into the pulmonary veins. Since this publication there have been a number
of equally conclusive demonstrations of the retrograde transport of venous
emboli, and the subject has been taken up again on the experimental side.

198 EMBOLISM

Retrograde venous embolism is an interesting, but, so far as at present
known, a rare occurrence.

The difficulty of making sure that a suspected thrombotic embolus in
a systemic vein is not an autochthonous thrombus is doubtless the reason
why most of the reports of retrograde transport relate to emboli of tumour-
cells or parenchymatous cells. In addition to Heller's and von Reckling-
hausen's cases already mentioned, reference may be made to Arnold's
observation of masses from a primary mammary carcinoma filling the
superior longitudinal sinus, with invasion of the wall of the sinus from
within by the new growth, but without any intracranial tumour outside
of this wall ; or indeed any metastasis elsewhere in the body except in the
axillary and cervical lymph-glands: and also to Ernst's ease of primary
angio-sarcoma of the left kidney, growing into the renal vein, with a loose
plug of sarcomatous tissue distending a branch of a coronary vein of the
heart without connection with a metastatic growth. Bonome's observa-
tion of cancer of the thyroid with metastatic nodules in the liver, develop-
ing from plugs in the hepatic veins, should probably also be included in the
list, as well as two cases of Bonome, reported by Lui, in one of which a
cancerous embolus secondary to cancer of the rectum was found in a branch
of the superior mesenteric vein; and in the other a similar retrograde
embolus, secondary to adeno-carcinoma of the liver, was met with in the
right pampiniform plexus.

To Schmorl's and Lubarsch's cases of emboli of Uver-ceUs in the cere-
bral and the renal veins may be added two observations from my labora-
tory, of which one has been reported by Flexner, of clumps of liver-cells
in branches of the renal vein in cases with extensive hepatic necroses.

That retrograde transport of ordinary venous thrombi may occur, is
demonstrated by Arnold's discovery in a large branch of an hepatic vein
of a riding embolus identical in appearance vrith a thrombus which occu-
pied the right ovarian vein and extended some distance into the inferior
vena cava. Cohn accepted, for a limited class of .cases, backward convey-
ance of venous emboli : and in this sense interprets an observation of throm-
bosis of the superior longitudinal sinus, with a plug in the right axillary
vein identical in appearance with an undoubted embolus in the pulmonarj'
artery. Von Recklinghausen has furnished evidence of the retrograde trans-
port of infective emboli into the renal veins.

Prom these cases it is seen that retrograde embolism of particles of
tumour, of tumour-cells, of parenchymatous cells, and of ordinary bland
and infective thrombotic fragments has been observed. Experiments have
demonstrated that, under certain conditions, light as well as heavy particles
may be transported in the veins in a direction contrary to that of the

EMBOLISM 199

normal blood-currerit. The veins in which retrograde embolism in human
beings has been found are the hepatic, the rtnal, the mesenteric, the
pampiniform plexus, the coronary of the heart, the cerebral veins and
sinuses, the axillary and the pulmonary. Experimental retrograde em-
bolism has been produced in many other veins, including those of the lower
extremities. While venous valves, when intact, are undoubtedly a pro-
tection against this occurrence, they are often imperfectly developed or
insufficient. Emboli have been repeatedly observed in the cerebral veins
and sinuses which should be protected by valves in the jugular veins.

Retrograde embolism is usually explained by a temporary reflux of the
venous current in consequence of some sudden obstacle to the return flow
to the right heart, as may occur with forced expiration and coughing.
Whatever increases the pressure in the veins near the heart, and impairs
the assistance to the venous stream afforded by the respiratory movements
and the suction of the right heart, favours this backward movement.
Increased intrathoracic pressure, stenosis of the respiratory passages, spasm
of respiratory muscles, distension of the right heart, tricuspid insufficiency,
slowing of the heart's beats from vagus-irritation, are among the conditions
believed to dispose to retrograde transport.

Eibbert does not accept the reflux theory of retrograde embolism; partly
for lack of any positive observation of such backward flow beyond the
immediate neighbourhood of the right heart, and partly on account of the
difficulty in explaining what becomes of all the blood which would be momen-
tarily pressed back toward the capillaries. His explanation is that in con-
ditions of high venous stasis, emboli, sticking loosely to the venous wall,
are not moved forward by the feeble current, but are slowly pressed back-
ward, step by step, by pulse-waves in the veins. For this view he finds
support in experiments which he has made. Observations, partlv experi-
mental, of Arnold and of Ernst, cannot readily be reconciled with Kibbert's
explanation; so that, notwithstanding difficulties needing further elucida-
tion, the reflux theorv^ seems at present the more probable for most cases.

Of a different nature from the preceding form of retrograde transport
is the conveyance of emboli by a blood-current reversed from its normal
direction in consequence of obstruction of veins by compression or other
causes. This kind of retrograde transport from more or less permanent
reversal of the normal current is far more frequent in lymphatic vessels
than in veins, and plays an important part in the metastases of tumours
by means of the lymphatics.

Anatomical Characters. — The appearances observed in embolised ves-
sels vary with the shape, size, consistence, and nature of the embolus, and
the duration of its impaction. Approximately spherical emboli, as a rule.

200 EMBOLISM

completely close the lumen of the artery in which they lodge Cylindrical,
elongated, or flat emboli are usually caught as riders at an arterial bifur-
cation; and often at first leave more or less of the channels by their side
open. Thrombi several inches long may be washed out of the femoral or
other peripheral vein. Such a transported thrombus may be found in the
trunk or a primary division of the pulmonary artery, folded two, three,
or even four times upon itself, and pressed at different points into several
of the main arterial branches at the hilum of the lung, as in an interesting
case described by Fagge. In this way an embolus may completely plug
a vessel three or four times its diameter. Irregularly-shaped emboli, if of
soft consistence, may be pressed into an artery so as to block the lumen
completely ; but if of firmer consistence they leave at first some space for the
blood to flow. Emboli may be of such consistence as to be shattered by
impact with the arterial wall, the fragments blocking many or all of the
small branches, and producing the same effect as if the plug had lieen
arrested in the main trunk.

An embolus is the starting-point of a secondary thrombus which usually,
although not always, completes the closure of the vessel, if this was not
effected by the embolus itself, and extends on each side to the nearest
branch. The same metamorphoses and process of organisation, with con-
secutive changes in the vascular wall, occur with emboli and encapsulating
thrombi, as described in the previous article for primary thrombi. Non-
absorbable emboli or parts of emboli, like foreign bodies, are encapsulated
by cells and tissue.

In cases of recent embolism, the plug can generally be recognised as an
embolus without much difficulty ; but, in those of long standing, the
anatomical diagnosis between embolism and thrombosis may be difficult,
or even impossible. The criteria for the recognition of a fresh embolus
are for the most ]iart sufficiently self-evident. Such a plug lies loosely or
is but slightly adherent to the vessel-wall. It often presents a broken or
fractured surface which, in fortunate cases, may be made to fit on the
corresponding surface of the thrombus from which it was originally broken
off. It may be bent or folded, or show the marks of venous valves, or
present ramifications which do not correspond to those of the artery in
which it lies. It is of course of the first importance to find, if possible,
the source of the embolus ; and, when this is done, to make a careful com-
parison between the thrombus and the embolic fragment as to resemblances
in structure and appearance.

After the embolus has become adherent and surrounded by a secondary
thrombus, some of these differential criteria may still remain for a while;
but, as time passes, the anatomical diagnosis becomes increasingly difficult.

EMBOLISM 201

The embolus may perhaps still be distinguished from the surrounding
thrombus by marked difiFerences in its age and general appearance and
structure, possibly by the presence of lime salts. An adherent plug
which rides an arterial bifurcation is much more likely to be an embolus
than a primary thrombus. In reaching a conclusion, weight must be
given to the condition of the arterial wall ; whether there be any local
cause for thrombosis, — such as compression, aneurysm, arterio-sclerosis ;
and whether the microscope shows such secondary changes in the arterial
wall as generally correspond to the apparent age and character of the
adherent plug. The detection of a source for an embolus will be an
important consideration. The clinical history may aid in the antomical
diagnosis ; and all attendant circumstances, especially the existence else-
where of undoubted emlx)li, should be taken into consideration. In some
situations, as in branches of the renal or splenic arteries, primary throm-
bosis is so uncommon that the chances are all in favour of embolism.

It is evident from what has been said that in the older cases the anatomi-
cal diagnosis must often be based upon a weighing of probabilities, and
that sometimes a positive conclusion cannot be reached.

Effects. — Bland or aseptic emboli produce chiefly mechanical effects
referable to the obstruction to the circulation ; toxic or septic emboli cause
also other changes which may be described as chemical or infective. We
shall consider first the mechanical effects.

The direct injury which may be inflicted upon the vessel wall by sharp
calcareous emboli is, according to Ponfick, a rare cause of aneurysm.
Embolic aneurysms, however, stand in much more definite relation to
chemical properties of the embolus, as will be shown subsequently (p. 218).

Necrosis; Infarction. — The fate of a part supplied by an artery closed
by a bland embolus depends altogether upon whether it is fed within a
certain time after the obstruction with enough arterial blood to preserve
its function and integrity. An embolus which does not completely plug
the vessel may cause no appreciable interference with the circulation ; but
the closure of the lumen is usually soon effected by a secondary thrombus.
The occlusion by a bland embolus of an artery with abundant anastomoses,
such as those possessed by the arteries supplying bone, the voluntary
muscles, the skin, the thyroid, the uterus, usually causes no circulatory dis-
turbance of any consequence. Even in these situations extensive multiple
embolism, or embolism with extensive secondary thrombosis, may cause
local ansemia with its consequences.

Sudden death may be the result of embolism of the trunk or a main
division of the pulmonary artery, of one of the coronary arteries of the
heart, or of the bulbar arteries.
16

20a EMBOLISM

If an adpquate collateral circulation be not established within the proper
time the inevitable fate of a part, supplied by an embolised artery, is degen-
eration or deatli. LcK-al death is tlie regular result of enibolism of branches
of the splenic artery, the renal artery, the basal arteries of the brain,
the central artery of the retina, and the main trunk of the superior mesen-
teric arterv. It is the usual result of embolism of one of the coronary
arteries of the heart, if the patient survive long enough ; and it is the
inconstant result, depending generally upon accessory circumstances, of
embolism of the medium-sized and smaller branches of the pulmonary
arteries, of cerebral arteries other than the basal, of the abdominal aorta,
iliacs, main arteries of the extremities, and some other arteries. A col-
lateral circulation may be established sufficiently to preserve the life of
a part, but not to maintain its full nutrition ; under these circumstances it
undergoes fatty degeneration or simple atrophy.

When the dead part is so surrounded with living tissue that it can be
permeated with lymph, as is usually the case in the viscera, the mode of
death is that described by Weigert, and named by Cohnheim " coagu-
lative necrosis." Here the dead protoplasm, and to some extent inter-
cellular substances, undergo chemical changes, believed to be in part
coagulative; and actual fibrillated fibrin may appear. If there be enough
coagulable material present, the necrotic part becomes hard, drj', opaque,
and somewhat swoUen. For a time its general architecture, both gross
and microscopic, is preserved; but the nuclei and specific granulations
disappear early, the former largely by karyorrhexis.

An area of coagulative necrosis resulting from shutting off of the
blood-supply is an infarct. Its shape corresponds to that of the arterial
tree supplying it, and is, therefore, as a rule, approximately conical, or
tliat of a wedge, the base being toward the periphery of the organ. The
wedge-shape is most marked in smaller infarcts; large ones may be round-
ish or irregular in shape. The size depends upon that of the occluded
artery. The colour is opaque, white, or yellowish, unless hfemorrhage is
added to the necrosis. We thus distinguish aua?mic, pale or white infarcts,
and red or hsemorrhagic infarcts; but, in the latter no less than in the
former, the essential thing is the coagulative necrosis, the hemorrhage
being merely something added to the necrosis. This was not always clearly
recognised, it being supposed at one time tliat the liffimorrliage was the char-
acteristic feature of infarcts, and that pale infarcts were simply decolour-
ised ha?morrhagic infarcts. The name " infarcts " (from infwrcire, to stuff),
like many other old medical terms, is therefore now used in a sense at
variance with its etymological meaning. In some situations, as the kidney
and the retina, the infarct is nearly always pale; in others, as the lungs and

EMBOLISM 203

the intestine, it is as constantly hasmorrhagie ; and in yet others, as the spleen
and the heart, it may be either white or red.

Where there is not a sufBcient quantity of eoagulable substances the
area of coagulative necrosis does not become hard; and it may be of
much softer consistence than normal, as is the case with the ischaemic
necroses of the brain and spinal cord. Necrosis of peripheral parts, as
the tees, foot, leg, hand, is not of the coagulative variety; for the dead
part is not surrounded by living tissue to furnish the lymph which brings
one of the factors essential for coagulation. This peripheral necrosis is
called gangrene or mortification, and may be either dry or moist.

Collateral Circtdation; Local Anamia. — As the state of the collateral
circulation is the decisive factor in bland embolism, it becomes important
to learn the conditions under which establishment or failure of this cir-
culation occurs. This subject is one eminently open to experimental
study; but more attention has been given to the anatomical than to the
physiological side. In fact many writers seem to assume that the physi-
ological factors can be so readily deduced from the laws of hydro-dynamics
that it is only necessary to investigate the size, arrangement, and distribu-
tion of the vascular tubes. Nevertheless experience has shown abundantly
the danger of accepting anything in the physics of the circulation which has
not been put to an experimental test on the living body. The experimental
study of the physiological conditions which determine the development of
a collateral circulation has demonstrated that this problem is by no means
so simple as has been often represented; while some old errors have been
corrected and new facts have been added, we are still far from an entirely
satisfactory solution or any definite agreement of opinion. It is impos-
sible here to do more than touch upon certain points bearing directly
upon the subject in hand.

If an artery with slender anastomoses to its area of distribution, such
as the femoral or the ligual in a frog's tongue, be tied, the immediate
effect is stoppage of the circulation and anemia of the part supplied by the
occluded vessel, accompanied by contraction of the artery below the obstruc-
tion. Almost immediately, or within a short time, the blood begins to flow
with greatly increased velocity through arteries arising above the point
of ligation, but more rapidly only through those which send blood by
anastomosing channels to the anaemic part. At the same time these
arteries with quickened flow dilate. Formerly this vascular dilatation
and increased flow were attributed to rise of blood-pressure above the hga-
ture, but experiments have shown that in most situations this is a factor of
relatively little moment. The rise of pressure cannot of course remain
localised, and after ligation of the femoral artery amounts at most to

204 EMBOLISM

only a Tew millimetres of mercury. Evidence of the relatively slight
importance of this increased pressure is that the ligated artery actually
contracts from the point of ligation to the first branch arising above the
ligature (Thoma, Goldenblum) ; and that the phenomena of dilatation and
increased velocity occur only in arteries which send blood to the ana?mic
area, although others which carry blood elsewhere may arise nearer to the
point of obstruction (Xothnagel). Moreover, it is hardly conceivable
that increased pressure above the ligature can persist for the days and
weeks which may be necessary for the full development of the collateral
circulation.

As the increased flow cannot be due to any change in the viscosity of
the blood, it must be due to increase of the pressure gradient. Therefore,
if it is not the result in any marked degree of rise of pressure aliove the
obstruction, it must be caused by lowered resistance to the stream in the
anastomosing vessels. A moment's reflection will show that this is a far
more purposeful and better mode of compensation than one brought about
exclusively by a rise of pressure which must act upon arteries in no way
concerned in the collateral circulation. The difficulty is an entirely satis-
factory and complete explanation of the lowered resistance. It seems
impossible that it can be due to anything but a widening of the bed of the
stream. Von Recklinghausen has pointed out that the stream-bed for the
anastomosing arteries is enlarged, inasmuch as after occulsion of the main
artery the blood can flow from these collaterals not only in its original bed,
but, also, with diminished resistance, into the stream-bed belonging to the
closed artery. The pressure gradient is thus increased, and consequently
the velocity of the current is quickened in the anastomosing arteries. The
cause of the dilatation of these arteries is not so clear. Thoma states as his
first histo-mechanical principle that increased velocity of the blood-current
leads to widening of the lumen, and eventually, if the increase continues,
to growth of the vessel wall in superficies. Admitting this to be true, it
can hardly be considered an explanation. As the collateral circulation
develops perfectly, and with the same phenomena, after severance of all
connection of the part with the central nervous system, it is evident that
vaso-motor influences which are under central control are not essential
to the process.

Satisfactory as von EeckUnghausen's explanation is, as far as it goes,
there is evidence that it does not cover all of the facts, and that there is
also some mechanism by which the vessels of an ischoemic part are opened
wide for the reception of the needed arterial blood. The existence of
such a mechanism has been recognised by Lister, Cohnheim, Bier, and
others. I must refer especially to the recent papers of Bier for a full

EMBOLISM 205

presentation of the evidence on this point, and shall merely mention, as
a familiar illustration, the extreme arterial hyperemia which follows the
removal of an Esmarch bandage. This flushing of a previously ischasmic
part with arterial blood has been iisually attributed to paralysis of vaso-
constrictor or stimulation of vaso-dilator nerves, but Bier has shown that
it occurs under conditions where this explanation can be probably excluded.

Without following Bier in his somewhat vitalistic conceptions, or specu-
lating regarding the explanation of the phenomenon, we must, I think,
admit that deprivation of arterial blood sets up some condition of a part
whereby the vessels which feed it are in some way dilated to receive any fresh
arterial blood which can reach them. The existence of such an admirably
adaptive, self-regulatory capacity must be an important element in the de-
velopment of a collateral circulation, and it may be remarked that it is a
physiological rather than an anatomical factor. Bier believes that this
capacity is very unequally developed in different parts of the body; being
highest in external parts, and feeble or absent in most of the viscera. He
is also of the opinion that the arterioles and capillaries of external parts have
the power, by independent contractions, of driving blood into the veins ; and
that, by contraction of the small veins the capillaries of these parts are in
large measure protected from the reception of venous blood.

A possible, but I think not fully demonstrated, variation in the power to
lower the resistance to the collateral stream of arterial blood is not, however,
the only physiological property which influences the varying effects following
obstruction to the arterial supply of different parts of the body. In some
situations there are physiological arrangements which seem calculated to
increase the difficulty of establishing an adequate collateral circulation.
Mall has shown that contraction of the intestine exerts a marked influence
upon the circulation through this organ. In the light of his results, it is
interesting to note that, immediately after closure of the main trunk of the
superior mesenteric artery of a dog, the intestine is thrown into violent tonic
contractions and remains in an anfemic, contracted condition for two or three
hours; after which the spasm relaxes and the bloodless condition at once
gives place to venous hypersemia and ha?morrhagic infarction, which appears
in the third to sixth hour after the occlusion of the artery (Mall and Welch) .
This intestinal contraction, which under these circimistances is equivalent to
arterial spasm, is probably one, although not the sole, reason why, in spite
of free anastomoses, occlusion of the arteries supplying the intestine is fol-
lowed by necrosis and ha?morrhage. That the explanation is not to be found
simply in the great length of intestine supplied by a single artery, is evident
from the fact that, if the extra-intestinal arteries supplying a loop much
more than 5 centimetres in length be suddenly closed, the loop becomes

206 EMBOLISM

h^morrliaijic and necrotic (Mall and Welch, Bier). That the conditions are
essentially identical in man is proven by the experience of surgeons, who have
repeatedly observed the same results after separation of the mesentery close
to the intestine over about the same length. The blood can enter at each
end of the short loop arteries, whose branches anastomose freely within the
walls of the loop with those of the closed arteries ; there being a particularly
rich arterial plexus in the submucous coat (Heller). But these anastomoses
are insufficient to preserve the part; although, with reference to the extent
of territory to be supplied, they are large in comparison with some of the
trivial anastomoses which in external parts can respond effectively to the
call for a collateral circulation to far larger areas. It must be left to future
investigations to determine how far the inability of the intestinal vessels
to compensate circulatory obstructions of a degree readily compensated in
many other situations may be due, as claimed by Bier, to an inherent inca-
pacity to lessen the resistance to the collateral stream, or to contraction of the
muscular coats of the intestine, or to other causes. As Panski and Thoma
have shown that slowing and interruption of the circulation in the spleen is
followed, for several hours, by contraction of the muscular trabecule, it is
probable that the development of a collateral circulation in this organ meets
an obstacle similar to that in the intestine.

The various organs and tissues differ so widely as regards their suscepti-
bility to the injurious effects of lack of arterial blood that local anaemia of
equal intensity and duration may in one part of the body produce no appre-
ciable effect, and in another cause the immediate abolition of function and
the inevitable death of the part. In general, the more highly differentiated,
specific cells of an organ are those which suffer first and most intensely. At
one end of the scale are the ganglion cells of the brain, which, after the
witiidrawal of arterial blood for half an hour, and probably for a much
shorter time, cannot be restored to life ; and at the other end may be placed
the periosteum, the cells of which may be still capable of producing Iwne
two or three days after all circulation has ceased. So susceptible to local
anaemia are the ganglion cells of the central nervous system, that not only is
embolism of the branches of the cerebral arteries with only capillary com-
munications, even of the minute terminal twigs in the cortex, always followed
by necrotic softening, but also embolism of the anastomosing arteries in the
pia very often causes softening of at least a part of the area supplied by the
plugged artery. In the well-known Stenson experiment, temporar}' closure
of the rabbit's abdominal aorta, just below the origin of the renal arteries,
for an hour, result-s in the inevitable death of the ganglion cells in the central
gray matter of the lumbar cord; and this notwithstanding the free anas-
tomoses of the anterior and posterior spinal arteries. Many of the lesions

EMBOLISM 207

which pass under the names of myelitis and hemorrhagic encephalitis pre-
sent the histological characters of ischoemic necrosis, although often no
arterial occlusion can be found.

Perhaps, next to elements of the nervous system, the epithelial cells of
the cortical tubules of the kidney are most susceptible to ischemia. Litten
has demonstrated that the temporary ligation of the renal artery of the
rabbit for one and a half to two hours is followed invariably by necrosis of
many of these epithelial cells. The cells in the walls of the blood-vessels and
of connective tissue are relatively insusceptible to temporary slowing or
cessation of tlie circulation.

It is evident from the preceding statements that the nature of the organ
or tissue has a very important influence in determining whether local
necrosis follows arterial embolism.

I have dwelt in some detail, although within the limited space necessarily
inadequately, upon certain physiological characters of the circulation and
of different organs and tissues, which appear to me deserving of more con-
sideration than is usually given to them in discussions of the causes of
embolic necroses and infarctions. It is, of course, not to be inferred that
the number and size of the anastomoses are not of prime importance in de-
termining the mechanical effects of arterial embolism, but, important as
they are, they are not the exclusive determinants of the result. There is no
single anatomical formula applicable to the circulatory conditions under
which all embolic infarcts occur. The nearest approach to such a formula is
that embodied in Cohnheim's doctrine of terminal arteries, a name which
he gave to arteries whose branches do not communicate with each other or
with those of other arteries, although capillaries are of course everywhere in
communication with each other. Terminal vessels in this sense are the renal,
the splenic, the pulmonary, the central artery of the retina, the basal arteries
of the brain, and in general all branches of cerebral and spinal arteries after
they have penetrated the brain or the spinal cord, the intramuscular branches
of the coronary arteries of the heart, and the portal vein.' Cohnheim's
teaching was that infarction occurs always after embolism of a terminal

' There is some confusion as to the sense in which the words " terminal arter-
ies " should be used, and it must be admitted that later investigations have de-
tracted from the precision given to this term by Cohnheim. Thus some do not
recognise the pulmonary artery as terminal, because the lung is supplied likewise
by the bronchial and several other arteries whose capillaries communicate with
those of the pulmonary artery. But unless we make the extent of a second
arterial supply the decisive point in the definition, we should have, for the same
reason, to exclude the renal and the splenic arteries from the class of " terminal
arteries." Then the conception of arteries which are " functionally " but not
automatically terminal, creates still further confusion.

208 EMBOLISM

vessel, except of tlie pulmonary artery, whose capillaries, under ordinary
conditions, are numerous and wide enough, after obliteration of an arterial
branch, to maintain a sufficient circulation ; and of the portal vein whose
capillaries commmiicate freely with those of the hepatic arterj-. Thoma and
Goldenblum have shown that, contrary to Cohnheim's results, no infarction
follows embolism or ligature of the frog's lingual artery, which is or can
readily be made a terminal artery, provided tlie tongue be replaced in the
mouth after the operation so as to avoid stretching and drying from exposure
to the air. It is, therefore, quite possible in some situations for an adequate
circulation to be carried on through merely capillar}' communications, al-
though the conditions are of course less favourable than when there are
arterial anastomoses. On the other hand, as we have seen, embolism of
anastomosing arteries, such as the mesenteric and the cerebral, may be fol-
lowed by necrosis or infarction ; and it cannot be said that the anastomoses
in all of these cases are so unimportant that the arteries are virtually terminal.

We may conclude then that, under ordinary conditions, embolism of an
artery having abundant and large anastomoses has no important mechanical
effect; that embolism of an artery with few and minute anastomoses,
especially embolism of an artery with only capillary communications, is in
many situations followed by necrosis, this result being favoured by certain
physiological conditions which have been considered ; and that embolism
of arteries with fairly well-developed anastomoses may in certain situations
also cause necrosis. Among the factors influencing the result, otlier than
those relating to the number and size of the anastomoses, are the varying
susceptibility of cells to ischaemia, interference with the circulation by con-
traction of muscular constituents of a part, and perhaps some inherent weak-
ness in the physiological part of the mechanism by which a vigorous collateral
circulation is established.

The compensation of sudden occlusion of an arter}', by means of the
collateral circulation, generally presupposes vessels with fairly normal walls
and a certain vigour of the circulation. When the arteries have lost their
elasticity, or the general circulation is feeble, or there is some pre-existing
obstacle to the circulation such as chronic passive congestion, the develop-
ment of an adequate collateral circulation is rendered correspondingly
difficult, and may be impossible. Hence embolism of arteries of the extremi-
ties is often followed by gangrene in the aged, in arterio-sclerosis, in heart
disease, and in infective, anjemic, and exhausting diseases. There are some
observations which suggest that arterial spasm may co-operate with embolism
in causing local antemia.

The agencies by which a sufficient collateral circulation is established may
be tlirown out of order to such a degree that embolism of arteries having

EMBOLISM 209

even the most ample anastomoses may be followed by necTOS.is. Foci of cere-
bral softening have been observed after occlusion of the internal carotid or
of one of the vertebral arteries; although the circle of Willis, the largest and
most perfect anastomosis in the body, was open, and no vascular obstruction
could be found beyond it. Here, doubtless, an important factor in this ex-
ceptional occurrence is the rapidity with which nerve cells die when insuffi-
ciently fed with arterial blood. Cohn narrates the interesting case of a
young woman rendered extremely anajmic by repeated hemorrhages from
cancer of the tongue. In order to control the bleeding the right carotid
was tied. The patient immediately, to all appearances, lost consciousness;
acquired ptosis of the right, then of the left eye, drawing of the angle of the
mouth to the right, and relaxation and almost complete paralysis of the left
extremities. The pulse almost disappeared and the face became very
anaemic. Eespiration was unaffected. The ligature was at once removed,
and at the same moment the patient awoke " as from a dream," and the
symptoms just mentioned quickly disappeared. She said that she had not
completely lost consciousness but was unable to speak, and that her will
had lost control over the organs. She had lost so much blood that she died
three hours later witltout again losing consciousness before death. At the
autopsy the carotids and all of the cerebral vessels were found open, and
there was no change in the brain except ana?mia. In this case, the general
ansemia was evidently so great that after closure of one carotid, which
probably lasted not more than a minute or two, a sufficient supply of blood
could not reach the brain through the circle of Willis.

H(Fmorrhag-ic Infarction. — The explanation of the accumulation and
extravasation of blood in haemorrhagic infarcts has been the subject of
much speculation and experimental study. It is only in certain situa-
tions that infarcts are hfpmorrhagic throughout; and. as already mentioned,
these are no less necrotic than are the white infarcts. The necrosis and
the haemorrhage are co-ordinate effects of the disturbance of the circula-
tion, neither being caused by the other. Yirchow, in his early writings,
suggested as possibilities, without definitely adopting any of them, most
of the explanations which have since been advanced to account for the
apparently paradoxical phenomenon that the occlusion of an artery may
be followed by hyperfemia and hemorrhage in the area of its distribu-
tion. Cohnheim, on the basis of experimental investigations published
in 1872, came to the conclusion that the hypersemia which may follow
arterial embolism is the result of regurgitant fiow from the veins, that
the haemorrhage occurs by diapedesis, and that this diapedesis is the
result of some molecular change in the vascular walls deprived of their
normal supply of nutriment. Although Cohn, in 1860, had shown con-

210 EMBOLISM

clusivcly, by numerous experiments on various orjjans, that the hyperaemia
and liivmorrhage are not the result of regurgitant flow from the veins,
Cohnheim's views were widely accepted until ]>itten, in 1880, in apparent
ignorance of Cohn's work, repeated the experiments of the latter upon
this point with the same results. The experiments of Dr. Mall and myself
upon haemorrhagic infarction of the intestine in 1887 convinced us that
the blood which causes the infarct is not regurgitated from veins. Cohn-
heim's results upon the frog as to the source of the blood in infarcts have
not been confirmed by subsequent experimenters (Zielonko, Kossuchin,
Kiittner, Goldenblum, Thoma).

In situations where closure of an artery is followed by hiemorrhagie
infarction, tying the veins also, so as to shut off all opportunity for reflux
of venous blood, increases the hyperannia and the hemorrhage; and it
may render an infarct ha?morrhagic which otherwise be anaemic. On the
other hand, if all vascular communication of a part be cut off except that
with the veins, the part undergoes simple necrosis without haemorrhagic
infarction; and the result is the same even if the artery be cut open, so
as to afford apparently the most favourable opportunity for backward flow
from the veins. Or, expressed differently, if after closure of an artery
all possibility of access of blood to the obstructed area through anastomos-
ing arteries and capillaries be prevented, the veins remaining open, the
part dies without hajmorrhagic infarction. Cohnheim was in error in
supposing that hjemorrhagic infarction cannot occur where the veins are
provided with valves, for it has been shown by Bryant, Koppe, and ilall
that the small intestinal veins of the dog have effective valves ; yet nowhere
can hfemorrhagic infarction be more readily produced experimentally by
arterial obstruction than in the intestine of this animal. It is, then, quite
certain that the blood wliich accumulates in the capillaries and small veins,
and is extravasated in haemorrhagic infarction, comes in through the
capillary, and, if they exist, the arterial anastomoses, and is not regurgitated
from the veins.

It cannot be doubted that the red corpuscles escape by diapedesis, not by
rhexis; but our experiments are in entire accord with those of Litten
in failing to furnish any support to the prevalent doctrine that the hemor-
rhage is the result of changes in the walls of the vessels caused by insuf-
ficient supply of arterial blood; in fact they seem to us more conclusive
upon this point. If a loop of intestine be completely shut off from the
circulation for three or four hours (by which time, after ligation of the
superior mesenteric artery, hfemorrhagic infarction begins to appear), and
the obstruction be then removed, the blood at once shoots in from the

EMBOLISM 211

arteries with great rapidity, and distends the vessels.' If, as usually
happens, the blood has not coagulated in the vessels, no hsmorrhagic infarc-
tion subsequently appears. If, immediately after the circulation has been
fully re-established in the loop, the superior mesenteric artery be ligated,
the intestine from the lower part of the duodenum into the colon becomes
the seat of hfeniorrhagic infarction in the usual time; but the infarction
does not appear earlier and is not more intense in the part which had been
previously deprived of its circulation for three or four hours than in the
rest of the small intestine. It is true, as Cohnheim has shown, that re-estab-
lishment of a local circulation, after its stoppage for many hours or days,
may be followed by hsmorrhages in the previously ischaemic area; but
hsemorrhagie infarction after arterial occlusion begins long before it is
possible to demonstrate this change in the vascular wall caused by lack of
blood-supply.

In a part undergoing hsemorrhagie infarction the circulation is greatly
retarded in consequence of the small difference between the arterial and
the venous pressures. This result may be brought about by rise of the
venous or lowering of the arterial pressure. If the veins are obstructed
sufficiently to render the outflow nil, or very small, and the arteries are
open, the infarction is intense, and occurs with high intracapillary pressure.
In consequence of the free anastomoses of veins this mode of production
of an infarct is rare, but it may occur after thrombosis of the mesenteric,
the splenic, and the central retinal veins. Its explanation offers no especial
difficulties. If the veins are open the arterial pressure must be reduced
in order to furnish the conditions necessary for the production of hsemor-
rhagie infarction. This later cases is the one present in arterial embolism
with hsemorrhagie infarction, and is the one especially needing explana-
tion. The intracapillary pressure in this case may vary, but will generally
be low. The arterial pressure is so low that the lateral pulse-waves nearly
or entirely disappear, so that the force which drives the blood into the
capillaries is no longer the normal intermittent one, which experiment
has shown to be essential for the long-continued circulation of the blood
through the capillaries and veins. This reduction, or absence of lateral
pulsation, to which, so far as I know, other experimenters have not called
attention, I believe to be the factor of first importance in the causation of
hsemorrhagie infarction following arterial embolism.

We are not sufficiently informed concerning the physical and vital
properties of the blood and of the blood-vessels to be able to predict posi-

" Bier's experimental results concerning the absence of hypersemia after tem-
porary ischaemia of the intestine do not, according to our experience, apply to
prolonged Ischaemia, which we found to be followed by intense hyperaemla.

212 EMBOLISM

tively what would happen under such abnormal circulatory conditions
as those named, and actual observation only can furnish a solution. The
difficulties in making such observations under the requisite conditions are
considerable. Dr. Mall and I, in examining microscopically, in a specially
constructed apparatus, the mesenteric circulation of the dog after liga-
gation of the superior mesenteric artery, observed that immediately after
the occlusion the circulation ceases in the arteries, capillaries, and veins.
In a short time the circulation returns.^ but with altered characters. The
arteries are contracted, but may subsequently dilate somewhat; and the
blood from tlie collaterals flows through them with diminished rapidity,
and without distinct lateral pulsation. The direction of the current is
reyersed in some of the arteries. The movement of the blood in the capil-
laries and veins is sluggish and irregular. The direction of the current
in some of the veins may be temporarily reversed, but we were unable
to trace a regurgitant venous flow into the capillaries. The distinction
between axial and plasmatic current is obliterated. Gradually the smaller
and then the larger veins become more and more distended with red
corpuscles, and all of the phenomena of an intense venous hyperemia
appear, so that one instinctively searches for some obstruction to the
venous outflow. The red corpuscles in the veins tend to accumulate in
clumps, and may be moved forward, or forward and backward, in clumps
or solid columns. Stasis appears in the veins. This is at first observed
only here and there and is readily broken up by an advancing column of
blood; but it gradually involves more and more of the veins, and in some
becomes permanent, producing an evident obstacle to the forward move-
ment of the blood. The same phenomena of distention with red corpuscles,
clumping, to-and-fro movement, and stasis appear gradually in the capil-
laries. An interesting appearance, sometimes observed in capillaries and
veins, is that of interrupted columns of compacted red corpuscles with
intervening clear spaces which are sometimes clumps of white corpuscles,
sometimes of platelets, sometimes only clear plasma. With the partial
blocking of the veins and capillaries, red corpuscles begin to pass through
the walls of these vessels by diapedesis ; and after a time the hemorrhage
becomes so great that it is difficult to observe the condition within the
vessels. The venous outflow is diminished immediately or shortlv after
the closure of the superior mesenteric artery; it then rises, but later it
continuously falls to a minimum.

An experiment which we made shows that the blood for hapmorrhagie
infarction need not necessarily enter from the collaterals, and it sheds
some light upon the condition of the circulation during the production
of the infarct. We ligated all of the va^icular communications of the

EMBOLISM 213

intestiue, with the exception of the main artery and vein, and then tied
the intestine above and below, so that the included intestine was supplied
only by the main artery and the blood returned by the main vein. Under
these circumstances no infarction results. We then by a special device
gradually constricted the main artery. In repeated experiments we found
that not until the artery is sufficienty compressed to stop the lateral pul-
sations in its branches — the pressure in these being then about one-fifth
of the normal — does hemorrhagic infarction appear. Precautions were
taken to make sure that the flow through the constricted main artery and
its branches continued, and that the vein remained open. We have often
measured the blood-pressure in branches of the superior mesenteric artery
after ligation of this artery and during the progress of an infarction, and
have found it to be generally one-fourth to one-fifth of the normal pressure.
If the pressure on the arterial side falls below a certain minimum no
hfemorrhage occurs in the infarction.

It is evident from the preceding description that the phenomena observed
under these peculiar circulatory conditions are in large part dependent
upon the physical properties of the blood, especially upon its viscosity
and the presence of suspended particles which readily stick together; and
differ in important respects from those which would occur under similar
conditions with a thin, homogeneous fluid. The pressure gradient from
arteries to veins of the ischoemic area is so low that the red corpuscles
cannot fully overcome the resistance in the veins and capillaries. They
accumulate in these situations, and probably undergo some physical change
by which they become adherent to each other and to the vascular wall.
The absence of the normal pulse-waves prevents the breaking up of these
masses of corpuscles, the longitudinal pulse-waves sometimes obsen'ed
having little or no efl'ect in disintegrating the masses. In this way numer-
ous small veins and capillaries become blocked, with a resulting rise of
intracapillary pressure and diminution of outflow of blood through the
veins. Von Frey has shown by interesting experiments that an intermit-
tent pulsating force is necessarj' to prevent the speedy blocking of veins and
capillaries with red corpuscles in carrying on artificial circulation with
defibrinated blood through living organs. Kronecker has also demonstrated
the influence of a pulsating force in increasing the venous outflow.

The diapedesis is due to the slowing and stagnation of the blood, and to
the blood-pressure. Without a certain height of pressure there is no
diapedesis; and, with a given retardation and stasis of the blood-current,
the higher the intracapillary and intravenous pressure the greater the
amount of diapedesis. The matter which needs explanation is that the
diapedesis may occur with lower than the normal pressure, and through

214 EMBOLISM

vessel walls apparently xinaltered. This I attribute to the fact that tlie
red corpuscles, in consequence of the slow circulation, have opportmiity
to become engaged in the narrow paths followed by the lymph as it passes
out between the endothelial cells. Diapedesis is a slow process, and the
channels for it are much smaller than the thickness of a red corpuscle.
Unless the red corpuscles can get started on the path between the endo-
thelial cells, they cannot traverse it; and unless the circulation is very
much slowed, and the outer plasmatic current obliterated, there is no
opportunity for the corpuscles to become engaged between the endothelial
cells, provided, that is, the vascular wall be normal. With greatly retarded
circulation there is opportunity, and when the way in front is blocked by
compact masses of red corpuscles, and sometimes by actual thrombi, the
only path open to the corpuscles is that followed by the lymph between
the endothelial cells. This then becomes the direction of least resistance
for their movement.

The reason why infarctions are haemorrhagic in some situations and
not in others offers difficulties chiefly in consequence of our ignorance
of the exact circulatory conditions which lead to the production of infarc-
tion in different parts of the body. It is generally assumed that these
circulatory conditions are everj-where essentially the same; but this is
by no means proven. As we have already seen, the physiological conditions
which influence the result are various. It may be, therefore, that the
requisite intracapillarj- and intravenous pressure, or some other condition
of the circulation essential for the production of haemorrhagic infarction,
is lacking when the infarction is anjemic. In general a high venous pres-
sure favours haemorrhage in an infarction, and a low arterial pressure
opposes it. The pressure in the superior mesenteric and portal veins is
higher than in any other veins of the body. Haemorrhagic infarction of
the lung occurs especially with high degrees of chronic passive congestion
in which the venous pressure is elevated. Thrombosis of veins seems to
be the cause of at least some of the hemorrhagic infarcts of the spleen.
Haemorrhagic infarction of the kidney may be produced experimentally
by ligating the renal veins.

The studies of recent years upon the formation lymph have demonstrated
that the blood-vessels in different regions differ markedly in their perme-
ability, those of the intestine being probably the most permeable. It may
be that this difference in the constitution of the vessels is an important
factor in determining the extent of diapedesis under similar circulatory
conditions. As pointed out by Weigert, however, the greatest influence
appears to be exercised by the resistance offered by the tissues to the
escape of red corpuscles from the vessels. Haemorrhagic infarction occurs

EMBOLISM 215

especially where this tissue-resistance is low, as in the loose, spongy' tex-
ture of the lungs, and in the soft mucosa and lax submucosa of the intestine.
The hemorrhage is far less in the dense muscular coats of the intestine.
The considerable resistance offered by the naturally firm consistence of
the kidney is increased by the swelling and hardness resulting from coagu-
lative necrosis of the epithelial and other cells of this organ; so that
infarcts in this situation are nearly always anaemic in the greater part
of their extent, although often hemorrhagic in the periphery. The spleen
is of softer consistence than the kidney; and here both white and red
infarcts may occur, the latter especially with increased venous pressure.
Although infarcts of the brain are soft, they are much swollen in the
fresh state from infiltration with serum, so as to displace surrounding
parte (Marchand). Here also there must be considerable resistance to
the passage of red corpuscles through the vascular walls; but it is not
uncommon for these softened areas to present scattered foci of hemorrhage,
and sometimes they are markedly hemorrhagic. The intraocular pressure
is probably a factor in making embolic infarcts of the retina anjemic.
Embolism of arteries of the extremities with insufficient collateral circu-
lation is often associated with extravasations of blood in the ischemic areas.
Metamorphoses of Infarcts. — A bland infarct is a foreign body most
of the constituents of which are capable of absorption and replacement
by connective tissue. The red corpuscles lose their colouring matter, some
of which is transformed into amorphous or crj'stalline hematoidin. Poly-
nuclear leucocytes, through chemiotactic influences, wander in from the
periphery, the advance guard being usually the seat of marked nuclear
fragmentation. This nuclear detritus mingles with that derived from
the dead cells of the part. Granulation tissue develops from the living
tissue around the infarct. Young mesoblastic cells wander in and assist
the leucocytes in their phagocytic work. In the course of time the debris,
which becomes extensively fatty, is disintegrated and removed ; new vessels
and new connective tissue grow in; and finally a scar, more or less pig-
mented according to the previous content of blood, marks the site of the
infarct. In chronic endocarditis, depressed, wedge-shaped scars are often
found in the spleen and the kidneys. They are rare in the lungs, not
because hemorrhagic infarcts in this situation usually undergo resolu-
tion like pneumonia or simple hemorrahges, but because pulmonary infarcts
generally occur under conditions not compatible with the prolonged sur-
vival of the patient. Partly organised infarcts are not uncommon in the
lungs. In the brain, ischemic softening may remain for a long time with
apparently little change; but the common ultimate result is a cyst-Uke
structure, which may be more or less pigmented, and is characterised by

216 EMBOLISM

a mesliwork of delicate neuroglia anrl ronnoftivo-tissue fibres, infiltrated
with milky or clear serum. Into the finer liistological details of the pro-
cess of substitution of an infarct by scar-tissue it is not necessary here
to enter.

Chemical Effects. Mclastajies. — Embolism and metastasis are some-
times employed as practically synonymous terms; but, in ordinary usage,
by metastasis is understood any local, morbid condition produced by the
transportation of pathological material by the lymphatic or blood-current
from one part of the body to another.

We have already considered the coarser bland emboli in respect of their
mechanical eilects. Similar emboli, so small as to become lodged only in
arterioles or capillaries, produce no mechanical effects unless, as rarely
happens, numerous arterioles or capillaries are obstructed. The subject of
transportation of pigment granules, and that of metallic and carboniferous
dust, producing the various konioses, does not fall within the scope of this
article. On account of certain special features, emboli of air, of fat, and of
parenchyma-cells are most conveniently considered separately (pp. 222-2"28^.
There remain, in contrast to the dead and inert emboli to which our atten-
tion has been especially directed, those containing tumour-cells and parasitic
organisms, or their products.

Masses of tumour growing into a blood-vessel may be broken off and
transported as course emboli, producing all of the mechanical effects which
we have described. There have been instances of sudden death from block-
ing of the pulmonary artery by cancerous or sarcomatous emboli, as in a case
reported by Feltz. It is, however, as a cause of metastatic growths that
emboli of tumour-cells have their chief significance. In individual cases it
is oftener a matter of faith than of demonstration that the metastasis is due
to such emboli, for opportunities to bring absolutely conclusive proof of this
mode of origin of secondary tumours are not common. There have, however,
been enough instances in wliich the demonstration has been rigorous to
establish firmly the doctrine of the embolic origin of metastatic tumours.
The evidence is that tumour-metastases are far more frequently due to
capillary emboli than to those of larger size. Cancers and sarcomas furnish
the great majority of emboli of this class; but in rare instances even benign
tumours may penetrate blood-vessels and give rise to emboli, which excep-
tionally are the starting-points of secondary growths of the same nature as
the primary. Mention has already been made of paradoxical and retrograde
transport of tumour-emlx)li, as well as of the possibility of emboli of timiour-
cells being so small as to traverse the pulmonary capillaries.

Certain animal parasites, as FUaria sanguinis, Bilharzia h^matobia,
and Plasmodium malariw, are inhabitants of the blood, or, in certain stages

EMBOLISM 217

of their existence witliin the human body, are frequently found there.
According to observations of Cerfontaine and Askanazy, the usual mode of
transportation from the intestine of the embn'os of trichina is by the lym-
phatic and blood-currents. Echinococci have been known to pass from the
liver through the vena cava; or primarily from the right heart into the
pulmonan,- artery; and emboli from echinococci present in the wall of the
left heart may be transported to distant organs (Davaine). Amaba coli
has been found in the intestinal veins; and, as stated by Dr. Lafleur in
his article on "Amoebic Abscess of the Liver" (Allbutt's "System of
Medicine," V, p. 156), it is probable that this parasite can reach the liver
through the portal vein.

On account of their frequency and serious consequences, infective emboli
containing pathogenetic bacteria are of especial significance. Such emboli
constitute an important means of distribution of infective agents from pri-
marv' foci of infection to distant parts of the body, where the pathogenetic
micro-organisms, by their multiplication and their chemical products, can
continue to manifest their specific activities. These emboli are often derived
from infective venous thrombi connected with some primary area of infec-
tion. The port<al of infection may be through the integument, tlie alimentary
canal, the respiratory tract, the genito-urinary passages, the middle ear, or
the eye, vvith corresponding infective thrombo-phlebitis in these various
situations. Or there may be no demonstrable atrium of infection, as in many
cases of infective endocarditis, which constitutes an important source of in-
fective emboli. Emboli may of course come from secondary and subsequent
foci of infection.

Coarse emboli are by no means essential for the causation of infective
metastases, nor is it necessary that there sliould be any thrombosis to afford
opportunity for the distribution of micro-organisms from a primary focus.
Bacteria may gain access to the circulation, singly or in clumps; and such
bacteria, without being enclosed in plugs of even capillar}' size, may become
attached to the walls of capillaries and small vessels and produce local metas-
tases. In this way infective material coming from the systemic veins may
pass through the pulmonary capillaries without damage to the lungs, and
become localised in various organs of the body.

We cannot explain the various localisations of infective processes in in-
ternal organs of the body exclusively by the mechanical distribution of
pathogenetic micro-organisms by the circulation. We must reckon with the
vital resistance of the tissues, which varies in different parts of the body, in
different species and individuals, and with reference to different organisms.
Even the pyogenetic micrococci, which are capable of causing abscesses any-
where in the body, do not generally produce their pathogenetic effects in
17

218 EMBOLISM

every place wliere tlicy may chance to lodge. They have their seats of prefer-
ence, which vary in difJcrcnt species of aJiimal and prohably in different
individuals.

The mere presence of pathofrenetic hacteria in an emholus does not neces-
sarily impart to it infective jiroperties. This is true even of emboli contain-
ing pyogenetic cocci. I have in several instances observed in the spleen and
kidney only the mechanical, bland efTccts of emboli derived from the vegeta-
tions of acute infective endocarditis, and have been able to demonstrate
streptococci or other pathogenetic organisms in the original vegetations and
in the emboli. As has already been remarked concerning thrombi, the line
cannot be sharply drawn between bland emlxdi and septic emboli, simply on
the basis of the presence of bacteria ; although of course the septic properties
must be derived from micro-organisms.

Infective emboli are capable of producing all of the mechanical effects
of bland emboli ; to these are added the specific effects of the micro-organisms
or their products. These latter effects are essentially chemical in nature,
and may occur wlierever the emboli lodge, being thus independent of the
particular circulatory conditions essential for the production of mechanical
effects. The most important of these chemical effects are ha?morrhages,
usually of small size, and of an entirely different causation from those of
hemorrhagic infarction; necroses; inflammation, often suppurative, and,
in case of putrefactive bacteria, gangrenous putrefaction. The most im-
portant function of infective embolism is in the causation of pya?mia. This
subject has been most competently presented by Professor Cheyne in All-
butt's " System of Medicine," I, p. COl. who has left nothing which requires
further consideration here.

Embolic Aneurysms. — Both the first recognition and the correct explana-
tion of cmlwlic aneurysms, at least of the great majority of cases, belong to
British physicians and surgeons. Tufnell, in l.S.'i.'i, called attention to the
influence of emboli in causing aneurysmal dilatation. There followed ob-
servations by Ogle, Wilkes, Holmes, Church, and R. W. Smith, before the
appearance, in 1873, of Ponfick's important paper on embolic aneurysms.
I'onfick explained their formation by direct injury to the vessel-wall, inflicted
usually by calcareous, spinous emboli : a view which has since been confirmed
only by Tlioma. In 1877, Goodliart, in reporting a case gave the first
satisfactory explanation of the mode of production of most of these aneu-
rysms. He pointed out their association with acute infective endocarditis,
and referred them to acute softening of the arterial wall, caused by toxic
emboli. OtJier observations followed; and in 1885 Osier reported a case
which, although not embolic, belongs etiologically to the same general cate-
gory. This was a case of multiple mycotic aneurysms of the aorta due to

EMBOLISM 219

infective endaortitis associated with infective endocarditis. In 188G and
1887 appeared the contributions of Langton and Bowlby, the most valuable
in English literature, who fully confirmed and expanded in detail the views
first briefly announced by Goodhart. Eppinger, in his extensive monograph
on aneurysms published in 1887, presented the results of a minute and care-
ful study of this class of aneurysm, which he calls aneurysma mycotico-
embolicum, and reported seven personal observations. Of later papers on
the subject may be mentioned tliose of Pel and Spronck, Duckworth, Buday,
and Clarke.

The evidence is conclusive that aneurysms may be caused by the destruc-
tive action of bacteria contained in emboli or directly implanted on the inner
vascular wall. The usual source for such emboli in relation to aneurysm
is furnished by acute infective endocarditis ; but as there is every transition
from ordinary warty endocarditis to the most malignant forms, and as the
same species of micro-organisms may be found in the relatively benign as
in the malignant cases, no single type of endocarditis is exclusively associated
with these aneurysms. As is demonstrated by Osier's case, the same result
may follow a mycotic endarteritis not secondary to embolism.

Eppinger has shown that at least the intima and the internal elastic
lamella, and usually a part, sometimes the whole, of the media, are destroyed
by the action of the bacteria, when an aneurysm is produced. The site of
the aneurysm corresponds to this circumscribed area of destruction, and
therefore to the seat of the embolus, and is not above it, as some have sup-
posed. Tlie aneurysm is usually fonned acutely, sometimes slowly. It may
remain small or attain a large size. Multiplicity and location at or just
above an arterial branching are common characteristics of embolic aneurysms.
Favorite situations are the cerebral and mesenteric arteries and arteries of
the extremities; but these aneurysms may occur in almost any artery.
Arteries without firm support from the surrounding tissues offer the most
favourable conditions for tlie production of embolic aneurysms.

Eppinger totally rejects direct mechanical injury from an embolus as a
cause of aneurysm in the manner alleged by Ponfick : and Langton and
Bowlby are likewise sceptical as to the validity of Ponfick's explanation be-
yond its possible application to some of his own cases. Certainly the great
majority of embolic aneurj'sms are caused Viy pathogenetic organisms, and
belong, therefore, to tlie class of parasitic aneurysms ratlier than to that of
traumatic aneurysms. The affection is not a common one.

In this connection mere mention may be made of the interesting and very
common verminous aneurysms of the anterior mesenteric artery of horses,
caused by Strongylus armafus.

Gexetial Symptoms. — The symptoms of bland embolism are dependent
mainly upon the degree and extent of the local anjemia produced by the

230 EMBOLrSM

artorial obstruction, and upon the specific functions of tlie part involved. la
infective embolism there are additional sjinptoms referable to local and
general infection. Here the constitutional sjTnptoms usually overshadow
those referable to the emiwiic obstruction and tlie local lesions.

It is not known that any symptoms attend the act of transportation of
an embolus, even through the heart. In some situation there is sudden pain
at the moment of impaction of tlie embolus (embolic ictus). This is more
marked in large arteries, especially those supplying the extremities, than in
smaller and visceral arteries. This pain has been attributed to various
causes; but the most probable explanation seems to me to be irritation, by
the impact of tlie embolus and by the sudden distension of the artery, of
sensorj' nerves and nerve-endings in the vascular wall, present especially in
the outer coat. It may \>e that the Pacinian corpuscles, which are particu-
larly abundant in and around the adventitia of the abdominal aorta, tiie
mesenteric arteries, the iliac and the femoral arteries, are susceptible to
painful impressions. Embolism of the arteries named is characterised
especially by the intensity of the pain, described sometimes as the sensation
of a painful blow, at the moment of impaction of the embolus. Surgeons
are familiar with the pain which attends the act of ligation of larger blood-
vessels.

Of the pain which follows arterial embolism there are other causes,
such as irritation of sensory nerves by local anaemia, altered tension of
the part, presence of waste and abnormal metabolic products, structural
changes in nerves, inflammation of serous membranes covering infarcts,
and so forth.

Some writers have spoken of the occasional occurence of a nervous or
reflex chiU at the time of the embolic act; but, without denj-ing the pos-
sibility of such an occurrence, I think that chills associated with embolism
have been due usually to infection rather than to vascular plugging.

Although Strieker has constructed a hypothesis of fever based largely
upwu experiments interpreted by him as demonstrating that the commo-
tion mechanically set up by emboli causes fever, I am not aware of any
conclusive observations which show that fever may be produced in tliis
way in human beings. Independently of the intervention of pathogenetic
micro-organisms, arterial embolism may, however, be accompanied by ele-
vation of temperature. Direct invasion of thermic nervous centres is, of
course, only a special case in certain localisations of cerebral embolism.
Gangolphe and Courmont attribute the fever sometimes observed after
arterial occlusion to the absorption of pyretogenetic substances which they
iind produced in tissues undergoing necrobiosis. Other possible causes
of fever may be the reactive and secondary inflammations consecutive to
embolism.

EMBOLISM 221

Only in external parte, or parts open to inspection, can the phenomena
of mortification, or '' local cadaverisation,'' as Cruveilhier designated the
results of shutting off arterial blood, be directly observed. Here are mani-
fest the pallor accompanied by patches of lividity, the cessation of pul-
sation, the loss of turgidity, the coldness, the annihilation of function,
the local death. The haemorrhages which result from arterial obstruction
may, however, be evident, not in external parts only, but also by the dis-
charge of blood from the respiratory passages, the intestine, and the urinary
tract; as the result of pulmonary, intestinal, and renal infarction respec-
tively. The phenomena following retinal embolism are open to direct
inspection by the ophthalmoscope. In part* not accessible to physical
exploration the symptoms are referable mainly to the disturbance or aboli-
tion of function, and, therefore, vary with the special functions of the
part. They will be considered in connection with embolism of special
arteries (p. 229).

Diagnosis. — The main reliance in the differential diagnosis of embolism
from thrombosis, or from other forms of arterial obstruction, is the dis-
cover}' of a source for emboli, the sudden onset and the intensity of symp-
toms referable to local arterial anaemia, occasionally the disappearance or
marked improvement of symptoms in consequence of complete or partial
re-establishment of the circulation, and to some extent the absence of
arterio-sclerosis or other causes of primary arterial thrombosis.

Valuable as these characters are for diagnosis, they are neither always
present nor infallible. For pulmonary embolism the source is to be sought
in peripheral venous thrombosis or cardiac disease with thrombi in the
right heart; for embolism in the aortic system, the usual source is the left
heart, the great majority of cases being associated with disease of the
aortic or mitral valves. It may, however, be impossible to detect the
source, and its existence does not exclude the occurrence of thrombosis or
other forms of arterial occlusion.

Xor are the symptoms consecutive to emlwlism always sudden in onset.
An embolus may at first only partly obstruct the lumen of the vessel, which
is later closed by a secondary thrombus; or it may be so situated that a
thrombus springing from it is the real cause of the local ansmia. For
example, an embolus lodged in the internal carotid artery usually causes
no definite symptoms, but a secondary thrombus may extend from the
embolus into the middle cerebral artery, in which case cerebral softening
is sure to follow. On the other hand, the complete closure of an artery
may be effected by a thrombus with such rapidity as to suggest embolism.

While the sudden occlusion of an artery by an embolus often causes
temporary ischeemia of greater intensity and over a larger area than the

222 EMBOLISM

more gradual closure of the same artery by a tlironibus, so tliat when the
collateral circulation is fully establislied tiie disappearance or reduction
of tlie symptoms may be more marked in tlie former ciisc than the latter,
there may be even in thrombosis very decided improvement in the symp-
toms with the development of the collateral circulation.

The existence of arterio-sclerosis, of course, does not exclude embolism ;
but in case of doubt the chances are strongly in favour of embolism in
children and young adults with healthy arteries, especially if cardiac dis-
ease be present; the most common association in the latter cases being with
mitral affections.

Notwithstanding all of these uncertainties, the diagnosis, of embolism,
when it produces definite symptoms, can be correctly made in the majority
of cases.

AiE Embolism. — The majority of cases in which death has been attri-
buted to the entrance of air into the circulation have been surgical opera-
tions and wounds about the neck, shoulder, upper part of the thorax and
skull, where air has been sucked into gapping veins and sinuses by thoracic
aspiration; and cases in which air has entered the uterine veins, chiefly
from the puerperal uterus, either spontaneously, as after alwrtions or
detachment of placenta praevia, or after injections into the uterine cavity.
Jiirgensen has reported cases in which he believes death was caused by the
entrance of gas into open veins connected with diseased areas in the stomach
and intestine. Gaseous embolism has been assigned as the cause of symp-
toms and of death in caisson-disease and in divers; and it has been observed
in connection witli the development of gas-producing bacilli in tiie body.

A large number of experiments have been made to determine the effects
of air introduced into the circulation. These have demonstrated that when
the air is introduced slowly and at intervals, enormous quantities can some-
times be injected in a comparatively short time without manifest injury.
Tlius Laborde and Muron injected into the external jugular vein of a dog
1120 cc. in the space of an hour and a half without causing death; and
Jiirgensen injected into the left femoral artcr}' of a dog, weighing 43. .5 kilo,
3550 cc. in the space of two hours and a half with only slight disturbance
of the respiration and of the action of the heart. Under these circumsttinces
the air-bubbles circulate with the blood, pass through the capillaries, and
are speedily eliminated. Small amounts of air introduced directly into
the carotids, the left heart or thoracic aorta, are often quickly fatal from
embolism of the cerebral or coronary arteries.

The sudden introduction of large amounts of air into the veins is quickly
fatal. Rabbits are much more susceptible to air embolism than dogs or
horses. 50 cc. of air, and even more, can often be injected at once into

EMBOLISM 233

the external jugular vein of a medium-sized dog without causing death ;
nor can a dog be killed by simple aspiration of air into the veins, even
when an open glass tube is inserted into the axillary or jugular vein and
shoved into the thorax ( Feltz ) . Barthelemy says that as much as 4000 cc.
of air must be introduced into the veins of horses in order to cause death.

After death from entrance of air into the veins, the right cavities of
the heart are found distended with frothy blood, and blood containing air-
bubbles is found in the veins — especially those near the heart, and in the
pulmonary artery and its brandies. It is exceptional under these cir-
cumstances for air to pass through the pulmonary capillaries into the
left heart and aortic system.

There are two principal explanations of the cause of death in these cases.
According to one, associated especially with Couty's name, the air is
churned up with the blood into a frothy fluid in the right heart, and on
account of its compressibility this mixture cannot be propelled by the
right ventricle, whicli thus becomes over-distended and paralysed. Ac-
cording to another hypothesis, supported by experiments of Passet and of
Hauer, blood mixed with air-bubbles is propelled into the pulmonary artery
and its branches, but the frothy mixture cannot be driven through the pul-
monary capillaries, so that death results from pulmonary embolism. The
paralysing influence upon the heart of obstruction to the coronary circula-
tion from accumulation of air in the right heart and in the coronary veins
must also be an important factor, as well as the cerebral anaemia. Prob-
ably all of these factors — over-distension of the right heart, embolism of
the pulmonary artery and its branches and of the coronary veins, and cere-
bral ana?mia — may be concerned in causing death, although not necessarily
all in equal degree in every case.

We have no information as to the amount of air required to cause death
by intravenous aspiration or injection in human i)eings. It seems certain
that man is relatively more susceptible in this respect than the dog or
the horse : but it is probable that the fatal quantity of air must be at least
several cubic centimeters, and tliat the entrance of a few bubbles of air
into the veins is of no consequence. Many authors have entertained very-
exaggerated ideas of the danger of entrance of a small quantity of air
into the veins.

A large proportion of the cases reported in medical records as deaths
due to air embolism will not stand rigid criticism. I have had occasion to
look through the records of a large number of these cases, and have been
amazed at the frequently unsatisfactory and meagre cliaracter of the evidence
upon which was based the assumption that death was due to the entrance
of air into the circulation.

224 EMBOLISM

So far as I am aware, the first attempt to make a bacteriologiral exami-
nation and to determine the nature of the pas-hubbles found in the blood
under circumstances suggestive of death from entrance of air into the vessels,
was made by me in 1891. A patient witli an aortic aneurysm, which had
perforated externally and given rise to repeated losses of blood, died sud-
denly without renewed hamorrhage. At the autopsy, made iu cool weather
eight hours after death, there was abundant odourless gas in the heart and
vessels without a trace of cadaveric decomposition anywhere iu the body.
It was proven that the gas was generated by an anaerobic bacillus, which
was studied by Dr. Nuttall and myself, and named by us BaciUus aerogcrKS
capsulatiis. This bacillus is identical with one subsequently found by
E. Fraenkel in gaseous phlegmons, and with that found by Ernst and
others in livers which are the seat of post-mortem emphysema (Schaum-
leher) . It is widely distributed in the outer world, being present especially
in the soil, and often exists in the human intestinal canal. Dr. Flexner
and I have reported twenty-three personal observations in which this gas-
bacillus was found, and since our publication we have met with several
additional ones. The only points concerning these cases which here concern
us are, that this bacillus not only may produce gas in cadavers, but may
invade the living body, and cause a variety of affections characterised by
the presence of gas. There is evidence that the bacilli may be widely dis-
tributed by the circulation before death, and that gas generated by them
may be present in the vessels during life. In most cases, however, in which
this bacillus was present, the gas found in the heart and blood-vessels was
generated after death. I do not consider that there is satisfactory evidence
that similar effects may be produced by the colon bacillus, as has been
asserted. There is, however, a facultative anaerobic bacillus, very closely
allied to B. aerogenes capsulatus, which may also cause gaseous phleg-
mons and produce gas in the vessels after death.

Our observations have demonstrated that the finding of gas-bubbles in
the heart and vessels a few hours after death without any evidence of
cadaveric decomposition is no proof that the gas is atmospheric air, or is not
generated by a micro-organism. In all such cases a bacteriological exami-
nation is necessary to determine the origin of the gas. In many cases
reported as death entrance of air into the veins, the evidence for this con-
clusion has been nothing more than finding gas-bubbles in the heart and
vessels after sudden or otherwise unexplained death. In the absence of a
bacteriological examination, the only cases which can be accepted as con-
clusive are those in which death has occurred immediately or shortly after
the actually observed entrence of a considerable amount of air into the
veins. There have ])ccn a number of carefully observed and indisputable

EMBOLISM 225

instances in which during a surgical operation in the " dangerous region "
life was imperilled or extinguished by the demonstrated entrance of air
into wounded veins. After the audible sound of the suction of air into the
vein, death was sometimes instantaneous ; or it occurred in a few minutes
after great dyspnoea, syncope, dilatation of the pupils, pallor or cyanosis,
occasionally convulsions, sometimes the detection by auscultation over the
heart of a churning sound synchronous with the cardiac systole, and the
exit from the wounded vein of blood containing air-bubbles. These vciy
alarming symptoms may disappear and the patient recover.

The evidence for this mode of death would seem to be almost as conclusive
for a certan number of the sudden deaths following injections into the uterus,
especially for the purpose of committing criminal abortion, and after the
separation of placenta prsevia. But I am sceptical as to this explanation of
many of the deaths which have been reported as due to the entrance of air
into the uterine veins. In the reports of Dr. Flexner and myself vill be
found the description of several cases of invasion of B. aerugenes capsu-
latiis, which without bacteriological examination would have the same claim
to be regarded as deaths from entrance of air into the uterine veins as many
of those so recorded. I have had the opportunity to examine the museum
specimen of a uterus of a much-quoted case so reported, and I found in its
walls bacilli morphologically identical with our gas-bacillus. Certainly all
cases of this kind should hereafter be reported only after a bacteriological
examination. Jiirgensen's cases of supposed entrance of gas into the general
circulation through the gastic and the intestinal veins are undoubtedly
instances of invasion, either before or after death, of gas-forming bacilli.

Since Paul Bert's researches, the symptoms and death which occasionally
follow the rapid reduction of previously heightened atmospheric pressure
upon exit from a caisson or diver's apparatus, have been plausibly attributed
to the liberation of bubbles of nitrogen in the circulating blood. This expla-
nation of the phenomena is not, however, free from doubt, and it is difficult
to bring conclusive evidence in its support in the case of human beings.
Little weight can be attached at present to the reports of finding bubbles of
gas in the blood-vessels of those who have died from caisson-disease, for these
reports have not hitherto been accompanied by any bacteriological examina-
tion to determine the source of the gas.

Ewald and Kobert have made the curious observations that the lungs are
not air-tight under an increase of intrapulmonary pressure which may
temporarily occur in human beings. They found in experiments on animals
that small air-bubbles may appear under these circumstances in the pul-
monary veins and left heart without any demonstrable rupture of the pul-

226 EMBOLISM

nioiiarj tissue; and they ar<,nie tliat this may occur under similar conditions
in human beings. The entnince into the circulation of a few minute air-
bubbles in this way would doubtless produce no effects. Ewald and Robert
cite two or three not at all convincing published cases in support of the
jMissibility of death resulting from the entrance of air through unruptured
pulmonary veins. Very jjlau^ible is Janeway's hypothesis that the transitory
hemiplegia and other cerebral symptoms, which have occa.sionally been
observed to follow washing-out the jjicural cavity with peroxide of hydrogen,
or some other procedure by which air or gas may accumulate in this cavity
under high pressure, are due to air embolism or gaseous embolism of the
cerebral vessels.

Not less remarkable are the experimental observations of Lewin and Gold-
schmidt concerning air-embolism following injections of air into the bladder
iuid its passage into the ureters ajul renal pelves. It has not been demon-
strated that the same phenomenon can occur mider similar conditions Ln
human beings.

Fat Embolism. — Fat embolism, first observed in human beings by Zenker
and by Wagner in 1862, is the most common form of embolism ; but its
practical importance does not correspond to its frequency. It is of greater
surgical than medical interest, inasmucli as the severer forms are nearly
always the result of traumatism. The usual conditions for its occurrence
are (i.) rupture of the wall of a vessel (ii.) proximity of liquid fat, and
(iii.) some force sufficient to propel the fat into the vessel.

Fat-embolism probably occurs in every case of fracture of bone contiiining
fat-marrow. \\Tien the bone is rarefied, and contains an unusual quantity
of fat-marrow, embolism resulting from its injury may be very extensive;
as is illustrated by several fatal cases of fat-embolism following the forcible
rupture of adhesions in an anchylosed joint. Eibbert has shown that fat-
emljolism may result from simple concussion of bone, as from falls or a blow.
Intlammations, haemorrhages and degenerations of the osseous marrow may
cause it. It may likewise result from traumatic lesions, necroses, haemor-
rhages, inflammation of adipose tissue in any part of the body, — of the brain,
of a fatty liver, in a word of any organ or part e-ontaining fat. Injury to the
pelvic fat during child-birth leads to fat-embolism. Oil-globules in the
hlood may come from fatty metamorphoses of tlironibi, of endotlielial cells
and of atheromatous plaques. Tlie lipiemia of digestion and of diabetes
mellitus has not been generally supposed to lead to fat-embolism, but Sanders
and Hamilton have observed capillaries filled with oil-globules after death
from diabetic coma, and they attribute; in certain cases dyspncea and coma in
diabetes to this cause.

EMBOTJSM 227

In the groat majority of cases, fat-embolism is entirely innocuous, and,
unless it is searched for, its existence is not revealed at autopsy, and then
only by microscopical examination. Plugging of capillaries and small
arteries with oil may, however, be so extensive and so situated as to cause
grave sj-mptonrs and even death. More moderate phigging may aid in caus-
ing death in those greatly weakened by shock, hasmorrhage, or other causes.
The detection of fat-embolism in the pulmonary vessels may be of medico-
legal value in determining whether injuries have been inflicted before or
after death.

The deposition of fat-emboli is most abundant in the small arteries and
capillaries of the lung, where in extreme cases the appearances of microscopic
sections may indicate that considerably over one-half of the pulmonary
capillaries are filled with cylinders and drops of oil. In rare instances of
extensive injury the amount of fat in the blood may be enormous, so that
post-mortem clots in the heart and pulmonary artery may be enveloped in
layers of solidified fat. Some of the oil passes through the pulmonary
capillaries and blocks the capillaries and arterioles of various organs ; those
which suffer most being the brain, the kidneys, and the heart. The extent of
the embolism in the aortic system varies much in different cases, being some-
times slight, at other times extensive. Probably the force of the circulation
determines the amount of fat which passes through the pulmonary capillaries.
Oil once deposited may be again mobilised and transferred to other
capillaries.

As already stated, it is only in the comparatively rare instances of extensive
fat-embolism that effects of any consequence are produced. The fat itself is
perfectly bland and unirritating, although it may be accidently associated
with toxic or infective material. The lesions and symptoms, when present,
are referable mainly to the lungs, the brain, the heart, and the kidneys.
These lesions are multiple ecchjTnoses (which in the lungs and the brain
may be verj- numerous and extensive), pulmonary cedema, and patchy fatty
degeneration of the cardiac muscle and of the epithelium of the convoluted
tubules of the kidney. Pulmonary oedema, referable probal)ly to paralysis of
the left heart, is common with extensive fat embolism of the lungs. Death
may undoubtedly be caused by fat-embolism of the cerebral vessels, possibly
also by that of the coronary vessels.

The symptoms in the extreme cases are quickened respiration, rapid pros-
tration, reddish frothy expectoration, tlie crepitations of pulmonary cfidema,
small frequent pulse, cyanosis, and — with cerebral invasion — coma, vomiting,
convulsions, and occasionally focal cerebral svTnptoms. The temperature
may either fall or rise. Oil-globules are often found in the urine, but it is
still an open question whether these are eliminated through the glomerular
capillaries, many of which are often filled with oil.

228 EMBOLISM

From tlie recent invcstijrations of Beneke it appears that the oil is readily
disposed of, in small part liy saponification, possibly oxidation, and emulsion
by means of the blood plasma ; but in larger part through the metabolic and
phagocytJc activities of wandering cells vdiich form a layer around the fat.
The saponifying ferment — lipase — which Hanriot has discovered in blood-
serum is probably one of the agents concerned in disposing of the fat.

Embolism by Parenchymatous Cells. — This is in general of more
pathologico-anatomical than clinical interest, and therefore need not be
considered here in detail. As has been shown by Lubarsch, Aschoff, and
^faxiniow, Ijonc-niarrow cells, with lar^e buddintr nuclei, usually undero-oinw
degeneration, may often be found lodged in the pulmonary capillaries after
injury to bone, in toxic and infective diseases, in leucocythasmia, and in asso-
ciation with emboli of other parenchymatous cells. I have seen them in large
number in capillaries of the liver in a case of spleno-medullary leuco-
cythaemia.

Next in frequency are emboli of liver-cells, which are found chiefly in
pulmonary capillaries, but may pass through an open foramen ovale so as to
reach capillaries of the brain, kidneys, and other organs. F. C. Turner in
1884 first observed liver-cells within hepatic vessels; and later Jiirgens,
Klebs, Schmorl, Lubarsch, Flexner, and others noted their transportation as
emboli after injury, hemorrhages, and nec-roses of the liver, and with especial
frequency in puerperal eclampsia. Secondary platelet-thrombi are usually
formed about the cells.

Especial significance was attached by Schmorl to the presence of emboli
of placental giant-cells (sTOcytium) in the pidmonary capillaries in cases of
])uerperal eclampsia; but these emboli, although frequent, are not constant
in this affection, and they may occur in pregnant women without eclampsia
(Lubarsch, Leusden, Ka.ssjanow).

To the group of parenchymatous emboli may be added the transport^ of
large cells from the spleen to the liver through the splenic and portal veins.
I have seen large splenic cells containing pigment and parasites blocking the
capillaries of the liver in cases of malaria ; and also the well-known large
splenic cells containing red blood-corpiL«cles in cases of malaria and of
typhoid fever. The crescentic endothelial cells of the spleen may enter the
circulation.

After traumatism and parenchymatous embolism fragments of osseous and
medullary tissue may be carried to the pulmonary vessels as emboli
(Lubarsch, Maximow). Emboli of large masses of hepatic tissue have been
found in branches of the pulmonary arter\- by Schmorl, Zenker, Hess, and
Gaylord as a result of traumatic laceration of the liver. Chorion-villi may
be detached and very rarely conveyed as emboli to the lungs (Schmorl), or

EMBOLISM 229

liy retrograde transport to veins in the vatrinal wall (Xeuniann. Pick).
This is much more likely to occur from chorionic carcinoma and moles thaji
from a normal placenta.

So far as kncR-n, emboli of marrow-cells, of liver-cells, of normal syn-
cytial cells, and of splenic cells imdergo only regressive metamorphoses,
which lead to their eventual disappearance. The possibility that without
the presence of any syncytial tumor in the uterus or tubes, emboli of
syncytial cells may give rise to malignant tumours with the typical structure
of those developing from syncytium, seems to have been demonstrated by
a case reported by Schmorl : hut it can hardly be supposed that the displaced
S}Ticytial cells were normal. Emboli of liver-cells manifest a distinct
c-oagulative intluence (Hanau, Lubarsch) ; and in two instances LubarscJi
attributed infarcts in the kidney and the liver to thrombi formed around
these cells. Marrow-cells and syncj-tial cells may likewise cause, in less
degree, secondary platelet and hyaline thrombi ; but it does not appear that
these thrombi have the importance in the etiology of puerperal eclampsia
which is attached to them by Schmorl. With a few exceptions, no important
lesions of the tissues or definite s\-mptoms have been conclusively referred
to emboli of these parenchymatous cells.

Although widely different in results, the transportation of tumour cells
by the blood-current is a process similar to that of parenchj-matous em-
bolism, for which indeed cellular embolism seems to me a preferable
designation. Benno Schmidt has found small branches of the pulmonary
arterj- plugged with cancer-cells derived from gastric cancer or its metas-
tases, both with and without growth of the cells into the walls of the
plugged arteries. Such cells may reach the lungs by conveyance through
the thoracic duct and innominate vein.

Embolism of Special Arteries.— I shall present the salient character-
istics of the more ini]x>rtant special localisations of embolism, so far as
these have not been sufficiently considered in the preceding pages, or do
not pertain to other articles in this work. Embolism of the central nervous
system will be discussed in the Volume VIII of AUbutt's " Syst. Med." under
" Diseases of the Brain and Spinal Cord." The pysmic manifestations of
infective embolism have been described in the articles on " Pyaemia" (All-
butt's "System of Medicine," I, p. 601) and on "Infective Endocarditis"
(AUbutt's " System of Medicine," I, p. 626, and V, p. 876).

Pulmonary Embolism. — The effects of pulmonary embolism vary with the
size of the plugged vessel, the rapidity and completeness of its closure, the
nature of the embolus, and associated conditions. Embolism of large, of
medium-sifeed and small arteries, and of capillaries may be distinguished.

The most frequent source of large emboli is peripheral venous thrombosis,
although they may come from the right heart. Sudden or rapid death

230 EMBOLISM

follows emliolism of the trunk or of both main divisions of tlie pulmonary
artery. It may occur also from embolism of only one of the main divisions
or from plugging of a large number of branches at the hilum of the lung.

Death may be instantaneous from syncope. !Morc frequently the patient
cries out, is seized with extreme precordial distress and violent suffocation,
and dies in a few seconds or minutes. Or, when tliere is still some passage
for the blood, tiie symptoms may be prolonged for hours or even days before
the fatal termination. The symptoms of large pulmonary embolism are the
sudden appearance of a painful sense of oppression in the chest, rapid
respiration, intense dyspncea, pallor followed by cyanosis, turgidity of the
cervical veins, exophthalmos, dilatation of the pupils, tumultuous or weak
and irregular heart's action, small, empty radial pulse, great restlessness,
cold sweat, chills, syTicope, opisthotonos, and convulsions. The intelligence
may be preserved, or there may be delirium, coma, and other cerebral symp-
toms. Particularly striking is the contrast between the violence of the
dyspnoea ajid the freedom with which the air enters the lungs and the absence
of pulmonary physical signs ; imless in the more prolonged cases it be the
signs of ffidema of the lungs. Litten found in two cases systolic or systolic
and diastolic stenotic murmurs in the first and second interco.-ital spaces on
the right or left side of the sternum. In prolonged cases the symptoms may
lie paro.xysmal with marked remissions. Recovery may follow after the
appearance of grave symptoms. There has been much and rather profitless
discussions as to the degrees in which the symptoms are referable to asphyxia,
to cerebral antemia, or to interference with the coronary circulation. Doubt-
less all three factors are concerned, but the exact apportionment to each of
its due share in the result is not easy, nor very import-ant.

The diagnosis is based upon the sudden appearance of the symptoms, with
a recognised source for an embolus. It is surprising to find in the larger
statistics, as those of Bang and of Bunger, how often the thrombosis leading
to fatal pulmonary embolism has been latent. Here tlie diagnosis cannot
always be made; but in many cases it may be suspected, or be reasonably
certain : as when the above-mentioned symptoms appear in puerperal women :
during convalescence from infective fevers, as enteric fever, influenza,
pneumonia: in marasmic and anaemic conditions, as phthisis, cancer, chlo-
rosis; after surgical operations, especially those involving the pelvic organs;
and in persons with varicose veins.

Even at autopsies the source for the embolus has sometimes been missed,
but this has been due generally to inability or failure to make the necessary
dissection of the peripheral veins, or to dislocation of the entire thrombus.
Serre has published a series of cases of pulmonary embolism with latent
thrombosis, showing the difficulties which may atft'nd the discovery of the

EMBOLISM 231

source, and the frequency with which patient search reveals the primary
thrombus. The majority of plugs in the trunk or main divisions of the
pulmonary artery, found in cases of sudden death, present the anatomical
characters of emboli, associated perhaps with secondary thrombi ; but there
remain a certain number of cases of sudden or gradual death from primary
thrombosis of the pulmonary artery, or from thrombosis extending into a
main division from an embolus in a smaller branch (see "Thrombosis,"
p. 167).

Bland embolism of medium-sized and small branches of the pulmonary
artery in normal lungs, and without serious impairment of the pulmonary
circulation, usually causes no symptoms and no changes in the parenchyma
of the lungs. Even in lungs structurally altered, and with serious disturb-
ances of the circulation, such embolism may be without eilects. The ex-
planation of the harmlessness of the majority of medium-sized and small
pulmonary emboli is that the collateral circulation tlirough the numerous
and wide pulmonary capillaries is, under ordinary conditions, quite capable
of supplying sufficient blood to an area whose artery is obstructed, to pre-
serve its function and integrity ; and that the pulmonary tissue, in contrast
to the brain and the kidney, is relatively insusceptible to partial local anemia.

Often enough, however, medium-sized and smaller branches of the pul-
monary artery are occluded by emboli or thrombi under conditions where the
pulmonarj- circulation is incapable of compensating the obstruction, and
then the result is hemorrhagic infarction of the lung. The most com-
mon and important of the conditions thus favouring the production of
liSBJiiorrhagic infarction is chronic passive congestion of the lungs from
valvular or other disease of the left heart. It is especially during broken
compensation of cardiac disease that hemorrhagic infarction of the lungs
occurs, sometimes indeed almost as a terminal event. Other favouring con-
ditions are weakness of the right heart, fatty degeneration of the heart,
general feebleness of the circulation, pulmonary emphysema, infective dis-
eases.

The source of the embolus causing pulmonary haemorrhagic infarction is
oftener the right heart than a peripheral thrombus. Globular thrombi are
often formed in the right auricular appendix and ventricular apex in uncom-
pensated disease of the left heart, particularly of the mitral valve (see
"Thrombosis," p. 141). The infarction may be caused also by thrombosis
of branches of the pulmonarv' artery, which are not infrequently the seat
of fatty degeneration of the intima and of sclerosis in cardiac disease and in
emphysema. Thrombi in larger branches often give rise to emboli in smaller
ones.

Pulmonary infarcts are usually multiple, more frequent in the lower than
the upper lobes, and occur on the right side somewhat oftener than on the

232 p:mbolism

left; cl)rrc^^pollding thus with the distribution of emboli. Their size varies
generally from that of a lia/.el-nut to a pigeon's egg; but it may be smaller
or much larfxer, up to half or oven an entire lobe. They are conical or of a
wedge-shape, the base being at the pleura. Infarcts are rarely buried in the
substance of the lung so as to be invisible from the pleural surface. Typical
fresh infarcts are strikingly hard, sharply circumsi-ribed. swollen, upon
section dark red, almost black, smooth or sliglitly granular, and much drier
than ordinary haemorrhages. Examined microscopically, the air-cells,
bronclii, and any loose connective tissue which may be included in the infarct
are stuffed full of red corpuscles. The capillaries are distended, and in all
but the freshest infarcts usually contain, in larger or smaller amount, hyaline
thrombi, to which von Eecklinghausen attaches nmcli importance in the
production of the infarct. Fibrin may be scanty in very recent infarcts, but
in older ones it is abundant. The walls of the alveoli in the central part of
the infarct are the seat of typical coagulative necrosis with fragmentation
and solution of the nuclear chronuitin. It is probable that the red corpuscles
also undergo some kind of coagulative change, for otherwise it is difficult
to explain the extremely hard consistence of tlie fresh infarct. It is possible
that small pubnonary infarcts and ver)' recent ones may occur without
necrosis; but the ordinary ones are necrotic, and cannot therefore be re-
moved by resolution ; but, if the patient lives long enough and suppuration
or gangrene of the infarct does not ensue, are substituted by cicatricial tissue
(WiUgerodt).

Ever since the first admirable description of hremorrhagie infarcts of the
lungs by Laennec there has been considerable difference of opinion as to
their explanation. The doctrine that they are usually caused by emboli,
however, gradually gained general acceptance. This explanation has al-
ways had opponents, chiefly on the grounds that emboli often occur in the
pulmonary arteries without infarction; that infarction is not always asso-
ciated with obstruction of the corresponding artery; tliat some have believed
that simple haemorrhages may produce the same appearances, and that until
recently attempts to produce pulmonary infarction experimentally have
been without positive or at least sufficiently satisfactory results. Hamilton
is strongly opposed to the embolic explanation, and attributes hemorrhagic
infarction of the lung to a simple apoplexy, resulting usually from rupture
of the alveolar capillaries in chronic passive congestion. Grawitz, likewise,
considers that embolism has nothing to do with the causation of pulmonary
infarction, which he explains by haemorrhage from newly-formed, richly-
vascularised, peribronchial, subpleural, and interlobular connective tissue
consecutive to the chronic bronchitis of cardiac and other diseases. He
emphasises structural changes in the lung as an essential pre-requisite for

EMBOLISM 233

infarction. Grawitz's attack especially has stimulated investigation which,
in my opinion, has strengthened the supports of the embolic doctrine of
haemorrhagic infarction.

The evidence seems to me conclusive that pulmonary infarcts are caused
by embolism and thrombosis of branches of the pulmonary artery. In the
great majority of cases the arteries supplying the areas of infarction are
plugged. Upon this point my experience is in accord with that of von Eeck-
linghausen, Orth, Hanau, Oestreich, and many others. That these arterial
plugs are secondary to the infarction is improbable, as hemorrhages else-
where, as well as undoubted ones in the lungs, often as they cause secondary
venous thrombosis, rarely cause arterial thrombosis. Moreover, there is
sometimes an interval of open artery between the plug and the infarct, a
relation not observed with the undoubtedly secondary thrombosis of veins
connected with tlie infarct, and not explicable on the assumption that the
arterial thrombosis is secondary. The plug often has the characters of a
riding embolus. Not a few of the plugs, however, are primary thrombi. The
occasional occurrence of pulmonary infarction without obstruction in the
arteries has as much, but no more, weight against the embolic explanation as
the similar, and I believe quite as frequent, occurrence of splenic infarcts
without embolism or thrombosis of the splenic arteries. Both the hfemor-
rhage and the necrosis of infarcts are essentially capillary phenomena, each
l>eing independent of the other ; and, undoubtedly can occur, in ways little
understood, in various regions, without plugging of the arteries.

The anatomical characters of pulmonary infarcts are essentially the same
as those of ha?morrhagic infarcts of the spleen and other parte. The conical
shape, the hard consistence, the peripheral situation, the coagulative necrosis
are distinctive characters of pulnionarj' as of splenic infarcts. The necrosis
cannot well be attributed to compression of the alveolar walls by the ex-
travasated blood, for the capillaries in these are usually distended widely
with blood. It has the general characters of the ischasmic necrosis of infarcts,
except that it apparently occurs somewhat later in the formation of the in-
farct and does not usually reach the periphery; phenomena which may be
explained by the relative tolerance of the pulnionarv- tissue of partial
ischiEmia, and by a better peripheral circulation than is present in infarcts
elsewhere.

Inasmuch as emboli do not ordinarily cause infarction in normal human
lungs with vigorous circulation, it is not surprising to find that similar emboli
under similar conditions do not cause infarction in the lungs of animals. It
is not easy to reproduce experimentally in animals the conditions under
which pulmonary infarcts occur in man ; yet there have been several valuable
contributions in recent years to the experimental production of pulmonary
18

234 EMBOLISM

infarction : these liavc furnished an exjx'iimental basis, which, if not all that
is to be desired, still marks a distinct advance for the embolic doctrine of
haemorrhagic infarction of the lung. Pulmonary infarcts, in all essential
respects identical with those in human lungs, have been produced by experi-
mental embolism or arterial occlusion by Cohnheim and Litten, Perl, Kiit-
tner, Mogling, Grawitz, Klebs, Gsell, Sgambati, Orth, Zahn, and Fujinami.
Most of these experimental infarcts have been produced under conditions
not very analogous to those of human infarcts; but the essential fact that
typical haemorrhagic infarction of the lung may be caused by arterial plug-
ging has been experimentally established. Into the details of these experi-
ments it is impossible here to enter.

Whether genuine haemorrhagic infarcts of the lung may ever be caused
by simple hEemorrhage from rupture of lilood-vessels is perhaps an open
question. At present this mode of tlieir production seems to me undemon-
strated and improbable, so that I hold that simple pulmonary apoplexies and
genuine infarcts should lie clearly distinguished from each other. Neither
the results of experimental introduction of blood into the trachea (Perl and
Ijppmann, Sommerbrodt, Notlinagel, Gluzinski), nor the appearances of
the lungs after undoubted bronchorrhagias, pneumorrhagias, and suicidal
cutting of the trachea support the opinion that aspiration of blood from the
trachea ajid bronchi causes genuine hjemorrhagic infarction. In only one
of Sommerbrodt's numerous experiments was such infarction observed, and
this he regards as accidental. The explanation of this exceptional result is
probably the same as in Perl's experiment with tlirombosis after venesection
and anaemia.

I have seen, in two or three instances, nearly white or pale-red fresh
anfemic infarcts in densely consolidated limgs.* Even when caused by
bland emboli puJmonary infarcts are exposed to the invasion of bacteria
from the air-passages; and such bacterial invasion may lead to suppuration
or gangrene. Completely cicatrised pulmonary infarcts occur, but they are
not common — life being usually cut short by the associated cardiac disease
before the infarct is healed.

Haemorrhagic infarction of the lungs may be entirely latent; often, how-
ever, the diagnosis can be made during life. The affection may be ushered
in by a chill or chilly sensation, increase of a usually existing dyspnoea, and
localised pain in this side. These s}-mptoms are far from constant. The
cliaracteristic symptom, although by no means pathognomonic, is bloody
expectoration. Profuse haemoptysis was noted by Laennec, but is very rare.
The sputum contains dots and streaks of blood, or small dark coagula ; or,

' In very rare instances pulmonary infarcts are anjemic in consequence of
extreme weakness of the circulation (87).

EMBOLISM 235

more frequently, the blood is intimately mixed with the expectoration, which
is in small masses and usually less viscid and darker red than that of pneu-
monia, although it may resemble the latter. Blood may be present in the
sputum for one or two weeks or even longer after the onset of the infarction.
It acquires aft^r a time a bro\vnish-red tint, and generally contains the pig-
mented epitlielial cells usually seen in the sputum of chronic passive con-
gestion. Circumscribed sero-fibrinous pleurisy is usually associated with
pulmonary infarction. Even with infarcts not more than four or five centi-
metres in diameter the physical signs of consolidation and subcrepitant
rales can sometimes be detected ; usually in the posterior, lower parts of the
lungs. These signs are referable not only to the infarct, but also t« the
surrounding localised opdema and perhaps reactive pneumonia. There may
be moderate elevation of temperature. When the characteristic bloody ex-
pectoration, together with signs of circumscribed consolidation, appears in
the later stages of cardiac disease, or with peripheral venous thrombosis,
there is generally little doubt of the diagnosis. Yet similar expectoration
may occur from simple bronchial ]ia>morrhages in intense passive congestion
of the lungs without infarction. The expectoration in cancer of the lungs
may resemble tliat of pulmonary infarction.

The sudden appearance of pain in the chest, cough, and elevation of tem-
perature, immediately after the hypodermic injection of undissolved prepa-
rations of mercury, is attributed to pulmonary embolism. The sjTuptoms
disappear in a few days witliout serious consequences. This complication
has been rare in the experience of most of those who have employed this
treatment of syphilis, but has led some to abandon the method.

The embolic pneumonias and abscesses caused by infarctive emboli are
pyaemic manifestations, and have been considered in tlie article on '' Pj'asmia "
in the first volume of Allbutt's Syst. Med.

Splenic Infarction. — Anaemic infarcts of the spleen, which are commoner
tlian the haemorrhagic variety, are not usually in the recent state
so pale and bloodless as those of the kidney; for the spleen is much
richer in blood than the kidney, and in chronic passive congestion, dur-
ing which the larger number of infarcts occur, the red pulp contains much
blood outside of the vessels. Many of these infarcts can be appropri-
ately described as mixed red and white infarcts. Splenic infarcts vary
greatly in size, but in general they are much larger than those occurring
under tlie same conditions in the kidney, as comparatively large arteries in
the spleen break up into numerous small terminal twigs. Averaging per-
haps two to six centimetres in diameter, a single infarct may occur one-half
or more of the spleen. The recent infarcts are hard, swollen, and more or less
wedge-shaped, with the base at the capsule, which is often coated with fibrin ;

236 EMBOLISM

or in older cases is thiclvemnl and adlii'rent t)v filirous tissue. The great
majority are caused by emboli from the left heart or the aorta; but both
haemorrhagic and pale splenic infarcts occur witliout arterial occlusion;
especially in certain acute infective diseases; oftenest in relapsint,^ fever, but
also in tyj)hus, enteric fever, cholera, and septicaemia. The causation of the
latter is unknown. Ponfick attributes them to venous thrombosis, which may
be the cause of the haemorrhagic infarcts; but it is difficult to understand
how it can produce the pale anaemic infarcts. Bland infarcts are mostly
absorbed and substituted by pigmented, occasionally calcified, scars, which
when numerous may cause a lobular deformity of the spleen.

Splenic infarction is oiten entirely latent. Of the symptoms attributed
to it chills and elevation of temperature belong usually to the accompanj-ing
acute or chronic endocarditis. Swelling of the spleen, which pertains to
chronic passive congestion, is produced also by infarcts. The most diagnostic
value attaches to the sudden appearance of pain in the region of the spleen,
perhaps increa.«ed by lying on the left side, by deep inspiration, and by
pressure; and to a perisplenitic friction rub, which can sometimes be de-
tected. These symptoms are not very certain diagnostic points; but when
they occur with some manifest source for a splenic embolus, and perhaps with
recognised embolism in other organs, they justify a strong suspicion of
splenic infarction.

Renal Infardion. — There have been a few instances, especially after
traumatism, of nearly total necrasis of a kidney from thrombosis of the
renal artery, combined usually with thrombosis of the vein. Usually plug-
ging of the main artery leads to multi[)lo infarction with intervening intact
areas. The capsular arteries suffice for the preservation of at least a narrow
outer rim of renal tissue.

Renal infarcts are nearly always anaemic, in the recent state somewhat
swollen, and of an opaque pale yellowish colour, with the base of the wedi^e
just beneath the capsule iuid the apex toward the hilum, most frequently near
the boundary between the pyramid and cortex. Three zones can often be
distinguished : — the main central yellowish white mass of necrotic tissue ;
next to this a narrow yellow zone of fatty cells, nuclear fragments, and
disintegrating leucocytes ; and an outer, irregular, variable rim of hyperaemia
and ha-morrhage which belongs partly to the infarct and partly to the sur-
rounding tissue. The hemorrhage may extend a variable distance into the
infarct, and in very rare instances genuine haemorrhagic infarcts occur in
the kidney. Numerous scars from old infarcts may produce a form of
atrophic kidney to which the epithet embolic is applicable. Thorcl finds that
a limited regeneration of the epithelium and even of uriniferoiLS tubules may
occur in healing renal infarcts.

EMBOLISM 837

Very large infarcts may so stretch the renal capsule as to induce severe
pain. In a case diagnosed by Traube an infarct two inches in diameter, pro-
jecting well above the surface, caused intense pain and tenderness in the
region of the infarcted kidney, ^vith extension of the pain into the corre-
sponding thigh. With the ordinary small infarcts pain is not usually a
prominent symptom. The chief sign of diagnostic value is the sudden
appearance of blood in the urine in association with disease of the left heart,
aortic aneurysm, or other recognised source for a renal embolus. The
amount of blood is usually only moderate or evident by microscopical exami-
nation of the urine. It is to be remembered that chronic passive congestion
of the kidney is itself one of the many causes of ha?maturia.

Infective emboli, which are often capillary in size, cause multiple, often
miliary abscesses in the kidney. This is the haematogcnous variety of acute
suppurative nephritis which occurs often in acute infective endocarditis and
other forms of pysemia. Here the pyuria and other renal symptoms are
usually of less consequence than those of general infection.

Embolism and Thrombosis of the Mesenteric and Intestinal Arteries. —
Thrombosis of the mesenteric veins, which causes lesions and symptoms
identical with those following embolism of the mesenteric arteries, has been
considered in the preceding article (p. 178). Since Virchow's first descrip-
tion of embolism of tlie superior mesenteric artery, in 1847, at least seventy
cases have been reported of embolism or thrombosis of the mesenteric arteries.
The affection, although not common, occurs often enough and is of such
gravity as to be of considerable clinical interest. In Watson's collection of
cases there are eight wliich occurred within a single year in Boston. Tlie
casuistic literature upon the subject is fairly extensive. The articles of
Litten and of Faber contain reports of most of the cases published up to 1875.
The principal clinical features were carefuUy studied by Gerhardt and by
Kussmaul in 1863-64. The papers of Watson and of Elliot in 1894-95 refer
to about fifty reported eases, of which they have analysed those with satis-
factory clinical histories with special reference to surgical treatment. The
effects of occlusion of the mesenteric arteries have been experimentally studied
by Beckmann, Cohn, Litten, Faber, Welch and Mall, and Tangl and Harley.

The principal conclusions drawn by Mall and myself from our experiments
have been stated already in the discussion of the collateral circulation, and of
hemorrhagic infarction following embolism (jip. "205 and 212). It may
here be repeated that, according to our experiments, the blood which produces
the hemorrhagic infarction enters by the anastomosing arteries and not by
reflux from the veins; that tlie haemorrhage cannot be explained liv any
demonstrable change in the vascular walls, but is the result of retardation
and stasis of the circulation and clumping of red corpuscles in the veins and

238 EMBOLISM

rapilliirics, attributable in lar<je part in cases of arterial obstruction to reduc-
tion or loss of lateral pulsation of the blood-current; that the ischtcinia is
increased by the tonic contraction of the intestinal muscle which follows for
two or three hours' closure of the superior mesenteric artery; and that the
sudden and complete shutting off of tlie direct arterial supply to a loop of
intestine 5 to 10 ctm. in length is followed by haemorrhage and necrosis of
the loop, even when the vessels at each end of the loop are open. Thexe
results we obtained by experimentation upon dogs, but there is no reason
to suppose that they do not apply to human beings. With the exception of
Cohn, the other experimenters explain the infarction by regurgitant flow
from the veins and alterations in tlie vascular walls.

The majority of the cases of haemorrhagic infarction of the intestine have
been due to embolism of the mesenteric arteries, the source of the embolus
being usually the left heart, sometimes an antheroniatous aorta or aortic
aneurysm, and in one instance a thrombus in the pulmonary veins caused by
gangrene of the lungs ( Yirchow) . Several cases have been caused by autoch-
thonous thrombosis resulting from arterio-sclerosis, aneurysm, pressure,
or the extension of a thrombus from tlie adjacent aorta. It is probable that
a certain nimiber of the cases reported as embolic were referable to primary
thrombosis of the mesenteric arteries, as no source for an embolus could be
discovered, and the plugs in some of these instances were fresh adherent
thrombi. As has been shown in the preceding article, primary thrombi may
form in arteries which are free from atheroma or other chronic disea.se.'

In the great majority of the cases the obstruction was in the superior
mesenteric artery. The few scattered instances of embolism or thrombosis
of the inferior mesenteric artery indicate tliat this also may, very rarely,
cause incomplete haemorrhagic infarction of the corresponding part of the
intestine, but that the collateral circulation here is better, and the lesions
likely to consist only in small hspmorrhages in the intestinal mucosa. The
inferior mesenteric artery may l>e obliterated without any manifest disturb-
ance in the structure or function of the part of the intestine supplied by it.

The obstruction may be situated in the main stem or in any of the branches
of the superior mesenteric artery. Intestinal infarction has been associated

' Litten has reported two cases of h;rmorrhagic infarction of the intestine from
thrombosis caused by what he calls " latticed endarteritis " (gitterformige En-
daitoriitis) of the mesenteric arteries. So far as I can learn he has not furnished
the fuller description which he promised in his article of nine years ago. With-
out such description there is room for the suspicion that Litten has mistaken the
latticework markings sometimes seen after detachment of an adherent thrombus
for a special form of endarteritis. It does not appear from his article that he has
observed this " latticed endarteritis " except after removing adhertn thrombi.

EMBOLISM 239

with embolism of the larger branches oftener than with that of the main
stem. As the anastomoses through the arterial arches are so free, obstruction
of single small branches is without mechanical effects. There have, however,
been several instances of intestinal infarction caused by multiple emboli or
extensive thrombosis of small branches of the superior mesenteric artery.

Intestinal infarction is not the imperative result of occlusion of the
superior mesenteric artery, as infarction is of occlusion of branches of the
splenic and renal arteries, and of the basal cerebral. Both the trunk and the
principal branches of this artery may be gradually closed without serious
effects. Tiedemann and Virchow have found the superior mesenteric artery
completely obliterated by old, firm thrombi or connective tissue without any
lesions in the jejunum or ileum. The most remarkable case is that of Cliiene,
who found in a woman sixty-five years old, with aneurysm of the abdominal
aorta, complete obliteration of the cceliac axis and both mesenteric arteries,
with an adequate collateral circulation through the greatly distended extra-
peritoneal anastomosing arteries. In a number of instances plugging of
large branches of the superior mesenteric artery has caused no more than
hypera^mia and superficial ecchjTnoses, without genuine infarction of the
intestine.

The rapid and complete closure of tlie superior mesenteric artery, how-
ever, is followed with great regularity, probably constantly, by haemorrhagic
infarction of the intestine. There have been several instances in which
embolism or thrombosis of the trunk of this artery has caiLsed hsmorrhagic
infarction extending from the lower part of the duodenum into the transverse
colon (Oppolzcr, Pieper, Faber, Kaufmann), as in the experimental cases.
More frequently the infarction is in the lower part of the jejunum and the
ileum, corresponding to the occlusion of a principal branch or of several
branches supplying this region. The infarction corresponds in general to
the area of distribution of the plugged arteries, but it may occupy only a part
of this area. In several instances a single small loop or several loops with
intervening normal intestine have been infarcted.

As already intimated, the infarction may be complete or only partial.
When completely infarcted, the wall of the affected intestine is thickened,
oedematous, of a dark red colour from infiltration with blood and covered
with lustreless peritoneum. The margins of the infarct are often sharply
marked but may pass gradually into the normal bowel. The mucous mem-
brane is necrotic, often defective, and may be coated with a diphtheritic
exudate. In a few instances the intestine has been gangrenous over consider-
able areas, without typical hjemorrhagic infarction, or with the haemorrhagic
appearance adjacent to the gangrene. The lumen of the intestine contains
black tarry blood. There is bloody fluid in the peritoneal cavity, and usually

240 EMBOLISM

a libriuous, sometimes a fibriiio-purulont exudate on the peritoneiuu covering
the infarction; and there may be general peritonitis. The mesentery is
succulent and hamiorrhagie, usually in patches, exceptionally in the form of
large flat masses of extravasated blood. Areas of fat-necrosis may lie present
in the mesentery. The mesenteric veins are distended and the mesenteric
glands often swollen and ha^morrhagic. Various intestinal l)acteria, most
commonly the colon bacillus, may make their way into the peritoneal cavity
through the necrotic wall. Flexner and I have reported an instance of
luTmorrhagic infarction of the jejunum in which evidences of pneumo-
peritonitis, supposed to be due to perforation, existed during life. At the
autopsy, made six hours after death, a large amount of gas was found in the
peritoneal cavity without perforation. B. aerogenes capsulaius was present
in large numbers in the peritoneal exudate. This ca.'^e demonstrates the
generation of gas in the closed peritoneal cavity. In the intestinal mucosa
were gas-blebs which were observed also in one of Faber's cases and in
Jiirgen's case of intestinal infarction.

The hemorrhagic infarction is by no means always so completely formed
as that just described. There may be no hsemorrhages in the mesenter}-.
The extravasation of blood may be limited to tlie mucosa, or even to the
submucosa, as in one of Ponfick's cases. In an instaaice of nearly complete
tlirombosis of the trunk of the superior mesenteric artery, reported by
Councilman, there were paralysis, great distension and eccln-moses of the
small intestine, but no infarction. Between mere venous hypenvmia with
scattered, superficial haemorrhages, and complete necrosis and infarction,
there are all gradations, the controlling factors being doubtless the rapidity
and extent of the arterial occlusion and the vigour of tlie general circulation.

There have been two or three instances in which the anatomical picture
of hemorrhagic infarction of the intestine has been present without dis-
covery of any obstruction in the corresponding arteries or veins. Lycett
reports an observation of hfemorrhagic infarction of the small intestine in
an infant one month old without discoverable cause.

Hemorrhagic infarction of the bowel may be insidious in its onset and
course; and, in patients profoundly prostrated or with cerebral symptoms,
it may occur without the attention of the physician being drawn to any
abdominal trouble. Usually, however, the onset is abrupt, and grave intes-
tinal symptoms are present. In the majority of cases, severe colicky pain
and abdominal tenderness, either without distinct localisation or most
marked near the umbilicus, are prominent and usually the first symptoms.
The pain at the beginning is perhaps attributable to the violent, tonic spasm
of the intestine which follows sudden occlusion of the superior mesenteric
artery. After a few hours this spasm gives place to complete paralysis of

EMBOLISM 241

the affected part of the bowel, and then the pain may be referable to peri-
tonitis. The local ana'mia, hivmorrhage. and necrosis seem, however, quite
sufficient to account for the pain. Vomiting, which often becomes bloody
and occasionally fsecal, is also usually an early and persistent symptom. By
far the most characteristic symptom, which is present in tlie majority of
cases but not in all, is the passage of tarry blood in the stools, which are
frequently diarrhceal, and sometimes have the odour of carrion. In nearly
all cases there is haemorrhage into the bowel, but the blood is not always
voided. Sjinptoms of intestinal obstruction — tympanitic distention of tlie
abdomen, faecal vomiting and obstipation — are in some cases prominent,
and readily explained by the complete paralysis of the infarcted bowel.
The subnormal temperature, pallor, cold sweats and collapse, which appear
in most cases, are explicable in part by the intestinal ha?morrhage, and in
part by the shock of the destructive lesion. The sensation of a palpable
tumour, referable to a collection of blood in the mesentery or to the infarcted
bowel, has been noted in only three or four cases.

The chief emphasis for purposes of diagnosis is to be laid upon the
occurrence of intestinal hfemorrhage, not expUcable by independent disease
of the intestine or by portal obstruction, in combination with other symp-
toms mentioned, and with the recognition of some source for an embolus,
perhaps of embolic manifestations elsewhere. In the majority of cases the
diagnosis has been intestinal obstruction, or acute peritonitis. The symp-
toms closely resemble those of intussusception, in which haemorrhage from
the bowel, although generally less abundant than with embolism of the
superior mesenteric artery, is common. Fortunately the distinction of
haemorrhagic infarction from intestinal obstruction is not of much practi-
cal importance ; for if the symptoms and condition of the patient warrent
it, an exploratory laparotomy is indicated in both conditions. Elliot, by
the successful resection of four feet of infarcted intestine, has brought
ha'morrhagic infarction of the intestine into the surgeon's domain.

The prognosis is grave; and with complete infarction and necrosis of
the intestine it is almost necessarily fatal, unless surgical relief be avail-
able. Watson estimates that in about one-sixth of the cases the location
and extent of the infarction are suitable for resection of the bowel. It is
impossible to say at present to what extent the prognosis of haemorrhagic
infarction of the intestine is favourably modified by the new possibilities
of surgical interference. Gordon has successfully resected two feet of
infarcted intestine. This and Elliot's case are the only two in which this
operation has been performed ; so far as I am aware.

When the infarction is incomplete, and is limited chiefly to the inner
coats of the intestine, recovery may doubtless take place. Cohn, Moos,

212 KMHOLISM

Lercboullot, and Fiiilay.soii have reporlud instances of recovery after symp-
toms indicative of liipmorrliagic infarction. Packard attributed cicatrical
areas found in the mesentery of an old man dead of rupture of the ascend-
insr aorta to healed infarction; but no previous history was obtained, and
Packard's interpretation does not seem to me to be free from doubt. Death
may occur within 20 to 48 hours after the onset, or the duration may be pro-
tracted over several days. Karcher has reported the survival of a patient
with mitral stenosis for two months after the complete occlusion of the
superior mesenteric artery by an embolus, the symptoms being suiBciently
characteristic to have permitted a probable diagnosis during life.

Intestinal ulcers due to embolism or thrombosis constitute a distinct
class, which has been studied especially by Ponfick, Parenski, and Noth-
nagel. Parenski relates an instance of operation for intestinal stricture,
which at the autopsy was found to be caused by cicatrisation of an ulcer
due to embolism of a branch of the superior mesenteric artery. Much
more common are ulcers caused by infective emboli lodging in the small
arteries and capillaries in the intestinal wall; they are observed especially
in acute ulcerative endocarditis and pyaemia. These emboli cause haemor-
rhages, necroses, and miliary abscesses with resulting ulceration. The
ulcers are usually multiple, sometimes numerous, and situated in the small
intestine and ctecum. The intestinal ulcers occasionally associated with
degenerative multiple neuritis are referred by ilinkowski and Lorenz
to thrombosis caused by disease of the small arteries, which has been
repeatedly observed in this form of neuritis.

Embolism and Thrombosis of the Thoracic Aorta. — Unless there be some
abnormal narrowing or obstruction of tlie aorta, it is hardly possible for
an embolus to lodge in tliis vessel, except at the ostiimi or the bifurcation.
An exception to this rule may result from the detachment of a large
aneurysmal clot, which, as in three cases of abdominal aneurysm reported
by Bristowe, may block the aorta at or just below the mouth of the aneurysm.

I know of but three instances of embolism of the mouth of the aorta —
two reported by Cohn with instantaneous death, and one by Reid in which
the patient lived an hour and a half after the first symptoms of partial
obstruction.

In a very few instances tlie lumen of an atheromatous thoracic aorta
has been seriously encroached upon, or even obliterated, by thrombotic
masses. Such cases have been reported by Trost, Tewat, Carville, Armet,
Chvostek, Jaurand, and Pitt. The thrombus may occupy the ascending,
the transverse, or the descending aorta, and may occlude the mouths of
the left carotid and subclavian arteries. If there remain a suiBcient channel
for the blood, as in Pitt's case, there is no resulting circulatory disturbance;

EMBOLISM 243

otherwise there may be paralysis, oedema, gangrene of the lower extremities,
and, if the left subclavian is obliterated, of the corresponding upper
extremity.

Bochdalek and Liittich have each described an instance of occlusion of
the aorta in infants by the extension of an obliterating thrombus from a
dilated ductus Botalli. Far more frequent is stenosis or atresia of the
aorta at or near the attachment of this duct, due usually to persistence of
the isthmus aorta^, as was first shown by Rokitansky. Of this latter condi-
tion about 100 instances have been recorded.

Embolism and Thrombosis of the Abdominal Aorta. — Graham in 1814
referred to a museum specimen in Glasgow, which had belonged to Allan
Burns, of occlusion of the abdominal aorta just above the bifurcation by
old laminated coagulum extending into the iliacs. I have found fifty-nine
subsequent reports of occlusion of the abdominal aorta by embolism or
thrombosis, and have seen references (which I have not consulted) to six
or seven other cases.' I have not included in this list the detachment of
clots from abdominal aneurj-sms, although Bristowe's three cases demon-
strate that this may occasion the same symptoms. The monographs and
articles of Meynard, C'ammareri, Selter, Eoussel, Charrier and Apert, and
Heiligenthal contain references to or reports of forty-seven cases; to these
I have added twelve published cases not mentioned by them. The refer-
ences are at the end of this article.

Three of the patients were living at the time of the reports, and ui
two fatal cases there was no autopsy. In the remaining fifty-four the
plug occupied the lower end of the a^rta and extended a variable distance
into the arteries below. In thirty-one the plug did not reach higher tliaii
the inferior mesenteric artery; in ten the upper extremity lay behveen
the inferior mesenteric and tlie renals; in three between the renals and the
superior mesenteric ; in two between the latter and the celiac axis ; in one
just below the pillars of the diaphragm, and in seven the length of the plug
is not stated. The upper part was often conical; so that, when the plug
extended higher than the inferior mesenteric, it was often not obliterating
until at or below this artery. In the great majority of cases only the last,
or the last two, lumbar arteries were blocked by the thrombus. In sev-
eral instances a thrombus, either independent or continuous with that in
the aorta, occupied the lumbar, the mesenteric, the renal, or other branches
of the aorta. In all instances the thrombus extended into the common

' I have not included von Weismayr's case (Wiener med. Presse, 1894, p. 1774),
as it was reported while the patient was living, and in the discussion some doubt
was expressed as to the diagnosis: nor the brief mention made by Teleky, at the
same time, of similar observation.

244 EMBOLISM

iliacs, and iu niauy into arteries lower down, sometimes even as far as
the posterior tibial, the end being usually lower on one side than on the
other.

It is difficult, indeed impossible, from the published descriptions, which
are only too often incomplete and unsatisfactory, to determine accurately
how many of the cases were referable to embolism and how many to throm-
bosis. Essentially similar cases have teen interpreted differently in this
respect by different observers. The plujr was usually adherent, and only
in relatively few cases were its anatomical characters such (or at least so
described) as to indicate positively its nature as embolus or primary- throm-
bus. The majority of cases with sudden or rapid invasion of character-
istic symptoms were associated with cardiac disease, or disease of the upper
part of the aorta ; and would, tlierefore. naturally be interpreted as embolic.
Still in many of these no satisfactory source for a large embolus was
demonstrated. Some cases not less abrupt in onset were without any affec-
tion of the heart or of the aorta above the plug. The sudden appearance of
symptoms of obstruction of the aorta, altliough strongly indicative of embol-
ism, are not decisive upon this point. Barth, in 1848, described a case of
obstruction of the aorta by a cylindrical thrombus extending from the
superior mesenteric artery to the l)ifurcation, and leaving only a narrow
channel for the circulation of the blood. There were no circulatory dis-
turbances. If this narrow channel had been suddenly closed at one point,
as might readily happen, the symptoms would probably have been those
of embolism. It is evident that aortic thromboses secondary to only partly
obliterative emboli riding the bifurcation of the aorta, or to emboli or
thrombi in the iliacs or lower arteries, may occasion sjinptoms like those of
primary thrombosis of the aorta. There are several instances of such
secondary thrombosis of the aorta in my collection of cases.

Without much confidence in the accuracy of the classification in several
instances, I have divided the fifty-nine cases into forty-five referable to
embolism of the aorta at the bifurcation, and fourteen due to thrombosis; of
the latter, seven were primarj', six secondary to embolism of the iliacs,
or possibly the femoral, and one to thrombosis of the arteries of the extremi-
ties. The source of the aortic embolus is believed to have been the heart in
thirty-five cases ; aneurysm of the ascending aorta iu one ; pressure of a
tumour on the aorta in two; atheroma of the thoracic aorta in one; in six
it was undetermined. The heart was found to be normal at the autopsy
in eleven of the fifty-three cases ; and in seven both the heart and the aorta
above the plug were normal.

Mitral stenosis existed in twenty cases (two of these being cau.«ed by
thrombi extending from the left auricle into the ventricle), acute mitral

EMBOLISM 245

endocarditis in three, mitral endocarditis, not further defined, in favour-
mitral insufficiency without stenosis in one, thrombus in the left auricle
without valvular disease in one, thrombi in the left ventricle, mostly with-
out valvular disease, in eight, and large aortic vegetations in one.

The most interesting point in the etiology of plugging of the abdominal
aorta, so far as it is permissible to draw conclusions from so few instances,
is that nearly thirty-four per cent of the cases were associated with mitral
stenosis. In many of these the stenosis was extreme. The question at
once arises of the source of the embolus in these cases for it cannot be
supposed that an embolus large enough to occlude the lower end of the
aorta could pass through the contracted mitral orifice. Some of the cases
may be explained by a smaller emlx)lus caught at the aortic bifurcation, or
in an artery lower down, with secondary- thrombosis of the aorta; but the
sudden onset of motor and sensory paraplegia and of cessation of pulsation
in both femoral arteries in a large number of cases seems to demand abrupt
stoppage of the circulation tlirough both common iliacs. A few observers
who have realised the difficulty here presented have assumed that a large
thrombus had formed in the left ventricle and been detached without any
trace behind ; for only in two or three of the cases with mitral stenosis was
there any evidence of a thrombus in the left ventricle or the aorta above
the plug. This explanation must be regarded as purely hypothetical. The
coexistence in a number of these cases of infarctions of the spleen, kidney,
or brain has seemed to some writers strong evidence in favour of the embolic
nature of the aortic plug. It is possible that the explanation even of the
cases witli acute bilateral symptoms referable to aortic obstruction and
associated with marked mitral stenosis may be the lodgment of a small
embolus followed by thrombosis of the aorta. Although in the classifica-
tion above given I have placed nearly all the cases with mitral stenosis
under embolism, I am nevertheless not disinclined in spite of the rapid
onset of the symptoms, and frequently coexistent infarctions, to interpret
many of them as primary thromboses of the aorta. The circulatory con-
ditions with extreme, uncompensated mitral stenosis seem favourable to
the occurrence of arterial thrombosis; and, if this view be accepted for the
plugging of the abdominal aorta, the question arises whether thrombi fre-
quently present in smaller arteries in association with this form of valvular
disease may not oftener be primary than is generally supposed.

In a few cases congenital narrowing of the aorta was noted. In three
instances plugging of the abdominal aorta was associated with embolism
or thrombosis of arteries of an upper extremity. Coincident thrombosis
of the vena cava, iliac, or femoral veins was observed in a few cases. In
Jiirgens' patient there was hajmorrhagic infarction of the intestine. In

24C EMBOTvTSM

Beveral instances liaiiiorrhagcs were found at autopsy in the mucous mem-
branes of the bladder and uterus. Herter, in his experiments in my labora-
tory witii ligation of the abdominal aorta in rabbits, found haemorrhagic
infarction of the uterus to be so common a result of this operation that,
when it was desired to keep the animals alive for any length of time, we
abandoned the use of female rabbits for Stenson's experiment. It does not
appear, however, that in human beings hiemorrhage of the uterus is a com-
mon sequel of occlusion of the abdominal aorta.' It is probable that if
search were made in suitable eases in human beings who have died of aortic
thrombosis or embolism, the interesting muscular clianges described by
Herter in the experimental cases would be found; as similar chauges had
been previously discovered by Litten in an instance of occlusion of the
right iliac and femoral arteries. The most important of these muscular
alterations are vacuolisation, proliferation of the sarcolemma nuclei, atrophy,
and fatty and pseudo-waxy degenerations.

Plugging of tlie abdominal aorta has occuiTcd most frequently in tlie
course of chronic cardiac or arterial disease; but in some instances it took
place during or after an acute infective disease, as acute articular rheu-
matism, puerperal fever, erysipelas, during convalescence from enteric
fever (Forgues), and after pneumonia (Leyden).

Of the fifty-nine cases thirty were females, twenty-seven males, and in
two the sex is not stated. Seventeen were between twenty and thirty years
of age, twelve between thirty and forty, eight between forty and fifty,
thirteen between fifty and sixty, one was nineteen, one sixty-one, and the
ages of seven are not given.' ilarked atheromatous chauges in the arteries
were noted in fourteen cases. Occlusion of the abdominal aorta by embolism
or thrombosis, therefore, is not especially a senile affection.

When one considers the manifold conditions under which the abdominal
aort<a mav become partly or completely plugged by embolism or by primarv*
or secondary thrombosis, it is evident that there can be no general imiformity
of symptoms. The plug may be so situated as to interfere with the circula-
tion in one leg more than in the other. Diversities arise from variations in
the collateral circulation in different cases. Still tJie majority of patients

' It may here bf- mentioned that Herxheimer, Popoff, and Chiari have each
described an instance of hemorrhagic infarction of the uterus after extensive
bilateral plugging of the vessels supplying this organ.

"In Liittich's case already mentioned (p. 243) of the thrombosis of the aorta
in an infant fourteen days old, a thrombus beginning 4 cm. below the insertion
of the ductus Botalll extended into the iliac arteries. Charrier and Apert include
in their collection of reports of thrombosis of the abdominal aorta two cases
from AHibert's thesis of 1828. one three, and the other three and a half years
old, with gangrene of one leg. 1 have not counted these three cases in my list.

EMBOLISM 247

have presented a -well-characterised group of symptoms. In the larger
nximber of cases the onset has been acute, in the minority insidious and grad-
ual. The symptoms have often appeared simultaneously in both legs, but
tliere may be a sliort or a long interval between tlie invasion of one and that
of the other leg. In the more acute ea.ses the leading s}'mptoms are pain in
the legs, — sometimes in the loins and abdomen, sudden or rapidly mani-
fested paraplegia, anesthesia of the legs, absence of femoral pulsation, and
phenomena of mortification extending from the feet upward. In several
instances the patients, while walking, have been seized with excruciating
j)ain in tlie legs, and have fallen paralysed to the groimd. The pain is often
atrocious and more or less paroxysmal. There may be tenderness on pressure
over the occluded aorta. In a few cases pain has not been a prominent
symptom.

Although the paraplegia has been repeatedly described as instantaneous
in its appearance, it is to be inferred from the histories of carefully observed
patients that at least a short interval of time and sometimes several hours
and even days elapse before it is complete. In forty-four cases in which
there are definite statements about the motor power, there was complete or
nearly complete paraplegia in twenty-four; incomplete paralysis of both
lower extremities, described in some instances merely as weakness, in ten ;
paralysis of only one leg in five, and no paralysis in five. The paralysis seems
to be usually of the flaccid variety, but in some cases the paralysed muscles
are stiff. In Barie's patient the paralysed legs were completely rigid, and
it may be inferred that a condition analogous to rigor mortis had set in.
With complete paralysis the reflexes and electrical excitability- are abolished.
Paralysis of the bladder and rectum, with retention of urine and involuntary
evacuations, was observed in several cases, but not in the majority.

Of the cases with satisfactorj' histories in only two was there no disturb-
ance of sensation. In some there was only numbness or some reduction of
sensation; but in most there was definite anaesthesia, extending in some in-
stances no higher than the knee, — more frequently to the middle or upper
third of the thigh, and in two cases as high as Poupart's ligament. There
was sometimes complete analgesia, which, however, did not exclude sensa-
tions of spontaneous pain in the legs. In many cases, however, there was
hyperalgesia, either in the anffisthetie area or above it.

The symptom of greatest diagnostic value is absence of pulsation in the
arteries of the lower extremities. In three or four instances it was deter-
mined that the abdominal aorta below the naval was pulseless. Wilbur
observed excessive aortic pulsation above tlie obstruction. The legs become
cold, and their surface temperature may even fall below tliat of the room
(Browne, ilauz). Absence of bleeding upon incision and of reactive hyper-

248 EMBOLISM

neniia after a])pIication of boat have heen noted. The skin, at first pale, soon
acquires a livid mottling, and the suix>rticial veins may be dilated. O'^dema
of one or both legs and cutaneous hajmorrhages are recorded in some of the
histories. If the patient lives long enough gangrene usually ensues, and
it may be manifest within twenty-seven to forty-eight hours. Gangrene was
bilateral in at least twenty-four cases, and unilateral in seventeen. The
e.xtent of the gangrene varied greatly in different cases, being sometimes
limited to the foot, sometimes reaching the middle of the thigh, and, in
Bell's patient, involving the scrotum. Tympanites, diarrhoea, and albumi-
nuria are common. Exceptional syniptf)ms are the appearance of blood in
the urine or stools, hiematemesis, and priapism. Bedsores appeared in many
cases, and may appear within a few days from the onset.

Death may occur within twenty-four hours from the beginning of the
attack. Fourteen patients died within the first four days, with collapse
and rapid, weak, usually irregular pulse. There may be marked improve-
ment in the initial sjonptoms either in one or in both legs. The larger num-
ber of patients die after a variable interval, which may extend over several
weeks or even months, from gangrene, decubitus, and sepsis.

Of the deviations from the type may be especially mentioned incomplete
manifestation of symptoms on one or both sides, transitory affection of one
leg, limitation of the symptoms to one lower extremity only (four cases),
and affection of one leg followed after days, weeks, or months by that of the
other (six cases). The two cases reported by Earth and by Jean are con-
sidered particularly characteristic of slowly forming thrombosis. Here the
first svTiiptoms were chiefly numbness and intermittent claudication, which,
after a long interval, deepened into paraplegia without gangrene.

All but three cases terminated fatally, more frequently from the remote
effects than from the immediate shock of occlusion of the aorta. The three
instances of survival with marked amelioration of all the symptoms are re-
ported by Gull, Chvostek, and Nunez. These cases began acutely with
severe pains, paraplegia, disturbances of sensation, coldness and lividity of
the lower extremities. The femoral pulse disappeared completely in Gull's
and in Nunez's cases, but in Chvostek's it could still be felt, although it was
feeble. In Chvostek's patient patches of superficial gangrene appeared ; but
in the other two ca.ses there was no gangrene. Nunez reports that after a
year and a half there was no return of the femoral pulse on either side.

Since the demonstration by Schiffer and Weil, confirmed by Ehrlich and
Brieger, Spronck, Herter, and others, that the paraplegia which follows
immediately or very shortly after ligation of the abdominal aorta just below
the renal arteries in rabbits (Stenson's experiment) is due to ischa^nia of
the lumbar cord, many have assumed that the same explanation applies to

EMBOLISM 249

the paraplegia in human beings after occlusion of the abdominal aorta. If
the rabbit's aort<a be tied for an liour, and the ligature be tlien removed, the
paraplegia and paralysis of the bladder and rectum are permanent, the gray
matter of the lumbar cord undergoes necrosis, and a genuine myelitis affect-
ing chiefly the gray but also the wliite matter ensues. The same experiment
gives negative results with the cat and usually with the dog. In view of the
great interest of the subject, it is, to Say the least, remarkable how few of
the reports of autopsies on persons dead of embolism or thrombosis of the
aorta have anything to say about the condition of the spinal cord. Eoussel
and Heiligenthal observed no macroscopic changes in the spinal cord. In
Bell's and Barie and du Castel's cases the cord was microscopically normal,
save congestion in the latter. Broca, Legroux, and Malbranc noted with the
naked eye changes in colour, from which no definite conclusions can be
drawn. The only detailed report of a microscopical examination of the cord
is that of Helbing, who found, in the lumbar region of a man who lived
thirty-nine days after embolism of the abdominal aorta, degeneration of the
anterior and posterior nerve-roois, more marked on one side than the other ;
and the degenerations in the cord for the most part expUoable by the changes
in the nerve-roots. The lesions of the cord were quite unlike those found in
experimental cases, and are interpreted by Helbing as essentially analogous
to those after amputation, and not referable to ischa?mia of the cord.

As the matter now stands, there are no direct observations to support the
opinion that the paraplegia following embolism or thrombosis of the abdomi-
nal aorta in human beings is caused by ischajmia of the cord, so that the old
explanation which refers it to ischemia of the peripheral nerves and muscles
has the most in its favor. The question of the possibility of this mode of
production of the paraplegia, however, seems to me still open, and it is to be
hoped that hereafter fatal cases of this rare condition will not be reported
without satisfactory microscopical examination of the spinal cord. The
anatomical investigations of Kadyi and of Williamson at least do not exclude
the possibility that the lumbar cord in himian beings is dependent to a con-
siderable extent for its blood supply upon the lumbar arteries.

The diagnosis of ischgemie paraplegia from spinal paraplegia can generally
be made without difficulty by the absence of femoral pulsation, by the coldness
and lividity of the extremities, and by the occurrence of gangrene in the
former.

Embolism of Arteries of the Extremities. — Of the arteries of the extremi-
ties the popliteal and the femoral are the most frequent recipients of emboli.
The results of embolism of arteries supplying tlie extremities are essentially
similar to those of arterial thrombosis, which have already been considered
(p. 166). The modifications resulting from the sudden advent of embolism
19

250 EMBOLISM

are sufficiently self-e\ ident. There may be severe pain at the moment of
impaction and at the site of lodgment of the embolus. The general principles
involved in the differentiation of embolism from thrombosis have been pre-
sented under Diagnosis (p. 221).

Hepatic Infarction. — As the effects of infective emboli in branches of
the portal vein and of the hepatic artery have been considered elsewhere
in this work (Allbutt's " System of Medicine," I, p. 601, and V, p. 123), only
the possible mechanical effects of hepatic emboli require consideration here.
Although the intrahepatic branches of the hepatic arterj' and of the portal
vein are terminal vessels, their capillary communications are so abundant
that, as a rule, embolism or thrombosis of the hepatic vessels causes no inter-
ference with the circulation in the liver. Experiments of Cohnheim and
Litten and of Doyon and Dufourt have demonstrated that complete interrup-
tion of the circulation through the hepatic arteries of the rabbit and the dog
is followed by necrosis of the liver. Chiari has observed an instance of
necrosis of the entire liver caused by closure of the trunk of the hepatic
artery beyond the origin of the pyloric branch.

In rare instances, and under circumstances at present not thoroughly
understood, a condition somewhat resembling hemorrhagic infarction may
follow plugging, either by an embolus or a thrombus, of branches of the
portal vein. Instances of this occurrence in human beings have been re-
ported by Osier, Eattone, Klebs, Lubarsch, Kohler, Pitt, Zahn, and Chiari ;
the last-named having seen 17 cases, of which 15 were embolic. A somewhat
similar condition was observed by Arnold after retrograde embolism of the
hepatic vein. Pale wedge-shaped areas have been observed, but in most of
the cases there were circimiscribed dark red or reddish-brown wedge-shaped,
rectangular or irregular areas.

Kohler and Chiari found that the red colour is due mainly to dilatation
of the intralobular capillaries, with atrophy of the liver-cells. Geniune coagu-
lative necrosis is not present. The affected areas are patches of circumscribed
red atrophy rather than tv^pical hjemorrhagic infarcts. Zahn observed the
same condition in a human liver after plugging of portal branches, and repro-
duced it experimentally by emboli of sterilised mercury injected into mesen-
teric veins. In his experimental cases the change in the liver did not begin
until the eighth day, and was distinct after thirty-five days. It is probable
that the areas do not imdergo cicatrisation.

Rattone's theory-, based upon experiments, that occlusion of branches of
both the hepatic artery and portal vein is essential for the production of
infarction of the liver, is not supported by the observations in human beings.
Klebs, whose two cases followed injury of the liver, as was true also of
Lubarsch's observation, attributes the infarction to extensive capillary throm-

EMBOLISM 251

bosis. Kohler considers that the essential factor is combination of occlusion
of branches of the portal vein with obstruction to the return flow from the
hepatic veins. Chiari believes that the second factor, to be added to the
plugging of portal branches, is feeble flow through the hepatic artery, from
weakness of the general circulation. Wooldridge, by injecting coagulative
tissue-extracts into the jugular vein of the dog, caused extensive clotting of
blood in the portal vein and its branches, followed by numerous haemorrhages
and necroses in the liver; but the interpretation of these results as actual
infarctions does not seen, to me certain, inasmuch as these extracts in toxic
doses produc-e a hfpmorrhagic diathesis, and may cause necroses in various
situations independently of thrombosis. The focal necroses so often met
with in the liver in various infective and toxic states do not usually stand in
any definite relation to closure of the vessels (Welch and Flexner).

Embolism of the Coronary Arteries of the Heart. — This is far less frequent
than thrombosis, but Marie's position, that scarcely more than one or two
of the reported cases of coronary embolism are free from all criticism, seems
to be too extreme. Metastatic abscesses in the heart are not particularly rare
manifestations of pyaemia. To what extent they are caused by coarse infective
emboli, or by the lodgment of isolated bacteria, or small bacterial clumps,
does not appear to be established. The heart ranks next to the kidney as the
most frequent seat of abscesses following intravascular injection of the
pyogenetic staphylococci in rabbits.

Virchow, Chiari, RoUeston, Hektoen, and others have published observa-
tions of bland embolism of the coronary arteries. I have observed an instance
in which the embolic nature of the plug seemed to me conclusively established.
A woman, 36 years old, who had presented symptoms of mitral insufficiency,
died suddenly after a paroxysm of dyspnoea and precordial distress lasting
two or three minutes. I found an entirely loose grayish plug, 4 mm. long,
with a rough irregular extremity, completely occluding the descending branch
of the left coronary arter\' near its origin. There was no atheroma at the
site of lodgment of the embolus, although there were a few patches in other
parts of the coronary arteries. The segments of the mitral valve were
tliickened. retracted, and beset with both old and fresh vegetations, and
globular thrombi were present in the left auricular appendix. There were
also fresh vegetations upon the aortic valve. There were infarcts in the spleen
and kidneys. There were no fibroid patches or infarction in the myocardium.

The effects of embolism of the coronary arteries are like those of throm-
bosis, which have already been considered (p. 168).

Embolism an^ Thrombosis of the Retin-al Vessels. — Plugging of the retinal
vessels is of general pathological as well as special ophthalmological interest,
for it is possible to observe with the ophthalmoscope the circulatory disturb-

252 EMBOLISM

aiiccs in the retina. Isclwmia and stasis follow immediately closure of the
central artery of the retina by an embolus. Vi.sion is lost with characteristic
suddenness. Both the arteries and the veins are narrowed, the latter being
often imequally contracted. Subsequently the veins may dilate to some
extent, especially in the periphery of the retina, and present ampulliform
swellings. An interesting phenomenon is the appearance in the veins of an
intermittent, sluggish stream of broken cylinders of rod corpuscles, separated
by clear spaces; and by pressure on the eye-ball a similarly interrupted cur-
rent may often be made to flow through arteries and veins. This appearance
of interrupted columns of blood is evidently similar to that observed by Mall
and myself after closure of the superior mesenteric arter}' and previously
described (p. 212). After a short time the optic papilla becomes pale and
gray, and the retina, especially in the neighborhood of the papilla and
macula, assumes an opaque, grayish white, oedematous aspect. Hoeniorrhages
are exceptional. A characteristic ophthalmoscopic appearance is the cherry-
red spot in the centre of the macula, caused by the red colour of the choroid
shining through. There may be more or less return of the circulation with
improvement and even complete restoration of vision ; but the prognosis as
regards sight is in general imfavourable, as atrophy of the retina and of the
optic nerve is likely to ensue. The prognosis is more favourable with em-
bolism of branches of the retinal artery. Here multiple haemorrhages usually
Of'cur.

Thrombosis of the central retinal vein is distinguished from plug-^ino- of
the artery especially by the abundant hemorrhages. With occlusion of the
central artery the condition is anaemic infarction, and with plugging of the
vein hemorrhagic infarction.

There is some difference of opinion as to the relative frequency of embo-
lism and of thrombosis of the central retinal arten*. Of 129 cases collected
by Fischer, uLnety-one had heart disease; whereas Kern reports that of
twelve cases in Haab's clinic only two had demonstrable cardiac disease; and
of eightj'-three cases, collected from the records, in GG per cent there was no
demonstrable source for an embolus. The latter author, therefore, regards
the majority of plugs in the central arterj' of the retina as primay thrombi.
The generally accepted opinion, however, is that embolism is more common
than thrombosis of the retinal arteries.

Treatment. — In the preceding pages mention has been made of the
surgical treatment of hamiorrhagic infarction of the intestine and of o-an-
grene of the extremities ; and under " Tlirombosis " the importance of pre-
venting so far as may be the separation of emboli has been emphasised. The
general indications in the treatment of emlwlism are essentially similar to
thos(> already considered for thrombosis (p. 184).

EMBOLISM 253

REFERENCES
See footnote to References to Thrombosis, p. 185.

Historical

1. Cohn, B.: Klinik d. embol. Gefasskrankh. Berlin, 1860.

2. J. Cohnheim: Untersuch. lib. d. embol. Processe. Berlin. 1872.

3. Idem: Vorles. iib. allg. Pathol. Berlin, 1S92.

4. Virchow: Gesammelte Abhandl. Frankf., 1856.

Aberrant Embolism

5. Arnold: Virchow's Archiv, 1891, CXXIV, p. 385.

6. Bonome: Arch, per le sc. med., 1889, XIII, p. 267.

7. Ernst: Virchow's Archiv, 1898, CLI, p. 69.

8. Firket: Acad. roy. de med. de Beige, 1890.

9. Flexner: Bull. Johns Hopkins Hosp., 1896, VII, p. 173.

10. Hauser: Miinch. med. Woch., 1888, XXV, p. 583.

11. Heller: Deutsch. Arch. f. kl. Med., 1870, VII, p. 127.

12. Lubarsch: Fortschr. d. Med., 1893, XI, p. 805.

13. Lui: Arch, per le sc. med., 1894, XVIII, p. 99.

14. Ribbert: Centralbl. f. allg. Path., 1897, VIII, p. 433.

15. V. Recklinghausen: Virchow's Arch., 1885, C, p. 503.

16. Rostan: These. Gen6ve, 1884.

17. Scheven: Inaug.-Diss. Rostock, 1894.

18. Schmorl: Deutsch. Arch. f. kl. Med., 1888, XLII, p. 499.

19. Schmorl: Path.-anat. Untersuch. iib. Puerp.-Eklampsie, Leipz., 1893.

20. Zahn: Virchow's Arch., 1889, CXV, p. 71, and CXVII, p. 1.

Anatomical Charactebs

21. Fagge: Trans. Path. Soc. Lond., 1876, XXVII, p. 70.

Effects

22. Askanazy: Virchow's Arch., 1895, CXLI, p. 42.

23. Bier: Virchow's Arch., 1897, CXLVII, pp. 256 and 444; 1898, CLIII, pp. 306

and 434.

24. Bryant: Boston Med. and Surg. Journ., 1888, CXIX, p. 400.

25. Cerfontaine: Arch, de biol., 1894, XIII, p. 125.

26. Davaine: Traits des entozoaires, p. 406. Paris, 1877.

27. Feltz: Schmidt's Jahrb., 1870.

28. V. Frey: Arch. f. Physiol., 1885, p. 533.

29. Goldenblum: Versuche iib. Collateralcirculation, etc. Inaug.-Diss. Dorpat

1889.

30. Koppe: Arch. f. Physiol., 1890, Suppl.-Ed., p. 168.

31. Kossuehin: Virchow's Archiv, 1876, LXVII. p. 449.

32. Kuttner: Ihid., 1876, LXI, p. 21, 1878, LXXIII, p. 476.

33. Lister: Bull. acad. de m6d., 1878, 2nd s., VII, p. 640.

34. Litten: Ztschr. f. kl. Med., 1880, I, p. 131.

35. Mall: Johns Hopkins Hosp. Reports, 1, p. 37.

254 EMBOLISM

36. Marchand: Berl. kl. Woch., 1894, p. 37.

37. Nothnagel: Ztschr. f. kl. Med., 1889, XV, p. 42.

38. Panski and Thoma: Arch. t. exp. Path., 1893, XXXI, p. 303.

39. Ponfick: Virchow's Arch., 1873, LVIII, p. 528.

40. V. Recklinghausen: Handb. d. allg. Path. d. Kreislaufs, etc. Stuttg., 1883.

41. Thoma: Lehrb. d. path. Anat., Th., I. Stuttg., 1894.

42. Weigert: Virchow's Archiv, 1877, LXX, p. 486; 1878, LXXII, p. 250; 1880,

LXXIX, p. 104.

43. Idem: Centralbl. f. allg. Path., 1891, II, p. 785.

44. Welch: " Hjemorrhagic Infarction," Trans. Assoc. Amer. Physicians, 1887,

II, p. 121.

45. Zlelonko: Virchow's Arch., 1873, LVII, p. 436.

Embolic Axeibtsms

46. Buday: Zlegler's Beitr., 1891. X, p. 187.

47. Clarke: Trans. Path. Soc. London, 1S96, XLVII, p. 24.

48. Duckworth: Brit. Med. Journ., 1890, I, p. 1355.

49. Eppinger: Pathogensis, Histogensis u. Aetiologie d. Aneurysmen. Berl., 1887.

50. Langton and Bowlby: Med.-Chir. Trans., 1887, LXX. p. 1117.

(Consult for references to Ogle, Wilks, Holmes, Church, Smith, Good-
hart, and other previous literature.)

51. Pel and Spronck: Ztschr. f. kl. Med., XII, p. 327.

52. Thoma: Deutsch. med. Woch., 1889, p. 362.

53. Tufnell: Dubl. Quart. Journ. Med. Sc, May, 1853.

Geneeal Stmptomatologt

54. Gangolphe and Courmont: Arch. med. exper., 1891, III, p. 504.

55. Strieker: Vorles. lib. allg. u. exper. Pathologic, p. 770. Wien, 1883.

Air E.mboli.sm

56. Bert: La pression barometrique, etc. Paris, 1878.

57. Couty: Etudes exper. sur I'entrge de I'air dans les veines Thgse Paris

1875.

(Also for reference to Barthelemy.)

58. Feltz: Compt. rend., 1878, LXXXVI, No. 5.

59. Ewald and Robert: Pfliiger's Arch., 1883, XXI, p. 160.

60. Hauer: Ztschr. t. Heilk., 1890, XI, p. 159.

61. Janeway: Trans. Assoc. Amer. Physicians, 189S, XIII, p. 87.

62. Jiirgensen: Deutsch. Arch. f. kl. Med., 1SS2, XXXI, p. 441.

63. Laborde and Muron: Compt. rend. soc. de biol., 1873, V.

64. Lewin: Arch. f. exp. Path. u. Pharm., 1S97, XL, p. 308.

65. Passet: Arb. a. d. path. Inst, zu Miinchen, p. 293. Stuttg., 1886.

66. Welch and Flexner: Journ. Exp. Med., 1896, I, p. 5.

67. Welch and Nuttall: Johns Hopkins Hosp. Bulletin, 1892, III, p. 81.

EJIBOLISM 255

Fat Embolism

68. Beneke: Ziegler's Beitr, 1897. XXII, p. 343.

69. Hanriot: Compt. rend. acad. des sc, 1896, CXXII, p. 753; CXXIII, p. 833;

1897, CXXIV, pp. 235 and 778.

70. Ribbert: Correspondenz-Bl. f. schweiz. Aerzte, 1894, XXIV, p. 457.

71. Sanders and Hamilton: Edin. Med. Journ., 1879-80, XXV, p. 47.

72. Wagner: Arch. d. Heilk., 1862, III, p. 241; 1865, VI.

73. Zenker: Beitr. zu norm. u. path. Anat. d. Lunge, Dresden, 1862

Embolism by Parenchymatous Cells

74. Aschoff: Virchow's Arch.. 1893, CXXXIV, p. 11.

75. Gaylord: Proc. Path. Soc, Philadelphia, 1898, N. S. I, p. 184.

76. Hanau: Fortschr. d. Med., 1886, IV, p. 387.

77. Lubarsch: Fortschr. d. Med.. 1893, XI, pp. 805 and 845.

(Consult for references to Turner, Jiirgens, Klebs, Schmorl, Zenker,
and Hess.)

78. Idem: Virchow's Arch., 1898, CLI, p. 546.

79. Maximow: Virchow's Archiv, 1898, CLI, p. 297.

(Also for references to Leusden and Kassjanow. )

80. Neumann: Monatsschr. f. Geburtsh. u. Gynakol., 1897, VI, pp. 17, 157.

81. Pick: Berl. kl. Woch., 1897, p. 1069.

(Also for Schmorl.)

82. Schmidt, B.: Centralbl. f. allg. Path., 1897, VIII, p. 860.

83. Schmorl: Centralbl. f. Geburtsh. u. Gynakol., 1897, p. 1216.

PiXMOXABY Embolism

84. Bang: Jattagelser og Studler over d^dellg Embolic og Thrombose i Lunge-

artierne. Copenhagen, 1880.

85. Biinger: Ueb. Embolie d. Lungenarterie. Inaug.-Diss. Kiel, 1895.

86. Cohnheim and Litten: Virchow's Archiv, 1875, LXV, p. 99.

87. Freyberger: Trans. Path. Soc. London, 1898, XLIX, p. 27.

88. Fujinami: Virchow's Archiv, 1898, CLII, pp. 61, 193.

(Also for Oestreich.)

89. Gluzinski: Deutsch. Arch. f. kl. Med., 1895, LIV, p. 178.

(For references to Perl and Lipmann, Sommerbrodt and Nothnagel.)

90. Grawitz: Virchow's Festschrift der Assistenten, Berlin, 1891.
90a. Gsell: Mittheil. a. Klinik u. med. Inst. d. Schweiz, III, R. Hft. 3.

(Also for Hanau.)

91. Hamilton: A Text-Book of Pathology, I, p. 683. London, 1889.

92. Kuttner: Virchow's Archiv, 1878, LXXIII, p. 39.

93. Klebs: AUg. Path., II, p. 20. Jena, 1889.

94. Litten: Charite-Annalen, 1878, III, 1876, p. 180.

95. Mogling: Ziegler's Beitr., 1886, p. 133.

(See also reference 90.)

96. Orth: Centralbl. f. allg. Path., 1897, VIII. p. 859.

97. Perl: Virchow's Archiv, 1874, LIX, p. 39.

98. Serre: De I'origine embolique des thromboses de I'artere pulmon. These.

Lyon, 1895.

256 EMBOLISM

99. Sgambati: Arch, ed atti d. soc. ital. di chir. Roma, 1897. XI, p. 37.

100. Willgerodt: Arb. a. d. path. Inst. In Gottlngen, p. 100. Berlin, 1893.

101. Zahn: Centralbl. f. allg. Path., 1897, VIII, p. 860.

Sple.n'ic Infabction. Renal Infabction

102. Ponfick: Virchow's Arch., 1S74, LX, p. 153.

103. Thorel: Virchow's Arch., 1896, CXLVI, p. 297.

104. Traube: Gesammelte Beitr. zu Path. u. Physiol., II, p. 347. Berl., 1871.

Emrolism and Tiikomkosis of the Mese.vtebic Abtebies

105. Beckmann: Virchow's Arch., 1858, XIII, p. 501.

106. Chiene: Journ. Anat. and Physiol., 1869, III, p. 65.

107. Councilman: Boston Med. and Surg. Journ., 1894, CXXX, p. 410.

108. Elliot: Annals of Surgery, 1895, XXI, p. 9.

109. Faber: Deutches Arch. f. kl. Med., 1875, XVI, p. 527.

110. Finlayson: Glasgow Med. Journ., 1888, XXIX. p. 414.

111. Gerhardt: Wiirzb. med. Ztschr., 1863, IV, p. 141.

112. Gordon: Brit. Med. Journ., 1898, I, p. 1447.

113. Karcher: CorrespondenzBl. f. schweiz. Aertze, 1897, XXVII, p. 548.

114. Kaufmann: Virchow's Arch., 1889, CXVI, p. 353.

115. Kussmaul: Wiirzb. med. Ztschr., 1864, V, p. 210.

116. Lereboullet: Rec. de mgm. de med., 1875, XXXI, p. 417.

117. Litten: Virchow's Arch., 1875. LXIII, p. 289.

118. Idem: Deutsche med. Woch., 1889, p. 145.

119. Lorenz: Ztschr. f. kl. Med., 1891, XVIII, p. 493.

120. Lycett: Brit. Med. Journ., 1898, II, p. 84.

121. Minkowski: Mitth. a. d. med. Klin, zu Konigsberg, 1888, p. 59.

122. Moos: Virchow's Arch., 1867, XLI, p. 58.

123. Nothnagel: Spec. Path. u. Therap., XVII, p. 156. Wien, 1898.

124. Oppolzer: Allg. Wien. med. Ztg., 1862, VII.

125. Packard: Proc. Path. Soc. Philadelphia. 1898, N. S. I, p. 288.

126. Parenski: Wiener med. Jahrb., 1876, p. 275.

127. Pieper: Allg. med. Centr.-Ztg., 1865, p. 493.

128. Ponfick: Virchow's Arch., 1870, L., p. 623.

129. Tangl and Harley: Centralbl. f. d. med. Wiss., 1895, p. 673.

130. Tiedemann: Von d. Verengung u. Schliessung d. Pulsadern in Krankheiten.

Heidelb. u. Leipz., 1843.

131. Watson: Boston Med. and Surg. Journ., 1894, CXXXI, p. 552.

132. Welch and Flexner: Journ. Exp. Med., 1896, I, p. 35.

E.MBOLISM AND THROMBOSIS OF TUE TlIOBACIC AOKTA

133. Armet: Thdse. Paris, 1881.

134. Chvostek: Wiener med. Blatter, 1881. p. 1513.

(Also for references to Trost, Carville. Liittich, and Tewat.)

135. Bochdalek: Vrtljschr. f. d. prakt. Heilk., 1845, VIII, p. 160.

136. Bristowe: Lancet, 1881, I, pp. 131 and 166.

137. Jaurand: Progr. mM., 1882, X, p. 147.

138. Pitt: Trans. Path. Soc. London, 1889, XL, p. 74.

EMBOLISM 257

Embolism and Thrombosis of the Abdominal Aorta

139. Cammareri: Morgagni, 1885, XXVII, pp. 1, 113.

140. Charrier and Apert: Bull. soc. anat. de Paris, 1896, 5th s., X, p. 766.

141. Graham: Med.-Chir. Transactions., 1814, V, p. 297.

142. Heiligenthal: Deutsch. med. Woch., 1898, p. 519.

143. Meynard: Etude sur I'oblitgration de I'aorte abdom. par embolie ou par

thrombose. These. Paris, 1883.

(Meynard's case is Identical with Bari§'s and du Castel's.)

144. Roussel: Etudes sur les embolies de I'aorte abdom. These. Lyon, 1893.

(The cases of Bari§ and of Desnos reckoned as separate cases by Seller
and Roussel are identical.)

145. Selter: Ueb. Embolie d. Aorta abdom. Inaug.-Diss. Strassburg, 1891.

(The references to my additional twelve cases of embolism or throm-
bosis of the abdominal aorta are Nos. 146 to 157 inclusive.)

146. Ballingall: Trans. Med. and Phys. Soc. Bombay, 1857, N. S. Ill, App. p. XXV.

147. Bristowe: Trans. Path. Soc. London, 1872, XXIII, p. 21.

148. Carter: Trans. Med. and Phys. Soc. Bombay (1859), 1860, N. S. V, App.

p. XXII.

149. Goodworth: Brit. Med. Journ., 1896, I, p. 1501.

150. Kirkman: Lancet, 1863, II, p. 510.

151. Mauz: Berl. kl. Woch., 1SS9, p. 812.

152. Nunez: Gaz. med. de la Habana, 1879-80, II, p. 160.

153. Osier: Trans. Assoc. Amer. Physicians. 1887, II, p. 135.

154. Pettit: New Orleans Med. and Surg. Journ., 1880-81, N. S. VIII, p. 1151.

155. Schilling: Miinch. med. Woch., 1895, p. 227.

156. Scholz: Ein Fall von Obturation d. Aorta abdom. Inaug.-Diss. Tiibingen,

1850.

157. Wilbur: Amer. Journ. Med. Sc, 1857, N. S. XXXIV, p. 286.

158. Barth: Bull. Soc. anat. de Paris, 1848, XXIII, p. 260.

159. Herter: Journ. Nerv. and Mental Dis., 1889, XIV, p. 197.

(For references to Schiffer, Weil, Ehrlich and Brieger, and Spronck.)

160. Herxheimer: Virchow's Arch., 1886, CIV, p. 20.

161. Kadyi: Ueb. d. Blutgefasse d. menschl. Riickenmarkes. Lemberg, 1889.

162. Litten: Virchow's Arch., 1880, LXXX, p. 281.

163. Popoff: Arch. f. Gyniik., 1894, XLVII, p. 12.

164. Williamson: On the Relation of the Spinal Cord to the Distribution and

Lesions of the Spinal Blood-Vessels. London, 1895.

Hepatic Infarction

165. Arnold: Virchow's Arch., 1891, CXXIV, p. 388.

166. Chiari: Centralbl. f. allg. Path., 1898, IX, p. 839.

167. Cohnheim and Litten: Virchow's Arch., 1876, LXVII, p. 153.

168. Doyon and Dufourt: Arch, de physiol., 1898, 5th s. X, p. 522.

169. Flexner: Johns Hopkins Hosp. Reports, 1897, VI, p. 259.

170. Klebs: Virchow's Festschrift der Asslstenten, 1891, p. 8.

171. Kohler: Arb. a. d. path. Inst, in Gijttingen, 1893, p. 121.

172. Lubarsch: Fortschr. d. Med., 1893, XI. p. 809.

173. Osier: Trans. Assoc. Amer. Phys., 1887, II, p. 136.

258 EMBOLISM

174. Pitt: Brit. Med. Journ., 1895, I, p. 420.

175. Rattone: Arch, per le sc. med., 1888, XII, p. 223.

176. Welch and Fiexner: Johns Hopkins Hosp., Bulletin, 1892, III. p. 17.

177. Wooldridge: Trans. Path. Soc. London, 1888, XXXIX. p. 421.

178. Zahn: Centralbl. f. allg. Path., 1897, VIII, p. 860.

E.MBOLI.S.M OF THE COEONABY ABTEBIES

179. Chiari: Prag. med. Woch., 1897. Nos. 6 and 7.

180. Hektoen: Med. News, 1892. LXI. p. 210.

181. Marie: L'infarctus du myocarde, p. 30. Paris. 1897.

182. Rolleston: Brit. Med. Journ.. 1896, II, p. 1566.

E-MBOI.ISM AND ThBOSIBCSIS OF THE RETI.NAI, VE.SSEI.S

183. Fischer: Ueb. d. Embolie d. Art. centr. retinae. Leipzig, 1891.

184. Kern: Zur Embolie d. Art. centr. retinae. Inaug.-Diss. Zurich, 1892.

VEXOUS THROMBOSIS IX CARDIAC DISEASE'

One of the most interesting points of view from which to consider the
subject of thrombosis is that of its association with different diseases.
The study of such association not only is of clinical interest, but is capable
of contributing to our knowledge of the causation of thrombosis, which
in many respects is still obscure. Infectious and chronic wasting diseases
are those most frequently complicated or followed by vascular thrombosis
of medical, as distinguished from surgical, interest; typhoid fever and
influenza heading the list among the former, and tuberculosis and cancer
among the latter. There are, however, a number of other diseases with
which peripheral thrombosis may be associated more or less frequently,
and to one of these less generally recognized associations I wish to call
attention in this paper.

Although there are scattered reports of a number of instances of the
occurrence of venous thrombosis in diseases of the heart, I cannot find
that particular attention has been called to this complication either in
text-books on these diseases or in special monographs. This is doubtless
attributable mainly to the infrequency of the complication, perhaps also
in part to a failure to recognize it. By far the largest number of cases
have been reported by French physicians.

As will appear from the following reports of ca^es, there are certain
peculiarities of the venous thrombosis of heart disease which render this
suject well worthy of investigation. For the clinical histories of the cases
from the Johns Hopkins Hospital I am indebted to my colleague. Dr.
Osier.

Case I. — Aortic and mitral insufficiency. Adherent pericardium. Broken
compensation. ThromboMs of left innominate, jugular, subclavian, and
axiUary veins. Death. — R. H., negress, aged seventeen years, admitted Xo-
vember 26, 1898, died January 16, 1899. Xothing of importance in family
history or in personal history, until the occurrence, six years ago, of a severe
attack of inflammatory rheumatism, with swelling and tenderness of most
of the Joints. Since then she has not been strong and has had at times rheu-
matic pains. In January, 1898, occurred a second attack of articular rheu-

• After its presentation before the Association of American Physicians, this
paper was published also in the Festschrift in honor of Abraham Jacobi, M. D.,
LL. D., New York, 1900. I have added to the article in its present form Case V,
which has necessitated changes in the statistical figures.

Tr. Ass. Am. Physicians, Phila., 1900, XV, 441-469.

239

260 VENOUS THROMBOSIS

iimtisni, since wliich she has suffprcd from shortness of breath on exertion,
|i:iliiitutioii, pain in the rej:ion of the heart, and some cough. These symp-
toms became aggravated during tiie last two months.

r}i(>n admission, patient, who is well nourished, is suffering from respira-
tory distress. No tt>dema of extremities. Pulse 112, somewhat irregular,
with fair volume and tension. Respirations 40. Temperature 99.5° f!
Large veins of neck full and pulsating. JJarked bulging of pnecordium, and
heaving impulse over heart, especially distinct below and out.side of left
nipple. Harked pulsation in episternal notch. Point of maximum intensity
in sixth left interspace, 12 cm. from midst^rnal line. Relative cardiac dul-
ness begins above in left tirst intercostal space. Systolic thrill at apex,
where on auscultation are heard intense musical systolic and rasping diastolic
murmurs transmitted into axilla. In the aortic area both sounds are re-
placed by a loud to-and-fro murmur, the diastolic portion being especially
rough. Second pulmonic sound intensely accentuated. Hearts action
irregular and \iolent. Capillary pulse visible.

At apex of right lung, slight expansion, dulness. prolonged, almost tubular
expiration. A few medium-sized moist rales at base of lungs. No tubercle
bacilli in sputum.

Liver somewhat enlarged. L^rine albuminous, with hyaline and granular
casts. Blood count: red corpuscles, 4,524,000; leucocytes, 12,400; hjemo-
glohin. (i5 per cent.

Patient improved somewhat after admission, but her general condition
continued much the same. The pulse at times was very intermittent, and
there was much tenderness over the pra?cordial area. The temperature varied
from normal to 101° F.

January lJ,th. For the first time cedema of the left arm is noticed, most
marked around the elbow-joint. The right arm is free from swelling. The
face and legs are moderately oedeniatous. Complains of severe headache.
Pulse 120, irregular and weak.

loth. (Edema of left arm. which is painful, has increased. Temperature
100.5° F. Pulse very intermittent. Death occurred rather suddenlv at
6.30 p. m.

Aufopsij by Dr. MacCallum, fourteen hours after death. Body of a girl,
rather slenderly built. 162 cm. long. ;Moderate cedema of ankles and feet.
Extensive wdema of left ann, especially about the elbow, the hand being but
little sw-ollen. No oedema of right ann and no definite swelling of face or
neck.

About 200 c. c. clear yellowish fluid in peritoneal cavity. Surfaces smooth
and glistening. Prscordial space greatly enlarged, meas"uring IG cm. trans-
versely and 10 cm. vertically. Firm adhesions between parietal jicricardium
and the pleura, diaphragm, and otlicr surrounding tissues. Eett pleural
cavity contains over .300 c. c. slightly turi)id, yellowish fluid, the left lun«^
being much compressed by this and the enlarged lieart. There are manv
easily torn pleural adhesions. The right pleural cavity contains a small
amount of fluid and presents a few light adhesions.

The pericardial sac is obliterated by fibrous adhesions. The heart weiglis
'i20 grammes, and gives the following measurements: right ventricle 8 cm.
long, its wall (i mm. thick; left ventricle 9 J cm. long, its wall H! mm. thick ;

IN CARDIAC DISEASE 261

tricuspid orifice 10| cm., mitral 10 cm., aortic 7 cm. All of the cavities
much dilated. Left auricle greatly dilated, reaching nearly to first rib.
Tricuspid and pulmonic valves delicate. Mitral orifice verj' wide; valvular
segments, particularly the posterior, thickness and retracted. Aortic valvu-
lar segments much thickened, stifl", and curled at their edges, so as to be
markedly shortened. Xo fresh vegetations. Coronary arteries patent and
free from sclerosis. The aorta shows yellow streaks of fatty degeneration of
the intima, and a few small elevated patches of fresh sclerosis.

The left innominate vein, the left internal and external jugular veins, the
left subclavian and axillary veins are occluded by a continuous fresh throm-
bus mass. The prevailing color of the thrombus is dark reddish. The part
occupying the innominate just before the reception of the jugular vein and
that filling the well-developed bulb of the internal jugular vein is gray or
grayish-red, firmer and more adherent to the wall, therefore older, than" the
dark-red, softer clot in the distal portions. The thrombus in the jugulars
stops somewliat below the level of the larynx. The brachial and other veins
of the arm are free from the thrombus. The tissues around the thrombosed
veins are (edematous, and freshly swollen lymphatic glands are present in
their neighborhood. The corresponding veins of the right side are free from
thrombus.

The lungs are dry, tough, and of a salmon-pink color, evidentlv the seat
of chronic passive congestion. The bronchi contain blood-stained mucus.
No areas of fresh consolidation. Pulmonic vessels free from thrombi.

The liver is moderately enlarged, and presents tj'pical nutmeg mottling.
Spleen also enlarged, firm, dark red. slightly adherent to surrounding tis-
sues ; Malpighian bodies distinct. Kidneys swollen, congested, the seat of
chronic passive congestion. Gastric and intestinal mucosfe deeplv congested,
the solitary follicles swollen. Xo important changes in other organs.

Microscopical Examinaiion. — The swollen lymph glands show marked
proliferation of the endothelial cells. The heart mtiscle is slightly fatty,
and shows scattered focal accumulations of small round cells, mainly of the
h-mphoid type. The kidneys show passive congestion and parenchvmatous
degenerations, without increase of the connective tissue. The lungs" present
the usual evidences of chronic passive congestion of moderate degree.

Sections of the thrombosed veins sliow that the gravish-red part of the
thrombus is composed of platelets, fibrin, and leucocytes with entangled red
corpuscles. A coral-like arrangement of the platelet masses is indicated,
but is not very distinct. Leucocytes are fairly ntmierous. There are no
evidences of organization. The intima and outer coats contain a few leuco-
cj-tes, and the intima is somewhat swollen, but there are no signs of sclerosis
or other chronic affection of the veins. The redder parts of the thrombus
are richer in red corpuscles, but here also islands and bands of platelets and
fibrillated fibrin are present. A few chains of streptococci are detected in
sections stained by Gram's metliod.

Bacteriological Examinaiion (Dr. Harris).— Plate cultures on agar made
with all necessary precautions from tlie thrombi in the jugular veins showed
a considerable number of small, grayish colonies, which were demonstrated
to be of Streptococcus pyogenes. Xo other organism appeared in the cultures.
Streptococcus pyogenes was cultivated also from the lungs. Cultures from

262 VENOUS THROMBOSIS

the heart's blood, (Edematous tissue in left axilla, the spleen and other organs
were sterile.

The principal points of interest in the preceding case are the following:
A <rir], seventeen years old, with chronic aortic and mitral endocarditis
following acute articular rheumatism, and giving rise to insufficiency of
both valves, witli relative insufficiency of the tricuspid valve, suffered from the
effects of broken compensation. Duriiij: the last days of life painful oedema
of the left arm made its appearance, without implication of tlie right arm. At
the autopsy, in addition to the advanced cardiac lesions and their customary
secondary eft'ects, an infectious thrombus was found filling the innominate,
subclavian, axillary, and lower parts of the jugular vein on the left side. The
oldest part of the thrombus occupied the lower bulb of the internal jugular
vein and the adjacent part of the innominate vein. The micro-organism con-
cerned was Streptococcus pyogenes, which was present in the lungs and the
thrombus, but was not found elsewhere.

The three following cases are also from Dr. Osiers service in the Johns
Hopkins Hospital:

Case II. — Mitral stenosi.''. Thrombosis of left jugular, axillary, sui-
clavian, and innominate veins. Embolism of left popliteal artery. Recovery
from effects of vascular occlusion. — E. 0., female, aged thirty-five years,
admitted January 4, 1899. History of rheumatism in family. Diphtheria
at ten, chorea at eleven years of age, accompanied by paralysis of the right
side. Since these attacks patient has not been strong. No history of scarlet
fever, poemnonia, nor typhoid fever. Obscure liistory of repeated attacks
of " rheumatism "' witliout definite articular symptoms. Patient has .suffered
for years from sliortness of breath on exertion, indigestion, nervousness, and
chronic invalidism. For three weeks before admission has been in bed with
epigastric pain and digestive disturbances.

Upon admission patient is very nervous. The point of maximum inten-
sity of cardiac impulse cannot be detected by palpation or inspection, but by
the stethoscope is located in the fifth intercostal space, 10 cm. from median
line. Area of cardiac dulness not much increased. Very distinct thrill can
l>e felt at the apex, where is heard a rough, inten.se. presystolic murmur ter-
minating in a short, sharp first sound. Xo second sound is heard at the
apex. Over the body of the heart the valvular sounds are distinct and snap-
ping. The second pulmonic sound is markedly accentuated. Pulse 144,
small, irregular both in force and rbvthm. Respiration 30. Temperature
99° F.

Medium-sized moist rales are heard behind, over the lower parts of both
lungs, where there is also some impairment of resonance.

The absolute hepatic dulness extends from the seventh rib to a point 5^
cm. below the costal margin in the mammar}' line. The border of the liver
can be distinctly felt. There is fairly distinct pulsation of the liver. The
epigastric and right hypochondriac regions arc somewhat tender to pressure.

There is slight (edema of Ixith ankles. Urine, sp. gr. 1017, contains a
small amount of albumin and hyaline and granular casts.

IX CARDIAC DISEASE 263

January 12th. The left ankle-joint is swollen, red, and tender.

19th. The left side of the neck is swollen, and painful upon pressure or
movement. Temperature 100°. Pulse 124. Respiration 32.

20ih. The fulness and tenderness of the left side of the neck have in-
creased, and a sensitive, cord-like body can be felt in the course of tlie in-
ternal jugular vein in its lower part, indicative of thrombosis. The pain
and swelling of the left ankle-joint have disappeared. There are evidences of
partial consolidation of the right lung below and beliind. iloist rales are
heard also at the angle of the left scapula. Patient is flighty.

2Gth. To-day ap])eared an edematous swelling of the'^left arm, extending
to the hand. The left ami measures 2 cm. more than the right just above
the wrist.

27th. The cedeniatous, painful swelling is now very marked, and occupies
the whole of the left side of the neck, the pectoral region on the left side,
the left shoulder, and the left arm to the hand. The oedema has a brawny,
indurated character, but there is pitting on pressure. There is no marked
difference in the superficial temperature of the two arms. Tlie superficial
veins of the arm and neck are distended. On account of tlie oedema tlie
deeper veins cannot be distinctly palpated. Temperature 101°. Pulse 112.
Respiration 40.

Slst. The swelling of the left arm is less ; that of the neck continues.

February 9th. A cord-like swelling of the left external jugular vein can
be traced up to the angle of the jaw. The axillary' vein is likewise thrombosed.

26th. The hard oi'dema of the left arm and "neck has continued, at times
lessening and then returning. There is a?dema of toth lower extremities.

March lOilt. Pain in the left side and a marked pleuritic friction rub on
auscultation.

Soon after this date the general condition of the patient improved, and
the oedema of the arm and neck gradually disappeared through the establish-
ment of a collateral circulation.

On Xovember 24th embolism of the left popliteal artery occurred, char-
acterized by loss of pulsation in left popliteal and tibial arteries, sudden pain,
numbness, cyanosis, and coldness of the left foot and leg. The historj' of
this embolic attack need not be given in detail. Suffice it to say that a col-
lateral circulation was completely re-established. The patient is still in the
hospital.

The diagnosis made by Dr. Osier in this case was mitral stenosis with
thrombosis of the left innominate, left internal and external jugulars, left
subclavian, and left axillary veins. The location, extent, and persistence
of the hard, painful oedema, lasting for nearly three months, make prob-
able the existence of thrombosis of the left innominate and subclavian
veins, while that of the jugulars and axillary vein was definitely recognized.
The history indicates that the thrombosis started in the lower part of the
internal jugular vein. It is to be noted that the onset of the thrombosis
was preceded for a few days by a red, painful swelling of the left ankle-
joint, and was accompanied by evidences of acute pneumonia and by ele-

264 VENOUS THROMBOSIS'

vation of temperature, also that rlurins: 'ts course acute pleurisy appeared.
There is, therefore, much probability in the supposition that the thrombus
in this ease, as in the preceding, was of infectious nature.

Case III. — Mitral and aortic insufjlcienqi ; general anasarca; thrombosis
of the left axillarij and brachial veins. Death. — H. M., aged sixteen years,
admitted February 24, 1900; died March 8th. No history of infectious
disease except pneumonia at seven years of age. Present illness began in
August, 189;i, with vomiting and indigestion. Says that he had rheumatism
in September, but no definite history of affection of joints was obtained. Re-
peated attacks of gastric pain and vomiting during the autumn. In January,
feet, legs, and abdomen became swollen, and he was confined to bed. The
dropsy increased, and a week ago the face and hands began to swell. Con-
tinued shortness of breath ; digestive disturbance continued.

Examination on Admission. — Patient is propped up in bed; respiration
32, somewhat labored, and irregular. Cyanosis of face and extremities;
oedema of face, thorax, upper and lower extremities, penis, and scrotum ;
marked cedema of left forearm and hands; ascites. Pulse 124, regular in
force and rhythm, fair volume, low tension, hyperdicrotic ; pulsation of
cervical veins.

Distinct praecordial bulging and general heaving in this region. Apex-
beat in fifth interspace 11 cm. to left of median line ; area of cardiac dulness
increased, extending 1 cm. to right of sternum and upward to left second rib.
At apex first sound replaced by loud systolic murmur heard far out in axilla ;
second sound faint. In aortic area both sounds enfeebled, tlie second soimd
being accompanied by a faint diastalic murmur traceable down along right
border of sternum; second pulmonic sound distinctly accentuated.

Physical signs of a moderate amount of fluid in left pleural cavity are
present, also some dulness and impairment of respiratory and vocal sounds
on right side below and behind, with a few fine moist rales.

Absolute hepatic dulness begins at sixth rib and is continuous with the
abdominal flatness due to ascites, which is marked.

The axlema of the left arm and hand is so much greater than that of the
right arm that thrombosis was suspected. Upon palpation the left axillary
and brachial veins can be distinctly felt as hard, swollen, somewhat sensitive,
cord-like cylinders, which can be made to roll beneath the finger.

Blood Counts.— Jled blood-corpuscles, G,900,000; leucocytes, 14,600;
ha?moglobin, 76 per cent ; 86 per cent of the leucocytes are pohnnorphonu-
elear. Urine contains a small amount of albumin and some hyaline casts;
specific gravity, 1027.

After admission the cedema of the left arm and hand continued to increase
and reached an extreme degree, so that splits appeared in the corium. The
superficial veins were distended. Temperature most of the time a little below
normal, only occasionally rising to 99" and once to 100° F.

March 1st. Jaundice appeared. The next day a hemorrhagic eruption
appeared over the abdomen. Cheyne-Stokes breathing set in, the sputum
became tinged with blood, and death occurred March 8th. Unfortunately,
permission could not be obtained for an autopsy.

IN CARDIAC DISEASE 265

In the preceding case of uncompensated mitral regurgitation the general
dropsy was so great that only the excess of ffidematous swelling of the left
arm led to examination for venous thrombosis, of which positive evidences
were found in the left brachial and axillary veins. ^Miether other veins
were also implicated could not be determined, as no autopsy was permitted.

Case IV. — Mitral insufficiency ; thrombosis of left femoral vein; recovery
from effects of tliromhosis. — M. H., male, aged seventy-eight years, admitted
December 27, 1898; discharged January' 10, 1890. Patient had been in
hospital a year ago, suffering irom abdominal pain and constipation. At this
time mitral insufficiency was recognized. Xo history of rheumatism or of
other infectious disease, except measles and smallpox in childhood. Has
suffered of late years from pain in the abdomen, constipation, bronchitis,
and increased frequency of urination.

Three days before admission was seized with pain on tlie inner side of left
ankle and inside of upper part of thigh, soon followed by swelling of the left
leg and about the ankle.

On admission a rough systolic murmur is heard at the apex, transmitted to
the axilla, aiid heard also over the body of the heart. Systolic whiff over
aortic and pulmonic areas. Point of maximum intensity of cardiac impulse
in fifth intercostal space 11 cm. to left of median line. Veins of neck full
and heaving, but without distinct pulsation. Superficial veins of nose and
cheeks dilated; physical signs of emphysema and bronchitis. Pulse 96,
regular ; respirations 20. Eadial and temporal arteries tortuous and sclerotic.

The left lower extremity cedematous from the groin to the foot, the swell-
ing being most marked around the ankle. Superficial temperature of
left leg somewhat higher than that of right ; superficial veins dilated. An
indurated, sensitive cord can be felt in the left Scarpa's triangle, running
obliquely downward and inward. The deep Ij-mphatic glands below Pou-
part's ligament on the left side are somewhat enlarged. The pulsation of the
left femoral artery is less distinct than that of the right ; slight oedema of the
right leg.

Blood Count— Tied blood-corpuscles, .3,800,000; leucocytes, 5000; haemo-
globin, 40 per cent. Temperature remained about normal, occasionally ris-
ing in the evening to a little over 99° F. Urine : specific gravity, 1020 ; acid,
faint traces of albimiin ; no casts.

The axlema of the left leg gradually lessened, and on January 10th ptatient
was discharged at his request with only a little a?dema of the extremities.

In the foresoincr case there were no marked evidences of disturbed com-
pensation of the mitral lesion, and there was arterial sclerosis. The rela-
tionship of the venous thrombosis to the cardiac lesion was not, therefore,
so evident as in the three cases first reported, and probably this case does
not properly belong in the same category.

For the notes of the following typical, unpublished case, occurring in
the service of Dr. James B. Herrick, at the Cook County Hospital, Chicago,
I am indebted to the kindness of Dr. H. Gideon Wells, who, when interne
at the hospital, observed the patient:
20

266 VENOUS THROMBOSIS

Case V. — Arteriosclerosis; mitral and tricuspid insufficiency ; fibrous
myocarditis and fatty heart; general anttsarca; chronic interstitial nephritis;
thrombosis of left internal jugular, subclavian, axillary, and brachial veins.
Death. — J. C, negro, aj^ed fifty-three years, admitted January 10, 1898 ; died
July 21, 1898. History of an old syphilitic infection and of excessive use
of alcohol. Patient stated that for three weeks preceding admission lie had
suffered from pain in the chest, cough, increasing difficulty in respiration,
and swelling of the legs and ankles, later of the face, with increased fre-
quency of urination.

Examination showed very marked general ana.«arca, with slight hydro-
peritoneum and extensive hydrothorax. The cardiac dulness extended 2 cm.
to the right of the sternum, and 11 cm. to the left of the sternal Wrder; the
base reached to the level of the second costal cartilage. There was a mitral
regurgitant murmur. The arteries were hard and tortuous ; tlie pulse in the
radial and carotid arteries almost imperceptible. Hepatic dulness extended
a short distance below the costal margin: the spleen could not be palpated.

The patient remained in the hospital until his death, six and a half months
after entrance. During this time he was generally bedridden and suffered
from severe dyspnoea, occasional attacks of precordial pain, and extensive,
general anasarca. The urine was loaded with albumin and contained large
numbers of cast^. At times the amount of fluid in the pleural cavities was
so large as to require paracente-sis.

About a month before death it was noticed that the left arm was much
more cedematous than the right, although there was more than a moderate
amount of fluid in the latter. This condition was observed accidentally,
being apparently of gradual development, and the patient experienced no
pain referable to this trouble. The oedema remained little changed until the
time of death, which was the outcome of a gradual cardiac exhaustion.

Autop.iy (Dr. S. M. White). — Body well nourished. Oedema of all parts
of the body, most marked in the left upper extremity, penis, and scrotum.
Ulcer, size of a dime, covered by a gray, false membrane, on the left leg.

About four litres of bloody, serous fluid in the peritoneal cavity, the walls
of which are thick, white, and fibrous. The left pleural cavity contains about
one litre of clear serum, with flakes of fibrin ; the right a somewhat smaller
quantity. A few fibrous adhesions at apices. The pericardial sac contains
about 1 00 c. c. of serous fluid ; a few fibrous adhesions bind the left auricle
to the aorta.

Lower lobe of the left lung carnified from pressure; general pulmonary
cedema: luTmorrhagic infarction in right lobe. Healed tuberculous nodules
in the apices and the peribroncliial lymphatic glands.

Coronarv arteries dilated and atheromatous. Kight auricle reaches 4 cm.
to the right of the median line. Right ventricle contains a large, adherent,
grayish, ante-mortem thrombus. The tricuspid orifice much dilated. The
cavity of left ventricle measures 8.5 cm. in length, its walls 1.5 to 2 cm. in
thickness; that of the right ventricle 9.5 cm. in length, its walls 5 to 6 mra.
in thickness. Aortic valves normal, save for a few yellowish thickenings at
the ba-scs. Mitral segment^!, thickened, retracted: the orifice wider than
normal. Endocardium everywhere somewhat thickened. Papillary muscles
mottled with vellowish dots" and streaks. :Myocardiuin firm, brownish-yel-

IN CARDIAC DISEASE 267

low, and contains many grayish-white fibrous areas and streaks. Arteries
atheromatous, especially the aorta at its beginning and at the origin of the
thoracic branches.

The left subclavian vein is filled with a mixed adherent thrombus, in places
grayish, but predominately brownish-black, which occupies also the axillary
and brachial veins to the middle of the arm. At tlie beginning of the left
subclavian vein is a yellowish, raised, sclerotic area, about the size of a bean,
to which the clot, which here seems to be channelled, is firmly adherent.
There is also a thrombus of a brownish-yellow color in the lower end of the
internal jugular vein, around wliich the hTuphatic glands are somewhat
enlarged and pigmented.

Spleen somewhat enlarged, dark-red, firm. Typical nutmeg liver. Kid-
neys are the seat of typical arterio-sclerotic nephritis, with adherent capsule,
irregular surface, thinned cortex and obscure markings. Other organs and
tissues normal.

Microscopical examination of the thrombus in the subclavian vein showed
it to be composed of platelets, fibrin, and blood-corpuscles, with a con-
siderable amount of connective tissue growing into it.

In the foregoing case the cardiac affection was associated with arterio-
sclerosis and advanced chronic interstitial nephritis, the patient being fifty-
three years of age. The excess of oedema of the left arm over that of the right
attracted attention a month before death, but it was unattended by pain
or other symptoms. The thrombus apparently started from a sclerotic patch
in the left subclavian vein and was undergoing organization at the time
of death.

Thrombosis of pulmonary vessels, which is not particularly uncommon
in uncompensated cardiac disease, is of course not to be included in the same
class as peripheral venous thrombosis. I have also excluded from considera-
tion the venous thromboses complicating general arterio-sclerosis and chronic
nephritis, even when associated with cardiac hypertrophy and dilatation,
imless, as in Case V., the symptoms are clearly referable to cardiac disease.
Our autopsy records contain five cases of thrombosis of the femoral and
iliac veins complicating arterio-sclerosis and chronic nephritis accompanied
by cardiac hypertrophy. In two of these there was atheroma of the aortic
valves, with some insufficiency. There is one instance of thrombosis of
the superior mesenteric veins associated with small kidneys and cardiac
hypertrophy. A case of thrombosis of the iliac and femoral veins on both
sides, associated with pulmonary emphysema and hypertrophy and dilata-
tion of the right side of the heart, has also been omitted as not falling under
the class considered in this article. For the same reason I have omitted
a case in our records of thrombosis of the right femoral vein complicating
cirrhosis of the liver with sclerosis, calcification, and insufficiency of the
aortic valves, and also instances of thrombi in varicose veins in cases of heart
disease.

268 VENOUS THROMBOSIS

The artorial thromboses complicating cardiac diseases are of mudi inter-
est. Doubtless most of those in the systemic arteries are of embolic ori^n,
but there is evidence that some, particularly in cases of extreme mitral
stenosis, are autochthonous. Tiiis subject, to which I have given some
attention in my article on " Thrombosis and Kmbolism " in Ailbutt's
" System of Medicine," does not fall within the scope of the present paper.

The only attempts, which I have been able to find, to collect from the
records cases of peripheral venous thrombosis complicating diseases of the
heart are those by Parmcntier (188!)),' l)y Ilirsclilatf (18'.)3), and by Kahn
(189()). Parmentier and Kahn each report a single case from Hanot's
clinic, and refer to four others which they say are the only ones they can
find in French literature. Hirschlatf adds to Parmentier's list two per-
sonal obsenations and the two eases of IJobort (1880) and of Orraerod
(1889). Peter, in 1873, in his " Lecons de clinique niedicale," reports
a case and devotes a part of one chai)ter to an interesting consideration of
venous thrombosis in diseases of the heart without adding further obser-
vations. Huchard's article (1897), " Cache.xie cardiaque et thomboses
veineuses," and Helen Baldwin's report of a typical case (1897), the only
one which I have met in American literature, deserve especial mention.
Without pretence to completeness I have been able to collect reports of
twenty-three cases to be added to the five observations already described.
I have little doubt that a more diligent search would bring to light other
reported cases. I shall present in chronological order abstracts of these
twenty-three cases, of some of which the histories are verv meaore.

Case VI. — Bouchut (1845). \\'onian with heart disease succumbed to
obliteration of the deep and superficial veins of the left leg. No further
details.

Case VII. — Bouchut (1843). JIan with heart disease, in whom occurred
obliteration of the suj>erior vena cava, juijular, a.xillary, and deep arm veins.
Engorged, painful, hard, venous cords could l)e felt in neck and arms. Cya-
nosis and a?dema of face, neck, and arms. Innumerable varicose, airijlomer
ated, large veins appeared in neck <uid over thorax. A satisfactory collateral
circulation developed, and the man left the Iiospital free from cyanosis and
anlenia.

Case VIII. — Cohn (18G0). Woman, sixty-one years old. Stenosis and
insufficiency of aortic valves, some thickening of mitral segments, cardiac
hypertrophy, and syanptoms of non-compensation. For fourteen weeks
U'dema of left foot and leg, later also of right foot, but here less marked.
At autoj)sy, adherent old thrombi in both iliac veins, extending on the left
side half-way down the thigh, and into some of the larger tributaries of the
femoral vein. | Cohn reports two other cases of thrombosis of veins of the

' The references will be found at the end of this article.

IN CAEDIAC DISEASE 269

lower extremities with cardiac disease, but in tliese there was general arterial
sclerosis and no pronounced valvular lesion.]

Case IX.— Jolly (18(10). Woman witli or<ranic disease of the heart had
phlep:masia alba doleiis of both upper extremities. Death occurred from an
ulcero-membrauous affection of the intestine. No further details.

Case X.— Kamirez (1807). Boy, aged twelve years. Acute articular
rheumatism one year before admission. Aortic and mitral insufficiency,
general anasarca, dyspncca, and other symptoms of extreme cardiac incom-
pet^'nce. Bloody expectoration. Throinlx)sis of jugular, axillary, and sub-
clavian veins on the right side. The obliterated external jugular vein very
evident. Painful oedema of right side of neck and right arm. Death in coma.
No autopsy.

Case XI.— Ramirez (1807). Man, aged fifty years. For six months fol-
lowing intermittent fever, dyspnoea, general oedema. Incompletely compen-
sated aortic and mitral insuthciency. CEdema of lower extremities almost
disappeared, while that of face and upper extremities persisted. Dyspnoea
increased. Painful, hard redema of left arm and left side of neck appeared,
and two large, hard, sensitive cords, formed by the obliterated jugular veins,
could be felt.

Autopsy showed thickening and retraction of aortic valves, with relative
mitral insufficiency. Great dilatation of all cardiac cavities. Blackish, firm
thrombi in left internal and external jugular, subclavian, and axillary veins.

Case XII. — Duguet (1872). Patient, who formerly had acute articular
rheumatism, was admitted for dyspnoea, cyanosis, palpitations, and oedema
of lower extremities. Three days before death there appeared painful, hard
oedema of left arm, and the axillary vein was felt as hard as a cord. Autopsy
showed marked stenosis, with insufficiency of the mitral orifice, without fresh
endocarditis, with cardiac hypertrophy and dilatation, hydrothorax and
hydropcricardium, pulmonary infarcts, and grayish-black, non-adherent
thrombi filling the left subclavian, axillary, and brachial veins.

Case XIIL— Peter (1873). Woman with mitral insufficiency and ob-
struction, and with relative insufficiency of the tricuspid valve, suffered from
oedema of lower extremities, ascites, dyspncca, cyanosis, and great congestion
of lungs and liver. For past ten days left arm oedematous throughout, witli
tenderness at certain points ; later outer and lower part of neck became
swollen and painful, first near the junction of jugular and subclavian veins.
The obliterated subclavian [axillary?] and external jugular veins could be
felt as hard, cylindrical cords. Venous pulse, formerly present in cervical
veins of both sides, is now evident only on the right side. The left radial
pulse is almost impercejitible from pressure of thrombosed veins on the
arteries. At the end of three weeks collateral circulation was established
and oedema of arm had disappeared. General condition otherwise unim-
proved.

Case XIV. — Roliert (1880). Woman, age between thirty and forty vears,
suffered for eight years with cardiac symptoms following pneumonia, of
late palpitation, dyspnroa, cyanosis, oedema of lower extremities and ab-
dominal wall, moderate asc-ites, pulsation of veins of neck, bronchitis, and

270 VEXUL'S TIIKOMBOSIS'

pulmonary coiifiestioii. Mitral stenosis and relative tricuspid insufficiency
diafrnoscd. For over a month before death patient had increasing oedema
of left arm (rijjht being free) and slight tumefaction of left side of face.
Ijcft internal jugular vein felt as hard cord ; veins over left pectoral region
became distended.

Aufopstj. — Extreme mitral stenosis, with hypertrophy and dilatation of
the right heart, double hydrotborax, i>ulnionary infarcts. Thrombosis of left
innominate, subclavian, and both jugular veins. The left innominate was
notably narrowed at confluence of jugular and subclavian veins, and here
and in the lower end of the ju.^ular was a firm, fibroid, adherent thrombus,
evidently tlie oldest part of tlie clot. The thrombus elsewhere was in places
centrally softened. The walls of the left subclavian vein were thickened.
The clot in tlie jugular could be traced to the entrance of the linguo-facial
trunk. Lymphatic glands in the neighborhood of the thrombosed veins are
enlarged. Superior vena cava free.

Case XV. — Parmentier (from Hanot's clinic) (188!)). Woman, aged
forty years. For four years, following puerperal infec'tion, cardiac symp-
toms; for last five months, palpitation, dyspnoea, cough, oedema of lower
e.xtremities ; and for three weeks before admission painful oedema of left arm
and corresponding mammary region ; later, slight oedema of right arm.
Upon admission : very rapid, irregular heart action ; irregular, small, inter-
mittent pulse : marked venous pulsation from systolic reflux, intense dvspnoea,
pulmonary rales, and albuminuria. The left upper extremity is tumefied
throughout its whole extent by a hard, tender oedema, which extends also to
the left mammar\' region. Symptoms increased in gravity and death oc-
curred four days after admission.

Autopsy. — Extreme mitral insufficiency and dilatation of all cavities of
the heart, left hydrotborax, ascites, nutmeg liver. I^eft subclavian vein and
small communicating veins completely obliterated by a reddish thrombus,
grayish and most adherent in the middle of the vein, where it is evidently
oldest, and where there is partial organization. Upon microscopical exam-
ination the coats of the veins were found thickened and the capillaries in the
outer coats dilated. The jugular veins were free, and no thrombus was
found in other veins of the extremities.

Case XVI. — Ormerod (1889). Patient wa.s admitted for mitral stenosis.

At autopsy was found complet« obstruction by adherent clot of both innom-
inate veins, internal jugulars, subclavians, anterior and external jugulars,
the clot being finner on right than left side. A projecting end of clot hung
into superior cava, but was not adherent there, and ceased at the opening of
the azygos. Left auricle and right cavities of heart much dilated. The
symptoms of thrombosis, which developed in the hospital, pointed to its com-
mencement in right subclavian vein. No local cause for it could l)e foimd.
Specimens were presented before the Ix)ndon Pathological Society and no
further details are given.

C.\SE XVII.— Hirscblaff (from Leyden's clinic) (1803). Woman. Re-
peated attacks during last ten years of articular rheumatism. Cardiac
.symptoms existed for some time before admission. Upon admission, respira-
tions hurried and labored, oedema of lower extremities. a.scites, moist p>il-

IN CAEDIAC DISEASE 271

nionary rales behind and below, heart's action violent, with diffuse praecordial
heaving, cardiac dulness much increased in all directions, loud systolic and
diastolic murmurs at apex, feebler systolic murmur, with indistinct diastolic
sound in aortic area, distinctly visible venous pulsation; pulse 120, of low
tension ; enlargement of liver and spleen, moderate albuminuria, diminished
excretion of urine. No material improvement followed. Both hands be-
came cedematous. Six days before death there appeared oedema of the left
half of the thorax, reaching the middle line, and also of the left supra-
clavicular fossa; later oedema of left half of face. Pulsation disappeared
from the left external jugular, while it persisted in the right. A painful
hard cord could be felt in the left supraclavicular fossa, extending upward
along the course of the external jugular vein, and a similar one along that
of the internal jugular. Erysipelas of the right leg set in after insertion of
Ziehl's needles to relieve the oedema, and patient died in collapse.

Autopsy. — Extreme stenosis and marked insufficiency of the mitral valve
and slighter insufficiency of the aortic valve ; cavities much dilated. Throm-
bosis of the entire left innominate, internal jugular and smaller tributaries,
external jugular, sut>clavian, and axillary veins. The thrombus is reddish-
yellow and oldest in the jugular bulb. The veins of tlie upper arm contained
fluid blood : cerebral sinuses free : red induration of both lungs ; small quan-
tities of fluid in both pleural cavities ; fresh hyperplasia of spleen.

Case XVIII. — Hirschlaff (1893). Woman, aged fifty-one years. Diph-
theria at eighteen; articular rheumatism, without evident sequels, at twenty
years of age. For past twenty years epilepsy with periodical swelling of both
legs, lasting for months ; for last two years persistent oedema of the legs, and
for a month before admission palpitation and dyspnoea. Shortly before
admission increasing painful swelling of left side of neck and left arm. On
admission, marked oedema of lower extremities and of the left side of neck
and left arm, slight ascites, slight cyanosis and icterus, systolic pulsation of
left external jugular, enlargement of heart, heaving impulse and thrill at
apex, loud murmur filling entire period before systole at apex, diastolic
murmur in aortic area, dulness and creditant rales over posterior, lower
chest ; urine diminished, concentrated and slightly albuminous ; pulse 108,
small, irregular. The veins in the left side of neck and over shoulder became
much distended and the oedema increased in extent. Three weeks later the
right side of the neck and thorax, and then the face, became cedematous.
Pulmonary svinptoms. Pepeated epileptic attacks occurred, accompanied
and followed by extreme cyanosis and dyspnoea. In one of these death ensued
a month after admission.

Autopsy. — Cardiac hj-perthrophy, extreme dilatation of right ventricle and
auricles; tricuspid valve thickened, its chordte shortened and grown together ;
extreme stenosis of mitral orifice, insufficiency of aortic valves, on which are
fresh vegetations ; myocardium flabby, pale, and yellow. Moderate accumu-
lation of fluid in pleural and pericardial cavities; recent and old pulmonary
infarcts; chronic passive congestion of liver, spleen, and kidneys. Throm-
bosis of superior vena cava, left innominate vein, left subclavian and both
internal jugular veins. The oldest part of the thrombus occupies the bulb
of the left jugular, where it is firm, closely adherent, and partly organized.
Tissues around thrombosed veins behind manubrium sterni cedematous.
Small thrombus in the left lateral sinus of the dura mater.

272 VEXOrs THROMBOSIS

Case XIX. — Gatay (1895). Woman, ajjcd twenty-eight years. Ten
years ago acute rheumatism and endocarditis, followed by palpitation and
articular jjains. A few day.'^ liefore admission patient was seized with chills,
followed liy dyHimcpa. On admission, cyanosis, a-dema of lower extremities,
areas of pulmonary consolidation, disorderly action of heart; pulse small
and intciTiiittcnt : alliumiiuiria ; temperature 3!t.8° C. Four days later hard
(cdenia of left arm, most marked in lower part, appeared. Fluid in wrist-
joint. Hard venous cord on inner side of left upper arm was felt.

Autopsy. — JIuch hypertrophy and dilatation of heart; the right ventricle
markedly dilated and tricuspid valve relatively insufficient; mitral valve
thickened, retracted, and incompetent; old fibrous plaques on endocardium;
no fresh endocarditis; pulmonary infarcts. Left brachial vein swollen and
filled with a nnl, adherent, centrally softened thrombus, 10 cm. long; venous
wall above and below thrombus red and thickened.

Case XX. — Kahn (from Hanot's clinic) (1896). Woman, aged fifty-two
years. Seven years ago, influenza, followed by some oedema of legs, which
soon disappeared. For four months before admission, cough, weakness,
fcdema of legs, loss of flesji. On admission, cardiac hypertrophy, systolic
munnur at ai>e.x traJismitted into axilla; no murmur at base; pulse 100,
small, soft ; radials sclerotic ; external jugular turgid, but without pulsation ;
respirations rapid and labored ; cedcma of lower extremities, emaciation.
Ten days after admission painless cedema of right hand and forearm ap-
peared. Temperature. 38.3° C. Subcrepitant rales at ba,«e of lungs. The
oedema rapidly spread, so as to involve the whole of right arm and corres-
ponding niammarv region. There was no pain. The skin was colder than
on the left side and somewhat mottled with violet patches. Dyspno-a in-
tense, respiration 42, urine allmminous, sputum bloody, temperature 39° C. ;
delirium and death in coma about three weeks after onset of thrombosis.

Autopsy. — Hypertrophy of the whole heart, right cavities much dilated,
mitral valve indurated, thickened, retracted, insulRcient without stenosis;
other valves normal, fibrous myocarditis. Fluid in left pleura, pulmonary
infarcts, chronic passive congestion of liver and kidneys, spleen swollen and
soft. There are five or six enlarged glands near the riglit subclavian vein,
which is completely filled with a reddish, fibrinous, firm, non-adherent
tlirombus 4 cm. long, extending to the origin of the axillar}- vein. Xo
thrombi in collateral veins. On microscopical examination, coats of throm-
bosed vein appear thickened, and capillaries in outer wall dilated.

Case XXI. — ilader (1897). Woman, aged fortj'-five years. Repeated

attacks of articular rheumatism, followed by palpitation, dyspnwa. and
U'dema of lower extremities. On admission evidences of stenosis and in-
sufficiency of the mitral and tricuspid valves, ^larked ascites. Three weeks
later patient com])lained of great tension in veins of arms and, in fact, these
Imame enonnously di.stended. a.s did also the cervical and upper thoracic
veins. Collateral veins could be traced to the epigastric veins. There was
vert.i"0, and the lips became cyanosed. With the establishment of a collateral
circulation there was gradual improvement in the symptoms. The diagnosis
was thrombosis of both innominate veins, possibly also of superior vena cava,
complicating the valvular affections mentioned.

IN CARDIAC DISEASE 273

Case XXII. — Helen Baldwin (18i)T). Girl, aged nineteen years. Three
attacks of rheumatic fever, the last seven years ago. Five weeks ago oedema
of the feet. A few days before admission, began to suffer from pain in left
axilla and left side of neck, also from swelling of the left side ot neck. The
latter at first would disappear in the erect posture. Amenorrhoea. On ad-
mission, great weakness, cedema of both legs, cyanosis, dyspncea, respirations
40, pupils dilated; pulse 108, small, rapid, and compressible; marked en-
largement of heart, double aortic and mitral murmurs, ascites, enlargement
of liver, albuminuria, granular and hyaline casts, quantity of urine dimin-
ished, sp. gr., 1033. On left side of neck is a hard, tender swelling of lower
part of external jugular vein, which is tortuous. There is a hard cord in
left axilla, extending for about five inches down the arm. Left arm oedema-
tous and jiale. The next day external jugular vein was felt as a cord up to
one-half inch of lobule of ear. QCdema of whole left side of neck. Signs
of beginning double pneumonia. For five days there was noted a persistently
low temperature when measured by thermometer in mouth, whereas that by
the rectum was 6 to 7.8 degrees higher. Bloody expectoration on the fifth
day. Death six days after admission.

Autopsy. — General oedema, ascites, double hydrothorax, marked hyper-
trophy of heart, the auricles extremely dilated, chronic changes in all of the
valves, the most marked being stenosis and insufficiency, of the mitral valve,
the edges of tricuspid valve thickened and curled. Pulmonary congestion
and infarcts and early stage of double lobar pnemiionia. Chronic passive
congestion of abdominal viscera. Firm thrombi fill the left innominate,
subclavian, external and internal jugular veins, extending nearly to lobe of
ear. V-cins of extremities could not be further examined. Enlarged lymph
nodes along trachea, not pressing on veins. Small extravasation of blood
along left side of trachea and behind the left auricle. On microscopical
examination the thrombi were found to be partly organized. There was
marked chronic thickening of the intima of the subclavian vein, which was
believed to l>e the starting-point of the thrombus.

Case XXIII. — Huchard (1897). Woman, aged twenty-four years. Seven
years ago had articular rheumatism with cardiac complication, followed by
mitral stenosis. Painful swelling of left arm appeared during convalescence
from an undetermined febrile disease. On admission severe dyspncea ; pulse
rapid, small, irregular; expectoration bloody, urine slightly alliuminous, no
cedema of lower extremities. Painful, hard oedema of entire left arm, with
prominence of superficial veins, and hard, sensitive, voluminous, venous
cords. Death in coma nine days aft<>r admission.

Auiopsij. — Double hydrotliorax, pulmonary infarcts, slight ascites, nut-
meg liver. Heart weighed 450 grnis. ; buttonhole mitral orifice causing ex-
treme stenosis, slight narrowing of tricuspid orifice, and marked dilatation
of right auricle. I^arge stratified thrombus in left auricle. A few pericardial
adhesions. Left brachial vein markedly dilated, and filled in upper part
•with an adherent thrombus 3 cm. long, starting from a valvular pocket.

Case XXIV. — Huchard (1807). .Male with mitral stenosis and throm-
bosis of veins of left lower extremity. No other details.

274 VENOUS THROMBOSIS"

Case XXV. — Nicolle and Hobincau ( 1807). Girl, aged sixteen and a half
years. Kepeated attacks of rlieumatisni during last four years. Chief symp-
tom on admission, respiratory distress; no cedema. Four months after
admission patient felt pain in the left side of neck and head, and a hard,
painful cord, 5 to 10 cm. long, was detected in the course of the left external
jugular vein. Three days later the thrombus had extended and painful
rodema of left side of neck and face appeared. Superficial veins dilated ;
urine slightly albuminous. Ten days after first symptoms of thrombosis
entire left upper extremity became cedematous. Expectoration bloodv.
QJdema increased, and appeared also in lower extremities. Death occurred
a little less than a month after the beginning of the thrombosis.
• Autopify. — Mitral orifice narrowed, numerous hard, papillarj' vegetations
on borders and surface of mitral segments, also on the aortic valves and the
free borders of tlie tricuspid. Chordse tendineae of mitral valve shortened.
Hydrothoras, many pulmonar\' infarcts, pneumonia of left lower lobe.
Tlirombosis of left external jugular vein and branches and of subclavian vein.
Thrombus black, rather soft, slightly adherent, unorganized. Venous walls,
especially inner coat, thickened. Swollen, hemorrhagic lymph glands sur-
round the thromlwsed veins. Tissues of neck verv' cedematous.

Case XXVI.— Poynton (from service of Dr. Lees), (1898). Girl, aged
nineteen years. Very severe attack of rheumatic fever, lasting thirteen
weeks, nine montlis before admission. Swelling of legs and abdomen noticed
two months before admission, and a few days before admission left arm sud-
denly began to swell. On admission great pallor and distress, evidences of
advanced organic disease of heart, systolic apical murmur, accentuated sec-
ond pulmonic sound; pulse 90, irregular in force and rhythm; cedema of
legs and thighs, of upper extremities and upper part of chest, the left arm
and hand being verv' much swollen; impairment of resonance and respira-
tory sounds over bases of limgs, liver large and tender, conjunctiva icteric,
urine somewhat albuminous, temperature subnormal and continuing so
throughout illness. Death, preceded by cerebral sjTiiptoms and coma, about
two weeks after admission.

Autopsy. — Totally adherent pericardium, evidences of old rheumatic endo-
carditis; aortic, mitral, and tricuspid valves incompetent, and mitral orifice
slightly narrowed; cavities dilated, especially right ventricle; weight of
heart, sixteen ounces. Pleurje adherent. Chronic passive congestion of vis-
cera. Adherent firm thrombi filled Ixitli innominate and Iwth internal jugu-
lar veins, the lower end of left internal jugular being white, narrowed, and
very firm. Adherent mural thrombosis in upper part of superior vena
cava. Mediastinal tissues cedematous. Brain generally soft ajid cedematous.

Case XXVII.— Poynton (from service of Dr. Cheadle) , ( 1898) . Woman,
aged twenty-one years. In childhood scarlet fever, followed by rlieumatic
fever. Two years ago second attack of rheumatism. Present illness began
gradually with weakness, dyspnoea, and o'dema of legs and face. On admis-
sion anaemia, cedema of legs, face puffy, bronchitic sounds, harassing cough,
systolic thrill, loud systolic munnur over front and back, dilatation of heart.
Temperature 101° F. ; respirations 28; pulse 128, of low tension. Urine
albuminous, sp. gr., 1020, contained blood and casts. Liver and spleen
enlarged. Irregular pyrexia and sweating continued throughout illness in

IX CARDIAC DISEASE 275

hospital. Twelve days after admission pain in vrrists and along inside of
left forearm. G£dema of face, which had almost disappeared, returned,
especially on left side. Irregularity of pulse, orthopncea, symptoms of renal
infarction and pneumonia api>eared, and death occurred five and a half weeks
after admission.

Autopsy. — Heart weighed 14 ounces, all its cavities much dilated; both
ventricles and left auricle hypertrophied ; muscle pale; mitral orifice
widened ; numerous exuberant vegetations of mitral segments, also on endo-
cardium of left auricle and left ventricle ; chordaj tendineffi ulcerated through ;
other valves normal, except slight widening of tricuspid orifice. Pulmonary
congestion; pnemnonia of left lower lobe; chronic passive congestion of
abdominal viscera, with infarcts in spleen and kidneys (microscopically no
evidence of interstitial inflammation or chronic nephritis). Left internal
jugular, from junction with subclavian vein to angle of jaw, occluded by a
thrombus, which was pale and adherent to wall, especially in lower part,
where vein was cord-like. Innominate vein and right jugular not thrombosed.
Brain normal. On microscopical examination no micro-organisms found in
cardiac vegetations or in thrombus. Diplococci, staining by Gram, in pneu-
monic area. Sections of left internal jugular showed organizing thrombus,
vrithout distinct thickening of venous wall. Walls of right jugular normal.
(No mention of cultures.)

Case XXVIII.— Poynton (from service of Dr. Cheadle), (1898). Girl,
ased nine years. Two years ago scarlet fever, since which heart was affected.
For three weeks before admission, thoracic pain and cough, and for one week
dropsy. On admission, February 19th, pallor, with some cyanosis; orthop-
noea; fingers clubbed; oedema of lower extremities, anterior chest wall and
face ; some ascites ; marked increase of cardiac dulness to right and left ;
pnecordial bulging; epigastric pulsation : systolic and diastolic thrill ; double
mitral and aortic murmurs ; doubtful pericardial friction rub ; impaired
resonance and respiratory soimds over bases of lungs ; scattered bronchitic
rales ; liver enlarged and pulsating. Temperature 97.4° F. ; respirations 30 ;
pulse 100, irregular, weak and small; urine, 1025, contained albumin and
blood, without casts. Improvement until ilarch 10th. when pleural friction
was heard in left axilla and dulness at left base, without rise of temperature.
Again improvement until April 10th, when pulmonary .symptoms reappeared
and swelling of axillary glands was noticed. Heart more dilated, pulse
feebler. 13th : left side of face swollen. Ifith : marked cedema of right side
of neck, eyelids, and lips ; face purple : both sides of neck tense, painful to
touch and on movement ; temperature subnormal. 17th : right arm began to
swell, shortly afterward oedema of left arm and chest: patient apathetic,
18th: drowsiness, cyanosis, sudden dyspnoea, with s}-mptoms of collapse.
19th: tender oedema of right arm extreme. SOth: two finn cords felt in
lower part of neck : legs and feet a little swollen ; area of cardiac dulness
enormous : loud pericardial friction, crepitation over both lungs ; urine
scanty, slightly albuminous, no blood. Death April 21st.

Autopsy. — Acute sero-fibrinous pericarditis: all cardiac cavities dilated
and h}-pertrophied. the right relatively more than the left. Mitral and tri-
cuspid valves incompetent : fresh vegetations on aortic, mitral, and tricuspid
valves. ITsual visceral changes secondan- to advanced cardiac disease. Ob-

276 VENOUS THROMBOSIS

literative tlirombosis of superior vena cava in its upper two-tliird.s, both
innominate, subclavian, internal and ext^Tiial juf,Ti]ar, and axillary veins,
and the left inferior thyroid vein. Small adherent mural thrombus in left
branchial vein. The oldest parts of the thromlius were in tlie lowest portions
of the internal jurrular veins and the left innominate, which were white,
small, and firm, and adherent to surrounding- tissues. Beyond these older
thrombi the vessels were bulged with soft clot. The thrombus in the superior
cava was soft, pale, non-adherent, except in its upper part.

Cultures and films from pericardial exudate and blood-clot negative; sec-
tions of soft clot in superior cava and of thrombus in right axillarv' showed
no micro-organisms. Thrombi were undergoing organization in older parts.
Early phlelx)-sclerosis, apparently secondary to tliromljus, in older throm-
bosed vessels. Venous wall not thickened where thrombus was fresh and not
adherent. Interstitial myocarditis in subpericardial layers and beneath in-
flamed endocardium.

The most remarkable feature of the foregoing twenty-eight eases of venous
thrombosis in heart disease is the location of the thrombi : twenty -four
were thromboses of veins conveying blood from the upper extremities or
the neck, or both, mostly of the left side, and only four were thromboses
of the veins supplying the lower extremities. I do not suppose that these
numbers represent the correct ratio between upper and lower venous throm-
bosis in heart disease, for thrombosis of veins of the lower extremities in
tliis condition is much more likely to be overlooked in consequence of the
more common and greater cedema of the lower limbs, and is also much
less likely to be reported. How often it is overlooked can be at present
only a matter of conjecture, but it is not probable that such thrombosis is
2t all frequent. In fact, the comparative infrequency of peripheral venous
thrombosis in cardiac disease is in itself a matter of interest, in view of
the slow, feeble and irregular venous circulation, and of the frequency of
so-called marantic thrombi in the heart itself during the failure of com-
pensation. The relatively small liability to venous thrombosis under such
conditions of the circulation is one of many evidences that mere slowing
of the blood current is not an efficient cause of thrombosis.

Even allowing for a consideralde increase in the number of instances
of thrombisis of the veins of the lower extremities as the result of more
thorough search in cases of heart, disea.^e, the relatively large number of
obfervations of thrombosis of the upper veins revealed in my collection of
eases still remains most remarkable. Bouchut places the ratio of venous
tliromboses of the upper extremity to those of the lower at one to tiftv.
Of sixty-seven cases of peripheral venous tlirombosis in our autopsy records
at the Johns Hopkins Hospital, only one was of the upper extremities,
although several instances of the latter have been observed clinically in
the hospital. Moreover, the four instances above recorded of venous throm-

TX CAEDTAC DISEASE 277

bosis of the lower extremities in heart disease had little in common with
the remaining cases. Two were in old persons, with some arterial atheroma,
and of two no satisfactory history is given. The thrombosis was on the
left side in three and bilateral in one, thus conforming to the rule. As
will appear from an analysis of the remaining twenty-four cases, the venous
thromboses of the neck and arms in cardiac disease constitute a separate
and distinct group, characterized by special features of unusual interest.

Analysis of Twextt-four Cases of Thrombosis of Yeixs of
Neck, Arm and Chest in Heart Disease

Sex. — Seventeen cases were females, five of males, and of two the sex
is not stated. While the total number of cases is too small to warrant per-
centage estimates, there can be no doubt that females are much more dis-
posed to this form of thrombosis than males. Whether this disposition is
more than an expression of the greater liability of females to the mitral
lesions present at the ages in the cases observed, I must leave an open ques-
tion. The figures seem somewhat out of proportion to this great tendency.

Age. — One patient was nine years old, 6 were between ten and twenty,
3 between twenty and thirty, 3 between thirty and forty, 3 between forty and
fifty, 3 between fifty and sixty, and of 6 the age is not stated. Of the 18
patients with thrombosis of the neck and arms whose ages are stated, nearly
one-half (8) were between fifteen and thirty years of age. The youngest
was nine and the oldest fifty-three.

Valvular Lesion. — In two cases the exact nature of the valvular lesion is
not stated. Of the remaining 22 cases, there was organic disease of the
mitral valve in 21; in the exceptional case there was aortic insufficiency
with relative mitral incompetence.

The mitral lesion is described as insufficiency in 9 cases, as stenosis in
6, and as stenosis and insufficiency in 6. In the last group there were at
least three instances of extreme stenosis. The aortic valves were affected in
10 cases, in all of these there being incompetence, sometimes also with
obstruction.

The organic valvular lesion was limited to the mitral valve in 12 cases,
to the aortic valve in one, to the mitral and aortic valves in 6, to tlie mitral,
aortic and tricuspid valves in two, and in one case all of the valves were
organically diseased.

In all of these cases there was chronic disease of the valves. In five
cases there appears to have t)een a fresh endocarditis engrafted upon the
chronic afi^ection, and it is possible that in some other cases this was present,
but in tlie majority of the observations there was not acute endocarditis.

Adherent pericardium was noted in four cases, acute pericarditis in one.

278 Vf:XOUS TllIUiMBOSIS

It is evident tlmt the association of thronil)osis of the upper veins with
valvular disease of the heart is almost, althouph not wholly, limited to
cases of mitral disease, those of mitral stenosis, with or without insufficiency,
takin-r the lead. The preponderance of females and of patients under mid-
dle age is thus, at least in preat part, explained. That the complication
may occur in men in advanced life with general artt'rio-sclerosis and chronic
Briglit's disease associated with cardiac disease is shown by Case V.

Relation to Rheumatism. — As is to be expected from its nature, the val-
vular lesion was most frequently caused by acute articular rheumatism, of
which there was a distinct history in a little over half the cases, but other
infectious diseases (scarlet fever, pneumonia, influenza, puerperal infection,
diphtheria, syphilis, and chorea) also had a share in the causation. In a
number of instances the valvular trouble seems to have developed insidi-
ously. There is, therefore, nothing peculiar in the antecedent histories.

Although several observers regarded the occurrence of the thrombosis as
a direct manifestation of rheumatism, only in three cases was there any
painful swelling of a joint present shortly before or during the attack of
thrombosis.

Relation to Cardiac Insufficiency. — In the great majority of cases the
thrombosis appeared during a condition of failure, generally extreme failure,
of compensation of advanced mitral disease. The frequencv with which pul-
monary infarction was observed at autopsy is one of the many evidences of
this. Relative insufficiency of the tricuspid valve and pulsation of the
cervical veins were noted in many of the cases, and very likely were present
in some of those in whose histories they are not noted, but it does not
appear that these conditions, although contributory, are necessary factors
in the causation of the thrombosis.

Location of the Thrombi. — A fact which at once arrests attention is that
the thrombosis affected veins of the left side in 22 out of the 24 cases, of
which 15 were unilateral and 7 bilateral. In only two cases were veins of tlie
right side alone affected. Bilateral thrombosis is, therefore, more common
than unilateral right-sided thrombosis, and unilateral left-sided throm-
bosis is by far the most common form of tlie disease. The livpotheses in
explanation of this distribution will be considered later.

In 7 cases the thrombosis was apparently limitx'd to the arm veins, in
one to veins of the neck, and in 16 cases veins both of the neck and arms wore
thrombosed. In one case the thrombus was confined to the left subclavian
vein, in one to the left internal jugular, and in two to the left brachial. In
all the other cases more than one vein was thrombosed, the combination
varying in different cases, the most common being continuous thrombosis of
the left innominate, internal and external jugular, subclavian, and axillary

IX CARDIAC DISEASE 279

veins. The superior vena cava was partly or wholly thrombosed in 6 cases
(confirmed by autopsy in four), the innominate in 11 (confirmed by autopsy
in 8), the internal jugular in 14 (autopsy in 11), the external jugular in
12 (autopsy in 8), the subclavian in 16 (autopsy in 13), the axillary in
11, the brachial in 6, the inferior thyroid in 1, and the left lateral sinus
of the brain in 1.

The commonest starting-point for the thrombus vras the lowest part of
the left internal jugular (bulb), or of the left external jugular vein and the
left innominate or subclavian vein near the entrance of the jugulars. In
many cases this was clearly demonstrated by the appearances of the throm-
bus and the venous wall in these situations. The thrombus may, however,
originate in other veins, especially in valvular pockets of the veins in the
left arm.

The most extensive tlirombosis was that recorded by Poyuton (Case
XXVIII), in which there was occlusion of the superior vena cava in its
upper two-thirds, of both innominate, internal and external jugular, sub-
clavian, and axillary veins, and the left inferior thyroid vein.

The thrombus was generally a continuous one, apparently originating
in one vein, whence it wa^ propagated into peripheral veins and also cen-
trally, even into the superior vena cava.

( liaracters of the Thrombi and Venous Walls. — The thrombi were mixed,
the prevailing color being dark red. The older parts were gray or reddish-
gray and adherent. The fullest description of the microscopical characters
is that which I have recorded under Case I. In a few instances the throm-
bus was centrally softened, but in most it was solid and completely occlud-
ing except at the ends and except in the mural thrombus mentioned in
Case XXVIII. The older thrombi were usually more or less advanced in
organization. Bacteria were searched for in apparently only three cases, and
were found only in my Case I, the organism here being Streptococcus
pyogenes.

In T cases it was not^d that the wall of the tlirombosed vein was thickened,
but tliis thickening was generally regarded as secondary to the forma-
tion of the thrombus, which was two or more weeks old. Only in Helen
Baldwin's case and in Case V is it distinctly stated that the appearances
indicated phlebo-sclerosis (subclavian vein) antedating the thrombus. In
two of Poynton's cases the jugular and innominate veins, where the oldest
part of the thrombus was situated, were narrowed, white, and firm, and a
similar condition was noted by Eobert. Chronic disease of the veins evi-
dently plays only a minor part in the causation of thrombosis in these
cases.

280 VENOUS THROMBOSIS

Effect and Siimpinintt. — The anatomii^al lesions outside of the vessels
directly referable to the thrombosis were oedema of the tissues and swelling
of the lymphatic glands. The oedema cannot always be explained entirely as
the result of venous congestion, but is in part inflanimatorj', as is true in
general of the (jedema in phlegmasia. Swollen lymphatic glands, which were
sometimes hemorrhagic or pigmented, were often observed in the neighbor-
hood of the tiiromboscd veins. This swelling was generally acute and evi-
dently secondary to tlie thrombosis, but Kahn attributed the exceptional
localization of the thrombus in the right subclavian vein in his case (XX)
to the pressure of previously enlarged glands. Poynton noticed cerebral
oedema in one of his cases which had manifested brain symptoms.

The local symptoms are the usual ones of venous thrombosis : pain,
tenderness, ccdenia, the presence of hard, sensitive venous cords, and dis-
tention of superficial veins. Often the pain, sometimes the oedema, was
the first symptom. The cedematous swelling may be hard and brawny,
or softer, as in dropsy. In some cases the pain and cedematous swelling
were first manifest in the neck, in others in the arm. Extension of the
oedema to the front and side of the upper part of the thorax was repeatedly
noted. Occasionally the side of the face corresponding to the thrombosis
was cedematous. The extent and distribution of the oedema, while depen-
dent in the first instance upon the extent and location of the thrombosis,
were influenced, as is usual in venous thrombosis, by other factors, so that
they varied much in cases with the same distribution of the thrombi.

Constitutional symptoms of the thrombosis, if present, could not readily
be separated from those of associated conditions. The marked difference
between the buccal and rectal temperatures observed in Helen Bakhvin's
case (XXII) is interesting. Cerebral symptoms, attributed by Poynton
to cerebral cedema, were observed in a few cases.

As is illustrated by Case V, the only symptom of the thrombosis may
be cedema, usually of the left arm, the patient suffering little or no incon-
venience from the swelling, and the affection being recognized sometimes
almost accidentally.

Hanot, in 1874, called attention in a short note to the more rapid onset
and the longer persistence of cedema of the left arm, as compared with
the right, in cardiac affections, and he explained this peculiarity by the
greater length and obliquity of the left innominate vein. It would appear,
therefore, that cedema limited to or in excess in the left arm in heart
disease should not bo regarded as positive evidence of thromliosis of veins
conveying blood from this extremity. While this is doubtless true, it is
desirable, in view of the cases reported in this paper, to search carefully
in these instances for other evidences of thrombosis.

IN CARDIAC DISEASE 281

Prognosis. — Of the twenty-four cases, twenty ended fatally and four
(Case II, VII, XIII, and XXI) recovered. The gravity of tlie prognosis
doubtless mainly results from the circumstance that the occurrence of the
thrombosis is in itself an index of extreme failure of compensation of the
valvular lesion, being sometimes scarcely more than a terminal event. We
know that occlusion of the sui>erior vena cava and its large tributaries, due
to other causes, may be completely compensated by the development of a
collateral circulation, and there are instances of this even in the present
group of case^ (Vll and XXI), so that it is less the venous occlusion than
the condition of the heart and the frequent presence of pneumonia or
other terminal infections which makes the issue so unfavorable. In rare
instances, thrombosis of the upper veins may occur at a period when the
compensation is not badly broken (Case II). Large pulmonary embolism
was not observed. Whether pulmonary infarcts, which were frequently
present, were attributable to emboli derived from the venous thrombi was
not determined. The duration in the fatal cases of thrombosis varied from
two days to six weeks.

Causation. — Although live of the cases were reported as instances of
rheumatic phlebitis, it does not seem to me demonstrated that even in these
cases (XII, XIX, XXVI, XXVII, XXVIII) this was the correct explana-
tion and it is certain that the great majority of cases cannot be explained in
this way. It is true that phlebitis, or venous thrombosis, is a genuine, al-
though infrequent, complication of acute rheumatism, and there is some evi-
dence that it may affect veins of the upper extremities somewhat more fre-
quently than does thrombosis due to most other causes, but there is no such
enormous preponderance of upper thromboses as in the class of cases now
under consideration. As already mentioned, the hist-ories of the cases do not
support the view that rheumatism had more than a minor share in the
immediate causation of the thrombosis. There is no reason, however, why
acute rheumatism, like other infections, may not directly participate in
the causation of the venous thrombosis.

French writers (Peter, Parmentier, Kahn, Huchard) attribute the throm-
bosis to cardiac cachexia combined with circulatory disturbances. They say
that this cardiac cachexia (so designated by Andral) is something to be
distinguished from asystole — that is, from mere breakage of compensation.
They bring this class of thromboses, therefore, into line with that com-
plicating tuberculosis and cancer, and explain the peculiar localization by
the particular disturbances of the circulation in cardiac disease. The under-
lying cause according to this view, is some alteration in the chemical composi-
tion of the blood. It is dilficult to say how much weight is to be attached to
this explanation. In many cachectic conditions there is an increase in the
21

282 VENOUS THROMBOSIS

blood platelets, attributable probably to weakened resistance of the red cor-
imscles, and some writers have brought cachectic thromboses into relationship
with this increase. According to van Emden, the number of platelets is
diminished in the chronic congestion of lieart disease. I know of no observa-
tions concerning the number of platelets in these cases of heart disease with
venous thrombosis. I could find nothing in the histories of most of the cases
indicating any peculiar cachexia, and I am not inclined to regard this ex-
planation of the thrombosis of heart disease as a satisfactorj- one.

The first thing which needs explanation is the localization of the throm-
bosis in the veins receiving blood from the upper part of the body, and
especially from the left side. Hanot and Pamientier explain the prefer-
ence for the left side by the greater length and obliquity of the left innomi-
nate vein, so that, like return flow of blood from the left leg, that from
the left arm and left side of the neck is more difficult than from the right
side, this diffiiailty being, of course, most in evidence in the venous conges-
tion of uncompensated cardiac disease. Hirschlaff suggests that an addi-
tional factor may be the greater frequency of imperfect development and
of insufficiency of the valve near the junction of the internal jugular and
subclavian veins on the left than on the right side. To these factors I
would add pressure, either direct or indirect, on the left subclavian vein
from the dilated left auricle and dilated large pulnumary vessels. PopotT
noted pressure from this source on tlie left subclavian artery in mitral
stenosis with insufficiency as a cause of relative weakness of the left radial
pulse (pulsus diflferens). I would refer to his article for a consideration
of the factors concerned in producing this pressure. A large accumula-
tion of fluid in the left pleural cavity, which was not«d in many of the
cases, may also contribute to this pressure.

Peter, in 1873, was the first to suggest that the frequency with which
the thrombus starts from the lower ends of the jugulars is to be explained
by the presence of valves in this situation. I am inclined to lay emphasis
upon the readiness with which an eddying or whirling motion of the blood
may be set up in heart disease in the lower ends of the jugulars and the
adjacent parts of the innominate and subclavian veins. Von Reckling-
hausen has brought forward strong evidence that this whirling movement
(Wirljelbewegung) of tlic blood is of great importance in determining the
localization of thrombi in general. The valves, tlie bulbous enlargement
at the lower end of the internal jugular, the attachment of veins to fascisR,
and the coming together here at oblique and right angles of current.* of blood
with different pressures and velocities, seem well calculated to cause in these
veins whirling or vertical motion of the blood current, especially in the
circulatory conditions of broken compensation of mitral lesions. Most

IN CARDIAC DISEASE 283

favorable to this peculiar disturbance of the circulation would be tricuspid
insufficiency with systolic reflux of blood into the veins. I would explain,
.therefore, the special localization of the venous tlirombosis complicating
cardiac disease, on the one hand by the particular disturbance of the cir-
culation, and on tlie other by the anatomical disposition and structure of
the veins.

These factors, however, explain only why certain veins are the seat of
election for the thrombi. The circulatory conditions described must often
exist within these veins in uncompensated cardiac diseases, whereas venous
thrombosis is a rare complication of heart disease. In the case which first
directed my attention especially to this subject, and which I have here
reported as Case I, an immediately exciting cause for the thrombosis was
discovered by the demonstration of bacteria in the thrombus. This is the
only case in the entire list in which micro-organisms were found, but, so
far as I can gather, in only three other cases were bacteria especially looked
for, and it does not appear that in any of these latter were cultures made
from the thrombus. Such cultures are, of course, necessary in order to
exclude the presence of bacteria, and, indeed, our experience has been that
even a negative result from cultures is not absolutely decisive. Evidence
has accumulated in recent years in support of the infectious origin of
many thrombi. Dr. Harris and Jlr. Longcope, who will report their obser-
vations later, have now examined in my laboratory bacteriologically forty-
four thrombi, mostly peripheral venous thrombi of the so-called marantic
type, and in thirty-four of these have demonstrated the presence of bacteria.
As has been shown by Dr. Flexner in my laboratory, terminal infections
are not uncommon in heart disease. The histories and autopsies of many
of the twenty-four cases now under consideration revealed some infectious
process, usually in the lungs, such as bronchitis, pneumonia, and pleurisy.
While, tlierefore, it would be quite unwarrantable, from existing evidence,
to refer this class of venous thromboses in cardiac disease positively to
infection, this seems to me at present the most probable explanation.

BIBLIOGRAPHY

Baldwin, Helen: Journ. Amer. Med. Assoc, August 21, 1S97, p. 371.

Bouchut: Gaz. m6d. de Paris, 1845, p. 245.

Cohn: Klinik der embolischen Gefasskrankheiten, Berlin, 1860, p. 118.

Duguet: De I'apoplexie pulmonaire. ThSse de Concours, Paris, 1872.

Gatay. Contribution a I'^tude de la phl^bite rhumatismale. Tli&se, Paris, 1895.

Hanot: Comptes rendus, Soc. de Biologie, 1874, 6 SSr., T. I, p. 80, Paris, 1875.

Hirschlaff: Betrag zur Lehre und Casuistik von der Tlirombose der Vena

Jugularis interna., externa, und subclavia. Inaug. Diss., Berlin, 1S93.
Huchard: Rev. gen. de clin. et de therap. (Journ. de praticiens), 1897, p. 787.

284 VENOUS THROMBOSIS l.\ ( AUDIAC DISEASE

Jolly: De la phlegmasia alba dolens. Th6se. Paris, 1861.

Kahn (and Hanot) : Arch. gen. de vaM., 1896, II, p. 469.

Mader: Jahrb. d. Wiener K. K. Kranken-Anstalten, IV, Jahrg. (1895), p. 252,

Wien u. Leipzig., 1S97.
NicoUe and Robineau: La Normandie med., 1897, XII, p. 68.
Ormerod: Trans. Path. Soc, London, 1889. XL, p. 75.
Parmentier (and Hanot): Arch. g6n. de mSd., 1889, II, p. 91.
Peter: Legons de clinique medicale, Paris, 1873, T. I, p. 209.
Popoff: Virchow's Festschrift (Internat.), Berlin, 1891, III, p. 333.
PojTiton: Lancet, 1898, 11, p. 206.
Ramirez: Gaz. med. de Paris, 1867, p. 716.
Von Recklinghausen: Handb. d. allgem. Pathologie, d. Kreislaufs u. d. Ernahr-

ung, p. 129. Stuttgart, 1883.
Robert: Bull, de la Soc. Anat. de Paris, 4 Ser., T. V, p. 314. Paris, 1880.
Welch: Allbutfs System of Medicine, VI, pp. 198 and 275. London, 1899.

MILIARY ANEUEISM OF A BRANCH OF THE GASTRIC ARTERY '

The patient was a man about 50 years of age, who had not been under the
observation of a physician before the fatal rupture of the aneurism occurred.
His health was not vigorous, but no definite clinical historj- of his previous
condition could be obtained. The patient was seized during the night with
profuse vomiting of blood which in a few hours terminated fatally. Gastric
ulcer was suspected.

At tiie post-mortem examination the stomach was found filled with dark,
partly coagulated blood. On removing this a thick layer of tenacious bloody
mucus coated the inner surface of the stomach. Xo ulceration of the
stomach could be detected. It was only after long-continued search, which
was rendered unusually difficult by the adherent bloody mucus, that a minute
loss of substance, not exceeding 3 or 4 mm. in diameter, was found in tlie
mucous membrane of the posterior wall of the stomach, about midway between
lesser and greater curvature and pylorus and cardia. In the floor of this
perforation of the mucosa lay a small aneurism about the size of a split pea.
Tlie aneurism was of a sub-mucous branch of the coronary artery and it had
ruptured at the point nearest the ca\'ity of the stomach so that a fine probe
could be passed through the perforation in the mucous membrane directly
into the lumen of the artery.

The aneurism was the result of an arteritis. There existed a wide spread
endarteritis ohliterans affecting the medium sized and small arteries over a
large part of the body, including those of the stomach, kidneys, spleen, heart
and lymphatic glands. Although this condition suggested the existence of
syphiHs, no further evidence of syphilis could be found at the autopsy. The
kidneys were the seat of advanced chronic interstitial nephritis, being small,
granular and with fibroid glomeruli. The heart was hypertrophied without
valvular lesions and presented patclies of fibroid induration.

The case is instructive on account of the comparative infrequency of
rupture of miliary aneurism of the stomach with fatal hsematemesis. The
readiness with which such a minute perforation of the gastric mucous mem-
brane might be overlooked at the autopsy is calculated to awaken scepticism
regarding certain cases of fatal gastrorrhagia reported without demonstrable
lesion of the stomach and therefore attributed to capillary or parenchyma-
tous hemorrhage in persons not affected with cirrhosis of tlie liver or otlier
conditions causing portal obstruction.

' Presentation of pathological specimen and report before the Johns Hopkins
Hospital Medical Society, October 22, 1S89.

Johns Hopkins Hosp. Bull., Bait., 1889-90, I, 12. 285

DUPLICATURE OF ARCH OF AORTA WITH ANEURISM '

Tlie specimen came from a negro 43 years old, who, for six months hefore
death, had suffered from paroxysmal cough, hoarseness increasing to aphonia,
dyspnoea increasing to orthopnoea, pain in the chest and loss of flesh. Nine-
teen years ago he had acut« articular rheumatism, and some years before
that pneumonia. On admission he had extreme dyspnoea; inspiration was
short and noisy; expiration was much prolonged and rough. His pulse was
32 and regular: respiration, 3G ; temperature, 97.6° F. There was moderate
engorgment of the superficial veins of the neck. Sternal notch was oblit-
erated. Apex beat of the heart was neither visible nor palpable. There was
dulness at the level of the third rib and diminished resonance over the
sternum at this level. Heart sounds were normal. Coarse and fine rales
were audible over the posterior part of both limgs. Breath sounds were
rough. The urine contained a moderate amount of albumen, with hyaline
and granular casts. The patient died suddenly three days after admission
to the hospital.

At the autopsy the lungs were found to be moderately emphysematous with
slight dilatation of the bronchi. There were numerous areas of fresh broncho-
pneumonia in the posterior lobes of both lungs and general pulmonary
oedema. The kidneys were small and granular and microscopically showed
increase of connective tissue, fibrous glomeruli and atrophied tubules. In the
cervical and portal lymphatic glands were encapsulated old caseous nodules.
The liver, spleen and alimentan,- tract presented no noteworthy lesions.

The heart was normal, no changes being present in the valves nor in tlie
size of the heart cavities or the thickness of their walls. On the posterior
wall of the ascending aorta, 3 cm. above the valves, is a distinct depression
5 mm. in diameter and 2 mm. in depth, over which apparently normal intima
is continuous. At the point where the innominate artery should be given
off the aorta divides into two branches, a larger anterior and a smaller
posterior branch which joins the anterior branch 2 cm. below the origin of
the left subclavian artery. The posterior branch passes behind the trachea,
between it and the oesophagus, so that the trachea passes through the ring
formed by the two divisions of the transverse arch of the aorta. From the
anterior division are given off in their usual position the left common carotid
and the left subclavian arteries. The beginning of the posterior trunk is the

' Presentation of pathological specimen and report before the Johns Hopkins
Hospital Medical Society, February 2, 1891.
Johns Hopkins Hosp. Bull.. Bait., 1891, II, 142.
286

DUPLICATURE OF ARCH OF AORTA 287

seat of a saccular aneurism about the size of a hen's egg, with a somewhat
triangular mouth measuring 2 by 1.5 cm. in diameter. The walls of tlie
opening are smooth and the inner surface of the aneurism only a little irre,gu-
lar and rough. The sac contains fluid and red freshly coagulated blood.
There are only a few scattered patches of endarteritis in the wall of the
aneurism and elsewhere in tlie course of the aorta, some of these being
atheromatous. From the posterior division of the arch are given off the
right carotid and subclavian arteries, the former arising from the sac of the
aneurism and the latter a short distance beyond tliis (t. e. further from the
heart). Beyond the aneurism the posterior division measures 3-J cm. in
length and 1 cm. in diameter.

The chief interest in the specimen is the duplicature of the transverse part
of the arch of the aorta. This congenital anomaly, as well as others affecting
the aortic arch, can be understood only by a consideration of the embrj'ologi-
cal development of the aorta and its branches, and from this point of view
and from that of comparative anatomy these anomalies are of great interest.
Duplicature of the transverse arch, of the aorta is to be explained by the
persistence after birth of conditions belonging to early foetal life, which
should have disappeared in the normal course of development. The fourth
right aortic arch (calling the arch nearest the heart the fifth) persists
throughout its course and constitutes the posterior division of the arch in
our specimen. In normal development the beginning of the right fourth
aortic arch becomes the innominate artery from which ascends the right
common carotid, corresponding to tlie prolongation of the right ascending
root of the aorta or the beginning of the third right aortic arch. The trans-
verse part of the right fourth aortic arch (the right fourth bronchial artery)
becomes the right subclavian, from which the vertebral is given off, and the
descending part of the right fourth arch, which in early development unites
with the corresponding part of the left fourth arch to make the aorta
deseendens, is obliterated. It is in the persistence of this descending part
of the fourth right aortic arch that the abnormality essentially consists by
which the so-called duplicature of the arch of the aorta is produced, and it
is interesting to note that in the amphibia this condition is normal, a right
as well as a left aortic arch existing.

The first record of an abnormality in the hiunan being similar to that in
our specimen appears to be by Hommel in 1T.37, but in Hommel's case both
the oesophagus and the trachea passed through the ring formed by the an-
terior and the posterior divisions, whereas in our case only the trachea
enters the ring. Since Hommel a number of cases of duplicature of the
aortic arch presenting considerable diversity in the exact arrangement and
the origin of branches in different cases have been recorded. I have not
found any case recorded in which the posterior division was the seat of an
aneurism as in the present case.

SUDDEN DEATHS FROM CARDIAC DISEASE'

The first specimen was one of thrombosis of tlie descending branc-li of the
left coronary artery.

The patient was a strongly built, wcll-iiourislied German, 55 years old.
Five years ago, he had an attack of acute articular rheumatism, and had
suffered from sub-acute attacks of rlieumatism for several years. He had
been a hard drinker. For several months before admission to the hospital,
he had suffered from pain in the region of the lieart, palpitation, shortness
of breath and bloody expectoration. He had paroxysmal attacks of cardiac
dyspnoea and pain. He had not noticed any swelling of the feet.

On admission the respiration was quiet. The pulse was 72, small and
regular. The arterial wall somewhat stiff. The apex beat of the heart was
in the fifth intercostal space below nipple. There was a presystolic thrill,
and marked shortness of the first sound. A loud presystolic murmur was
heard at apex. Both aortic sounds were clear. The urine contained albu-
men, hyaline and granular casts. Patient was in the hospital for four weeks,
during which he had occasional paroxysmal attacks of dyspnciea, lasting for
an liour or more. In the intervals his condition was fairly comfortable. On
the morning of November 30th, he was suddenly seized with pain in the chest
and shortness of breath, and in a few moments before any assistance could
be rendered he was dead.

At the autopsy the essential lesions were found in the heart. The mitral
orifice was greatly narrowed, measuring 13x8 mm. The chordae tendine.-e
of the mitral valve were thickened and shortened; the mitral segments
thickened and atheromatous, free from thrombi. The other valves were
normal. The heart was greatly hypcrtrophied and dilated. The hyper-
trophy and dilatation of the left auricle were most extreme, its wall meas-
uring in places 6 mm. in thickness. The wall of the left ventricle measured
23 mm. and that of the right ventricle 5 mm. in thickness. The heart muscle
was firm and of a dark reddish-bro\\ai color. On microscopical examination
it presented slight fatty degeneration.

The coronary arteries were markedly atheromatous, their walls being
irregularly thickened and presenting on the inner surface irregular, elevatecl,
opaque, yellowish white patches. The left coronary artery contained, 3 cm.
from its origin, a fresh dark red, almost black, thromlnis, adherent to iui
atheromatous plaque, and alMnit one-half centimeter in length. TJiis
tlirombus completely occluded the lumen of the artery at this point. It was
situated in the descending or vertical branch of the left coronary artery.

' Presentation of pathological specimens and report before the Jclms Hopkins
Hospital Medical Society, December 2, 1SS9.

Johns Hopkins Hosp. Bull., Bait., 1889-90, I, 34-35.

288

STJDDEX DEATHS FROM CARDIAC DISEASE 289

The aorta throughout its entire extent appeared thickened, dilated, and
presented numerous elevated atheromatous patches.

The lungs, liver, spleen, and kidney presented marked chronic passive con-
gestion. The spleen and kidney contained the scars of old infarctions. The
large and small bronchi contained niuco-pus.

There was an area of old softening involving the cortex of the left second
and third frontal convolutions near the anterior central convolution and the
adjacent part of the island of Reil.

The chief interest of the case is the explanation of the sudden death of
the patient. This is undoubtedly referable to the fresh thrombus which was
found attached to an atheromatous patch in the main branch of the left
coronary artery. Although marked atheromatous disea.se of the coronary
arteries existed, the circulation in tliese vessels had not been sufficiently
impeded to give rise to fibroid patches in the myocardium. The appearance
of the thrombus and the absence of infarction or anaemic necrosis of the
heart muscle, are evidence that the clot must have been of recent formation.
The cause of the thrombosis was doubtless the irregular atheromatous pro-
jecting plaque to which the thrombus was adherent. As is weU known, dis-
eases obstructing the circulation of blood through the coronary arteries,
such as arterio-sclerosis, thrombosis, embolism of these vessels, are among
the most frequent causes of sudden death.

The second specimen was one of complete occlusion of the mouth of the
right coronary artery.

The patient, a negro 36 years old, about six months before admission to
the hospital began to suffer from shortness of breath on exertion, and palpita-
tion of the heart. CEdema of the lower extremities appeared, but he was
unable to do the work of a laboring man until six weeks before admission.
Upon admission there were obsen'ed severe dyspnoea, general anasarca, pul-
sation of the veins, increased area of cardiac dulness, the apex beat being in
sixth intercostal space in middle line of axilla, and diastolic and systolic
murmurs heard most distinctly over base of heart. The urine was scanty,
specific gravity 1010 and contained granular and hyaline casts, and some
red blood corpuscles and pus cells. For a time he improved under treatment
but a few hours before death his pulse became very irregular, small, feeble
and compressible, and he died somewhat suddenly.

At the autopsy the heart was found greatly hypertrophied and dilated,
the left ventricle being 14 and the right 12 cm. long. The heart weighed 858
grammes. The thickness of the wall of the left ventricle was 25 mm. : that
or right ventricle 9 mm. The segments of the aortic valve were much thick-
ened, roughened, retracted, and adherent to each other. The muscular sub-
stance of the left ventricle presented several grayish, irregular fibroid patches
taking the place of the muscular tissue. The papillary muscles were ex-
tensively fibroid. The aorta for a distance of 4 cm. above the valves pre-
sented a remarkable nodular thickening of the intima resulting from arte-
rio-sclerosis. There Avere a few small nodules of calcification, but most of

290 SUDDEN DEATHS FROM CARDIAC DISEASE

the endarteritis was gelatinous and frosli in appearance. Beyond this cir-
cumscribed zone of arterio-sclerosis the aorta presentc<l only a few small
patches of atheroma, and in general the arteries of the body were but slightly
atheromatous. The coronary arteries of the heart, however, presented a
number of atheromatous patches. The most interesting feature of the case
was the complete obliteration of the mouth of the right coronary artery.
This mouth was involved in the extensive fibrous endarteritis affecting tiie
aorta just above the valves, so that it was impossible to discover any opening
from the aorta into the right coronary artery. This artery, however, was
present in its normal situation and distribution and its hmien, apparently
intact, could be traced nearly to the origin, where even the finest probe could
not be made to pass from the lumen into the aorta. The left coronary artery
appeared dilated but no large branch of anastomosis, connecting the left and
the right coronary arteries, could he discovered. The right coronary must
have been supplied with blood from the left artery.

The muscular substance of the heart, save the fibroid growth, was normal
in appearance and free from fatty degeneration.

The organs of the body showed evidences of chronic venous congestion,
and in the right kidney and ureter were fresh tubercle deposits associated
with caseous tuberculosis of the prostate gland.

The case is interesting as showing complete obliteration of the right
coronary artery at its origin by arterio-sclerosis of the aorta. Notwith-
standing the absence of any large anastomosing branches between the left
and the right coronary arteries, sufficient blood reached the regions of the
heart, supplied by the right coronary, to nourish these parts and to prevent
any fatty degeneration. The fibroid patches were chiefly, in parts, supplied
by the left coronary artery.

Tiie third specimen was one of extreme atheroma and thrombosis of the
coronary arteries with multiple white infarctions in wall of left ventricle.

The patient was a woman 67 years old who, for twenty years preceding
death, had complained of occasional attacks of pain in the region of the
heart. During the last three months of life she had suffered from par-
oxysms of typical angina pectoris, from attacks of extreme dyspnoea, from
great restlessness and some mental disorder. The pulse was irregular and
feeble. The heart sounds ap{>eared to be normal. Some adema of the lower
extremities developed. The urine contained a small qu.uitity of albimien and
a few liyaline casts. During the last few days of life she suffered from great
pain and distress in the region of the heart, and she expectorated small dark
clots of blood.

At the post-mortem examination the heart was only moderately enlarged,
and this enlargement was due chiefly to a considerable deposit of adipose
tissue beneath the epicardium. There was general obesity of the body. The
left ventricle, at about its middle, measured 1 cm. in thickness. Below this
it became gradually thinner, and at the apex measured only 4 mm. in tliick-
ness, of which one-half was fat. The average thickness of the right ven-
tricular wall was 5 to 6 mm., of which only 2 mm. represented muscular
tissue, the rest being fat. The right cavities of the heart were distended

STTDDEX DEATHS FROM CARDIAC DISEASE 391

with coagulated blood, chiefly cruor clots, but some decolorized ; but little
blood was found in the left ventricle. The aortic valves and the aortic se>;-
ment of the mitral valve presented several yellowish, fatty and atherom-
atous pat<.hes, but the edges of the valves were delicate and there were no
evidences of any change which would interfere with the functions of the
valves. There were numerous ante-mortem thrombi athvched to the inner
surface of the left and of the right ventricles in their lower halves, and
filling the appendices of the auricles. Many of these thrombi were globular
and had undergone central softening. In the left ventricle they were con-
tinuous with areas of necrosis in the ventricular wall, and it was not always
possible to recognize the line of separation between the thrombus and the
necrotic wall.

The coronarj- arteries were extremely atheromatous, standing out as rigid
tortuous calcified vessels with atheromatous projections on their inner sur-
face. Even the small branches could l>e traced through the heart wall by
means of the calcified beaded thickenins'S which they presented. Both
coronary arteries were greatly narrowed by atheromatous degeneration near
their origin. In many places grayish-red thrombi were present in the
branches of the left coronary artery, sometimes parietal and sometimes,
especially in the smaller Ijranches. occluding. They occurred in situations
where there was well marked atheroma. The left coronarv- artery was more
extensively diseased than the right.

A large part of the wall of the left ventricle was the seat of white infarc-
tion or anaemic necrosis. These areas of coagulation-necrosis had an opaque,
yellowish-white color, a firm consistence and well defined but irregidar
margins. They projected on the cut surface above the level of the sur-
rounding muscle which, in the immediate neighborhood of tlie infarctions,
appeared depressed, sielatinous, reddish in color and soft. The areas of
necrosis were foimd only in the wall of the left ventricle and in the septmn
ventriculorum ; they occurred chiefly in the part of the myocardium nearest
the endocardiimi, and usually, but not in all cases, reached the endocardium.
Sometimes they had more or less of a wedge-shape, but generally they were
irregular in contour. They varied from 2 to 6 mm. in thickness, and
appeared to have coalesced with each other so as to form a nearly continuous
band of coagulation-necrosis in the lower part of the left ventricle. They
occurred both on the anterior and on the posterior wall of the ventricle as
well as in the septum. The papillary muscles of the left ventricle were
affected with coagulation-necrosis throughout nearly their entire extent.

In addition to the infarctions the myocardimn of lioth ventricles was
affected by marked fatty degeneration, and presented a characteristic faded-
leaf mottling as seen through the endocardium.

The lungs were the seat of chronic passive congestion, of general bron-
chitis, of oedema ; and in the right lung were many firm, black, large, wedge-
shaped hemorrhagic infarctions.

The liver, spleen, kidneys and stomach presented the usual appearances of
chronic passive congestion.

The aorta and its principal branches were the seat of marked arterio-
sclerosis, presenting both gelatinous, elevated, fresh plaques and old calcified
plates.

292 STJDDEX DEATHS FROM CARDIAC DISEASE

Microscopical sections were exhibited showing the appearances of the in-
farctions in the heart wall. In the necrotic areas the muscular fibres were
entirely devoid of nuclei, and presented a homogeneous, hyaline or indis-
tinctly striated appearance. In the edge of the infarction were accumulat<^'d
between tlie muscular fibres masses of small irregular particles presenting
a nuclear stain and doubtless the result of nuclear fragmentation. Beyond
this zone was found an accumulation of leucocytes between the fibres, and a
large nimiber of red blood corpuscles. Mixed thrombi, rich in fibrin, leuco-
cytes and blood-plates appeared on the sections attached to the necrotic
cndocardimn. Such thrombi, however, were not limited to the necrotic areas.

In addition to the recent infarctions, the muscular wall of the left ven-
tricle contained a number of old fibroid patches. Along the borders of some
of the infarctions genuine granulation tissue, rich in cells and in blood-
vessels was present.

AN EXPEEIMENTAT. STUDY OF GLOMEEULO-NEPHRITIS '

Of the various processes which make up the pathological anatomy of
Bright's disease, perhaps the two which at present awaken the greatest in-
terest and the study of which promises the most fruitful results, are the
changes which take place in the glomeruli and atrophy and necrosis of the
epithelial cells in relation to interstitial changes. Not that by any means
unanimity of opinion has been reached regarding other fundamental ques-
tions involving the relationship between the glandular, the interstitial, and
tlie vascular lesions of Bright's disease, but the two processes named have
acquired especial prominence within the last few years by the recognition of
their frequency and importance.

Alterations of the Malpighian bodies, with which alone the present paper
is concerned, were descril>ed with much accuracy and fulness by Beer in his
excellent treatise on " The Connective Tissue of tlie Human Kidney in the
Healthy and the Diseased State," published in 1859,. but until recently little
attention was paid to his observations. Klebs, by his description in 1876
of tlie lesion to which he gave the name of glonierulo-nephritis, incited re-
newed investigation of this subject. During the last ten years processes
embraced imder the name of glomerulo-nephritis have been studied by Cornil,
Hortoles, Friedlander, Ribbert, Nauwerck, and many others, but we owe to
Langhans the most extensive and accurate observations on this subject.

A comparison of the statements of different writers concerning glomerulo-
nephritis -nill show a wide diversity of views, not only as to the interpreta-
tion of the facts observed but as to the facts themselves. Without attempt-
ing a critical analysis of these divergent views, the following summary of
some of the conclusions of different observers will show this to be true.

At present little or no credence is given to Kleb's belief that the essential
lesion of glomerulo-nephritis is proliferation of connective tissue cells which
he supposed to exist between the capillaries of the glomerulus, although tliis
belief still receives some support from the conception of Hortoles, and of
Cornil and Brault, as to the connective-tissue nature of these intercapillar}'
cells.

Langhans, in his publication in 1879, dwelt especially upon swelling,
proliferation, and desquamation of the epithelial cells both of the glomerulus

' Presented at the first meeting of the Association of American Physicians and
Surgeons, Army Medical Museum, Washington, D. C, June 18, 1886.
Tr. Ass. Am. Physicians, Phila., 1886, I, 171-183.

293

294 EXPEKIME.NTAL STUDY OF

and of Bowirian's capsule; wliereas in his last artirle, published in 1885, he
regards swelling and proliferation of the endotlielium lining the glomerular
capillaries as the primary and essential lesion of glomerulo-nephritis, as
indeed of all fomis of acute nephritis. Similar views are held by Fried-
lander and by Nauwerck.

Kibbert considers that the only changes are swelling and desquamation
of the glomerular and capsular epithelium, changes which he regards as
essential to all forms of acute and chronic Briglit's disease and as answerable
for many of the symptoms. He, as well as Hortoles and Cornil, refers the
appearances described by Langhans as proliferation of the capillary endo-
tlielium to an accumulation of white blood-corpuscles in the capillaries.

Cornil and Brault assign an insignificant and inconstant role to changes
in the epithelium of the glomerulus and of its capsule, and find the funda-
mental lesion of acute glomerulo-nephritis to be an exudation from the
glomerular capillaries of inflammatory products composed of white blood-
corpuscles, red blood-corpuscles, and an albuminous fluid.

On the other hand. Hortoles and Ribbert deny altogether the occurrence
of emigration through the glomerular capillaries, basing this view on the
failure to find leucocytes in the capsular space when their presence cannot be
explained by emigration from capillaries adjacent to Bowman's capsule.
In furtlier support of their view they urge tlie peculiar structure of the capil-
laries of the glomerulus.

But it is not necessary to consume time in a further enumeration of the
different views which are held upon this subject. Enough have been cited
to show that there is room for much more investigation, as well as to bring
out some of the leading points which require further study.

In the expectation that light might be thrown upon some of these doubtful
points by experiments upon animals, I have made a study of the nephritis
produced by acute cantharidin poisoning with especial reference to the altera-
tions induced in the Malpighian bodies. I was led to select cantharidin
because several experimenters with this substance have described in can-
tharidin nephritis notable changes in the Jfalpigliian Iwdies. and because
Cornil bases his description of acute glomerulo-nepliritis chiefly upon ob-
servations of tlie kidneys of rabbits poisoned by cantharidin.

My experiniont.«. which have not yet reached their completion, were made
upon white rats and upon rabbits. A concentrated solution of cantharidin
in acetic ether was used. I injected, subcutaueously, in rabbits usually from
one-half to one centigramme of cantharidin, and in rdt.« from one to three
milligrammes. When a number of injections were made upon successive
days smaller doses were used. The number of injections did not exceed five,
and usually not more tJian two or three.

GLOMEBDLO-NEPHRITIS 295

After the injection of a toxic dose the urine becomes diminished and
finally suppressed; it contains albumen, liyaline casts, and a large numl)er
of leucocytes and red blood-corpuscles. The kidneys appear swollen, con-
gested, and more succulent than normal.

The microscopical appearances in the rat's kidney will be first described.
Here and tliere foci of infiltration witli small round cells, doubtless emi-
grated white blood-corpuscles, can be found. They are most common around
the veins at the base of the pyramid. They are often but not constantly
present.

The epithelium of the convoluted tubes is in places normal in appearance,
in other places it is swollen, and oft^n the inner part of the epithelial cells
is broken off and appears as a granular mass in the lumen of tlie tubes.
Sometimes a large number of epithelial cells axe devoid of nuclei, and have
apparently undergone c-oagulation necrosis. In general, tlie convoluted
tubes are wider than normal.

The most marked changes are to be found in the Malpighian bodies. In
by far tlie greater number of these bodies tliere is between the glomerulus
and Bo-mnan's capsule a -wide space partly or wholly filled with cells and
granular material. These cells may be round or oval, but they are usually
polyhedrical in shape. They are much larger than white blood-corpuscles,
have granular protoplasm, and oval, vesicular nuclei. They are frequently
arranged as a crescentic mass around the glomerulus.

Evidently we have here appearances such as have been often described as
glomerulo-nephritis in the liuman kidney, and naturally one seeks for the
same origin of these cells as that assigned for tlie cells similarly situated in
human glomerulo-nephritis, namely, swelling and desquamation, and possi-
bly proliferation of either the capsular or the glomerular epithelium.

The microscopical appearances in the rat's kidney, however, do not admit
of this explanation. The epithelium lining the capsule of Bowman is often
intact, and can be traced in its normal situation and with its normal appear-
ances around the mass of cells occupying the capsular space. The glomerular
epithelium may also preserve its normal position ; more frequently it is some-
what swollen and granular, and it may desquamate. Such desquamated
glomerular epithelial cells may lie mingled with the cells free in the capsular
space, but there are no appearances which justify the derivation of tlie
majority of these latter cells from the epithelium of the glomerulus.

Both Cornil and Eliaschoff, whose descriptions of cantharidin nephritis
are the best which I have found, and who experimented on rabbits, also came
to the conclusion that the cells occupying the capsular space cannot be de-
rived from either the epithelium of Bowman's capsule or that of the glomer-
ulus. They argue that there remains but one other possible source, namely,
emigration of white blood-corpuscles from the glomerular capillaries. They

296 EXPERIMENTAL STUDY OF

therefore consider the cells in question as white blood-corpuscles, of which
the cell bodies and the nuclei are greatly swollen and altered by the action of
the cantharidin or of the urine.

So far as the rat's kidney is concerned, this explanation of Cornil and of
Eliaschoff cannot be admitted. These authors are in error in supposing that
the cells occupying the capsular space, if not originating from the capsular
or glomerular epithelium, must come from the capillaries. These cells may
be derived also from the convoluted tubes in immediate communication with
the Malpighian bodies, and tliat this is their origin, at least in part, in the
cantharidin nephritis of rats can be proven, I believe, beyond question. The
cells in the capsular space are identical in appearance ^Tith the epithelial
cells of the adjacent convoluted tubes. The appearances presented on sec-
tions which show the communication between the capsular space and the
corresponding convoluted tube hardly admit of any other interpretation than
that which I have given. Here it can be seen that the mass of cells in the
capsular space is in direct connection with the epithelium of the convoluted
tube, and, what is especially demonstrative, there can frequently be found
in this mass a group of cells arranged regularly in the form of a ring with
a central space, just like the epithelium of a uriniferous tube. Without the
explanation given, such an arrangement of the cells is, of course, very
puzzling, especially when the Malpighian body is cut so as not to show the
connection with the tube. The appearance is as if the epithelial cells lining
the mouth of the uriniferous tube (or the neck of the capsule), together with
the cells immediately adjacent, had been pushed mechanically int« the
capsular space. A similarity in appearance between the cells accumulated
in the capsular space and the epithelial cells of the convoluted tubes, might
be explained by the fact that under nonnal conditions the epithelium of the
convoluted tubes may extend for a variable distance along Bowman's capsule.
Such an extension of the tubal epithelium to tlie capsule is not particularlv
noticeable in the rat's kidney, and cannot be adduced to explain the peculiar
appearances described.

Observations concerning the passage of epithelial cells from the con-
voluted tubes into the capsular space, have been made by KoUiker ' and bv
Argutinski.' While discussing the nature of the normal glomerular epi-
theliimi, Kolliker says:

" In hardened kidneys the epithelium of the convoluted tubes is not infre-
quently pressed up into the capsules, so that in many cases a membranous
layer is formed which is arranged like a funnel around one end of the
glomerulus."

' Kolliker. Handb. d. Gewebelehre. Leipzig, 1867, p. 504.

' .\rRutinski, Beitrage zur Normalen und Pathologlschen Histologle der Niere,
p. 18. Inaug. Diss. Halle. 1877.

GLOMERTJLO-NEPHRITIS 297

Kolliker's obsen-ations relate, therefore, to artefacts produced by the
action of the hardening fluid. In the cases of cantharidin nephritis which I
have studied, the accumulation of tubal epithelium within the capsules can-
not be regarded as an artefact, for the same appearances can be seen in sec-
tions of the fresh kidney as in sections of kidneys hardened in Miiller's fluid,
chromic acid, Flemniing's solution, picric acid, osmic acid, and alcohol.
The change is, therefore, one which occurs during the life of the animal.
The same appearances in the Malpighian bodies which I have observed in
the cantharidin nephritis of white rats, have been described and figured
b}' Argutinski as occurring in the embolic infarctions experimentally pro-
duced in dogs by injecting into the renal arteries plugs of wax. He also
speaks of the possibility of producing the same change by forcible injection
of fluids into the renal bloodvessels. He therefore assigns as the cause of
this phenomenon the pressure exerted by dilated bloodvessels upon the
convoluted tubes, whereby the protoplasmatic contents of the latter are forced
upward into the capsular spaces.

The following are among the factors which may be adduced to explain the
mechanism by which the cells in cantharidin nephritis make their way from
the convoluted tubes into the capsular spaces : Obstruction of the uriniferous
tubes, both in the cortex and in the pyramid, by desquamated and by necrotic
epithelial cells, and by hemorrhages within the tubes, pressure upon the
tubes from without by congested bloodvessels and by transuded serum, and
cessation of the excretion of urine from the glomeruli. In consideration of
these alterations in the kidney, it is comprehensible that swollen and des-
quamated epithelial cells in the beginning of a convoluted tube might find
toward the capsular space the direction of least resistance.

There is, of course, no propriety in designating as glomerulo-nephritis the
changes in the Malpighian bodies of the rat's kidney which have been de-
scribed. The term glomerulo-nephritis, however, is one which is used with
much latitude of significance, and embraces nearly all of the changes ob-
served in acute nephritis in the Malpighian bodies and a large number of
those found in chronic nephritis. Many of these changes are not proven to
be inflammatory.

I am not able to say whether a process similar to that which I have found
in the ilalpighian bodies of the kidney of the rat poisoned by cantharidin,
occurs also in the nephritis of otlier animals and of man. In the acute can-
tharidin nephritis of rabbits the capsular spaces also contain granular ma-
terial and cells, but the cells do not form such compact masses as in the
rat's kidney, and more frequently undergo necrosis. I have not been able
as yet to reach a positive conclusion as to the origin of these cells. To the
descriptions which have been repeatedly given of the cantharidin nephritis
22

298 EXPERIMENTAL STUDY OF

of rabbit'*, I have to add tlic almost constant occurrence of necrosis of epithe-
lial cells in certain tubes occupying the boundary zone of the pyramid and
the medullary rays. These tubes appear to be temiiual portions of the
proximal convoluted tubes (Endstiickchen, spiral tubes). Hemorrhages
witliin the tubes, particularly those of the pyramid, are not infrequent.

In human glomerulo-nephritis one is not generally at a loss to account
for the crescentic mass of cells which frequently occupies the capsular space.
The presence of tliese cells is accompanied with swelling and desquamation
of either the glomerular or the capsular epithelium, usually of both, and
these changes explain the accumulation of cells in the capsular space.

One of the leading objects in making these experiments on cantharidin
nephritis was to determine whether changes were thereby produced in the
glomerular capillaries. Friedliinder, Nauwerck, and Langbans have called
attention to the accumulation of cells in the interior of the glomerular capil-
laries as a frequent and important lesion of acute and of chronic nephritis.
These cells they regard, for the most part, as proliferated capillary endo-
thelial cells. Previous experimenters on nephritis may no mention of altera-
tions in tlie glomerular capillaries, so far as I have been able to learn.

The technical difficulties attending the microscopical investigation of the
glomerular capillaries are considerable. It is often desirable, as recom-
mended by Langhans, that these capillaries should Imj injected with color-
less gelatine, although when they are widely distended with cells, as in some
instances of Bright's disease, such a procedure is not necessary. The sections
of the glomeruli must be extremely thin, and this is best accomplished by
embedding pieces of the kidney either in celloidin or in paraffin, in the
latter case cutting the sections, of course, vnth the dry ra^or placed at right
angles to the specimen.

In some eases of cantharidin nephritis no changes can be detected in
the glomerular capillaries; in some instances, however, especially in tlie
rabbit, tliese capillaries contain a large nmnber of small, darkly staining
nuclei, readily distinguished from the larger and paler nuclei of the
glomerular epithelium. These nuclei belong for the moit part to spherical,
granular cells, which I am inclined to interpret as white blood-corpuscles.
Positive evidences of proliferation of the capillary endothelium could not be
found. Changes in the capillaries comparable in degree to those observed in
many cases of nephritis in human beings, I have not been able to find in
experimental cantharidin nephritis.

The occlusion of the glomerular capillaries in acute and chronic Bright's
disease by granular material and cells, has been most fully described in all
of its histological details by Langhans. My own studies of human kidneys
are essentially confirmatory of Langhans's descriptions.

GLOMERULO-NEPHRITIS 299

Swelling of the endothelium, and accumulation of cells in the glomerular
capillaries, are nearly constant lesions in acute scarlatinal nephritis. These
changes in the capillaries may be the only marked lesions in the kidney,
although, as a rule, there is more or less accumulation of lymphoid cells in
tlie interstitial tissue. I have observed similar accumulation of cells in the
glomerular capillaries in acute Bright's disease complicating typhoid fever,
and in a number of cases of chronic Bright's disease. The changes in tlie
capillaries are usually accompanied by other lesions of diffuse nephritis.

I would, liowever, call especial attention to certain cases of Bright's
disease wliicli usually pursue a subacute course, in which the accumulation
of cells in the capillaries of the glomerulus is the predominant, and some-
times tlie only evident lesion. The following case may serve as an illustra-
tion.

The patient, who had had malaria, was the subject for two months of
anasarca. The urine was scanty, albuminous, and contained casts. Death
resulted from uraemic convulsions. At the autopsy there was found malarial
pigmentation of the spleen and other organs, the heart was considerably
hypertrophied, and the kidneys were large, the surface smooth, the capsule
non-adherent, and the cortex swollen. The Malpighian bodies were large
and pale. Upon microscopical examination of the kidneys, with the excep-
tion of the change about to be described, there was very little abnormal.
The epithelial cells were normal. Only after careful search could a few
patches of infiltration with lymphoid cells be discovered. The Malpighian
bodies were rich in nuclei. The glomeruli filled completely the space en-
closed by Bowman's capsule. The case seemed a puzzling one, until after
the examination of very thin sections it was found that almost everj-where
the glomei-ular capillaries were dilated, and contained a large number of
cells, partly resembling white blood-corpuscles, but mostly larger, and of an
endothelioid type.

Probably many pathologists have met with kidneys in which the lesions
seemed entirely inadequate to explain the symptoms. Doubtless a certain
nxmiber of these obscure cases belong to the class just described. It certainly
is important that a careful examination be made of tlie condition of the
glomerular capillaries.

It is not necessary to dwell upon tlie importance which attaches to the
lesions of the glomerular capillaries which have been described. When one
considers the physiological functions of the glomeruli, it is difficult to think
of any lesion of the kidney more destructive of its functions than the occlu-
sion of the capillaries of tlie glomerulus. It is more reasonable to refer the
production of albuminuria to changes in the capillary walls of the glomeruli
than to desquamation or other alteration of the glomerular epithelium.

300 EXPERIMENTAL STUDY OF

C\<rtainly sonic swelling and desquamation of tliis epithelium are extremely
common, even in oases witiiout renal symptoms.

But while I am disposed to attach such importance to alterations of the
jrlomerular capillaries, we are not justified in assertinj::, as has been done,
that these changes constitute the primary and essential lesion of all cases
of Bright's disease. The glomerular lesions are coordinate with the paren-
chj-matous, the interstitial, and the other vascular lesions of diffu-se nephritis.

As regards nomenclature, there is not much use in fighting against names
which have gained currency, although the term glomerulitis seems to be more
suitable than glomerulo-nephritis, and equally expressive. It is customary
to include all of the changes of the Jlalpighian bodies which are not either
atrophic or purely degenerative, under tiie name glomerulo-nephritis ; but it
is to be borne in mind that this term is used to designate a group of lesions
belonging to diffuse nephritis, and not a disease by itself. I would suggest
that the form characterized by an accunmlation of cells between the glomer-
ulus and Bowman's capsule be designated desquamative glomerulitis, and
that characterized by accumulation of cells, or other changes in the interior
of the capillaries, be called intra-capillary glomeruUtis, and this without
prejudging the question as to the propriety of considering all of these changes
as inflammatory.

DISCUSSION

Di!. Welch. — Experiments have l)een performed by Guarnieri and Ago-
stuielli which bear upon the poinfc? raised by Dr. Jacobi. In a fatal case of
cantharidin poisoning in a human being these observers failed to find marked
lesions of the kidney, such as had been described by Cornil in his experi-
ments on rabbits. They concluded tliat these severe lesions occur onlv when
the cantharidin is administered subcutaneously, and not when it is" taken
into the stomach. This conclusion they confirmed by experiments on rabbits.

It is said that cantharidin acts upon various organs of the body, producing
changes especially in the capillary endothelium. I have confined my atten-
tion to the kidney, my purpose being not so much to study the action of can-
tharidin as such, but to investigate certain lesions of the "ilalpighian bodies.

As to the permanency of the alterations of the glomeruli, this depends
upon their character. The accumulation of cells in the capsular space has
Jiothing about it which is irremediable.

Whether or not we are to regard this or some other change of tlie glomeruli
as the necessary starting-point of acute and chronic Bright's disease it is
impossible to say positively. "It seems to me that our present knowledge
does not justify us in assigning to any one particular process the oriijin of
the different forms of ne])hritis. It is sufficient to describe the various
processes occurring in Bright's disease, without expressing positive opinions
as to the dependence of one process upon another.

GLOMERULO-NEPHKITIS 301

I do not wi;;]! to be misunderstood in regard to the use of the term glo-
merulo-nephritis. I do not understand this to indicate a separate disease of
the kidney. The term glonierulo-nephritis or glomerulitis is a convenient
one to designate all of the changes, not degenerative or purel}' atrophic
whicli occur in the JIalpighian bodies.

I think that too much importance is sometimes attached to mere desqua-
mation of the capsular and of the glomerular epithelium. This desquama-
tion is a very common condition even when there is not much disease of the
kidney, and when there have been no marked renal symptoms during life. I
question the propriety of attributing alliuminuria to" changes in the glomer-
ular epithelijjn. There is more reason to suppose that changes in the walls
of the glomerular capillaries are the essential factor in the production of
albuminuria. The capillaries of the glomerules differ in structure from the
capillaries in other parts of the body, and these differences may explain the
fact that normally they do not permit the transudation of an albuminous
liuid.

THE CAKTWEIGHT LECTURES
ON THE GENERAL PATHOLOGY OF FEVERS

Lectuue I

THE NATURE OF FEVER

There is no subject in medicine of more general and varied interest than
fever. The practitioner in every department of medicine, the pathologist
and the physiologist are equally interested in the investigation of tlie nature
and effects of fever. Even the physicist and the chemist, who are not directly
concerned with medical science, have lent their aid to tlie study of animal
heat and its disorders. The history of opinion regarding fever is in great
part the history of medicine itself, for no feature of tlie great systems of
medicine from Hippocrates and Galen to tlie present century so character-
izes these systems as the views held concerning the nature of fever. In con-
sequence of the importance of the subject and of the number and ability of
those engaged in its investigation, it might be supposed that no chapter in
medical science would be better understood than that pertaining to fev(;r.
That such is not the case is due to the fact which is becoming more and more
evident that the reaction of the animal system wliich we call fever is depen-
dent upon the most fundamental and essential properties of protoplasm and
of nerve energy. In proportion as our knowledge of these properties in-
creases and becomes more accurate, we gain a clearer insight into the com-
plicated processes involved in the production of fever.

I should hardly have selected for this course of lectures a subject where
so many problems remain unsolved and wliich must necessarily be presented
in so fragmentary a form, were it not that in all ages the opinions held con-
cerning tlie nature of fever have controlled measures employed in its treat-
ment. In proof of this, one need not go back to the time when fever was re-
garded as an almost conscious struggle of an anima with a noxious principle,
in which struggle the physician was to interfere as little as possible, or to
the time when fever was suppo.sed to result from morbid humors which the
physician should aim to eliminate by the production of a critical discharge, or
to the period when the treatment hinged upon the belief either in tlie sthenic

' Delivered before the Association cf the Alumni of the College of Physicians and
Surgeons, New York, March 29, April 5 and 12. 1888.
Med. News, Phila., 18SS, LII, 365; 393; 539; 565.

302

GEXERAL PATHOLOGY OF FEVER 303

or the asthenic- nature of fever. In our own time the treatment of fever is
intimately connected with the answers variously given to such questions as
whether fever aids in the elimination or destruction of infectious agents
concerned in its production ; whether increased waste of tissue is a constant
condition and a source of danger in fever ; what part is played by infection
and what part by elevation of temperature in causing the grave sjTnptoms of
fever; what in addition to lowering of temperature are the effects of so-
called antipyretic measures of treatment?

I need hardly say that the subject of these lectures relates to fever as a
condition common to all febrile diseases. Some writers understand by tlie
term fever used in this sense merely abnormal elevation of temperature,
others elevation of temperature and the symptoms directly caused by this,
and still otliers a eoniplex of synijitnnis of wliich increased temperature is
the most prominent but not necessarily the cause of the others. In con-
sidering the general pathology of fever it is convenient to adopt the last
meaning, althougli it would doubtless be less confusing if the word fever were
applied only to abnormal elevation of temperature.

Increased temperature being the dominant and essential system of fever,
all discussions as to the nature of fever centre around the question. How
is the febrile rise of temperature produced? It is to the consideration of
this question that I first invite your attention. As there are otfter aspects
of fever which I wish to discuss, it will be necessarj' to present the matter
belonging to this division of the subject in as succinct a form as is com-
patible with clearness. Twelve years ago Burdon-Sanderson ' brought to-
gether in an admirable critical review the results of investigations upon this
subject up to that period. Since that time important additions have been
made to our knowledge of the mode of production of fever.

In the wonderful preservation of a nearly constant temperature which
characterizes in health the warm-blooded animals three factors are con-
cerned, viz., the production of heat within the body, the loss of heat from
the body, and the regulating mechanism by which the varj'ing heat produc-
tion and heat loss are so balanced that tlie internal temperature remains
practically constant. It is theoretically possible that the rise of temperature
in fever may be due to the disturbance of any one or more of these factors.
It becomes necessarj', therefore, to consider the behavior of heat production,
of heat loss, and of the regulating mechanism in fever.

We will begin with the consideration of the production of heat in fever.
The amount of heat produced by the body is estimated by two methods, one
known as direct calorimetry, the otlier as indirect calorimetry. In the
method of direct calorimetry the animal is placed in a closed ventilated box

' Burdon-Sanderson : The Practitioner, 1876.

304 CARTWRIGHT LECTURES

surrounded on all sides by a compartment containing water or air, and the
amount of heat discharged from the body is determined by the quantity of
heat imparted to the surrounding water or air. If the temperature of the
animal remain unchanged during the period of observation, tlic heat pro-
duction is equal to the heat loss ; if the temperature rise or fall, the amount
of heat corresponding to this change of temperature — an amount determined
by multiplying the weight of the animal by its specific heat and by the
number of degrees of altered temperature — is added to or subtracted from
the quantity of heat imparted to the calorimeter. Time will not permit me
to enter into e.xperimental details in this connection ; it must suffice to say
that the method of direct calorimetry necessitates the introduction of a num-
ber of corrections which cannot be determined with absolute accuracy, so that
the results obtained are of relative rather than of absolute value.

Hitherto the estimation of heat production in fever by determining the
entire amount of heat liberated from the body has been made only upon
animals in which fever has been artificially produced. The most elaborate
researches of this nature are those of Senator ' and of AVood.' The experi-
ments of Wood are of the greater value because he extended his observations
over longer periods of time.

In four of the seven calorimetrical experiments of Wood on different
fevered dogs comparison can be made of the amount of heat produced hourly
in fever with that produced by the same animal when fed and when in a
state of hunger. During the period of fever the animal was also in a con-
dition of hunger. I have computed from Wood's tables that the average
hourly heat production during seven days described as first and second fever
days, is a little over 23 per cent greater than that of the healthy animal dur-
ing a state of hunger, the minimum excess being 1 per cent and the maxi-
mum 55.5 per cent.' If a comparison be made of different periods during
the existence of fever there are found to be even greater fluctuations m the
amount of heat production than these figures would indicate, this amount
being sometimes more than double that in hunger and sometimes consider-
ably less than the average production in hunger. Moreover, these experi-
ments show no definite relation between the height of the temperature ancl
the amount of heat produced, nor is it possible to deduce from them any
relation between heat production and the different stages of fever, such as
the more recent calorimetrical experiments of Wood, Reichert, and Hare '

' Senator: Untersuchungen iiber d. Pieberhaften Process, Berlin. 1873,
•Wood: Fever, A Study in Morbid and Normal Physiology, Philadelphia, 18S0.
' In making this computation I have corrected some numerical errors in Wood's
tables; these errors are not serious and do not affect his conclusions.
•Wood, Reichert, and Hare: Therapeutic Gazette. 1SS6.

GENEKAL PATHOLOGY OF FEVER 305

appear to sliow and which will be described later. An important outcome of
these as well as of all similar calorimetrical experiments is that, although
the heat production of an animal in fever is greater than that under like
conditions of nourishment, it is, as a rule, less than that of the same animal
upon a full diet.

There are many reasons which make it important to control the experi-
mental results obtained from animals in fever by corresponding obsen-a-
tions of human beings. The agents used in producing experimental fever
have been generally putrid fluids or pus, the injection of which causes some-
times diminution instead of elevation of temperature. When fever is thus
produced, it is usually of short duration and of only moderate intensity,
tlie rise of temperature being rarely more tlian four degrees, and sometimes
not more than one degree Fahrenheit. Moreover, a large part of the im-
portant role played by the skin in the regulation of the bodily temperature in
man is assumed by the lungs in these animals.

Complete calorimetrical observations of human beings in fever encounter
difficulties which have not yet been overcome. The imperfect or incomplete
methods employed by Liebernieister ' and by Leyden ' in determining the
heat production of human beings in fever justify the inference that this
productio)! is increased, and, apparently, as a rule, to a greater extent than
in animals, but they do not warrant positive conclusions as to the quantity
of heat produced.

We turn now to the results regarding febrile production of heat obtained
by what has sometimes been called indirect calorimetry. Inasmuch as the
heat energj- of the body is the result of chemical changes of its proteids, fats,
and carbohydrates, it is evident that if we know the kind and the amount
and the heat value of the substances consumed in a given time within the
body, we can compute their heat production.' These chemical changes, so
far as their final products are concerned, are processes of oxidation. The
heat values of the substances consumed in the body were determined first by
Frankland and more recently with accuracy by von Rechenberg, Danilewsky,
and Eubner. The investigations of Pettenkofer and Voit have shown that
in hunger almost exclusively fats and proteids are oxidized, and that in this
condition by determining the amount of oxygen absorbed and of nitrogen

'Liebermeister: Handb. d. Path. u. Therap. d. Fiebers. Leipzig, 1875.

•Leyden: Deutsches Arch. f. klin. Med., Bd. 5.

" The energy resulting from these chemical changes appears partly in the form
of heat and partly in mechanical work. As practically all of the internal mechan-
ical work is transformed within the body into heat energy, it is only the external
mechanical work which is to be considered in estimating the actual heat produc-
tion. The influence of this factor in fever will be spoken of later.

306 CAllTWRIOIlT LECTURES

and of tarboii excreted, wc can estimate the quantity of fat and of proteid
substances oxidized during the period of obsen-atiou.

Physicians of past centuries regarded increased consumption of the ma-
terial of the body in fever as so evident that it needed no especial demonstra-
tion, and after Lavoisier made apparent the sources of animal heat, it was
accepted almost unquestioningly until the last quarter of a century that
fever is essentially a process of increased combustion or oxidation. The im-
mense historical importance of the promulgation in 1863 of Traube's theory,
which denied the dependence of fever upon increased production of heat,
is that this theory has led to a careful inquiry into the grounds of beliefs
hitherto generally accepted, and to the demonstration of the unsatisfactory
nature of the evidence hitherto thought to be conclusive.

The striking loss of weight of most fever patients is, as is well known, a
fact of great clinical importance. Weber, and Tinkler have demonstrated
that animals in fever lose weight more rapidly than healthy animals in
hunger, and although observations on human beings with reference to this
point are not concordant in their results, there can be little doubt tha*- the
tendency of fever is to cause a greater loss of weight than can be explained
simply by insufficient nutriment. This tendency, however, may be masked
by the retention of water within the body as the investigations of Leyden
and others have shown. While, therefore, the studies of the loss of weight
in fever leave no doubt that there is increased destruction of tissue in this
condition, we cannot consider this loss as an accurate measure of the in-
creased destruction, nor, without further knowledge, as an indication of
increased oxidation, still less as proof of excessive production of heat.

It was for a long time believed that the excessive excretion of urea in fever
afforded satisfactory evidence of increased oxidation and of greater produc-
tion of heat. We now know, especially from the researches of A. Friinkel,"
that this is so far from being true that we could explain the excessive elimina-
tion of urea better upon the assumption of diminished than of increased
oxidation of tissue. In certain pathological conditions, notably phosphorus
poisoning, the amount of urea excreted may be increased more than three-
fold, notwithstanding, or, as Frankel believes, in consequence of diminished
absorption of oxygen and elimination of carbonic acid. It can, moreover,
be computed that even without any diminution of the respiratorj- gases the
discharge of urea may be increased without greater production of heat.
Wliile, therefore, the enormous increase in the discharge of urea in fever
sheds valuable light upon a most obscure subject, the nature of febrile me-
tabolism, it does not, regarded by itself, atl'ord us any information as to the
production of heat.

■° Friinkel: Virchow's Archiv, Bd. 67.

GENERAL PATHOLOGY OF FEVER 307

Failing to find satisfactor}' proof of increased oxidation in the loss of
weight of the body, or the excessive excretion of urea in fever, attention was
then directed to the elimination of carbonic acid, an excretory product which
bears a much closer relation to the production of heat than does urea. Im-
mense importance has been justly attached to the determination of the
amoimt of carbonic acid excreted by an individual in fever. Xo point in
the whole battle-ground of fever patholog}' has been more liotly contested
than whether increased production of cardonic acid is an essential part of
the febrile process. The first investigators of this question, Leyden, Lieber-
meister. Senator, contented tliemselves with the determination of the ainoiint
of carbonic acid eliminated by an individual in fever and in apyrexia. There
are several considerations which greatly diminish the value to be attached
to the mere estimation of carbonic acid excreted without simultaneous de-
termination of the amount of oxygen absorbed. As has been urged by Sena-
tor, and with especial clearness by Pfiiiger, increased discharge of carbonic
acid does not necessarily imply increased production of the same. The dis-
charge of carbonic acid varies, independently of its production, with tlie
rhythm and depth of respiration, and with the temperature and the alka-
linity of the blood, all factors which are altered in fever in such a manner
as to favor increased liberation of carbonic acid. It is true that the influence
of these factors would cause increased discharge of carbonic acid out of pro-
portion to its production only for a limited period, and that the prolonged
increase in tlie amount of carbonic acid discharged in fever, which has been
found by several observers, can hardly be interpreted otherwise than in favor
of increased production. There is another point which detracts still further
from the value of exclusive determinations of the quantity of carbonic acid
discharged, and this is that it makes a great difference, so far as the produc-
tion of heat is concerned, whether the carbonic acid is the residt of oxidation
of carbohydrates, of fats, or of proteids, a difference amounting, according
to Rubner," to 29.5 per cent ; or, if only the proteids and fats be considered,
to over 20 per cent. In investigations of nutrition it is now known to be of
the utmost importance to determine the so-called respiratory quotient —
that is, the ratio between the amount of carbonic acid discharged and that of
oxygen absorbed. This quotient varies in a definite way with the kind of
material oxidized in the body, and an accurate knowledge of it would enable
us to draw conclusions as to the substances consumed in fever.

The investigations which have been published within the last few years
upon the absorption of oxygen, as well as the discharge of carbonic acid in
fever, are to be ranked as most valuable contributions to our knowledge of
the subject. The first determination by trustworthy methods of the amount

"Rubner: Zeitschrift f. Biologie, Bd. XXI.

308 CAETWRIGHT LECTURES

of oxypcn absorbed and of carbonic acid excreted in fever was made in
Pfliiger's laboratory by Colasaiiti upon a guinea-pig, and Wiis publit-hed in
1877. Since that time two careful and elaborate researches upon this sub-
ject have been made, the one by Finkler. and the other by Lilienfeld."

These experimenters found that in fever there is increa.«e of the amount,
both of oxygen absorbed and of carbonic acid excreted. Making comparison
with healthy animals under the same conditions of nutrition, Colasanti
found that the increase in the absorption of oxygen amounted to 18 per cent,
and in the excretion of carbonic acid to 24 per cent; Finkler, whose experi-
ments were made also upon gTiinea-pigs. found, under varying conditions of
external temperature, the average febrile increase of oxygen to be 13.8 per
cent, and of carbonic acid 15.3 per cent, and Lilienfeld, who experimented
on rabbit'^, found the average increase of oxygen to be 13.9 per cent. The
statement of these averages gives an incomplete conception of the oxidation
in fever, as they are derived from all stages of fever, and varying elevations
of temperature. No constant proportion was found to exist between the
height of the temperature and the amount of oxidation. On the other hand,
a relation was observed between the oxidation and the stages of fever, viz.,
tlie initial stage v\ith rising temperature, the acme with constant high tem-
perature, and tlie defervescence with falling temperature. During the period
of rising temperature oxidation was increased, and in this stage Finkler
found the highest percentages, amounting to 36.6 per cent in the increase
of oxygen, and 37.6 of carbonic acid. There were, however, marked fluctua-
tions in this stage, both in the temperature and the amount of oxidation.
In tlie stage of constant liigh temperature such high percentages were not
noticed, and the fluctuations were less marked. The processes of oxidation,
according to Lilienfeld, are increased, on the average, less in the acme than
in tlic initial stage of fever." During defervescence of fever the increased
oxidation falls, and may sink below the normal. Tiilcing a broad view of
tliese stages, we may say, therefore, that the periods of rising, constant, and
falling temperatures in fever, correspond to periods of rising, constant, and
falling oxidation, but we must bear in mind that the fluctuations in oxida-
tion are much greater than, and bear no constant relation to, those of tem-
perature; so that, in each period, there are times when oxidation may rise
or fall most decidedly without corresponding changes of temperature.

Inasmuch as these experiments have shown that the increased excretion
of carbonic acid in fever is accompanied by increased absorption of oxygen,

"Colasanti: Pfliiger's Archiv, Bd. XIV. Finkler: /6i<f., Bd. XXIX. Lilienfeld:
Ihid., Bd. XXXII.

" In the period of rising temperature there was an increase of oxygen absorbed
of 27 per cent, in the acme of 14.9 per cent.

GENERAI. PATrrOT.OGY OF FEVEr; 309

and, as -will be explained presently, that the respiratory quotient, if it
changes at all, sinks, it is evident that we need not discard experiments in
which only the amount of carljoiiic acid excreted has l)een estimated by good
methods. The most accurate of these experiments are those of Leyden and
Frankel upon fevered dogs." They found that, without exception, carbonic
acid is excreted in larger amount in fever than in health under the same
nutritive conditions, the excess amounting sometimes to 70 per cent, and
in general being larger than in the experiments which have been previously
considered. The earlier and meritorious experiments of Senator upon this
point did not give uniform results, and he felt justified in concluding that
there is no evidence of increased production of carbonic acid in fever. Subse-
quent experiments witli far more accurate methods have demonstrated the
incorrectness of Senator's conclusions. It may be well to call to mind that
Burdon-Sanderson's deductions, which have naturally had great influence
among physicians here and abroad, were based, in great part, upon the data
derived from Senator's experiments.

Hitherto, the methods employed in studying the respiratory gases of
himian beings in fever have not approached in accuracy those used in the
experiments described. If the discordant results of Wertheim. which were
obtained by methods manifestly very inaccurate, be discarded, all other in-
vestigators have obsen-ed augmented discharge of carbonic acid in fever of
human beings. Leyden found an excess of 50 per cent in the febrile dis-
charge of carbonic acid ; and Liebermeister, whose observations were made
chiefly on cases of intermittent fever, found an excess of 30 to 40 per cent
in the period with rising temperature, and of 19 to 31 per cent in the acme
of the fever. During the deferversence of the fever the excess of carbonic
acid discharged diminished, and sometimes wholly disappeared. In one
instance, in which the determination was made during the rigor of intermit-
tent fever, the carbonic acid excreted was two and a half times the normal
amount; an excess so enormous that it was undoubtedly due, in great part,
to the muscular movements which attended the chill.

Although we cannot consider these figures as absolutelv accurate, they
indicate clearly that in human beings, as well as in animals, fever is char-
acterized by increased oxidation, and apparently that, as a rule, in man tlie
excess of oxidation is greater than in the experimental fever of animals.
This was to be expected, as it is difficult to produce experimentally in animals
anything approaching in intensity the well-marked fevers of human beings.

As the result of these laborious researches we may consider it established
that increased oxidation is a part of the fever process. It has been claimed
that this augmented oxidation is simply the result of the elevation of tem-

" Leyden and Frankel: Virchow's Archiv, Bd. 76.

310 CAliTWRIGHT LECTURES

perature, but it can be proven tbat this is not true. Pfliiger has demon-
strated that the processes of oxidation are more active at high than at low
temperatures of the body, and he has also established the increment of oxi-
dation which corresponds to each degree of rise of temperature. By means
of these data Finkler has computed tliat in guinea-pigs the febrile elevation
of temperature of 1° C. could cause an increase of the absorption of oxygen
of only 3.3 per cent. Moreover, Lilienfeld found decided increase in the
processes of oxidation before there is any marked elevation of temperature,
and all the experiments have rendered it quite evident that there is no such
relation in fever between the height of the temperature and the energy of
oxidation, as would be expected if the augmented oxidation were merely the
result of the increased temperature.

There is no reasonable doubt that the more energetic oxidation which we
find to be an essential part of the process of fever indicates increased pro-
duction of heat. Exactly what amount of heat production corresponds to
the increased oxidation we cannot know until the kind and the quantity of
substances oxidized in fever have been determined. It is to be regretted that
no experiments have been made in wliich tlie amount of nitrogen excreted
has been determined at the same time with the estimation of the oxygen
absorbed, and of the carbonic acid discharged. These data would enable us
to form some estimate, although not an accurate one, of the amount of heat
production corresponding to the oxygen absorbed, unless very different laws
from those in health control the oxidation processes of fever.

llention has already been made of the importance of determining in fever
the respiratory quotient, or the ratio between the carbonic acid discharged
and the oxygen consumed. A few words will make this clear. It is well
known tliat under ordinary circumstances in health not all of the oxygen
consumed reappears in the carbonic acid discharged. This indicates that
a part of the oxygen absorbed is used in other oxidations than those result-
ing in the production of carbonic acid. According to the extent of these
other oxidations, therefore, the respiratory quotient must vary. It is prob-
able that these oxidations, of which carbonic acid is not a product, result at
least in part, in the formation of water, which is, therefore, one of the ex-
cretory products of the body, as has been urged especially by Austin Flint,
The influence of various circumstances upon the respiratory quotient has
been studied, but what especially concerns us here is tliat in hunger this
quotient sinks, which is to be expected from the fact that in this condition
almost exclusively fats and proteids are oxidized. We evidently possess in
the determination of the ratio of carbonic acid discharged to the oxygen con-
sumed a means of reaching a conclusion as to a cardinal point in the path-
ology of fever, viz., whether the processes of oxidation in fever conform

GENERAL PATHOLOGY OF FEVER 311

to the laws which govern them in hoaltli, and particularly whether, as has
been often asserted, unusual or incomplete products of oxidation are formed
to any considerable extent in fever. Colasanti and Lilienfeld found that
the respiratory quotient in their fevered animals did not vary from that of
healthy animals under similar nutritive conditions. Finkler observed that
the respiratory quotient fell in fever somewhat more rapidly than in hunger,
and this he explains by the more active oxidation in fever. All three ex-
perimenters reached the conclusion that the substances oxidized are the same
in fever as in health, and that other than the normal products of combustion
are not formed in fever in any considerable amoimt. That the metabolism
in fever does differ in at least one important respect from that in hunger, is
evident from the excessive amount of urea excreted in fever, but considerable
variations in the disintegration of albuminous material may occur without
much change in the respiratory quotient.

The only determinations of the febrile consumption of oxygen and dis-
charge of carbonic acid in man are those of Wertheim and of Regnard. Both
investigators found a decided diminution of the respiratory quotient. The
method employed by Wertheim was so defective that no confidence can be
placed in his results. The experiments of Regnard " are presented with great
neatness, but his results on other points differ so much from those obtained
by trustworthy physiologists and by better methods, that we cannot accept
his conclusions as to respiratory quotient in fever without confirmation.
Regnard found in all fevers which he studied a most marked diminution of
the respirator}' quotient. If this were true it would follow that in fever a
much larger part than in health of tlie oxygen consumed is employed in
other oxidations than those j'ielding carbonic acid. This would confirm the
widely accepted belief that water and products of incomplete oxidation are
formed in excessive amount in fever.

From the unfortunate discrepancy of these results it is evident that the
knowledge which we now possess of the processes of oxidation in fever is
not sufficient to enable us to form from tlieni an accurate estimate of the
heat production. In hunger, from one-fourth to one-third of the absorbed
oxygen is available for combination with hydrogen to form water, the re-
mainder uniting with carbon to form carbonic acid (Regnault and Reiset).
If in fever the same ratio exists, then the excess of heat production would be
proportionate to the excess of oxygen absorbed, assuming that the substances
oxidized are the same in both conditions; if, however, as Regnard's experi-
ments indicate, a larger proportion of oxygen is available in fever for the
oxidation of hydrogen, then the increment of heat production would be still

"Regnard: Recherches Exp. sur les Variations Pathologiques des Combustions
Respiratoires. Paris, 1878.

313 CARTWRirjIIT LECTURES

greater, for the same amount of oxygen produces more heat when employed
in the oxidation of hydrogen than in that of carbon. It is also to be con-
sidered that the same quantities of hydrogen and of carbon in their oxida-
tion yield varying amounts of heat according to the chemical compounds in
which they are contained, and we cannot say positively whether the com-
pounds oxidized are the same in fever as in health under like conditions of
nutrition. Upon the whole the weight of evidence is in favor of the view
that the excess of heat production in fever is approximately proportionate
to the increase in the consumption of oxygen, but it would be ra.sh to assert
this positively. It is evident that in fever ordinarily a much smaller amount
than in health of the energy resulting from chemical processes is transformed
into external mechanical work, so that relatively more remains in the form
of heat.

In connection with this discussion of the possibility of unusual sources of
heat in fever may be mentioned an hypothesis which has been advanced with
much ingenuity by Dr. Ord." This hypothesis is based upon the assump-
tion, which is probable enough, that there are in the body chemical processes
in which heat energy is transformed or rendered latent. These processes are
thought to be chiefly those concerned in the building up of tissue. It is
argued that inasmuch as the construction of tissue is manifestly in abeyance
in fever, the amount of heat in the body may be increased not only by dis-
integrative processes, but also by "the persistence in the form of heat of
energy which sliould have taken anotlier form." Tliat these building up
processes influence decidedly the amount of heat produced in the develop-
ing ovum has been demonstrated by d'Arsonval's calorimetrical determina-
tion that the egg during incubation absorlis heat, notwithstanding tlie con-
sumption of oxygen and tlic excretion of carbonic acid. This fact, which
might have been predicted, certainly does not justify us in refusing to attiuli
any calorimetrical value to tlie determination of the respiratory gases and
the urinary nitrogen. From the little we know of these constructive proc-
esses in human beings we should infer that the amount of energy in the form
of heat which they appropriate bears only a very small ratio to the total heat
energ)' set free by heat-producing processes, so tliat their cessation would not
bring a large increment to the heat of the body. Moreover, these construc-
tive processes are also in abeyance, although doubtless to a less extent, in
starvation, with which experimental fever is usually contrasted as regards
heat production and heat loss. It is not probable that any extraordinarj-
difl'erence in the behavior of the processes of tissue-building in fever and in
starvation can occur without affecting the respiratory quotient. For the
present, therefore, we caDnot attach any great importance, so far as the

"Ord: British Medical Journal, 1885, II.

GENERAL PATHOLOGY OF FEVER 313

increase of heat energy in fever is concerned to the inactivity of heat-ab-
sorbing processes.

We have gone over now the evidence which, in my judgment, establishes
the fact that there is increased production of heat in fever. The same con-
clusion is reached also by the study of the loss of heat from the body in
fever. That fever is accompanied by increased production of heat and by
more active combustion, has been in all ages the belief of the majority of
physicians. This belief, however, has been rather instinctive than based
ujjon actual demonstration. It has been contested by investigators of great
ability, and on the ground of scientific observation. For these reasons, and
on account of the importance of the subject, it has seemed to me desirable to
present to you tlie exact evidence, although many of its details, I fear, may
have wearied you. We have learned, moreover, certain facts concerning
febrile thermogenesis which the mere ol>servation of fever patients does not
render so apparent. We have found that there is no definite relation between
heat production and the height of the tempterature, so that we may have
excessive thermogenesis with low as well as with high temperatures. There
appears to be, however, a relation between the stages of fever and heat pro-
duction, this being in spite of remarkable fluctuations greatest in the initial
stage, and least in defen'escence.

Although for reasons which have been mentioned, and otliers might have
been adduced, we can attach hardly an approximative value to figures which
purport to give the actual heat production in fever, still, unless far more
serious errors than seems possible in here in the methods of direct and of
indirect calorimetry, we can draw one important conclusion. This is that
while an individual in fever produces more than he would in health under
similar conditions as to food and muscular movements, he does not produce
necessarily in fever more heat than he would in health on a full diet. And
it is certain that he usually produces far less heat in fever than he often does
under circumstances which normally increase heat production, such as a
cool environment and muscular exercise. That one in health, with little or
no change of temperature, may produce twice or more the quantity of heat
which he produces in fever, makes it plain that it is impossible to explain
febrile rise of temperature simply on the basis of increased thermogenesis,
or what probably comes to the same thing, of increased oxidation. That in
health vastly increased heat production may occur with comparatively little
change of temperature is, of course, due to the fact that the dissipation of
heat is proportionately increased. It is self-evident, and, so far as I know,
has never been disputed that in fever the equilibrium is so disturbed that
heat loss does not correspond to heat production as it should in healtli.
This disturbance of equilibrium can be brought about in various ways, and
23

314 CARTWRIGHT LECTURES

it is only by the determination of the actual lieat production and heat loss
in fever that we can say in what direction the balance is disturbed.

We have found that the production of heat is increased in fever when the
comparison is made with like conditions of nourishment and of environment.
It is obvious that the total loss of heat cannot equal the total production of
heat durinjj the period of febrile rise of temperature.

As is well known, most of the heat of the body is liberated from the skin
and from the lungs ; from the former by radiation and conduction and by the
evaporation of moisture, and from the latter by evaporation of moisture
ajid warming the respired air. It has been estimated that in man about
eighty per cent of the total heat dissipation is from the skin.

The method of direct calorimetrj-, already described, has been applied
only to animals for the determination of the total heat loss in fever. Here
Wood's experiments are the best which we possess. Leyden and Liebermeis-
ter have furnished calorimetrical data which, although unsatisfactory m
many respects, indicate the general direction of febrile heat loss in human
beings. All of these experiments show that more heat is dissipated in fever
than under like conditions in health. The fluctuations of lieat loss during
a febrile paroxysm are so great that the statement of an average for the
entire period has little significance. Such an average, according to Wood's
results on fevered dogs, would fall between twenty to thirty per cent excess
of heat loss as compared with the loss in health under like conditions of food.
The dissipation of heat in fever, however, may be at times more than double
the normal aniomit, and again may sink below the norm. We have not
sufficiently accurate estimates either of the total amount of heat produced
or of that dissipated during a febrile attack to enable us to strike a balance
between the two. Some persons have been so impressed with the large
amount of heat lost during certain periods of fever, that they have concluded
that there must be far greater excess of heat production than previous in-
vestigations have sho\^^l to he proba!)le. They suggest that there are sources
of febrile heat of which at present we have no idea. Such conclusions seem
to me quite unwarranted, when we consider the behavior of heat-loss, not for
a limited time but throughout the dill'ercnt stages of a paroxysm of fever.
We have already seen that we ol)tain no satisfactory conception of febrile
production of heat unless we follow it during the stages of fever, and this
is no less true of heat dissipation. The observation of the condition of the
skin as regards temperature and moisture must in all ages have afforded an
insight into the general behavior of heat dissipation during the different
periods of fever. It does not require any instruments of precision to make
plain the fact that a cold, dry skin, suih as we obscn'e during a febrile chill,
liberates less heat than normal, or that a hot, moist skin, such as we are

GENERAL PATHOLOGY OF FEVER 315

likely to find at the defenescence, loses more lieat tlian normal. Not quite
so evident is the direction of heat loss duriaig tlie hot .stage or acme of a
febrile paroxysm or fastigium of a continued fever. Here the skin usually
appears liot and dry. The ordinary impression that more heat than normal
is dissipated during this stage is supported by calorimetrical experiments.
There can be no doubt that the elevation of the cutaneous temperature which
we obsene in the hot stage of fever causes an increa.se in the amount of heat
lost by radiation and conduction. Similar elevations of cutaneous tempera-
ture in health, sueli as those caused by muscular exercise, are accompanied
by increased moisture of the surface. Not only is visible perspiration usually
absent during the hot stage of fever, l)ut the invisible perspiration is, as a
rule, relatively although not absolutely diminished, as Leyden has shown.
The dryness of the skin, therefore, is a factor which in the hot stage of a
fever tends to lessen heat dissipation. Clinical observation, however, shows
that fevers differ markedly from each other as regards perspiration during
the hot stage, the skin being sometimes bathed in perspiration without any
depression of temperature. It would undoubtedly be of great interest to
possess trustworthy data as to the exact loss of water from the surface of
the Ixjdy in different fevers and at different stages of fever. We cannot place
much reliance upon the indications afforded by Weyrich's hygrometer, which
has been repeatedly used for this purpose. 3Iore is to be expected from the
method employed by Peiper " in studying insensible perspiration under
physiological conditions.

The general impressions regarding febrile loss of heat derived from clinical
observations, are supported by calorimetrical experiments. The dissipation
of heat is least during the initial stage of fever, and greatest during the
period of defervescence. During the hot stage or fastigium heat dissipation
exceeds the normal, but usually, on account of the dryness of the skin, not
so much as one might infer simply from the impression of heat received by
tlie hand when placed upon the skin.

During the initial period the loss of heat, although on the average less
than in the following stages, is usually greater than normal. If, however,
the rise of temperature be rapid the heat loss falls below the normal amount.
As tliere is now increased production of heat, there is evidently a glaring
disproportion between the two factors, heat production and heat loss, and
under these circumstances the febrile attack is likely to be ushered in by a
chill. During the febrile chill all the efforts of nature combine to produce
in the shortest time the greatest possible elevation of temperature. Not
only is heat loss reduced to a minimum, but heat production is excited to
the utmost.

"Peiper: Zeitschr. f. klin. Med., Bd. 12.

316 CAKTWRIGHT LECTURES

During the period of defervescence, on the other hand, the relation be-
tween heat loss and heat production is reversed. This is, of course, most
apparent when the fever terminates by crisis with rapid fall of temperature.
Tiien the loss of heat is excessive, being sometimes threefold that in the
normal state, and the production is relatively and often absolutely dimin-
ished.

It is of importance to remember that there are continual and irregular
fluctuations in the dissipation of heat during the different stages of fever.
These fluctuations bear no definite relation either to the momentary produc-
tion of heat, or to the height of the internal temperature. We deal in
ordinary life so much more with units of temperature than with units of
heat tliat it is difficult for us to keep constantly in mind the fact that no
inference can be drawn as to the height of the internal temperature from
the knowledge of the momentan,- heat production and heat loss. If the heat
loss fall behind heat production the temperature of the body rises, and it can
remain at this elevated point with either diminished or increased heat pro-
duction so long as the heat loss equals heat production.

No correct conception of the condition of the heat-regulating mechanism
in fever can be obtained without taking into consideration these irregular
variations in the discharge of heat, and it is a merit of Senator and his
pupils to have emphasized particularly this point. These variations are
made apparent not only by calorimetric measurements and direct observa-
tion, but also by the studies which have l)een made of the cutaneous tem-
perature in comparison with the internal temperature in fever. Hankel's
law that the difference between the t«nperature in the axilla and that of the
surface of the body in the febrile condition is less than in the normal con-
dition manifestly does not hold for the chill, in wliich it has been proven
that the superficial temperature fails while the internal temperature rises.
Jacobson, Wegscheider, Schiileiu," find that there constantly occur in the
course of most fevers changes of the superficial temperature, which stand in
no relation whatever to alterations of the internal temperature. Schiilein
thinks that he has discovered some facts in this regard which are available in
diagnosis. However this may be, these observations indicate that contrac-
tion and dilatation of the cutaneous vessels are constantly occurring, and
without any regularity, in fever. These irregular variations in the calibre
of the bloodvessels are also apparent to the eye in the vessels of the rabbit's
ear during fever. When it is considered, furthermore, that these irregulari-
ties of cutaneous circulation vary decidedly in different situations, no further
proof is needed that the mechanism which regulates the discharge of heat
from the surface of the body is profoundly disturbed in fever.

"Jacobson: Virchow's Archiv, Bd. 65. Schulein: /bi<J.. Bd. 66. Wegscheider:
Ibid., Bd. 69.

GENERAL PATHOLOGY OF FEVER 317

These alterations in cutaneous circulation are such striking phenomena
that it is perhaps not surprising that two great medical autliorities should
have based upon them exclusively theories of fever, Traube assuming excita-
tion and Marey paralysis of vaso-motor nerves as the primal element in fever.
AVe need not discuss these theories, now generally abandoned in their ex-
clusive form. From what has been said concerning the loss of heat in fever,
it is evident that we cannot explain febrile rise of temperature solely by the
behavior of heat dissipation any more than we can explain it solely on the
basis of increased heat production. In rejecting Traube's theory that fever
is the result solely of retention of heat we must still recognize the fact that
decrease in the dissipation of heat, at times absolute, at other periods relative,
is a factor of the utmost importance in the febrile process.

From whatever point of view we consider the question we cannot avoid
the conclusion that it is the mechanism which controls the relation of heat
production to heat loss, which is disturbed in fever.

Heat production is increased in fever, but if the regulating mechanism
were normal, then tlie discharge of heat would be proportionately increased
and the temperature not be materially ailected. Nor would the force of this
argument be changed if febrile thermogenesis were twice as energetic as we
suppose it to be.

The loss of heat is increased in fever, so that on this ground alone we
should be obliged to assume increased heat production. But, even if it were
proven tliat heat dissipation is diminished, as has been recently claimed
again by Rosenthal," and that fever is the result of heat retention alone, it
would still be necessary to admit that the regulating mechanism is at fault,
for Pfliiger has demonstrated that when this is normal, clianges in the tem-
perature of the skin are attended by such changes in heat production that
the internal temperature remains within wide limits unaltered.

I repeat then that the conclusion is forced upon us that the fever-produc-
ing agents must act either directly or indirectly upon the mechanism regu-
lating the harmonious relation of heat loss to heat production.

That the heat-regulating mechanism, although profoundly disturbed, is
not entirely paralyzed in fever, is proven by the effect of heat and cold upon
fevered individuals. Although Colasanti believed that his fevered guinea-
pig had lost all power of heat regulation under varying external tempera-
tures, a similar conclusion has not been reached by others who have investi-
gated this question.

We can best describe the condition of heat regulation in fever as unstable
or ataxic. External cold stimulates to some extent the heat production of
an individual in fever, but by no means as much as it does in health. A

"Rosenthal: Deutsche med. Wochenschrlft, 1888.

318 CAK'TWIMIJHT J.ECTURES

person in fever is not able to maintain bis bodily temperature under tbe
influence of beat and cold to tbe same degree that he can under normal con-
ditions. Liel>ermeister, as is well known, held that beat regulation in fever
is simply adjusted for a biglier point, although be admits not perfectly
adjusted. Experience shows that this .so-called adjustment is so unstable
tiiat it does not seem proper to compare it with that to normal temperatures
in health, so that it is not clear what deep meaning lies in Liebermeister's
idea.

We cannot imagine tbe beat-regulating mechanism to be other than a
nervous one.

Some years ago this was a!)out as far as tbe theory of tbe mecbiuiism of
fever could be carried. All paths led to this mysterious nervous apparatus,
and beyond this nearly all was speculation. We stood, as has been said,
before imposing processes veiled in the deepest obscurity. Since then tbe
veil has been lifted here and there and we have caught glimpses of the
nature of these processes. I refer particularly to tbe results of researches
which have brought to light a more immediate and direct dependence upon
nerve energy-, than had been supposed, of chemical processes concerned in tbe
disintegration and construction of tissue, and tlierefore, in the production
of heat.

With one side of the nervous mechanism concerned in temperature regu-
lation, the classical investigations of Claude Bernard have made us tolerably
familiar. This is the vaso-motor nervous apparatus presiding over the
circulation of blood in the superficial parts of the body, and thereby con-
trolling in great measure the discharge of heat. That tbe important part
taken by the perspiration in the dissipation of heat is likewise under nervous
influence, has been demonstrated by Luchsinger. Tbe facts concerning this
side of tlie regulation of heat are too well known to require elucidation on
this occasion.

Heat regulation, however, is effected not only by variations in tbe elimina-
tion of heat, but also by changes in the production of heat. Familiar as the
fact is, it can never cease to arouse our admiration that the temperature of
the body remains the same in cold and in warm atmospheres. ^laii has be-
come so dependent upon clothing that in the naked condition his capacity
of preserving his normal temperature in a cold environment is much less
than that of most animals. Ptliiger has demonstrated that tbe iieat regula-
tion under varying external temperatures is accomplished by changes both
in iieat production and in beat loss, so that in a cold atmosphere more heat
is produced and in a warm atmosphere less heat, provided the external tem-
perature is not so high or so low as to make it physically impossible to pre-
serve the body temperature. It is evident that this is tbe most rational and

GEXERAL PATHOLOGY OF FEVER 319

economical method of retaining the internal temperature of the body. To
regulate tlie body temperatxire simply by variations in the discharge of heat,
as was fonncrly supposed to be the method, would be, as has been said, like
regulating the temperature of our rooms summer and winter by opening and
shutting the windows without controlling the source of heat.

A heat-producing or thermogenic apparatus, therefore, is no less a part
of tlie heat-regulating mechanism than is the heat-discharging or thermo-
lytic apparatus, to use the terms employed by Foster. As the thermogenic
apparatus is less generally understood it is not permissible to dismiss its
physiology in this connection so brietiy as I have the thermolytic, although
our knowledge of the former is very imperfect.

I can assume that the convincing reasons are known to you which have
led physiologists to conclude that most of tlie animal heat is produced in
the muscles and tlie glands, and that the muscles have the larger share in this
function. It is also well kno^m that stimulation of secretory and motor
nerves causes not only visible physical alterations in the glands and muscles,
but also production of heat. This sort of dependence of heat production
upon innervation has been long admitted. It may, however, not be so gener-
ally known that there are reasons to believe that nervous impulses control
chemical changes which result in the production of heat independently of
visible physical alterations of the tissues; in other words, that heat produc-
tion or therniogenesis is at least in considerable part under the immediate
and direct control of the nervous system. The idea is not a new one, and
was advocated especially by Claude Bernard. Recent discoveries, however,
have given it unexpected support.

This subject of the relation of innervation to thermogenesis is most perti-
nent to the pathology of fever, but it is essentially a physiological one, and
as I wish to confine to a single lecture what I have to say concerning the
theory of fever, it is impossible for me to do more than summarize tlie most
essential points belonging here. This I can do the more readily as Dr.
MacAlister," in his admirable Goulstonian Lectures on the " Xature of
Fever," which were delivered last year, lias clearly and forcibly presented
the main facts.

The larger part of these facts relates to the chemical changes and heat
production of muscles under varj'ing conditions.

That a large part of the chemical changes in a muscle in the condition
which we call repose is under the influence of the nervous system, is made
apparent by the great diminution in its consumption of oxygen and forma-
tion of carbonic acid, which follows the separation of the muscle from all
connection with the central nervous system. This is conclusively shown by

^•MacAlister: The Lancet, 1887, I.

320 CARTWRIGHT LECTURES

the experiments of Bernard, Pfliiger, von Frey. and others. It is, of course,
possible, and it has generally been supposed that under these circumstances
it is simply the withdrawal of motor impulses which lowers the heat-produc-
ing energy of the muscle.

Far more suggestive as regards the point under consideration are tlie re-
sults of investigation which have been carried on in Ludwig's laboratory by
Meade Smith, ^MacAlister, and Lukjauow. These experimenters have shown
that heat production and contraction are in a measure independent proper-
ties of the muscle. By various influences the thermogenic property may be
so impaired that a stimulus causes contraction with scarcely any develop-
ment of heat. The laws governing the restoration and the fatigue of the
thermogenic function differ from those controlling the mechanical function.
These researches, upon which I here only touch, have made it extremely
probable that there are in the muscle chemical processes resulting mainly
in the production of heat and chemical processes causing mainly contraction,
and that these processes, although coordinate, are not identical. A new
light is shed upon the meaning of the term chemical tonus of muscle, which
has for some time been used by some physiologists. Great caution is prop-
erly exercised by Ludwig and his pupils in the interpretation of these inter-
esting results. They do not infer from them, necessarily, the existence of
so-called thermic of calorific nerves. They suggest that it is possible to
explain the phenomena upon the supposition that there are in the muscle
two kinds of material, thermogenic and contractile, and the nervous impulses
acting upon these may pass through the same set of nerves.

Proof of the existence in connection with muscles of thermic in distinc-
tion from motor nerves, would be afforded if we could succeed, after paralvsis
of the motor nerves, in exciting by nerve stimulation the thermogenic func-
tion of tlie muscle. AVe possess, in curare, a drug which paralyzes the termi-
nations of the motor nerves. Meade Smith attempted by ib* aid to deter-
mine whether possible thermic nerves may be differentiated from motor,
but he reached no positive conclusion on this point. There are. however,
on record some observations which suggest the possibility that in moderate
doses curare may leave intact thermic nerves after the suspension of the
function of motor nerves. When an animal is profoundly under the influ-
ence of curare the internal temperature falls, and the processes of oxidation
are greatly reduced. The animal is no longer able to resist the changes of
external temperature, its own temperature rising and falling Uke that of a
cold-blooded animal when exposed to heat or cold. This effect of curare
poisoning is another proof of the dependence of heat production upon nervous
influences. Claude Bernard in his early researches on the action of curare
noted elevation of ten"iperature soon after its administration. Voison and

GENERAL rATHOLOGY OF FEVER 321

Liouville " observed after subcutaneous injections of curare in man rigors,
perspiration, headache, and elevation of temperature to 104.7° F. They
attribute to curare the power of producing all of the essential phenomena of
fever. Fleischer " noticed in dogs and in rabbits rise of temperature after
curare injections, and tlie same was obsen^ed in a rabbit in one case by
Hogves."" Recently Mosso" claims that an animal may be placed so far under
tlie influence of curare as to paralyze completely the voluntary muscles, and
tlie internal temperature either remain normal or rise. He infers that these
moderate doses of curare, althougli sufficient to paralyze the motor nerves,
must have left intact the thermic nerves. That rise of internal temperature
is not due to retention of heat, he thinks is evident from the normal or ele-
vated temperature of tlie skin. Mosso is strengthened still further in his
conclusion as to the existence of thermic nerves, by finding that after com-
plete paralysis of tlie motor nerves by curare injections of str\-chuine cause
an elevation of rectal temperature, which may amount to three degrees centi-
grade. Under these circumstances strychnine produces no spasms or other
visible mechanical effect upon the muscles. Mosso brings forward a num-
ber of other experiments (decidedly open to criticism) intended to demon-
strate the existence of nerves directly controlling heat production, but tliose
whicli I have mentioned are by far the most striking. It seems to me that
the natural interpretation of these experiments is in favor of the view that
there are nerves controlling heat production in the muscle distinct from
motor nerves. Far more conclusive as to this point than thermometric ob-
servations would be calorimetric experiments determining the heat produc-
tion of animals under varying doses of curare.

• This whole line of experimentation directed toward the differentiation of
the mechanical and the chemical functions of muscle is certainly most sug-
gestive, but so long as the interpretation of the results is not perfectly clear,
we should be very guarded in drawing far-reaching conclusions. I cannot
refrain, however, from pointing out that, as mentioned by MacAlister, all
of these thermogenic phenomena may be found eventually to depend upon
nerves whose chief function, on the one hand, is the disintegration, the
metabolism of tissue, and, on the other hand, the restoration, the anabolism
of tissue. From the study of the electrical changes which stimulation of the
pneumogastric nene produces in the heart muscle, Gaskell concludes that
tliis nerve puts the heart in a condition of relative rest during which the
energ}' of the muscle is increased. During this period there is reason to

" Voison and Liouville: Virchow u. Hirsch's Jahresbericht, 1866, I, p. 330.

" Fleischer: Pfliiger's Archiv, Bd. II, p. 441.

==H6gyes: Arch. f. exp. Path. u. Pharm., Bd. XIV, p. 136.

** Mosso: Virchow's Archiv, Bd. 106.

322 CARTWRIGHT LECTURES

believe that the material of the muscle, which, when disintegrated, gives rise
to heat and mechanical work, is in the process of restoration. Hence Gaskell
speaks of the pneumogastric or inhibitory nerve of the heart as anabolic —
that is, it directs the restorative, fonnative, anabolic processes in the muscle.
On the other hand, the accelerator nerve of the heart induces the opposite
electrical changes in the heart muscle. Gaskell descries this nen-e as katab-
olic — that is, its stimulation causes disintegration of the muscle materials,
and liberates energ}- in the form of heat and of mechanical work. If it be
found that similar inhibitory and accelerator nerves preside over the chemical
changes in the voluntary muscles and other tissues of the body, then Gas-
kell's induction as to the existence of anabolic and katabolic nerves must be
regarded as one of the most important and profound in modem physiology.
Tliernio-excitory nerves we should then rank as katabolic, thermo-inhiliitory
as anabolic.

These investigations tending to demonstrate the independent existence
of thermogenic properties in the muscles and possibly of nerves directly con-
trolling thermogenesis, have prepared us for the consideration of the relation
of the central nervous system to the heat-producing properties of the body.
Here you will willingly permit me to confine my remarks to the more essen-
tial and best established facts, without entering into a full discussion of one
of the most perplexing subjects in the physiology of the nervous system.

The clinical basis of the doctrine that lesions of the central nervous system
influence directly the temperature of the body was laid by Sir Benjamin
Brodie, who reported the well-known case of fracture of the cervical verte-
brae and injury of the spinal cord followed within a few hours by a rise of
temperature to 111° F. measured between the scrotum and the thigh. Since
then many similar instances have been reported. It is well to remember, in
framing theories on the basis of these cases, that there are also on record not
a few instances in which apparently similar injuries of the same parts of the
spinal cord have been followed by equally striking fall of temperature.

The experimental basis for the acceptance of an influence of the nervous
system on temperature was laid by Bernard, in his celebrated experiments on
the effects of division of the sympathetic nerve in the neck. Bernard inter-
preted the increased temperature of the ear following this operation as
referable not oidy to the larger amount of lilood in the part, but also to
increased tisane metamorphosis and consequent heightened heat production.
The latter part of this interpretation is not generally accepted. It may be
said here that the common idea that an organ or tissue simply because it
receives a larger supply of blood indulges in more active metabolism is
opposed by the investigations of I*fliiger, who finds that the amount of
o.xygen taken up by the cells depends in a far higher degree upon the state

GENERAL PATHOLOGY OF FEVKR 323

of their innervation at the time tliari it does upon the supply of oxygen. The
demand of the tissues for oxygen is not increased simply because the supply
is greater. The arguments upon which Pfliiger bases this line of reasoning,
although not without opposition, would dispose of the idea that when any
considerable increase of heat ])roduction in the muscles occurs tliis can be
explained simply by vasomotor changes. I mention this here, because the
opinion has been advanced that a large part of the increased production of
heat in fever and after certain injuries to the nervous system is referable
simply to vasomotor changes in the muscles.

In 1866 Tscheschichin " published experiments which he interpreted as
indicating the existence in the brain of centers which, when irritated, moder-
ate the production of heat, and which he called heat-moderating or heat-
inhibitory centres, and in the spinal cord of centres which when stimulated
excite the production of heat, heat-excitive centres. These conclusions were
not justified by the experiments, but they have been widely accepted.

I may here say that, in this connection, I use the term heat centre as a
convenient and generally adopted one. There is a proper reaction against
the prevailing misuse of the word centre for all sorts of little understood
localization of nervous functions. It would undoubtedly be more accurate
to use some such expression as thermically active region instead of heat
centre.

It is not easy to reconcile the clinical fact tliat in Imman beings lesions
of the spinal cord may be followed at once, or in a very short time, by
extraordinary elevations of temperature with the results of experiments on
animals. That the rise of temperature in human beings is not due to inflam-
matory fever is apparent from the rapidity with which it follows the injury.
It cannot be explained by vasomotor lesions, for the paralysis of the vaso-
motor nerves accelerates the discharge of heat from the surface of tlie body.
The high temperature can be explained on Tsehesehichin's assumption. The
lesion either stimulates the spinal thermogenic centers or removes the influ-
ence of the thermo-inhibitory centres. These clinical observations are the
strongest support which has been found for the belief in the existence of
centres in the spinal cord which accelerate heat production. Complete sec-
tion of the cervical part of the spinal cord in a dog or rabbit is, under ordi-
nary conditions, always followed by a rapid fall of the internal temperature
and diminished oxidation. These varying results in man and in animals
have been explained by supposing that after section of the cervical cord, on
the one hand, the discharge of heat is increased by dilat<ition of the super-
ficial bloodvessels, in consequence of vasomotor paralysis ; and, on tlie other
hand, the production of heat is increased by withdrawal of thermo-inhibitorj-

*> Tscheschichin : Relchert iind Du Bois — Raymond's Archiv. 1866.

324 CARTWRIGIIT LECTURES

cerebral iiiipul.'^es. If, as ordinarily happens in dogs and smaller animals,
the first factor predominates then, in consequence of sinking of the internal
temperature, the heat-producing processes are so reduced that the influence
of the second factor is not manifest. The attempt has been made to test this
explanation by placing the animal in a warm atmosphere. If thereby the
heat discharge be reduced to a minimum, it is found that the internal tem-
perature of the ammal often rises more rapidly than that of a normal one
under tJie same external conditions. Here thermometrie observations are not
conclusive as to the point to be tested, for the more rapid rise can be ex-
plained simply by failure of the heat-regulating mechanism. Wood's calori-
metric experiments seem to show that there is greater heat production, under
these circumstances, in the animal with cut cord. These experiments admit
of various interpretations, but if they be regarded as establishing the assump-
tion from which we started, then it is evident that in man and in large
animals the increased heat production after injury of the cord would not be
so readily overcome by the increased discharge of heat from the surface, for,
in proportion to its volume, a large animal has less surface than a small one.
The interplay, therefore, of these opposing tendencies might cause different
results, according to the size of the animals.

Tscheschichin found that a transverse section made at the junction of the
pons and medulla oblongata is followed, in a short time, by rise of internal
temperature. As the superficial temperature is also elevated, he concludes
that tliere is no retention of heat; moreover the section is made above the
dominant vasomotor centre. Wood has shown by means of the calorimeter
that after this operation there is actual increase in the production of heat.
He, as well as Tscheschichin, interprets the experiment as indicating thermo-
inhibitory centres above the lower border of tlie pons. Bruck and Giinter "
repeated and modified these experiments under Heidenhain's directions.
Out of seven cases in which they separated the pons from the medulla, they
observed in only two rise of temperature ; of eleven cases in which they punc-
tured the pons with a needle, in five they noted increased temperature.
Heidenhain thinks these experiments indicate heat-exciting rather than
heat-moderating centres, and it must be admitted that the evidence is not
conclusive in support of either view.

By far the most interesting and conclusive experiments, showing the
influence of the central nervous system on thermogenesis are those of Isaac
Ott, followed by Eichet, Aronsohn and Sachs, Eaginskv, and Girard." The

"Bruck and Giintlier: Pfliiger's Archiv. Bd. III.

"Ott: Journal of Nervous and Mental Diseases. April. 1SS4: Medical News,
July, 1885. Therapeutic Gazette, Sept., 1887. Ricliet: Arch, de Ph>-s.. 1SS4.
Aronsohn and Sachs: Pfluger's Archiv, Bd. XXXVII. Baginsky and Lehman,
Virchow's Archiv, Bd. CVI. Girard: Arch, de Phys., 1886.

GENERAL PATHOLOGY OF FEVER 325

observations of Ott, Eichet, and Aronsolin aud Sachs were made independ-
ently and at about the same time, but Ott was tlie pioneer. The experiments
of Aronsohn and Sachs are reported with espet-ial fulness and detail. These
investigators found that if tiie skull of a rabbit be trephined at the junction
of the coronal and sagittal suture, and a needle be passed vertically down so as
to puncture the anterior part of the caudate nucleus near its median con-
vexity, there follows a rise of temperature, which may amount to three degrees
or more, and which may persist for two or three days. The rapidity and the
duration of tliis elevation of temperature van,- somewhat with the depths of
the puncture, parts immediately beneath the caudate nucleus being also
thermically active. Puncture of the overlying cortex or medullary sub-
stance has no such effect u])on temperature. With the exception of some
increase in the frequency of the respiration and of the pulse, the animal after
puncture of the anterior median part of the caudate nucleus presents no
abnormal symptom other than the rise of temperature.

I have several times repeated this experiment and always with the result
described. That the pyrexia induced by puncture of the caudate nucleus is
not due to vasomotor changes causing retention of heat, is proven by Richet's
and Ott's calorimetric experiments, aud by the determination by Aronsohn
and Sachs that the consumption of oxygen and the elimination of carbonic
acid, and urinary nitrogen are increased. Aronsohn and Sachs and Girard
find that electrical stimulation of the anterior median part of the caudate
nucleus causes the same thermic phenomena as the puncture, and they, there-
fore, conclude that this region contains a thermo-excitor heat centre. This
is the natural interpretation of their experiment, although Baginsky and Ott
regard the centre as thermo-iuhibitory on grounds which cannot be con-
sidered convincing.

Ott claims that there are four cerebral heat centres, one about the corpus
striatum, the second in the caudate nucleus, tlie third in the anterior inner
end of the optic thalamus and the fourth near the median line between the
optic thalamus and the corpus striatum. The greatest rise of temperature he
found after injury of the thalamic centre.

Xo adequate demonstration has been afforded of any influence of the
cerebral hemispheres upon thermogenesis. Corin and van Beneden " find
that pigeons, after removal of their cerebral hemispheres, exhibit no change
of temperature, no failure of the heat-regulating mechanism, and no alter-
ation in the excretion of carbonic acid.

I have endeavored to present to you the main physiological facts bearing
uix)n the relation of the nervous system to thermogenesis. It must be ad-

^^ Corin and van Beneden: Arch, de Biol., 1887.

326 CARTWRIGHT LECTURES

niitted that wo are left to surmise as to the interpretations of many of the
facts, and jmrticuhirly as to their connection with eacli other. Hut certain
important points come out clearly. We have found evidence of the existence
in the hodv of chemical ]irocesses resuUin-; chiefly in the production of heat
energy. We have learned that these processes are under the direct control
of the nervous system, and possihly of nerves distinct fnun those now recog-
nized as motor or secretory. We have seen that there are re^'ions in the
central nervous system which are douhtless in some way connected with these
nerves, and through them control the chemical processes resulting in the
production of heat.

The hearing of these facts upon the theory of fever is evident. The study
of heat production and of heat loss in fever has led ns, by arguments which
need not he repeated, to the conclusion that the pyrogenic agent must in some
way act upon the heat-regulating mechanism. The study of this mechanism,
more particularly of its thermogenic side, affords some insight into the
manner in which the fevpr-jiroducing agent may affect the regulation of heat.
The main difficulty iu the neurotic theory of fever has hcen to understand
how by any action of the fever-producing agent directly upon the nervous
system the chemical processes leading to heat production could he stimulated.
I have dwelt thus at length upon the innervation of thermogenesis to show
that this difficulty has been in great part overcome.

To some it seems more reasonable to suppose that the pyrogenic agent
circulating in the blood acts directly upon the tissues, altering and stimu-
lating their chemical changes. This is the haemic theory, which, in some
form, has always stood over against the neurotic tlieory of fever. Although
it may at first glance appear simpler, the haemic theory is really the more
complicated, for it has already been set forth that we cannot explain fever
pimply by increased heat production, so that even if tlie primary effect of the
fever agent were upon the heat-producing processes there must be a secon-
dary influence upon the nervous system, for heat dissipation is no less dis-
turbed than heat production.

If an animal be thoroughly curarized so that no impulses from the nervous
centres can reach the muscles, the great heat producers, then it is found to
be impossible to produce febrile elevation of temperature by the injection of
pyrogenic agents. This fact, first demonstrated by Zuntz, is justly held to
weigh heavily in favor of the neurotic theory of fever.

Contrary to the results of Murri," I have not been able to induce rise
of temperature or check its fall by the injection of pyrogenic agents into
the jugular veins of dogs whose spinal cords have been cut in the lower

"Murri: Teoria della Febbra, Fermo, 1874.

GENERAL rATHOLOGY OF FEVER 327

cervical region. In these experiments I have employed various pyrogcnio
agents, and especially pepsin and papoid. One specimen of the latter wliich I
used possessed very striking pyrogenic properties.

The pyrexia produced by puncture of the caudate nucleus in the manner
already described, possesses all of the essential properties of fever, regarded
as abnormal elevation of temperature. In this experimental condition there
are increased production of heat, increased dissipation of heat, excessive
elimination of urea and of carbonic acid, and excessive absor)itiou of oxygen.
The breathing and the pulse are increased in frequency. The elevation of
temperature (usually after a brief fall) begins within half an hour after the
puncture, attains a febrile height and persists sometimes for days. As no
observations exist as to the heat regulation of these animals, I have made
experiments on rabbits after puncture of the caudate nucleus, by placing
them in a cold environment and in a box heated to various temperatures,
and I find that their power of temperature regulation is less than that of
normal animals.

These animals, in a word, present all of the essential symptoms of fever,
and I do not know why we should not call the condition fever. If so, we must
admit that injury to a circumscribed definite region of the brain is capable
of causing fever. This experiment, therefore, is of the greatest importance
in support of the neurotic doctrine of fever. It indicates, of course, that we
may have fever of purely nervous origin, without any pyrogenic agent in the
blood. This experimental evidence is supported by the clinical cases col-
lected by White in " Guy"s Hospital Reports," 188-1. It is to be hoped that
by careful thermometrie study of focal brain and cord lesions a more accu-
rate idea may be reached than is now possible of the topograjihy of the ther-
mically active regions in the central nervous system of man.

Admitting the dependence of fever upon the nervous system, I do not
regard as particularly profitable with our present knowledge tlie discussion
as to whether febrile thermogenesis is excited by the withdrawal of thernio-
inhibitory impulses or by the stimulation of thermo-excitorj' nerves or nerve
centres. If we regard, and there are forcible arguments for doing so, possible
heat-inhibitory nerves as anabolic, and the heat-exciting nerves as katatx)lic,
then inasmuch as tlie formative or anabolic processes are manifestly in
abeyance in fever, we can reasonably infer that the function of the heat
inhibitory nerves or centres is impaired. The phenomena of the febrile chill
in which both the contractile and the thermogenic properties of muscle are
stimulated, speak strongly in favor of direct irritation of the heat-exciting
nerves in fever. We might infer, therefore, that both sets of nerves or nerve
centres are affected.

328 CAKTWKilJilT LECTURES

But niv aim in this letturo lias l)cen not so much to construct a theory of
fever, a theory which, although it may be useful, must necessarily be largely
Bpeculative if it be coherent and rounded but to bring before you the main
facts concerning heat production, heat loss, and heat regulation in fever,
and to point out the physiological basis on which their solution is to be
expected.

Lecture II

THE EFFECTS OF INCREASED TEMPERATURE OF THE BODY

In the last lecture I endeavored to bring before you the main facts which
we possess bearing upon the explanation of febrile rise of temperature.
After a review of our knowledge concerning heat production, heat dissipa-
tion, and heat regulation in fever, we were led to the conclusion that neither
the changes hitherto observed in the production of heat nor those in the
loss of heat suffice to explain febrile temperatures. Such an explanation
seemed possible only upon the assumption that the fever-producing agents
act either directlj' or indirectly upon the nervous mechanism controlling the
relations to each other of the production and the discharge of heat. We
then turned our attention to the relations of the nervous system to tliese
processes, and found that the investigations of recent years have enabled us
to obtain a much clearer conception than was formerly jwssible, of the man-
ner in which the complicated heat relations in fever may be brought about
by an action upon the nervous system. We found even substantial experi-
mental basis in support of cliniial facts which show that circumscril)ed
lesions of certain parts of the central nervous system may induce directly
febrile disturbances of animal heat.

To carry the subject further, to consider whether pyrogeuic agents act
primarily or only secondarily ujwn the processes concerned in heat produc-
tion or ujjon those concenied in heat dissipation, or upon the apparatus
regulating the relations to each other of these two sets of processes, to dis-
cuss whether these agents act directly upon the central nervous system, and
if so upon what part ; or upon the peripheral nerves or their terminations,
or upon the tissues ; to follow out more fully than we have done hitherto the
themes here suggested would lead us with our present knowledge into a sea
of speculation. We should find oidy here and there a faint light of fact to
guide us. Even upon foundations as insecure as this speculations have their
legitimate uses. A good hypothesis is a most valuable incentive to scientific
work. It is not my purpose, however, to carry you witli me further in this
direction, although I realize that a single lecture has been far from sufficient
for a thorough exposition of this subject.

GENERAL PATHOLOGY OF FEVER 329

After dismissing the considerations bearing upon the so-called theory of
fever, there still remains a host of questions properly belonging to our sub-
ject. It is evidently impossible, even if it were desirable, that these lectures
should include a discussion of all of these questions. I have, therefore,
selected certain ones, partly because they seem to me of immediate interest
and partly because I have given some attention to their study.

In the present lecture I wish to present to you some observations concern-
ing the relation of elevation of temperature to otlier disorders of fever, and
as to the question. How far increased temperature is a source of danger
in fever?

Here I may repeat tliat the word fever is used as a convenient name for a
group of symptoms commonly associated together in febrile diseases. The
association of these s}'mptoms, however, is so loose that we regard only the
dominant one — the increased temperature — as the essential criterion of the
existence of fever. It Saves circumlocution to adopt this somewliat vague
and common signification of the term fever, although I think it would be an
improvement to confine the term to abnormal elevation of temperature. The
literature of fever is full of misapprehensions resulting from the various
meanings attached to the word by different authors.

All of the bodily functions may be disordered in fevers. The various
s}'mptoms or classes of symptoms which are so commonly associated as to
be regarded by many as belonging to the febrile process are, in addition to
heightened temperature, increased frequency of the pulse and other circu-
latory disturbances, increased rapidity of respiration, muscular weakness,
lessened secretions, disordered nutrition and digestion, and nervous symp-
toms.

What is the connection, if any, between these symptoms and the elevation
of temperature? What degrees of elevated temperature are dangerous to
life, and in what does the danger consist? This subject can, at least, claim
the interest that attaches to the questions of the day. The various opinions
which have been held by clinicians on these points are too well known to you
to require an historical review. I need only remind you that until within
a few years the views advocated \vith especial force for nearly thirty years
by Liebermeister have prevailed, although not without, considerable opposi-
tion. According to these views, the chief source of danger in uncomplicated
essential fevers is the elevation of temperature, and the main indication for
treatment is the reduction of temperature. Above all, it was ur^ed with
apparently convincing arguments that the weakness of the heart, which is
undoubtedly one of the gravest dangers of fevers, is the direct effect of pro-
longed high temperature, and is manifested anatomically by parenchjTuatous
or fatty degeneration of the cardiac muscle. Liebermeister sharply defined
24

330 CARTWRIGHT LECTURES

hig position when he said, " A man whose temperature measures continu-
ously 104° (40° C.) or more surely dies in consequence of the elevation of
temperature, one in a few days, anotlior after a somewhat lonijer time,
according to the resistance of the individual." " If his temperature reaches
108.5° (42.5° C.) or more, then is he irrecoverably lost.""

At the present moment tliere is a decided reaction a<rainst these views, a
reaction which in some quarters goes to the extent not only of denying tliat
there is danger in febrile temperatures which do not exceed a very high point,
but of asserting that the elevation of tem])eraturp is a benefieient provision,
a most important vis medicatrix naturae, which should not be checked by the
interference of the physician. This reaction of opinion is plainly due, in
great jiart, to the disappointment which has followed the high hopes raised
by the discovery of a number of drugs which are admirable antithermic
agents and, nevertheless, do not exert over febrile diseases that controlling
influence which had been anticipated.

These questions, you may say, are clinical ones, and nut much edification
is to be expected from their discussion by a pathologist. So far as the pro-
priety of the use of antipyretic agents or of any other mode of treatment in
fever is concerned, it is true that the decision must be reached at the bedside
and cannot and never should be controlled by the results of experimental
pathology. But an appeal has properly been made to experimental path-
ology to shed light upon such questions as the effects of heat upon the func-
tions of the whole body and of its various organs, and upon tiie causes of
parenchymatous and fatty degenerations. The arguments advanced in sup-
port of the view that all of the characteristic symptoms of fever are directly
dependent upon the increase of temperature and that high temperature is
the chief source of danger, are derived no less from experimental pathology
than from clinical observations.

Three methods have been employed to determine the effects of increased
temperature in fever : one is to study the effects of external boat upon man
and animals; the second is to examine in different fevers and in different
cases of the same fever the relation of the temperature to the other symptoms,
and to the general condition of the patient; and the third is to note the
influence of reduction of temperature upon these symptoms. Each method
has its limitations.

The condition produced by exposure to external heat, even if it be called
thermic fever, is something quite different from ordinarj' fevers, and we
cannot transfer the results obtained by this method directly to the explana-
tion of febrile phenomena. On the other hand, in the clinical study of fevers
it is very diflicult and often an arbitrary matter to separate the effects of in-

" Lieberraeister : Volkmann's Sammlung, No. 31, p. 240.

GENERAL TATHOLOGY OF FEVER 331

creased temperature from tlioso of otlier factors nearly always present.
Hence we find no agreement of opinion among physicians as to what symp-
toms or lesions in fever are referable to the heightened temperature, and what
are due to infectious or other conditions often present. Even the frequent
or constant association of certain symptoms wth elevated temperatures and
their subsidence or disappearance by reduction of temperature do not justify
us in inferring that the high temperature is the cause of the symptoms, for
both may be coordinate effects of the same cause, and the so-called antipyretic
treatment may influence other conditions as well as the temperature. As
has been frequently said of late, the high temperature may be rather an index
of the severity of the disease than a source of danger in itself.

In hyperpyrexia and in many cases of insolation there can be no doubt
that the high temperatures, as such, are the main elements of danger. But
both of these conditions have important points of distinction from ordinary
febrile processes. In hypeqiyrexia there is probably almost complete paral-
ysis of heat regulation, and we shall find that an analogous condition with
similar dangers sometimes develops in animals artificially heated. The
cases of insolation in which the high temperature is so dangerous are analo-
gous to the condition which may be produced in animals by brusque elevation
of the bodily temperature through exposure to heat, and which differs from
that resulting from more gradual increase of temperature.

The most direct way of determining the influence of heat upon the body
is to raise the internal temperature by the external application of heat.
Here we are not disturbed by the presence of other factors, such as infection,
■which render doubtful so many of the conclusions derived from clinical
observations as to the effects of high temperatures. For the solution of many
problems it is evidently irrelevant whether the source of heat be within or
without tlie body.

These experiments, if properly conducted, are calculated to shed much
light upon many questions relating to the effects of febrile temjieratures.

According to the testimony of all experimenters, a mammalian animal,
artificially heated, dies when its internal temperature reaches 111.2° F.
(44° C.) or 113° F. (45° C). Death is preceded by convulsions and imme-
diately or soon after death rigor mortis appears. At the moment of death
the irritability of the heart and muscles ceases. Death seems to be due to
heart paralysis, and the cause of this is usually set downi as heat rigor, but
this is not probable as death generally occurs at a temperature several degrees
below that at which rigor of the heart muscles appears.

It is generally argued that temperatures several degrees below those which
are fatal must exert toxic ett'ects, and this conclusion seemed to be substan-
tiated by the majority of experimenters, who found that animals whose tern-

332 CARTWUIUIIT LECTURES

peratures were artifioially raised to 105° F. (40.5° C.) or 10r° P. (41.7° C),
or even to a lower point, manifested sio;ns of illness. Tiiese latter results,
however, are opposed to those obtained by Rosenthal, and especially
Naunyn," who ]x)ints out tliat the conditions in most previous experiments
were not favorable, as the animals were generally placed in small, dark,
poorly ventilated metallic boxes. Naunyn succeeded in keeping a rabbit
alive for thirteen days with an average temperature of 10H.7° F. (41.5° C).

Following Naiuiyn's example, I have had constructed a wooden box, tliree
feet long, two feet high, and two feet broad, which fits closely within a double-
walled galvanized iron box. The wooden box is provided with a perforated
movable bottom, which allows the urine to escape. The space l)etween the
two walls of the iron box measures three inches across, and is filled with
water, which, therefore, surrounds the inner box on all sides, except at tiie
top, which is left open. The dimensions of this apparatus are .somewhat
larger than those of Xaunyu's heating-box. A folded woollen blanket was
drawn over each end of the box, so as to leave uncovered at least one-third,
and generally n.ore of the top. A rose burner placed underneath serv?d to
heat the box. At first a thermo-regulator was employed, but this was found
unnecessary, as the temperature of the room varied but little, and there was
no difficulty in keeping a sufficiently constant temperature in the box. The
experiments were made upon rabbits, and only a single one was placed in
the box at a time. Corrected thermometers were used. The temperature
of the box was taken a short distance above the bottom, and that of the rabbit
at a depth of three to four inches in the rectum. This occasion does not seem
an appropriate one to describe these experiments in detail with their pro-
tocols. I shall take another opportunity for that, and at present give only a
general account of those results which relate to the subject before us.

In the box described I have succeeded in keeping for three weeks two large
black rabbits, the one with an average rectal temperature of 107.3° F.
(41.8° C), the other wth an average temperature of 10G.6° F. (41.4° C).
The rectal temperature fluctuated usually between 105.5° F. (40.8° C.)
and 108° F. (42.2° C), scarcely ever sinking below 105° F. (40.5° C), but
occasionally rising as high as 109.5° F. (43.1° C). The temperature of the
box varied between 96° F. (35.5° C.) and 106° F. (41.1° C). The rabbits
lav most of the time stretched out, breathing very rapidly. They took their
food greedily, and did not appear ill. At the end of the experiment the first
animal was removed from the box, and appearing perfectly well for ten days
afterward it was used for another experiment ; the second animal was killed
at the end of the experiment, and presented marked fatty degeneration of

"Rosenthal: Zur Kenntniss der Warmeregulirung u. s. w.. Erlangen, 1872.
Naunyn: Archiv f. exp. Path. u. Pharm., Bd. IS.

GENERAL PATHOLOGY OF FEVER 333

the heart, liver, and kidneys. Both animals lost weight while in the box.

In these and similar experiments tlie rabbits were given only moist, green
fodder, and were allowed to drink plenty of water, which they took eagerly.
It is important for the success of the experiment that the temperature should
be gradually, and not suddenly, raised.

Different rabbits offer varying degrees of resist^mce to the effects of high
external temperature. It has seemed to me that black and gray rabbits
surpass, in this respect, white rabbits. The same temperature of the box
does not produce, in all cases, the same rectal temperature in different
animals, or in the same aniriial at different times. Xo factor is of more
importance in determining the effects of external heat than the animal's
power of temperature regulation. Failure of this power is manifested by a
sudden rise of internal temperature, which may quickly attain a point in-
compatible with life. This event may take place without any alteration in
the box temperature. The degree of internal temperature at which this
paralysis of heat regulation occurs varies in different animals. One may be
able to hold his temperature, for a short time, from further rise at as high a
point a.s 109.5° F. (43.1° C.) ; in another, after the temperature has reached
10T.6° F. (41.5° C), there may occur, without any change in the box tem-
perature, a sudden, and often fatal, elevation of temperature. In general,
temperatures between 108° F. (42.2° C.) and 109° F. (42.8° C.) may be
regarded as critical temperatures for tliese animals. One is forcibly re-
minded by these sudden and dangerous elevations of temperature of the
occurrence of hyperpyrexia in certain fevers of human beings, and there is
reason to believe that tliis, too, is caused by paralysis of heat regulation.

It seemed to me of some practical interest to determine what effect upon
the rabbit's power of resisting high temperature is exerted by exhausting
influences, particularly by anaemia. For this purpose rabbits which had
been moderately bled, and others which had been used for some other experi-
ments, were placed in the hot tox. It was found tJiat these animals are.
although not without occasional exceptions, unmistakably less resistant to
the effects of high temperatures than are robust animals. They succumb
sooner, and at lower box temperatures.

We may now consider what inferences may be drawn from these and
similar experiments as to the effects of high bodily temperatures. It seems
clear that a considerable part of the current arguments based upon experi-
ments concerning the injurious effects of high temperatures must be revised
in the light of Naunyn's experiments, and of those which I have briefly
related. Because an animal may be killed by raising its temperature to
111° F. (43.9° C), or 113° F. (45° C. ), it does not follow that an increase
of temperature up to within 4° or 5° F. of this fatal point involves danger

334 CAIiTWKKJlIT LECTURES

to life, or even any serious disturbance of the functions of the body. Al-
though experiments in liot-air chaml)ors show that in man brusque elevations
of the temperature by only a few degrees give rise t« serious symptoms,
Krishaber" found that by habituation his temperature could be raised to
10(!.5° F. (41.4° C), or"lOr.-r F. (41.8° C), without much discomfort.
As small animals generally succumb more readily than large ones to artificial
heating, it is not likely that the power of resistance in human beings is less
than that found to exist in rabbits, and there is reason to believe that it is
greater.

We cannot transfer directly to liuman beings the highest temperature at
which we found rabbits can exist without serious discomfort save increased
respiration. A rabbit's temj)erature is normally considerably liigher than
that of man, and apparently slight causes suffice to produce marked fluctua-
tions. The normal rectal temperature of the rabbits used in my experiments
was generally between 102° F. (38.9° C.) and 10:5° F. (;59.4° C). The
highest average temperature at which a rabbit was kept for three weeks in
the hot box exceeded, therefore, by 4° to 5° F. the average nornial tempera-
ture. Such an increase would not correspond to a high febrile temperature
in man. We can, however, with equal, and probably greater propriety, com-
pare this temperature with that at which death surely occurs in a condition
bordering on heat rigor. This temperature (111° to 113° F.) is prol>ably
about the same for man as for rabbits and other mammalians. From this
point of view the inference may be drawn, although, of course, with much
reserve, that human beings may tolerate temperatures of 107" F. (41.7° C),
or even higher, for a considerable time. This inference is supported by clini-
cal observations, especially in cases of relapsing fever.

As already pointed out, the condition produced by artificial heating is
not directly comparable with that in fever. In the former tiie loss of heat
from the liody is reduced to a minimum; tlie superficial temperature is
three or more degrees higher than the internal, so that the average temper-
ature of the whole body is higher than in fever with the same internal tem-
perature. We cannot say, therefore, but that man may tolerate considerably
higher internal temperatures wlien the elevation is brought alwut under
conditions in wliich the discharge of heat is not checked than when the
temperature is forced up by stopping heat dissijiation. This would be
proven if confidence could be placed in tlie enormous elevations of tempera-
ture reported by Teale and others. In these cases, however, even if authenti-
cated, it is probable tliat lieat is abnormally distributed in tlie body, and we
cannot infer that tlie internal temperature is uniformly raised to such para-
doxical heights.

"Krishaber: Gaz. M^d. de Paris, 1S77.

GENERAL PATHOLOGY OF FEVER 335

It is of tlie utmost importance to bear in mind that, as my experiments
have shown, not only do animals differ in their power of tolerating high
temperatures of the body, but this resistance may be weakened by various
depressing causes. Nothing would be more irrational than to conclude,
because one individual in a certain condition can tolerate very high tempera-
tures, another in a different condition possesses the same power. In fevers
we have various factors, particularly infection, which we may well believe
can lower the tolerance of high temperatures. That in some fevers, par-
ticularly relapsing fever, this does not appear, or only partially, does not dis-
prove that in another fever, such as typhoid or pneumonia, the system may
be placed by other factors of the disease in such a condition that even
moderately high temperatures are injurious. It does not seem to me proper
in these cases to lay, as some seem inclined to do, the sole stress upon the
element of infection. This is in all likelihood the determining factor, but
the practitioner cannot shut his eyes to the possibility that under its influ-
ence the high temperature, as such, is a source of danger to his patient.

With these restrictions I shall surely not be misunderstood when I assert
that temperatures which are ranked as high febrile temperatures do not in
themselves, independently of other factors, exert any such injurious influ-
ence as has been usually attributed to them.

Our attention up to this point has been directed to the effects of high
temperatures upon the general condition of the Iwdy. It is of importance
for the proper understanding of fever to determine the influence of heat
upon the structure and functions of the various organs. To what extent
can the febrile disorders of respiration, of circulation, of secretion, of nutri-
tion, of innervation be attributed directly to the elevated temperature?
These are questions which can be answered better by experimental methods
than by clinical observation, for the latter has to deal with the effects of heat
complicated by other circumstances whose influence cannot be accurately
determined. The one method, however, should be made to control the other.

The most striking immediate effect of heat upon an animal is increased
frequency of respiration. AVhen a dog or a rabbit is placed in an atmosphere
of 100° F. (37.8° C), it at once begins to pant and the respiration may run
up to 150° or more. The causation of this increased respiration, to which
the name heat dyspnoea has been applied by Ackermann," has been re-
peatedly investigated. Goldstein " in Fick's laboratory found that by apply-
in" to the carotid arteries tubes through which hot water is flowing the
respirations may be greatly increased in frequency. Goldstein's experiment
is usually cited as the crucial one, showing that the increased breathing is

" Ackermann : Deutsches Archir f. kiln. Med., Bd. II.
"Goldstein: Wurzburger Verhandl., 1871.

336 CARTWRIGHT LECTURES

due to the effect of the heated blood upon tlio respiratory centres in the
nifflullii oblongata. Sihler," working in the Iiit)lo{,'i(al Lal)oratory of the
Johns Hopkins University, however, has demonstrated that the increased
respiration of an animal exposed to heat is due to two causes, warmed blood
and stimulation of the skin by the heat, and tbat probably skin stimulation
is tlie more important factor. Some of Sililer's criticisms of Goldstein's ex-
periments have been met by Gad and von Mert«chinsky " wlio have made it
evident that increased temperature of the blood stimulates the respiratory
centres, or increases their irritability. Section of the vagi does not check
heat dyspnoea, so that this does not result primarily from the action of the
increased temperature upon the terminal pulmonary expansion of these
nerves. The removal of afferent impulses form the skin by section of the
spinal cord does, however, exert so marked an influence that it cannot be
doubted that heat stimulation of the skin is an important element in the
cauiJation. I have convinced myself of the correctness of Sihler's explanation
by observing that in the hot box at temperatures of 90°-95° E. (32.2''-35° C.)
rabbits often preserve their normal temperature, and still their breathing
is markedly increased, and that, on the other hand, upon taking them out
of the box the respirations may sink before the internal temperature begins
fo fall. In one striking experiment the respirations fell immediately to
about normal upon removing from the hot box a rabbit whose skull had been
trephined on each side of the median line, ajid the optic thalami punctured
with a needle.

We cannot transfer directly to human beings tlie results of experiments
on heat dyspnoea in animals, because in tlie latter respiration has a far more
important function in temperature regulation than in tlie former. To keep
cool a dog pants under circumstances when a man sweats. As heat regulation
is largely influenced by the cutaneous temperature, it is not improbable that
in man heat stimulation of the skin is less prominent than the warmed blood
acting upon the respiratory centres in increasing the frequency of respira-
tion in fever.

Inasmuch as disturbances of the heart and of the circulation in general
are among the most important symptoms of fever it is natural that much
attention should have been given to the study of the effects of heat upon the
organs of circulation. Tlie supposed injurious effects of prolonged high
temperatures in fe\er have l>een usually attributed especially to some toxic
action of heat upon the heart.

"• Sihler; Journal of Physiology, II, and Studies from the Biological Laboratory,
Johns Hopkins University. Baltimore, II.

"Gad and v. Mertschinsky: Virchow u. Hirsch's Jahresbericht, 18S1, Bd. I,
S. 197.

GENERAL PATHOLOGY OF FEVER 337

That the pulse-rate is quickened by artificially heating rabbits and dogs
has lon<; been kno^^^l. Tlie positive demonstration that this acceleration is
due to the direct action of the heated blood upon the mammalian heart itself
was first given by my colleague, Prof. Martin." By conducting through the
dog's heart, isolated physiologically by the ingenious method which he de-
vised, ^Martin proved tliat the heart " beats quicker when supplied witli
warm blood and slower wheii cold blood is supplied to it; also, that the rate
of beat depends much more upon the temperature of the blood in the coron-
ary arteries than on its temperature in the right auricle or ventricle."
These experiments make it unnecessary to recur to any action of the heated
blood upon extrinsic cardiac nerves or nerve centres in order to explain the
quickened pulse of fever. Moreover, Fick "^ found that the nervous centres
of the heart and bloodvessels are unaffected by heating the blood flowing
through the carotid arteries ip the manner adopted by Goldstein in his ex-
periments on heat dyspnoea.

Prof. Martin has kindly permitted me in this connection to mention cer-
tain unpublished results of experiments which he is now conducting upon
the effects of heat and cold on the isolated heart. As these results are perti-
nent to our subject I gladly avail myself of this privilege. The table of an
experiment which I have examined shows that the isolated cat's heart beats
regularly and more and more rapidly as the temperature of the blood is
gradually raised to 111.2° F. (44° C). At this point the beats become
irregular, but are restored to their normal rhythm by feeding the heart with
cooler blood. The temperature of about 111° F. (43.9° C.) appears to be
a critical one for the isolated heart. Above 111.2° (44° C.) to 113°
(45° C.) the pulsations tecome slower instead of quicker as the temperature
is raised. At 122° F. (50° C.) the heart's action ceased, but the heart was
made to beat again by supplying it with cooler blood, showing that the
cessation was not due to heat rigor. This interesting experiment teaches
among other things that very high temperatures may produce results differ-
ing not only in degree but also in kind from those of temperatures only a
degree or two lower.

We may consider it then established that increased frequency of the pulse
in fever is referable to the direct action of the warmer blood on the nerTO-
niuscular substance of tilie heart itself. Clinical observation of cases of fever
makes it evident that there may be and often are present other circumstances
which influence the rapidity of the heart's pulsations, circumstances which

"Martin: The Direct Influence of Gradual Variations of Temperature upon the
Rate of Beat of the Dog's Heart, Philosophical Transactions of Royal Society,
part II, 1883.

"Fick: Pfluger's Archiv, Bd. V.

338 CARTWRKillT LECTURES

in tliemselves may slow or may quicken the juilsi'. Ijarge series of statistics,
therefore, are required to brinj^ out the ratio between the pulse-rate and the
temperature in fever and even then for any fjiven temperature the maximum
and the niinimuni pulse-rates lie so far apart that the statement of the
average increase in the frequency of the pulse for each degree of rise of
temperature, such as has been computed by Liebermeister, has very little
value.

Not only is tlie pulse-rate quickened in fever, but there are often other
and more serious circulatory disturbances. In the fever produced in rabbits
by injection of the swine plague bacillus I find a reduction of the blood-
pressure measured in the carotid artery, and others have obtained similar
results in the artificial fevers of animals. The determination of the blood-
pressure in fevers of human beings by means of Basch's sphygmomanometer
has given, in the hands of different experimenters " such contradictory
results, that no conclusion can be drawn, unless it be the ver)- probable one
that the blood-pressure varies, being sometimes high, sometimes low, and
sometimes normal in fever. That the arterial tension is often reduced is
made evident by the marked dicrotism of the pulse wave. This dicrotism,
however, characterizes particularly septic and typhoid types of fever and is
absent during the chill of intermittent fever and often in exanthematous
and some other fevers, so that we cannot consider the blood-pressure and
arterial tension as having any such definite relation to fever as does the
pulse-rate.

It has been observed by Paschutin, Senator, and Mendelson,** that the
blood pressure rises with increasing bodily temperature, produced by ex-
posure to heat. Mendelson found that the pressure begins to sink as the
temperature approaches a point incompatible with life. In these experiments
the animals were subjected to rapid elevations of temperature. I find that
when a rabbit is gradually and cautiously heated in the hot box used in my
experiments, the rise of temperature is less marked, and may not surpass
even for temperatures of 107° F. (41.7° C), the normal limits of variation
which may be found in tlie blood-pressure of the same animal examined at
different times. These measurements, however, are not very conclusive,
for, as has been already remarked, rabbits which have been operated upon
do not stand well artificial heating.

T have observed that the rhythmical contractions of the bloodvessels of the
rabbit's ear arc feeble or absent when the temperature is much elevated by

"Von Basch, Zadek. Arnheim, Wetzel.

*° Paschutin: Ludwig's Arbeiten, 1873. Senator: DuBois-Reymond's Archfv,
1883, Supplant-Band. Mendelson: On the Renal Circulation during Fever. Amer.
Journ. Medical Sciences, October, 1883.

GENEKAL PxVTHOLOGY OF FEVER 339

artificial heating; whereas, it will be remembered that in experimental septic
fever these contractions are irregular and exaggerated.

Upon the whole, 1 tl'.ink that we are justified in concluding that the
variations of arterial tension in fevers are much less dependent upon
increased temperature than upon other factors, such as infection.

But the corner-stone of the doctrine which teadics that a chief source of
danger in fevers is the elevation of temperature is not the effect of increased
temperature upon the pulse-rate or the arterial pressure, hut it is the belief
that prolonged high temperature exerts a directly paralyzing influence upon
the heart. The main support of this belief is not the admitted fact that
extremely high temperatures paralyze the heart, for these critical tem-
peratures lie far above the ordinary high temperatures of fever, and in a
region where all admit the dangers of the excessive internal heat. The
stately superstructure has been built up chiefly on the ba.sis of experiments
showing that when the internal temperature of animals has been main-
tained for some time at a high point by exposure to external heat, paren-
chymatous or fatty degeneration of the heart muscle ensues. It is true that
all experiments are not in accord upon this point, and that, as a rule, patho-
logical anatomists have not given adherence to the doctrine that parenchy-
matous degenerations are chiefly dependent upon high temperature, still
this doctrine has gained a wide acceptance among clinical men, and is advo-
cated with especial force by Liebermeister. I have therefore, thought it
desirable in my experiments to give especial attention to this question.

Among previous experimenters on artificial heating of animals, Iwaschke-
witsch, AVickliam Legg. and Litten may be mentioned as finding parenchy-
matous or fatty degeneration of the heart, hver, and kidneys ; and Walther,
Obernier, and Xaunyn as obtaining only negative results.

It is not necessary here to enter into a criticism of these different experi-
ments, which are of very unequal value. Litten's " experiments on the one
side, and Xaunyn's " on the other, appear to be the most carefully conducted.
Litten, whose experiments are those usually cited, kept guinea-pigs in a
double- walled metallic box which was at a constant temperature of 98.8° F.
(37° C.) with dry air, or of 96.6° F. (36° C.) with moist air. He never
failed to find fatty degeneration at the end of thirty-six to forty-eight hours.
The liver was first affected, and then the heart and kidneys, which become
fatty by the second or third day. The animals did not survive longer than
five or six days, and by that time the fatty degenerations had reached an
extreme degree. Yon Recklinghausen " urges with apparent justice against

"Litten: Virchow's Arcliiv. Bd. TO.
** Naunyn : Op. cit.

"Von Recklinghausen: Handb. d. Allg. Pathologie d. Kreislause u. d. Ernah-
rung. p. 512, Stuttgart, 1883.

340 CAIJTWIJKIIIT IvECnHKS

these experiments that the enforced inactivity of the muscles and the imper-
fect ventilation may have had as much to do in causing the degenerations
as had the high temperature. These objections find support in the experi-
ment* of Xaunyn, who, making use of a much larger and better ventilat«d
heating box than Litten failed to find any parenchymatous or fatty degener-
ation in his rabbits after they had been exposed for two weeks to higher tem-
peratures than Litten employed.

As my experiments confirmed in other respects Xaunyn's results, I was
quite unprepared to find that my rabbits, after a variable period of artificial
heating quite constantly presented fatty degeneration of the heart, liver,
and kidneys, and sometimes of the diaphragmatic and intercostal muscles.
I never found the degeneration at so early a period as did Litten. It was
not until the rabbit had been kept for at least a week with an average rectal
temperature of 10G° F. (41.1° C.) that the degeneration was noticed, and
then only in moderate degree. The higher and the less fluctuating the
internal temperature, the more certain was the degeneration to appear. I
could reckon upon obtaining rabbits with well-marked fatty degeneration
of the heart by keeping them for ten days with a rectal temperature Ijctween
107° F. (41.7° C.) and 108° F. (42.2° C). I am not prepared to account
for the discrepancy in this respect between Nauiiyn's and my experiments.
The box used wa.^ larger than that employed by him, and every care was
taken to keep it well ventilated by leaving at least one-third and often one-
half of the top open.

I do not think that my experiments altogether do away with the force of
von Recklinghausen's criticisms. The fact that in these experiments the
degeneration made its appearance at the end of a week or ten days, and in
Litteu's in forty-eight hours, to say nothing of Wickliam Legg finding it at
the end of twelve hours, would suggest that if the rabbits were heated in a
still larger and better ventilated apartment, the degeneration might not
occur at all, or might be deferred to a much later period. In my ojiinion,
however, even if full allowance be made for this line of argument we must
still admit tliat prolonged high temperature is a factor in the causation of
fatty degeneration.

That it is not the sole factor no one can doubt. As is well known, fatty
degeneration is produced by anaemia and by a variety of poisons, and even
in fevers most pathologists are convinced tliat it bears a closer relation to the
kind and degree of infection tlian it does to the height of the temperature.
It is more frequently absent than present in pneumonia, even where there
have been symptoms of heart failure.

The kind of degeneration present in my rabbits was fatty and not paren-
chymatous. Probably all who make many poet-mortem examinations will

GENERAL PATHOLOGY OF FEVER 341

agree with von Retklinghauson, that altogether too liberal use has been
made of the diagnosis of pareiuhymatous degeneration, and not sulBcient
account has been taken of the anatomical clianges of the parenchyma pro-
duced by post-mortem chemical changes, such as acid formation, etc.

In order to determine what influence is exerted by infection combined
with high temperature, I inoculated a rabbit which had been in the hot box
for four days, with the bacilli of swine plague. These bacilli, if not identical
with, are closely allied to those of rabbit septicaemia, and are extremely
virulent for rabbits. In thirty-six hours the animal, which had remained
at a high temperature in the box, was dead, with characteristic lesions of the
disease, and the most extreme fatty degeneration of the heart and other
organs was found. As in other experiments the degeneration had not made
its appearance at this early date, there can be no doubt that the infection
was an important element in the causation. Tliat it received powerful sup-
port in the high temperature however, is proven by the fact that little or no
degeneration of the heart is observed after infection with this organism
when the animal is kept at ordinary temperatures.

Admitting, then, that high temperature aids in the causation of fatty
degeneration of the heart in fever, the question arises. What do we know of
the effects of this degeneration upon the functions of the heart? I will say
nothing of the growing tendency to transfer a large part of the classical
symptomatology of Quain's fatty heart to other conditions, particularly to
disease of the coronary arteries and chronic myocarditis; we are concerned
at present only with the occurrence of this degeneration in fever. Have we
not been somewhat hasty in assigning to degeneration of the heart's muscle
so large a share in the production of heart failure in fevers? One cannot
look at a muscular fibre in which the striated substance is all replaced by
fatty globules, and suppose that its functional activity was unimpaired ; but
into what serious errors should we fall if we attempted to deduce from the
anatomical changes in the liver cells or the renal epithelium the correspond-
ing functional disturbances ? Certain it is that symptoms which are usually
considered those of heart failure are often enough present in fevers without
finding at the autopsy any degeneration of the heart; and, on the other
hand such degeneration may be discovered without any history of these
symptoms, although, of course, the two are often associated.

In the face of these doubts it seemed desirable to determine, if possible,
experimentally the damage inflicted upon the cardiac functions by the pres-
ence of fatty degeneration of the heart muscle. That this degeneration may
exist without apparent injury is rendered probable by the fact that a rabbit
which has been kept for three weeks in the hot box at a high temperature,
and in which there is every reason to suppose that fatty degeneration has

343 CAirrWKMGlIT LECTURES

Odurred. iiiiiy present no symptoms of heart paralysis, and when removed
from tlie box appear and remain perfectly ndrnial. An instance has already
been mentioned wliere one rabbit at the end of three weeks was killed and
presented marked fatty degeneration of the heart; and another, whieh had
possessed a higher average rectal temperature, was removed from the box
at the end of the same ])eriod, and ajipcared for ten days perefctly normal,
wlien it was used for anotlier purpose. TJiat this degeneration can be recov-
ered from is, moreover, rendered probable by clinical experience, and is
universally admitted.

Once in teasing out, in a warm room, a bit of fatty heart musi-le from one
of the rabbits, I made a curious observation. Near the edge of the cover
glass, where there was a slight current in the physiological salt solution,
rhythmical contraction was observed in a group of muscle-fibres. This
interesting spectacle could be watched under the microscope for ten minutes.
These contracting fibres were filled with fatty globules, and only here and
there, and then indistinctly, could any trace of striation be detected. This
observation teaches that a fatty degenerated muscular fibre is capable of con-
traction, but, of course, warrants no further conclusions.

Far more important than any inferences which can be drawn from such
observations is the measurement of the actual blood-pressure in animals
whose hearts have undergone fatty degeneration. Tiiis I have done in three
instances. The rabbit was removed from the box at the end of ten days to
two weeks, and the pressure in the carotid artery was measured by a mercury
manometer attached to Ludwig's kymograph. In no instance was the blood-
pressure found to be lower than that normally present in rabbits. In an
experiment recently performed, the average pressure was 125 mm. of mer-
cury ; the pulsations were regular ; the heart resjionded to stimulation of the
vagi in an entirely normal manner. After such stimulation the pressure in
one case rose to 176 mm. of mercury. Immediately after the measurement
of the blood-pressure the rabbit, as in the previous instances, w'as killed, and
marked fatty degeneration of the muscular fibres was found. In many of
the fibres the striation could not be made out, and only fatty globules were
visible; in others, which also contained fatty granules, the striation was dis-
tinct. The degeneration involved the whole muscular substance of the
heart. \ similar appearance in a human heart would be considered to indi-
cate well-marked fatty degeneration.

These experiments show that a rabbit's heart wliicji has undergone marked
fatty degeneration from exposure to heat, may perform its functions to all
appearances, and for the time being, in a perfectly normal manner.

There is at least one consideration which should make us cautious in
drawing far-reaching conclusions from these experiments. There are dis-

GENERAL PATHOLOGY OF FEVER 343

eases of the heart — I need only refer to lesions of tlie coronary arteries — in
which the functions of tlie organ are performed for a longer or shorter time,
apparently in a perfectly normal way, and then heart failure suddenly
appears. It is probable that here too the blood pressure would be found
normal at a certain period of the disease, and still it would be an error to
suppose that the lesion does not damage the heart.

Whatever force there may be in this analogy, I still think that these
experiments, as well as careful pathological and clinical observations, neces-
s'tate some revision of the current opinions concerning the significance of
fatty degeneration of the heart in fever.

So much time has been devoted to a consideration of the effects of heat
upon the respiration and the heart that the limits of the present lecture will
permit hardly more than a summary of the effects exerted by heat upon
other functions and organs of the body. On account of the great clinical
importance of the subject it seemed desirable to treat with especial fulness
the influence of increased temperature on the heart.

What part has increased temperature in producing febrile consumption
of tissue ? In the first lecture mention was made of Pfliiger's experiments
showing that animals with elevated temperature, produced by exposure to
heat, absorb more oxygen and excrete more carbonic acid than at the normal
temperature. This is in conformity with the general law that within certain
limits cell activity is more energetic at high than at low temperatures. It
was also shown in the first lecture that only a comparatively small part of the
increased oxvgen absorption and carbonic acid elimination in fever can be
referred to the immediate effects of high temperature. It has not been
demonstrated that the respiratory gases in human beings are increased by
artificial elevation of temperature. Indeed Voit" was unable to find any
such effect of increased temperature in human beings on the respiratory
gases as both he and Pfliiger observed in animals.

Inasmuch as increased disintegration of nitrogenous material is such a
prominent disorder in fever, much attention has naturally been given to
determining how far this can be explained by elevated temperature. That
it cannot all be so explained is proven by the interesting observation of
Sydney Ringer, that excessive elimination of urea antedates the rise of
temperature in intermittent fever, and Xaunyn has found the same to be
true of the septic fever of dogs. The experiments whicli have been made
to determine the influence of artificial heating on the amount of urea
excreted by man and by animals have yielded contradictory results. A num-
ber of these experiments are of little or no value, because no attention was

"Voit: Zeitschrift fur Biologie, Bd. XIV.

344 CART WRIGHT LECTURES

given to establishing beforehand nitrogen equilibrium. Sichleicli's " ex-
periments may be mentioned as, perhaps, the most accurate of those show-
ing an increase in the urea excreted under the influence of exposure to heat.
The more recent experiments of Simanowsky "" were made in Voit's labora-
tory upon a dog with especial precautions as to the establishment of nitro-
gen equilibrium. He failed to find any increa.'^e in the excretion of urea
as the result of exposure to external heat. While then this question must
be left at present sub judice, there can be no doubt that only a part at least
of the excessive disintegration of nitrogenous substance in fever can be
assigned to the influence of the increased temperature.

The loss of weight exhibited by animals kept for a long time in a hot
atmosphere is usually explained by the excessive evaporation of water from
the body. In many of my experiments the rabbits were freely supplied with
food and water, and still the loss of weight was very noticeable. I am
inclined, therefore, to attribute to the increased temperature under these
conditions a decided influence upon the consumption of tissue.

Senator" found the urine of rabbits artificially heated to contain more
albumen than is ever found in the urine of healthy rabbits. This observation
I have not been able to confirm on the rabbits in my experiments and prob-
ably this difference is to be explained by the more rapid and intense heating
employed in Senator's experiments. Senator explains the heat albuminuria
by the rise of arterial pressure in the renal vessels, but this is not in con-
formity with the interesting experiments of Mendelson," who found by
means of Roy's oncometer that both in thermic and in septic fevers of dogs
the kidney is anaemic, while the general blood-pressure is elevated.

No satisfactory explanation has yet been offered of the diminution of
perspiration which distinguishes fever so strikingly from the condition pro-
duced by exposure to high external temperatures. Luchsinger's assertion
that this is the result of lessened irritability of the sweat centres in the
spinal cord remains to be proven, and at the best is not a satisfying
explanation.

Bokai," in a recent experimental research on intestinal peristalsis in
thermic and in septic fevers, comes to the conclusion that the constipation
of fever is to be explained by the heated blood stimulating the nerves inhibit-
ing intestinal peristalsis. If this should be confirmed, then it would be
proven that at least three symptoms of fever, the quickened respiration and
pulse and the constipation are direct effects of elevated temperature.

"Schleich: Arch. f. exp. Path. u. Pharm., Bd. IV.

"Simanowsky: Zeitsclir. f. Biologie, Bd. XXI.

"Senator: DuBois-Reymond's Archiv, 1S83, Supplement-Band.

" Mendelson : Op. cit.

" Bokal: Archiv f. exp. Path. u. Pharm., Bd. 23.

GENERAL PATHOLOGY OF FEVEE 345

When we consider the important nutritive changes in the muscles accom-
panying increased thermogenesis, we shall be inclined to attribute in part,
at least, to these alterations and the associated abnormal innervation, rather
than to increased temperature, the muscular pains and weakness which form
such an early and frequent complaint in many fevers.

The investigations hitherto published of changes in the blood produced by
increased temperature within febrile limits are not of sufficiently definite
and satisfactory nature to warrant any consideration on the present occasion.

Xor am I acquainted with any experimental evidence (save Bokai's work
already mentioned) that increased temperature is concerned in the produc-
tion of the digestive disorders of fever. It has already been said that the
rabbits with high internal temperatures in the hot box ate greedily, but these
voracious animals cannot be considered favorable subjects to test this
question.

Especial emphasis has been laid by Liebermeister and those who accept
his teachings upon the dependence of the nervous symptoms of fever, par-
ticularly the so-called typhoid symptoms, on the elevation of temperature.
There is, however, abundant clinical evidence to disprove this doctrine.
Reference need be made only to relapsing fever, and especially to the aseptic
fever described by Genzmer and Volkmaun, in which there is entire absence
of the whole group of so-called nervous symptoms. Moreover, Lieber-
meister's opinion in this respect is not supported by adequate experimental
evidence. Unless the temperature of the brain or of the entire animal be
brusquely raised to a high point by coarse methods, no disturbance of the
cerebral functions is noticed imtil the temperature reaches a critical point,
beyond which further increase is likely to prove rapidly fatal. At this
critical point the animal, which before has lain quietly, becomes very uneasy,
and if the temperature rise higher it has convulsions and coma and dies.

I have endeavored to bring before you in this lecture the experimental evi-
dence relating to the effects of increased temperature upon the general con-
dition of the body and upon the functions of its various organs. I have
given account, as briefly as possible of some experiments which perhaps shed
additional light upon this important subject. In the course of this lecture
emphasis has repeatedly been laid upon the necessity of controlling the
results of the experimental method by clinical observation, and here and
there I have endeavored to institute this control. Further than this I shall
not attempt to set before you the clinical evidence regarding the effects of
increased temperature in fever. There are those here more competent than
I to deal with this side of the question. We may feel assured that when all
the facts are before us and are properly intor]5reted, there can be no lack of
harmony between the results of experimental and those of chnical investi-
gations.
25

346 cai;t\vi;i(;iit lectures

Lectube III

THE ETIOLOGY OF FEVER

We considered in the last lecture the experimental evidence concerning
the efl'ects of increased bodily temperature. An advantage of the experi-
mental over the clinical method of investigating this subject is that it enables
us to study the effect* of heat upon the whole body and its various functions
without the intervention of disturbing factors, such as infection, which
complicate the clinical analysis of febrile phenomena with reference to this
question.

We foTind that animals may be kept at high febrile temperatures for at
least three weeks without manifesting any serious symptoms. The only
functional disturbances which could be attributed directly to the influence
of the elevated temperature were increased frequency of respiration and
quickened puJse. The rapid respiration was found to be due partly to stimu-
lation of the skin by external heat and by the warmed blood, and partly to
the action of the warmed blood on the respiratory centres. The quickened
pulse could be positively referred to the effect of the warmer blood upon the
heart itself. No definite relation could be established between the varia-
tions of arterial tension which occur in fever and the height of the tempera-
ture.

Although the experiment-s narrated showed that prolonged high tempera-
ture is an element in the causation of fatty degeneration of the heart, they
also indicated that other factors, such as infection, are concerned in the
production of this lesion. Moreover, experimental evidence was found in
support of clinical facts showing that this alteration may exist without
serious interference with the functions of the heart, so that the conclusion
seems justified that failure of the heart's power in fever is less an effect of
high temperature than of other concomitant conditions.

Of the other disturbances in fever we learned that the increased con-
sumption of tissue can be explained only in relatively small part by the
elevation of temperature. The lessened perspiration, the renal disorders,
and the digestive disturbances (with the possible exception of constipation)
are referable also chiefly to other causes than- the increased temperature.
Both experimental and clinical observations strongly support the view now
widely accepted that the disturbances of the sensorium which constitute so
prominent a part of the group of so-called typhoid symptoms, are dependent
in far higher degree upon infection or intoxication than upon the heightened
temperature.

Although no attempt was made to analyze in detail the clinical evidence
relating to the effects of high temperature, attention was called to the fact

GENERAL PATHOLOGY OF FEYER 347

tliat the absence of all serious symptoms in many cases of relapsing fever,
and in tlie so-called aseptic fevers in spite of prolonged high temperatures,
strongly support the conclusions derived from the experimental study of the
effects of heat upon man and animals. Even in fevers, such as typhoid fever
and pneumonia, where the height of the temperature is undoubtedly a most
important index of the severity of the disease, there exists no such parallelism
between the temperature and the nature and the severity- of the other symp-
toms as we should expect if these s}inptoms were caused by the increased
heat of the body.

It was emphasized that the results of experimental investigations should
not be permitted to control the treatment of fevers, more particularly the
use of so-called antipyretic agents. These agents, whether hydrotherapeutic
or medicinal, influence, as is well known, many functions besides reducing
the temperature. I need only refer to the powerful influence of cold baths
upon the circulation and the nervous system, and to the action of antipyrin
and other antithermic drugs upon the nervous system.

Reasons were given for assigning to hyperpyrexia and insolation a position
separate from other febrile conditions in the discussion as to the effects of
elevated temperature.

Before leaving this subject of the effects of increased temperature, I wish
to call attention to one consideration which should perhaps influence our
opinion on this much disputed question. Is it a matter of indifference, so
far as the effects of febrile temperatures are concerned, in what manner the
increase of temperature is brought about? We have seen that heat regula-
tion, heat production, and heat loss are disturbed in fever ; but, as experience
shows, not always in the same manner or the same degree. In one case the
incoordination of the regulating mechanism may be most apparent, the
temperature fluctuating strangely up and down; in another case the heat-
producing processes are excited to the utmost; and in another the circulatory
changes in the skin, the vasomotor disturbances, are the most prominent
phenomena. Xow this varying interplay of the factors which cause febrile
rise of temperature doubtless corresponds to varying conditions of innerva-
tion, of structure and of function of certain tissues of the body. May we not
reasonably suppose that these varying conditions of the tissues directly
associated with the rise of temperature may influence their tolerance of
increased body heat? We have not the experimental or the clinical data
which would enable us to give a definite answer to the question here pro-
pounded, and it would lead me too far from the theme of the present
lecture to attempt to sift the equivocal evidence which might be gathered.
I suggest this question, however, as one worthy of more attention than it
has hitherto received.

348 CAltTWIJinilT LECTURES

I wisli now to invite your attention to some considerations concerning the
otiolofiy of fever. In this era, when etiolojjical studies occupy the foremost
rank in medical science, it will naturally he expected that a discussion of
the general pathology of fever, even though it does not aim at completeness,
will not leave wholly untouched the etiolofjical aspect of the subject.

The general etiologj' of fever relates mainly to a consideration of the
agents producing fever, the so-called pyrogenic substances. It is, moreover,
only certain general characters of these agents which can be properly con-
sidered here. Most of the questions which at present engage so prominently
tiie attention of physicians concerning the specific causes of individual
fevers belong, of course, to the special etiology- of fevers, and therefore do
not lie within the limits of our subject. But even with these limitations we
cannot in treating of the general etiology of fever consider the febrile proc-
esses so much in the abstract as we have done hitherto. We must come into
closer contact with the individual forms of fever.

At the start it should be said that probably in no instance are we ac-
quainted with the actual substance or substances upon which the febrile dis-
order of animal heat immediately and directly depends. We deal here, as
elsewhere in medicine, not with direct but with remote causes. But in no
department of etiologj' have we advanced nearer the proximate causes than
in many of the infectious fevers. To be convinced of the immense progress
which has been brought about by the etiological study of fevers, let one glance
over some of the older books on fevers, such as Percy's or Selle's," with their
endless divisions into symptomatic genera and species, and their barren
speculations. Percy, for instance, describes no less than one hundred and
fifteen different kinds of fever.

In all ages it has been customary to divide fevers into two great groups,
viz. : those which are secondary to some local cause, usually an inflammation,
and those which cannot be explained by the presence of any local lesion. The
explanation of the sjinptamatic seemed so much clearer than that of the
essential fevers that attempts have repeatedly been made to place all fevers
in the symptomatic group. It is a curious fact that the two methods which
have been of the greatest service in the study of fevers, each, wlien first
introduced, led to an entire misconception of the nature of fever. Boerhaave,
who was the first to make any extensive use of the thermometer at the bed-
side, supposed that this instrument indicated a reduction of the bodily tem-
perature during the fclirilc chill. He therefore taught that increased fre-
quency of the pulse and not tlie elevation of temperature is the constant and
essential symptom of fever. If we except de Haen's correction, which never

"Percy: Die gesammte Fleberlehre, Pesth, 1820. The original is in French.
Selle: Rudimenta Pyretologiae Methodicae, Berolini, 1773.

GEXEKAL rATHOLOGY OF FEVER 349

became widely known, it was not until the middle of the present century
that Boerhaave's error was overthrown. A no less serious misconception
sprang from the study of the pathological anatomy of fevers in France dur-
ing the early part of the present century. The exaggerated ideas of the
immediate followers of Bichat as to what can be accomplished by pathological
anatomy led them to the belief, for a long time widely accepted, that there
is no such thing as an essential fever, that all fevers are symptomatic of some
local disease. This error of Broussais, one of the most influential and elo-
quent medical teachers of this century, is plainly traceable partly to the fact
that his autopsies were chiefly of typhoid fever, and partly to the belief that
the lesions found at the autopsy suffice to explain all of the manifestations
of the disease during life. But we need not stop to trace the fate of the
various attempts to overthrow the doctrine of essential fevers. I have men-
tioned one attempt chiefly on account of the suggestive lessons it conveys
rather than from a desire to enter into historical details which I have hitherto
purposely avoided.

The division of fevers into symptomatic and essential fevers is one of un-
doubted practical utility, and is not likely to be abandoned. But it cannot
truthfully be said that this popular classification has been of much assist-
ance in advancing our knowledge. Close inspection shows that the boundary
lines between the two groups of fevers are vague and shadow}'. Probably no
one any longer believes that traumatic fever, the principal type of the
sjTnptomatic group, is due to increased production of heat in the seat of
inflammation, which, acting like a furnace, was once thought to warm the
whole organism, or to the irritation of nerves connected with the inflamed
region. The opinion of Billroth and of Weber is now generally accepted,
that traumatic fevers are caused by the absorption of pyrogenic substances
from the inflamed district. Symptomatic fevers as well as essential fevers,
therefore, are dependent upon the presence within the blood of fever-produc-
ing agents, ilany essential fevers, moreover, resemble the symptomatic ones
in the existence of inflammation, or necrosis at the portal where there is
reason to believe that the pyrogenic agents gain access to the general circu-
lation. A distinction in these cases cannot be based on the ground that in
symptomatic fevers only chemical substances, although possibly the products
of bacteria, enter the circulation, and in essential fevers microorganisms
invade the blood, for such a distinction would place cholera and possibly
tetanus and typhoid fever among the symptomatic fevers. These considera-
tions show how vague and unsatisfactory are the distinctions between symp-
tomatic and essential fevers. Still, similar criticisms can be made of many
of our artificial classifications which nature is under no compact to observe,
and we should undoubtedly be put to great inconvenience if we attempted to

350 CARTWRIGIIT LECTURES

dispense with the epithets symptomatic and essential as applicable to differ-
ent forms of fever. There are, however, other points of view which seem to
me more fruitful in tlie study of the etiolog}' of fever than those embodied
in these distinctions. I refer to the differences in the nature of fever-pro-
ducing agents, concerning which our knowledge, although still verj' imper-
fect, has been materially increased within recent years. And here agam we
are greatly indebted to the results of experiments upon animals.

Much light has been shed upon the causes of a certain class of fevers by a
series of experiments, which received their impulse from the important
studies of Alexander Schmidt and his pupils upon the physiology of the
blood. A particular direction was given to these experiments by the often
repeated observation that fever and other injurious effects may follow the
transfusion of blood, especially when the blood of one species of animal is
transfused into an animal of another species. In order to test the supposi-
tion that these bad symptoms are due to an excess of fibrin ferment Kohler "
injected into the vessels of animals blood made rich in fibrin ferment and
fibrino-plastic substance, and found that this blood when injected in large
amount into the jugular vein causes sudden death by rapid coagulation of
the blood in the right heart and pulmonar)' arteries, but when injected in
smaller amount or in a different manner produces a typical febrile attack
bearing a close resemblance to that following the injection of putrid fluids.
Angerer " then found that a similar fever, although less intense and more
gradual in its development, may be produced by the injection of blood into
the peritoneal cavity or the subcutaneous tissue, or even by an extravasation
of blood. Although in these experiments it was believed that fibrin ferment
is the pyrogenic agent, Edelberg" was the first to produce fever and other
symptoms of intoxication by the injection of this ferment isolated according
to Schmidt's method.

In the light of these experiments it was to be expected that other ferments
would be examined wiUi reference to their pyrogenic power. Schmiede-
berg" discovered that injections of histozyme into the blood of dogs pro-
duced high fever associated with general illness, and particularly with
diarrhoea. The ferment to which Schmiedeberg has given the name histo-
zyme he believes to be present normally in small amount in the body, and to
be concerned in the dissociation of the nitrogenous constituents of the tissues.
He roncludcs from his experiments that an excessive accumulation in the

" Kohler: Ueber Thrombose und Transfusion, u. s. w. Inaug. Diss.. Dorpat, 1877.
"Angerer: Klin. u. Exp. Untersuch. iib. d. Resorption v, Blutextravasate,
Wiirzburg. 1879.
"Edelberg: Arch. f. exp. Path. u. Pharm., Bd. XII.
"Schmiedeberg: /bid., Bd. XIV.

GENERAL PATHOLOGY OF FEVER 351

body of this normal ferment gives rise to fever with increased metamorphosis
of nitrogenous materials. Schmiedeberg thinks it probable that the fibrin-
ferment solutions employed by Edelberg in his experiments contained also
histozyme, and that the pyrexia was due to the latter substance.

Following these observations concerning the pyrogenic power of fibrin-
ferment and histozyme comes the discovery of von Bergmann and Angerer "
thi'.t injection of pepsin and of trypsin into the blood of dogs causes a well-
marked fever with characters like those of the other ferment intoxications
described. A valuable calorimetrical study of pepsin and trysin fevers has
been made by Wood, Reichert, and Hare.°° These authors, as well as Ott,"
have demonstrated that it is not the pepsin and the trypsin ferments them-
selves which constitute the pyrogenic agents, but some contaminating sub-
stance, which seems to be a peptone. That peptones artificially prepared
contain poisonous principles has been kno^vn for some time, and Brieger"
has succeeded in isolating a crystallizable poisonous ptomaine, called pepto-
toxin, from commercial peptone and from that formed by the artificial diges-
tion of fibrin. This ptomaine, however, is not identical with the pyrogenic
agent found by Ott and by Wood and his colleagues in commercial pepsin.
To this list of pyrogenic substances obtained from impure ferments may be
added leucin, and, according to Ott, papayotin and neurin which produce
marked fever when injected into the blood in small quantity. The substance
sold under the name of papoid possesses marked pyrogenic power when its
filtered aqueous solution is injected into the blood. This substance contains
principles belonging to the peptone or albumose group. Dr. JIall, Fellow
in Pathology at the Johns Hopkins University, has isolated from commercial
papoid a bacillus, which in pure cultures exerts a powerful peptonizing
action on fibrin and on connective and elastic tissues. The bacillus itself
is not pathogenic, but an albumose or some similar substance produced by
its activit}-, has pyrogenic power when injected into the blood.

It does not appear that any one has actually isolated the pyrexial agent
from the various ferments employed in these experiments. Certainlv no such
agent has been obtained in a crystalline form, which is the test of its purity,
if we except Brieger's pepto-toxin, the pyrogenic capacity of which has not
been established. It has been alleged that the fever-producing agent is the
same in all these ferment intoxications, but this has not been proven nor
does it seem probable.

"Von Bergmann u. Angerer: D. Verhaltniss d. Fermentintoxication. Fest-
schrift; Wurzburger Universitat, 1SS2, I, 135.

=*W'ood. Reichert, and Hare: Therapeutic Gazette, 1886.
"Ott: Journal of Physiology, VIII.
"Brieger: Ueber Ptomaine, Berlin, 1885.

352 CATJTWIITOTTT T.Kf'TURES

On better grounds it has been urged by von Bergman n and Angerer, that
all of the substances in the group of jiyrexial a.L'ents now under consideration,
cause fever by jiroducing the same change in tlie blood. These authors claim
that this change is the formation in the circulating blood of an excessive
amount of fibrin ferment, wliich leads either to coagulation or to stasis in
the capillaries, particularly tliose of the lungs and of the intestines. One
of the main arguments for this view is the fall of blood pressure which von
Bergmann and Angerer observed after injections of ])cpsin and of pancreatin,
but this fall c;in be explained in other ways than by supposing that the
pulmonary capillaries are occluded, and, moreover, Wood, Reichert, and
Hare find that the blood pressure often rises in the course of pepsin fever.
It does not seem to me that we are any more able to explain in exactly what
manner the pyrogenic substances act in this class of fevers than in other
fevers. The idea, however, that the liberation of fibrin ferment in abnonnal
quantity is capable of causing fever, finds support not only in experiments
which have been mentioned, but also in the fact that injections of haemo-
globin solutions, and of large quantities of water into the blood, produce
fever.

But you, perhaps, by this time have asked yourselves what bearing all of
these experiments with various pyrogenic substances have upon the etiology
of human fevers. They have, in my judgment, an important bearing on this
subject. However, obscure may be the explanation of the mode of action of
these substances, however doul)tful may be their exact chemical composition,
they have certain common characteristics which are calculated to shed light
upon the causation of some obscure febrile disorders of human beings. In
the first place, the members of this group of pyrogenic substances, if not
identical with certain physiological ferments, are readily produced by them,
quite independently of the action of bacteria or other microorganisms. In
the second place, some of these substances are present normallv in small
amount in the body, and if their elimination is impeded, or their formation
is excessive, there is reason to believe that they become efficient causes of
fever. In the third place, these pyrogenic substances may be produced, again
without the action of bacteria, in extravasated blood, or by the abnormal dis-
integration of tissues, and if they are absorbed from these sources in such a
condition, or in so large an amount that nature cannot render them harmless,
they are capable of producing fever. It is customary to call the morbid condi-
tion produced by the absorption of these substances, ferment intoxication in
analogy with the term putrid intoxication, applied to the diseases caused by
the absorption of the products of putrefactive bacteria. The tenn ferment
intoxication seems to me to imply more than our knowledge warrants, but it
is not of much use to contend against names which have sained currencv.

GENERAL PATHOLOGY OF FEVEE 353

It is probable tbat some of tbe pyrogenie agents in this group belong to the
class of leucomaines, but our present information regarding these bodies
does not justify any positive statement on this point.

Although the etiology of individual fevers, does not belong to our subject,
I cannot forbear calling your attention to certain febrile conditions which
seem to be produced by the accumulation of substances that are either normal
constituents of the body or are the result of chemical processes, differing
but little from physiological ones.

To this category probably belongs the so-called aseptic fever, first de-
scribed by Genzmer and Yolkmann." These surgeons have established the
fact that there are traumatic fevers not caused by the absorption of septic
material, and that severe injuries and wounds which pursue an entirely
aseptic course, are not infrequently associated with consideraltle elevation
of temperature. This aseptic fever is usually to be observed with extensive
wounds or injuries in which there is much lacerated tissue or extravasated
blood to be disintegrated and absorbed. It occurs not only with wounds
correctly treated by antiseptic methods, but also with subcutaneous injuries,
particularly fractures of the large bones, where there can be no suspicion
of the action of bacteria. Aseptic traumatic fever differs by such marked
characteristics from septic fever, that there can be no doubt that the two
types of fever are etiologically distinct. Aseptic fever has no prognostic
significance ; its only symptoms are the elevation of the temperature, which
may mount to 104° (40° C), or even 105.8° (41° C), and the increased
frequency of the pulse. The entire absence of all the intoxication symptoms
of septic and infectious fevers, such as the benumbed sensorium, the dry
tongue and skin, the lessened secretion of urine. I have already referred
to in confirmation of the belief that these sj'mptoms are not dependent upon
the rise of temperature. Genzmer and Volkmann assign as the cause of
aseptic traumatic fever, the absorption of substances resulting from the dis-
integration of the wounded tissues and of the extravasated blood, and state
that these substances probably do not differ markedly from those produced
by physiological tissue metamorphosis. This explanation certainly has re-
ceived decided support by the experiments which I have described in this
lecture, a large part of which have been performed since the publication of
Genzmer and Volkmann's article. It has been suggested that aseptic trau-
matic fever is a reilex neurosis, and this suggestion cannot be absolutely
rejected as a possible explanation, but for various reasons, which cannot here
receive further consideration, the usually accepted explanation is the more
probable one.

"Genzmer and Volkmann: Volkmann's Sammlung, No. 121.

354 CARTWRIGHT LECTURES

An instructive case of ferment intoxication has been reported by Cramer."
There existed in a young woman a cyst, the size of a goose's egg, between
the fibres of the semiteudiiiosus muscle. The cyst was developed from a
cavernous angioma, and was filled with dark fluid blood. The patient had
had fever for almost two years up to the day of the operation. The cause
of the fever could not be discovered. Immediately after the removal of the
cyst the fever stopped and did not return. In this case the cavernous struc-
ture of the cyst wall accounts for the ease with which we must suppose a
considerable quantity of pyrogenic substance was continuously absorbed
from the bloody contents of the cyst. The results of Angerer's experiments,
already mentioned, enable us to explain the source of the fever in this case.

Another instance may be cited in which fever is probably to be explained
by the accumulation within the body of products of normal metabolism.
More or less fever appears to be a constant accompaniment of the agonizing
method of treatment known as the Schroth cure. In this treatment the
patient is kept for a number of successive days on dry food with scarcely
any fluids. Both Bartels and Jiirgensen," who have investigated the
nutritive changes of individuals under this treatment, beheve that the body
becomes so poor in water that some of the products of regressive metamor-
phosis cannot be carried out of the system. This certainly seems very prob-
able, and, if true it affords in the light of recent experiments an explanation
of the accompanying fever.

I believe that good reasons can be adduced in support of the opinion that
the febrile conditions sometimes associated with Icucocythaemia profound
anaemias and chlorosis belong to the group of fevers we are now considering.
It is probable that some of the obscure ephemeral fevers are also to be
included here. But to consider these febrile disorders in detail would lead
us into the domain of special etiology upon which we have already perhaps
encroached too far. My purpose has been to bring before your attention
only a few clinical examples in illustration of the experimental results.

I think that you will agree with me in the conclusion that experimental
and clinical evidence justify us in recognizing as a distinct group of pyro-
genic agents substances which have no necessary connection with micro-
organisms and which are either not foreign to the healthy organism or are
readily formed by unorganized fennents from normal or abnormal con-
stituents of the body. These substances may be described as homologous in
distinction from the heterologous agents concerned in the production of
septic and infectious fevers.

"Cramer: Verhandl. d. Deutschen Gesellschaft f. Chirurgie, 13th Congress,
18S4.
"'Jiirgensen: Deutsches Arch. f. klin. Med. Bd. I.

GENERAL PATHOLOGY OF FEVER 355

A class of pyrogenic agents of far greater clinical importance than those
previously considered is formed by the products of microorganisms which in
themselves are not pathogenic. A considerable number of bacteria which
when inoculated in pure culture into the body are not capable of further
invasion or of multiplication produced in culture fluids and in dead animal
or vegetable material poisonous substances often of great virulence. Excep-
tion may be taken to the description of these organisms as non-pathogenic,
inasmuch as the products of their activity are poisonous, but the epithet
pathogenic is usually assigned by bacteriologists only to such microorgan-
isms as are capable of multiplication within the body. If we called all of the
microorganisms pathogenic which produce poisonous ptomaines we should
have to include in this category a far larger number of the known species
of bacteria than has hitherto been customary.

The best known and most important of the fevers produced by chemical
products of saprophytic bacteria are those grouped under the name putrid
intoxication. Until the introduction of the modern era in bacteriology by
Koch nearly all of the experimental work on the etiology of fevers related
to the causation of the septic and putrid fevers. It is instructive with our
present knowledge to follow the experiments on this subject from the period
of Gaspard, Magendie, and Sedillot up to recent times. What light has been
shed upon the mass of contradictory and perplexing results of experiments
with putrid fluids by the recent chemical and biological studies of putre-
factive processes? Some of the putrid substances experimented with
undoubtedly contained parasitic microorganisms, and others contained only
obligator}' saprophytes. Some were rich in poisonous ptomaines, and others
were nearly devoid of them. The whole doctrine of the parasitic nature of
infectious fevers seems to have hinged in the minds of some upon the
determination of the question whether septic and putrid fevers are produced
by the absorption of chemical substances, or by the invasion of pathogenic
bacteria. The ideas concerning putrid intoxication dominated at one time
the whole field of fever etiology, and were applied not only to septicaemia
but to typhoid fever, typhus fever, yellow fever — in fact, to nearly all
infectious fevers. Nor have the echoes of this period even now entirely
died out.

Panum was the first to isolate from putrid materials some chemical sub-
stance or substances in tolerable purity, certainly free from bacteria. This
substance, when injected into animals, produced symptoms of putrid intoxi-
cation. Subsequently, von Bergmann and Schmiedeberg isolated from
putrefying yeast a poisonous crystalline substance, their celebrated sepsin.
For a time the opinion prevailed that this sepsin is the source of all putrid
intoxications. Thanks to the investigations of Nencki and others, and par-

356 CARTWRIGHT LECTURES

ticularly of Brieger, wo now know that many alkaloiflal substances can be
separated from putrefying materials. Some of these so-called cadaveric
alkaloids or ptomaines are poisonous, fever-producing, others are harmless.
There is no reason to suppose that the list of the ptomaines of putrefaction
has been e.xhausted, nor is it necessary to believe that all of the poisonous
constituents of putrefying materials of an alkaloidal nature.

Jlost of the Bacteria concerned in ordinary putrefactive processes are
purely saprophytic. They are incapable of multiplication in the living
animal tissues. In a mixture of putrefactive bacteria it is not, however,
uncommon to find genuine pathogenic or parasitic bacteria. It was from
such sources that the bacilli of mouse septicaemia and of rabbit septicaemia
(Koch) were obtained. The bacillus of malignant oedema is also often
found in tlie early stages of post-mortem decomposition.

There is, of course, no doubt that the absorption of the chemical products of
putrefaction may produce fever with septic symptoms, quite independently
of the penetration and multiplication within living tissues of bacteria.

Here belong certain cases usually described as septic, in which fever and
other bad symptoms subside upon the thorough cleansing and disinfection
of a foul wound, or of a puerperal uterus. The majority of cases of septi-
caemia are not to be included here, for they depend upon the invasion of
pathogenic bacteria. But, excluding the cases of genuine septicaemia, there
remain the putrid intoxications which result from the absorption of poison-
ous substances produced in necrotic or disintegrating tissues, or exuda-
tions, or extravasated blood, by the action of purely saprophytic bacteria.
The ideas which I have expressed on this subject are now so generally ad-
mitted that they require no further elucidation.

It is probable that fever, with symptoms of intoxication, although gen-
erally of a much milder nature than in the class of cases just considered, may
be produced by abnonnal fermentations and putrefactions caused by sapro-
phytic bacteria in the alimentary canal. But here the essential morbid
conditions seem to be abnormalities in the gastric and intestinal contents,
due partly to the character of the iugesta, but chiefly to alterations of the
digestive juices. Fermentative and putrefactive bacteria are normally pres-
ent in the intestinal canal, and have abundant opportunities to gain access
to this situation. The number, however, which can multiply and thrive
there is quite limited, for under normal conditions, according to Escherich,
only such bacteria can multijily to any extent in the intestinal canal as are
capable of growing with little or no o.xygen, and of deriving their nourish-
ment from the anaerobic fermentation of the food supplied to them in this
situation. Suitable conditions for the excessive multiplication of putre-

GENERAL PATHOLOGY OF FEVER 357

factive or fermentative bacteria may, however, be furnished by abnormalities
of the gastric or intestinal contents.

Of a far more serious nature are the putrid or ptomaine intoxications
which result from the ingestion of substances which have undergone outside
of the body putrefaction, or clianges whicli lead to tlie formation of poisonous
ptomaines. To this group of cases belong at least many of the instances of
poisoning which have lieen caused by eating certain kinds of meat, sausage,
fish, clieese, etc. In some of these instances poisonous ptomaines have been
isolated from the suspected substances, but we know scarcely anything of
the microorganisms which are concerned in their production.

It is important to bear in mind that it is not stinking putrefaction alone
which gives rise to poisonous products. Brieger has found that such products
may be absent in very advanced decomposition, and that in general the most
virulent products are formed in the early stages of putrefaction. We know,
furthermore, that putrefactions and fermentations differ in the character of
their products. There are differences according to the kind of bacteria
present, according to the substances dec'omposed, and according to various
other conditions, such as the presence of oxygen, the temperature, etc. This
is not the proper occasion to discuss these details.

Enough has been said to prove that we are justified in recognizing as a
second class of pyrogenie agents substances wliicli are the products of
bacteria in themselves not pathogenic. These pyrogenie agents may be
formed on or within the body, or they may be produced outside of the body.
I would not by any means have you infer that it has been proven in all of
the special examples which I have mentioned, that the bacteria involved are
not pathogenic, or capable of multiplication within the living tissues. We
have not sufficient knowledge to assert or to deny this in every instance, but
I do not think that it is likely exception will be taken to the classification
which I have adopted for most of these cases. As has repeatedly been men-
tioned, our purpose here is not an analysis of individual cases of fever, l)ut
an attempt to classify systematically the various pyrogenie substances.

We come now to the third and most important group of fever-producin"
agents, the pathogenic microorganisms. So overshadowing is their impor-
tance that it has been claimed tliat they are the sole causes of fever. In
contrast with former times it is no longer the symptomatic fevers whose
etiology is clearest. We have much more definite ideas as to the mode of
production of some of the essential fevers which were once the most obscure,
than we have of symptomatic fevers. It does not seem to me worth while to
go over the chain of evidence which establishes the doctrine that the infec-
tious fevers are caused by microorganisms. There is probably no one who
has thoroughly investigated the subject, and is competent to form an opinion

358 CARTWIMCHT LKCTFRES

on it, who does not to-day admit that a number of infectious diseases have
been proven to depend upon specific microorganisms, and that it is a logical
inference that all infectionus diseases are caused by parasitic organisms.

It is not germane to our subject to enter into a morphological or biological
description of the different species of pathogenic organisms which are
causes of febrile diseases. The only question which concerns us in this con-
sideration of the general etiology of fever is how the microorganisms produce
fever. Are they themselves the pyrogenic agents, or do they produce chemical
substances which arc pyrogenic? A number of other possibilities might be
mentioned. These and similar questions have suggested themselves to in-
vestigators since the beginning of any knowledge of parasitic microorgan-
isms. Our information is far from sufficient to enable us to an.swer these
questions in a positive manner, and still we are not left wholly to vague
surmises in attempting to form some sort of an opinion.

That bacteria can produce mechanical effects by plugging up capillaries
and in other ways is certain, but the wide differences presented by the various
infectious diseases cannot be reconciled with the idea that pathogenic bac-
teria act chiefly by mere mechanical interference with the fluid and the solid
constituents of the body. Notwithstanding the fact that Strieker and
Albert succeeded in producing fever by the injection of starch granules mto
the blood, probably no one will be inclined to attribute the pyrogenic activity
of bacteria in any considerable extent to occlusion of bloodvessels.

In a certain number of infectious diseases, particularly of animals, bacteria
are present in such enormous number in the blood and tissues that some are
inclined to refer the disastrous effects of the organisms to the withdrawal of
oxygen and other nutritive pabulum from the cells of the body. So far as
the appropriation of oxygen is concerned, this idea is not supported by the
results of most of the examinations of the blood in cases of anthrax. This
explanation was more pojjular in the cariy days of bacteriology than it is
at present, and at the best its value is limited, for it cannot be applied to a
large number of infectious diseases, such as cholera or typhoid fever where
the circulating blood is not largely invaded by the parasites. Furthermore,
it is not clear how the appropriation by bacteria of nutriment intended for
the tissues would help us to explain the production of fever.

It has been suggested that the increased temperature in infectious fevers
may be explained by the heat jirdduccd by oxidation or other chemical
changes in the microorganisms themselves. But this is not at all a satis-
factory explanation. Not only is the quantity of heat which can come from
this source in all probability very small compared with that constantly pro-
duced in the liody, but sm-li an explanation of febrile rise of temperature is

GENERAL PATHOLOGY OF FEVER 359

not in harmony with wliat we know concerning the mode of production of
fever (see Lecture I).

The failure to explain the pathogenic power of bacteria in these and
similar ways led to the supposition that the morbid activity of pathogenic
bacteria is exerted chiefly by means of injurious chemical products. The
demonstration of such products leaves no room for doubt as to the correct-
ness of this supposition for some infectious diseases. This explanation is
probable for most such diseases, but experience has shown that it is particu-
larly dangerous to indulge in hasty generalization in this department of
medical science.

Sterilized and filtered cultures, particularly old cultures, of various patho-
genic bacteria are capable of producing fever and other symptoms when in-
jected into the blood or tissues. This, of course, makes it evident that the
bacteria in question give rise to poisonous substances. It is necessary to
distinguish between the intoxication produced by the injurious products of
bacteria and the infection caused by multiplication of the microorganisms
within the body. That this distinction may be readily overlooked is shown
by the recent experiments with the inoculation into animals of pure cultures
of the typhoid bacillus. Small quantities of these cultures may be inoculated
without any apparent effect; if, however, larger quantities are injected into
the veins or the peritoneal cavity of a rabbit, the animal dies in a short time
and the characteristic bacilli are found in the blood, spleen, and elsewhere.
It was supposed by Friinkel and Simmonds,'" to whom we owe this latter
observation, that actual infection took place, but it has been demonstrated
by Sirotinin and by Beumer and Peiper " that under these circumstances no
multiplication of the injected bacilli occurs, and that the same results may
be obtained by the injection of sterilized typhoid cultures.

The isolation in a chemically pure state of the poisonous products of
pathogenic bacteria encounters great difficulties, and we owe to Brieger "
nearly all that has been accomphshed in this direction. Two substances
which he has obtained from cultures of pathogenic bacteria are of great
interest. Brieger isolated from pure cultures of the typhoid bacillus a very
poisonous ptomaine or toxine, as he prefers to call this group of substances.
He has given to it the name tvphotoxine. It may be somewhat significant
that he failed to find typhotoxine in a culture which had stood for twenty-
four hours at a temperature of 102.2° F. (39° C). The injection of typho-

"Frankel and Simmonds: Die Aetiologische Bedeutung des Typhus-bacillus,
Hamburg und Leipzig, 1S86.
" Sirotinin: Zeitschrift f. Hygiene, Bd. I, 465.

Beumer u. Peiper: Hid, p. 489.
"Brieger: Untersuchungen iiber Ptomaine, Berlin, 1886.

360 CARTWRinilT l.P^CTURES

toxine into guinea-pigs produced great muscular weakness, diarrhoea, in-
creased frequency of pulse and of respiration, and death. Nothing is said
as to the etfoct upon the temperature of the animal.

A tosine has been isolated by Brieger in a crystalline form from an im-
pure culture of the tetanus bacillus. This substance, called tetanin, pro-
duces, when injected into animals, the characteristic symptoms of tetanus.

It is evident that these important discoveries render far more definite
than was formerly possible, the belief that bacteria produce fever by means
of their chemical products.

A dangerous influence exerted by poisonous ptomaines is that under their
agency the power of the body of resisting the invasion of various micro-
organisms may be impaired or overcome. Thus, ^Yyssokowitsch has shown
that the immunity of some animals against certain species of bacteria may
be destroyed by ptomaine poisoning.

lu order to observe the effects upon the temperature, I have injected
into rabbits sterilized cultures of the typhoid bacillus. Injections of very
small quantities of these cultures produce no effects, somewhat larger
amounts cause a rise of temperature without other marked symptoms, still
larger quantities produce increased temperature, diarrhoea, weakness, and
otiier manifest symptoms of severe illness, but the animal may recover;
relatively large amounts are followed by fall of temperature, grave illness,
and death. I have also obtained results similar to those of Sirotinin, who
inoculated two rabbits with the same amount of a typhoid culture. In one
rabbit fever developed and the animal recovered ; in the other, the tempera-
ture fell after the injection, and the animal died. This certainly does not
indicate that the rise of temperature in itself is an unwelcome attendant of
intoxication with the poisonous products of bacteria. My experiments cer-
tainly showed that the animals were more likely to die after injection of
typhoid cultures when the temperature fell than when it rose, independently
of the quantity of material injected. One is reminded here of the very
malignant cases of typhoid fever reported by Frantzel, and others, in which
the temperature throughout a great part of the disease was subfebrile, or
even at times subnormal.

In no disease is tlie dependence of the febrile paroxysm upon the presence
of bacteria so apparent as in relapsing fever, where, according to the state-
ments of most, although not of all, observers the spirilla appear in the blood
at the beginning of a paroxysm and disappear at the end. Whether or not,
here and in malaria, the pyrogenic agent is a chemical product of the micro-
organisms causing the disease, we do not know.

I must content myself with having brought before you evidence showing
that at least in some of the infectious fevers the specific bacteria produce

GENERAL PATHOLOGY OF FEVER 361

pyrogenlc substances. We have no right to saj- that this is the only way in
which pathogenic bacteria can cause fever.

We have considered now three groups of agents concerned in the produc-
tion of fever, viz. : first, unorganized ferments and other relatively homolo-
gous substances; second, ptomaines and other chemical products of sapro-
phytic microorganisms; third, pathogenic microorganisms and their chemi-
cal products.

It is not to be understood that these groups correspond to sharply defined
classes of fever-producing agents. The same substance may be produced by
the action of unorganized ferments, as well as by saprophytic bacteria or by
parasitic bacteria; hence, we may find the same fever-producing agent in
each of the three groups. As has already been mentioned, our knowledge
does not justify us in regarding these various substances as the immediate
and direct pyrogenic agents. The epitliet pyrogenie is applied to them only
by a certain latitude of signification. It is possible that these various sub-
stances, which we are in the habit of describing as pyrogenic, may produce
in the body some common change which gives rise to the real fever-producing
agent. This is the view of von Bergmann and Angerer, who believe that this
common change is a liberation of fibrin ferment by destruction of leucocytes.
While we cannot consider this view as more than an hypothesis, it is, never-
theless, well to remember that apparently heterogeneous substances, which
are usually designated as pyrogenic, may produce similar changes which are
to be regarded as the real source of the febrile disorder of animal heat. But,
notwithstanding these limitations and these elements of uncertainty, it seems
to me that some such classification as that suggested of the agents producing
fever is more useful than that usually employed in the discussions of the
etiology of symptomatic and of essential fevers.

There is one point which must be impressed upon every one who makes
many experiments with pyrexial agents. This is, that once in a while a
substance of undoubted pyrogenic power causes a fall instead of a rise of
temperature. This occurs frequently when the substance is injected in large
quantity and under these circumstances there is usually produced a condi-
tion of collapse. But in exceptional cases the same dose which will cause in
one animal a rise of temperature may give rise in another animal of the same
species to a distinct reduction of temperature. In these latter cases there
must be some idiosj-nerasy on the part of the animal. Aronsohn " refers this
unusual phenomenon to some peculiarity of the heat centers in the brain, and
he draws an interesting parallel between this contrar}- effect of pyrogenic
substances and the exceptional cases in which antipyretic drugs give rise to
elevation instead of lowering of temperattire.

"Aronsohn: Deutsche med. Wochenschritt, 1888.
26

362 CAirrwrvTOHT LECTURES

The causes of fever which we have thus far discussed, have been sub-
stances which exert a pyrojienic effect wlicn introduced into tlie circulation.
We suppose that these substances act in sonic way upon tlie nervous system,
but whether or not this action is a primary one it is impossible to say. Even
if wc assume, as is often done, that tbc.«c substances incite directly in the
blood and tissues chemical changes which lead to increased production of
heat, we must still have recourse to some action upon the nervous system, as
has already been sufTiciently set forth in the previous lectures.

It cannot be doubted that fever may be caused by other agencies than
pyrogenic substances present in the blood or tissues. The effects of exposure
to external heat have already been considered. We found experimental
evidence in support of the view ably advocated by H. C. Wood, that in typical
cases of thennic fever or sunstroke, the strain placed upon the heat-regulat-
ing centres by exposure to excessive heat results in paralysis of these centres
with rapid elevation of the internal temperature.

The cause of the elevation of temperature in tetanus is not altogether
clear. In this disease the temperature may vary but little from the normal,
but it is not uncommon to find excessive elevations of temperature toward
tlie termination. Temperatures of 113° F. (45° C), or more, have been
recorded. The idea would naturally suggest it.self that the rise of tempera-
ture is due to the tetanic muscular spasms, which we know to be accompanied
by production of heat. Leydeii was led to adopt this explanation by the
results of experiments made upon animals. He succeeded by producing
violent tetanic contractions of the muscles of a dog, in raising the internal
temperature in the course of one hour and a lialf from 103.3° F. (39.6° C.)
to 112.6° F. (44.8° C). Clinical observations, liowever, do not support the
supposition that the hyperpyretic temperatures of tetanus are dependent
upon the muscular contractions. In spite of violent and prolonged tetanic
spasms, the internal temperature may n^main normal or be but slightly
elevated. There is a decided similarity between the hyperpyrexia of tetanus
and that which occurs in rheumatism and some other diseases, particularly
in affections of the central nervous system, and it certainlv seems probable
that in all of these cases there is a profound disturbance of the heat-regulat-
ing centres. As the elimination of urea in tetanus is not excessive, we find
additional reason to separate tetanic hyiierpyrexia from orrlinarv febrile con-
ditions. Recent investigations of the etiologj- of tetanus, have rendered it
certain that at least some forms of this disease are caused by infection with
a sfiecial niicrdorganism. This has been demonstrated not only in the tetanus
of animals but also in that of human beings. The tetanus bacillus has been
found wide-spread in the ground in Germany, and I find it abundant in the
ground in Baltimore and its neighborhood. In experimental tetanus, the

GENERAL PATHOLOGY OF FEVER 363

bacillus, which has not yet been obtained in perfectly pure cultures, develops
chiefly in the tissues near the seat of innoculation, and does not invade other
parts of the body and the blood to any great extent. This indicates that the
s}inptonis are referable chiefly to poisoning by some chemical products of
the specific microorganism. As has already been mentioned, this view is
sustained by Brieger's discovery in cultures containing the tetanus bacillus
of a peculiar ptomaine which he has called tetanin, and which produces
tonic spasms of the muscles. It is, therefore, reasonable to believe that the
hyperpyrexia of tetanus is caused by the action of poisonous products of the
tetanus bacillus on the nervous centres concerned in temperature regulation.
Our present knowledge, however, does not warrant us in asserting that all
forms of tetanus in human beings are of an infectious nature.

In tlie first lecture of this course, evidence was presented to show that
pyrexia may be caused by affections of the nervous system without the agency
of any pyrogenie substance. It may jar upon the sensibilities of some to
call this form of pyrexia fever ; but this hesitation can be due only to the idea
that symptoms which are referable to infection or intoxication are essential to
the conception of fever. In my judgment, we shall be led into confusion if
we attempt to incorporate into our definition of fever, more than properly
belongs to the febrile disorder of animal heat, and from this point of view
there can be no impropriety in designating as fever, the pyrexia dependent
directly upon affections of the nervous svstem.

It is not necessary to repeat here the conclusive experimental evidence for
the existence in the nervous system of centres or regions which control the
dissipation of heat and the chemical processes concerned in the production
of heat. Those who are not much impressed by experiments upon animals,
can hardly fail to be convinced by the clinical evidence which demonstrates
that lesions of the nervous system may cause elevation of temperature, which
cannot be referred to the action of any pyrogenie substance. Such evidence
must, of course, be collected from eases where the fever cannot be explained
by inflammation, bed-sores, or other lesions which can give rise to absorption
fever. W. Hale White," in the interesting article already referred to, has
collected a number of cases of tumor, hemorrhage, softening, sclerosis, injury
and functional disturbance of the spinal cord and brain, in which the pj'rexia
or hyperpyrexia is to be explained only by the lesion of the nervous system.
The number of such cases might be considerably increased. These eases
show that lesions of the cervical part of the cord, of the pons, of the corpus
striatum, and of the neighboring white matter, are most likely to be asso-
ciated with high temperature, but the cases hitherto reported hardly justify

"W. Hale White: The Theory of a Heat Centre from a Clinical Point of View.
Guy's Hospital Reports, 42, 1884.

364 CAHTWHinTIT T.ECTURES

positive statements as to the exact situation in man of thermieally active
nerves or rejrions in the brain and spinal cord. As nii<rht he expected, not
only focal lesions, but also diffuse diseases such as occur in general paralysis
of the insane, locomotor ataxia, multiple sclerosis may give rise to pyrexia
wliicli sometimes assumes the form of temperature crises. It is in harmony
with what we know of oilier disorders of the nervous system, to find that not
only demonstrable anatomical lesions, but also functional disturbances may
produce nervous pvrexia. Such functional disturbance furnishes the most
probable explanation of the singular and erratic elevations of temperature
which have been occasionally observed in hysteria.

A question which merits more consideration than it is possible to give to
it on the present occasion, relates to the possibility of the occurrence of fever
as a reflex neurosis. The advance in our knowledge of the etiology of trau-
matic and inflammatory fevers, has pushed aside almost wholly the old
doctrine of irritative fever. There are, however, cases of fever where still
the simplest, and apparently most rational, explanation of the causation, is
peripheral nerve irritation. As examples may he mentioned, the fever re-
sulting from teething in children, that sometimes accompanying the passage
of gall-stones or urinary calculi, and that occasionally following the insertion
of a catheter into the urethra. It must bo admitted that the evidence on this
point is not conclusive. Especially is there lack of satisfactory experimental
evidence. Electrical irritation of the exposed sciatic nerve is, under ordinary
circumstances, followed by a moderate fall of temperature, although Ott"
finds that in atropinized cats such irritation is followed by a decided rise
of temperature. But these experiments cannot be held to weigh for or
against the doctrine of irritative fever. Observations on human beings
indicate that peripheral nerve irritation, if ever a cause of fever, is so only
in certain situations and under certain forms of stimulation, and in certain
individuals. In infants temperature regulation is more labile than in adults,
so that it may be that nerve irritation can more readily disturb the tempera-
ture in the former tliau in the latter. The chief controversy as to the ques-
tion now before us, has been as to the explanation of certain forms of urethral
or catheter fever. It cannot be doubted that a large number, probably most,
of the cases of so-called urethral fever, are instances of genuine absorption
fever. Even if we exclude all cases with diseased kidneys, or with cystitis
or other inflammatorj- disease of the urinary passages, there remains a cer-
tain number of cases in which the gentle insertion of a disinfected catheter
is followed by distinct febrile reaction. It seems unwarrantable to assume
that in all of these cases the catheter has caused a laceration of the uretlira

"Ott: Therapeutic Gazette, August, 1887.

GENEEAL TATHOLOGY OF FEVER 365

through which pyrogenic substances are absorbed. What is the nature and
whence the source of these substances? In the cases now under considera-
tion, they can be sought only in the normal urine, and of their existence there
no proof has been afforded. In these cases it is certainly very difficult to
understand how the fever can be interpreted as due to the absorption of some
pyrogenic agent, and failing this explanation, the idea that the fever is
dependent upon nerve irritation is most plausible.

I have now presented to you an imperfect survey of tlie general etiology
of fever. The attempt has been made to classify the leading causes of fever,
but it cannot be claimed that every variety of fever can be assigned to one
of these groups of causes. Our knowledge of the etiology of special fevers
is still too imperfect to warrant any such generalization. This is an attrac-
tive field for much patient investigation. I need only remind you of the
uncertainty which still pertains to the causation of many of the fevers of
warm countries. There is reason to believe that there remain yet to be
differentiated etiologically, specific types of fever which occur among us, and
particularly in our Southern States. It may be, that increasing knowledge
will necessitate the recognition of varieties of pyrogenic agents entirely dis-
tinct from any with which we are now familiar. It is certain that future
investigations will add clearness and precision to our ideas of the nature and
mode of action of causes of fever which, at the best, we can now understand
only imperfectly.

I cannot conclude this course of lectures without saying a few words on a
subject which must engage the attention of every one who gives much thought
to the nature of fever. 'Wliat is the significance of fever, is a question which
thrusts itself upon us no less than it has upon physicians in all ages. Un-
fortimately, we cannot to-day, any more than could our predecessors, give
other than a speculative answer to this question. There have been in all
ages enlightened physicians who have held the opinion that fever is a process
which aids in the elimination or destruction of injurious substances which
gain access to the body. Under the influence of ideas which sought in in-
creased temperature tlie origin of the grave symptoms of fever, we have in
recent times in great part lost sight of the doctrine once prevalent, that there
may be in fever a conservative element. There is much which speaks in
favor of this doctrine. The real enemy in most fevers, is the noxious sub-
stance which invades the body, and there is nothing to prevent us from
believing that fever is a weapon employed by nature to combat the assaults
of this enemy. The doctrine of evolution indicates that a process which
characterizes the reaction of all warm-blooded animals against the invasion
of a host of harmful substances, has not been developed to so wide an extent,
and is not retained with such pertinacity without subserving some useful

366 CAlJTWRir.IIT LECTURES

purpose. This is a point of view from wliicli many patliological processes
can he regarded witli advantage. Even .suppuration, which one does not
"•enerally look upon as a beneficent provision, is a most import^mt in.strument
of nature in forming a l)arrier against general infection of the body with
cert.ain microorganisms. It is im()0ssihle with our present knowledge, to
say in exactly what way fever accomplislies a useful i)uri)ose. There are
fact.s wliich suggest that in some cases of fever the increased temperature
as .such may impair the vitality or check the virulence of pathogenic micro-
organisms, l)ut there are many circumstances which make it difficult to
suppose tiiat this is the agency by whidi fever usually exerts a favorable
action.

The supposition seems to me more proljable that the increased oxidation
of fever aids in the destruction of injurious substances. According to this
view, the fever-producing agents light the fire which consumes them. It is
not incompatible with this conception of fever, to sujjpose that the fire may
prove injurious also to the patient and may require the controlling hand of
tlie physician. Time will not permit me to elaborate further the ideas here
suggested. In the course of these lectures some facts have been presented
and others might be drawn from clinical and experimental observations
which favor the hypothesis that fever is in a certain sense a conservative
process. Unproven and intangible as tiie hypothesis may seem to some, no
apologj' is needed for bringing to your attention a conception of fever in
favor of which much can be adduced, and which, if true, is of fundamental
importance, both tlieoretically and practically.

HYPERTHERMY IN MAN"

An even more i-emarkalble case has been reported tliaii tliat described by
Dr. Jacobi. It was reported by Dr. W. J. Galbraith, of Omaha, Neb., in an
article entitled " A Remarkable Case," and published in the " Journal of
the American Medical Association," March 31, 1891. The temperature in
this case was observed by Dr. Galbraith to rise to 151° F., while the nurse's
record shows it to have reached 171° F. The patient was a married woman,
twenty-six years of age, who is said to have had repeated attacks of perito-
nitis during the period of observation of the high temperature, and to have
passed per vagi/mm over one thousand pieces of bone, which were believed
to come from a dead foetus of extra-uterine pregnancy. Dr. Galbraitli's
description of the case is most graphic. At first, entirely skeptical, he
refused at the first call even to see the patient in consultation, but personal
examination later made a complete convert of him. Suspecting some decep-
tion, he says the following test was made : " The patient was placed in a
chair, all clothing removed, and a careful examination made of her month
and axillary region, every possible precaution taken in order to prevent any
deception, and holding the end of the thermometer so that it couJd not be
tipped in any way, we again proceeded to take her temperature; but, gentle-
men, the result was the same; the thermometer under the axilla registered
137° F., while that under tlie tongue registered 131° F."

There was nothing in the pulse or the general condition of the patient to
indicate any elevation of temperature. Especially constructed and carefully
tested thermometers were used.

So far as one can judge from the description of Dr. Galbraith's case, and
the same is true of Dr. Jacobi's case, there was no apparent mode of decep-
tion. Still, Dr. Jacobi must pardon me if, with the greatest respect for his
skill as an observer, I express complete skepticism as to the trustworthiness
of these observations. I do not undertake to explain in what way deception
was practised, but there is no doubt in my mind that there was deception.
Such temperatures as those recorded in Dr. Galbraith's and Dr. Jacobi's
cases are far above the temperature of heat-rigor of mammalian muscle and
are destructive of the life of animal cells. They could not be present even in

' Remarks on a paper by A. Jacobi, before the Association of American Physi-
cians, Washington, D. C, May 31, 1895.

Tr. Ass. Am. Physicians, Phila., 1895. X, 189-191.

367

368 HYPEirniHi;MY IN :\IAX

the integument alone for any length of time without leaving behind mani-
fest lesions where they existed. I consider them to be physical impossibili-
ties under the conditions described.

[Addendum. When making the preceding remarks I was not aware that
Dr. (Jalbraitli's case had already been tlioroughly discredited by subsequent
developments. A physician — Dr. Bridges — wlio liappened to be present
when I was speaking, immediately afterward told me that he was familiar
with the case, having been an interne in the hospital where this woman was
admitted, and where she atteni])ted again to practise deception, which was
detected. Two articles relating to the case, published since Dr. Galbraith's
article, liave come to my notice, and I believe that Dr. Bridges referred to a
tliird article, in wliich his experiences were narrated ; but this last one I have
not seen. One article is by Dr. J. E. Summers, Jr., in the " Omaha Clinic,"
September, 1891, and is entitled "Omaha's Remarkable Case of High
Temperature — an Undoubted Hysterical Fake." Tlie patient's temperature
had continued to oscillate from several degrees below normal to any point
below 150° F., with symptoms interpreted as those of peritonitis. On Hay
19, 1891, Dr. Summers perfonned abdominal section, and, save the presence
of old adhesions about the uterine adnexa, found no evidences of peritonitis
or of the previous existence of an extra-uterine pregnancy. Several pieces
of bones wliich had been removed from the vagina, and had been attributed
to a macerated foetus, were sent to Dr. Billings, at the Army Medical
Museum, where they were pronounced to be " portions of the sternum of
some bird, probably a chicken ; also one of the long bones nearly complete,
and a portion of the skull of a cliicken or some bird about the same size.
Other fragments are of larger boues than those of a fowl ; in fact, they re-
semble splinters of ordinary beef or mutton bones. You may be positively
certain that none of the fragments of bones have come from any organism
developed in a liuman female." Before sending the specimens Dr. Summers
had liimsclf come to the conclusion that the bones were not those of a hiunan
foetus, hut bad been placed in the genital passages by the woman herself.
Tliese bones are still preserved in the Army Medical iluseum, where I have
seen them. The patient had " never been able to make lier temperature go
up," as she expressed it, when Dr. Summers tested it.

A second article was published in February, 1892, in the same journal, by
Dr. C. T. Poe, entitled " A Chronic Malingerer." Dr. Poe describes his
experience with this patient two years previous to tlie ])ublication of Dr.
Galliraitb. Dr. Poe narrates a remarkable attempt on the ]iart of tlie patient
to represent that slio had recently bwMi delivered of a child, although ex-
amination precluded the possibility of this, and he exposed her in the attcnijit
to palm off on him a temperature of 112° F. Here tlie trick was the simple

HYPERTHERMY IN MAN 3G9

one of heating the thermometer with a hot-water bottle in tlie bed. It may
be stated that in the fall of 1889 this versatile malingerer attended a course
of lectures in the Woman's Medical College at Chicago. There were many
other interesting phenomena of malingering presented by this patient. I
am not aware that any explanation has been given of the precise method by
which she deceived Dr. Galbraith. The points in the case most interesting
to me are not the extraordinary height of the temperature, but the entire
good faith, with which Dr. Galbraith, one of the most experienced and best-
known surgeons in Omalia, reported the case, and the apparent thoroughness
of tlie tests to which he subjected the patient.]

ADAPTATION IN PATHOLOGICAL PROCESSES'

Grateful as I am for the personal good-will manifested by my selection as
President of tliis Congress, I interpret this great and unexpected honor as
an expression of your desire to give conspicuous recognition to those branches
of medical science not directly concerned with professional practice, and as
such I acknowledge it with sincere thanks.

All departments represented in this Congress are working together toward
the solution of tliose great problems — the causes and the nature, the preven-
tion and the cure, of disease — which have always been and mu;5t continue
to be the ultimate objects of investigation in medicine. It is this unity of
purpose which gives to the history of medicine from its oldest records to
the present time, a continuity of interest and of development not possessed
in equal degree by any other department of knowledge. It is this same
unity of jiurpose which joins together into a single, effective organism the
component parts of this Congress, representing, as they do, that principle
of specialization and subdivision of labor which, notwithstanding its perils,
has been the great factor in medical progress in modern times.

Medical science is advanced not only by those who labor at the bedside,
but also by those who in the laboratory devote themselves to the study of the
structure and functions of the body in health and disease. It is one of the
most gratifying results of the rapid advance in medical education in this
country during the last few years, that successful workers in the laboratory
may now expect some of those substantial rewards which formerly were to
be looked for almost exclusively in the fields of practical medicine and sur-
gery. We already have abundant assurance that the steady improvement
in opportunities and recompense, and other material conditions essential for
the prosecution of scientific work in medicine, will enable this country to
contribute to the progress of the medical sciences a share commensurate with
it^ great resources and development in civilization.

The subject of " Adai)tation in Patliological Processes," which I have
selected for my address on this occasion, is one which possesses the broadest
biological, sis well as medical, interests. It is this breadth of scientific and
practiial interest that must justify my ciioice of a theme which involves

' President's address before the Congress of American Physicians and Surgeons,
Washington, D. C, May 5, 1897,

Tr. Cong. Am. Phys. & Surg., N, Haven, 1897. IV, 284-310.

370

ADAPTATIOX IX PATHOLOGICAL PROCESSES 371

many technical considerations and many problems among the most obscure
and unsettled in the whole range of biology and of medicine.

I shall employ the epithet " adaptive " to describe morbid processes which
bring about some sort of adjustment to changed conditions due to injury or
disease. In view of the more technical and restricted meaning sometimes
attached to the term " adaptation " in biology, objection may be made to
this broad and general application of the word in ])athology; but no more
suitable and convenient epithet than " adaptive " has occurred to me to
designate the entire group of pathological processes whose results tend to
the restoration or compensation of damaged structure or function, or to the
direct destruction or neutralization of injurious agents. Processes which
may be described variously as compensatory, regenerative, self-regulatory,
protective, healing, are thus included under adaptive pathological processes.
These processes are, in general, more or less advantageous or useful to the
individual; but for reasons which will be stated later the conception of
pathological adaptation and that of advantage to the individual are not
wliolly coextensive.

Within the limits of an address I cannot hope to do more than direct
attention to some of those aspects of the subject which seem to me to be of
special significance. Although most striking examples of adaptation are to
be sought in comparative and vegetable pathologj-, what I shall have to say
will relate mostly to human pathology. My purpose is not to point out the
beauties or the extent of adaptations in pathological processes, but rather
to say something concerning the general mechanism of their production
and the proper attitude of mind regarding them, and to illustrate the general
principles involved by a few representative examples.

It has been contended that the conception of adaptation has no place in
scientific inquiry; that we are justified in asking only by what means a
natural phenomenon is brought about, and not what is its meaning or pur-
pose ; in other words, that the only question open to scientific investigation
is How ? and never Why ? I hope to make clear by what follows in what light
I regard this question, and in this connection I shall simply quote Ijotze,
who, beginning as a pathologist, became a great philosopher : " Every
natural phenomenon may be investigated not only with reference to the
mathematical grounds of its possibility and the causes of its occurrence, but
also as regards the meaning or idea which it represents in the world of
phenomena."

The most wonderful and characteristic attribute of living organisms is
their active adaptation to external and internal conditions in such a way
as tends to the welfare of the individual or of the species. Of the countless
physiological examples which might be cited to illustrate this principle, I

372 ADAl'TATlUN I.N I'ATIIOLOGICAL PROCESSES

select, almost at random, the preservation of the normal temjx'rature of the
body in warm-blooded animals under varying external temperature^; anJ
varying internal production of heat, the regulation of respiration according
to the need of the tissues for oxygen, the influence of the load upon the work
performed by muscles, the accommodation of the lieart to the work demanded
of it, the response of glands to increiised functional stimulation, the adjust-
ment of the iris to varying degrees of illumination, the influence of varying
static conditions upon the internal architecture of bone.

The most striking characteristic of these countless adaptations is their
apparent purposefuliicss. Even if it be true, as has been said by Ijange, that
" the formal purposcfulness of the world is nothing else than its adaptation
to our understanding," it is none the less true that the human mind is so
constituted as to desire and seek an explanation of the adaptations which it
finds everywhere in organic nature. From the days of Empedocles and of
Aristotle up to the present time there have been two leading theories to
explain the apparent purposefulness of organic nature — the one, the tele-
ological, and the other, the mechanical theory. The teleological theory, in
its traditional signification, implies something in the nature of an intelli-
gence working for a predetermined end. So far as the existing order of
nature is concerned, the mechanical theory is the only one open to scientific
investigation, and it forms the working hypothesis of most biologists. This
theory, in its modem form, seeks an explanation of the adaptations of living
beings in factors concerned in organic evolution. What these factors are we
know only in part. Those which are most generally recognized as operative
are variation, natural selection, and heredity. That additional factors, at
present little understood, are concerned seems highly probaljle. The accep-
tance of the explanation of physiological adaptations furnished by the doc-
trine of organic evolution helps us, I believe, in the study of pathological
adaptations.

As the word " teleology " has come to have, in tlie minds of many, so bad
a repute in the biological sciences, and as I desire, without e.itering into any
elaborate discussion of the subtle questions here involved, to avoid miscon-
ceptions in discussing subjects whose ultimate explanation is at present
beyond our ken, I shall here briefly state my opinion that all of those vital
manifestations to which are applied such epithets as adaptive, regulatory,
regenerative, compensatory, protective, are the necessary results of the action
of forms of energy upon living matter. The final result, however useful
and purposeful it may be, in no way directly influences the chain of events
wiiich leads to its production, and, tlierefore, the character of the result
affords no explanation whatever of the mechanism by which the end, whether
it appear purposeful or not, has been accomplished. In every case the ulti-

ADAPTATION IN PATHOLOGICAL PROCESSES 373

mate aim of inquiry is a mechanical explanation of the process in question.
Notwithstanding valuable contributions, especially within recent years,
toward such mechanical explanations, we are still far removed from the
attainment of this aim.

The knowledge of the fact that the living body is possessed of means
calculated to counteract the effects of injurious agencies which threaten or
actually damage its integrity must have existed as long as the knowledge of
injury and disease, for the most casual observation teaches that wounds are
repaired and diseases are recovered from. It is no part of my present purpose
to trace the history of the numerous speculations or even of the development
of our exact knowledge concerning the subjects here under consideration. I
cannot refrain, however, from merely referring to the important role which
the conception of disease, as in some way conservative or combative in the
presence of harmful influences, has played from ancient times to the present
in the history of medical doctrines. Whole systems of medicine have been
founded upon this conception, clothed in varying garb. There is nothing
new even in the image, so popular nowadays, representing certain morbid
processes as a struggle on the part of forces within the body against the
attacks of harmful agents from the outer world. Indeed, Stahl's whole con-
ception of disease was that it represented such a struggle between the anima
and noxious agents. What lends especial interest to these theories is that
then, as now, they profoundly influenced medical practice and were the
origin of such well-known expressions as vis medicatrix naturae and medicos
est minister naturae.

It is needless to say that there could be no exact knowledge of the extent
of operation or of the nature of processes which restore or compensate
damaged structures and functions of the body or combat injurious agents,
before accurate information was gained of the organization and workings
of the body in health and in disease. Although the way was opened by
Harvey's discovery of the circulation of the blood, most of our precise
knowledge of these subjects has been obtained during the present century,
through clinical observations and pathological and biological studies. In
the domain of infectious diseases wonderful and hitherto undreamed-of pro-
tective agencies have been revealed by modern bacteriological discoveries.
Here, as elsewhere in medicine, the experimental method has been an in-
dispensable instrument for discoveries of the highest importance and for the
comprehension of otherwise inexplicable facts. Very interesting and sug-
gestive results, shedding light upon many of the deeper problems concerning
the nature and power of response of living organisms to changed conditions,
have been obtained in tliose new fields of experimental research called by
EoiLS the mechanics of development of organisms, and also in part designated

374 ADAPTATION IN rATIIOLOGICAL PROCESSES

pliysiological or experimental morpholofry. Although we seem to be as far
removed as ever from the solution of the most fundamental problem in
biology, the origin of the power of living beings to adjust themselves actively
to internal and external relations, we have learned something from these
investigations as to the parts played respectively by the inlierited organiza-
tion of cells and by changes of internal and external environment in the
processes of development, growth, and regeneration.

In physiological adaptations, such as those wliich have been mentioned,
the cells respond to clianged conditions, to meet which they are especially
fitted by innate properties, determined, we must believe, in large part by
evolutionarj- factors. In considering pathological adaptations the question
at once suggests itself whether the cells possess any similar peculiar fitness
to meet the morbid changes concerned; whether, in other words, we may
suppose that evolutionary factors have operated in any direct way to secure
for the cells of tlie body jiroperties especially suited to meet pathological
emergencies. Can we recognize in adaptive pathological processes any
manifestations of cellular properties which we may not suppose the cells to
possess for physiological uses? This question appears to me to be of con-
siderable interest. I believe that it can be shown that most pathological
adaptations have their foundation in physiological processes or mechanisms.
In the case of some of these adaptations, however, we have not sufficiently
clear insight into the real nature of the pathological process not into all of
the pliysiological properties of the cells concerned to enable us to give a posi-
tive answer to the question.

While we must believe that variation and natural selection combined with
heredity have been important factors in the development and maintenance
of adjustments to normal conditions of environment, it is difficult to see
how they could have intervened in any direct way in behalf of most patho-
logical adaptations.

An illustration will make clear the points here involved. Suppose the
human race, or any species of animal, to lack tlie power to compensate the
disturbance of the circulation caused by a damaged heart-valve, and that an
individual should happen to be born with tlie exclusive capacity of such
compensation. The chances are that there would arise no opportunity for
the display of this new capacity, and it is inconceivable that the variety
would be perpetuated through the operation of the law of survival of the
fittest by natural selection, unless leaky or clogged heart-valves became a
common character of the species. When, however, we learn that the dis-
turbance of circulation resulting from disease of the heart-valves is com-
pensated by the performance of increased work on the part of the heart, and
that it is a general law that such prolonged extra work leads to growth of

ADAPTATION IN PATHOLOGICAL PROCESSES 375

mujjcle, we see at once that tins compensation is only an individual instance
of the operation of a capacity which has abundant opportunities for exercise
in normal life, where the influence of natural selection and oilier factors of
evolution can exert their full power.

In a similar light we can regard other compensatory and functional
pathological hypertrophies — indeed, I believe, also tc a considerable extent
the pathological regenerations, inflammation, and immunity, although here
the underlying factors are, of course, different.

We may, however, reasonably suppose that natural selection may be
operative in securing protective adjustments, such as racial immunity,
against morbific influences to which living beings are frequently exposed
for long periods of time and through many generations.

These considerations help us to explain the marked imperfections of most
pathological adaptations as contrasted with the perfection of physiological
adjustments, although I would not be understood to imply that the absence
of the direct intervention of natural selection in the former is the sole ex-
planation of this difference. The cells are endowed with innate properties
espec-iaUy fitted to secure physiological adaptations. Xo other weapons than
these same cells does the body possess to meet assaults from without, to
compensate lesions, to restore damaged and lost parts. But these weapons
were not forged to meet the special emergencies of pathological conditions.
Evolutionary factors have not in general intervened with any direct reference
to their adaptation to these emergencies. Such fitness as these weapons
possess for these purposes comes primarily from properties pertaining to
their physiological uses. They may be admirably fitted to meet certain
pathological conditions, but often they are inadequate. Especially do we
miss in pathological adjustments that co-ordinated fitness so characteristic
of physiological adaptations. So true is this that the propriety of using
such terms as compensation and adaptation for any results of pathological
processes has been questioned.

A heart hypertrophied in consequence of valvular lesion does not com-
pletely restore the normal condition of the circulation. Experience has
sho■^\^l that a kidney hypertrophied in consequence of deficiency of the other
kidney is more susceptible to disease than the normal organ. Wliat an in-
complete repair of defects is the formation of scar-tissue, and with what
inconveniences and even dangers may it be attended in some situations!
If we look upon inflammation as an attempt to repair injury, and, therefore,
as an adaptive process, with what imperfections and excesses and disorders
and failures is it often associated ! How often in some complex pathologi-
cal process, such as Bright's disease or cirrhosis of the liver, can we detect
some adaptive features, attempts at repair or compensation, but these
overshadowed by disorganizing and harmful changes !

376 AIJAI'TATION IX rATIIOLOGlCAL PROCESSES

It is often difficult to dist'ii tangle, in the complicated processes of disease,
those elements which we may appropriately regard as adaptive from those
which are wholly disorderly and injurious. There are usually two sides
to the shield, and one observer from his point of view may see only the side
of disorder, and another from a different point of view, only that of
adaptation.

The conception of adajjtation in a pathological process is not wholly
covered by that of benefit to the individual. I understand, as has already
been said, by an adaptive pathological process one which in its results
brings about some sort of adjustment to changed conditions. This adjust-
ment is usually, wholly or in part, advantageous to the individual ; but it
is not necessarily so, and it may be harmful. The closure of pathological
defects by new growths of tissue is a process which must be regarded as
adaptive. But one would hardly describe as advantageous the scar in the
brain which causes epilepsy. A new growth of bone to fill in defects is often
highly beneficial ; but what grave consequences may result from thickening
of tlie skull to help fill the space left by partial arrest in development of
the brain in embryonic life or infancy ! We see here, as everywhere, that
" Nature is neither kind nor cruel, but simply obedient to law, and, there-
fore, consistent."

In turning now to the more special, but necessarily fragmentary, con-
sideration of a few of the pathological processes in which adaptation, in
the sense defined, is more or less apparent, I shall have in view the answers
to tliose two questions. What is the meaning of the process? and How
is it caused ? which confront us in our investigation of all natural phenomena.
At the outset it must be admitted that our insight into the nature of many
of these processes is very imperfect, and that here answers to the world-old
riddles Why? and How? are correspondingly incomplete and liable to err.

Although almost all of tlie elementary morbid processes, even the degen-
erations and death of cells, may, under certain conditions of the body, serve
a useful purpose — the pre-eminent examples of pathological adaptation, in
the sense of restoration or compensation of damaged structure or function,
or the direct destruction or neutralization of injurious agents, are to be
found among the compensatory hypertrophies, the regenerations, and the
protective processes. To this last ill-defined group I refer parasiticidal and
antitoxic phenomena, and some of the manifestations of inflammation, and
perhaps also of fever. In the last analysis tliese protective processes, no less
than the others mentioned, must depend upon the activities of cells.

As it is manifestly impossible, within the limits of a general address, to
attempt a detailed consideration of any large number of these adaptive path-
ological processes, and as such consideration would necessarily involve the

ADAPTATION IX PATHOLOGIC.\L PEOCESSES 377

discussion of many technical and doubtful point*, I have thought that my
purpose would be best served by the selection of a few representative ex-
amples.

The compensatory hypertrophies afford admirable illustrations of certain
fundamental principles regarding adaptations in pathology which I have
already stated. The hypertrophy secures a functional adjustment, often of
a highly beneficial character, to certain morbid conditions. This useful
purpose is attained by a succession of events determined from beginning to
end of the necessary response of cells and tissues, in consequence of their
inherent organization, to the changed conditions. Given tlie changed con-
ditions, on the one hand, and the organization of the cells, on the other, the
result must follow as surely as night follows day, and this final result in-
fluences the preceding series of events no more in the one case than in tlie
other. That the cells possess the particular organization determining the
manner of their response to these changed conditions, and, therefore, the
beneficial character of the result, is dependent upon innate properties whose
fitness for the purpose doubtless has been largely fixed by evolutionary
factors, operating, however, mainly in behalf of physiological functions and
not directly toward pathological adjustments. In correspondence with this
view we find tliat our knowledge of the manner of production of the com-
pensatory hypertrophies of various organs and tissues stands in direct
relation to our knowledge of the physiology of the same organs and tissues.

Those compensatory hypertrophies into the mechanism of whose produc-
tion we have the clearest insight are referable to increased functional activity,
and are, therefore, spoken of as work-hypertrophies. This has been proved
for the muscular hypertrophies and compensatory hj'pertrophy of the kidney ;
but the demonstration is not equally conclusive for the compensatory hyper-
trophy of other glands. I know, however, of no instance in which this factor
in the explanation can be positively excluded.

The relationship between increased functional activity and hypertrophy
is so evident in many cases that there is strong presumption in favor of this
explanation of tliose glandular compensatory hypertrophies which have not
as yet been clearly referred to the class of functional hypertrophies. The
very occurrence of compensatory hypertrophy of an organ may direct atten-
tion to the fact that it is endowed with definite functions, and the conditions
under which the hypertrophy occurs may shed light upon the nature of these
functions. I need only remind you of the significance, from this point of
view, of the compensatory hypertrophy of the thyroid, adrenal, pituitary,
and other glands with internal secretions. I fail to see whv Nothnao-el
should consider a priori improbable the occurrence of compensatorj- hyper-
trophy of one sexual gland after loss of the other, even before sexual ma-
27

378 ADAPTATION IN PATHOLOGICAL PROCESSES

turity, or why Ribbert, who has apparently demonstrated experimentally
such an occurrence, should find it necessary to seek the explanation in reflex
nervous influences or mere hyperaemia. The so-called secondary sexual
characters and the changes following castration, including the influence upon
a hypertrophied prostate, point to important, even if little understood, func-
tions which for the present we can perhaps best attribute to so-called internal
secretions of these sexual organs.

The name compensatory hypertrophy is sometimes applied to growths of
tissue that merely take the place of another kind of tissue which has fallen
out, as, for example, the growth of adipose tissue around a shrunken kidney
or pancreas, or between atrophied muscle-fibres. Here there is only com-
pensation of space, but no compensation of structiire or function. Such
hypertrophies and growths are described better as complementary than com-
pensatory.

Familiar examples of pathological hypertrophies from increased work
are the hypertrophy of the heart from valvular disease and other causes,
that of the muscular coats of canals and bladders behind some obstruction,
and that of one kidney after loss or atrophy of the other.

In order to understand fully the manner of production of work-hyper-
trophy of a part resulting from some morbid condition, it is essential to know
the nature of the disturbances induced by the underlying morbid condition,
how tliese disturbances excite increased functional activity of the part which
becomes hypertrophied, and what the relation is between this greater activity
and the increased growth of the part.

It is impossible on this occasion to go through the whole list of compen-
satory hypertrophies with reference to the application of these principles.
In no instance can the requirements stated be completely met in the present
state of our knowledge. It will suffice for an understanding of the principles
involved, and it is only with these that I am now concerned, if I take a con-
crete example. I select the classical and best studied one — compensatory
hypertrophy of the heart. I trust that I shall be pardoned for selecting so
commonplace an illustration, as the main points involved must be familiar
to most of my audience ; but it is possible that the application made of them
may not be equally familiar. The only matters essential to my present hne
of argument are the mechanism of produttion of the hypertrophy and the
general character of the adaptation tliereby secured.

The heart, like other organs of the body, does not work ordinarily up to
its full capacity, but it is capable of doing at least three or four times its
usual work. The excess of energy brought into play in doing this extra
work is called conveniently, althougli not without some impropriety, " re-
serve force." It has been proved experimentally that this storehouse of

ADAPTATION IX PATHOLOGICAL PROCESSES 379

reserve power is sufficient to enable the healthy heart, at least that of a dog,
to accommodate itself at once or after a few beats to high degrees of in-
snlficiency or obstruction at its valvular orifices without alteration in the
mean pressure and speed of the blood in the arteries. But even so tireless
and accommodating an organ as the heart cannot be driven at such high
pressure without sooner or later, becoming fatigued, and consequently so
dilated as to fail to meet the demands upon it. If it is to continue long the
extra work, it must receive new increments of energj-.

The cardiac muscle is far less susceptible to fatigue than the skeletal
muscles, but that it may become fatigued seems to me clear.

Leaving out of consideration some doubtful causes of cardiac hypertrophy,
such as nervous influences, the various morbid conditions which lead to this
affection are such as increase either the volume of blood to be expelled with
each stroke, or the resistance to blood-flow caused by the pressure in the
arteries or by narrowing at one of the valvular orifices, or both. Unless
some regulating mechanism steps in, each of these circulatory disturbances
must increase the resistance to contraction of the cardiac muscle, and it is
evident that the heart must do extra work if it is to pump the blood through
the arteries with normal pressure and speed. It is, however, no explanation
of this extra work simply to say that it occurs because there is demand for it.
Increased work by the heart in cases of disease of its nutrient arteries would
often meet a most urgent demand on the part of the body, but here the heart
flags and fails.

Tlie physiologists have given us at least some insight into the mechanism
by which the heart responds through increased work to the circulatory dis-
turbances which have been mentioned. These disturbances aU increase the
strain on the wall of one or more of the cavities of the heart ; in other words,
increase the tension of the cardiac muscle, in much the same way as a weight
augments the tension of a voluntar\- muscle. Xow it is a fundamental physi-
ological law that with a given stimulus greater tension of a muscle, within
limits, excites to more powerful contraction, and tlius to the performance
of greater work. It seems clear that this law applies to the muscles of the
heart, as well as to voluntary muscle. We do not know precisely how in-
creased tension facilitates the expenditure of greater muscular energj'.

Another well-known fact in the mechanics of muscle is of importance in
tliis connection. With increase of muscular tension under a given stimulus
a point is reached where the extent of contraction is diminislied, although
the mechanical work done, determined by multiplying the height to which
the load is lifted by the weight of the load, is increased. This law applied
to the heart, whose contractions are always maximal for the conditions
present at any given time signifies that, with increased resistance to tlie

380 ADAPTATION IX PATHOLOGICAL PROCESSES

contraction of the muscular wall of one of its cavities, this cavity will empty
itself during systole less completely than before. In other words, dilatation
occurs, and, as has been shown by Roy and Adami, to whom we owe important
contributions on this as well as on many other points relating to the me-
chanics of the heart, dilatation regularly antedates hypertrophy. This
primary dilatation, however, is not to be looked upon as evidence of beginning
heart-failure, for, as these investigators have pointed out, it is within limits
only an exaggeration of a physiological condition, and can be subsequently
overcome by hj^pertrophy, which, in consequence of increase in the sectional
area of the muscle, lessens the strain upon each fibre, and thereby permits it
to shorten more during contraction. If this result is completely secured,
we have simple hypertrophy. More often the dilatation remains, and must
necessarily remain, and we have eccentric hy]>ertrophy, which secures, for
a time at least, adequate, but I do not think we can say perfect, compensation.

The weight of existing evidence favors the view that the power of the
heart to adapt its work to the resistance offered resides primarily in its
muscle-cells, and not in intrinsic or extrinsic nervous mechanisms, altliough
doubtless these latter in various ways, which cannot be here considered, in-
fluence and support this regulating capacity. Nor can I here pause to dis-
cuss the influence of blood-supply to the cardiac muscle upon the force of
ventricular contraction, althougli Porter has demonstrated that this is
important.

In tracing the steps from the primary morbid condition to the final hj'per-
trophy, we have thus far had to deal mostly with known mechanical factors.
We now come to the question, How does increased functional activity lead to
increased growth ?

Inasmuch as greater functional activity is regularly associated with a
larger supply of blood to the more active part, the view is advocated by many
that the increased growth is the direct result of this hyperaemia, and one
often encounters, especially in biological literature, this opinion expressed
as if it were an indisputal>le fact. There is, however, no conclusive proof
of this doctrine, and many facts speak against it. The examples from human
pathology commonly cited to support the doctrine that local active hyper-
aemia incites growth of cells are, so far as I am able to judge, complicated
with other factors, such as injur}', inflammation, or trophic disturbances.
Transplantation-experiments, such as John Hunter's grafting the cock's
spur upon the cock's comb, sometimes adduced in this connection, are not
decisive of this question, for here a new circumstance is introduced which
some suppose to be the determining one for all morbid cell-growth, namely,
the disturbance of the normal equilibrium between parts. Local active
hyperaemia may exist for a long time without evidence of increased growth

ADAPTATION IX PATHOLOGICAL PPOCESSES 381

in the congested part. To say that the hyperaemia must be functional is
at once to concede that it is not the sole factor. Experiments from Bizzo-
zero's laboratory, by Morpurgo and by Penzo, indicate that local hyperaemia
due to vaso-motor paralysis, or to the application of heat, favors cell-multi-
plication in parts where proliferation of cells is a normal phenomenon or is
present from pathological ccuses, but that it is incapable of stimiilating to
growth cells whose proliferating power is suspended under physiological
conditions, as in developed connective tissue, muscles, and the kidneys.

It has been usually assumed that the way in which local hyperaemia may
stimulate cell-growth is by increasing the supply of nutriment to cells.
The trend of physiological investigation, however, indicates that the cell
to a large extent regulates its own metabolism. If the cell needs more food,
of course it cannot get it unless the supply is at hand, and in this sense we
can understand how a larger supply of blood may be essential to increased
growth ; but this is a very different thing from saying that the augmented
blood-supply causes the growth.

It is by no means clear that the question as to the influence of increased
blood-supply upon cell-growth is identical with that of increased IjTuph-
supply. The experiments of Paschutin and of Emminghaus, from Ludwig's
laboratory, nearly a quarter of a century ago, indicate that local hyperaemia
due to vaso-motor paralysis does not, as a rule, increase the production of
IvTuph ; and more recent experiments, although not wholly concordant in their
results upon this point, tend to the same conclusion. Functional activity,
however, has a marked influence in increasing the quantity and affecting the
quality of hmph in the active part. Our knowledge of the physical and
chemical changes in working muscles and glands enables us to conceive why
this should be so, for all are now agreed that the formation of IjTnph is due
not simply to filtration from the blood-plasma, but also to diffusion, and
some believe likewise to active secretion by the capillary endothelium.
Doubtless arterial hyperaemia is essential to the maintenance of the increased
flow of h-mph in working organs.

There are dilBculties in the way of supposing that increased supply of
IjTnph in itself furnishes the explanation of cell-growth, and especially of
that which characterizes hypertrophy of muscles and glands. Pathologists
have frequent opportunities to study the effects of all degrees of increased
production and circulation of lymph associated with venous hj-peraemia. A
kidney or a muscle may from this cause be subjected for months and years
to an excess of lymph-flow, but there is no demonstration of any consequent
hypertrophy or hyperplasia of renal epithelium or muscle-cell. It is true
that the chemical composition of the lymph is not the same as that of IjTuph
resulting from increased function, and it is possible that in this chemical

382 ADAPTATION IX PATHOLOCICAL PROCESSES

difference lies the kernel of the whole matter. It may also be urged that in
Venous liy])eraeniia there arc circumstances which restrain or prevent growth.
Nevertheless, if overfeeding, merely in consequence of increased supply of
nutriment, were the real explanation of work-hypertrophies, one would
e.xpect to find some evidence of this in the class of cases mentioned.

Ivihhert has recently given a new shape to the doctrine that local hyper-
aemia excites growth. While rejecting the usual explanation that it does
so hy supplying more food, he contends that distention of the blood vessels
and lymph-spaces, by mechanically disturbing the mutual relations of parts,
removes obstacles to growth. This theory cannot be advantageously dis-
cussed until the fact is first established that uncomplicated local hyperaemia
does incite growth.

As the matter now stands, it seems to me that any satisfactory explana-
tion of the cell-growth causing work-hypertrophies must start from physical
or chemical changes in the muscle- or gland-cell itself directly connected
with the increased function. These changes are the primum mobile, and,
however important increased supply of blood or lymph may be in the subse-
quent chain of events, it is not the determining factor. The whole problem
is part of the general one of the causes of pathological cell-growth, to which
I shall have occasion to refer again.

It is interesting to not* that not all kinds of excess of functional activity
lead to hypertrophy. A heart may beat for years faster than normal with-
out becoming hypertrophied. Small movements of muscle, often repeated,
do not cause hypertrophy. It would appear that the amount of work done
in each functional act must attain a certain height in order to stimulate
growth. On the other hand, if the muscle be stretched beyond certain limib?,
it does not hypertrophy; on the contrary, it may atrophy, as may be seen in
greatly distended canals and cavities with muscular walls. This behavior
is also in accordance with physiological observations.

The compensatory hypertrophy of muscle seems to be due mainly to
increase in the size of cells, although there are observations indicating that
they may also multiply. That of most glands is referable to increase both
in number and size of cells. Within four or five days after extirpation of a
kidney karyokinetie figures may be fouiul in increased number in the cells
of the remaining kidney.

The general character of the adaptation secured by compensatory hyper-
trophy of the heart is sufficiently well-known. I wish to point out certain
of its imperfections. I shall not dwell upon the well-known abnormal con-
ditions, with their remote consequences, of the systemic or pulmonar}- circu-
lation, which are present during the stage of compensation, nor shall I speak
of the various circumstances which may interfere with the establishment of
compensatory hypertrophy.

ADAPTATION IN PATHOLOGICAL PROCESSES 383

The muscle of a hypertrophied heart is sometimes compared to that of
the blacksmith's ami, and the statement is made that there is no reason
inherent in the muscle itself why the one should fail more than the other.
This may be true, but it is not self-evident. Exercise may influence in
various ways the nutrition, function, and growth of muscle as well as of other
parts. Mere increase in bulk is a coarse effect. Quality may be improved as
well as quantity. The biggest muscle is not necessarily the best or the most
powerful. As every trainer knows, various conditions under which work is
done influence the result. Increase in the reserve energy of the heart, secured
by judicious exercise — and this is tlie main factor in endurance — probably
cannot be attributed mainly to hypertrophy; indeed, enlargement of this
organ from exercise is often a serious condition. Much more might be said
in this line of thought, but I have indicated why it seems to me unjustifiable
to assume, without further evidence, that the condition of the muscle in
pathological hypertrophies is necessarily identical in all respects with that
in physiological hypertrophies.

There is an important difference in the working-conditions between most
hypertrophied hearts and the normal heart. Although the maximal available
energy of a hypertrophied heart during compensation is greater than that of
the normal heart, clinical experience shows that in the majority of cases the
energy available for unusual demands — that is, the so-called reserve force —
is less in the former than in the latter. Sometimes, especially when the
hypertrophy has developed in early life, the hypertrophied heart is at no
disadvantage in this respect. As pointed out with especial clearness by
Martins, the significance of this alteration in the ratio normally existing
between the energy expended for ordinary needs and that available for
unusual demands, is that it furnishes an explanation of the greater liability
of the hypertrophied heart to tire upon exertion. Fatigue of the heart is
manifested by dilatation of its cavities, and when this dilatation from fatigue
is added to that already existing in most cases, relative insufficiency of the
mitral or tricuspid valve is likely to occur, and the compensation is, at least
for a time, disturbed. The circulation through the coronary arteries, whose
integrity is so important for the welfare of the heart, is impaired, and a
vicious circle may be established. Notwithstanding the valuable contribu-
tions from the Leipzig clinic as to the frequency of various anatomical lesions
in the muscle of h^-pertrophied hearts, it does not seem to me necessary to
have recourse to them as an indispensable factor in the explanation of the
breakage of compensation ; but I shall not here enter into a discussion of the
general subject of the causes of failure of compensation.

I have described with some detail, although very inadequately, the manner
of production of compensatory hypertrophy of the heart, in order, by this

384 ADAPTATION IN PATHOLOGICAL PROCESSES

representative example, to make tlear wliat seem to me to be certain general
characteristics of many adaptive pathological processes, and I beg here to
call attention especially to the following; points. As has been emphasized
by Nothnapel and others, no teleological idea or form of language need enter
into the explanation of tlie mechanism of the process. The final result is
the necessary consequence of the underlying morbid conditions. We have
satisfactory mechanical explanations for essential steps in the process, and
there is no reason to assume that other than mechanical factors are con-
cerned in those vital manifestations which at present we are unable to ex-
plain by known physical and chemical forces. The properties of the cells
which determine the character of their response to the changed conditions
are none other than their well-known physiological properties. The adapta-
tion finally secured, admirable as it is in many respects, and perhaps adequate
for long and active life, is generally attended with marked imperfections,
and strictly speaking, is not a complete compensation. It does not present
that co-ordinate and special fitness which we are accustomed to find in
physiological adaptations, for the explanation of which so much has been
gained by the study of the factors concerned in organic evolution.

It may be argued that under the circumstances no better kind or degree
of adaptation can be conceived of than that which actually occurs, and that
the operation of evolutionary factors, ■with especial reference to the adjust-
ment of the organism to the conditions causing cardiac hypertrophy, could
not secure any better result. I think that it is not difficult to conceive how
improvements might be introduced. It is, however, permissible to suppose
that the introduction into the workings of the organism of some better
mechanism to compensate the morbid conditions, might be at the sacrifice
of more important physiological attributes of the body. More perfect path-
ological adaptations might in many instances involve a deterioration of the
physiological characters of the species. It is often the case that the more
highly organized living beings lack some capacity possessed by those lower
in the scale of organization to resist or compensate injury and disease. This
is notably true of the power to regenerate lost parts. It is, however, along
the lines of improvement in the physiological characters of the individual
or species that the opportunity often lies for securing increased resistance
to disea.se or better pathological adaptations.

It would be interesting to continue our consideration of the compensatory
hypertrophies by an examination of those of glandular organs from points
of view similar to those adopted for the heart. For the kidney, at least, the
materials are at hand for such a purpose; but, as I desire, in the limited
time at my disposal, to touch upon other varieties of pathological adaptation,
I must refer those interested especially to the investigations of Grawitz and

ADAPTATION IX PATHOLOGICAL PROCESSES 385

Israel, Eibbert, Xothnagel, and Sacerdotti as to the conditions underlying
compensator}- hypertrophy of the kidney. I can likewise merely call atten-
tion to the interesting researches of Poniick upon the most wonderful of the
compensatory hypertrophies in higher animals, that of the liver. Ponfick,
as is well kno\ni, has demonstrated that after removal of three-fourth of this
organ new liver-substance, with normal functions, is recreated from the re-
mainder and to an amount nearly equalling that which was lost.

The chapter of pathological adaptations in bones and joints I shall leave
untouched, notwithstanding the admirable illustrations which might be
drawn from this domain.

There is no more fascinating field for the study of pathological adapta-
tions with reference to the mechanical factors involved than that furnished
by the blood vessels, as has been shown especially by the brilliant researches
of Thonia. With wonderful precision can a vessel of system of vessels adjust
itself to changes in the pressure, velocity, and quantity of blood, and thereby
serve the needs of the tissues for blood. Under pathological, as well as
phj-siological conditions, this adjustment may be brought about not only
through the agency of vaso-motor nerves and the physical properties of the
vascular wall, but also, when the necessity arises, by changes in the structure
of the wall.

The changes in the circulation introduced by the falling out of the placen-
tal system at birth are essentially the same as those resulting from amputa-
tion of an extremity, and the consequent alterations in the structure of the
umbilical artery are identical with those in the main artery of the stump
after amputation. The closure of the ductus Botalli and the ductus venosus
soon after birth, and, still better, transformations of vessels in the embryo,
furnish physiological paradigms for the development of a collateral circu-
lation. Many other illustrations might be cited, did time permit, to show
that in the processes of normal development, growth and regressive meta-
morphosis of parts, both before and after birth, and in menstruation and
pregnancy, changed conditions of the circulation arise analogous to certain
ones observed under pathological circumstances, and that the mode of adjust-
ment to these changes by means of anatomical alterations in the vessels may
be essentially the same in the physiological as in the morbid state. I see in
these facts an explanation of the relative perfection of certain vascular
adaptations to pathological or artificial states, as may be exemplified by
changes in a ligated artery and by tlie development of a collateral circulation.
The mechanisms by which the adjustments are secured have, in consequence
of their physiological uses, for reasons already explained, a special fitness to
meet certain pathological conditions. That this fitness should be greater in
youth than in old age is in accordance with laws of life, indicated with

386 ADAPTATIOX IX IWI'IIOLOrilCAI. PROCESSES

especial clearness by Minot in bis interesting studies on " Senescence and
Kt^juvenation."

Hut these mechanisms are not equally well adapted to meet all morbid
changes in the vessels. Although Thoma's interpretation of the fibrous
thickening of the inner lining of vessels in arterio-sclerosis and aneurism as
compensator}', or, as I should prefer to say, adaptive, is not accepted by all
pathologists, it seems to me the liest explanation in many cases. But the
adaptation, if it be such, is here usually of a very imperfect nature, and it is
not surprising that it should be so, when one considers the improbability of
any mechanism developing under physiological conditions which should be
specially fitted to meet the particular morbid changes underlying aneurism
and arterio-sclerosis.

I shall not be able to enter into a consideration of the mechanical factors
concerned in adaptive pathological processes in blood vessels, although per-
haps in no other field are to be fomid more pertinent illustrations of the
views here advocated concerning pathological adaptations. The whole sub-
ject has been studied from the mechanical side most fully and ably by
Thoma, whose four beautifully simple histo-mechanical principles are at any
rate very suggestive and helpful working-hypotheses, even if it should prove,
as seems to me probable, that tliey are too exclusive. I shall call attention in
■this connection only to the inadequacy of the old and still often adopted
explanation of the development of a collateral circulation. The rapidity
with which a collateral circulation may be established after ligation of a
large arterj', even when the anastomosing branches are very small, is known
to every surgeon. This was formerly attributed to increase of pressure above
the ligature ; but this rise of pressure has been shown to be too small to
furnish a satisfactory explanation, and Xothnagel has demonstrated that
there is little or no change in the calibre of arteries coming off close above
the ligature unless they communicate with branches arising below the liga-
ture. Von Recklinghausen several years ago suggested a better explanation.
The bed of the capillary stream for the anastomosing arteries is widened
by ligation of the main arterj-, inasmuch as the blood can now flow with
little resistance from the capillaries of the anastomosing branches into those
of the ligated artery. The result is increased rapidity of blood-flow in tlie
anastomosing vessels. According to one of Thoma's histo-mechanical
principles, increased velocity of the blood-current results in increased growth
of the vessel-wall in superficies — that is, in widening of the lumen. The
tension of the vessel-wall, which is dcixMidcnt on the diameter of the vessel
and the blood-pressure, is, according to Thoma, thus increased ; and, accord-
ing to another of his principles, this greater tension results in growth of the
vascular wall in thickness. The chaJiges in the walls of the anastomosing

ADAPTATION IN PATHOLOGICAL PROCESSES 387

Vessels seem to nie best interpreted as referable to a gouuine work-hyper-
trophy, a conception which has already been advanced by Ziegler.

The pathological regenerations constitute a large group of adaptive mor-
bid processes of the highest interest. Their study has become almost a
specialized department of biology, and occupies a very prominent place in
the extensive literature of recent years relating to experimental or physi-
ological morphology. It has revealed in unexpected ways the influence of
external environment upon the activities of cells, as is illustrated in a very
striking manner by Loeb's studies of heteromorphosis.

Although the capacity to regenerate lost parts must reside in the inherited
organization of the participating cells, there are observations which seem to
indicate that in the lower animals tliis capacity may exist independently of
any opportunity for its exercise during any period of the normal life of the
individual or species or their ancestors, including the period of embryonic
development. This is the inference which has been drawn from Wolff's
observation, that after complete extirpation of the ocular lens with the
capsular epithelium in the larval salamander, a new lens is reproduced from
the posterior epithelium of the iris. There are other observations of similar
purport. Tlie acceptance of this inference, however, seems to me to involve
such difficulties that we may reasonably expect that further investigations
will afford more satisfactory explanations of these curious and puzzling
phenomena of regeneration. Of much interest and significance are the so-
called atavistic regenerations, where the regenerated part assumes characters
belonging not to the variety or species in which it occurs, but to some an-
cestral or allied species. For these and other reasons Driesch refers the
pathological regenerations to what he calls the secondary self-regulations,
by which term he designates those adjustments of artificially induced dis-
turbances which are brought about by factors foreign to the normal develop-
ment and life of the individual.

The view advocated by Barfurth seems to me more probable, that the
pathological regenerations depend upon cellular properties pertaining to
the normal life of the organism. This view is supported by the fact that,
with a few probably only apparent exceptions, the regenerations conform to
the law of specificity of cells. The pathological regenerations occurring
after birth can be referred to the retention in greater or less degree of forma-
tive powers possessed by the cells pre-eminently in embryonic life. These
powers in general tend gradually to diminution or extinction as the indi-
vidual grows older, although in some cells, such as the covering epithelium
of the skin and mucous membranes, this loss of regenerative power with
advancing years is scarcely manifest. Even after the cessation of growth
the regenerative capacity is not wholly in abeyance under physiological con-

388 ADAPTATION IX PATHOLOGICAL PROCESSES

ditions. Bizzozero has studied and classified tlie various tissues of the body
according to the activity of tlicir physiological regeneration.

In general, the more highly dillcrcntiatcd and specialized a cell, the less
is its capacity for regeneration; but we now know that such differentiation
is attended with less sacrifice of its regenerative power than was once sup-
posed. Even such highly specialized cells as those of striped muscle are
capable of regeneration. Indeed, the nerve-cells seem to be the only ones
incapable of proliferation, and even this is not certain, for there are compe-
tent observers who claim tiiat these cells may multiply, although there is no
evidence that in the higher animals they can give rise to functionally active
new nerve-cells. The ease with which a part of the nerve-cell, namely, its
axis-cylinder process, can be regenerated is well known.

The cell-proliferation in regeneration is attributed to the removal of re-
sistance to growth in consequence of the defect resulting from loss of tissue.
It has been pointed out^ especially by Ziegler and by Ribbert, that not only
cells in the immediate neighborhood of the defect multiply, but likewise
those at such a distance that it is difficult to suppose that the latter have been
directly influenced by the loss of tension in the tissues caused by the defect.
Ziegler refers the proliferation of the distant cells to compensatory hyper-
troi)hy. and Ribbert attributes it to hypcraemia resulting from the presence
in the defect of foreign materials, such as extravasated blood, exudation, and
necrotic tissue.

We are brought here, as we were in the consideration of the compensatory
hypertrophies, to one of the most fundamental and important questions in
pathology — the causes of pathological cell-growth. The interpretation of
many pathological processes as adaptive or not, hinges often upon opinions
held concerning the underlying causes of cell-proliferation. The main ques-
tion at issue is: How far is one willing to go in attributing cell-growth to
primary defects in the tissue, and interpreting the growth as for the purpose
of regeneration or filling up a defect? Differences of opinion upon this sub-
ject are illustrated by the different interpretations of the cell-proliferations
in acute and chronie inflammations, some pathologists considering these to
be essentially regenerative and compensatory ; others regarding them, at least
in large part, as directly incited liy iiitlamniatury irritants and not to be
ranked wholly with the regenerative processes.

The doctrine of Yirchow was long accejifed without question, that inflam-
matory cell-growth is the result of the action of external stimuli, the so-
called intlammatory irritants, upon the cells, which are thereby directly
incited to grow and multiply. The attack upon tliis doctrine has been most
vigorously led by Weigert, who denies absolutely the power of any external
agencies to stimulate directly cells to proliferation. He considers that to

ADAPTATION IN PATHOLOGICAL PROCESSES 389

concede such a bioplastic power to external agents is equivalent to the accep-
tance of a kind of spontaneous generation of living matter.

Weigert's views upon this subject have undoubtedly had a most fruitful
influence upon patholog}-. It lias been such an influence as a good working-
hypothesis, whether finally demonstrated to be true or not, has often had in
the development of science. In putting to the test of actual observation
Weigert's hypothesis, we have been led to recognize the frequency and the
importance of primary injuries to cells inflicted by external agencies. Not
only various degenerations and necroses of entire cells, but more subtle and
partial damage of cytoplasm and nucleus have been made the subject of
special study. It has been recognized that our older methods of hardening
tissues reveal often only very imperfectly the finer structure of cells, and
new and better methods have been introduced which enable us to detect
more delicate lesions of cell-substance which formerly escaped attention, as
is well illustrated in recent studies in neuropatliology. Weigert's postulate
of some primary injury to the tissues as the immediate effect of mechanical,
chemical, and other external agencies, which were formerly regarded as the
direct stimuli of cell-growth and multiplication, has been fulfilled in many
instances where such damage had previously been overlooked or unsuspected.
It is his belief that in cases where we cannot now detect such primary injury
more thorougli search and better methods will enable us to do so. One may,
of course, reasonably cherish such an expectation ; but at the same time we
must recognize the fact that morbid cell-proliferations occur under circum-
stances where we cannot at present associate them with any demonstrable
injury to the tissues — indeed, in some cases where our insight into the struc-
ture of the part seems to be so clear and satisfactory that one is very reluctant
to admit the existence of an undetected damage to the cells.

Perhaps the most important modification of former pathological concep-
tions, resulting from the belief that cell-growth is .caused by primary defects
and injuries of tissue, relates to the chronic interstitial inflammations or
fibroid processes. The older view that in these processes the active and
essential feature of the disease is the new growth of connective tissue, which
strangled the more highly organized cells of the part, has been replaced to a
large extent by the opinion that the primarj' and most important lesion is the
degeneration, atrophy, or necrosis of the more specialized cells, whose place
is taken by the new growth of interstitial tissue. In many instances, as in
fibroid patches in the myocardium, and in many scleroses of the central
nervous system, this latter conception forms the best and most natural inter-
pretation of the facts. There are, however, great difiiculties in explaining all
chronic interstitial inflammations by this doctrine, and I must take side with
those who admit the occurrence, for example, in the kidney and in the liver,

390 ADAPTATION IN PATHOLOGICAL PROCKSSES

of primary interstitial iiiflainniations characterized by proliferation of the
connective tissue and endutlidial cells.

Indeed, it seems to me that Weigert's formula is too narrow to cover all
of the observed facts concerning cell-proliferation. Essential features of
tlie theory that cells cannot be directly stimulated to growth by external
agents were present in Boll's doctrine of border warfare between neighboring
cells. Weigert's presentation of this theory is in a far more acceptable shape
than that of Boll. A still more comprehensive statement of the general
theory is that cells are incited to growth through removal of obstacles to
growth in consequence of some disturbance in the normal relations or
equilibrium of the cells with surrounding parts. The capacity to proliferate
must be present in the cells, but with the cessation of growth this capacity is
rendered latent or potential by the establishment of definite relations or an
equilibrium between cells and neighboring parts, including under the latter
not only adjacent cells, but also basement-substance, lymphatics, blood vessels,
tissue-juices, chemical substances, etc. It is evident that under these cir-
cumstances in only two ways can the cells be incited to growth, either by
removal of resistance or obstacles to growth, or by an increase in the forma-
tive energ}' resident within the cell, and that in either way energy must be
used, whether it be employed to remove obstacles to growth, or to increase
the proliferative forces within the cell.

It appears to me by no means an easy matter to decide in all cases in which
of the two ways mentioned cell-proliferation is brought about. Eemoval
of obstacles to growth, not only in the way indicated by Weigert, but also by
other disturbances in the neighborhood-relations of the part, and very prol>-
ably by the presence of definite chemical substances, may be the explanation
of all pathological cell-growths. Certainly it would not be easy conclusively
to disprove this view. Nevertheless, I fail to comprehend the inherent diffi-
culties which some find in admitting the possibility of forms of energy, act-
ing from without, directly increasing the formative energy of the cell; in
other words, directly stimulating the cell to growth and multiplication. If
such a possibility be admitted, the natural interpretation of some examples
of cell-proliferation is that they are directly caused by the action of external
forces, in the sense advocated by Yirchow.

Students of the problems of pathological cell-growth must take into con-
sideration not only the facts of human and allied pathology, but also those
which are so rapidly accumulating in the domain of experimental embry-
olog}' and morphologj-, to the importance of which I have repeatedly referred
in this address. I would call attention especially to the observations from
this source as to the influence of various changes of environment, particu-
larly of definite chemical, thermic, and mechauical changes in surrounding

ADAPTATION IX PATHOLOGICAL PEOCESSES 391

parts, upon the direction of movement and of growth of cells. The use at
present made of chemotactic phenomena in explaining the direction of move-
ment of cells in human pathological processes is only a very limited and in-
adequate application of these important observations concerning tactic and
tropic stimuli. AYe shall probably come to realize more and more the opera-
tion of these factors m determining cell-movements and cell-growth in
human pathology. We already have evidence that different kinds of leuco-
cytes not only possess different specific functions, but also respond in differ-
ent ways to definite tactic stimuli. The long-standing problem of the lymph-
oid cell in inflammation approaches solution along these lines of investiga-
tion.

A burning question, and one of perennial interest, relating to our sub-
ject is: How far are we justified in regarding acute inflammation as an
adaptive or protective morbid process? There is fair agreement as to the
essential facts of observation, but regarding their interpretation there are
wide differences of opinion, and when one considers the complexity of the
process and its still unsolved riddles, it is not hard to see why this should
be so. Much depends upon the point of view, and in this respect there can
be recognized a certain antagonism between the purely clinical and the purely
pathological and experimental views, an antagonism, however, which must
be reconciled by a fuller knowledge of the subject.

It is not likely that the purely clinical study of inflammation would ever
lead to the idea that the general tendency of this process is advantageous to
the patient. The more severe and extensive the inflammatory affection, the
more serious, as a rule, is the condition of the patient. The surgeon sees his
wounds do well or ill according to the character and extent of inflammatory
complication. Measures directed to the removal of inflammatory exudation,
such as the evacuation of pus from an abscess or an empyema, are the most
successful methods of treatment, and the rules are embodied in ancient
surgical maxims. How can one conceive of any purpose useful to the patient
served by filling the air-cells of his lung with pus-cells, fibrin, and red
corpuscles in pneumonia, or bathing the brain and spinal cord in serum and
pus in meningitis? If nature has no better weapons than these to fight the
pneumococcus or meningococcus, it may be asked, " What is their use but
to drive the devil out with Beelzebub ? "

But the pathologist and bacteriologist sees another aspect of the picture.
An infectious micro-organism has invaded the tissues, where it multiplies
and where its toxic products begin to work havoc with the surrounding cells,
and by their absorption to cause constitutional sjinptoms and perhaps
damage to remote parts. Is the destructive process to go on witliout any
defence on the part of the body ? There are attracted to the injured part

392 ADAPTATION IN PATHOLOGICAL PROCESSES

an arniv of leucocytes from the blood vessels, and perhaps other cells, from
the ncifihltoring tissues, and it has been conclusively sliown that these cells
can pick up foreign particles and remove them, and that they contain sub-
stances capable of destroying many micro-organisms. At the same time
serum accumulates in and anmiiil tiic injured arcii, and this may aid by its
chemical properties in destroying bacteria, in diluting poisons, in flushing
out tlie part. Fibrin may appear, and some think that this may serve in some
situations as a protective covering. If these agencies, hostile to the invading
micro-organism, gain the upper hand, the debris is cleared away by phago-
cytes and other means, and the surrounding intact cells, which had already
begun to multiply, produce new tissue which takes the place of that wliich
had been destroyed. The victory, however, is not always with the cells and
other defensive weapons of the body. The struggle may be prolonged, may
be most unequal, may cover a large territory, and the characters and extent
of the inflammation furnish an index of these difl^erent phases of the battle.

Such in bald outlines are two divergent views of inflammation.

I do not see how we can fail to recognize in that response to injury which
we call inflammation, features of adaptation. Inflammation may be in some
cases the best response to secure the removal or destruction of injurious
agents, but we cannot look upon it as the most perfect mode of protection
of the body against invading micro-organisms. One may inoculate into
three animals, even of the same species, but possessed of different individual
resistance, the same quantity of the same culture of a pathogenic micro-
organism and obtain sometimes the following results: The first one will
present no appreciable inflammatory reaction whatever, and no evidences
of any other disturbance, and examination will show tliat the micro-organisms
have quickly disappeared. The second one will develop an extensive local
inflammation and survive, but after a long illness. The third one will offer
little resistance to the micro-organism, which rapidly multiplies without
causing marked inflammation, invades the blood or produces toxaemia, and
quickly destroys the life of the animal. Now, it is evident that the best
protective mechanism is that brought into action by the first animal, but that
the inflammatory reaction set up in the second one is better than the absence
of reaction and of other defences in the third animal.

I can scarcely do more on this occasion than to indicate some of the point.s
of view from which it seems to me that we can best approach the study of
inflammation as an adaptive process. With inflammation, as with other
adaptive processes, any useful purpose subserved affords no explanation of
the mechanism of the process. We should guard against all ideas whicii
introduce, even unconsciously, the conception of something in tlie nature of
an intelligent foresight on the part of the participating cells. The response

ADAPTATION IN PATHOLOGICAL PROCESSES 393

of these cells in inflammation is a necessary and inevitable one, determined
by their innate properties. Our efforts should be directed, in the first place,
toward as near an approach as possible to a mechanical explanation of in-
flammatory processes by a study, on the one hand, of tlie properties and
mode of action of the causes of inflammation, and, on the other hand, of the
nature and source of the cellular properties concerned. We may properly
inquire whether these properties fit the cells to counteract the effects of
injury, and if so, whence comes this fitness. Has the fitness those attributes
of relative perfection which we find in most physiological adaptations? Is
the character of the response to injur)- in inflammation such as to indicate
that the agencies concerned have acquired through evolutionary factors a
special fitness to meet the pathological emergencies? Are all or only a part
of the manifestation of the inflammatory processes adaptive?

It cannot be doubted that there are innate properties of certain cells, called
into action in inflammation, such as those manifested in the attraction of
leucocytes and otlier cells by definite chemical substances, the capacity of
cell-proliferation from causes connected with injury, the power of phago-
cytosis and other bactericidal properties, which may lie adapted to counter-
act the effects of injurious agents. When these forces bring about the
prompt destruction or removal of the injurious substances and the defect
is quickly repaired, the adaptation is complete and unmistakable. When,
however, the inflammatory irritants and their destructive effects persist,
and the proliferation of cells and accumulation of inflammatory products
become excessive and occupy large areas, the features of adaptation are not
so easily recognized. The mere occupation of territory by inflammatory prod-
ucts is often a serious injury and it can be regarded as an adaptive feature
only when they fill some artificial defect. Such occupation may be in itself
enough to counteract any useful work in which tliese products may be en-
gaged.

We can reasonably seek in the relations of the body to the outer world an
explanation of the development of certain properties of cells which serve a
useful purpose in mechanical and other injuries. These properties find
application also in the normal life of the organism. Their exercise in re-
sponse to injurj' imparts to inflammation important adaptive or protective
characteristics, but I fail to see in this process any such special fitness as
would justify extravagant statements which have been made, to the effect that
inflammation ranks among the adaptations of living beings by the side of
digestion and respiration.

I have endeavored in this address to present certain general considera-
tions concerning pathological adaptations. It has been possible to bring
under consideration only a small part of an immense field, and this very
28

394 ADAPTATION IN PATHOLOGIC.U^ PROCESSES

inadequately. We have geen that in the sense in which adaptation was de-
fined we can recognize in the results of morbid processes frequent and mani-
fold evidences of adjustment to changed conditions. These adjustments
present all degrees of fitness. Some are admirably complete; more are
adequate, but far from perfect; many are associated with such disorder ajid
failures that it becomes difficult to detect the element of adaptation. The
teleological conception of a us^cful purpose in no case affords an explanation
of the mechanism of an adaptive process. I have suggested that the adapta-
bility of this mechanism to bring about useful adjustments has been in large
part determined by the factors of organic evolution, but that in only rela-
tively few cases can we suppose these evolutionary factors to have intervened
in behalf of morbid states. For the most part, the agencies employed are
such as exist primarily for physiological uses, and while these may be all
that are required to secure a good pathological adjustment, often they have
no special fitness for this purpose.

The healing power of nature is, under the circumstances present in dis-
ease, frequently incomplete and imperfect, and systems of treatment based
exclusively upon the idea that nature is doing the best thing possible to
bring about recovery or some suitable adjustment, and should not be inter-
fered with, rest often upon an insecure foundation. The agencies employed
by nature may be all that can be desired ; they may, however, be inadequate,
even helpless, and their operation may add to existing disorder. There is
ample scope for the beneficent work of the physician and surgeon.

HYDROPHOBIA'

Of the many subjects suitable for the Report of the Chairman of tliis
Section I have selected hydrophobia, on account of the numerous and im-
portant contributions to it* pathologj- and etiology during the past four years,
and especially because the time has come when we can form an intelligent
estimate of the value of the Pasteurian inoculations against hydrophobia.
Although these inoculations constitute the central point about which con-
troversy has waged, it is not to be forgotten tliat Pasteur's discoveries and
tlie investigations aroused by them have shed much light in many directions
upon the nature of one of the most mysterious and fatal diseases. 'What-
ever had been the outcome of Pasteur's antirabic treatment, his researches
upon hydrophobia would still have remained an important scientific con-
tribution to our knowledge of the disease.

We are still insuiRciently informed concerning the pathological anatomy
of hydrophobia. I have had opportunity to make post-mortem examination
of three cases of hydrophobia in human beings. In one case serial micro-
scopical sections were made of the medulla oblongata and pons from the
second cervical nerve upward. The lesions consisted in small hemorrhages,
in accimmlations of small round cells in large numbers, both in the peri-
vascular Ij-mph spaces, and in scattered foci in the neuroglia between the
nerve elements, and in thrombi, composed of hyaline material and of leuco-
cytes, in small blood vessels. These lesions were microscopical, and their
extent and distribution could he determined only by the examination of a
large number of sections from different parts. The lesions were especially
well marked in and near the nuclei of origin of the spinal accessory, pneu-
mogastric and glosso-pharjngeal nerves, and in the motor nucleus of the
trigeminus. Cases have been reported in which even more extensive lesions
than these have been found ; their intensity depending apparently in large
measure upon the duration of the disease. While it can not be claimed
that these lesions are peculiar to hydrophobia, or by themselves suffice for
its diagnosis, it is incorrect to suppose that hydrophobia is a disease without
demonstrable anatomical lesions which bear a manifest relation to the
symptoms of the affection.

' Report of the Chairman of the Section on Anatomy, Physiology and Pathology,
before the Medical and Chirurgical Faculty, Baltimore, April 26, 1889.
Tr. M. & Chir. Fac. Maryland, Bait., 1889, 162-180.

395

396 llYDKoniUBlA

Far more important than the additions to our knowlodge of the path-
ological anatomy of ral)it's following Pasteur's discoveries, are the con-
tributions to a better comprehension of the causation of the disease. Before
Pasteur's publications on liydrojjhobia, dating from 1881, about all that we
knew of the virus of rabies was that it was contained in the salivary glands
and their secretions, and that infection often followed the bites of rabid
animals. We knew that after cliaractcristic symptoms appeared, the disease
was unifonnly fatal ; but we possessed no positive means of diagnosis. Hence
it was impossible to secure trustworthy statistics of the mortality among
those bitten by rabid animals; for we could not determine accurately how
many of tlie animals were rabid. There obtained among a few an unwar-
rantable scepticism even as to the existence of such a disease as hydrophobia.

We now possess positive means of diagnosis of hydropliobia by the inocu-
lation of animals, particularly of rabbits; so that the last vestige of doubt as
to the existence of the disease must disappear. We have now valuable in-
formation concerning the properties of the rabid virus, its distribution in
the infected body, the manner of its transmission, the singular differences
in its action, according to the mode and seat of its inoculation, and the
means of producing immunity against its destructive action on the body.

Althougli there is no reason to doubt that the infectious agent of rabies
is a micro-organism, no actual demonstration of this organism has yet been
made. If fluids containing the rabid virus be filtered through substances
impenetrable to particulate matter, the filtrate is free from infectious
properties. In the Pathological Laboraton,' of the Johns Hopkins Univer-
sity, we have had opportunity to study the effects of the rabid virus upon a
series of rabbits, the original material having been obtained from the medulla
oblongata of a man dead of hydrophobia. We were able abundantly to con-
firm the statements of Pasteur and otliers as to the behavior of these animals
when inoculated in succession with the virus of rabies. We endeavored by
cultures and by staining re-agents to demonstrate some specific micro-
organism ; but with entirely negative result. A repetition of the methods
indicated by Fol, failed to confirm his statements as to the presence in the
nervous centres of a demonstrable species of bacteria. But while we are not
acquainted with the specific organism causing hydrophobia, we know many
of its properties.

The virus of rabies is destroyed by comparatively low temperatures, ex-
posure for one hour to a temperature of 50° C. (1-22° F.) sufficing for this
purpose. It is killed in a short time by drying, certainly within four days
when exposed in thin layers capable of rapid desiccation. It is .said to be
destroyed by exposure to the direct rays of the sun, even when under condi-
tions preventing elevation of temperature. According to Babes, the virus is

HYDKOPHOBIA 397

more resistant to the action of corrosive sublimate and carbolic acid than
most bacteria; but it loses its infectious properties after exposure for three
hours to the action of 0.1 per cent sublimate, or of 1 per cent carbolic acid
solution. Galtier has point<?d out a fact of practical importance, that the
virus of rabies may be aemonstrated after forty-four days, and perhaps
longer, in the cadavers of buried animals. An easy means of preserving
the virus is to place the brain or cord of the infected animal in pure glycerine,
which may be diluted with water, and which should be occasionally changed.
In cases in which persons are bitten by animals suspected of rabies, the
animal should be secured and watched, and if it dies, the nervous centres
should be removed and preserved in dilute glycerine for subsequent inocula-
tion of rabbits, whenever such inoculation can not be performed at once by a
competent person.

It has been ascertained that the certainty of infection with rabies depends
largely upon the part of the body and the character of the tissues into which
the virus is inoculated. The disease develops always and with the shortest
period of incubation after inoculation of the virus into the brain, or upon
its surface. Those who have asserted that the same group of symptoms may
follow the intra-cranial inoculation of substances other than rabid virus,
have fallen intx) serious error. Equally certain in the efiects are inoculations
of the virus into the eye, although here the period of incubation is less
definite. Inoculations into the substance of nerve trunks appear to be
uniformly successful in rabbits, but somewhat less certain in dogs, although
even in the latter animal inoculation into the pneumogastric nerve does not
fail. Intra-venous injection does not produce the disease in ruminants
unless large quantities of the virus are used; but it is a ready means of con-
ferring immunity upon these animals. The same mode of injection suc-
ceeds often in dogs, and usually in rabbits, in produeing the disease; but it
may fail in both classes of animals. Especial importance attaches to the
behavior of subcutaneous injections of the virus of rabies. Dogs often resi.st
infection from the injection of considerable quantities of the most intense
virus into the subcutaneous tissue. Indeed, Pasteur finds that the more
intense the virus, aad the larger the quantity injected subcutaneously, the
less likely is the dog to develop rabies, and the more certain is it to acquire
immunity. Ferran's super-intensive method of producing immunity in
human beings, is to inject at once the strong ^irus into the subcutaneous
tissue. Although he has done this in over 400 cases without injurj', the
method does not rest upon a safe basis so far as experiments upon dogs are
concerned ; for these animals sometimes contract the disease after this mode
of inoculation. Infection is more likely to follow injections into the muscu-
lar tissue tlian into the subcutaneous connective tissue. Of course the in-

398 HYDROPHOBIA

jection of the virus into the subcutaneous tissue by means of a hypodermic
syringe I'an not be considered analogous to inoculation hy means of bites
which wound the skin and subcutaneous tissues. Di Vestea and Zagari have
shown that while simple subcutaneous injections are often unsuccessful in
producing rabies, the application of the virus to the divided ends of nerve
filaments in a cutaneous wound is generally efficacious in causing the disease.
Although deep and severe bites of rabid animals are, the most dangerous,
hydrophobia may result simply from a mad dog licking an abrasion or
scratch. Intra-peritoneal injections of the rabid virus produce the disease
in rabbits, and guinea-pigs, if considerable quantity of the virus be used.

As regards the distribution in the body of the infectious material of rabies,
it has been demonstrated by Pasteur that in human beings or animals which
have died of hydrophobia, the virus is contained most abundantly in the
central nervous system, and especially in the medulla oblongata and brain.
It is found also in the nerves near their exit from the brain and cord, but
less constantly and in less amount in the peripheral nerves. The virus is
probably always present in the salivary and lachrraial glands, and some-
times in the pancreas, but it is usually absent from the blood, kidneys, spleen
and liver. Only exceptionally is it present in the mammary glands and the
milk. It is very rarely transmitted to the foetus through the placenta. We
see, therefore, that the virus is very unequally distributed in the body, and
that its chief habitat is the central nervous system.

A point of much interest is the manner in which the virus is conveyed
from tlie seat of inoculation to the central nervous system. The chief possi-
bilities which present themselves are transmission by the blood-current, by
the lymph-current, and along the nerve trunks. There is evidence that the
virus may be conveyed in each of these three ways. The production of the
disease by intra-venous and by intra-peritoneal injections of the virus, speaks
for the first two modes of transmission. But there are considerations which
favor the view that the usual mode of transmission is along the nerves.
Inoculations made directly into nerve trunks are more certain to produce
rabies than either intra-venous or intra-peritoneal injections, and by the
first method a smaller quantity of the virus suffices. The symptoms of
rabies, which are chiefly nervous, frequently bear a certain relation to the
seat of inoculation in the order of their development. Thus when the in-
oculation is made into the anterior extremities or the head, the first symp-
toms are bulbar, whereas, when the inoculation is into tlie posterior ex-
tremities or tail, spinal symptoms, especially paralysis of the posterior ex-
tremities, appear first. No such regularity in the sequence of sjTnptoms is
observed after intra-venous injections. In a large proportion of cases of
hydrophobia in human beings, tlie first sj-mptoms are referable to disturb-

HYDROPHOBIA 399

ances in the nerves in or near the injured part, and paraplegia or the
paralytic form of rabies is most likely to follow bites in the lower extremities.
By killing animals at the proper period, it has been ascertained that after
inoculation in the head or anterior part of the body the virus makes its
appearance in the medulla oblongata sooner than in the posterior part of
the spinal cord, while the reverse holds true when the inoculation is made in
the tail or the posterior extremities. The virus propagates itself in steps,
as it were, along the spinal cord. Eoux and Bardach have found the virus
present in the nerves of a bitten extremity when it has been absent in the
corresponding nerves of the opposite side; whereas, the reverse of this has
never been observed. Di Vestea and Zagari have succeeded, in rabbits, by
making resections of the spinal cord, and keeping the divided ends separated
by a plug of antiseptic cotton in preventing the virus from extending from
one segment of tJie cord to the other, so that, after intra-cranial inoculations,
the upper segment contained the virus and the lower did not, and after
inoculations into the sciatic nerve, the virus was prevented from passing
from the lower to the upper segment. Division of a nerve trunk above the
point of inoculation may retard, but does not prevent the development of
the disease, but here there is the possibility of the propagation of the virus
along anastomotic nerve filaments. It must be admitted that the facts and
experiments which have been mentioned speak strongly for the view that the
virus passes along the nerves, although we have no information as to how
this is accomplished, and it is not worth while to consider the theories which
have been framed to explain this interesting and curious phenomenon.

One of the most important discoveries of Pasteur in this subject, is
that the virus of rabies may undergo changes in certain of its properties by
transmission through a series of animals of the same species. The principal
change is an increase of virulence, characterized by a shortened period of
incubation of the disease. This change is brought about by the transmission
of the virus through a long series of rabbits, each one being inoculated
l>eneath the dura mater with an emulsion made with the medulla oblongata
of the preceding rabbit which has died of hydrophobia. When a rabbit is
inoculated beneath the dura with the medulla of a dog dead of rabies, the
so-called rabies of the street {rage des rues), the period of incubation of
the disease is usually between 15 and 20 days, and apparently never less
than 11 days. By inoculating intra-cranially rabbits in series, beginning
with this first rabbit, the period of incubation is gradually reduced to seven
and finally to six days, at which it remains indefinitely. In the series of
rabbits emploj'ed by Pasteur for his preventive inoculations, the period of
seven days had been reached before the 80th passage, and at the time of the
ITSth passage, the period of incubation had been for a year 6 days in at

400 HYDROPHOBIA

least two out of three of the rabbits. Tlie virus from the medulla of rabbits
with this uniformly short period of incubation of 6 or 7 days is spoken of as
fixed virus (virus fixe). The time required for obtaining the fixed virus
may be very much shortened by employing young rabbits and by inoculating
several at a time, selecting for successive inoculations from each group the
one presenting tlie shortest period of incubation. In this way Hogyes ob-
tained tlie fixed virus in the 16th passage, about five months after the be-
ginning of the successive inoculations.

If the medulla of a rabbit which has died of inoculation with the fixed
virus be preserved in a dry atmosphere, its virulence progressively diminishes,
as is indicated by the lengthening of the period of incubation. The loss of
virulence is rapid in proportion to the temperature at which tlie medulla is
kept. The infectious properties, as a rule, disappear at the end of a fort-
night if the temperature be from 23° to 25° C. (71.6°— 7:° R), and sooner
than this if the medulla be of small size.

The question arises whether these changes in virulence depend upon altera-
tions in the quantity or in the quality of the infectious agent. We judge of
the degree of virulence mainly by the length of the period of incubation after
the intra-cranial inoculation of a rabbit. It has been shown experimentally
that this period may he progressively lengthened by dilution of the virus
inoculated, and this fact may be put in evidence in favor of a quantitative
change to explain varying degrees of virulence. On the other hand, fixed
virus would seem to differ qualitatively from the virus of rabies of the streets,
for no matter how prolonged the period of inoculation may be rendered by
dilution of the fixed virus, or in other words, by diminution in the quantity
of the infectious agent, if this rabbit develops rabies, its medulla always
contains the fixed virus — that is, when inoculated intra-cranially into an-
other rabbit, its period of incubation is 6 or 7 days, which is shorter than
ever occurs with the virus from the rabies of the street. Pasteur is inclined
to attribute the progressive loss in virulence of the rabbit's medulla preserved
in a dry atmosphere, to a gradual diminution in the quantity of the infec-
tious material, rather than to any diange in its quality.

It is a significant fact, which should be remembered in judging the results
of Pasteur's treatment, that there is a period of so-called latent development
of the virus in the central nervous .system. In rabbits inoculated with the
fixed virus, the period of inoculation is six or seven days, but as early as
the fourth day the virus has been found in the medulla oblongata. Doubt-
less, therefore, in human beings the virus is present in the central nervous
system for a period before any characteristic symptoms of rabies appear,
so that it may readily happen that treatment is begun too late, even when
undertaken before there are manifestations of the disease. Careful obser-

HYDROPHOBIA 401

vation has shown tliat in rabbits tliis period is not, strictly speaking, a latent
one, but it is accompanied by elevation of temperature, increased frequency
of respiration, slowing of the pulse rate and loss of weight, symptoms which
point to an action of the rabid virus primarily upon the heat centres and
upon the vagus.

It is customary to divide rabies according to its clinical manifestations
into two forms, furious or convulsive rabies and dumb or paralytic rabies.
A third form, however, should also be distinguished — namely, mixed rabies,
which represents a combination of convulsive and of paralytic rabies. The
most common form of rabies in human beings is furious or convulsive rabies,
but paralytic rabies also occurs in man, especially after bites on the lower
extremities, and is more common, according to recent reports, than was
formerly believed. In dogs, furious rabies is tlie predominant variety
whereas, in rabbits, paralytic rabies is the more common, and in Pasteur's
series it became the sole form after inoculation with the fixed virus. A
careful study of the symptoms, however, renders less sharp the distinction
between furious and paralytic rabies, for in either form it is often possible
to distinguish a stage of excitation and a stage of paralysis, but in the
furious form the stage of paralysis is short and may be wanting; whereas,
in the paralytic form, the stage of excitement is of short duration, and
may be characterized only by acceleration of the breathing, elevation of
temperature and symptoms referable to irritation of the vagus nerve. There
is probably no difference in the quality of the virus causing tlie two clinical
forms of hydrophobia, the distinction depending rather upon the nature of
the animal infectx^d, and the seat of inoculation, possibly also upon the
quantity of virus inoculated. The only observation in favor of differences
in the character of the virus causing the two varieties of rabies are those of
Helmann. who claims to have a virus which will produce in rabbits invariably
furious rabies, and another virus which produces the customary paralytic
rabies, but these observations have not been confirmed, are not free from
objections, and are not in harmony with the observations of Past-eur and
others, who find that the virus of rabies of the street, which is generally
furious in character, produces paralytic rabies in the rabbit, and that the
latter causes furious rabies in the dog, there being occasional exceptions to
these rules. The occasional occurrence of paralytic rabies in human beings
who have not been subjected to treatment after the bite of a mad dog, dis-
proves the assertion of Peter that paralytic rabies is only rabies of the
laboratory, and when it has occurred in persons treated by Pasteur's method,
it can be attributed only to the anti-rabic inoculations and not to the bite
of the animal, an assertion which, moreover, can be positively disproven by
experiment, as will be explained subsequently.

402 HYDROPHOBIA

There can be no doubt whatever that it is possible to render animals
immune against rabies both before and after inoculations which would
otherwise cause the disease. The independent and careful experiments of
Ernst in this country are free from all partisan bias, and have fully con-
firmed the statement's of Pasteur and others upon this point. The methods
employed by Pasteur for protective inoculation against hydrophobia have
been so often and so fully described in medical and other journals, that it
is not necessar}- to repeat the description on this occasion. The method is
based upon the injection subcutaneously (sometimes in certain animals
into the blood) first of attenuated virus contained in the medullae, dried
for a certain period, of rabbits dead after inoculation with the fixed virus,
and then of stronger and stronger virus contained in medullae dried for
shorter periods, until strong or the strongest virus is reached. These in-
oculations are most effective in preventing the disease when undertaken soon
after the reception of the poison, and with a large quantity of virus and with
the speedy emploj-ment of material containing the strongest virus {virus
fixe). Animals may be rendered immune by a single injection into the blood
or into the subcutaneous tissue of a large quantity of strong virus, whereas
dogs which are bitten by mad dogs and which do not develop the disease,
as mav happen, are not usually left immune, evidently because not sufficient
quantity of tlie virus has been received. Dogs which have once been rendered
immune against rabies preserve this immunity for at least two years, and
doubtless for a longer period.

The experiments of von Frisch are often quoted in opposition to the
validity of Pasteur's conclusions. Von Frisch claimed that it is impossible
to produce immunity after tlie virus of rabies has been received in a manner
certain to produce the disease. He urged that Pasteur's experiments demon-
strated the possibility' of producing immunity only before and not after the
reception of the rabid virus. In this latter assertion he was in error. Von
Frisch's failure to produce immunity after the reception of the strong nrus
was due partly to his selection of rabbits for his experiments, and partly to
imperfect methods of preventive inoculation. On account of their extreme
susceptibility to the rabid virus, and of the short period of incubation after
intra-cranial inoculations, rabbits are much less suitable animals for these
experiments regarding immunity tlian dogs. But even in rabbits immunity
may sometimes be produced if the preventive inoculations be undertaken
speedily after the reception of the virus, and be according to the intensive
method. Pasteur and others have shown that in a large proportion of cases
the development of rabies may be prevented in dogs even after subdural
injection of the strongest virus, if preventive inoculations by the intensive
method be begun not later than the second day after the reception of the
poison. Bardach succeeded in this way in saving 60 per cent of the dogs

HYDROPHOBIA 403

inoculated beneath the dura mater. This test is evidently the most severe
one to which Pasteur's preventive treatment can be subjected, one far more
severe than is required to meet the ordinary channels of infection with rabies
in human bein^rs, in whom the period of incubation is longer and the virus
is received in less intense form and in situations from which infection is
slower and less certain. It must be admitted, therefore, that Pasteur's treat-
ment rests upon a satisfactory experimental basis, and one which forms a
complete justification of the application of the treatment to human beings
bitten by rabid animals.

We have no positive knowledge as to the manner in which immunity is
caused by the Pasteurian vaccination against rabies, any more than we have
as to the causation of immunity in other diseases. Pasteur is inclined to
attribute the immunity to the action of some substance, which he calls
" matiere vaccinale," contained in the inoculated material, but not identical
with the micro-organism causing rabies. That immunity against infectious
diseases may be secured by the injection of chemical substances produced
by the growth of specific bacteria, was demonstrated by Salmon and Smith
in the case of hog cholera, and has been since demonstrated by Eoux and
Chamberland for malignant oedema, and by Wooldridge for anthrax. It
has not yet been found possible to prove the correctness of Pasteur's sup-
position in the case of rabies, and although there are arguments in its favor,
it is hardly worth while for us to consider further a question at present in
so hypothetical a state.

Encouraged by the results of his experiments upon animals, Pasteur, in
July, 1885, first applied to a human being his method of preventing hydro-
probia by successive injections of the virus contained in the rabbit's medulla
subjected to drying for different periods, the medulla being taken from rab-
bits which had died after inoculation with the fixed virus.

During the years 1886, 1887, and the first half of 1888, there have been
treated under Pasteur's supervision, either by the simple or by the intensive
method of vaccination, 5374 persons who have been bitten by animals
either proven or suspected to be rabid. The mortality from hydrophobia,
including even the cases which developed within a day after the cessation of
treatment, was for 1886 1.34 per cent; for 1887, 1.12 per cent; for the first
haK of 1888, 0.77 per cent. If the fatal cases wliich developed within a fort-
night after the end of treatment, and in which there is reason to beliere that
the inception of treatment was too late, be excluded, the mortality for 1886
falls to 0.93 per cent; for 1887, to 0.67 per cent; and for the first half of
1888, to 0.55 per cent. From May 1, 1888, to May 1, 1889,' there were

' I have endeavored to bring the statistics of this paper up to the date of its
publication (July, 1889), and have therefore added certain statistics which have
appeared since the time the paper was read in April, 1889.

404 IIYDKOniOBIA

treated at the Pasteur Institute, in Paris, 1673 persons bitten by dogs,

either rabid or suspected to be rabid. Of these 6 died during treatment, 4
in less than a fortniglit after treatment, and 3 died later than a fortnight
following the cessation of treatment. Only the last 3 cases, therefore, are
to be counted as failures. If all the deaths, both during and after treatment,
be included, which would be illogical, the mortality equals 0.78 per cent;
if only the deatlis after treatment be reckoned, the mortality becomes 0.42
per cent; and if only those occurring more thaji a fortnight after the end
of treatment be estimated, the death-rate sinks to 0.18 per cent This
mortality may !« somewhat increased by subsequent deaths, as sufficient
time has not elapsed for full completion of tlie returns. Pasteur, in a recent
letter to Sir H. Koscoe, says that up to the end of June, 188'J, over 7000
persons have been treated in his laborator}-, and that the general mortality
applicable to the whole number of the operations was 1 per cent.

Doubtless a considerable number of cases are included in the ioTe"-oinz
statistics of persons subjected to treatment who have not been bitten by
animals actually rabid. How large is this number, it is impossible to say;
but even if ample allowance be made for tliis class of cases, the results of the
treatment can hardly be interpreted otherwise than in favor of its efficacy.

It is possible, however, to select from the rejwrts only those cases in which
the animal inflicting the injury has been actually proven to be rabid. This
proof is the most exact which can be furnished, and consists in the results
of the inoculation of animals with the brain or cord of the animal, or in the
development of hydrophobia in persons or animals bitten at the same time
as those treated. Pasteur's statistics, which are published monthly, are
arranged in tables which embrace: A — Persons bitten by animals proven
to be rabid: B — Cases in which the existence of rabies in the animal is cer-
tific-d by a veterinarian : C — Cases in which there is reason to suspect rabies
in the animal, although the evidence furnished in the foregoing classes was
not obtained.

If the cases be analyzed according to tliis classification, we obtain the
following results: Since the beginning of his operation* in Julv. 1885, up
tfl the end of the first half of 1889, there have been treated under Pasteur's
supervision 6950 patients. There were bitten by animals suspected, but not
proven to l)e mad, 1 187, of whom 12, or 1.01 per cent, died ; by animals pro-
nounced rabid by veterinarians, 4()8ti persons, of whom 44, or 0.94 per cent,
died; and by animals proven experimentally to be rabid, 1077 persons, of
whom 15, or 1.39 per cent, died. The similarity of the results in the three
chisses shows that the second and third groups must contain a large number
of cases in which the wounds were inflicted by rabid animals. If we exclude
from the preceding statistics those who began treatment a fortnight or more

HYDROPHOBIA 405

after being bitten, we find the death-rate in Class C to be 5, or 0.42 per cent ;
in Class B, 31, or 0.6G per cent, and in Class .1, 11, or 1.2 per cent.

The most convincing presentation of the case is to select the results of
treatment in persons bitten on the head and face by animals proven to be
rabid. In all statistics purporting to give the mortality from tho bites of
rabid animals, by far the largest death-rate is afforded by the bites on the
head and face. I have collected from Pasteur's reports for 1887 and 1888,
those bitten on the head and face by animals proven experimentally to be
rabid. There were 72 cases, with 4 deaths from rabies during treatment,
and 3 following treatment. Of the latter, one was seized three days after
the end of treatment, and it is therefore reasonable to suppose that in this
case the treatment was Ijegun too late. If this ease and those dying during
treatment be excluded, there remain 67 cases bitten on the head or face by
animals proven to be rabid, with 2 deaths, a mortality of 3 per cent. I was
not able to obtain the data for an analysis of all of the cases in this group
since the beginning of Pasteur's treatment ; but after collecting these cases,
I have met the statement that the total number of persons bitten on the face
and neck by animals proven to be rabid is 540 ; of whom 21 died, leaving
a mortality of 3.89 per cent; but how many of these are fairly attributable
to failure of the treatment does not appear. These cases undoubtedly
l)elong to both Class A and Class B.

Unless it can be showqi that the mortality following the bites of rabid
animals is as small as that derived from the foregoing statistics, no other
conclusion can be drawn than that Pasteur's treatment is efficacious ; for
we can dismiss as unworthy of consideration all attempts to cast doubt upon
the trutlifulness of the statistics published by Pasteur. Notwithstanding
the out-cry of those who assert that nothing can be proven in medicine by
statistics, it is apparent that Pasteur could have proceeded in no other way
than he has done, in order to demonstrate the value of his treatment, and
that the statistical method is the only one applicable to this demonstration,
although we are to keep in mind all possibilities of error belonging to the
method.

There are various careful collections of statistics which show that a con-
servative estimate of the average mortality of persons bitten by rabid animals
is about 15 per cent (Lablanc, Dujardin-Beaumetz, Horsley). The results
of different statistics on this point vary widely, as is to be expected from
the fact that they include generally in large but variable numbers bites from
animals not proven to be rabid. On this point Pasteur's statistics have the
merit of greater accuracy. It is logical to suppose that the statistics with
large mortality include a greater proportion of bites from actually rabid
animals than those with small mortality.

40C, TIYDKOPHOBIA

All agree tliat bites on the head and face by rabid animals furnish the
highest mortality. This is given by Brouardel as 88 per cent. If we place
it at GO to SO per cent, we are likely certainly not to exaggerate the mortality.

If now we contrast with these moderate estimates of the mortality follow-
ing the bites of rabid animals, the results obtained by Pasteur's metliod of
treatment, there is left no room for doubt that this treatment has been
proven to be efficacious, and has saved already hundreds of lives. I call
attention especially to the convincing character of the results in persons
bitten on the head and face by animals proven to be rabid.

The Pasteurian treatment, as is apparent from the preceding statistics,
has a certain number of failures to record. It is not therefore unfailing,
although if we compare its results with those obtained by methods of medical
treatment in various diseases, it takes a very high rank, perhaps second only
to vaccination in small-pox. The death from hydrophobia in two instances
of persons over two years after treatment, casts a cert-aiu shadow upon the
results, but can not invalidate the general conclusions as to the efficacy of
tlie treatment.

It is most encouraging tliat the results of the treatment have improved
with each successive year of its application. This is attributable to improve-
ments in the methods, and is even more strikingly illustrated in the statistics
of some others than in tliose of Pasteur, but I liave preferred in this article
to consider only the results obtained under Pasteur's immediate supervision.
Essentially similar results, however, have been obtained in various places,
chiefly in Eussia, Italy and South America. The principal improvement in
the method, as first applied by Pasteur, is in the elaboration of the so-called
intensive method of preventive inoculation which is applicable to severe
cases, especially to those bitten in the Iiead or face and by wolves. In some
anti-rabic institutes the intensive metliod has entirely superseded the simple
method.

It is a sufficient answer to the assertion that has been made that Pasteur's
intensive inoculations are dangerous, in that they may actually produce the
disease, that the mortality from rabies is strikingly smaller after the appli-
cation of the intensive method than after the simple treatment. There is,
furthermore, a method of demonstrating experimentally that those who
may die from rabies after preventive inoculations have not contracted the
disease by means of the inoculations. These inoculations are made with the
fixed virus, of wliich the period of incubation in rabbits after sub-dural
injection is six or seven days ; whereas those treated were bitten by animals
affected with rabies of the street, the virus of which after sub-dural inocula-
tion of rabbits has a period of incubation of fifteen to twenty days. As has
been already mentioned, even if the period of incubation of the fixed virus

HYDROPHOBIA 407

be lengthened by dilution or attenuation of the virus, or if it be used to kill
another animal as a dog, the virus as obtained from the brain or cord of
the latter animal is still fixed virus, and will destroy rabbits with a period
of incubation of six or seven days. Now, in all instances in which the brain
or cord of a human being dyipg of rabies after the Pasteurian treatment has
been used to inoculate rabbits, it has been found to contain virus with the
period of incubation of rabies of tlie street, and not fixed virus, or in other
words, not the kind of virus which was used for tlie preventive inoculation.
We are not to forget tliat the measures which are of first importance in
preventing hydrophobia must be directed against the development and ex-
tension of the disease in dogs; for if canine rabies could be eradicated, there
need be no fear of tlie disease, at least in this country and in eastern Europe.
These measures consist in good dog laws, and their efficient application. A
proper tax-rate upon dogs, their muzzling, and the destruction of stray and
ownerless dogs, are the principal measures. It may be well also to enforce
quarantine measures against dogs imported from countries where rabies is
prevalent. In most parts of Germany these preventive measures are
thoroughly enforced, and the result is an almost total disappearance of
rabies ; whereas in France similar measures are not carried out, and rabies is
consequently alarmingly prevalent. I do not know of any data which enable
us to determine the extent of prevalence of rabies in this country ; but so far
as can be judged by general impressions, it does not seem to be common with
us. Its occurrence at all, however, is sufficient reason for the enforcement of
those measures which have been found most efficient in its prevention.

CIRRHOSIS nEPATIS AXTHRACOTICA.'

I have placed under the microscopes sections of a liver showing a peculiar
form of cirrhosis associated with the deposition of coal pigment. The
specimen of liver together with portions of other organs were sent to me
recently by Dr. Unger, of Mercersburg, Pa., for microscopical diagnosis.
All that I have been able to learn of the history of the man from whom the
specimens were obtained is as follows: He was a German, about 70 years
of age, who had lived for many years as a farmer in tlie neighborhood of
Mercersburg, Pa. He is said to have worked as a weaver in Germany, but
nothing more definite concerning liis occupation or life in that countr}- could
be learned. The place where he lived in Pennsylvania is not particularly
smoky. His health was good until about two years ago when he began to
suffer from vomiting, loss of appetite and severe pain in the abdomen.
Accumulation of fluid in the peritoneal cavity necessitated repeated tappings
by which serous fluid was withdrawal. The patient grew very weak and
emaciated.

The autopsy was made by Dr. Unger, and on account of special external
circumstances was necessarily hasty and incomplete. Only the abdominal
organs were examined and Dr. Unger as regards these, was chiefly interested
in the character of the new growth which was found. The peritoneum was
found much thickened and presented many nodular masses, mostly of small
size. The omentum was thickened and retracted into a hard, nodulated,
cord-like mass. The mesentery was likewise thickened and retracted. A
miniber of small, hard, whitish, circumscrilied nodules were found in the
superficial part of the liver. Pieces of the liver, omentum and peritoneum
were sent to me for examination. Sections of the nodular tumors sliowed
them to be carcinomata, presenting a fibrous stroma rich in cells and irregu-
lar alveoli filled with polyhedrical and cuboidal cells. The jiriinary origin
of the cancer was not determined, although doubtless a more complete
autopsy would have revealed it.

The most interesting feature of the case, however, is the condition of the
liver. Of this organ several pieces hardened in alcoliol were sent. On the
cut surface as well a.s through the caiisulo of the liver can l)e seen with the

' Delivered before the Johns Hopkins Hospital Medical Society. December 15.
1890.

Johns Hopkins Hosp. Bull.. Bait., 1891, II. 32-3.'?.

403

CIPRHOSIS HEPATIS ANTHRACOTICA 409

naked eye numerous small black specks and small streaks. These little black
lines and dots are present everywhere throughout the liver scattered irregu-
larly at intervals not more than 0.5 to 1 mm. apart. They are irregular in
size and shape. They are not present in the cancerous nodules nor more
abundant in their neighborhood than elsewhere. Some of the pieces of liver
which were sent do not contain any cancerous nodules. Around many of the
black specks tlie tissue has a grayish color. The prevailing color of the liver
substance between the black deposit is yellowish brown.

On microscopical sections tlie little black spots and streaks, sometimes
lying in a gra3'ish tissue, sometimes in the yellowish brown liver substance,
can be seen distinctly with the naked eye. By microscopical examination the
block foci are seen to be due to the deposit of black granules in all respects
identical with the coal pigment found in the lungs. The granules are of a
pure black color, vary in size from granules about one-quarter the diameter
of a red blood corpuscle to very minute granules, occur sometimes in large
conglomerate masses evidently composed of a close aggregation of granules,
and are sometimes quite regularly round, but may be slightly irregular and
angular in shape. They occur both free and enclosed in cells. They remain
unchanged when the sections are treated with concentrated sulphuric acid
as well as with boiling glacial acetic acid, hydrochloric acid, nitric acid,
aqua ammoniae or concentrated liquor potassae. Compared with the coal
pigment found so often in the lungs and bronchial glands absolutely no
points of difference can be detected and I have therefore no hesitation in
saying that they are coal particles.

The particles of coal pigment are not distributed uniformly throughout
the liver as is the case with malarial pigment but occur in scattered areas.
There are in some places small deposits of the pigment between unchanged
liver cells. These deposits between liver cells are generally within round
or irregular cells lying against the capillary walls and sometimes appear to be
contained in Kupfer's cells. The black pigment is never within the hepatic
cells. As a rule the pigment lies within bands and nodules of dense fibrous
tissue, and it is the character of these fibrous areas and the relation to them
of the coal pigment that make the unusual feature of the case.

These fibrous areas differ in distribution and in appearance from the
formation of fibrous tissue in ordinarv' hepatic cirrhosis. The fibrous areas
are sharply circumscribed. They never completely surround a lobule. They
occur most frequently in the interlobular tissue, but they are also often
formed around the central vein as well as at any point in the interior of the
lobule. They vary in size. Some are not larger than a group of five or
six liver cells, others occupy nearly the entire field of the miscroscope with
29

410 CIRRHOSIS HEPATIS ANTHRACOTICA

Zeiss objective A, ocular 3. The majority are much smaller than this latter
dimension, averaging about one-sixth to one-eighth the diameter of a liver
lobule. Five to eight such noduJes can usually be seen in each field of the
microscope with Zeiss A, ocular 3. The shape of the fibrous patches varies,
but there is a general tendency to assume a round or oval shape. Many of
the patches, however, are long and narrow following the course of the inter-
lobular vessels or the rows of liver cells. The fibrous area.s are in general
composed of dense sclerotic fibrous tissue poor in cells, these cells being
chiefly elongated connective tissue cells closely applied to the fibres and
cells containing black pigment. Some of the areas, especially the smaller
intralol)ular ones are composed of a hyaline indistinctly fibrillated material
poor in cells. In the interlobular fibroid formations can be seen very much
compressed interlobular veins, branches of the hepatic artery with thickened
walls resulting from an obliterating endarteritis leading in some instances to
complete obliteration of the vessel, and bile ducts. The bile duets are few
and there appear to be no so-called newly fonned bile ducts so often observed
in ordinary cirrhosis. All of the fibroid formations, whether intralobular
or interlobular, contain in large amount black coal pigment, both free and
in round oval, and elongated, sometimes branching cells. With the excep-
tion of the comparatively few small deposits seen between normal liver cells,
the coal deposits are found only in the fibroid masses and the growths of
fibrous tissue do not occur except in association with the pigmentary deposits.
There can be seen on careful examination unmistakable evidences that the
new growth tissue is referable directly to the deposition of coal pigment.
Where the pigment is surrounded by normal liver cells, it is present only in
comparative small amount. There are places where a clump of the pigment
is surrounded by two or three homogeneous liver cells devoid of nuclei or by
a little hyaline or finely granular material replacing two or three imme-
diately adjacent liver cells, and places where a small area of nearly homo-
geneous basement substance cont^iining a mass of coal pigment has taken
the place of not more than five or six liver cells in the interior of a lobule
and all transitions exist between these small areas and the larger ones. The
appearances indicate that small deposits of the coal pigment do not injure
the surrounding liver cells, that larger deposits lead to a death of the immedi-
ately adjacent liver cells, and as a result of this loss of liver cells, a new
growth of dense fibrous tissue is developed.

The histological picture is quite different from that of ordinary hepatic
cirrhosis. Instead of interlacing bands of connective tissue more or less
completely surrounding lobules or groups of lobules, we have in the present
instance sharply circumscribed, round, oval and elongated discrete areas of

CIRRHOSIS HEPATIS ANTHRACOTICA 411

sclerotic, at times nearly homogeneous, fibrous tissue, containing such masses
of coal pigment as to appear in places almost uniformly black. Different as
are the appearances from ordinary cirrhosis, there is manifestly a close
analogy between the changes in this liver and those occurring in indurative
anthracosis of the lungs. In both is found the same formation of circum-
scribed bands and nodules of dense fibrous tissue, colored black, with coal
pigment.

This anthracosis of the liver has no relation to the presence of the secon-
dary cancerous nodules in the liver which are entirely free from pigment.

Besides the changes mentioned there is no other lesion of the liver save
a considerable bile pigmentation of the liver cells.

The presence of a small amount of coal pigment in the liver is not par-
ticularly uncommon. Instances have been reported by Arnold, Soyka, Wei-
gert and others. We owe to Weigert and to Arnold especially the establish-
ment of the especial conditions leading to this occurrence. Whereas under
ordinary conditions the bronchial lymphatic glands form an effectual fil-
ter against the entrance into the blood of coal pigment inspired into the
lung, Weigert has shown that adhesions and destructive inflammations may
open the way for the passage of this pigment from the glands directly into
adjac^ent blood vessels, and it is probable that similar alterations in the lungs
may lead to the same result. Arnold has pointed out the frequent associa-
tion of emphysema of the lungs with the presence of coal pigment in the
spleen, liver and elsewhere. It is unfortunate that in the present case we
have no clue as to the condition of the lungs or of the bronchial glands, but
we can hardly be mistaken in assuming that some abnormal condition
existed which permitted an imusually free entrance into the circulating
blood of coal pigment from these situations. I have repeatedly had the
opportunity of confirming the observations both of Weigert and of Arnold,
but I have never before seen a liver containing such a large amount of coal
pigment as the present one, which is speckled everywhere with black dots and
streaks. Ordinarily the presence of coal pigment in the liver is not asso-
ciated with any important lesions referable to the deposition of the pigment.
Careful exammation, however, will often reveal atrophied liver cells and a
small quantity of dense fibrous tissue poor in cells around coal deposits of
considerable size, but as far as I can learn, this is the first instance recorded
of a peculiar form of wide-spread cirrhosis of the liver dependent upon the
presence of coal pigment, and I propose to designate the condition cirrhosis
hepatis anthrocotica.

From the description already given, it is clear that the primary change
leading to the cirrhosis is the atrophy and death of liver cells. Whether we
are to attribute this cell death to a mechanical or to a chemical action of

412 CIRRHOSIS IIEI'ATIS ANTIIRACOTICA

the pigment deposits cannot be positively determined, but the former seems
the more probable view. Still, as pointpd out by Weigert, the coal particles
inhaled may carry with them substances of an irritating nature, which may
give to the particles an injurious action which the pure carbon granules
themselves would not possess. Although occasionally the coal particles were
present immediately around and in some places appeared to be within the
capillary vessels, there was no such obstruction of the blood vessels by coal
pigment as would explain the death of liver cells.

THE PATHOLOGICAL EFFECTS OF ALCOHOL'

Introduction. — In considering the action of alcohol upon the living body,
it is convenient and customary to distinguish between the physiological, the
pharmacological, and the pathological action or effects of this agent, altliough
in a broad sense all marked deviations from the normal condition produced
by alcohol are pathological. Inasmuch as previous articles in this book
have treated of the composition and relative toxicity of the constituents of
alcoholic beverages, and of the action of alcohol on the digestion, the circu-
lation, the respiration, and the nervous and muscular activities, this article
is intended to be a concise statement of the pathological effects of alcohol
and of alcoholic drinks in the more restricted sense of the term " path-
ological," and especially of these effects which are characterized by demon-
strable anatomical changes in the body.

It may at the outset be stated tliat the injurious effects of alcohol upon
the body are represented only in part by known anatomical lesions, for we
are still ignorant of the anatomical basis of many of the morbid manifesta-
tions produced by this substance. With improvements in methods of micro-
scopical investigation our knowledge in this respect has materially increased,
and from still more refined methods further advance in the same direction
may be expected.

The questions of primary importance concerning the effects of alcoholic
beverages relate to the action of ethyl alcohol, which is the chief harmful
constituent of such drinks, although the effects of other possible ingredients,
such as the flavoring essences and the higher alcohols, and the influence of
concentration of the alcohol are by no means to be ignored. In this article,
by the word " alcohol," unless otherwise specified, ethyl alcohol is to be
understood.

Our sources of information concerning the morljid effects of alcohol are
experiments upon animals and observations upon himian beings. The ex-
perimental method has the advantages that the conditions can be better
controlled and are less complicated, and the results, therefore, are generally
dearer of interpretation than in the case of observations on human beings,
but great caution should be exercised in applying directly to human beings
the conclusions derived from animal experiments.

'In: Physiological Aspects of the Liquor Problem, Best. & N. Y., 1903, II,
349-374.

413

414 rATTTOT.Or.ICAL EFFECTS OF ALCOITOL

I. Kesdlts of Experimental Ixvestigatioxs

Alcohol in sufficient quantities is a poison to all living organisms, both
animal and vegetable. Our chief interest in this connection is with those
experimental results which shed light upon the pathological-anatomical
effects of alcoholic drinks upon human beings. During the last fifty years
many experiments to elucidate this subject have been made upon animals,
most frequently upon rabbits, dogs, and swine. Different sorts of alcohol
and of alcoholic drinks in varying doses and for varying lengths of time have
been administered to animals in different ways, the best and most commonly
employed method being injection into the stomach through a soft rubber
tube passed down the gullet.

An elaborate experimental investigation, extending over four years, of the
pathological effects of alcoliol upon rabl)its has been made in behalf of the
Physiological Sub-Committee of the Committee of Fifty by Dr. Julius
Friedenwald in the Pathological Laboratory of the Johns Hopkins Uni-
versity and Hospital. Reference will be made to conclusions derived from
these experiments, which have hitherto been published only in part.

The symptoms of acute alcoholic intoxication in the animals named
resemble so closely those in human beings that the experimental method
would seem adapted for the study of anatomical changes which may be
produced under these circumstances. On the other hand, most experi-
menters record unsatisfactory, although not wholly negative, results in their
attempts to reproduce experimentally the characteristic symptoms and
lesions of chronic alcoholism as observed in human beings.

Experimental Acute Alcoholic Intoxication. — Ina.<;much as the symptoms
of acute alcoholic intoxication in animals, as well as in man, are referable
almost entirely to the nervous system, it is not surprising to learn that the
only significant anatomical changes produced by this condition are of the
nerve cells and their processes. Hyperaemia of the stomach with increased
secretion of mucus is also often present, especially when the alcohol is given
in a concentrated form. The nervous changes are of such a nature that they
can be detected only by the delicate modem methods introduced by Golgi,
Nissl, and Marchi for the study of the microscopical characters of the
nervous system, and hence our knowledge concerning them dates back
scarcely a decade. Berkley's paper published in 1895 and preceded only by
the brief articles of Vas in 1804, and of Deliio in 1895, wliich were based
upon examination of a small material, is tlie first systematic and elaborate
study by modern methods of the changes of the central nervous system in
experimental acute and chronic alcoholic intoxication. Dr. Berkley's ex-
aminations were made, in behalf of the Committee of Fifty, upon the brains
and spinal cords of rabbits used in Dr. Fricdenwald's experiments. Another

PATHOLOGICAL EFFECTS OF ALCOHOL 415

valuable investigation of the influence of acute alcoholic poisoning on nerve
cells is tliat conducted under Dr. Hodge's direction for the Committee of
Fift}' by Colin Stewart, and published in 189G. Among later investigators
of this subject ma)' be mentioned Marinesco (1897), Jaccotet (1897), Car-
rara (1898), H. Braun (1899), and Kloefeld (1901).

Two different kinds of lesion of the nerve cells have been found in acute
poisoning of animals by alcohol, the one, revealed by the Golgi method, being
of the cellular processes, and the other, shown by Nissl's stain, being of the
body of the cells. The former, described as " the moniliform change," is
characterized by the appearance of irregular swellings or varicosities in the
course of the protoplasmic processes of some of the nerve cells, associated
with partial loss of the delicate bud-like or spinous projections normally
present on these processes. The other change, designated " chromatolysis,"
is the disintegration of the small, stainable granules, knomi as the Nissl
bodies, which can be demonstrated by certain methods of hardening and
staining within normal nerve cells. It is not within the scope of this article
to describe the finer histological details of these lesions.

The extent and the intensity of these changes in the nerve cells depend
upon the depth of the alcoholic intoxication. Nerve cells altered in the ways
described have been found in the cerebral hemispheres, the cerebellum, the
medulla oblongata, the spinal cord, and the sympathetic ganglia, but even in
extreme degrees of the lesions it is only a minority of the cells which are
affected. Kleefeld claims that the moniliform change occurs almost instan-
taneously, and may be found within a few minutes after the entrance of
toxic doses of alcohol into the circulation. Stewart found beginning chroma-
tolysis in nerve cells of a cat killed in fifty minutes by the injection of a large
dose of alcohol into the abdominal cavity. The most extensive changes have
been found in animals subjected to repeated, profound intoxication.

There is consideraljle difference of opinion concerning the interpretation
of these changes and their relation to the symptoms of alcoholic intoxication,
but the weight of evidence favors the view that they cannot be satisfactorily
utilized to explain the s^-mptoms. The same changes occur from various
causes and under a great variety of conditions which have nothing in com-
mon with the phenomena of alcoholic intoxication. They do not represent
any serious or permanent damage to the nene cells, but are readily recovered
from after disappearance of the causative factor. It has even been questioned
whether these changes are really of a degenerative nature, some authors
being inclined to refer them to abnormal movements of protoplasm or other
manifestations of cell life.

Experimental Chronic Alcoholism. — Since the publication in 1851 of the
important work by ilagnus Huss on chronic alcoholism many experiments

416 PATHOLOGICAL EFFECTS OF ALCOHOL

have been made to determine the effects upon animals of the long-continued
use of ali'oliol. The most extensive and prolonged series of experiment* of
this nature hitherto made is that for the Committee of Fifty by Dr. Frieden-
wald in the pathological laboratory of the Johns Hopkins -University and
IIospitAl. The details of tliese experiments will be published elsewhere.
Jlost of the one hundred and twenty rabbits used in these experiments re-
ceived daily, through a soft rubber stomach tube, from five to eight cubic
centimetres of alcohol largely diluted. These quantities sufficed to induce
within half an liour a drunken stupor which lasted from three to five hours,
tlie animal generally appearing well on the following day.

Dr. Friedenwald observed, as other experimenters have done, marked in-
dividual variations in susceptibility to the injurious effects of the continued
use of alcohol. While the tolerance of any given animal could not be posi-
tively foretold, young rabbits, pregnant females, and those weighing under
one thousand grammes were the most susceptible. Certain individuals
were found to be so resistant that they seemed capable of tolerating daily
intoxicating doses of alcohol for an indefinite period. Thus, one rabbit
was given alcohol for over four years, receiving in this time over four litres
of absolute alcohol without permanent ill effects ; others were fed with alco-
hol for three and a half and for three years. These animals had the best of
care and were kept under excellent sanitary conditions. On the other hand,
some of the rabbits died from acute intoxication after a few doses, and the
majority succumbed after shorter or longer periods of time, with gradual
loss of weight and exhaustion. If especial care was taken to lessen or to
intermit the dose of alcohol when the animal began to lose weight, it was
found possible later to increase the dose and to keep a considerable number
of the rabbits alive for an indefinite period. Under favorable conditions
the animals tended to gain in weight when taking alcohol, especially during
the early period.

As regards the pathological effects, there have been considerable differ-
ences between the results reported by various experimenters. Some of the
earlier experimenters found practically no anatomical changes in animals
to which intoxicating doses of alcohol had been fed for weeks or months.
The experiments of Dujardin-Beaumetz and Audige (18T9-1884) on swine,
extending over three years, which are among the most elaborate and pains-
taking investigations of this subject ever made, yielded practically negative
results, so far as pathological lesions are concerned. On the other hand, the
more recent experimental researches, although not altogether in accord,
have in general been more fruitful in positive results.

While these discrepancies are at present partly inexplicable, some at least
may be accounted for by differences in the animals selected for experimenta-

TATHOLOGICAL EFFECTS OF ALCOHOL 41?

tion, by variations in the quantity, quality, and mode of administration of
the alcohol, by the duration of the experiments, by the technique employed
in the microscopical examinations, and by the concentration of attention
upon changes in special organs.

It is to be noted that in mott of the experiments the amount of alcohol
given at a single dose sufficed to produce marked symptoms of intoxication,
this quantity being in ratio to the body weight generally much greater than
that taken by heavy drinkers. No systematic experiments have been made
to determine the pathological effects upon animals of the long-continued
use of alcohol in quantities so small as to produce no manifest symptoms of
intoxication ; but in view of tlie comparatively meagre results in the experi-
ments with moderately intoxicating doses, it seems improbable that experi-
ments of the former character would yield positive results.

Naturally the attention of the experimenters has been drawTi mainly to
the examination of those organs which are known to be most frequently
affected in man in cases of chronic alcoholism, namely, the stomach, the
liver, the kidneys, the heart and blood-vessels, and the nervous system.

Stomach. — Congestion of the gastric mucous membrane and increased
secretion of mucous are among the most common conditions noted by the
various experimenters. Haemorrhages, erosions, and actual ulceration of the
stomach have also been repeatedly recorded. Several experimenters have
reported degenerative changes in the cells of the gastric tubules and chronic
interstitial inflammation of the mucous membrane.

There is evidence that some of these alterations, especially the more pro-
found ones, are attributable to administration of the alcohol in too con-
centrated a form and sometimes to mechanical injuries inflicted by the
stomach tube.

In Friedenwald's experiments on rabbits there was frequently observed
during life a gradual reduction in the amount of free hydrochloric acid in
the gastric contents. In some cases hyperaemia, increased secretion of
mucus, and fatty degeneration of the epithelial cells of the gastric tubules
were found, but in many instances, even after the prolonged use of diluted
alcohol, the stomach appeared entirely normal, both to the naked eye and
under the microscope.

As a rule, no pathological changes were present in the intestine.

Liver. — Inasmuch as the long-continued excessive use of alcoholic drinks
is by far the most common and important cause of cirrhosis of the liver in
human beings, the attention of experimenters has been directed especially
to the condition of this organ in chronic, experimental alcoholic poisoning.

Of the various anatomical changes noted by the different experimenters,
fatty metamorphosis of the liver cells is the one most frequently recorded.

418 PATHOLOGICAL EFFECTS OF ALCOHOL

This change is not usually present in an extreme degree, and it is not gen-
erally associated with lass of the cellular nuclei or other evidences of death
of cells. It readily disaj)pears after cessation of the administration of alco-
hol. Hyperaemia of the liver is not unconunon.

Actual necrosis or death of the liver cells, either singly or in groups,
occasionally occurs, but this, at least in marked degree, is exceptional.

An increase in the number of lymphoid cells in the interlobular tissue has
been found by a minority of the experimenters. It was noticed in varying
degree in some of Friedenwald'.s experiments, but its occurrence was incon-
sistent and rather exceptional.

Genuine cirrhosis of the liver has not been satisfactorilv reproduced by
the experimental use of alcohol. It was present in one of the rabbits of
Friedenwald's early experiments, but as this was an isolated instance of its
appearance, it is not certain that it was attributal)le to tlie alcohol. The few
experimenters who have reported successful results in this regard have
probably mistaken mere accumulations of lymphoid cells for early stages of
cirrhosis, or have not excluded changes due to accidentiil infections, particu-
larly from unintended injuries of the stomach. This failure to produce
experimetally cirrhosis of the liver by the use of alcohol cannot be at-
tributed in Friedenwald's series to the too short duration of the experi-
ments. It lends support to the opinion held by many that in human beings
alcohol acts only indirectly in leading to cirrhosis of the liver, or that special
predisposing or associated conditions must be present in addition to the
action of the alcohol.

Kidneys. — Most of the experimenters have not noted serious anatomical
changes in the kidneys, but von Kahlden in a careful research lays especial
emphasis upon lesions of this organ in dogs. He describes fattv dejener-
ation and necrosis of the renal epithelium, liyperaemia of the veins and capil-
laries, liaemorrhages, and transudation of an albuminous fluid, and con-
siders that with longer duration of the experiments a chronic interstitial
nephritis would appear as a result of these grave lesions.

8even of the rabbits in Friedenwald's series of experiments had marked
albuminuria, associated in five cases with casts. Fatty degeneration of the
epithelium of the convoluted and Henle's tubules was common, although not
constant. In a few instances there was necrosis of the epithelium, and
atroi)liy of the glomeruli. On tiie other hand, a number of the rabbits
showed no changes in the kidneys after long-continued use of alcohol. An
actual chronic interstitial nei)]iritis was not produced.

Heart, Blood'Vesseh, and Blood. — In Friedenwald's experiments fatty
degeneration of the muscle of the heart was found in most of the ralibits
whicli died from chronic alcoholic intoxication, but was absent in tiiose
which were killed after cessation of the use of lacohol.

PATHOLOGICAL EFFECTS OF ALCOHOL 419

In these experiments, as well as in those of others, now and then a
sclerotic or atheromatous patch was found on the inner surface of the aorta
or other blood-vessel. This lesion was present, however, too inconstantly to
be attributed with any certainty to the action of the alcohol, especially as
similar changes occasionally a.e found in animals which have not received
alcohol. Petrov, however, describes progressive sclerosis of blood-vessels in
experimental alcoholism.

Fatty degeneration of the endothelial cells and sometimes of the smooth
muscle is found with sufficient frequency in the blood-vessels of different
organs to be ascribed to the effect of the alcohol.

Often the distribution of the blood does not differ materially from the
normal, but tliere may be hyperaemia of certain organs, most commonly of
the stomach, liver, kidneys, and brain.

Friedeuwald noted in many instances a considerable reduction in the per-
centage of haemoglobin. In those chronic intoxications which terminated
fatally there was usually, during the last month or so of life, a distinct
anaemia, with reduction in the number of both red and white corpuscles.
Fatty degeneration of leucocytes may occur.

yervous Si/stem. — The more recent experimental studies of the patho-
logical effects of alcohol have been concerned especially with the condition of
the central and the peripheral nervous system. In animals, dead from
chronic alcoholic poisoning, changes of the nerve cells have been found
identical with those described under " Experimental Acute Alcoholic Intoxi-
cation " (p. 414). There is reason to think that these changes belong, even
in the chronic cases, to the more immediate, acute effects of alcoholic poison-
ing, for in Friedenwald's experiments they were often absent in animals
which did not die, but were killed in the course of the experiments, and they
were not observed in animals allowed to live a few days after the alcohol was
stopped.

Of other lesions of the brain and spinal cord ascribed to chronic alcohol-
ism in animals Afanassijew and Braun describe fatty and vacuolar degen-
eration of nerve cells; Braun also describes a vacuolar rarefaction of the
medullary substance, fatty degeneration of the myelin, and the appearance
of fatty granular cells along the blood-vessels, and Berkley alterations in the
calibre and walls of the blood-vessels and the peri-vascular hinphatics, and
accumulations of leucocytes: Small haemorrhages are occasionally found.
Xone of these changes is constant. Some of the rabbits of Friedenwald's
experiments which were killed after daily intoxication with alcohol for over
two years showed practically no lesions of the nervous system.

In view of the importance of peripheral neuritis in the pathology of
chronic alcoholism in man, much interest attaches to the observations of

420 PATHOLOGICAL EFFECTS OF ALCOHOL

Spaink, and later of Braun, who found both in rabbits and in dogs subjected
to chronic poisoninj:^ with alcohol degenerations of various peripheral nerves.
Only in the more chronic cases was this defeneration, which is characterized
especially by breaking-up of tlic myelinc, well marked. These experimenters
claim to have observed in these animals most of the nervous, muscular, and
other symptoms characteristic of chronic alcoholism iu man. Further con-
firmatory investigations are needed before these results can be unhesitatingly
accepted, especially as similar extensive chanjres in the peripheral nerves
were not observed in Friedenwald's experiments.

Other Orgam. — Although hyperaemia, oedema haemorrhages, and actual
inflammation of the lungs have been described as result* of alcoholism in
animals, there is no good reason for this interpretation. Doubtless in many
cases these lesions, when found, were attributable to the accidental escape of
alcohol into the windpipe. There is no satisfact^rj' evidence that alcohol,
administered by the stomach, acts injuriously upon the lungs of animals.
In Friedenwald's rabbits a diffuse, fine deposition of fatty granules in the
epithelial and interstitial cells of the testicles was often obser^'ed. More
profound changes in these organs, even atrophy, induration, and softening,
are described by Bouin and Gamier as the result of alcoholic poisoning of
white rats for eight to eleven months ; but these observations need confirma-
tion before acceptance. The same caution is applicable to Sodokow"s state-
ments concerning changes in the ovules and spermatozoa.

Experimental Investigations of the Influence of Alcoholism upon Resist-
ance to Infection. — There have been at lea^t a dozen experimental investiga-
tions published concerning the influence of alcohol upon susceptibility to
infection, the flrst extensive series of experiments being that of Dr. Alibott,
published in 1896, and made in behalf of the Committee of Fifty. These
various experiments are in remarkable accord, nearly all showing that ani-
mals intoxicated by alcohol are more susceptible to bacterial infection or to
toxines than are normal animals. Eoos, however, found no increase in sus-
ceptibility to the tubercle bacillus of guinea pigs fed with wine, and Kogler,
under Grubcr's direction, noted a favorable influence of alcoliol ui>on the
survival of animals treated with this agent during the stage of acute collapse
produced by intT-aperitoneal injection of killed cultures of Bacillus prodigio-
sus. Delearde has found that the process of experimental immunization is
unfavorably influenced by alcohol.

These researches furnish an experimental basis for the generally recog-
nized lowering of resistance to many infectious diseases manifested by alco-
holic patients. They are not however, decisive as to the usefulness of alcohol
in the treatment of infectious diseases in human beings, for the amount of
alcohol used in experiments proportionately to body weight far surpasses

PATHOLOGICAL EFFECTS OF ALCOHOL 421

that generally given for therapeutical purposes, and the question is one
which must be answered by clinical experience.

In this connection may be mentioned the unfavorable influence of alcohol
upon pregnant females observed by Friedenwald in his experiments. Of
twenty pregnant rabbits fed with alcohol seventeen aborted, and of these
eight died soon afterward of septicaemia. Nearly all of the young which
were born at full terra died a few days after birth. Laitinen reports a
similar experience with pregnant guinea pigs intoxicated with alcohol.

SUMMARY OF THE PATHOLOGICAL CHAXGES IN EXPERIMENTAL ALCOHOLISM

1. There are no satisfactory experimental data to determine the patho-
logical effects upon animals of alcohol or of alcoholic beverages taken for a
long time in quantities which produce no marked symptoms of intoxication.
In most of the experiments the amount of alcohol administered at a dose,
in proportion to body weight, considerably exceeded that usually taken
even by heavy drinkers.

2. Animals exhibit marked individual differences in their susceptibility
to the injurious effects of the prolonged admiuistraton of intoxicating doses
of alcohol. While certain individuals succumb quickly, otliers may be kept
alive under these circumstances for at least four years without presenting
any serious anatomical lesions attributable to the alcohol. Between the ex-
tremes there are all gradations in susceptibility, young animals and pregnant
ones being generally the most susceptible.

3. In acute experimental alcoholism there can be demonstrated certain
delicate changes in the nerve cells, which readily disappear after stopping
the alcohol.

4. The experimental reproduction in animals of certain of the more
characteristic diseases of human beings, attributable to the abuse of alcohol,
such as cirrhosis of the liver, chronic Bright's disease, and arterio-sclerosis,
has not been satisfactorily attained. The most common pathological con-
dition noted in experimental chronic alcoholism of animals is a fatty meta-
morphosis affecting especially the cells of the liver, the heart muscle, and
the kidneys. This lesion soon disappears after stopping the use of the
alcohol. Death or necrosis of limited groups of cells in the liver and kidneys
may occur, but is inconstant, and, according to most experimenters, is ex-
ceptional. More common is an acute or chronic catarrhal gastritis, but this,
is often absent or but slight. Changes in the central nervous system, similar
to those in acute alcoholism, as well as certain additional ones, may be pres-
ent in experimental chronic alcoholism. Tliere may also be degenerations
of the periplieral nerves. Hyperaemia and small haemorrhages may occur,
especially in the stomach, the kidneys, and the brain. In view of considerable

422 PATHOLOGICAL liFFECTS OF ALCOHOL

difTerences in the results reported by different experimenters, and of many
still unsolved problems, additional experiments upon the pathological effects
of tlie lonji-eontinued use of alcoiiol and of alcoholic drinks are needed.

5. Alcoholic intoxication increases the susceptibility of animals to many
infections, and influences unfavorably the process of immunization. Preg-
nant rabbits or guinea pigs repeatedly intoxicated by alcohol are likely to
abort, and to die soon afterward from some accidental infection. Many of
their young die a few days after birth.

IL Alcohol as a Cause of Human Diseases
It is universally recognized that alcoholic intemperance is the direct or
the contributory cause of an immense amount of sickness and disability, and
of a very large number of deaths, concerning which, for obvious reasons,
mortality returns furnish only imperfect and partial statistical information.
According to Vacher the Registrar-General's Reports for England and
Wales show during the twenty years from 1881 to 1900 a total of 110,215
deaths due to chronic alcoholism, delirium tremens, and cirrhosis of the
liver, these being the only causes of death, registered in the refwrts, which
directly represent the mortality from alcoholic intemperance. These deaths
correspond to an average death-rate per million living for the twenty years
from tliese three diseases of 188.45, that among the male population between
226.7, and that among the female population 152.6. A large majority of
these deaths occurred between twenty-five and fifty-five years of age, when
men and women should be at their best. During the twenty years there
was an increase in the mortality from each of these diseases, but only in
the case of chronic alcoholism was this very remarkable. The three causes
of death included in these statistics by no means represent the total mor-
tality from alcoholic intemperance, for the agency of alcohol in the causa-
tion or the fatality of Bright's disease, diseases of the heart and blood-
vessels, apoplexy, paralysis, insanity, pneumonia, tuberculosis, and other
diseases is not recorded in these or in most other mortality returns.

For the last twelve years the ollicial mortality reports from the larger
Swiss cities contain data concerning alcoholic excess as a contributory as
well as a direct cause of death. The statistics (cited from Delbriick) from
the fifteen largest Swiss cities for the eight years from 1801 to 1898 show
that in C.4 per cent of all deaths of persons over twenty years of age
alcoholism was either the direct cause or a contributory cause. The per-
centage is 10 for men over twenty years old. DifTeront jilaces and countries,
of course, show marked differences in the mortality from intemi>eranee.
Switzerland ranks among countries with a medium consumption of alcohol.
Individual predisposition and also predisposition of special organs of the

PATHOLOGICAL EFFECTS OF ALCOHOL 423

body are important factors in tlie etiology- and pathology of alcoholism. It
is a matter of common experience that many persons drink beer, wine, and
spirits in moderation throughout a long life without apparent impairment
of the general health. There are, however, others so extremely susceptible
to the action of alcohol that they are intoxicated by quantities so small as to
be without manifest effect upon most persons. In some individuals, also,
the symptoms of intoxication assume an unusual so-called pathological type.
Unusual susceptibility to the toxic influence of alcohol, as well as a morbid
craving for alcoholic liquors in increasing quantities, have been attributed
in many instances to an inherited or acquired degeneracy or instability of
the nervous system, but the opinions of authorities are much divided as to
the relative importance to be attached to this factor in the causation of
alcoholism. The periodical excessive drinking which characterizes dipso-
mania is now generally regarded as a manifestation of a disease which some
physicians consider to be analogous to epilepsy. Of the injurious effects of
the continued use of even small quantities of alcoholic liquors upon infants
and children Demme and others have brought abundant evidence.

The importance of predisposition is further illustrated by the familiar
fact that some persons after a relatively short period of immoderate indul-
gence in alcoholic liquors present the symptoms and lesions of chronic
alcoholism, whereas others under the same conditions, or perhaps even more
intemjjerate, are affected only after a much longer interval or, it may be, not
at all. Evidence of predisposition on the part of organs is furnished by the
remarkable differences in the manifestations and the localization of alcoholic
diseases in different persons, so that in one the kidney, in another the liver,
in another the heart, and in still another the brain is the organ chiefly
damaged by alcohol. These differences can be explained only in part by the
kind and concentration of the alcoholic beverages used.

There being no constant and definite relation between the amount of
alcohol consumed and its pathological effects, it is difficult to make state-
ments which shall be both precise and truthful concerning possible patho-
logical effects of what is ordinarily called " moderate drinking." This sub-
ject is one concerning which widely divergent views have been expressed
even by those whose opinions are authoritative in medicine. Its scientific
investigation encounters peculiar difficuJtes, and at present the established
facts are too few to permit secure, broad generalizations. The increasing
recognition, especially within recent years, of the importance of this matter,
is sure to lead to more exact knowledge concerning it, but it will probably
be a considerable time before an entire agreement of medical opinion in this
regard is reached.

A difficulty at the beginning is encountered in attempting to define moder-
ation in drinking. What is moderate for one person may be immoderate for

424 PATHOLOGICAL EFFECTS OF ALCOHOL

aiiotlicr. The discussion of this funJamcntal aspett of the subject belongs
to the consideration of the physiological and the piiarmacological action of
alcohol, and has been presented in other articles, particularly in Dr. Abel's
" Review of the Pharmacological Action of Ethyl Alcohol," which were
pul)lished in the book on " Physiological Aspects of the Liquor Problem."
There it has been pointed out that the closer analysis of the physiological
effects of alcohol, especially upon the nervous centres, has led many to adopt,
in comparison witli earlier standards, a considerable reduction in the quan-
tity of alcohol wliicli may be properly designated as " moderate," that is, the
quantity which may be habitually taken without bad results of any kind. It
may here be said that increased knowledge of the pathological effects upon
the body of the continued use of alcoholic beverages has drawn many physi-
cians who have carefully studied the subject to a similar conclusion, the
demonstration of the causative relation of beer-drinking to diseases of the
heart and arteries having been of especial influence upon medical opinion in
this regard. Alcoholic diseases are certainly not limited to persons recog-
nized as drunkards. Instances have been reported in increasing number in
recent years of the occurrence of diseases of the circulatory, renal, and ner-
vous systems, reasonably or positively attributed to the use of alcoholic
liquors, in persons who never became really intoxicated and were regarded
by themselves and by others as " moderate drinkers." Striirapell believes
that the daily consumption of three to four litres of beer will eventually act
injuriously upon the heart. No precise figures are available concerning the
frequency with which alcoholic indulgence in its lesser degrees causes disease.
It is well established that the general mortality from diseases of the liver,
kidney, heart, blood-vessels, and nervous .system is much higher in those
following occupations which expose them to the temptation of drinking
tlian in others.

The bodily injury inflicted by alcoholic abuse may be entirely latent until
it is made manifest by some accessory circumstance. Thus delirium tremens,
neuritis, and other nervous manifestations of alcoholism often make their
first appearance as an accompaniment or sequel of some acute febrile disease,
such as pneumonia, or of traumatism, loss of blood, emotional shocks, or
other affection. Or the bad effects of immoderate drinking may be unsus-
pected until they influence unfavonil>ly the course and outcome of some in-
fectious disease or of a surgical operation.

Alcoholism, as pointed out by Striimpell, represents the summation of
injuries inflicted upon the tissues of the body by alcohol, each injur}- being
perhaps minimal in amount but the total constituting serious disease. It is
not necessary to consider here the various theories concerning the mode of
action of alcohol as a poison, or the extent to which it does injury by actmg

PATHOLOGICAL EFFECTS OF ALCOHOL 425

directly as sucli upon the cells, or indirectly through nutritive or other dis-
turbances. In one way or another most of the organs and tissues of the body
may become the seat of morbid chanjres attributable to the poisonous act;ori
of alcohol. For the purposes of this article it is not necessary to at*-empt
more than a brief specification of the more characteristic and common path-
ological effects of alcohol. Xone of the lesions of either acute or chronic
alcoholism is absolutely pathognomonic of this condition, but in many cases
of death from chronic alcoholism the anatomical changes in their entirety
are sufficiently characteristic to establish a probable diagnosis without
knowledge of the history of the case.

The poisonous effects of alcohol may be referred to the following classes
of morbid change, which may occur either singly or in combination: (1)
disturbances of function, (2) irritative effects marked by hyperaemia, with
which may be associated haemorrhages and transudation of serum, (3)
cellular degenerations of various kinds, (4) production of new connective
tissue, (5) abnormal metabolism, characterized especially by increased for-
mation of fat or deposit of fat in abnormal situations. When brought
directly in a concentrated form into contact with the tissues alcohol is an
inflammatory irritant. The most important and characteristic pathological
action of alcohol is that of a cellular poison. It is probable that the new
growth of fibrous tissue in certain alcoholic diseases, especially in cirrhosis
of the liver, is consecutive to a primarv' degeneration or death of cells,
although this opinion is disputed.

In the rare instances of fatal acute alcoholic poisoning, when a large
quantity of strong spirit is taken at once, no characteristic lesions are found
after death. There may be redness and inflammation of the stomach and
congestion and haemorrhages in the brain, the lungs, and perhaps other
organs, but these changes are not invariably present, and they are in no way
diagnostic. We have experimental evidence, which has already been pre-
sented, that acute alcoholic intoxication causes certain changes of a transi-
tory nature in the nerve cells, and similar changes have been found in
human beings in the acute cerebral disorders of alcoholism.

CHRONIC ALCOHOLISM

Alimentary and Eespiratory Tracts. — Chronic catarrhal inflammation of
the stomach is a common affection of alcoholic patients, but the lurid descrip-
tions and pictures of the drunkard's stomach in certain popular or pseudo-
scientific " temperance " tracts and books are drawni from the imagination
and not from nature. There may also be intestinal catarrh, but usually no
marked lesions are found in the intestine, except in cases of cirrhosis of the
liver. Catarrh of the pharynx, larynx, and bronchi is common in alcoholic
patients.
30

426 TATHOLOGICAL EFFECTS OF ALCOHOL

Liver. — Cirrhosis of tlie liver. iilth<iuj.'h not. the most common, is the
most characteristic patliologiial-aniitoniical condition produced by alcohol.
The liver is hard and nodular, and usually reduced in size, although it may
be larger tlian normal. The microscope shows a new growth of connective
tissue between the liver lobules and atrophy of liver cells, which may also be
fatty. The immoderate use of alcohol is the cause of probably over ninety
per cent of the cases of hepatic cirrhosis, and some think tliat it is the sole
cause. This disease is the result especially of drinking strong spirits, being
rare in beer drinkers, although not so infrequent in France from excessive
use of wines. The disease is sometimes called " the gin-drinker's liver."
Cirrhosis of the liver was found by Formad in only six of 250 postmortem
examinations on confirmed drunkards who had died suddenly from the effects
of alcohol. Altliough other statistics show a much higher percentage of
cases, this disease is upon the whole a relatively infrequent form of chronic
alcoholism, except in regions where excessive drinking of strong spirits
prevails. Deposition of fat in tlie liver cells is common in alcoholism, and
large fatty livers, as well as cirrhotic livers, are found in drunkards.

Pancreas. — With or without cirrhosis of the liver, chronic interstitial in-
flammation of the pancreas may be the result of alcoholic intemperance. In
eight of tliirty cases of this disease studied by Opie there was a history of
alcoholic excess, but in three of these eases the affection was only indirectly,
if at all, referable to the use of alcohol.

Kidnexjs. — There has been much discussion concerning the effect of
alcohol upon tlie kidneys. Large hyperaemic kidneys are found with great
frequency in those who drink beer to excess, but this is a condition of func-
tional hypertrophy rather than of actual disease, the kidneys being called
upon for extra work in ehminating the excessive amount of fluid taken into
the circulation. The evidence, however, is strong that alcoholic excess is
injurious to the kidneys. The observations of Glascr made in 1891 have
since been repeatedly confirmed, that the urine, even after a single alcoholic
excess, often contains abnormal elements, such as leucocytes, casts, and
crystals of oxalate of lime and of uric acid, indicative of transient irritation
or even slight inflammation of the kidneys. The experimental evidence
upon this subject furnished by von Kahlden and by Friedenwald has already
been cited (p. 418). Although some English authors, following Anstie and
Dickinson, deny any causative relation of alcoholic abuse to Bright's disease,
Striimpell regards renal disorders as the most common of all tlie pathological
effects of alcohol. The weight of authority and of evidence supports the
view that excessive indulgence in alcoholic liquors, fermented as well as dis-
tilled, is an important cause of chronic Bright's disease, especially of the
small, granular kidney. Striimpell describes also a form of acute nephritis

PATHOLOGICAL EFFECTS OF ALCOHOL 427

which may rarely result from the long-continued use of alcohol, and occa-
sionally passes into the chronic form.

Heart.— BisoTdcTS of the heart are among the most important manifesta-
tions of chronic alcoholism, these depending not so much upon any direct
injury inflicted upon the heart by alcohol as upon associated conditions
resulting from alcoholic abuse. Bollinger and Bauer in JIunich were the
first prominently to call attention to the frequency of h\-pertrophied and
dilated hearts in those who drink large quantities of beer. This so-called
" Munich beer-heart," which is commonly associated with the " beer-kidney,"
is probably the result mainly of the extra demand upon the heart for work in
propelling the excessive volume of fluid in the vessels. The compensation
thus established is likely sooner or later to be broken, and then appear serious
symptoms referable to cardiac insulBciency. Other causes of hypertrophy
of the heart in alcoholic patients are sclerosis of the arteries and chronic
Bright's disease. Chronic myocarditis, or new growth of fibrous tissue in
the muscle of the heart, although sometimes ascribed to the direct action of
alcohol on the heart, is rather the result of disease of tlie arteries of the
heart.

Fatty degeneration of the heart muscle may be caused by alcoholic excess,
but a more important condition clinically is the overgrowth of adipose tissue
upon the surface and in the substance of the heart, which is found particu-
larly in association wath the general obesity of some eases of chronic alcohol-
ism. This latter condition may interfere seriously with the normal action
of the heart.

Blood-Vessels. — Alcohol is usually regarded, and probably correctly, as
one of the causes of sclerosis or atheromatous degeneration of the arteries, a
disease of great clinical importance and attended by varied symptoms and
organic lesions according to the particular arteries chiefly affected. In this
way alcoholic excess may stand in a causative relation to cerebral disorders,
such as apoplexy and paralysis, and also to diseases of the heart and of the
kidneys. Dilatation of the veins, particularly about the nose and face, are,
together with acne rosacea, familiar manifestations of chronic alcoholism,
although they may occur quite independently of tliis condition.

Xerrou.9 System. — The special toxic action of alcohol is, in the first in-
stance, upon the higher nervous centres, a fact which is manifest enough in
the familiar symptoms of a drunken fit. Although the special affinity of
alcohol for the nervous system has long been known, the most interesting
and important clinical and pathological studies of alcoholism in recent years
have related to this subject, and have added materially to our knowledge.
These researches have shown that the relationship of alcohol to mental dis-
orders and other disturbances of the nervous system is in many instances less

428 PATHOLOGICAL EFFECTS OF ALCOHOL

pim]ile and flirect tlian was formerly and is still often represented. A
problem of fundamental importance, as yet awaiting final solution, is the
determination of the part to be assigned to underlying inherited or acquired
constitutional defects of the body, chiefly of the nen-ous system, in the
causation and the pathology of the various disorders of the nen'ous system
caused by or associated with alcoholic excess. That this part is a very
important one cannot be questioned, but the limits to be assigned to it are at
present uncertain. Both the general and the statistical statements current
in many medical as well as popular writings upon the causative relation of
alcohol to insanity, to epilep.sy, and to certain other nervous diseases are
often of little value with reference to the question of causation of these
diseases in previously normal persons by alcoholic poisoning.

It is important to know that the immoderate drinking of alcoholic liquor
may be the first symptom of some disease which, when later recognized, is
erroneously ascribed to alcohol as the cause. It is furthermore established
that many of the mental and nervous disorders of alcoholism, while they are
attributable to the toxic action of alcohol, are dependent in large measure
upon an underlying psychopathic constitution, excessive indulgence in
alcohol rarely producing certain of these disorders in persons of normal
constitution. Inebriety in the parents or more remote ancestors ranks
among the important causes of this inherited instability of the nervous
centres. After making the necessarily large, but not precisely definable
allowance for the share of inherited or acquired organic or constitutional
defects in the etiology of the nervous manifestations of alcoholism, there
still remain cases enough in which alcoholic poisoning is the cause of serious
disease of the brain, spinal cord, and nerves in persons of previously normal
constitution, so far as can be ascertained.

Much has been done in recent years by psychiatrists in the careful analysis
of the precise psychical defects characteristic of the various alcoholic psy-
choses, and in this way the features particularly distinctive of the mental
disturbances due to alcoholic poisoning have been more .«haqily defined than
was formerly the case. Investigations of this nature have been made by
Wernicke, Kraepelin, Bonhoeffer, Cramer, and others on delirium tremens,
alcoholic neuritis, with the corresponding cerebral and spinal diseases,
especially chronic alcoholic delirium or Korsakow's psychosis, acute hallu-
cinatory mania, the " pathological " drunken paroxysm of chronic alcoholics,
attended often with acts of violence, and alcoholic epilspsy, but it is not
within the scope of this article to attempt a consideration of these interesting
results.

Correspondingly sharp anatomical definitions of the various alcoholic
diseases of the nervous system are still lacking. The pathological lesions of

PATHOLOGICAL EFFECTS OF ALCOHOL 429

the brain found with greater or less frequency in cases of chronic alcoholism
are thickening, opacitj-, and adhesions of the membranes, chronic haemor-
rhagic pachymeningitis, transudation of serum, atrophy of the cerebral con-
volutions, a granular condition of the ependyma, atheromatous arteries, and
increase of neuroglia in the sup-rficial layers of the cortex. These lesions
belong to chronic alcoholism as such rather than to any one of the special
alcoholic diseases of the brain. In the acute alcoliolic psychoses, of which
delirium tremens is the most common and familiar type, the modem histo-
logical technique, particularly the Nissl and the Marchi methods, have re-
vealed changes in the nerves and the nerve cells of the brain and spinal cord,
but the functional significance of these alterations is not at present well
understood.

Since the investigations of Leyden and of iloeli about twenty years ago,
alcoholic neuritis has been recognized as an important, although not very
common, manifestation of chronic alcoholism. The paralyses, disturbances
of sensation, ataxia, and other symptoms of the disease had been previously
noted. Eecent studies, particularly those of Oppenheim, Gudden, and Cole,
have led to the important conclusion that peripheral neuritis is only one
part of an affection which may implicate the nerve cells and their processes
throughout the whole nenous system. In some cases the peripheral neurones,
in others the central neurones are chiefly affected, but the degeneration may
affect in a single case various groups of neurones in the brain and in the
spinal cord and ganglia, including widely distributed peripheral nerves.
The lesion in all cases is primarily a degenerative one. The results of these
researches bring into close relationship various alcoholic diseases of the brain,
the spinal cord, and the peripheral nerves, especially delirium tremens, Kor-
sakow's psychosis, and multiple neuritis. The imderhing condition is a
toxaemia induced by alcoholic excess. It is especially in this group of
affections that the cooperation of various contributor}- or exciting causes,
such as pneumonia, tuberculosis, or other infection, shock, surgical injury,
privation, etc., is most apparent. The patient may have been addicted to
alcoholic excess for years, but the introduction of one of these accessory
causes suddenly gives rise to the outbreak of one of these disorders of the
nervous system.

In this connection may be mentioned various disturbances of vision which
are often associated with chronic alcoholism and which are referred by
Uhthoff mainly to changes in the optic nerves or their tenninations.

The excessive use of absinthe and other cordials and liqueurs is particu-
larly injurious to the nervous centres, for here the flavoring essences in vary-
ing degree, as well as the alcohol, are poisonous to the nerve-cells. Epileptic
disorders may be caused by the immoderate use of this class of alcoholic
liquors.

430 rATIl01>()(iI('AL EFFECTS OF ALCOHOL

Disorders of Metabolistn. — One of the symptoms of chronic alcoholism,
most common in beer-drinkers, is obesity. Adipose tissue may appear in
situations wliere it is not normally present, the most dangerous localization
in this regard being between the muscle fibres of the heart. Much of the
fine, molecular fat deposited in the hepatic and other cells is the result of
abnormal metabolism of the fats rather than of a true fatty degeneration.
An excess of fatty particles in the blood of drunkards has been observed.

The use of alcoholic liquor, especially in the form of the stronger wines,
and heavy beer or porter is a well-recognized cause of gouty manifestations
in those predisposed by inheritance to this disease.

Striimpell was the first to call attention to the influence of beer in inter-
fering with the oxidation of sugar in the body. He ob.served in certain cases
that the drinking at once of as much as 1^ to 2 litres of beer was followed
by a transitory alimentary glycosuria. These observations have since been
confirmed and exteiulcd. Striimpell recognized a special form of diabetes
mellitus due to alcohol, and he brings the three conditions — obesity, gout,
and diabetes — into a group of correlated alcoholic disorders of metabolism.

Lowered Resistance to Disease. — A much larger number of the victims of
alcoholic intemperance die of some infectious disease than of the special
alcoholic affections. Attention has repeatedly been called in this article to
the lowering of the resistance of alcoholic patients to many infectious dis-
eases, and the experimental data bearing upon this point have been sum-
marized. This lowered resistance is manifested both by increased liability
to contract the disease and by the greater severity of the disease. Phvsicians
generally recognize the graver prognosis of pneumonia, cholera, erysipelas,
and other infections in persons who habitually drink to excess than in others.

The belief was once widely held that those who indulge freely in alcoholic
liquors thereby acquire a certain degree of protection from tuberculosis, but
this opinion is now completely discredited. Alcoholism, if it does not
actually predispose to tuberculosis, as some believe, certainly furnishes no
protection against it. The course of tuberculous disease in alcoholic patients
is often more rapid than usual.

REFERENCES

Abbott: The Journal of Experimental Medicine, 1896, I. 447.

Afanasijew: Ziegler"s Beitrage, 1S90. VIII, p. 443.

Anstle: Alcoholism, System of Medicine (Reynolds). London, 1868, II. p. 63.

Baer, A.: Der Alcoholismus. Berlin, 1878.

Bauer and Bollinger: Ueber idlopathische Hehzvergrosserung. Munchen, 1893.

Berkley: Brain, 1895, XVIII, p. 473.

Bonhoeffer: Die akuten Geisteskrankheiten der Gewohnheitstrinker. Jena, 1901.

Bouin and Garnier. Compt. rend. Soc. de biol. Paris, 1900, LII, p. 23.

PATHOLOGICAL EFFECTS OF ALCOHOL 431

Braun, H.: Ueber die experimentell durch chronische Alkoholintoxikation her-

vorgerufenen Veranderlungen im zentralen und peripheren Nervensystem.

Tubingen, 1S99.
Carrara: Abstract in Jahresb. iib. d. Leistungen und Fortschritte a. d. Gebiete

der Neurologie u. Psychiatrie, 1S9S, II, p. 222.
Cramer: Monatsschr. f. Psychi£*rie u. Neurologie, 1903, XIII, p. 36.
Cole: Brain, 1902, Part XCIX, p. 326.

Dehio: Centralbl. f. Nervenheilk. u. Psychiatrie, 1895, VI, p. 113.
Del^arde: Echo m§d. du nord. Lille, 1897, I, p. 563.
Delbruck: Hygiene des Alkoholismus, p. 42. Weil's Handb. d. Hygiene, 1'"

Suppl.-Bd. Jena, 1901.
Demme: Ueber den Einfluss des Alkohols auf den Organismus des Kindes.

Stuttgart, 1S91.
Dickinson: Med.-Chir. Trans. London, 1873, LVI, p. 27.
Dujardin-Beaumetz and Audig6: La Temperance. Paris, 1884.
Formad: Trans. Assoc. American Physicians, 1886, I, p. 225.
Glaser: Deutsche med. Wochenschr., 1891, XVII, p. 1193.
Gruber: Wiener med. Wochenschr., 1901, p. 1265.
Gudden, H.: Arch. f. Psychiat., 1896, XXVIII, p. 643.
Magnus Huss [Translation]: Chronische Alkoholskrankheit Oder Alcoholismus

chronicus. Stockholm u. Leipzig, 1852.
Jaccotet: Ziegler's Beitrage, 1897, XXII, p. 449.
von Kahlden: Ibid., 1891, IX, p. 349.

Kleefeld: Journ. de physiol. et path. g6n., 1901, No. 4, p. 563.
Kogler: See Gruber.
Kraepelin: Psychiatrie, Leipzig, 1899.

Korsakow: Abstr. in Arch, di psichiat. Torino, 1890, XI, p. 279.
Laitinen: Zeitschr. f. Hygiene, XXXIV. Heft 2.
Leyden: Zeitschr. f. klin. Med., 1880, I, Hft. 3.
Marinesco: Internat. Med. Congress. Moscow, 1897.
Moeli: Charit§-Annalen, 1884, IX, p. 524.
Oppenheim: Zeitschr. f. klin. Med., 1886.
Roos: Abst. in Hygien. Rundschau, 1902, p. 1276.

Sodokow [Russian]. These de St. Petersb. Acad. Imp. M6d. Milit., Feb., 1902.
Spaink: Ueber die Einwirkung reinen Alkohols auf den Organismus u. insbe-

sondere das peripherische Nervensystem. Inaug.-Diss. Jena, Published in

Amsterdam, 1890.
Stewart, C: The Journal of Experimental Medicine. 1896, I, p. 623.
Striimpell: Ueber d. Alkohol-frage vom arztl. Standpunkt, aus Vortage gehalten

in d. 11. allgem. Sitzung d. 65. Versamml. deutscher Naturforscher u. Aerzte

zu Niirnburg am 13 Sept., 1893. 2 Aufl. Leipzig, 1898.
Uhthoff: V. Grafe's Archiv, XXXII, pp. 95; 257.
Vacher: The Practitioner, 1902, LXIX, p. 594.
Vas: Arch. f. exp. Path. u. Pharm., 1894, XXXIII, p. 141.
Wernicke: Lehrb. d. Psychiatrie, 1900.

OSTEO-FIBROMYOMA OF THE UTERUS'

Sections from the different pieces which were sent show a variety of
tissues.

Smooth Muscle. — This is present in considerable amount, althoufrh not
predominating in these pieces. It occurs especially around masses of bone,
and around areas of soft connective tissues; in places, making a kind of
capsule for these structures. It is, as usual, in irregular interlacing bundles,
and is the seat of considerable hyaline degeneration.

Bone. — True bone is present, showing bone corpuscles, with canaliculi,
typical basement substance, lamellae and Haversian canals, with marrow
substance. The lamellae arc arranged around the marrow spaces with more
or less regularity. Some of the bone seems to be formed by a direct meta-
morphosis of connective tissue, and is, therefore, so-called osteoid. But
there are places which show osteoblasts, forming bone in the usual way.

The tissue within tlie marrow spaces varies. It is well supplied with blood-
vessels. In some places it is dense, fibrous tissue, in others more delicate
tissue, and in the latter case may contain large numbers of lymphoid cells.
Particularly abundant in the marrow are large cells, filled with granules,
which may be fine droplets of fat. Adipose-tissue cells occur, but are few.

Embryonic Types of Connective Tissue. — There are large areas, in some
pieces composing most of the tissue, of a delicately fibrillatcd tissue, very
rich in cells. These cells are predominantly young connective-tissue cells,
but there are also lymphoid and plasma cells, and eosinophiles. Thin-walled
blood-vessels are fairly abundant. This embryonic tissue is apparently of
soft consistence. In addition, in connection with this tissue, and also in-
dependently, are areas of soft mucoid tissue, with large, elongated and
branching connective tissue cells. In one set of sections this embryonic
tissue occupies all except a narrow, peripheral rim, which is composed of
smooth muscle. There are hyaline and necrotic changes in these tissues.

Ordinary Adult Fibrous Tissuf. — This is present in connection with the
bone and other tissues.

Degenerations. — There are extensive areas of degeneration: (a) Calcifi-
cation botli of muscle and hyaline connective tissue, (b) hyaline and necrotic

' Report on a pathological specimen. In : Osteo-Flbromyoma of tlie Uterus, by
George B. Johnston, Richmond, Virginia.
Am. Gynaec. & Obst. J., N. Y., 1901, XVIII, 307-30S.

OSTEO-FIBROMYOMA OF THE UTERUS 433

changes have affected considerable areas, (c) actual disintegration of the
necrotic areas, with fatty metamorphosis and deposit of cholesterin crystals.

Diagnosis. — Histologically, Dr. Randolph's designation of the tumor as
osteo-fibromyoma is unobjectionable.

liemarks. — The tumor must, J think, be referred to embryonic remnants,
and there is no objection to considering it as a teratoid formation, although
not a very eomple.^ one. Besides the bone and smooth muscle, there is a
great deal of peculiar embryonic connective tissue in the growth, partly
mucoid in character, and partly more cellular, and this tissue is quite unlike
any found in ordinary myomatous tumors.

MEDrLT>AKY FOEM OF SARCOMA OF THE STERXlBr, WITH
.METASTASES IX THE LYMPHATIC GLANDS'

I am indebted to Dr. D. F. Unger, of Mercersburg, Pa., for this specLmen.
I extract the following points from Dr. Unger's history of the case :

Mrs. S., aged 32 years, weight 120 pounds, mother of three children, had
previously enjoyed good health. Parents are healthy. On September 2, 1892,
she called my attention to a small, deep seated, firm swelling just above the
sternal notch. This gradually increased in size. On November 30, 1892, an
operation was performed by "a surgeon in Philadelphia, who regarded the
art'eution as a tubercular adenitis. The operation consisted iu curetting the
growth above the sternum, trephining the sternum about IJ inches from the
top, curetting through this opening, passing a tube from the upper to the
lower opening and washing through this canal with a solution of bichloride
of mercury and peroxide of hydrogen. Following this, the suprasternal
growth increased in size so as to form an irregularly elevated, somewhat
nodular 11 rm mass about 6 cm. in diameter, adherent to the skin, and involv-
ing for a short distance the tissues over the upper anterior surface of the
sternum. In the latter situation the skin ulcerated over a small area. The
openings made by the operation did not close but became fdled with .grayish,
soft tissue. Examination of the patient on February 1, 1893, showed a
swelling projecting about i inch at the right margin of the sternum, at the
level of the tirst and second intercostal spaces. This swelling increased so as
to touch the opening made in the middle of the sternum and to reach the
margin of the suprasternal tumor. February 14 were noticed several swollen
and somewliat painful lymphatic glands just above the middle of the right
cla\icle. After this tiiere developed enlargement of other cervical and of
axillary glands, and several nodules could be felt beneath the skin of the
upper "part of the thorax in front. The right arm became slightly oedema-
tous and the veins over the right shoulder distended. Dullness on percus-
sion, and absence of respiratory sound over the upper part of the right side
of the chest were determined. General itching of the skin became a most
troublesome svTnptom. The pulse became accelerated, respirations increased
in frequency," and an irregular fever developed, the temperature running
from 98° to" 103° F. A note made on July 1, 1893, records increase in the
number and size of enlarged lymiihatic glands on both sides of neck and in
the axillae, and the presence of many nodules feeling like marbles beneath
tlie skin of upper part of the thorax on both sides. These nodules are mov-
able and not painful, except when they first appear. Cough became trouble-

' Report of a case before the Johns Hopkins Hospital Medical Society, Decem-
ber 4, 1893.

Johns Hopkins Hosp. Bull., Bait, 1893. IV. 103-105.

434

METASTASES IN LYJIPIIATIC GLANDS 435

some only durin? the last two months of life, and was attended with little
expectoration. During the last two months of life the pulse ranged from
120 to 130, the respiration from 30 to 45, and the temperature from 98° to
102°. Urine diminished in amount, but was free from sugar and albumen.
The patient became weaker and weaker and more emaciated, and died
apparently from exhaustion on September 2, 1893, just one year from the
date attention was called to the first swelling above the sternum.

The autopsy was made by Dr. linger, from whose notes I extract the
following :

The anterior mediastinum is occupied by a large, firm, irregularly nodular
tumor mass, so closely adherent to the sternum that it is necessary to remove
most of the tumor with the sternum. The tumor consists in part of swollen
and adherent lymphatic glands. It presses upon the vena cava superior,
the arcli of the aorta, the arteria innominata, the trachea and the base of the
heart, but the caliber of these channels does not seem to be much diminished.
The glands at the bifurcation of the trachea and at the root of the lungs are
also the seat of new growth. The tumor on section is grayish white, with
more opaque yellowish white areas, which in some places are softened and
breaking down.

The right pleural cavity contains i pints of clear serum, and the left 1 pint
of the same fluid. The right upper lobe is adherent to the co.stal pleura,
and is closely incorporated with the tumor behind the sternum, which seems
to have grown continuously into it. This lobe is consolidated throughout
with diffuse and nodular masses resembling in structure the tumor and pre-
senting areas of necrosis. The right middle lobe is filled with tumor nodules
of similar appearance. The lower lobe is compressed. The left lung is
adherent only at its upper part. In the anterior edge of the left upper lobe
is a separate tumor nodule the size of a marble. The rest of the lung appears
normal. Pericardium and heart normal, likewise the spleen, liver, kidneys,
abdominal lymphatic glands. Inguinal glands not enlarged.

Dr. Unger sent to me specimens from this case removed at autopsy. I
had previously, during the life of the patient, examined microscopically a
small piece of tissue excised from the suprasternal tumor and found it to be
a sarcoma composed of variously shaped cells, including giant cells of the
type found in giant-celled sarcoma.

The specimens from the autopsy were preserved in alcohol, and consisted
of the sternum with adherent tumor, of parts of the lungs containing tumor
nodules, of lymphatic glands from the mediastinum, neck and axillae, and
of detached pieces of tumor. For convenience of transportation the sternum
has been divided transversely through the middle piece. The ribs are
severed close to the sternum.

The upper part of the sternum, consisting of the manubrium and adjacent
half of the gladiolus, is covered posteriorly by a large, irregular, adherent,
firm tumor mass, extending to the upper margin of the bone and laterally to

436 SARCOMA OF STERNUM

the right 4 cm. bej'ond the niarfjin of the sternum and to the left a little
beyond the margin. Parts of this tumor mass have been cut away. The
remaining part measures 8 cm. in length from above dowTiwards, 7 cm. later-
ally and 4 cm. in thickness. The free surface of the tumor is irregularly
lobulated. To the right margin of the tumor is attached a piece of lung
measuring 4x6x3 cm., which is completely invaded by the new growth and
inseparably incoroporated with the tumor behind the sternum.

There is a defect in the manubrium 2 cm. below the top near the median
line. This defect, 1 cm. in diameter, is surrounded by bone to the left, and
is continuous to the right, with an outgrowth of the tumor through the
bone. It corresponds to the opening made during life by the trephine. On
the anterior surface of the manubrium are two detached firm tumor nodules,
the larger measuring 2 cm. in length and 8 mm. in breadth.

In order to determine the relation of the tumor to the sternum the bone
was sawed through to the median line and the tumor partly cut through in
the same plane. This section shows that the manubrium throughout nearly
its whole extent is invaded by the new growth, which has caused perhaps
some general enlargement of the bone, but has not materially altered the
normal size and shape so that from external examination the extent of
involvement of the bone would not be suspected. The manubrium measures
5.3 cm. in length, 5 cm. in width, and 2.5 cm. in thickness at the level of the
clavicular articulations.

Throughout an area of considerable extent the osseous substance is entirely
replaced by a grayish white or yellowish white tissue of medium consistence,
in places rather soft. This area begins on the posterior surface just below
the center of the manubrium and extends downwards for 2 cm. Its vertide
length on the anterior surface of the bone measures 1.5 cm. It occupies over
this extent the entire thickness of the right half of the manubrium, and in
the left half occupies the posterior part of the bone leaving Iwne substance
only in front and on the left margin. The hole made with the trephine, now-
filled with the new growth, corresponds to the central part of this area in
which no bone substance is present.

Above and below this area of complete destruction of bone the spongy
texture of bone can be made out, at first very much rarefied, and gradually
becoming near the upper and lower ends of the manubrium more nearly nor-
mal in arrangement. The soft part of the tumor replacing bone merges
gradually into the part where plates of bones are present. Throughout the
manubrium the marrow spaces, much dilated near the soft area, are filled
with grayish white tissue of the same general appearance as that in the
tumor. This filling up of the medullar}- spaces with new growth renders the
cancellous tissues of the manubrium markedly different in aspect from the

METASTASES IN LYMPHATIC GLANDS 437

normal appearance in the adjacent middle piece of the sternum. The whole
manubrium on section has a nearly uniform, solid, g^-ayish white appearance,
in which the bony plates can be more readily appreciated by the touch than
by the eye. The cartilage between the first and second pieces of the sternum
and the remainder of the sternum are normal.

The tumor on the posterior surface of the sternum is directly continuous
with that part of the new growth in the manubrium which occupies the area
in which the bone is entirely gone. At the upper and lower margins of this
area the periosteum on the posterior surface of the manubrium can be traced
as a grayish fibrous band outwards over and into the post-sternal tumor for
a distance of 2 to 3 cm., giving the impression of a growth from the interior
of the bone pushing the periosteum out and then breaking through it.
Above and below this apparent outgrowth of the tumor from the bone the
tumor has developed to the extent already indicated, and has come into con-
tact with the periosteum, from which, however, it can be separated without
diflBculty.

To the right of the sternum the tumor has grown laterally and forwards
so as to form a projecting mass 4 cm. in width, filling the first intercostal
and part of the second intercostal spaces. This is the swelling which was
recognized during life at the upper part of the right margin of the sternum.

Upon section the prevailing aspect of the tumor is firm and grayish white,
with some denser grayish fibrous bands running through it. In many places
can be seen more opaque yellowish white areas of coagulation necrosis.
These areas are irregular in size and shape, some being 5 or 6 mm. in
diameter. In three places these areas are softened and broken do\ra so as to
form little cavities with friable, necrotic contents and irregular walls.

The consolidated upper lobe of the right lung presents in general a similar
appearance, difl'use growth and circumscribed, often coalescing nodules of
grayish white firm tissue, in places necrotic. The swollen lymphatic glands,
some as large as a pullet's egg, and the separate tumor nodules over the
sternum are likewise of a nearly uniform grayish white color, with areas of
firm coagulation necrosis, and in a few places with areas of broken down
necrotic tissue. The pigmented bronchial lymphatic glands are similarly
affected. In places the new growth has extended through the capsules of the
lymphatic glands and involved the surrounding tissues.

The microscopical examination reveals essentially the same structures in
the main tumor in and attached to the sternum and in the metastases. The
grayish white, fresher parts of the growth are composed of cells and scanty
stroma. The cells are of various shapes, small romid cells with deeply
staining single nuclei, larger cells of an epithelioid habitus, fusiform cells,
giant cells, and cells with deeply staining, large, irregular budding nuclei,

438 SARCOMA OF STERNUM

such as occur normally in the marrow of the bones. In places one or the
other of these various forms of cells may predominate, but in general they
are mixed together. The stroma is in places scanty, the tissue being com-
posed mostly of cells ; in other places it is more abundant, and it may form
dense bands of sclerotic fibrous tissue with few cells. There is no regularity
in the arrangement of the cells, especially no suggestion of an alveolar
arrangement. The giant cells are present both in the sternal tumor and in
the metastases. They are not abundant, but are seen here and there in all
of the sections. They are large protoplasmic bodies with large multiple
nuclei, usually clumped in the central part of the cell. None are seen with
a mural arrangement of the nuclei or suggestive of tubercle giant cells.
Allied to these giant cells are large round and oval cells with deeply staining,
often very irregular large nuclei, some ring-like, some like the letter S, and
many budding {cellules a noyau hourgeonnanl) . These cells are abundantly
present. Transitional forms suggest the development of the giant cells from
the cells with the budding nuclei. In the more opaque yellowish areas the
appearance is that of typical coagulation necrosis, absence of nuclei or pres-
ence of fragments of nuclei. These areas are usually dense and somewhat
fibrous in appearance, but, as already mentioned, some are disintegrated into
a structureless detritus. The margins of the necrotic areas show the same
structure as in the rest of the tumor, or may be more fibrous in texture. In
no places are seen tubercles of appearances indicating tuberculosis. Stain-
ing for tubercle bacilli and for other bacteria fails to show any bacteria.

The appearances described establish the diagnosis of sarcoma. The possi-
bilitj^ that the growths are syphilitic was considered. The areas of coagula-
tion necrosis are not unlike those which occur in gumma, but the structure
of the surrounding parts and other clinical and anatomical characters cannot
well be reconciled with the diagnosis of syphilis. Areas of coagulation
necrosis of the character present in this specimen are not uncommon in
some kinds of sarcoma.

The sarcoma is of the mixed-celled type with cell elements belonging to the
marrow of the bones. Giant cells of this type and large cells with large,
irregular, budding nuclei occur more frequently in sarcoma of bone than in
any other kind of sarcoma. The relation of the tumor to the manubrium
sterni cannot well be explained otherwise than upon the supposition that the
tumor originated in this bone, a view confirmed by the histological structure.
The most natural interpretation is that the tumor sprang from the marrow
of the bone, but tumors of similar structure may spring from the periosteum.
The relation of the periosteum to the tumor as already described cannot be
considered conclusive proof of the central origin of the tumor, as a similar
anatomical arrangement may occur with primary tumors of the periosteum

METASTASES IX LYMPHATIC GLANDS 439

and secondary invasion of the bone. While therefore I am inclined to the
view that the growth originated in the medullary part of the bone, I do not
think that the possibility of a periosteal origin can be positively excluded.

There are several points of especial interest which suggest themselves in
connection with this case.

It is interesting that there has been no new production of bone coincident
with the extensive destruction of bone. This type of sarcoma in the long
bones is likely to contain newly formed bone, but it does not always, and
when originating in the short bones it is less likely to do so.

The main tumor topographically belongs to the group of tumors of the
anterior mediastinum, and the present case is one of imusual origin of such
tumors.

The extensive secondary involvement of Ipnphatic glands in this case is an
unusual feature of sarcoma. This involvement was limited to the glands
within the thorax and in the neck and axillae. At one time during life
Hodgkin's disease was suspected. The numerous discrete nodules over the
sternum and thorax occurred in situations where there are no preexisting
lymphatic glands. These metastases were probably of h-mphatic origin
and invaded the fasciae and muscles, which were replaced by the new growth.

Giant celled sarcoma is ranked as a comparatively benign type of sarcoma,
and is not likely to metastasize. The present tumor cannot be considered as
a typical giant celled sarcoma like the ordinary epulis. The giant cells
were less numerous and the rest of the tumor was richer in cells, especially
in small round cells, than an ordinan,- epulis. It is however, a somewhat
arbitrary matter as to what proportion of giant cells is necessary to establish
the diagnosis of giant celled sarcoma. In the present case the giant cells
were of the regular medullary type, and although not very abundant, they
were present in fair number both in the primary growth and in the metas-
tases. More numerous were the large marrow cells with budding nuclei,
which appear to merge into the giant cells. The histological evidence of
malignancy, however, was expressed in this case by the abundance of such
cells as are found in common forms of rapidly developing mixed celled
sarcoma.

The occurrence of the necrotic areas and the occasional disintegration of
these areas are not so rare in sarcoma, especially sarcoma of the bones, as to
need especial emphasis.

Several cases of primary sarcoma of the sternum have been recorded, and
nearly the whole sternum has been successfully excised for this disease, but
this bone is not a common seat of primary sarcoma.

DIFFUSE INFILTRATING CARCINOMA OF THE STOMACH*
I. Abstract of Clinical History by F. R. Smith

Dr. Welch has requested me to give a brief history of the ease from which
the specimen came. The man came into the hospital in the beginning of
April, but had been under observation iu the dispensary sometime before,
complaining of indigestion, with flatulence and pyrosis, which had lasted
for six months. He absolutely denied that he had ever vomited ; then he
corrected himself and said that he did not vomit but spat up a good deal
of bitter stuff. On asking him if he ever vomited in large quantities he
said no.

The family history of the patient is negative, except that the family fear
that his sister may have a similar trouble, for which reason they have
allowed the autopsy. His personal history is entirely negative. He has no
long history of indigestion. Up to four or five months before coming into
the hospital he had been a thoroughly healthy man, a very moderate drinker,
and had no venereal disease and had lived a very regular life.

His occupation, that of a tailor, liad been a sedentar}- one. The symptoms
that he complained of were slight pain in the epigastric region and loss of
appetite. When the stomach was empty he complained more of an uncom-
fortable feeling than of pain. The pain was rarely sharp. He went to
St. Joseph's Hospital in December and was treated he said, for indigestion.
While there he caught cold and had a swollen gland under the left clavicle.
When he came into the dispensary the epigastric region was examined and
nothing whatever was found. Dr. Finney was asked to look at this gland
in the left axilla, and after examining it and hearing the man's symptoms,
he made the diagnosis of carcinoma of the stomach. He was seen by
Dr. Osier about a fortnight aftens-ards. Dr. Osier said he felt something
indefinite in the epigastric region but he would not positively say anything
about its size, except that it was probably a very small lump. The man
came to the dispensary from January to April. All his symptoms grew
worse, and he developed swollen glands under the other clavicle, and then
after a few weeks, there was a distinct lump or ridge in the epigastric
region. This grew larger and the patient became more and more distressed,

• Report of a case before the Johns Hopkins Hospital Medical Soc, May 15,
1893.
Johns Hopkins Hosp. Bull., Bait.. 1893, IV, 98-99.

440

INFILTRATING CAECINOMA OF THE STOMACH 441

He came into the hospital April 4. The ridge was then very distinct and
was found to occupy the right hypochondrium and exiended as low down as
the umbilicus. The stomach tube was inserted and brought up some blood.
It distressed the patient so very much that it was not tried again. Two
attempts were made to dilate his stomach with bicarbonate of soda and
tartaric acid. He had hardly swallowed the tartaric acid when he vomited,
and therefore the outlining of the stomach was always somewhat imsatis-
factory. This ridge-like mass extended, when the stomach was distended
as well as could be, slightly below the umbilicus. It was said in the note
to feel something like a rolled-up omentum. The resonance of the tumor
suggested that it might be connected with a cavity. Dr. Finney's diagnosis
was confirmed by Dr. Osier. Although suffering some pain, the patient was
fairly comfortable, but he gradually grew worse. The patient lost weight
verj- rapidly and the tumor increased in size. The only other thing of
interest in the case was that one morning he complained of great pain in
the left leg, which was swollen and very painful to the touch and which made
him take to his bed. The inguinal glands on that side seemed to be enlarged,
but no thrombosis of the vein could be felt. The leg got better, but he
gradually sank, and at his own desire he went home. The same night he was
taken very ill and died in the morning.

II. Pathological Eeport

This case was diagnosed during life as one of carcinoma of the stomach.
If it were only that, perhaps it would not he worth while to exhibit it here,
but it is a form of carcinoma of the stomach not very common, although you
■n-ill find it described in the literature. The interest of the case is due also to
the fact that the disease can be readily confounded with fibrosis or cirrhosis
of the stomach, so that the literature of the subject of cirrhosis of the
stomach is of very little value so far as cases are reported as fibrosis of the
stomach, induration of the pylorus, etc., without microscopical examination.
In other words, a large proportion of the older cases to be found in the
Literature reported as cirrhosis of the stomach are in reality this disease,
viz., diffuse cancer of the stomach. At the autopsy the parts around the
stomach were the seat of marked fibroid induration. The transverse colon,
the mesentery, the duodenum and the pancreas were all more or less matted
together. I exhibit here the entire stomach. You will observe that the size
and the shape of the organ are about the size and shape of the kidney. The
cavity of the stomach is reduced to an extremely small capacity. The walls
are enormously thickened; the mucous membrane is everj-where intact; no
ulceration and no nodular growth. It is entirely a diffuse disease involving
all of the coats and all of the parts of the stomach. The thickening is univer-
31

4-12 INFILTRATING CARCINOMA OF THE STOMACH

sal, but is somewhat greater towards the pylorus than at the fundus. Exam-
iiiiniT more carefully, we find that certain coat* of the ptomach are very much
thiikeiicd. The grayish, more translucent, muscular coat is extremely
hypertropliicd and makes up one-third to one-half of the entire thickness
of the walls of tlie stomach. The peritoneum is smooth and glistening and
distinctly tliickcned, but not extremely so. The submucous coat of the
stomach is enormously thickened, is extremely dense and fibrous in char-
acter, and looks as though it was the primary seat of the disease. The
mucous membrane is a very thin line, and is distinctly atrophied. The
firm consistence and unyielding character of the walls of the stomach cause
it to remain open on incision. There is nothing at all suggestive of a tumor;
there is no circumscribed or lobulated new growth. Cirrhosis of the stomach
consists in a fibrous overgrowth in the walls without cancerous involvement.
This condition, which cannot be distinguished by the naked eye from cir-
rhosis, is really cancerous, as determined by the microscope. The micro-
scope shows the following condition of things : 'J'be mucous membrane is an
extremely thin membrane indeed. The tubules can lx> made out. hut they are
very much altered in size and broken up in general arrangement. You can
make out rows of cells suggesting a tubular arrangement, and that is about
all. The muscularis miuosae is extremely hypcrtrophied and is everywhere
provided with nests of cancer cells running down in strands connecting the
mucous membrane with the submucosa. The submucous coat is the seat of
large cancerous alveoli. The cancer cells are to be found in all of the coats
of the stomach. They are present in the mucous membrane where they have
a tendency to conform more or less to the tubular arrangement of the
mucous membrane, but they are different from the cells which Iwlong nor-
mally to the tubules of the stomach. Many of them are very large, irregular
cells, with large deeply staining vesicular nuclei. Similar clumps of cells
extend in bands and alveoli through the muscularis mucosae, and form the
largest masses in the submucosa. The alveoli containing cancer cells extend
into the muscular coats along the septa and between individual fil)ers. There
is no coat of the stomach which has escaped. This is the type of infiltrating
cancer as distinct from the one which grows in the form of a circumscribed
tumor. Here the infiltration is uniform throughout the walls of the
stomach. This type of cancer is found also in the ovary, which is then like
a very large ovary, the regular outlines being preserved. There is such a
thing also as infiltrating cancer and sarcoma of the serous membranes, which
spread out flat like a pancake and do not form tumor masses. I have seen
one in the meninges of the brain which was simply a uniform thickening,
preserving accurately the normal appearances of the dura mater so far as
bhape was concerned. We have no jiositive information as to which coat of

INFILTRATING CARCINOMA OF THE STOMACH 443

the stomach is primarily involved in this case. The general idea is that the
growth originates in tlie nmcosa. One would almost be tempted to think
that there was a uniform involvement of the tubules and that everywhere
they tended to grow down through the muscularis mucosae and into the sub-
mucosa. I have alluded to this fcrm of carcinoma in the article in Pepper's
System of Medicine on Cancer of the Stomach and called attention to the
danger of confounding it with cirrhosis of the stomach. The growth in this
instance was primary in the stomach. The only secondary nodules present
are in the neighboring lymphatic glands.

I was particularly interested in this case, because some years ago I made
an autopsy on a somewhat similar one, also a case of diffuse infiltrating car-
cinoma of the walls of the stomach, but it was secondary. The woman,
about 40 years of age, had double carcinoma of the ovary, of that form in
which we have this exaggeration of the nonnal shape. There was marked
ascites in that case, and the fluid was withdrawal during life. From the
character of the fluid I ventured a diagnosis of carcinoma involving the
peritoneum. No operation was done in the case. There was no suspicion
during life that the stomach was involved. We fouaid in the stomach a uni-
form enlargement of all the walls without ulceration of the mucous mem-
brane, and with e.xtreme narrowing of the lumen of the stomach. I have
placed under the microscope a section of this stomach for your inspection.
The peritoneal coat is thickened, the muscular coat considerably hyper-
trophied, and the submucous coat shows interlacing bands of fibrous tissue.
The mucous membrane in this case, instead of being atrophied, is hyper-
trophied. There is a marked lengthening of the gastric tubules and a
marked hypertrophy of the muscularis mucosae in this case. It looks like
a diffused fibroid induration of the organ, and would correspond to descrip-
tions of fibroid induration of the stomach or cirrhosis of the stomach. It,
however, contains nests of cancer cells. In this case the involvement was
from the peritoneum and secondary. The type of the cancer was that of
carcinoma of the ovary. We have three diseases which can produce gross
alterations in the stomach, indistinguishable from each other to the naked
eye : cirrhosis or fibroid thickening of the stomacli, primary infiltrating car-
cinoma of the stomach, and secondary infiltrating carcinoma of the stomach.

SYRINGO-CYSTOMA '

The case is a perfectly typical one of tlie Jacquet-Darier group of cases.
In general there has been such a remarkable uniformity in the reported
cases referred to this group that it is quite improbable that, as claimed by
Moller, some are of endothelial and others of epithelial origin. While a
considerable number of authors (since the report of the first case by Kaposi
in 1868 as a lymphangioma) have adopted the hypothesis of endothelial
origin (some as a lymphangioendothelioma and others as haemangioendo-
thelioma), I believe that the epithelial nature of the tumors has been demon-
strated.

I also believe that the evidence is very strong that tumors of the Jacquet-
Darier type originate from sweat ducts or the " Anlagen " of sweat ducts.
It is triie that actual connection of the epithelial strands and cysts with
preexisting sweat glands has been missed by most of the investigators, and
it may be exceptional, but there are now several well authenticated reports
where such a connection has been recognized, as for example in cases reported
by Blaschko, Neumann, Joseph and Deventer, Fiocco, Winkler, Dohi, Land-
stiener and Matzenuer, Stockmann and others, so that this side of the evi-
dence is fairly strong. Dohi's observation is interesting of narrow epithelial,
tube-like connection of cysts with the interpapillary epithelial processes,
such connections resembling sweat ducts and being probably such. Then
weight is to be given to Torek's argument, who made the first thorough
study of the histogenesis of these tnmors, that the absence or rare occurrence
of sweat glands in the area of the tumor, in contrast to their presence in the
adjoining skin, is indicative of the transformation of preexisting sweat
tubules into the tumor elements.

I attach, however, even greater importance in support of the sweat gland
theory of histogenesis of these tumors to the resemblance between the epi-
thelial strands, nests and cysts and the tubules of sweat glands, and your
sections show this resemblance very well. There is a manifest resemblance
between the narrow, often wavy or twisting strands of epithelium connected
with the cyst and the tubules of the sweat glands, but most significant, and
it seems to me conclusive, is the presence in many of the cysts aiid tubular

■Report on a Pathological specimen of R. L. Sutton,- Kansas City, October 18,
1911. [Quoted in article by R. L. Sutton and C. C. Dennis: J. .\m. M. Ass.,
Chicago, 1912, LVIII, 333-336.]

Unpublished.

444

SYEINGO-CYSTOMA 445

strands of the double row of epithelial cells, the outer row being flat and the
inner row cubical, precisely with the arrangement so characteristic of the
cellular lining of the sudoriparous tubules. Of course this arrangement is
not in all places apparent in consequence of the pressure of the contents of
the cyst, of proliferation of cells and other obvious causes, but it can be
recognized in so many places that it cannot be doubted that it is a character-
istic histological feature of this class of tumors. I do not see how this can
be interpreted otherwise than as evidence of the origin of the tumor from
sweat glands.

Much more problematical, it seems to me, is the decision of the question as
to whether the tumor springs from previously normal sweat ducts or from
congenital or acquired defects of the sweat glimds. In favor of the con-
genital theory is the occurrence of so many instances of tlie affection in
early life and especially its occurrence in several members of the same
family, a point emphasized by many of those who have reported cases, as
Quinquad, Stockmann, Elschnig, Gassmann, Winkler, Csillag and others.
Of much interest are Schidachi's experiments in which he succeeded in pro-
ducing similar cysts, even with epithelial strands, by occlusion of the sweat
ducts.

Now as regards the relation of these tumors of the Jacquet-Darier type, to
which such a confusing multiplicity of names have been given, and the
benign multiple cystic epithelioma of Brooke and Fordyce, I am inclined to
hold them apart. I cannot weigh the value which has been attached to the
clinical points, especially the difference in location, but in Brooke's type of
tumor connection of the growth with the epidermis, with hair follicles and
outlets of sebaceous glands is usually very evident.

In your sections I see the two cysts to which you refer in your letter lying
close to a sebaceous gland, but I fail to make out any connection between the
two, and, so far as I know, Hartzell is the only one who claims to find con-
nection. His case is so poorly described and the photographs so poor that I
do not think it can be satisfactorily interpreted. It may be, as you surmise,
that it is a combination of the two types (Jacquet-Darier and Brooke).
Hartzell speaks of the tube-like structures being lined with cylindrical epi-
thelium, and does not seem aware of the importance of the two layers of cells
in the true syringo-cystomata.

In Brooke's tumor the outer row of cells is cylindrical, whereas in the
Jacquet-Darier tumor it is flat. Of course the occurrence of colloid degenera-
tion in both types of tumor, with the resulting cysts, points to analogies,
which are all the closer from the fact that horn cysts have occasionally been
found in the upper layers of syringo-cystoma, such keratinisation being of
course a marked feature of the Brooke's tumor, although, as Csillag has

446 SYRINGO-CYSTOMA

demonstrated, the colloid cysts and the horn cysts in tlie benign cystic epi-
thelioma have not the same origin.

In spite, however, of such iipparent analogies and even transitions I hold
with the majority of authors that syringo-cystoma is histogenetically distinct
from benign cystic epithelioma, the former originating from sweat tubules,
either fully developed or congenital rest, and the latter from the basal cells
of the epidermis, hair follicles and sebaseous glands.

As you perhaps know. Pick and some others object to regarding the so-
called syringo-cystadenoniata as true adenomata, the question being whether
there is any thing of the nature of a true secretion. If the hyaline or colloid
material in the cysts is merely the result of cellular degeneration the propriety
of such names as cystoma or cyst adenoma would be questionable, but Stock-
nuinn has apparently shown that in some instances the cysts and tubules
contain genuine secretion, so that I see no particular objection to calling the
Jacquet-Darier tumor a syringoma, or syringo-cystoma. or hydrocvstoma or
the like. Still strictly .six-aking it is a benign cystic epithelioma, although
the latter name had better be reserved for the Brooke-Fordyce type of tumor.

I have found Stockmann's article in the " Archiv fiir Dermatologie und
Syphilis," 1908, Bd. XCII, Hft. I, a good one. You will find there refer-
ences to Schidachi's experiments and other authors to wliom I have referred.

CHRONIC JAUNDICE WITH XANTHOMA MULTIPLEX '

I hope that a careful histological study will be made of specimens of the
xanthomatous lesions in this case, as the subject is one offering many un-
solved problems. My attention was directed a few years ago to xanthoma
through the opportunity of examining sections sent to me by Dr. Pollitzer of
New York, whose specimens were utilized by Unna in his description of gen-
eralized xanthoma. The specimens which I examined were of ordinary
xanthoma palpebrarum. There appear to be at least three, and probably
more, clinical types of disease which have been called xanthelasma or xan-
thoma, namely, xanthoma ^-ulgare of the eye lids, an extremely common and
unimportant affection, juvenile xanthoma multiplex, and generalized xan-
thoma of adults, most frequently secondary to jaundice and diabetes mellitus,
but occurring also without any apparent cause. Unna makes a sharp his-
tological difference between the common form of palpebral xanthoma and
generalized xanthoma. According to him, in the former the fat, which gives
the yellow color to the lesion, is of a peculiar character and lies in extra-
cellular masses within the lymphatic spaces and vessels, there being no true
xanthoma cells. I am not aware that Unna's views, which are not in accord-
ance with those usually accepted, have been confirmed. Waldeyer in his first
publication and most other investigators following him find the fat in small
granules or droplets within large cells believed to be derived from connective
tissue cells or endothelial cells, these fatty cells being the so-called xanthoma
cells. Later Waldeyer suggested that these cells may come from his plasma
cells or Toldfs embryonic fat forming cells, and this view has had a number
of advocates. Dr. Pollitzer finds evidence in his sections of palpebral xan-
thoma that the characteristic cells containing fat are derived from striped
muscle, partly displaced through congenital abnormality into the corium.
Virchow objects to the designation " Xanthelasma " or " Xanthoma," as not
based upon histological characters, and has proposed, as a substitute, fibroma
lipomatodes, but this suggestion seems to have met with little success. There
is a rare form of lipoma which bears considerable anatomical resemblance to
certain of the larger neoplasms which have been described as xanthomata. I
examined such a specimen some years ago. It was a lobulated and encapsu-

' Remarks on a case of Dr. Osier and report of pathological specimen, before
the Johns Hopkins Hospital Medical Society, February 4, 1901.
Johns Hopkins Hosp. Bull., Bait., 1901, XII, 220-221.

447

448 XANTHOMA MULTIPLEX

lated subcutaneous tumor, the size of a hen's egg, removed from the groin
of a j'oung man, and believed at the operation to be an ordinary lipoma. On
section it presented a imiform, yellow surface, and microscopically it was
composed entirely of vascular stroma and large cells filled with minute
granules or droplets of fat. After removal of the fat single, or occasionally
multiple, round or oval nuclei with nucleoli were found usually about the
middle of cells filled with a finely porous or reticulated protoplasm. There
was a stroma around individual cells or groups of cells. I interpreted the
timior as composed of embryonic adipose tissue. There were no adult adi-
pose-tissue cells with single, large oil drops. I mention this tumor on account
of its histological resemblance to certain xanthomatous tumors, but other-
wise it has no relation to xanthoma, as it was the only new growth and was
in the subcutaneous tissue. It is highly probable that a variety of distinct
affections have been described under the name of xanthoma.

CHRONIC PERITONITIS WITH COMPLETE OBSTRUCTION,
CAUSED BY NUMERCU.3 CONSTRICTIONS OF A PRE-
VIOUSLY UNDESCRIBED CHARACTER, THROUGHOUT THE
INTESTINE'

I. Abstract of Clinical Histoky by Miles F. Porter

History. — Dr. L. A. H., aged 35, married, had au attack of pneumonia 21
years previously, followed by empyema for which a rib was resected and
drainage instituted. Complete recovery followed, but the diseased chest
still remained considerably contracted. He drank excessively throughout
1903, but now is a total abstainer. In December, 1906 (six montlis before
admission), after a full meal of sausage, he was taken with very severe
abdominal cramps and vomiting, for relief from which he took f grain of
morphine hypodermically. The pain was worse in the lower abdomen, and
especially on the right side, and some tenderness, localized over the painful
area, followed. This attack caused him to quit work for one day. Six weeks
later he had a similar attack, accompanied by vomiting of a light, bright
green-colored fluid and a more severe one followed on Jlarch 28, 1907. The
bowels were constipated. A few days before coming to the hospital he had
a formed putty-colored stool. No elevation of temperature was present dur-
ing these attacks. The patient stated that his abdomen was sore when he was
jolted; he complained of accumulation of gas in the stom.ach, which wa^ re-
lieved by belching or the use of the stomach pump. He frequently vomited
bright green-colored fluid and complained of a metallic taste in the mouth.
It was very difficult to get the bowels to move ; the stools were not formed.

Examination. — The patient was a fairly well nourished man of good color,
and of dark complexion. His abdomen was rather retracted and boogy. An
indistinct mass was felt in the pelvic region, both on rectal and on abdominal
palpation. Examination of the chest was negative. The pulse was 62 ; the
temperature, 97.6° F. The blood picture was normal. The urine was normal
in character but reduced in amount, only 18 ounces being passed in the 24
hours. Bacteriological examination of the vomitus showed a bacillus which
culturally and microscopically gave characteristics of Bacillus typhosus.
The Widal reaction was positive. There was no reaction to two injections

' Report on a specimen of Miles F. Porter, August 14, 1907.
J. Am. M. Ass., Chicago, 190S, LI, 719-722.

449

450 ClIl.'oNK I'HRITOXITIS

of old tuberfuliii of 5 and 10 in<x., respectively. Pernieahility of the intes-
tinal tube was demonstrated by tlie charcoal test. Xo clinical diagnosis could
be made other than lliat of a low grade, wide-spread peritonitis with incom-
plete obstriution of the bowels.

Operation. — An exploratory laj)arotoiny with the patient under ether
anaesthesia was done two days after admission to the hospital. Practically
universal close adhesions were found between contiguous bowel surfaces.
There was some fluid. Very little adhesion between the visceral and the
parietal peritoneum was found. The appendix was freed and removed, but
])rescnted notliing ahnonnal. The bowel adhesions were fairly completely
broken up. The small intestine seemed abnormally short and nowhere con-
stricted, but on the contrary unusually large in its transverse diameter, and
on palpation felt as though it w'ere filled with angle worms. Attempts to
empty sections of the bowel by stripping were ineffectual. The surface of
the bowel was grayish white, and the non-adherent surfaces perfectly smooth.
An incision was made into the ileum. There was no escape of faeces or gas.
The bowel seemed full of mucous membrane arranged in accordion-like folds.
A probe could not be made to pass in either direction ; but the finger could
be made to pass in either direction by carefully working the folds aside.
It was concluded that the case was hopeless, even temporary relief being out
of the question. The incisions in the ileum and the abdominal wall were
closed.

Just previous to the operation tlie patient's pulse was TO, and temperature
97.6° F. Twelve hours after the operation his pulse was 102 and his tempera-
ture 98.2° F. Sixteen hours after the operation a catheter was inserted and
the bladder found empty. Only eight ounces of urine were secreted during
the three days that intervened from the time of operation untQ his death.
There was no vomiting for 20 liours after the operation, when it commenced
again and continued until death. At first the vomitus was green, but later
became dark brown in color. The temperature gradually rose to 102° F.,
while the pulse rate increased and became more feeble in quality, and death
occurred from a gradual failure, T2 hours after operation.

Autopsy. — About two hours' time intervened between the time of death
and the autopsy. Both the wound in the abdomen and that in the intestine
were found to be healing normally. There was no evidence of recent peri-
toneal infection. The stomach presented nothing abnormal except some
adliesions to the abdominal wall. Tlie whole of the small intestine and all of
the large intestine except tlie rectum were covered by a layer of grayish white,
rather strong, plastic material about -^ of an inch in thickness, which could
be strip])ed olf, leaving the underlying peritoneum looking, to the naked eye,
normal. This membrane was smooth on the free surfaces of the bowel but

WITH COMPLETE OBSTRUCTION 451

ragged where it had been adherent. The adventitious coat did not reduce the
transverse diameter of the bowel, but shortened it by actual measurement by
70 to 80 per cent. Closely placed parallel incisions around the bowel would
allow it to be drawn out to its normal length, as would stripping off the
false membrane. Mesentery and omentum were normal. The liver, spleen,
and peritoneal surface of the bladder were covered, as were the bowels, by
this membrane, but not diminished in size. Transverse section of the bowel
shows its lumen to be occluded by transverse folds of mucous membrane.

II. Pathological Report

Gross Appearances. — The specimen, which had been preserved in for-
malin and alcohol, was a portion of the small intestine, evidently jejunum,
"■\hich had been severed from the mesenteric attachment except at one end,
where a small piece of the mesentery was retained.

The specimen measured 31 cm. in length opposite to the mesenteric
border, and 15 cm. in length along the mesenteric border. For a distance of
13 cm. from one end the intestine had been cut open along the mesenteric
margin, the remaining 8 cm. being unopened. The unopened part of the
intestine measured 10 cm. in external circumference, was not collapsed and
felt from the outside as if filled with a rather elastic and moderately firm
material. The transverse section presented by the cut end of this solid,
unopened part of the intestine showed no recognizable lumen, but in its
place a complicated mass of folded mucous membrane. Only with difficulty
and after much twisting and turning could a metallic probe be passed
from the lumen corresponding to the opened part of the intestine through
the lumen of the unopened part; after inserting the probe this latter part
was cut open opposite to the mesenteric attachment, when it was seen that
the obstruction was due entirely to the infoldings of the intestinal wall
occurring at short intervals and kept in place by an organized false mem-
brane attached to the peritoneal surface. This false membrane covered the
entire peritoneal surface of the intestine, but over the opened part of the
specimen, as stated in Dr. Porter's letter accompanying the specimen,
" closely placed parallel incisions around the gut, made through the false
membrane," had permitted this part of the intestine to be stretched to its
normal length and had effaced the involutions of the intestinal wall, so that
here the lunien was free from obstruction and the mucous surface showed
no especial abnormality. It was evident that by a similar procedure the
same result could be obtained in the remaining part of the specimen. There
were no contents found in the lumen of the obstructed intestine after open-
ing it as described.

452 CllKUMC rERlTOMTlS

As has already been stated, the entire peritoneal surface of the intestine
was covered with a false membrane. This membrane, which was from
0.5 to 1 mm. in thickness, was grayish in color, of firm consistence, almost
cartilaginous in transluccnce over most of its extent and smooth over the
greater part of its free surface, although careful inspection showed that
much of this surface was finely granular or slightly shaggy, as would result
from a thin coating of fibrous exudate on an organized fibrous membrane.
Xo remnants of fibrous threads or bands projected from the free surface of
the false membrane. This dense and nearly uniform false membrane, con-
sisting apparently of organized fibrous tissue with superficial fibrinous
exudate, was attached to the underlying wall of the intestine by fibrillated
connective tissue, which w'as evidently also of new formation. This attach-
ment was in general so loose that there was no difficult}' in peeling the dense
false membrane off from the intestine, the surface thus exposed appearing
smooth in consequence of the delicacy of the severed threads of tissue. The
attachment of the false membrane was firmer and more intimate over the
intestine situated between the infoldings of the wall, while it was very
loosely attached directly over these infoldings. No tubercles could be seen
with the naked eye in the outer covering of the intestine or elsewhere.

In this examination the greatest interest attached to the infoldings of the
intestinal wall wliich have filled up and obstructed the lumen of the bowel.
As these infoldings had been entirely obliterated in the opened part of the
intestine by numerous transverse incisions through the false membrane they
could be studied only in the 8 cm. of the intestine which had not been cut
open previous to the reception of the specimen. The folds were the result of
a sharp bending inward of all the coats of the intestinal wall from a direc-
tion parallel to the long axis of the intestine to one perpendicular to this
axis, much as if a contraction of a narrow band of the circular muscular coat
had occurred and persisted or been held in place. These segmental, trans-
verse constrictions of the intestinal wall followed each other longitudinally
at short intervals, as many as eight being present in a length of 8 cm. of
intestine. Each of the infoldings extended as a rule transversely nearly
around the circumference of the intestine, but some were shorter. There was
a certain alternating arrangement of the folds such that the shallower part
of one fold fitted in between the deeper parts of adjacent folds, whereby a
spiral-like arrangement of the intestinal ridges on the mucous surface
resulted. This arrangement suggested that each infolding corresponded to
the course of the larger vessels which run transversely round the bowel, and
in many of the folds it wsis possible to see these vessels in the lax tissues
bridging the depressions. The depth of the folds averaged from 1 to 2 cm.,
the tendency was for each fold to become shallower in its course and to dis-

o

WITH COMPLETE OBSTRUCTION 453

appear before it had completely encircled the bowel. The thickness of the
folds was about 1 cm., the adjacent muscular coats on each side of a fold
being nearly in apposition in the deeper part of the depression and separating
slightly above, so as to approximate a V-shape. Between successive folds the
lumen appeared of normal din^°nsions, but this lumen was evident only on
stretching the intestine longitudinally as the folds were so close together and
so deep as to obstruct it completely. The dense false membrane which cov-
ered the outer surface of the intestine did not follow the involution of the
intestinal coats into the folds, but it extended bridge-like over the depres-
sions, arid it was evident that it was these bridges of false membrane which
kept the folds in place. By incising these bridges transversely over the folds
the latter were readily obliterated on stretching the bowel longitudinally.
There was little evidence of the constrictions on inspection of the outer wall
of the unopened intestine, which appeared merely invested in a uniform
grayish coat of false membrane; still, careful inspection showed frequent
slight external furrows corresponding to the constrictions. The delicate
loose connective tissue already noted as present beneath the denser part of
the false membrane was, however, present in the depressions, stretching be-
tween the adjacent sides of an infolding. It was evident that the existence of
the constrictions or folds described must have caused an extraordinary short-
ening of the intestine. By actual measurement of the part of the intestine
in which the constrictions were in place (not having been obliterated by
transverse cuts through the false membrane) there was found to be a short-
ening of from TO to 80 per cent of the nonnal length. The inner or mucous
surface of the intestine showed no abnormalities other than the ridges re-
sulting from the constrictions. Yulvulae conniventes were high and numer-
ous as in the jejunum. There was no ulceration, necrosis or haemorrhage
to be detected with the naked eye. The small tag of mesenter}' which still
remained attached to one end of the intestine was moderately rich in adipose
tissue and contained two or three small lymphatic glands, free from any
abnormality.

Microscopical Ejamination-s. — The mucous membrane was well preserved
and appeared entirely normal. The submucosa also was free from any patho-
logical change. The circular muscular coat appeared somewhat thicker in
the part of the intestinal wall included in the constrictions than in that
between these, but this was probably due to the obliquity of the section of
the muscle in the former situation. The spaces between the muscular
bundles of the circular coat appeared rather wider than normal. The longi-
tudinal muscular coat also appeared somewhat thicker near and in the de-
pressions, but the same explanation probably applies here also. The coat was
in places moderately invaded by new connective tissue extending in from the

454 CHRONIC PEEITOXITIS

peritoneal surface. The existence of the constrictions was sharply defined
on the microscopical sections hy abrupt change of the direction of the
mucous, submucous and muscular coats, the angle of the bend being almost a
right angle, but with its apex rounded off. The distance between the muscu-
lar coats on each side was about 2 or 3 mm. at tlie angle and beciime less as
tliey approached the point of union of the muscle at the bottom of the con-
striction. The peritoneum was entirely replaced by organizing exudate and
connective tissue. The original subperitoneal tissue could be made out as
a layer firmly connected with the longitudinal muscle. Over this was, first,
a layer of richly vascularizing fibrillated connective tissue, containing many
fibroblasts, plasma cells and lymphocytes. This layer was \eT\ lax, with
wide meshes and numerous blood vessels over and between the layers of the
infoldings of the subjacent coats, whereas it was denser and more intimately
connected with the adjacent tissues between the successive constrictions.
This layer passed gradually into a dense layer of organizing connective
tissue of a rather sclerotic or, in places, hyaline appearance, containing
fibers and long fibroblasts, disposed mostly parallel to the longitudinal axis
of the intestine, leucocytes and developing capillaries. In this layer, old
fibrin in process of substitution by connective tissue was enclosed. On the
free surface was a fibrinous exudate, in places old, dense and hyaline in char-
acter, and in other places fresh with fibrillated fibrin and many pol}-morpho-
nuclear leucocytes, with fragmenting nuclei. The layer described under the
gross appearances as " false membrane " consisted mainly of the organizing
connective tissue and exudate. Corresponding to the constrictions in the
intestinal wall the denser part of the organizing exudate stretched across the
interval between the walls of a fold, and did not follow the intestinal wall as
if bent abruptly inward. The subjacent delicately fibrillated, ven- vascular,
lax, newly formed connective tissue extended down in long threads which
appeared to be stretched and which ran perpendicularly from the under sur-
face of the dense membrane into the depressions, which were thus occupied
by this lax tissue with wide meshes. Corresponding to the tops of many of
the constrictions the denser texture of the bridges of false membrane
extended do^fm for perhaps 3 or 4 mm. as a wedge-shaped mass from the
imder surface of a bridge into the depression, the apex of the wedge lying
in the center of a depression. Xo tubercles were seen in any of the sections.
Sections stained for bacteria (for tubcrcule bacilli. Gram's st-ain, and
methylene blue) showed various bacilli and cocci on tlie surface of the exu-
date, but these resembled bacteria foimd on the surface of the mucous mem-
brane, and were probably the result of postmortem contamination.

Pathological Diagnosis. — Clironic organizing peritonitis of unrecognized
etiology. Intestinal obstruction resulting from numerous transverse infold-

WITH COMPLETE OBSTEUCTION 455

ings or constrictions of the intestinal wall, these being held in place by
bridges of dense, organizing false membrane.

Interpretation of Findings. — After completing the foregoing examination
and description I received from Dr. Porter two other parts of the intestine
from the same case. These were bci,h of small intestine. One measured
48 cm. in length, and the folds had been largely obliterated by transverse
cuts through the false membrane. The other piece was still unopened. The
appearances and pathological changes in these parts were identical with
those already described, the same obstruction from infoldings of the intesti-
nal wall existing as in the specimen already described.

The mode of production of intestinal obstruction in this case is most
remarkable and quite unfamiliar to me, and, so far as I am aware, pre-
viously unrecorded, although I have not searched the literature. The peri-
tonitis was of the organizing, proliferative type, associated with fibrinous
exudation. It was probably the primary lesion. Anatomical features of
interest relating to the peritonitis were the uniformity of the false membrane
enveloping the bowel, the absence of fibrous adhesions to any notable extent,
the laxity of the layer of connective tissue connecting the dense false mem-
brane with the intestinal wall where the constrictions occurred, and the
bridging of the tops of the constrictions by the dense false membrane of such
a nature that when these bridges were cut through around tlie bowel the con-
strictions could be completely obliterated and the intestine restored to its
normal length and appearance, save for the evidences of peritonitis. Most
remarkable were the extent of intestine, implicated in this luiusual form of
intestinal obstruction, all of that submitted for examination being similarly
affected, the great shortening of the intestine in length resulting from the
myriads of transverse constrictions, and the symmetry and regularity of the
segmental constrictions entirely unlike the nicks and puckerings of tlie
intestinal wall resulting from peritoneal adhesions.

It is evident from the description that the dense false membrane was
responsible for keeping the constrictions in place. A further question is
whether it was also responsible for their original production. If it be as-
sumed that in process of organization of a progressive fibrinous exudate a
false membrane, composed partly of connective tissue, was formed, that this
surrounded the bowel uniformly, and was firmly adherent around the bowel
at intervals, then it would seem that contraction of this false membrane in a
longitudinal direction in consequence of the growth of cicatricial tissue
would draw the intestinal wall into transverse folds at the situations where
the contracting membrane is loosely attached. Mr. Brodel, who contributed
the drawings, has called my attention to the possibility of explaining such a
disposition of tlie false membrane and the situation and regularity of tlie

456 CHRONIC PERITONITIS

constrictions by taking into account the arrangement of the intestinal vessels.
On an injected and moderately distended small intestine slight transverse
furrows can be seen, each corresponding to tlie course of the artery wliich
passes from the mesenteric border over the side of the intestine, these arteries
alternating as they pass now to one, now to the other, side of the intestine.

As already noted, the constrictions seemed to correspond to the situation
of these arteries. The suggestion is advanced, therefore, that the situations
where the false membrane was loosely attached and where, therefore, the
constrictions occurred, correspond to these arterial furrows, and that the
constrictions themselves were due to contraction in a longitudinal direction
of the organizing false membrane which was firmly adherent to the intestinal
wall between the furrows. The distinguishing feature of the process in
accordance with this view and as seems supported by the histological charac-
ters described, is the peculiar mode of organization of a peritoneal exudate
whereby the resulting membrane is firmly adherent in places to the intestinal
wall and only loosely adherent in intervening places. As already noted, the
fibers and fibroblasts in the organizing membrane had a prevailing direction
parallel to the long axis of the intestine, and this arrangement may account
for preponderance of contraction in this direction.

The mechanical explanation which is offered is advanced as an hypothesis
without strong proof. Other hypotheses have suggested themselves which
take into account the participation of muscular contraction during life in
producing the constrictions. In the stage of chronic peritonitis represented
in this case, at which the acute exudate is far removed by intervening newly
formed connective tissue from the muscular coats, there is no reason to
assume paralysis of these coats during life.

While it is apparent that the anatomical condition in this case was in no
sense intussusception, the possibility may be entertained that muscular con-
tractions causing the bowel contractions may have been such as would
initiate intussusception, but that the dense false membrane covering the
intestine was an obstacle to the production of actual intussusception.

Nothing was found to indicate the cause of the peritonitis by examination
of the specimen sent me.

Unopened piece of p:ut, enveloped in a fal>^ nienibrdne. The shallow circular
furrows on the surface are located at the region of the infolding of the gut wall.
The cut end of the gut shows the lumen practically obliterated by folds of
intestinal muc-ous membrane. A probe forced through the folds demonstrates
the difficulty of locating the lumen.

Intestine opened longitudinally, showing infoldings (a) of the intestinal wall (b), occurring at short intervals and kept in
place bv an organized false membrane (c), attached to the peritoneal surface. On the right, the intestinal wall (6) has beea
unfolded to its normal length by cutting the false membrane (r). The brackets indicate the extent of unfolding.

IDIOPATHIC PHLEGMONOUS GASTRITIS'

I recall a case of diffuse phlegmonous gastritis which I exaniiued at autopsy
several years ago at Bellevue Hospital, New York. The patient was a man
beyond middle life, with a history of chronic alcoholism. Abdominal pain,
vomiting, and fever were among the symptoms, the diagnosis during life
being acute peritonitis. The walls of the stomach were nearly one centimetre
in thickness and were diffusely affected, although the pyloric region was the
most thickened. The thickening was most marked in the submucosa, which
presented a yellowish-white, rather firm appearance. There was no tumor
or large ulceration, but small drops of pus could be squeezed in many places
from the surface of the mucosa as through a sieve, and also from the incised
wall of the stomach. There was diffuse seropurulent peritonitis.

The microscope showed an immense diffuse infiltration of the submucous
coat with leucocytes, chiefly polymorphonuclear. In scattered foci were
small submucous abscesses. Lines of pus cells extended up between the gas-
tric tubules and opened upon the free surface. The accumulation of pus cells
was most abundant in the inner layers of the submucosa near the muscularis
mucosae but the outer layers were also infiltrated, and strands of pus cells
extended through the muscular coats, the intermuscular and subserous layers
of connective tissue being considerably thickened by purulent infiltration.
The peritonitis appeared to be secondary to the phlegmonous gastritis. I
did not at the time of the autopsy examine for the presence of bacteria, but I
have since done so, and have been able to discover in the microscopical section
numerous streptococci.

Phlegmonous gastritis was described by Brinton under the peculiar name
of " suppurative linitis," and I recall that in my student days we were ex-
pected to know about it under this latter designation.

'■ Report of a case, during remarks on a paper of Francis P. Kinnicutt, before
the Association of American Physicians, Washington, D. C, May 1, 1900.
Tr. Ass. Am. Physicians, Phila., 1900, XV, 133.

32 457

THE EFFUSION OF CHYLE AND OF CHYLE-LIKE MILKY,
FATTY, AND OILY FLUIDS INTO THE SEROUS
CAVITIES '

I have brought with me and here present a specimen of the fluid from a
case of chylous ascites. The specimen was recently sent for my examination
by Dr. McNamara, of New York, who has at different times withdrawn by
tapping several quarts of similar fluid, exactly like milk in its optical proper-
ties, from the abdominal cavity. The patient is a boy, whose clinical history
does not render clear the cause of the affection. %

Save here and there a stray leucocyte or red blood corpuscle, the only
morphological element* to be seen microscopically in the fluid are extremely
minute granules, so minute that they cannot be recognized as fatty globules.
This granular matter can be dissolved in ether, and on evaporating the ether
drops of oil remain. No filaria are present.

Those who will look through the literature relating to chylous effusions,
will perhaps be surprised to find that the pathology of the affection is in-
volved in considerable doubt and differences of opinion. Quincke advanced
the subject by distinguishing clearly between chylous and fatty hydrops, a
distinction of much importance, although oft^n lost sight of. The micro-
scope enables us to distinguish between these two affections, as in fatty
hydrops there are larger oil globules, and also fatty granular corpuscles and
lymphoid and other cells in various stages of fatty degeneration.

There are many writers who entirely reject the view that the chyle-like
effusions in the peritoneal and the pleural cavities are due to the escape of
chyle from tlie chyle vessels. They argue that in such cases postmortem
examination has not furnished satisfactory demonstration of the existence
before death of rupture of chyle-containing vessels, that the chemical con-
stitution of tlie fluid differs in some respects from that of chyle, notably in
the absence of sugar, and that similar effusions are to be found in parts of
the body where no chyle-containing vessels exist

Notwithstanding these objections, it seems to me to have been demon-
strated that the chyle-like effusions in the serous cavities of the abdomen

' Presentation of specimen and remarks on a paper of Samuel C. Busey, before
the Association of American Physicians, Army Medical Museum, Washington,
D. C, September 18, 1SS9.

Tr. Ass. Am. Physicians, Phila., 1889, IV, 102.

458

EFFUSION^ OF CHYLE-LIKE FLUIDS 459

and chest are in realitj' the result of the escape of chyle by rupture of the
lacteal vessels or of the thoracic duct. In many instances cancerous and
tuberculous masses obstructing large numbers of the lacteals at the root of
the mesentery have been found, with plain evidences of damming back of
chyle and rupture of lacteal vessels. I do not think that the mere occlusion
of the thoracic duct, still less obstruction to the venous flow in the subclavian
veins, is followed by serious interference with the flow of lymph or chyle. I
have found the thoracic duct completely occluded by a tuberculous throm-
bus in a case of acute miliary tuberculosis, without any such effect. Straus
has shown in his interesting paper that the ingestion of substances like butter,
which are absorbed by the lacteals, causes a corresponding change in the
composition of tlie chjdous effusion. In Whitla's case the guarantee that the
perforation found in the thoracic duet occurred during Hfe, is furnished by
the character of the hole and by the dissection of the skillful anatomist,
Eedfem.

CATHETERIZATION OF THE URETERS IN" THE MALE'

I recall a case in Xew York in which I made an autopsy — a case in which
a serious mistake was made which would have been avoided had this method
of determining the presence or absence of the kidneys been used. The
patient was a vigorous young German girl who had atresia of the vagina. An
effort had been made to reach the uterus by cutting through this closed va-
gina. They opened the canal up to a certain distance and then abandoned the
attempt. Then they found a mythical tumor on the left side. Various
diagnoses were made as to the nature of that tumor. The prevailing opinion
was that it was connected with the left ovarj-, and, indeed, that was the
opinion of one of the most distinguished surgeons of New York. Dr. Lusk,
who saw the case, made a correct diagnosis of movable kidney. The case
was operated upon before the class at Bellevue Hospital and the kidney
removed. There was nothing the matter with the kidney other than it was
movable. The kidney was brought at once over to my laboratory. It was a
very large, succulent kidney. I happened to have made an autopsy a few
days before on a man who had only one kidney, and the appearance of the
kidney was impressed upon my mind; the thick cortex and the beautiful
markings of the cortex, the normal structure greatly exaggerated but per-
fectly healthy. This kidney looked so much like the one just mentioned that
I surmised at once that it was the only kidney the patient had and suggested
that, to the horror of the surgeon. The patient lived 11 to 13 days, voiding
no urine. For 7 or 8 days there were no svTiiptoms to occasion alarm. Dur-
ing the last 48 hours uraemic symptoms manifested themselves and the pa-
tient died. The autopsy showed that the patient had but one kidney, and
that had been removed by the surgeon. The operator was very frank in bring-
ing the case to the notice of the medical profession and published it in all ltd
details in .one of the medical journals in 1881 or 1882. He discussed at that
time all the methods that his ingenuity could suggest as to the possibility of
recognizing the presence of a second kidney. I do not know that he at that
time even thought of the possibility of catheterizing the ureter. I remember
that he discussed the advisability of pressing on the ureter on one side and
determining in that way whether the other was present. This is simply
one case which shows that tliere is a practical use for this procedure.

• Remarks on a paper of James Brown, before the Johns Hopkins Hospital
Medical Society, Baltimore, December 17, 1S94.
Johns Hopkins Hosp. Bull., Bait., 1S95, VI, 16.

460

PEIMAEY ECHINOCOCCUS CYSTS' OF THE PLEURA'

I have examined the sections of the cysts. I am of the opinion that the
cysts are degenerated echinococcus cysts. The gross appearances of the
specimens which you showed me were like those of echinococcus cysts. The
microscopical characters of the fresh teased material and of sections of the
hardened specimens seem to be best explained upon the assumption that the
cysts are much degenerated hydatids. Cholesterin crystals and fatty de-
tritus, such as were present in these cysts, are common in degenerated
hydatids. Xo organized tissue is present in the walls of the cysts. These
walls, as shown in the sections, present an outer, thin, hyaline membrane,
with irregular inner surface continuous with fragments and shreds of a
structureless material which occupies a considerable part of the interior of
the cysts on the sections. There are scarcely any intact cells in the sections :
here and there a few are attached to the outer wall and a few nuclear frag-
ments are seen in the interior, but there is nothing indicative of suppura-
tion, or of previously organi2ed tissue, nor is there any suggestion of fibrin
or inflammatory exudate in the sections.

As no booklets can be detected, I have looked carefully for the character-
istic lamellation of the cuticular layer of echinococcus cysts. I think that
there are suggestions of such lamellation in the parallel striae occasionally
seen in some of the more coherent and hyaline membranous fragments
attached to the wall and in the interior of the cysts, but they are not so dis-
tinct as to be convincing.

It is well known that echinococcus cysts may perish and undergo com-
plete disintegration. Davaine, Leuckart, Neisser and others have described
such degenerative changes in the dead cysts. In some of these cases nothing
but the booklets remain to establish the diagnosis. Sterile echinococcus
cysts occur, and should these undergo similar degeneration, it is evident that
not even booklets would be present to aid in the diagnosis.

' Pathological report taken from a letter to Charles Gary and Irving P. Lyon
and published.

In: Primary Echinococcus Cysts of the Pleura. Report of a Case of Primary
Exogenous Echinococcus Cysts of the Pleura. Showing Hyaline Degeneration of
the Cuticle without Lamellation, with Notes from the Literature, by Charles Cary
and Irving P. Lyon.

Tr. Ass. Am. Physicians, Phila., 1900, XV, 371-373.

4G1

462 riMMARY ECHINOCOCCUS CYSTS OF PLEURA

In your case the degeneration lias not reached a stage in which the gross
appearances of echiuococcus cysts have been obliterated, but the character-
istic physical and microscopical features do not seem to me reconcilable with
any other sort of cysts than much degenerated echinococcus cysts. As
already mentioned, the large amount of fatty detritus and of cholesterin crys-
tals within the cysts is in favor of the diagnosis of degenerated hydatids.

Echinococcus cyste, of couri^o, receive their nourishment from the tissues
in which they are embedded, and impairment of this nutrition tends to the
production of sterility and degeneration of the cysts. In your case the
partial and small attachment of the cysts to the pleural membrane must
have favored tlicse results of imperfect nutrition, and in this way I should
explain at least in part, the sterility of the cysts and their degenerated con-
dition (April 1, 1900).

In my previous letter I did not speak particularly of the outward curling
of incised echinococcus cysts. This physical property is well known, and is
demonstrable readily in fresh, undegenerated cysts. As it depends upon the
integrity of the parasite, it, of course, is likely to disappear after the parasite
dies and undergoes degeneration, as certainly occurred in your ease, assuni-
in<r it to be a bladder-worm. It would not be contended, of course, that the
absence of this property would exclude the diagnosis of a degenerated
echinococcus cyst.

As I wrote you, I attach more importance in explaining the sterility of
the cysts, and the evidence of death and degeneration of the parasite, to the
comparatively limited attachment of the cysts to the sxirrounding living
structures, and their consequent feeble nutrition Most of the instances of
pleural echinococci have been of single or few large cysts, firmly attached
in their circumference. The topographical relations of the cysts in your
case are rather peculiar and unusual (April 5, 1900).

MALAEIA •

DeFINITKiN

ilalaria comprises the diseases caused by the specific protozoan parasite
called Ha-ematozoon malarme.

The name "malaria," derived from the Italian maV aria and signifying
" bad air," was applied originally to the miasm or poison which was sup-
posed to produce the disease. It is now used to designate the disease itself,
and is the most convenient term for this purpose.

The most characteristic malarial manifestations are intermittent or remit-
tent fever, certain forms of the disease described as "pernicious," and a
chronic cachexia with enlarged spleen and anaemia. The parasite discovered
by Laveran is invariably present in malaria and produces from the haemo-
globin of the red blood corpuscles the brown or black pigment granules which
are characteristic of the disease.

Stxoxtms

Malarial fever; Intermittent fever; Chills and Fever; Fever and Ague;
Paludism or Paludal fever; Swamp or Marsh fever; Miasmatic fever;
Periodical fever; Autumnal fever.

Xames derived from localities where the disease has prevailed with especial
intensity have sometimes been used; as, Walcheren fever, Batavia fever,
Hungarian fever, African fever, Panama fever, Chagres fever.

Special names have been applied to certain types or manifestations of
malaria ; as, remittent fever, bilious remittent fever, hemorrhagic remittent
fever, congestive fever, dump ague, black-water fever, black jaundice.

History

There are few diseases which can be traced so surely and continuously as
malaria in medical writings from ancient times to the present. Various
types of malarial fever are described by Hippocrates, Celsus, Galen, and
other ancient writers, although it is often impossible to determine the pre-
cise characters of many of the fevers described by these authors.

Celsus and Galen divide intermittent fevers into quotidian, tertian, quar-
tan, semi-tertian, and irregular. They recognized intermittent fevers with
long intervals. The nature of their semi-tertian fever (hemitritaeus) has

' In: Syst. Pract. M. (Loomis), N. Y. & Phila., 1S97, I, 17-154.

463

464 MALARIA

given rise to mucli discussion. Certain forms of intermittent fever were
believed by Galeu to have tlieir seat iu the spleen, others in the liver. The
influence of marsh effluvia and of seasons of the year in the causation of cer-
tain of these fevers was recognized. Various symptoms were discriminated
as to their prognostic significance, often with much aiuteness of observation.
A passage in Celsus clearly alludes to the type of malarial fever now called
aestivo-autumnal fever.

The Arabian physician Ehazes described the so-called subintrant malarial
fevers. No important advance beyond the knowledge of Celsus and of Galen
concerning malarial fevers was made until toward the end of the sixteenth
century, when Mercatus in his work on malignant fevers described various
forms of pernicious paroxysms in association with intermittent fever, par-
ticularly with the tertian type.

The introduction of cinchona bark from Peru into Europe by the Countess
del Chinchon and her body-physician, Juan del Vego, in 1640, gave great
impetus to the study of malarial fevers, and, indeed, in its revolutionizing
influence upon medical doctrines this event marks an epoch in the history of
medicine.

In the latter half of the seventeenth and the beginning of the eighteenth
century there appeared a voluminous literature regarding malarial fevers.
The most notable of the works upon this subject of this period are those of
Sydenham, Richard Morton, Torti, Ramazzini, and Lancisi. These works
remain to this day the great classics upon malaria. They contain the funda-
mental clinical and therapeutical facts and many etiological data relating to
this disease. Morton and Lancisi demonstrated clearly the relation of
malaria to marsh miasm. Sydenham jwinted out the differences between
vernal and autumnal intermittent fevers. Especially complete and keen
in analysis is the nosography of Torti," whose classification of the malarial
fevers, particularly of the pernicious and mixed forms, has been followed
by most subsequent authors. The diagnostic as well as the tlierapeutic value
of the preparations of Peruvian bark was recognized, and assisted materially
in the discrimination of the malarial fevers from the other so-called essen-
tial fevers. It is interesting to note the relative accuracy of diagnosis and
of description of tlie group of malarial fevers from the latter half of the
seventeenth century onward, in contrast to the confusion which existed re-
garding the other essential fevers until the discrimination of the latter by
the pathological-anatomical studies of the present century.

Tlie military and colonial enterprises of England in the eighteenth century
served to extend the knowledge of the geographical distribution of malaria,

'Torti: Therapeutice specialis ad febres quasdam perniciosas, etc., Mutinae,
1712.

MALARIA 465

particularly in tropical climates, the works of Pringle and of Lind contain-
ing especially noteworthy observations on this point. But the great mass of
the very extensive literature on the epidemiography of malarial diseases
which has been so industriously collected and ably analyzed by Hirsch ' be-
longs to the present centurj-.

The significance, as regards malaria, of the active studies in morbid an-
atomy of the first half of the present century relates to the clear differentia-
tion of typhoid fever from malarial and other fevers rather than to the actual
contributions to the pathology of malaria, although these were not lacking.
The occurrence of enlarged spleens, so-called fever cakes or ague cakes, and
even the dark color of the organs in association with malarial fevers, had
been occasionally observed by the older writers, notably by Lancisi, but the
intimate relation of these alterations to malaria was not established until
during the first half of the present century.

Audouard (1808, 1812, 1818) emphasized congestion and enlargement
of the spleen as the essential anatomical lesion of malarial fever. Bailly
(1825) noted in a series of autopsies on cases of pernicious malarial fever
observed in Rome in 1822 the dark color of the cortical gray matter of the
brain and the congestion of the cerebral meninges and substance. He laid
especial emphasis upon evidences of supposed inflammation of the central
nervous system and of the stomach and intestine. These anatomical obser-
vations, together with those of Nepple (1828, 1835), and, to a less extent,
of Maillot (1835), were interpreted in favor of Broussaisism, which at this
period exerted such a pernicious influence upon medical practice.

Valuable contributions to the pathological anatomy of malarial fevers,
especially of the remittent type, were made in the United States during the
fourth decade of this century by Stewardson in Philadelphia, Swett in Xew
York, and Anderson and Frick in Baltimore. Stewardson demonstrated the
bronzed color of the liver in remittent fevers, and regarded this as the char-
acteristic anatomical criterion of the disease. His observations were con-
firmed and extended by the other writers named. Alonzo Clark in 1855
demonstrated that the bronzed color of these livers is due to the presence of
granules of yellow, brown, and black pigment, which he regarded as derived
from the coloring matter of red blood-corpuscles. The monumental work of
Daniel Drake on " The Principal Diseases of the Interior Valley of Xorth
America" (1850, 185-1) contains a large amount of valuable information,
based upon personal observation and research, as to the distribution and
characters of the malarial fevers in the then Western States of this country.

In the light of recent discoveries it is interesting to note the ingenious
arguments advanced by John K. ^Mitchell in his work " On the Cryptogamous

'Hirsch: Handbuch der historisch-geographischen Pathologie, Stuttgart, 1881.

■UiG MALARIA

Origin of ^lalarious and Epidemic Fevers," published in 1849, in favor of
the doctrine of contagium aniniatum. This book deserves to rank with the
more frequently quoted work of Henle relating to the same line of argument.
At about the same period Bassi and Easori in Italy also advocated the para-
sitic theory of malaria.

The discoverer of the malarial pigment is Heinrich Meckel, who found and
described the pigment in 1848 in the blood and organs of the dead body of
an insane patient. He was, however, ignorant of the relation of this pigment
to malaria. The nest report concerning the pigment was in 1849 by Virchow,
who observed it in the body of a man who had suffered from chronic malaria.
There soon followed the observations of Heschl, Planer, A. Clark, Tigri,
Frerichs, and others, fully establishing the relation of the pigment to malaria.
The source of the pigment was regarded by Meckel and Virchow as in the
spleen, and this doctrine was elaborated by Frerichs. Planer (1854) was
the first who saw the pigment in the fresh blood of living patients, and he
suggested that the pigment may be formed in the circulating blood — a view
which was more fully presented and advocated by Arnstein (1874) and by
Kelsch (1875).

There is no doubt that some of the pigmented bodies which are now recog-
nized as parasitic organisms had been seen by earlier observers without
knowledge of their true nature. Thus Meckel noted the presence of pigment
granules in colorless, hyaline bodies devoid of definite nuclei. He, and more
particularly Virchow and Frerichs, observed pigment in fusiform and curved
bodies in the blood, which, although interpreted as endothelial cells of splenic
origin, in all probability were, at least in part, the crescentic forms of the
parasite. Some of the larger pigmented spherical organisms must have been
seen and mistaken for pigmented leucocytes.

In November, 1880, Laveran discovered the parasitic nature of these and
previously unrecognized forms in the blood of malarial patients, and thereby
introduced a new era into our knowledge of the malarial diseases.

The discovery of the malarial parasite has furnished an unfailing means
of diagnosis of malarial diseases, has materially advanced our knowledge
of their patholog}', has led to a better understanding of their clinical phe-
nomena and various types, has furnished important data for prognosis, and
has led to improvements in methods of treatment.'

•The so-called BariUus malariar described in 1879 by Klebs and Tonimasi-
Crudeli, which for a short period had a certain vogue, chiefly with Italian writers,
never rested upon satisfactory observations which indicated that it bore any
relation to malaria, and it deserves no more consideration than the palmella of
Salisbury and the other alleged malarial organisms described before Laveran's
discovery.

MALARIA 467

Paeasitologt
historical

In 1879, A. Laveran, a French military surgeon, stationed at the time in
the province of Constantine, Algeria, began tc Gtudy the pathological anatomy
of malaria, and at once directed his attention to the mucli discussed question
of the origin of the pigment. He observed in the blood of malarial patients
certain pigmented bodies different from the melaniferous leucocytes, but he
was uncertain as to their nature until, on November 6, 1880, he discovered
that some of tliese pigmented bodies threw out long flagella endowed with
such active lashing movements as to convince him, as they have convinced
every one who has since then seen them, that they are living parasites.
Laveran published his observations in a note to the Academic de Medecine
in Paris, presented November 23, 1880. This was followed by the publica-
tion of several notes in 1880 and 1881, and in the latter year appeared a small
monograph by Laveran on the parasitic nature of malaria.'

In these various early publications Laveran describes (1) pigmented cres-
centic and ovoid bodies; (2) spherical, transparent bodies, sometimes free,
sometimes applied to the surface of red blood corpuscles, the smallest about
one-sixth of the diameter of a red blood corpuscle and containing only one or
two fine pigment granules, these representing an early stage of development
of (3) larger, pigmented, spherical bodies averaging 6 /* in diameter, but
sometimes larger than a red blood corpuscle, and containing numerous, often
moving, pigment granules; (4) bodies similar to the last mentioned, but
beset with actively motile flagella; (5) free motile flagella; and (6) swollen
spherical or deformed bodies 8-10 ft. in diameter, containing pigment, and
regarded as cadaveric forms of spherical parasites. Laveran noted amoeboid
movements of the spherical forms, grouping of the small spherical bodies
together and the occurrence of small, colorless, motile bodies, without specifie
characters, wliich he suggested may perhaps represent the first phase of
development of the parasitic elements. He regarded all of the forms as
different stages of development of the same species of organism, and con-
sidered the free flagdla, wliieh he believed were formed within the spherical
bodies and escaped by rupture of the enveloping membrane, as the most
characteristic and perfect stage of development of the parasite.

° Only occasional references to the voluminous literature on the parasitology
of malaria are given in this article. A full table of references to the works treat-
ing of malarial fever since the recognition of its parasitic origin up to and partly
including the year 1S95 will be found in The Malarial Fevers of Baltimore, by
William Sydney Thayer, M. D., and John Hewetson, M. D. (The Johns Hopkins
Hospital Reports, V, 1S95).

468 MALARIA

Laveran communicated his results to his colleague Richard, stationed in
I'hilippeville, Algiers, who in February, 1882, published a communication
confirming Laveran's observations and adding certain points of importance.
He describes the development of the parasite from small, perfectly trans-
parent bodies contained in otherwise normal red blood corpuscles. This
clear body grows larger, forms pigment out of the haemoglobin of the
enveloping red corpuscle, which thereby becomes gradually decolorized and
reduced to a mere colorless shell-like rim, which finally ruptures and sets
free the parasite. This now generally accepted view as to the intracorpuscu-
lar development of the parasite, which was first announced by Richard, was,
however, in the following year abandoned by him in favor of Laveran's
view that the parasites develop either free in the plasma or in close attach-
ment to the surface of red corpuscles or in depressed spots on the surface.
Richard observed amoeboid movements of the parasites, and noted spherical
bodies with a central block of black pigment from which delicate lines
radiated so as to produce rosette forms.

Laveran continued to publish brief communications in 1882 and 1883,
and in 1884 he published a larger work ° presenting his observations and
views in detail. In this work he describes more fully the forms already
mentioned, and he notes the occurrence of segmenting forms, which, how-
ever, he interpreted as forms of degeneration, not of reproduction.

The observations of Laveran and of Richard were made by microscopical
examination of the fresh blood. In 1883 and 1884, Marchiafava and Celli
published in a number of articles the results of their studies of stained speci-
mens of dried malarial blood. With the exception of small, spherical stained
bodies in the red blood corpuscles, which they thought might be micrococci,
they interpreted the various other stained and usually pigmented bodies
found in the red corpuscles of malarial patients as probably degenerative
changes. As a matter of fact, the coccus-like dots were probably in part Ehr-
lich's degenerations, whereas their drawings show that the supposed degen-
erative forms were in reality the actual parasites, which in many of their
phases were accurately depicted, although not recognized as such.

In 1885, Councilman and Abbott in the organs from two cases of per-
nicious comatose fever found and described small pigmented hyaline bodies
in and outside c f red corpuscles, most abundantly in capillaries of the brain.

In 1885, Marchiafava and Celli, as the result of the examination of fresh
malarial blood, came to a correct interpretation of these bodies and described
them fully and accurately. They emphasized especially the amoeboid, un-
pigniented, transparent intracorpuscular bodies, to which they gave the

'Laveran: Traitfi des Fi&vres palustres, Paris, 1SS4.

MALARIA 469

inaccurate name of plasmodia, which has been widely adopted. They
described clearly the intracorpusciilar development of the parasite, the for-
mation of pigment out of the blood coloring matter, the consequent changes
in the blood corpuscles, and they pointed out the probable reproductive
nature of the segmenting bodies, which they described more fully and accu-
rately than had been done by Laveran and Richard.'

The publications of Marchiafava and Celli attracted wider attention than
had those of Laveran, and from the year 1885 up to the present time there
has been a steady flowing stream of literature upon the various questions
connected with the parasitologj' of malaria.

Immediately following the confirmation of Laveran's discoveries by Italian
observers came similar confirmation from Sternberg, Councilman, and
Osier (1886-87), and somewhat later by James (1888) and Dock (1890), in
this country, and withiu a few years numerous reports from various parts of
Europe, America, Asia, and Africa demonstrated the invariable association
of Laveran's parasites with all cases of malarial fever. There are no observ-
ers of any prominence who, with sufficient opportunity and training for
such examinations, have failed to recognize the parasites in cases of malaria,
nor is there now any authoritative voice of dissent from the acceptance of
the parasite as the specific cause of this disease.

Since the fundamental researches of Laveran, Richard, and Marchiafava
and Celli (1880-85) other observers have greatly extended our knowledge as
to many details concerning the structure and life historj- of the parasite and
its relation to various types, phenomena, and lesions of malaria, although
not a few important questions still remain unsettled. The most important
of these later discoveries are due to the demonstration by Golgi (1885-86)
of a definite relation between the cycle of development of the parasite and the
diiTerent stages of malarial fever, and to the recognition by Golgi (1885-86)
of the two varieties of the parasite belonging respectively to quartan and to
tertian fever, and by Marchiafava and Celli and Canalis (1889) of the
varietj' or varieties belonging to aestivo-autumnal fever. These observations
have led to two schools of doctrine — the one, headed by Laveran, holding to
the unity of a pleomorphic malarial parasite, the other, headed by Golgi and
other Italian writers, upholding the pluralitj' of malarial parasites. The
latter doctrine has the larger number of supporters.

' Marchiafava and Celli claim for themselves the discovery of the intracorpus-
cular amoeboid forms with and without pigment, and of the segmenting forms,
but as is apparent from the review of Laveran's and Richard's preceding publi-
cations, this claim cannot be admitted. Marchiafava and Celli, however, des-
cribed and interpreted these phases of the parasite far better than Laveran, and
to them belongs the credit of demonstrating the intracorpuscular development of
the parasite.

470 MALAIHA

Dock (1890-92) was the first to differentiate the three principal varieties
of the malarial parasite in the United States, and recently Thayer and
Hewetson' have published a thorough study of the malarial fevers of Balti-
more with careful descriptions of these varieties.

Investigations concerning the intimate structure of the malarial parasites
have been made especially by CeUi and Guarnieri, Grassi and Feletti, Roman-
cwsky, Sacharoff, Mannaberg, Antolisei, Bastianelli and Bignami, and others.

The results of these later studies concerning the malarial parasites will be
considered in various parts of this article. They are fully and systematically
presented in the recent monograph of Tha^'er and Hewetson, already cited.

NOMENCLATURE

Various names have been suggested for the malarial parasite. Among
these may be mentioned OsciUana malariae (Laveran), 'Plasmodium
malariae (Marchiafava and Celli), Haematomonas malariae (Osier), Haema-
tophyllum malariae (Metchnikoff), Haemamoeba malariae (Grassi and
Feletti), Haemococcidium malariae (L. Pfeiffer), Haemosporidium mala-
riae (Danilewsky), Haematozoon or Haemocyiozoon malariae (Osier and
various authors).

Of these names, Plasmodium malariae has gained wide currency, but it is
on zoological grounds singularly inappropriate, and there is no reason why it
should be perpetuated.

The name Haemosporidium malariae has much to recommend it, but it
has not been generally adopted. Upon the whole, the name Haematozoon
malariae, which expresses nothing as to the zoological classification of the
parasite, and which has been adopted by many writers, may be provisionally
accepted until more precise knowledge is reached concerning the zoologic"al
position of the parasite. Haemocytozoon is more precise, but the other term
has the advantage of greater brevity.

ZOOLOGICAL POSITION OF THE MALARIAL PARASITE

The malarial parasite belongs to the class of Protozoa, under which name
are grouped the unicellular organisms with the physiological characters of
animals. Biitschli divides the Protozoa into the orders — Sarcodina, Mas-
tigophora, Sporozoa, and Infusoria. Grassi and Feletti classify the malarial
parasite among the Sarcodina, subdivision Ehizopoda, and adopt the name
Haemamoeba malariae. Antolisei considers that the parasite belongs to the
Gymnomyxa, or, more precisely, the Proteomyxa of Ray Lankester. The
great majority of authors classify the malarial parasite among the Sporo-

• Op. cit.

MALARIA 471

■loa, which are divided by Balbiani into the groups Gregarinida, Sarcospo-
ridia, Myxosporidia, and Microsporidia. Under the Gregarinidae are in-
cluded the Coccidia, with which some writers group the malarial parasite.
Kruse makes under the Gregarinidae a special family which he designates
as Haemogregarinidae, and to which he refers the malarial parasite and
similar haemocytozoa in lower animals. Danilewsky suggests forming a
new group under the Sporozoa to be called Haemosporidia, in which he places
the malarial and similar haematozoa, and Labbe calls the group Gymno-
sporidia.

As we know nothing of the malarial parasite in the outer world, it is
evident that our knowledge of its life history is incomplete, so that any
attempt at zoological classification must be regarded as onh' provisional.
Such information as we possess favors classifying the parasite among the
Sporozoa, but it possesses characters which do not enable us to fit it exactly
into any of the existing subdivisions of the Sporozoa, so that the suggestions
of Kruse and of Danilewsky of establishing a new subdivision of the Sporo-
zoa or of the Gregarinidae to include the malarial parasite and similar
organisms in birds seems to be a good one, and the name Haemosporidia for
this new subdivision appears to be appropriate. According to this classifi-
cation, the malarial parasite may be called Ha-emosporidium malariae.

METHODS OF INVESTIGATION

The methods for demonstrating and studying the malarial parasite will
be described under the heading " Diagnosis." It may here be stated that
generally the most useful procedure is the examination of thin la3xrs of
fresh blood with an oil-immersion objective. The description of the parasite
which is to foUow is based mainly upon this method. This procedure may be
advantageously combined with the examination of stained specimens. For
the study of the finer details of structure this latter method is indispensable.

GENERAL MORPHOLOGY AND BIOLOGY

The malarial parasite is a unicellular, protozoan organism which develops
within the red blood corpuscles, and therefore belongs to the group of
IIaemoc}i:ozoa. As wiU be described subsequently, organisms closely resem-
bhng the malarial parasite have been found in the blood of birds. The
numerous attempts to cultivate artificially the malarial parasite have
hitherto been unsuccessful, nor has this organism been recognized in the
outer world. Our entire knowledge of it is derived from its study in human
beings.

Three varieties of the parasite have been differentiated. These varieties
are that of quartan fever, that of tertian fever, and that of aestivo-autumnal

472 MALARIA

fever. This last variety it is proposed by the writer to call TTaematozoon
vialariae falciparum. Before considering the justification of this division
and the special characters of each of these varieties it is desirable to describe
tlie more important characters common to all varieties of the malarial
parasite.

The cycle of development of the malarial parasite embraces a vegetative
and a reproductive phase. Its duration varies from 24 to 72 hours, accord-
ing to the variety of parasite.

The vegetative phase begins in the form of small, colorless, amoeboid,
hyaline bodies, 1-2 ju. in diameter, within the red blood corpuscles.' These
amoeboid bodies increase in size, and, with the occasional exception of the
aestivo-autumnal variety, they develop within them a variable number of
dark pigment granules, situated, as a rule, near the margin of the parasite.
The pigment increases in amoimt and in the coarseness of the granules as
the organisms continue to develop. It occurs in the form of irregular grains
and of fine rods, which may be in active motion within the parasite.

Having attained a certain stage of development, which differs as regards
the size of the organism in the different varieties, the parasite gradually
ceases its amoeboid movements, assumes a spherical or oval shape, and be-
comes somewhat sharper in contour. lu this condition it may continue for
a while to grow. When it has reached its full size it may completely fill the
red blood corpuscle or may occupy only a small part of it, these differences
depending mainly upon the variety of parasite. The parasite now may be
called the full-grown or adult form.

" As has already been mentioned, Laveran believes that the forms of the
parasite which have, since the publications of Marchiafava and Celli, usually
been regarded as within the red corpuscles, are attached or applied (accolfes) to
the outer surface of the corpuscles. Mannaberg (1S93) has again raised this ques-
tion by his statement that many of the amoeboid forms, particularly in their
younger stages of development, are attached to the corpuscles, often In little
niches or indentations on the surface. There is no doubt that the organism may
be situated as described by Mannaberg. Marchiafava and Celll, who had previ-
ously noted this appearance, interpreted it as Indicating the extrusion of the
parasite from the red blood corpuscle. It is, in fact, often very difficult to deter-
mine with precision whether the organism is on the surface of or within the
corpuscle, but the evidence is that the majority of the younger forms are intra-
corpuscular. Marchiafava and Bignami (1894) describe in the following words
their conception of the manner of penetration of the youngest forms into the
corpuscle: "The youngest amoebae, the offspring of sporulation, by virtue of
the viscidity of their protoplasm adhere to the surface of, and by their move-
ments bury themselves in, the contour of the red corpuscle. In this position the
parasite attacks the external strata of the corpuscle as a means of nourishment,
and after altering these layers is able to penetrate within, and thus becomes
entirely endoglobular."

MALARIA 473

Coincidently with these stages of development the enveloping red blood
corpuscle may undergo various changes, which are of significance in dis-
tinguishing tlie varieties of parasite from each other. The corpuscle may be-
come swollen and pale, or shrunken, or brassy green in color, or otherwise
deformed, or it may appear unaltered, as will be described in considering
the varieties of the parasite.

The subsequent stages in this cycle of development belong to the reproduc-
tive phase, which is shorter in duration than the vegetative. The first evi-
dence of this reproductive phase is the collection of the pigment into a mass
of granules or a solid block situated usually at or near the centre, but some-
times near the periphery, of the organism. These bodies with clumps of
pigment may be designated, in accordance with Thayer and Hewetson's sug-
gestion, as the presegmenting forms {corpi con blocchetto of the Italian
writers).

Coincidently with or following this gathering of the pigment into a clump,
sometimes without a definite collection of the pigment, the process of seg-
mentation begins. In its most typical form segmentation is ushered in by
the appearance of delicate lines radiating from the periphery toward the
centre. Eventually the substance of the spherical organism is divided into a
variable number of round or oval bodies called spores. The enveloping red
corpuscle, which now may be reduced to a narrow pale rim, bursts and the
spores are set free, or the corpuscle may have disappeared before the process
of segmentation is completed. The pigment remains behind, and is quickly
engulfed by phagocytes. Sometimes in the aestivo-autumnal variety seg-
mentation occurs in organisms entirely devoid of pigment. These segment-
ing bodies are called also sporulating forms.

The free spores speedily invade fresh red blood corpuscles, where, as the
small, colorless, amoeboid, hyaline bodies already mentioned, they begin
again the cycle of development. The direct transformation of the motion-
less " round spores into the small, hyaline, amoeboid bodies has been very
rarely observed, but there is no reason to suppose that there exists any stage
intervening between these two forms.

In the complete sporulating cycle of development which has been described
we can distinguish, therefore, the following forms of the parasite : ( 1 ) un-
pigmented, amoeboid, hyaline bodies; (3) pigmented, amoeboid, hyaline
bodies; (3) full-grown or adult bodies ; (4) presegmenting bodies; (5) seg-
menting or sporulating bodies; and (6) spores.

•° Plehn claims to have observed that the spores are actively motile and flagel-
lated, but this statement is opposed to the observations of all others.

33

474 MALARIA

As already mentioned, in the aestivo-autumnal variety this cycle may be
completed without the appearance of pigment. These bodies are to be
thought of, not as separate and distinct forms, but simply as successive stages
of development with all transitions from the youngest to the most advanced.
Especially can no sharp distinction be drawn between bodies (1) and (2)
and between bodies (3) and (4). The recognition, as a distinct form, of the
body designated as presegmenting is of less practical importance for the
quartan and tertian varieties than for the aestivo-autumnal.

The name " plasmodium " was applied by Marchiafava and Celli originally
to the unpigmented, amoeboid forms. It is frequently employed to designate
both the pigmented and the unpigmented amoeboid bodies, as well as the
parasite in all of its forms. These amoeboid bodies may be called, in general,
hyaline forms or amoebae.

As will be explained subsequently, it is only the quartan variety which is
found in all its forms with equal frequency in the peripheral circulation
and in the blood of internal organs ; whereas segmenting tertian parasites
are more abundant in the spleen and bone marrow than in the peripheral
vessels, and the aestivo-autumnal parasite develops mainly in the internal
organs, its segmenting forms being extremely rare in the peripheral circu-
lation.

Each of the forms of the parasite which have been described as developing
within the red blood corpuscles may also be found free in the plasma. They
probably escape by rupture of the enveloping corpuscle, a process which one
can often witness when examining the fresh blood microscopically. Extra-
corpuscular mature forms may possibly segment in the usual way, but there
is no evidence that forms in the earlier stages may complete their cycle of
development free in the plasma.

The important discovery was made by Golgi that all of one generation of
the parasite form a group, the members of which develop approximately at
the same time, and that a definite relation exists between the phases of de-
velopment of the parasite and the stages of malarial fever. The onset of a
paroxysm corresponds to the ripening of one generation of the parasite. A
few hours or shortly before the paroxysm segmenting forms appear, and
enable the observer to predict the approaching paroxysm. The spores which
are set free by the act of sporulation invade the red blood corpuscles and
start a fresh generation, which pursues during the paroxysm and the subse-
quent apyrexia so regular a development that in typical cases the experienced
observer can tell approximately by examination of the blood the stage of the
disease — that is, the time which has elapsed since the last paroxysm and the
time when the next paroxysm may be expected.

MALAEIA 475

It is not, however, always the ease that the parasite develops with the
regularity expressed by Golgi's law, and especially in the aestivo-autumnal
fevers irregularities are very common. The simultaneous occurrence of two
or more generations in different stages of development may render difficult
the interpretation of tlie phases observed, although even here careful observa-
tion will enable the observer to draw correct conclusions in tertian and quar-
tan fevers.

It has not been satisfactorily demonstrated that there occurs any other
cycle of development of tlic malarial parasite in human beings than that
which has been described, although the possibility of such an occurrence is
by no means disproven. Canalis (1889) believes that he has found evidence
that a second, slower cycle of development of the aestivo-autumnal parasite
occurs, which is represented in certain of its phases by bodies of the crescentic
group, to be described subsequently; and this view, with certain modifica-
tions, has been accepted by Golgi, Antolisei and Angelini, Grassi and Feletti,
and Sacharoff. Tliis doctrine is, however, opposed by many observers, and
it does not at present rest upon sufficient evidence.

It seems necessary to suppose, on the basis of clinical evidence, that the
malarial parasite may remain for months in a latent condition in the human
body, and then begin to develop again, causing a relapse of the fever. As
such relapses may occur in forms of malaria in which crescents do not appear,
there must be in these cases some resistant organism other than bodies be-
longing to the group of crescents. We know nothing as to the nature of
these resistant bodies. The hypothesis is advanced by Bignami that they
may be spores which are enclosed witliin leucocytes and other cells, and which
have become surrounded by a resistant membrane and have lost their usual
staining properties.

Besides the forms which have already been described as representing
phases of the regular sporulating cycle of development of the malarial para-
site, there occur other forms which cannot at present be referred to any cycle
of development. These other forms are — (1) crescentic bodies and fusi-
form, oval, and roimd bodies belonging to the same group; (2) flagellate
bodies and free flagella; and (3) degenerative forms.

The crescentic and flagellate bodies, from their size and remarkable appear-
ance, are the most striking forms of the parasite, and from the beginning
have attracted much attention. Their significance, although there are many
hypotheses concerning it, is not understood.

(1) The crescents develop only from the aestivo-autumnal parasites, and
will therefore be described in connection with these. They are never formed
from quartan and tertian parasites.

476 MALARIA

(2) Flagellate bodies, on the other hand, may form from each variety
of the parasite, tertian, quartan, or aestivo-autumnal. The weight of evi-
dence is that they do not exist in the circulating blood, but develop after the
blood has been withdrawn from the body, usually within ten to twenty
minutes, sometimes earlier. Some observers have found them frequently,
others only rarely. They are frequently found if the blood is examined at
the right stage of the disease and time is allowed for their development.
Councilman showed that they are more commonly found in blood aspirated
by a hypodermic needle from the spleen than in the peripheral blood. They
develop in tertian and quartan fevers from the mature, full-grown extracor-
puscular forms — in tertian especially from swollen forms larger than the red
blood corpuscles. They are therefore found most frequently a short while
before and during the paroxysm. In infections with the aestivo-autumnal
parasite the flagellate bodies develop from round bodies belonging to the
group of crescents, and do not occur in definite relation to the stage of the
fever. Earely intracorpuscular bodies may develop flagella.

The spherical bodies which become transformed into the flagellate bodies
are always or nearly always pigmented. Marchiafava and Celli state that
they once saw an unpigmented flagellate body. These bodies may be some-
what smaller or larger than the red blood corpuscles, the size varying to some
extent with tlie different varieties of the parasite, as will be explained later.
The process of development of the flagella may be studied under the micro-
scope. The pigment granules, wliich at first (aestivo-autumnal variety)
may have been in repose, usually begin to dance about within the organism,
often in a lively "way. In the aestivo-autumnal variety they usually gather in
the central part, but in the others they may be near the periphery or irregu-
larly distributed. The spherical body may acquire an oscillatory or jerking
movement. Projections may be formed and retracted at the periphery, and
the whole edge may acquire a vigorous undulating movement. These changes
are attributed to the movements of the flagella within the body or in its
peripheral layers, and have been graphically compared by Richard to the
struggles of an animal to get free. Suddenly the flagella shoot out from the
peripliery, and with their active lashing movements produce a violent com-
motion among tlie red blood corpuscles and other small particles which may
be in their neighborhood.

The flagella are pale and thin, and present often at their extremities and
along their course small olive shaped swellings which may change their
position. Here and there a pigment granule is occasionally seen in a flagel-
lum. The flagella vary in size, nvuuber, and position. Their length may be
three or four times the diameter of a red blood corpuscle or not more than
half that size. One to six may be attached to the spherical body. They may
project from one side or from any part of the circumference of the body.

MALARIA 477

Their movements may be somewhat rhythmical; they may become slow or
even cease, and again start up.

Flagella may become detached and move about freely among the red blood
corpuscles. On account of their pallor such free flagella would usually be
overlooked were it not for the commotion which they produce among tlie red
blood corpuscles. The motion of the flagella may be observed on the slide
for half an hour, sometimes longer.

These flagellate bodies are the most startling forms of the malarial organ-
ism, and no one who sees them doubts for a moment that he is looking at a
living parasite. It is not surprising that they attracted in an especial man-
ner the attention of Laveran, who, as already mentioned, regarded the flagella
as the most characteristic and perfect form of development of the parasite.
Subsequent studies have not, however, tended to confirm the conception of
Laveran as to their significance. As has already been made clear, the flagel-
lated bodies do not belong to the regular sporulating cycle of development
of the malarial parasite in the human blood. The most prominent theories
as to their significance are the following:

(a) They are forms of degeneration or appearances belonging to the death
agony of the parasite. In support of this view it is urged that the flagellate
bodies do not belong to any known cycle of development; that they are de-
veloped only outside of the human body; that they are developed from
mature forms which are known frequently to imdergo undoubted degenera-
tion, such as hydropic swelling, vacuolation, and fragmentation, and which
may already show beginning evidences of degeneration; that nuclear sub-
stance is absent from the flagella ; and that similar appearances of extrusion
of motile filaments in other unicellular organisms are known to zoologists
and are interpreted as degenerative.

(6) Sacharoff, from the study of their structure on stained specimens,
believes that the flagella are extruded chromatin filaments derived from
perverted karyokinetic nuclear division. He regards the process as degen-
erative.

(c) Dock suggests that the fiagellate bodies "represent resting states of
the organism, capable of existing independently, perhaps even of reproduc-
ing themselves, but also able, under favorable circumstances, of reproducing
the typical growth of the parasite."

(d) Mannaberg's opinion is that the flagellate bodies may represent a
state belonging to the saprophj'tic existence upon which the mature forms
of the parasite enter soon after the blood is withdrawn from the body. On
account of unsuitable conditions of environment they are unable to continue
this existence in the blood outside of the body and soon perish. A similar
view is advanced by Manson, who suggests that the flagellate bodies repre-

478 MALAETA

sent the first stage, and the detached flagella, in search of their appropriate
host, represent the second stage of life of the parasite outside of tlie body.
Manson " conjectures that the mosquito is the extracorporeal host of the
malarial parasite, and he reports observations of Ross showing the develop-
ment of flagellate forms in the stomach of mosquitoes fed on malarial blood.

There are arguments for and against each of these theories. Eeluctant as
one may be to consider such striking forms as the flagellate bodies as phases
of degeneration, the existing evidence seems upon the whole to be more in
favor of this hypothesis than of any other which has been advanced. Still,
if Sacharoff' s observation as to the presence of nuclear material in the flagella
be correct, the objection of Grassi and Feletti, that the flagella are incapable
of reproductive development because the nucleus of the parasite does not
divide and enter them, would be overthrown and the hypothesis of Manna-
berg and Jlanson would become more probable. It is evident from the de-
scription of these bodies that the use of the word " flagella " to designate the
motile filaments is of doubtful propriety, but it is the term commonly
employed.

(3) There are various bodies, often seen in the examination of malarial
blood, which are vmdoubtedly degenerative forms of the parasite, and others
which are probably degenerative, although opinions concerning the latter
are divided. The more common signs of degeneration of the parasite are
vacuolation, pseudo-gemmation, fragmentation, deformities of shape, par-
ticularly swelling, granular condition of the protoplasm, certain alterations
in the arrangement and appearance of the pigment, disappearance of nuclear
material, defects and irregularities in staining, and changes in the refraction
of the organism. These various degenerative changes produce forms too
numerous to describe in detail. They have often been misinterpreted and
described as special forms of the parasite, some of them, particularly certain
vacuolated and budding forms, as special modes of reproduction.

Degenerations may occur in any form of the parasite, but they are par-
ticularly common in the cxtracorpuscular forms. Mannaberg describes the
disintegration of young intracorpuscnlar forms, with disappearance of their
nuclei. Fragmentation of forms extruded from the blood corpuscles can
sometimes be watched while examining fresh blood under the microscope.
As a rule, only a certain number of the mature forms actually enter into re-
productive segmentation, and many of the spores or segments perish. If all
segmented and the oifspring survived, tlie number of the parasites after a

" Manson: The Goulstonian Lectures on the Life History of the Malaria Germ
Outside the Human Body (The British Medical Journal, 1896, March 14, 21, 28).
Manson lays much emphasis upon supposed analogies between the malarial germ
and Filiaria sanguinis. Only future investigations can determine the correct-
ness of Manson's hypothesis.

MALAEIA 479

few paroxysms would become enormous. As a matter of fact, degenerations
of full-grown parasites are often observed. An interesting form of such
degeneration, found most frequently in the mature forms of the tertian
variet}', is the appearance of swollen, pigmented, so-called hydropic bodies,
often much larger than red blood corpuscles, and sometimes containing
vacuoles. Eound bodies simulating spores are sometimes seen in these
vacuoles, but on properly stained specimens they are devoid of the nuclear
material of genuine spores. Pseudo-gemmation, or the appearance of
sarcodic buds on the surface of the organisms, is doubtless a form of degenera-
tion. Such buds may become separated, in the form of hyaline balls, from
the parent organism. These evidences of degeneration may appear also in
crescents and bodies belonging to this group and in flagellate bodies. From
the latter small hyaline balls with a ilagellum attached may break oif and
move around actively. Such bodies might be mistaken for flagellated spores.

There is no good evidence that the malarial parasite ever multiplies by
budding " or by simple cell division. The only form of multiplication which
has been demonstrated is that of sporulation, also called segmentation,
already described, although it cannot be denied that other forms of repro-
duction may exist.

Various interesting degenerative changes are produced by the influencu
of quinine. These will be fully described under Tkeatmext, Action of
Quinine on Malarial Parasites (page 146, Vol. I, Syst. Pract. M. [Loomis]
1897).

As the malarial parasite passes its vegetative life mostly within the red
blood corpuscles, it is evident that it finds its food in this situation. This
food may be appropriated both by intussusception and by diffusion. Evi-
dence of intussusception is found in the occasional presence of fragments
of the corpuscular substance within the body of the amoeboid forms. Doubt-
less diffusion is the more important mode of nutrition of the parasite.

The question has been raised whether the parasite may develop in other
cells of the body than the red blood corpuscles. Nearly all forms of the
parasite have been found enclosed in cells, chiefly leucocytes, splenic or
medidlary cells, and endothelial cells. As such included parasites often
present evidences of degeneration, these appearances have been generally
interpreted as referable to phagocytic destruction of the parasites, and such
they unquestionably usually are. Golgi and Monti have, however, recently

" Celli and Guarnieri for a time believed that spherical bodies of the crescentic
phase may multiply by the formation of buds (gemmation), but they subs&
quently abandoned this view and adopted the now generally accepted opinion
that these budding forms are degenerative. The " buds " are now devoid of the
structure of genuine spores.

480 MALARIA

published observations intended to show tliat the aestivo-autumnal parasite
may develop within endothelial and other cells, as will be explained in con-
sidering this variety of parasite.

The malarial parasite in the condition in which it exists in tlie human
body is very susceptible to injurious agencies. It is quickly killed by the
addition of distilled water and of dilute acids and alkalies. Under ordinary
conditions it does not long survive in blood withdrawn from the body. Under
certain special circumstances it has been kept apparently alive from two to
four days, possibly for a week. Sacharoff observed amoeboid movements in
aestivo-autumnal hyaline bodies which had been for a week in the intestinal
canal of leeches kept on ice, and he obtained a positive result by inoculating
himself with malarial blood preserved in this way for four days in leeches.
The tertian and quartan parasites were found to be less resistant than the
aestivo-autumnal. Ripe bodies may segment in blood outside of the body,
but no further development or multiplication of the parasites has been posi-
tively observed in the various attempts made to preserve or cultivate them.
The parasite does not continue to develop and multiply in the human body
after death.

Of course no inferences can be drawn from these observations as to the
resistance of the parasite in its natural condition in the outer world. As to
what this natural condition is we can only speculate. Grassi and Caland-
ruccio have thought that certain species of amoebae which they have ob-
served in malarial districts might be the extraparasitic form. Tlie failure
of artificial cultivations and certain analogies drawn from the zoological
characters of the parasite have led to the prevalent theory that the malarial
parasite passes at least a part of its existence as a parasite in animal or
vegetable organisms. Mention has already been made of Hansen's hj-pothe-
sis that the mosquito may be a host for the malarial parasite. That the
germ is capable of entering upon some resistant phase of development seems
highly probable in view of the evidence that malaria can be contracted from
the air. There is no evidence that the malarial parasite is eliminated from
the human body in a condition capable of infecting another individual or
the locality. The disease, however, can be trarLsmitted by inoculating
into healthy individuals, either subcutaneously or intravenously, blood from
a malarial patient.

UNITY OR PLURALITY OF THE MALARIAL PARASITE

As lias already been mentioned, there are two schools of doctrine as to
the malarial parasite — the one led by Laveran holding that the malarial
parasite is a single species with pleomorphic characters, the other believing
that there are three or more species, or at least varieties, of malarial parasites.

MALAEIA 481

The observations upon which the latter doctrine is based originated with the
Italians, and have been supported by investigations in this country and
elsewhere.

Golgi in 1885 and 1886 first differentiated the parasite of quartan fever
from that of tertian fever, and Marchiafava and Celli and Canalis in 1889
and 1890 differentiated the variety of parasite characteristic of aestivo-
autumnal fever." There is much difference of opinion as to the number of
aestivo-autumnal parasites. All adherents of the doctrine of plurality agree
that there are at least three varieties of malarial parasite — namely, the
quartan, the tertian, and the aestivo-autumnal — distinguished from each
other by morphological and biological characters to be subsequently de-
scribed. The discovery by Golgi of the definite c}'cle of development of the
malarial parasite and the recognition of several distinct varieties have done
much to bring order out of the earlier chaotic condition when a multitude
of parasitic bodies were described without knowledge of their significance
or relations to each other. There remain, however, many imsolved problems
which it may be expected that further investigations will clear up.

In opposition to the doctrine of plurality it is urged by Laveran that all of
the so-called varieties of the parasite may be explained simply as phases of
a single pleomorphic organism influenced by various conditions of environ-
ment, such as locality, season, individual predisposition, and various un-
known circumstances. He contends that the characters upon which a

'= Marchiafava and Celli on the one hand, and Canalis on the other hand, have
conducted a polemic as to which of them belongs the credit of first distinguishing
the aestivo-autumnal parasite. The differentiation of this parasite was not made
all at once, and with the same precision in all details, as in the case of Golgi's
sharp separation of the quartan and tertian parasites. Golgi from the beginning
of his researches (1885-86) suggested that the crescentic bodies belong to a
special cycle of existence different from that of the tertian and quartan organ-
isms, and noted their occurrence in irregular malarial fevers. Councilman in
1887 emphasized the association of crescents with remittent fevers and malarial
cachexia. Golgi in February, 1889, definitely expressed the opinion that in
addition to the malarial fevers caused by the quartan and the tertian parasites
we must recognize another type of fever associated with unpigmented amoeboid
forms and crescents. On September 13, 1889, appeared a preliminary commu-
nication of Marchiafava and Celli, which must be regarded as furnishing the
first clear and sharp description of the essential differential characters of the
aestivo-autumnal parasite, with especial emphasis on the occurrence of unpig-
mented organisms. On October 10, 1889, appeared the preliminary communica-
tion of Canalis, in which likewise the essential characters of this parasite were
discribed, and greater emphasis was laid upon its relation to the crescents than
had been done by Marchiafava and Celli. The full publication of Canalis antici-
pated by a short time the complete article of Marchiafava and Celli on the
aestivo-autumnal parasite.

482 MALARIA

division into separate varieties is based are insufficient for such a purpose
and inconstant; that one so-called variety under certain conditions may he
transformed into another; and that there is no definite, necessary relation
between the types of fever, such as quartan, tertian, quotidian, irregular,
continued, and the form of parasite present. The variations of the malarial
parasite can be explained, he thinks, in large part by the varying rapidity
of development. He emphasises the view that malaria with all its diver.se
manifestations is nevertheless clinically and anatomically one disease, and
has always been so regarded. He argues that the experimental production
of malaria by inoculation does not support the doctrine of plurality.

In considering the force of these objections it must be admitted that so
long as we are unable to cultivate the malarial parasite artificially, and are
ignorant of its life history and the conditions of existence outside of the
human body, the possibility must be admitted that under certain conditions,
at present unknown, one variety may be transformed into another. But, on
the other hand, the existing evidence — and it is already considerable — goes
to show that under the conditions which we can at present control and study
each of the three principal varieties of the parasite preserves its identity
and is not transfonned into anotlier variety; that is to say, there is no evi-
dence that a quartan parasite ever becomes metamorphosed into a tertian,
or either of these into an aestivo-autumnal parasite.

The principal arguments in support of this doctrine of plurality may be
summarized as follows:

(1) Each well-established variety of parasite presents morphological and
biological characters which suffice for its identification.

(2) Each variety of parasite corresponds to definite types of fever.
Genuine quartan fever can be produced only by the quartan parasite. As
will be explained in the clinical jjart of this article, other t\pes of fever may
be caused by more than one variety of parasite, and much complexity may re-
sult from multiple and mixed infections and various irregularities; but all
of this does not prevent the recognition of certain fundamental types of
fever especially characteristic of each variety of the parasite.

(3) Cases of pure infection with one variety of parasite have been care-
fully studied for weeks and months without any indication of the transfor-
mation of one variety into another (Calandruccio, Grassi and Feletti).
Opportunities for such study are exceptional. The appearance of a second
variety of parasite in localities where there is opportunity for renewed in-
fection cannot of course be interpreted in favor of the metamorphosis of one
variety into another.

(4) In certain localities only one or two of the varieties of the parasite
are met with. In a few places only the quartan, or more frequently only the

MALAEIA 483

tertian, parasite is observed; in most places where malaria is mild and in-
frequent only tertian, and occasionally quartan, parasites, with entire absence
of aestivo-autumnal parasites, are found. Instances of this localized dis-
tribution of the parasites, which manifestly is a strong argument in favor
of the doctrine of plurality, will be subsequently mentioned (page 99, Vol.
I, " Syst. Praet. M." [Loomis], 1897).

(5) Strong arguments in favor of the constancy of the varieties of the
malarial parasite are furnished by the experimental production of malaria.
Gerhardt in 1882 and 1883 (reported in 188-1) was the first to produce
malaria experimentally by the subcutaneous injection of blood obtained
from malarial patients. At this time the malarial organism was not generally
recognized. Since these first experiments similar ones have been repeated,
usually in the manner of intravenous injections of malarial blood, with
positive result in over thirty cases. The experiments before 1889 were made
without determination of the exact variety of parasite injected and found
in the experimental case. In 1889, Gualdi and Antolisei, without full knowl-
edge of the critical nature of the experiment, injected two patients intra-
venously with 3 c. e. of blood from a patient suffering with quartan fever
and possessing quartan parasites. In each of the inoculated individuals
irregular fever with aestivo-autumnal parasites developed. These two cases
are constantly adduced as a main support of the doctrine of mutability of
the varieties of the parasite, but unjustly so, for it was subsequently de-
termined that the patient from whom the blood was obtained had previously
suffered from irregular fever, and he subsequently developed characteristic
aestivo-autumnal organisms, so that the experimenters themselves later
expressed the opinion that at the time of the inoculation the patient furnish-
ing the blood had combined quartan and aestivo-autumnal organisms, the
latter being overlooked. In view of the uniform results yielded by the
numerous subsequent experiments in support of the doctrine of immuta-
bility of the varieties of the parasite there can be little doubt that this later
opinion of Gualdi and Antolisei is correct. It has been found regularly
since these experiments that if blood containing only the tertian or the
quartan or the aestivo-autmnnal parasite be injected intravenously into a
person imaffected with malaria, the variety of parasite injected, and only
that variety, appears in the blood of the experimental case. When two
varieties of parasite are injected, or when the malarial blood is injected into
a patient already affected with a malarial organism other than that injected,
then it usually happens that one variety supplants the other, most frequently
the one injected supplanting that already existing in the inoculated indi-
vidual. For such displacement of one organism by another we have nu-
merous examples in bacterial infections.

484 MALAEIA

The bearing of the inoculation experiments upon the determination of
the periods of incubation of malaria will be considered in the clinical part
of tliis article (pages 97, 98, Vol. I, " Syst. Pract. M." [Loomis], 1897).

These already numerous inoculation experiments, showing the identity
of the parasite in the experimental case with that in the blood used for in-
jection, furnish the strongest existing arguments in favor of the plurality
of the malarial parasites."

Whether accepting this doctrine, we shall designate the different types
of the malarial organism as separate species or separate varieties is with
our present knowledge a matter of secondary importance and of individual
judgment. If it be admitted that under no existing circumstances one type
is transformed into another, then we are justified in speaking of separate
species of malarial parasites. As at present we can study only a small
part of the conditions which surround the entire life-history of the parasite,
it seems to the writer preferable to designate the different types as varieties
rather than species.

CLASSIFICATION

We have already had occasion repeatedly to mention the division of the
malarial parasites into three principal varieties — the quartan, the tertian,
and the aestivo-autumnal. Xo further subdivisions of the quartan variety
has ever been suggested. Nor has any attempt been made to subdivide the
tertian parasite originally described by Golgi ; but, as it has since been found
that the aestivo-autumnal parasite — or, according to some observers, one
form of this parasite — may likewise produce tertian fever, the latter form
of the aestivo-autumnal organism is designated by Marchiafava and Bignami
as malignant tertian or aestivo-autumnal (summer-autumn) tertian, and
the former called mild or vernal (spring) or genuine tertian or Golgi's
tertian parasite. This so-called aestivo-autumnal or malignant tertian is,
however, in no sense a subdivision of the tertian parasite originally de-
scribed by Golgi, which remains a well-differentiated, separate variety.
When the name " tertian organism " is used without any epithet, it is always
this variety which is meant.

The name " parasite of aestivo-autumnal fever," introduced by ]\Iarch-
iafava and Celli and already adopted by many writers, leaves much to
be desired. It is intended to indicate that this form of the parasite is the
cause of the malarial fevers prevailing in summer and autumn. This appli-
cation, however, is correct only for certain localities, chiefly those warmer
regions where severe as well as mild types of malaria occur. In localities

" Di Mattel: Contribute, alio Studio della Intezione Malarica Sperimentale
neir Uomo e negli Animali, Arch, per le Scienze Mediche, XIX, N. 4, 1895.

MALAEIA 485

where the prevailing tj-pe of the disease is mild at all seasons the summer
and autumn malarial fevers are caused generally or exclusively by tertian
or quartan parasites. Even in the warmer situations where the aestivo-
autumnal parasite is common, not all of the summer-autumn fevers are
caused by this parasite, but often a large proportion are caused by the ordi-
nary tertian parasites. In subtropical and tropical regions the aestivo-
autumnal parasites may occur in winter and spring fevers. It is evident
that the epithet " aestivo-autumnal," as applied to a special varietj' of ma-
larial parasite, is sufficiently designative for many localities, as, for example,
the southern parts of the United States and Central and Southern Italy,
but it is not so for all.

The term " parasite of aestivo-autumnal fever " does not at once suggest
the relation of the parasite to a definite type of malarial fever, and is there-
fore out of harmony with the designations " parasite of quartan fever " and
" parasite of tertian fever." But it is characteristic of a large proportion of
the fevers caused by aestivo-autumnal organisms that they do not correspond
to any definite type, but are notably irregular. Hence these organisms were
designated by Golgi and by Sacharoff as the " parasite of irregular malarial
fevers." But the objection to this latter name is that aestivo-autumnal
organisms may cause typical quotidian and tertian fevers. Indeed, this is
the only form of malarial parasite which, it is believed, may complete its
cycle of development in twenty-four hours, and thus when present in only a
single group or generation may cause quotidian fever.

As leading characters of the aestivo-autumnal organisms are their small
size, their slight formation of pigment, and the ring-like shape of the
amoeboid forms, they are sometimes spoken of as the small malarial organ-
isms {forme piccole), or the unpigmented, colorless, or slightlv pigmented
organisms, or the ring-like annular organisms. They are also called the
organisms of grave or pernicious malaria, although they may likewise cause
mild tv'pes of the disease.

As it is to the group of aestivo-autumnal parasites that the crescents ex-
clusively belong, these parasites have been described as the semi-lunat
variety. They may be designated as crescent-producing. Eaematozodn
falciparum is suggested by the writer as a suitable technical name for this
variety of parasite.^"

" The name Eaematozodn falciforme suggested by Antollsei and Angelinl is
objectionable, as it implies that the shape is always falciform, and is applicable
only to the crescentic forms. The adjective " falciparum " (falx, " sickle,"
parire, "to bring forth," "to produce"), on the other hand. Indicates that the
property of forming crescents is a distinctive character of the organism, and it
is therefore applicable to the variety of the parasite which possesses exclusively
this property.

486 MALAEIA

Tlie three varieties of the malarial parasite may therefore be technically
designated — (1) Haematozoon febris quartanae; (3) Haematozoon jehris
tertanae; (3) Haematozoon malariae falciparvm. The name aestivo-
autunmal parasite, as the more commonly used and generally understood
designation, will, however, continue to be used, as well as the term " Haema-
tozoon falciparum," in this article for the last named variety.

There is no difference of opinion, except among the vinicists, that the
aestivo-autumnal organisms form a variety or group which is to be differen-
tiated from both the quartan and the tertian organisms even more sharply
than the tertian and the quartan are differentiated from each other. But
the question as to the unity or the plurality of the aestivo-autumnal organ-
isms is still an open one, and is the most important unsolved problem re-
lating to the divisions of malarial parasites. Its solution is attended with
unusual difficulties, but we may reasonably expect that they will be sur-
mounted by future investigations.

In distinction from the quartan and the tertian organisms the aestivo-
autumnal are often irregular and atypical in their cycle of development.
Some, it is believed, may complete their cycle in twenty-four hours, others in
forty-eight or a longer period : their tendency to develop simultaneously in
well defined generations is far less marked than is the case with tertian and
quartan organisms, so that several or all phases of development of aestivo-
autumnal forms may be observed in the internal organs at the same time.
The occurrence of multiple groups of the parasite is common. Forms
appear which pass through their amoeboid, mature, and segmenting phases
without any formation of pigment within the parasite. The development
takes place largely in the internal organs. The development of crescents
occurs at a variable period after the onset of the disease, but rarely in less
than a week. Corresponding to these variations and irregularities the types
of fever with which aestivo-autumnal organisms are associated are various
and irregular.

The attempt has been made to deduce certain laws controlling these
variations and apparent irregularities, and to subdivide the aestivo-
autumnal organisms into certain varieties or subvarieties, but there is little
agreement of opinion as to this subdivision.

The following are the principal divisions of the malarial parasite which
have been proposed, the essential differences in these various divisions re-
lating, of course, to the different views held concerning the aestivo-autumnal
organisms :

I. Marchiafava and Celli (1889) recognized a short cycle of development
of the aestivo-autumnal parasite, unaccompanied by development of pig-
ment, and a longer cycle with formation of a few pigment granules. Mar-

MALAEIA 487

chiafava and Bignami (1891) make two varieties of this parasite — viz.
the amoeba of aestivo-autumnal quotidian, with twenty-four-hour cycle,
and the amoeba of aestivo-autumnal tertian, with a forty-eight-hour cycle —
Amoeba febris quotidianae and Amoeba febris tertinae aestivo-autumnalis.
The latter variety is the malignant tertian organism of these authors. The
main differences between these varieties, according to Marchiafava and Big-
nami, relate to the length of the cycle of development, but there are claimed
to be also minor morphological and biological differences to be mentioned
subsequently (pp. 503 and 504).

These authors, therefore, make four different varieties of the malarial
parasite. They divide the malarial fevers into two main groups :

1. Mild malarial fevers which prevail in winter and spring. These are —
(a) Quartan fever (-n-ith its varieties of double and triple quartan). This

caused by the Amoeba febris quartanae (Golgi), which completes its life
cycle in seventy-two hours.

(6) Tertian fever (%vith double tertian and rarely certain subcontinued
fevers). This is caused by the Amoeba febris tertianae (Golgi), which
completes its life cycle in forty-eight hours.

2. Severe or aestivo-autumnal fevers, including the pernicious and most
of the subcontinued fevers. This group comprises —

{a) Aestivo-autumnal quotidian fever (to be distinguished from quo-
tidians of tertian and of quartan origin), caused by the Amoeba febris quo-
tidianae, which completes its cycle in twenty-four hours. This is the only
variety of malarial parasite which can complete its life cycle in so short a
period as twenty-four hours.

(&) Aestivo-autumnal or malignant tertian fever, caused by the Amoeba
febris tertianae aestivo-autumnalis, which completes its cycle in forty-eight
hours. Most of the pernicious cases belong to this variety, the remainder
to the aestivo-autumnal quotidian variety.

II. Canalis (1889) does not subdivide into varieties the aestivo-autumnal
parasite, which he calls the " semilunar variety," but he considers that it has
two cycles of development: (a) a rapid cycle with the usual phases of
amoeboid, mature, segmenting forms and spores, and (b) a slower cycle
associated with the development of crescentie bodies, which he considers to
be reproductive and to represent one phase in this second cycle. A similar
view is held by Antolisei and Angelini.

III. Grassi and Feletti (1890) regard the crescent-producing forms as
an entirely separate species, which they call Laverania malariae, and which
they distinguish both from the directly spore-forming unpigmented aestivo-
autumnal forms, which they call Haemamoeba immuailata and from similar

488 MALARIA

rapidly developing, but pigmented, aestivo-autunmal parasites, without
crescents, which they call Haemamoeba praecox. Their classification of
the malarial parasite is as follows: (a) Haemamoeha malariae, identical with
the quartan parasite; (b) Haemamoeba vivax, which is identical with the
tertian parasite of Golgi; (c) Haemamoeba praecor, a form of the aestivo
autumnal parasite, giving vise to quotidian fever; (d) Haemamoeba imma^
cidata, similar to the preceding, but without development of pigment; {e)
Laverania malariae, the crescent-producing variety, giving rise to irregular
fevers.

Sacharoff formerly regarded the crescents as belonging to a separate species
of malarial parasite, and adopted the following classification : (a) Haema-
moeba febris qiuirtanae (Golgi), (6) Haemamoeba febris tertianae (Golgi),
(c) Haemamoeba praecox (Grassi), {d) Laverania (Grassi). Kecently
(1896) he holds that all variations of the aestivo-autumnal parasite are
modifications of a single variety due, mainh', to the development of the
parasite within nucleated red blood corpuscles.

lY. Mannaberg (1893) accepts Marchiafava and Bignami's division of
aestivo-autumnal parasites into quotidian and tertian, and also adopts Grassi
and Feletti's division into pigmented and unpigmented quotidian parasites.
He does not, however, consider the crescents as belonging to a species or
variety distinct from these, but considers them as developing from each of
these three divisions of aestivo-autumnal parasites. He has a peculiar view
as to the origin of the crescents from conjugation of cells, and regards them,
therefore, as forms of syzygia. He divides the malarial parasites into two
groups — the first group, with sporulation and without syzygia, comprising
(a) the quartan and {b) the tertian parasites of Golgi; the second group,
with sporulation and with syzygia, comprising (a) the pigmented quotidian
parasite, (6) the unpigmented quotidian parasite, and (c) the malignant
tertian parasite.

Y. Golgi (1893), an admirable and successful investigator of the malarial
parasites, does not consider the semilunar forms as belonging to a species or
variety distinct from the ordinary sjwrulating aestivo-autumnal parasite.
He attempts no subdivision of the aestivo-autumnal parasite. His concep-
tion of the mode of development of this parasite differs in essential points
from that of Marchiafava and Bignami and of most other investigators, as
will be explained in considering the special characters of the aestivo-
autumnal parasite.

The following statement of Golgi's classification of the malarial fevers is
quoted from Thayer and Hewetson's work on "The Malarial Fevers of

MALARIA 489

Baltimore," already cited." Golgi divides the malarial fevers into two
groups :

(1) Fevers the pathogensis of which is connected with parasites which
have their principal habitat in the circulating blood where, by preference,
they accomplish the phases of their cycle of existence.

(2) Fevers the pathogenesis of which is connected with parasites which
have their chief seats in the internal organs, particularly the bone marrow
and the spleen, where, by preference, they accomplish their cycle of existence
in conditions of relative stability.

(1) The fevers of the first group are unquestionably associated with dif-
ferent species or varieties of the parasite — viz. (a) the quartan parasite;
(6) the tertian parasite.

(2) "To the second group belong the fevers which appear clinically
under multiform types, very often irregular, of which for the present it is
impossible to make a grouping based upon an ascertained biology or cycle

of development of the parasite We are dealing in these cases with

generations of parasites which, occurring in the parenchjTna of organs in
different stages of development, give origin, at periods of a certain regularity
or in a more or less continuous succession, to colonies of young forms which,
in large or small numbers or in insignificant quantity, may escape into the
blood current, permitting one to discover by microscopical examination of
the blood the presence of the small endoglobular amoebae." Golgi refers to
the crescents as " forms the biology of which has not yet been well deter-
mined."

VI. Thayer and Heweston (1895) were likewise unable to confirm Mar-
chiafava and Bignami's subdivision of the aestivo-autumnal parasite into a
quotidian and a tertian variety. They say : " We have lieen unable to trace
a constant length of the cycle of development, and we have been imable fur-
ther to separate two or more types of the [aestivo-autumnal] parasite de-
pending either upon the length of the cycle of development or upon any
other morphological or biological differences. We believe that the length of
the cycle varies greatly in different cases, lasting usually from twenty-four
hours, or even a little less, to forty-eight hours or more. After the infection
is five days or a week old certain of the organisms, instead of segmenting,
pursue a further growth, developing into the hyaline, refractive, ovoid, and
crescentic bodies." They do not feel justified in making any positive state-
ment as to the significance or capacity of reproductive development of the
crescentic bodies.

" The writer wishes to acknowledge his indebtedness to this excellent mono-
graph for much valuable assistance in the preparation of this article.
34

490 MALARIA

The question has been raised whether in tropical regions, where pernicious
types of malaria are common, any form of malarial parasite different from
those already mentioned occurs. The observations of Vandyke Carter,
Dock, van der Scheer, Plehn, and others show that the same parasites are
found in India, Panama, Java, and other tropical countries as elsewhere.
The negative reports which have been published are referable doubtless to
insufficient training in such examinations on the part of the observers. The
fact that a large part of the tropical malarial fevers are caused by aestivo-
autimmal organisms which appear in the red blood corpuscles as small, pale,
feebly staining, delicate, diaphanous, often unpigmented amoeboid rings of
hyaline protoplasm, difficult to detect in many cases, and sometimes scanty
or at times even absent, will account for many of these negative observations.

The singular distribution of the haemoglobinuric type of pernicious
malarial fevers in certain definite localities suggests the possibility that this
may be caused by a special type of organism. The sporadic cases of malarial
haemoglobinuria examined in Italy have shown, however, ordinary aestivo-
autumnal organisms. Plehn " found in cases of black-water fever occurring
on the West Coast of Africa small, annular amoeboid forms, staining with
great difficulty and never pigmented, in the red blood corpuscles. " Out of
the amoeba there develops by thickening of the peripheral zone an oval or
egg-shaped body, with well staining double contour. In course of time this
divides into five or six small oval forms, staining at one pole, which, when
they are set free, move about with great rapidity in the blood. These prob-
ably develop into the amoeboid forms." The organism never attained a size
larger than one-quarter of the red blood corpuscle. Crescents were occa-
sionally found. Plehn seems to regard this organism as allied to, but not
identical with, the aestivo-autumnal parasite described by Italian writers.
Although his description presents certain peculiarities of the parasite which
he observed in the pernicious malarial haemoglobinuria and other pernicious
fevers of the West Coast of Africa, especially the constant absence of pig-
ment, the extremely small size, the sporulation in the blood, and the appar-
ently motile spores," nevertheless it is not sufficiently complete and satis-
factory to justify the inference that the organism differs from forms of
the ordinary aestivo-autumnal parasite as previously observed.

Prom the preceding review of the various investigations and opinions
concerning the divisions of varieties of the malarial parasite, especially of the

"Plehn: Ueber das Schwarzwasserfieber an der afrikanischen Westkiiste,
Deutsche med. Wochenschrift, 1S95, Nos. 25, 26, 27.

" It may here be mentioned that Plehn considers that the spores of all varieties
of the malarial parasite are flagellated — a view which has not been confirmed by
other observers.

MALARIA 491

aestivo-autumnal form, we may draw the conclusion that whereas the separa-
tion into quartan, tertian, and aestivo-autumnal varieties rests upon a
sound basis of fact, the various attempts to further subdivide the aestivo-
autumnal group have not as yet been suificiently successful to justify our
acceptance at the present time of any of these subdivisions. There is, how-
ever, some reason to believe that this last group, as at present constituted,
may comprise varieties which will hereafter be satisfactorily differentiated
from each other.

We will now consider the special characters of each of the three varieties
of the malarial parasite.

I. THE PARASITE OF QUARTAN FEVER (BAEMATOZOON FEBRIS QUARTANAE)

In most malarial regions this is the rarest form of the malarial parasite,
but there are certain places (none of these have been recognized in this
country) where it is the prevailing variety. Being particularly common in
the neighborhood of Pavia in Italy, the quartan parasite was the first to be
differentiated and described by Golgi (1885-86), to whose masterly descrip-
tion nothing of essential importance has been added by subsequent investi-
gators, with the exception of certain details of intimate structure.

The quartan parasite completes its cycle of development in seventy-two
hours and entirely within the circulating blood. The youngest forms of
the parasite are small, amoeboid, when at rest discordial, hyaline bodies,
within the red blood corpuscles. They are about one-fifth to one-fourth
the size of the red blood corpuscles. The central part of the body may
appear paler than the peripheral. These unpigmented, youngest forms are
found during and for several hours after the paroxysm ; they may begin to
appear two hours before the paroxysm. The very earliest forms are not to be
distinguished from the youngest tertian parasites, but as they begin to
develop they present a sharper outhne and somewhat more refractive appear-
ance, and their amoeboid movements are more sluggish and restricted than
those of the corresponding stages of the tertian organism. These movements
become more active on the warm stage of the microscope. The presence of
more than one parasite in a red blood corpuscle is sometimes observed.

Shortly, or within twelve to eighteen hours, after the paroxysm pigment
granules appear within these hyaline bodies, which continue to increase
slowly in size, and for a while to exhibit lazy amoeboid movements. The
pigment appears in the form of brownish or black rods and grains, which
are coarser and darker than those seen in tertian parasites. The rod form of
pigment is less common than in the tertian organism. These pigment
granules are arranged generally in the peripheral part of the parasite, and
they present only a sluggish movement in comparison with the active motion

1!)2 MALARIA

of the pi^niK'iit ill tliu tertian parasite. With the gradual inorease in size
of the hyaline bodies and in the amount of contained pigment the red blood-
corpuscles enclosinij them may appear unchanj^ed, or often tiicy become a
little smaller, more refractive, and deeper in color, which may be somewhat
greenish or coppery in tint. There is not that tendency to decolorization and
Rwellinp; of the infected red blood corpuscles which is noticed in the case of
the tertian parasite, although in the more advanced stages of development
there is usually some loss of color in red corpuscles containing quartan
organisms.

In the process of development the amoeboid movements cease, and the
parasite appears as a quiescent, pigmented, spherical, or ovoid body occupy-
ing perhaps one-half to two-thirds of the red corpuscles. Such bodies are
usually seen within forty-eight hours after the paroxy.sm. These bodies
continue to grow, and when they have reached their full development in
sixty to seventy hours after the paroxysm they are somewhat smaller than the
normal red blood corpuscles. These full-grown forms are spherical or ovoid,
refractive, hyaline bodie.s, with nearly or quite motionless dark pigment
granules of variable size, but coarser than in the tertian parasite, and with
a tendency to peripheral arrangement, but at times irregularly distributed.
Around these bodies a thin layer of the colored, refractive substance of the
red blood corpuscle can usually still be seen, or the haemoglobin may be en-
tirely removed, so that only a delicate, thin, colorless rim or line surrounding
the parasite is all that is left of the original red blood corpuscle. In unstained
specimens these latter forms often appear to be free in the plasma, and are
sometimes spoken of as free bodies, which may also occur.

In six or eight to ten hours before the febrile paroxysm the first phases of
reproduction begin to appear. These are ushered in by the gradual with-
drawal of the pigment from the periphery toward the centre of the body.
The pigment in this process is often arranged in definite radial striae. Such
regular stellate arrangements of the pigment as are seen in this stage of the
quartan parasite are rarely, if ever, observed in the tertian (Thayer and
Hewetson). Finally the j)igment is concentrated into a central mass of
granules or a solid block of coalesced pigment, less frequently into two or
more collections, and the organisms assume a somewhat more refractive
and slightly granular appearance.

At the same time or soon afterward radial divisional striae begin to appear
in the periphery, and quickly extend to the central part of the j^arasite,
whereby the substance of the splierical organism becomes divided into six to
twelve ovoid or pear-shaped segments arranged with characteristic and ex-
quisite regularity around tlic central muss of pigment like the petals of a
daisy (rosettes of Golgi). In each of the segments can be seen a small round

MALAEIA 493

glistening body which represents the niieleus or nuclear material. The
pyriform segments assume rapidly a round or oval shape, and become
separated from the central mass and from each other. The delicate envelop-
ing membrane, which may not be recognized on unstained specimens, de-
rived from the red blood corpuscle ruptures, or it may previously have disap-
peared, and the small round or oval bodies, each provided witli a bright
nucleiform dot, are set free in the plasma. These bodies are the so-called
spores. Simultaneously with this process of sporulation young amoeboid
liyaline bodies, formed directly from the spores, make their appearance in
the red blood corpuscles, and the cycle of development is completed and
another cycle is begun.

Segmenting or sporulating forms of the parasite may appear six or eight
hours before the paroxysm, and are most abundant .shortly before and during
tlie onset of the paroxysm. It is of course not to be understood tliat all of
the parasites of one group pass through their developmental phases and
mature at exactly the same moment. One parasite of the group may be
several hours in advance of another, but this does not interfere with the
recognition of distinct groups or generations, each standing in definite rela-
tion to a paroxysm, or with the establishment of Golgi's law that the onset
of each paroxysm corresponds to the maturation of one group of organisms.

The cycle of development of the quartan parasite it attended with fewer
irregularities than that of any other variety of the malarial parasite. Never-
theless, certain irregularities may occur. As pointed out by Antolisei, seg-
mentation may occur exceptionally in pigmented bodies considerably smaller
than the usual fuU-grown forms, containing less pigment and filling only a
part of the red blood corpuscle. Here the segments do not usually exceed
four to six or eiglit. The accumulation of pigment in the segmenting forms
may be peripheral, or distributed between the spores, or otherwise irregular.

As the quartan parasite completes its development entirely within the
circulating blood, there is no appreciable difference at any stage between
the splenic and the peripheral blood as regards the number and variety of
the parasitic forms observed. Moreover segmenting forms of the quartan
parasite are often seen in small number in the blood at a period before
the total number of organisms is siifficiently large to produce by their ripen-
ing a paroxysm, whereas segmenting tertian parasites are very rarely seen
in the peripheral blood without the occurrence of a paroxysm in relation
to the segmenting forms.

Not all of the mature forms proceed to sporulation. Some, especially
those which may have escaped from the red corpuscles, swell up, become
transparent and larger than a red blood corpuscle, and present irregularly
distributed and actively moving pigment granules. These swollen, hydropic

494 MALARIA

forms are probably sterile. It can often be seen in examining these bodies
in fresh blood that the pigment becomes quiescent, the outlines of the body
become irregular and indistinct, and evidently cadaveric forms result. Or
these bodies may break up into a number of fragments which become mis-
shapen and indistinct, or tlie whole body may become vacuolated. Bodies
more or less resembling spores, but without the nuclear structure of spores,
may appear in these vacuoles.

As may occur with any variety of the malarial parasite, the mature forms
of the quartan parasite, instead of sporulating, may develop into flagellate
bodies in the manner already described. These bodies are smaller and con-
tain coarser pigment than the flagellate forms of the tertian parasite. De-
generated and flagellate forms are less common in quartan than in tertian
infections.

Not only may mature forms degenerate in the ways described, but forms
in earher stages of development may be liberated from the red corpuscles
and likewise degenerate.

The phenomena of phagocytosis are observed with regularity during and
for some hours after the paroxysm in quartan as well as in other malarial
infections. The pigment set free by the process of sporulation is taken up
by phagocytes. Extracorpuscidar organisms, particularly the various de-
generated forms, are engulfed by phagocytes. The assault on the flagellate
bodies by leucocytes can be watched with interest on the slide of fresh blood.
The leucocytes can also be seen to take up segmenting bodies and spores when
the specimen of blood is kept for a while. The details and the significance
of these phagocytic phenomena will be considered subsequently (page 519).

Tlie intimate structure of the quartan and other malarial parasites, as
revealed by methods of staining, will also be described subsequently.

Two or more groups of quartan parasites are often present in the blood at
the same time, causing double and triple quartan infections. On account of
the regularity in the development of the quartan parasite, anticipating, re-
tarding, and irregular fevers are less common in quartan than in the other
malarial infections. Careful examination of the blood enables the obsen-er
to recognize the presence of two or more groups of the parasite by noting the
simultaneous occurrence of bodies in noticeably different stages of develop-
ment; as, for example, during the paroxysm the association of segmenting
and young hyaline bodies with half-grown pigmented bodies.

II. THE P.^RASITE OF TERTIAN FEVER (HAEMATOZOOS FEBRIS TERTIANAE)

This variety of the malarial parasite is common in most malarial regions.
Where only mild types of malaria occur it is, as a rule, the prevailing, and
sometimes the sole, variety observed. The tertian and the quartan parasites

MALARIA 495

cause most, or in some places all, of the winter and spring intermittents,
but they, and especially the tertian parasite, may cause in districts of even
severe malaria not a few of the malarial fevers of summer and autumn,
although the more severe and irregular of these latter fevers are caused
chiefly by the aestivo-autumnal parasite. The tertian parasite may, how-
ever, produce severe, as well as mild, types of malaria.

The tertian parasite was differentiated from the quartan and described in
its essential characters by Golgi in 1886 and 1889. Other observers, par-
ticularly Antolisei (1889-90) and Bastianelli and Bignami (1890), have
added to, and in some points corrected, Golgi's first description.

The chief points to be emphasized in this description of the tertian para-
site are those which distinguish it from the quartan parasite. Unlike the
quartan parasite, certain stages of development of the tertian — namely, those
concerned with sporulation — take place by preference in the spleen and the
bone marrow, although segmenting forms are seen also in the peripheral
blood. The cycle of development is completed in forty-eight hours.

During the paroxysms or shortly after it small, unpigmented, hyaline,
amoeboid bodies are found within the red blood corpuscles, of which they
are about one-fifth to one-fourth the size. Usually one hyaline body is
found, but not very infrequently two or more are present, in a single blood
corpuscle. The tertian amoebae, especially m their pigmented stage, change
their shape and position within the corpuscles much more actively than the
quartan amoebae, these movements being vigorous at ordinary room tem-
perature. Several branching pseudopodia are sent out, often reaching
nearly or quite the periphery of the corpuscle, and are retracted. All sorts
of shapes may thus be assumed by the parasite, which with its long branch-
ing processes may seem to pervade nearly the whole corpuscle. By the union
of two pseudopodia the shape may be that of a ring enclosing a bit of the
corpuscular substance. The tertian amoebae are paler, less sharply outlined,
than the quartan. In a short time fine reddish brown or yellowish brown
rods and granules of pigment, varying somewhat in size, appear in the
margins of the amoebae. Pigment granules often collect in the bulbous
ends of pseudopodia, and the iatervening parts of the pseudopodia may be
so thin and dehcate as to be readily overlooked, so that the appearance may
be that of several distinct bodies within one red blood corpuscle. Careful
examination will, however, detect the fine connecting processes or the re-
traction of the apparently separate bodies into the substance of one parasite.
Two or more parasites may, however, be present occasionally within one red
corpuscle. The pigment is in finer grains and rods, and of a lighter, some-
what different, tint in the tertian, than in the quartan parasite. It is also in
much more active movement in the tertian amoebae. This movement is

496 MAL.\rjA

not altofTcther like the Brown ian or molecular motion, and is probably due
to intrinsic protoplasmic movements or currents.

With the continued growth and increased pigmentation of the amoebae
the infected corpuscles as a rule become distinctly swollen and paler than
normal — a change which may be already indicated even with quite small
pigmented forms, and which is one of the most distinctive characters of the
tertian parasite. Occasionally the enveloping corpuscle is not noticeably
swollen or altered, and exceptionally it may even shrink and acquire some-
thing of the brassy appearance commonly seen with red corpuscles infected
with aestivo-autumnal parasite.

On the day of apyrexia the parasite, now with somewhat sharper contour
and more richly pigmented, may attain a size equalling one-half to two-
thirds that of the infected blood corpuscle. The amoeboid movements have
become more sluggish, but they persist in stages of development correspond-
ing to which forms of the quartan parasite have become quiescent. The pig-
ment continues in active motion.

The fully developed parasite is about the size of a normal red corpuscle,
sometimes a little smaller, sometimes somewhat larger, and it is therefore
smaller than the swollen corpuscle in which it is contained. It is nearly or
quite spherical in shape, and without amoebic movements. The pigment
for a while preserves its marginal arrangement or less frequently is irregu-
larly distributed. The expanded red blood corpuscle enveloping the parasite
becomes still paler.

These fully grown forms change into the presegmenting bodies by the
collection of the pigment, which has already become quiescent into a mass
of granules or into a solid block situated usually in or near the center or
Bometimes near or at the margin. As with the other varieties of the mala-
rial parasite, the pigment with the development of the parasite becomes
coarser, and the delicate rod-like forms of pigment become relatively less
numerous. These spherical bodies with central pigment clumps are more
refractive than is the parasite in preceding stages of development. Stained
specimens show that in these presegmenting bodies there appear multiple,
deeply staining chromatin granules, which represent nuclear substance,
and which are the first indication of the inception of sporulation.

This phase of segmentation ])rescnts more variation than is observed in
the quartan parasite. Sometimes it begins with the appearance of radial
striation extending from the periphery to the center, and proceeds by a divi-
sion of the substance of the parasite into twelve to twenty or even more seg-
ments arranged in a rosette form around the central clump of pigment. A
little later the pigment clump is surrounded by a group of small round
bodies, which are the spores. More commonly, without the formation of

MALAEIA 497

such regular figures, the protoplasm breaks up into a mass of fourteen to
twenty or more spores. Sometimes one sees an outer and inner ring of
spores concentrically arranged around the central mass of pigment. The
larger number of segments or spores formed by the tertian as contrasted
with the quartan parasite is an important differential characteristic.

The modes of segmentation described correspond in the main to Golgi's
second type of segmentation. His first mode of segmentation of the tertian
parasitemias not been noted by other observers. It is as follows: After the
collection of the pigment in the centre the organism is differentiated into a
peripheral zone sharply separated from a central body containing the pig-
ment. The peripheral ring becomes radially striated, and then divides
into fifteen to twenty small hyaline segments. The central pigmented body
does not segment, but remains behind after the separation of the spores.
Golgi's third variety of segmentation is now generally recognized as a process
of degenerative vacuolation.

Sometimes the segmenting bodies show, instead of one central accumu-
lation of pigment, two or more clumps excentrically placed, or the pigment
may be concentrated in the periphery or distributed between the spores or
otherwise irregularly arranged.

The spores are set free by rupture of the enveloping membrane derived
from the red corpuscles, or this membrane may have disappeared before the
segmentation is completed. The individual spores are somewhat smaller
than those of the quartan parasite. They usually show a refractive nuclei-
form dot, which is, as a rule, less distinct than in the quartan spores.

Coincidently with sporulation the young colorless, amoebae, formed from
the spores, make their appearance in the red blood corpuscles and start on
a fresh cycle of development.

The segmenting bodies may make their appearance several hours before
the paroxysm. They are most numerous shortly before and during the
onset of the paroxysm. They may be scanty in the peripheral blood, for
the process of sporulation takes place largely in the internal organs. The
red corpuscles containing mature and presegmenting bodies accumulate
especially in the spleen and the bone marrow, and there the organisms com-
plete their reproductive development. During most of the period of apyrexia
no noticeable difference is observed in the number and kinds of parasites
between the peripheral blood and that withdrawn by hypodermic syringe
from the spleen. But shortly before and during the paroxysm far more ripe
and sporulating forms are found in the splenic than in the peripheral blood.

Precocious segmentation into five to ten spores may occur in bodies,
sometimes containing only a grain or two of pigment, which have not
attained a size exceeding one-half to tw-o-thirds that of the red blood

498 MALARIA

corpuscles, the usual size of a segmenting body being about that of a red
corpuscle, but sometimes considerably larger. Such immature forms of seg-
mentation are associated by Bastianelli and Bignami with anticipating
fevers, but Mannaberg and Thayer and Hewetson, although not inclined to
discredit this interpretation, were unable to convince themeslves of this
relation.

Partly developed and mature tertian parasites are often seen free in the
plasma. Swollen, transparent, extracorpuseular forms which may attain
the size of large leucocytes, and which contain scattered dancing pigment
granules, are generally considered to be degenerative or incapable of repro-
ductive development. These so-called hydropic forms are considerably
larger and paler and more common than the similar forms of the quartan
parasite. These swollen, richly pigmented forms are very common in tertian
infections. In general, the various forms of degeneration which have
already been described, such as fragmentation, vacuolation, pseudo-gem-
mation, are more common with the tertian than the quartan parasite. Flag-
ellate bodies are likewise more common. They are, as a rule, larger and
contain finer pigment than the quartan flagellates. They develop chiefly
from the round, swollen, extracorpuseular forms with scattered pigment,
although flagella have been observed to develop from forms still surrounded
with a distinct layer of hemaglobin containing substance of the red blood
corpuscle. Flagellate bodies are most abundant in blood withdrawn from
the spleen shortly before and during the paroxysm. Phagocytosis occurs
with the same regularity and with similar phenomena in tertian as in
quartan infections.

Infection with two groups of tertian parasites (double tertian), as des-
cribed for quartan infection, is more common than with a single group,
especially in the later period of the malarial season in the spring and in
summer and autumn. The resulting type of fever is quotidian. In some
cases there seem to be several irregularlv distributed generations causing
remittent or subcontinued fevers. It is not necessary to attribute the pres-
ence of two or more groups of the same variety of parasite to corresponding
multiple infections from without. There is evidence that certain members
of a group may, in their development, lag behind or advance beyond others
of the same group, and in course of time by further multiplication may con-
stitute a separate group capable of causing its own paroxysms of fever. It
is remarkable, however, that the second group should be separated in its
cycle of development by such definite intervals from the first as we usually
observe in quotidian fevers of tertian origin. Genuine mixed infections with
malarial parasites, the most frequent combination being that of the tertian
and of the aestivo-autumnal parasites, are not very uncommon.

MALAEIA 499

The length of the cycle of development of the tertian parasite may occa-
sionally be noticeably shorter than forty-eight hours, perhaps only forty
hours or less, or, on the other hand, it may be longer than the normal period.
This may explain the anticipating and the postponing fevers.

III. THE PAKASITE OF AESTIVO-AUTUMNAL FFVER (.HAEMATOZOOlf FALCIPARUM)

This was first clearly differentiated from other varieties ot the malarial
parasite by Marchiafava and C'elli (1889), and was subsequently more fully
described by the same authors and by Canalis (1889-90). (See footnote,
page 481.) The extensive literature concerning the parasitology of malaria
during the last six years has been concerned to a large extent with this
variety, but we are still far from possessing so full and accurate knowledge
regarding the characters and development of Haematozoori falciparum as
regarding those of the quartan and tertian parasites. Such knowledge is
much to be desired in view of the frequency of the aestivo-autumnal parasite
in regions, such as the southern part of the United States, where the more
severe t}-pes of malaria occur, and of the almost exclusive association of this
parasite with pernicious malarial fevers.

Chief reasons for the difficulty in investigating the entire life history of
Eaematozoon falciparum are that it develops mainly witliin the internal
organs and often in multiple groups, and that the later reproductive phases
of development are met with in the circulating blood only very exceptionally.
Under the Classification of the malarial parasites we have already presented
the more important opinions which have been advanced concerning possible
subdivisions of the aestivo-autumnal variety (page -484: et seq.).

The youngest forms of this parasite are small hyaline bodies, about one-
sixth the diameter of a red blood corpuscle, which make their appearance in
the blood corpuscles during or shortly after the paroxysm. It is not uncom-
mon to find two or more hyaline bodies in a single corpuscle. The aestivo-
autumnal hyaline bodies are in general the smallest forms of the malarial
parasite which are observed in the red blood corpuscle. The youngest forms
may be quiescent, but as they develop they manifest amoeboid movements
resembling in their activity those of the tertian amoebae.

The young aestivo-autumnal amoebae nxay not be readily distinguishable
from the similar forms of the quartan and tertian parasites. Particularly
characteristic, however, the young hyaline forms of Eaematozoon falciparum
when in repose and in stained specimens is the ring shape. The appearance
in fresh specimens is that of a somewhat refractive, clear, hyaline ring,
usually thicker on one side, surrounding a small round central, or oftener
excentric, shaded part, or sometimes two or three such parts, through which
the color of the red corpuscle shows. In stained specimens the ring appears

500 MALAIUA

thinner than in fresh specimens, and the central or oftener excentric part is
unstained, while a minute deeply stained granule is situated in the outer ring.

The study of the further development of these forms, especially on
stained specimens, has demonstrated that these apparently annular bodies
are not actual rings, as some have supposed, enclosing a bit of the red cor-
puscle, but that the clear area which does not stain is a transparent part of
the organism, which, as wilL be subsequently explained, some regard as the
nucleus. Actual rings, however, as has already been mentioned, may be
formed by the junction of pseudopodia, wliich thereby enclose some of the
corpuscular substance, but such is not the explanation of the typical annular
appearance of the aestivo-autuninal hyaline bodies. It is not uncommon to
find free hyaline bodies in the blood plasma.

These hyaline bodies may, while under observation, become somewhat
expanded and paler and lose their annular appearance, and again resume
the ring shape. \Yhile the very smallest intracorpuscular hyaline bodies
maj' present no amoeboid movements, as they grow larger these movements
become active. Hyaline bodies are occasionally observed to change their
position within the corpuscle without change in their shape, ilanifold
shapes are assumed during the amoeboid movements.

Usually in the course of development a few very fine dark reddish brown
or black pigment granules appear in the outer layer of the hyaline bodies.
They may be situated near the periphery or on the inner margin of the ring
near the clear part. Sometimes the pigment does not appear until shortly
before a paroxysm. Tlie presence of many bodies containing a considerable
number of grains of pigment is generally indicative of an impending par-
oxysm. The pigment granules are at first ver}' minute and few, and may
be readily overlooked. The granules of pigment increase in number and size,
but it is one of the characteristics of the aestivo-autuninal amoebae that the
formation of pigment is, as a rule, scanty and in fine grains. Often only
one or two very fine pigment granules are seen in the periphery or on the
inner edge of the refractive border of the hyaline bodies. Usuallj^ about
six or seven granules of pigment are developed in the hyaline bodies. The
pigment generally shows but little motion in contrast with that in the tertian
amoebae.

The aestivo-autuninal amoeboid forms do not generally grow larger than
one-quarter to one-third the diameter of the red blood corpuscle, and they may
remain smaller. The infected red corpuscles may appear otherwise normal.
They do not become swollen and decolorized in tliis stage, as is the case in
the tertian infections. On the other hand, tliey often become shrunken,
creased, or otherwise deformed, and present a deep brassy color {glohuli
rossi ottonati of the Italian writers). Sometimes the haemoglobin separates

MALAEIA 501

from a part or the whole of the outer part of the stroma of the corpuscle and
collects around the enclosed hyaline body. These changes in the red cor-
puscles, which are particularly characteristic of the aestivo-autumnal variety,
although not absolutely limited to it, are to be regarded as degenerative or
necrobitic. Marchiafava and Celli and some others have thought that the
parasite within these profoundly altered corpur?les is also dead or incapable
of further development. Bastianelli states that sporulation forms are not
observed in the brassy corpuscles, but this statement is opposed to observa-
tions of Marchiafava and Bignami and others. The view that parasites
within profoundly altered corpuscles are incapable of further development
is by no means proven, and is opposed to the natural interpretation of many
observations.

As the time for the onset of a paroxj'sm approaches, the hyaline bodies
gradually cease their amoeboid movements, assume a spherical or ovoid
shape, become somewhat more refractive and homogeneous, and present a
small collection of quiescent or but slightly moving pigment granules at
about the centre or often near the periphery. This pigment usually fuses
into a single small, black, round or irregular mass or block, or there may be
two such blocks.

These round, refractive bodies with pigments blocks or collections of
pigment granules (corpi con blocchetto) are the presegmenting bodies, and
when they are present the onset of a paroxysm, within at most a few hours,
may generally be safely predicted. These bodies are much smaller than the
corresponding forms of the quartan and tertian parasites. They do not
generally exceed one-quarter or one-third of the size of the corpuscle, al-
though they may be considerably larger. They are surrounded with haemo-
globin containing substance of the corpuscle, which is often of a brassy color.

The next phase of development is that of sporulation, but the segmenting
forms are found in the peripheral blood only most exceptionally, save in
some pernicious cases, in which they may in rare instances be even abundant.
Sacharoff observed in the Transcaucasus sporulating forms in the blood, and
on this account, but apparently without sufficient reason, he regards this
form as a special variety. For a few hours before and during the early stage
of the paroxysm very few parasitic forms of any kind are to be found in the
circulating blood, and at this period they may be entirely absent, in marked
contrast to quartan infection. During this period the presence of pigmented
leucocytes in the blood may aid in the diagnosis. In tertian infections an
analogous condition is found, but not in the same degree. The disappearance
of the parasites from the blood is believed by most authorities to be due to
their deposition in internal organs, especially the spleen and the bone
marrow, and is attributed to the profound changes in the red blood corpuscles

503 MALARIA

containing them, these changes rendering the corpuscles virtually foreign
bodies which, like other foreign particles, are caught and retained especially
in the spleen and tlie hone marrow.

Blood withdrawn by puncture of the spleen at this time will, with rare
exceptions, show abundant intraeorpuscular and free round bodies with
central or peripheral pigment, and also segmenting forms. In certain
cases segmenting forms are few in the spleen, but abundant in certain other
internal organs, as has been shown by postmortem examinations. These
sporulating bodies are smaller than those of the quartan and tertian parasites,
and occupy, as a rule, only a relatively small part of the corpuscle, which is
always altered in appearance, being shrunken and brassy colored or more
frequently decolorized. They may appear to be free or may be actually free.
In pernicious cases they are present in large, often enormous, numbers in
the internal organs, especially in the spleen and bone marrow, and in some
types of pernicious fever in the capillaries of the brain and in those of the
intestinal mucosa. This varied distribution of the parasites in internal
organs is in relation with the tj'pes of pernicious fever. The stage of sporu-
lation occupies a rather long period and takes place in successive groups.
This circiunstance is believed to explain the long duration of the paroxysm
in aestivo-autumnal fevers. In pernicious cases sporulation seems to be
going on continually in the vascular areas of certain internal organs.

In aestivo-autumnal infections the process of sporulation is in general
similar to that of the tertian parasite, but it is more irregular and variable
and the spores are much smaller. The number of spores formed by a seg-
menting aestivo-autumnal organism is extremely variable. There may be
not more than six to ten spores, or even fewer ; often there are ten to twenty,
and the number may exceed thirty. Some segmenting forms are much larger
than others. Golgi has observed exceptionally very large ones containing as
many as forty to fifty spores. There are slight differences often to be ob-
served in the finer structure between the aestivo-autumnal spores and those
of the quartan and tertian parasites, as will be described when we consider
the intimate structure of the malarial parasites.

The young hyaline bodies of the new generation may be found in the blood
in the early part of the paroxysm, but often they do not make their appearance
until several hours after the beginning of the paroxysm or during its decline.

Not all of the aestivo-autumnal amoebae develop pigment. Sporulation
may occur in bodies, usually of small size, entirely devoid of pigment. As
a rule in these cases both pigmented and unpigmented forms occur, but cases
of aestivo-autumnal malaria have been observed, especially in tropical cli-
mates, in which only unpigmented bodies could be found at any stage of the
fever before the appearance at a later period of ercscentic bodies which always
contain pigment.

MALARIA 503

As has already been mentioned (page 487) Grassi and Feletti regard the
parasites which do not develop pigment as belonging to a distinct variety
{Haemamoeba immaculata) , but it is difficult to reconcile this view with
the frequent association of pigmented and unpigmented forms, the frequent
transitions from one to the other as regards tlie quantity of pigment de-
veloped, and the absence of any points of distinction other than the presence
or absence of a variable, but generally small, amount of pigment. Still
further researches, especially of the grave tropical malarias, may perhaps
demonstrate the existence of a distinct unpigmented variety of the parasite.

There is considerable uncertainty as to the length of the cycle of develop-
ment of Haematozodn falciparum. This uncertainty is due to the manner
of development of the parasite, usually in multiple groups, in the internal
organs, the most characteristic reproductive phases being absent from the
circulating blood. So far as one can judge from the study of these phases
in connection with the different tv'pes of fever with which they may be asso-
ciated, the length of the cycle of development may vary from twenty-four
hours or less to forty-eight hours or more.

Haematozodn falciparum may be associated with t}'pical quotidian fever
or with tertian fever, and in some of these cases the blood shows apparently
only one group of organisms. As already mentioned, Marchiafava and Big-
nami believe that there are two distinct varieties or subvarieties of the
aestivo-autumnal parasite, the one a true quotidian organism, with a cycle
of twenty-four ho\irs' duration, and the other their so-called malignant or
summer-autumn tertian variety, with a cycle of forty-eight hours' duration ;
and this division has been accepted by some other authors. This distinction
is based mainly upon the apparent duration of the cycle of development —
in the quotidian about twentj'-four hours, and in the malignant tertian
fortj'-eight hours, more or less — but there are claimed to be other difEerences
of a minor character relating to the pigmentation, the size, and the amoeboid
movements of the organisms." The differential diagnosis is said to be pos-

^' The following are the biological and morphological differences between the
aestivo-autumnal quotidian and malignant tertian parasites, according to Mar-
chiafava and Bignami (On Summer-Autumn Malarial Fevers, translation, p. 83,
The New Sydenham Society, London, 1894): Duration of cycle development in
the quotidian, about twenty-four hours, in the summer tertian, forty-eight hours,
more or less; in the quotidian sporulation on rare occasions is completed before
the amoebae have become pigmented — this is not observed in the summer tertian;
the fine granules of pigment in the periphery of the summer tertian are some-
times endowed with oscillatory movements — this is not noticed in the quotidian;
in the same relative stage of development the tertian amoeba is usually larger
than the quotidian, the adult pigmented tertian forms may be one-third of the
size of the red blood corpuscles, and the forms of segmentation may be one-half or

504 MALARIA

Bible only with the adult forms. The ditfereiitial characters claimed to exist
between the quotidian and the tertian varieties of the aestivo-autumnal
parasite arc, for the most part, only such as one would expect with a
malarial parasite developing more rapidly in some cases than in others, and
they, at least so far as at present formulated, scarcely suffice for a distinction
into two well defined varieties.

Thayer and Hewetson, while confirming Marchiafava and Bignami's
recognition of quotidian and tertian fevers caused by the aestivo-autumnal
parasite, emphasize the occurrence of intermediate types of fever, and in
general the essential irregularity of the fevers caused by this organism.
They were unable to distinguish any morphological or biological differences
between the parasites associated with these various types of fever. Although
unwilling to commit themselves to a positive conclusion, they are " inclined
to believe that the irregularity of the febrile manifestations is due chiefly
to the tendency on the part of the parasite to irregularities in the length of
its cycle of development (this variability being dependent, perhaps, upon
the malignity of the organism or upon the resistance of the individual
affected) ; to the fact that the period of time required for the sporulation of
one group of organisms is materially greater than in the regular infections,
owing to the fact that the arrangement of the parasites in definite sharp
groups, sporulating nearly at the same time, is much less distinct than in
the tertian and quartan intermittents ; to the fact that, frequently, organisms
in all stages of development are present at one time, segmentation occurring
almost continuously." "

Golgi also considers that Marchiafava and Bignami's division into quoti-
dian and tertian aestivo-autumnal organisms is based upon insufficient
evidence, and that the duration of the cycle of development of the aestivo-
autumnal parasite is indeterminate, or at least has not as yet been accurately
ascertained. This cycle is probably, he thinks, longer than is supposed by
Marchiafava and Bignami. This form of parasite, according to Golgi, is
characterized by the fact that it develops entirely in the internal organs, and
that the forms, chiefly of the earlier stages of development, which appear in
the circulation, although they are found there at certain periods of the dis-

two-thirds of it; in the tertian the amoeboid movements are maintained longer,
even in the adult pigmented forms, and the motion is more lively than in the
quotidian during the pigmented phase; the duration of the non-pigmented amoe-
boid phase in the tertian is relatively long and may exceed twenty- four hours; the
young forms of the new generation in the tertian usually appear in the blood
several hours after the beginning of the paroxysm, which is much later than in
the quotidian.

"Op. cit., pp. 151. 153.

MALARIA 505

ease in practically all cases, are, in a sense, accidentally present in this situa-
tion, being washed into the circulation from tlieir foci of development, as
nucleated red blood corpuscles may be conveyed from the bone marrow into
the blood current in certain anaemias. Golgi at first thought that the fonns
present in the circulation degenerate, but he does not now deny that they
mav lodge in internal organs and there develop into segmenting organisms.
Marchiafava and Bignami with much reason vigorously contest Golgi's
conception of the " accidental " nature of the presence of aestivo-autumnai
organisms in the circulating blood, although they also believe that a large
part of the parasites develop wholly in the internal organs, and that sporula-
tion occurs only most exceptionally in the circulating blood.

The two most important and original points in Golgi's doctrine concern-
ing the aestivo-autumnai parasite are that groups of the parasitic organisms
are variously distributed in vascular areas in the internal organs, and there
develop more or less independently of each other, " with relative stability,"
and that a large number of the organisms develop within leucocytes, endo-
thelial cells, and other tissue cells. All phases of development, according to
Golgi, are found within these cells. The spleen and the bone marrow are
situations preferred by the parasite, but the capillaries of the liver, of the
brain, of the lungs, of the intestinal mucosa, may also contain them enclosed
within cells.

A. Monti " has recently described these intracellular forms in pernicious
malaria, and he confirms the observation of many others that cells containing
parasites frequently degenerate and die. He finds apparently intact parasites
not infrequently within cells, particularly endothelial cells.

It is contended by Marchiafava, Bignami, and Bastianelli that the intra-
cellular inclusions of the parasite, upon which Golgi bases his doctrine, are
simply the well known phagocytic phenomena, and that such enclosed para-
sites belong chiefly to the later stages of development ( presegmenting and
segmenting bodies and spores), and that, instead of developing, they de-
generate within the cells. The young amoeboid bodies, which, according to
Golgi's doctrine, should be frequently found within cells, they found only
with comparatively infrequency within phagocytes, and then almost always
within their corpuscular hosts, which had been swallowed by cells. They
admit the possibility of some development of intracorpuscular parasites
which have been taken up by phagocytes, but not of free parasites within
cells.

As with the other varieties of the malarial parasite, the aestivo-autumnai
do not all mature and segment. Extracorpuscular forms are common, and

"A. Monti: BoUettino della Societa medico-chirurgica di Pavia, 1895.

506 MALARIA

it is iiioro particularly these forms, deprived of the protective covering of the
red blood corpuscles, which degenerate. Adult and preseginenting bodies
and bodies of the crescentic phase frequently become swollen and pale or
vacuolated or fragmented, or throw off buds, or present other degenerative
changes which have been described.

Phagocytism in the aestivo-autumnal, as in all malarial infections, is a
phenomenon of much importance, as will be subsequently explained.

The frequency with which two or more groups of parasites in different
stages of development are found in aestivo-autumnal infections has already
been repeatedly emphasized. Marchiafava and Bignami believe that even
in tlie pernicious fevers tliere are not generally present more than two groups
of the aestivo-autumnal parasite, and that the short cycle of development and
the prolonged period of sporulation suffice to explain the simultaneous pres-
ence of parasites in notably different stages of development. Combined in-
fections with the aestivo-autumnal parasite and one of the other varieties
occasionally occur.

It is important to bear in mind the discrepancy which characterizes
aestivo-autumnal malaria between the number of parasites in the blood and
the number in the internal organs. In the majority of cases the more severe
the infection the greater the number of parasites found in the circulating
blood, but there are so many exceptions to this that the number of parasites
in the blood cannot be considered a trustworthy index of the number within
the body. Pernicious cases have been repeatedly observed where tlie splenic
blood examined during life or the internal organs examined after death
contained enormous numbers of aestivo-autumnal parasites, although the
blood of the finger showed very few. The organisms may be few even in the
spleen when they are abundant in the cerebral capillaries or in some other
situation. As will be explained subsequently, the varying s}Tnptoms and
types of pernicious malaria can be explained in large part by the varying
distribution of the parasites in internal organs.

It is evident from the description which has been given of the aestivo-
autumnal parasite that this variety is characterized especially by its great
activity in multiplication, and it will appear from the consideration of the
clinical features of the infections caused by this parasite that other most
important characteristics are its virulence, greater than that of other varie-
ties, and its greater resistance to quinine.

There is a group of bodies of crescentic, fusiform, oval, or round shape,
presenting certain common and peculiar characters, which develop only from
Haematozoon falkiparum. The crescents are the most typical of these
bodies, which may be designated, therefore, as bodies of the crescentic (or
semilunar) phase or group. They merit special consideration.

MALARIA 507

Bodies of the Crescentic Group. — When a malarial fever caused by Haema-
tozoon falciparum has lasted a week or more bodies of the crescentic or
semilunar phase are likely to appear in tlie blood. They are very rarely
found in the blood in the latter part of the first week. If the fever is treated
with sufficient doses of quinine during the early part of the first week, cres-
cents do not appear, but the administration of nuinine after the fever has
lasted much longer than a week does not prevent their appearance. They
may persist in the blood two weeks or more after all other forms of the para-
site have disappeared. In such cases they are often unassociated with any
febrile manifestations or any symptoms which can be definitely referred to
their presence. If a relapse of tlie fever occurs, then the young hyaline
bodies already described are always present. The crescents themselves are
very resistant to the action of quinine. Councilman in 1887 called attention
to the occurrence of crescentic bodies as characteristic of the irregular and
remittent forms of malarial fever and malarial cachexia.

There was for a time much doubt as to the origin of the crescents, but
JIarchiafava and Celli's demonstration in 1886 of their intracorpuscular
development has been abundantly confirmed by the later studies of Canalis,
Bastianelli and Bignami, and others. The early intracorpuscular stages of
development of the bodies of the crescentic group are rarely seen in the cir-
culating blood, except in certain pernicious cases, but they can often be
found in the splenic blood. Bastianelli and Bignami have found these early
phases so abundantly in the bone marrow that they consider that they de-
velop by preference in this situation.

Certain of the intracorpuscular spherical forms of Haematozoon falci-
parum with collected pigment granules, instead of continuing their regular
cycle of development into segmenting forms, are transformed into the young
bodies of the semi-lunar phase. Tliis transformation takes place only after
a number of febrile paroxysms ; that is to say, only after the parasite has
repeatedly passed through its regular sporulating cycle of development.

The young bodies of the crescentic group occupy perhaps one-quarter of
tJie red corpuscle. Their shape is round, oval, or fusiform. They present
a characteristic homogeneous, refractive appearance, being more refractive
than the presegmenting bodies with central blocks of pigment. They con-
tain dark pigment, usually in the shape of fine rods, sometimes collected in
a mass, but oft«ner irregularly distributed. In the fusiform bodies the pig-
ment is often arranged along the longitudinal axis of the spindle. The
haemoglobin is frequently retracted into a denser stratum around the bodies.
These bodies increase in size without a correspondingly large increase in the
amount of pigment, and, as will be explained later, without a corresponding
increase in their chromatic or staining substance — a point which distin-

508 MALARIA

guislics the direction of cresceiitic development from thut of the regular
sporuliiting development.

It is some time after these young semilunar bodies have begun to form in
the bone marrow and spleen before the adult crescents appear in the circulat-
ing blood. These completely developed typical crescents are on the average
8-10 fi long, and in the middle 2-3 ft broad. They do not often exceed in
length one and a quarter or one and a half times the diameter of a red
corpuscle. They present a characteristic, homogeneous, refractive appear-
ance. An outer double-contoured border can sometimes be seen, especially
after treatment with certain reagents, and this is interpreted by Laveran,
Mannaberg, and many authors as evidence of a distinct enveloping mem-
brane ; but the weight of evidence is opposed to the view that the crescents,
any more than any other form of the malarial parasite, possess a membrane
other than that which pertains to the enveloping red corpuscle. The outer
refractive margin of the crescents, as pointed out by Antolisei and Angelini —
who interpret it as a cuticular envelope derived from the red blood cor-
puscle— may be slightly colored by haemoglobin, and it may show evidence
of this presence of blood coloring matter by the staining with eosin. On the
typical crescent shaped forms a fine line can often be seen stretching like a
bow across the concavity, its attachment at each end being within the ex-
tremities of the horns. This line is derived from the red blood corpuscle
within which the crescent has developed, and represents the outer contour
of the partly or completely decolorized corpuscle. This contour of the
corpuscle can sometimes be detected also on the convexity of the crescent,
and parts of the corpuscle still containing haemoglobin may occasionally be
seen on the margin of the crescent, or the whole crescent may be surrounded
with haemoglobin containing corpuscular substance. Similar evidences of
the partly or completely decolorized enveloping blood corpuscle can fre-
quently be seen on the margin of the round and oval bodies.

Bodies of the creseentic group are always pigmented. The pigment is
very dark in color, often black, and mostly in fine rods. In the typical cres-
cents the pigment, which is without movement and in fine rods and grains,
is usually collected in the middle, sometimes in a single clump or in two
clumps, often in a coronal shape. Mannaberg emphasizes the frequency
with which the pigment is arranged in two adjacent clumps near the centre,
presenting a figure-of-8 shape. In the immature crescents the pigment is
often scattered, or is arranged longitudinally, as it often is in the fusiform
bodies. The amount of pigment varies ; it is often considerable. In certain
pernicious fevers young crescents with scattered pigment may be abundant
in the blood. In the oval and round bodies the pigment is usually con-
centrated in the centre, often in the form of a circle, but it may be distributed

MALARIA 509

througliout the body. Ovoid, round, and fusiform bodies may be changed
into typical crescents, and, on the other hand, crescents may change into
fusiform, oval, ajid round bodies. The appearance of a fusiform or ovoid
body may be presented when a crescent is seen from the convex side.

From the round bodies flagellate forms may develop in the manner already
described. The aestivo-autumnal flagellate bodies develop only from round
bodies of the crescentic group. They are smaller than the tertian flagellates,
resembling rather the quartan. The process of transformation of crescentic
bodies into oval and round forms, and the development of flagella from the
latter, can sometimes be observed in studying tlie fresh blood microscopically.
Councilman once observed a rapid imdulatory movement of a body present-
ing the general appearance of a crescent.

Crescents and the other bodies belonging to the same phase not infre-
quently become vacuolated or contain or throw off from the margin little
hyaline balls (pseudo-gemmation), or disintegrate or present other degen-
erative changes. Danilewsky has observed crescents of unusually large size,
as much as 20-23 ix long and 4-6 ^ broad.

The biological significance of the crescents is unknown. These bodies do
not belong to the regular sporulating cycle of development of the parasite,
and there is no positive proof of their capacity for further development.

Dr. Thayer in a personal communication to the writer reports a valuable
experiment made by himself which demonstrates the incapacity of crescents
when inoculated into the blood of healthy individuals to develop or to cause
any symptoms. The blood was taken from a patient who had had acute
aestivo-autumnal fever, which was arrested by administration of quinine.
Crescents persisted in the blood. For seven days the blood was examined
without finding hyaline bodies or any form of the malarial parasite other
than crescents. Seven days after the disappearance of the hyaline bodies
a hypodermic syringeful of blood containing crescents in considerable num-
ber was withdrawn from the median basilic vein of the patient and imme-
diately injected into the corresponding vein of a healthy man. No elevation
of temperature or other sj-mptoms followed the injection, nor did crescents
or any parasitic forms make their appearance in the blood, which was
examined daily for two weeks and at intervals for over a month. In the
inoculation experiments of Gualdi and Antolisei and others in which it is
stated that the blood contained only crescents and infection with Eaemcv-
tozobn falciparum followed in the inoculated individual, it is probable that
hyaline bodies were present in the blood used for the inoculation in such
small number that they escaped detection.

The following are the principal views which have been advanced regarding
the interpretation of the crescents :

510 MATERIA

1. Laveran regards the crescentic bodies as encysted forms from which the
flagella develop. There is no proof that these bodies are encysted.

2. Canalis and Antohsei and Angelini believe that they have found evi-
dences of sporulation in the crescents and the ovoid and round bodies be-
longing to the crescentic phase. Grassi and Feletti and Sacharoff likewise
believe that these bodies may sporulate. Golgi considers them capable of
reproductive development in long cycles, and brings them into special rela-
tion with relapses and with fevers of long intervals. Host observers have
been unable to find genuine sporulation or other evidences of reproduction
in these bodies.

3. Grassi and Feletti consider that the crescents belong to a separate
species which they call Laverania, and of which they represent a regular
phase of development. The sporulating hyaline bodies with which the
crescents are usually associated constitute, according to these writers, dif-
ferent species. This view is not generally accepted, and is opposed to the
observed facts.

4. Mannaberg regards the crescents as encysted syzygies formed by con-
iugation of two aestivo-autumnal parasites and capable of reproduction by
segmentation. His view is unconfirmed by any other obsen-er, and is im-
probable. It fails to explain the ovoid and round bodies which belong to
the same phase of development, and it cannot be reconciled with the appear-
ances noted in the steps of development of the crescents, as has l>een shown
by Bastianelli and Bignami.

5. Councilman suggests that the crescents may he of the nature of spores.
Several authors have called attention to a resemblance between these bodies
and the falciform spores of coccidia, but there are such essential differences
between the two that the apparent resemblance is only of the most sujjerficial
character.

6. Bastianelli and Bignami have described the crescents as deviate and
sterile forms. This has been interpreted to mean that they regard the cres-
cents as degenerative forms — a view held by Kruse and some others — but
in their latest publication "^ they suggest that these bodies are a rudimentary
phase of a second developmental cycle which cannot be completed within
the human body, but requires for its continuation some new environments
in the outer world. They call attention to the occurrence of two cycles of
development in several unicellular parasites, especially the coccidia, which,
after passing through several generations in the ordinary parasitic life,
enter upon forms belonging to a second cycle. The forms of this second

"Bastianelli and Bignami: Studi sulla Infezione Malarica, Bullettino della R.
Accademia Medica di Roma, Anno XX, 1893-94.

MALAEIA 511

cycle remain sterile, degenerate, and die, unless the parasite can escape
from its host and find its appropriate new conditions of life. Manson inde-
pendently also has advanced the hypothesis that the crescents are intended
for the continuance of the life of the species in the external world. It has
already heen mentioned that a similar view has been suggested also regard-
ing the significance of the flagellate bodies, and that JIanson believes that
the mosquito may serve as the host for this second cycle of development.

DIFFEREXTIAL DIAGXOSIS OF THE VARIETIES OF THE MALARIAL PARASITE

An inexperienced observer may possibly mistake for the unpigmented
intracorpuscular hyaline forms of the malarial parasite the vacuoles which
occasionally are present within red blood corpuscles or the clear spots which
may result from certain deformities in the shape of the corpuscles. These
vacuoles and clear spots may be distinguished in the fresh specimen by their
sharp outlines, the absence of amoeboid changes of shape and difference in
refraction often suggestive of an empty space or hole, and which can be
described less readily than it can be appreciated by actual observation. The
absence of definite staining readily distinguishes these vacuoles from the
hyaline bodies of the parasite in stained specimens.

There are occasionally seen in red corpuscles in stained specimens of the
blood, especially in anaemic conditions, small stained dots which do not bear
much resemblance to forms of the malarial parasite, but which should be
known to the observer in order to avoid the possibility of mistake. They are
believed by some to be the result of degenerative changes in the corpuscles,
and by others to be remnants of nuclear chromatin derived from the orig-
inally nucleated condition of the red corpuscle.

Blood plates can be mistaken only for free spores or very small extra-
corpuscular hyaline bodies. In general no attention should be paid as
regards diagnosis to bodies free in the plasma which resemble blood plates.
In fresh specimens it is practically impossible to diagnose free spores with
any certaint}'. Clumps of blood plates have been mistaken for sporulating
bodies, but they can be readily distinguished from the latter by the absence
of pigment.

For the sake of convenience the principal characters which enable U9
to distinguish each of the three varieties of the malarial parasite, and which
have already been described in detail, will here be summarized. For modi-
fications and amplification of these general statements the reader must
consult the detailed descriptions already given.

1. Duration of the Cycle of Development. — In the quartan parasite,
seventy-two hours; in the tertian, forty-eight hours; in the aestivo-autum-
nal, irregular, varying from twenty-four hours to forty-eight hours.

512 MALARIA

2. Amoeboid Hyaline Bodies. — In their earliest stages often indistin-
guishable from each other. Later, those of the quartan parasite, sharply
outlined, somewhat refractive, sluggishly amoeboid, with development of
dark brown or black, relatively coarse pigment granules, which have but
little motion. Amoeboid movements cease in a relatively early stage of
development of the pigmented hyaline body.

Those of the tertian parasite, pale and indistinct, actively amoeboid,
with development of reddish brown, actively motile, relatively fine pigment
granules, which tend to accumulate in the bulbous swellings at the extrem-
ities of the delicate branching pseudopodia. Amoeboid movements continue
in late stages of development of the pigmented amoebae.

Those of the aestivo-autumnal parasite, small, somewhat refractive, in
repose ring shaped, actively amoeboid, with development of a few very fine
dark reddish brown or black, only slightly motile, pigment granules, or
sometimes without pigment throughout all phases of the sporulating cycle
of development.

3. Fullij Developed Hyaline Bodies. — Those of the quartan parasite are
somewhat smaller in size than the normal red blood corpuscle, and are
usually surrounded by a border of the colored refractive substance of the
enveloping red blood corpuscle.

Those of the tertian parasite attain the full size of a normal red blood
corpuscle and lie in swollen decolorized red blood corpuscles. Swollen,
extracorpuscular, transparent bodies with dancing pigment granules are
common.

Those of the aestivo-autumnal parasite do not generally exceed one-
quarter to one-third the size of the red blood corpuscle. The enveloping
corpuscle is often shrunken and brassy. They contain much less pigment
than the quartan and tertian forms, and sometimes none at all.

4. Presegmenting Bodies. — In the process of collection of the pigment
into a mass or block in the centre or excentrically, the pigment granules
often assume a more regular stellate arrangement in the quartan than in
the tertian forms. The differential points between the three varieties in
this stage relate to the same differences in size, in the amount of pigment,
and in the condition of the infected corpuscles as have been mentioned
under the preceding heading. The presence in the blood of quartan and
tertian presegmenting bodies is associated with that of sporulating forms,
whereas with the aestivo-autumnal presegmenting bodies sporulating forms
are almost always missed in the circulating blood.

5. Sporulating Bodies. — Those of the quartan parasite in equal propor-
tion in the peripheral and the splenic blood. They are somewhat smaller
than in the red corpuscles, and present typical rosette forms with a division

MALARIA 513

into six to twelve ovoid or pyriform segments, each segment becoming au
oval or round spore containing a bright nucleiform dot.

Those of the tertian parasite are more numerous in the splenic than in
the peripheral blood. They are as large as the red blood corpuscle, and
present less regularity in segmentation than the quartan parasite. They
segment usually into from fourteen to twenty spores, which are a little
smaller and with less distinct nucleiform dot than those of the quartan
organism.

Those of the aestivo-autumnal parasite are found only most exceptionally
in the circulating blood in ordinary cases. They are abundant in certain in-
ternal organs, including, as a rule, the spleen. They do not generally exceed
one-third to one-half the size of the red blood corpuscle. They segment irreg-
ularly, the number of spores being sometimes six to ten, sometimes ten to
twenty or even more. The spores are smaller than those of the quartan and
the tertian parasites. The stage of sporulation is a prolonged one.

6. Behavior of the Infected Corpuscles. — These often become somewhat
shrunken and deeper in color in the quartan infections ; swollen and decolor-
ized in the tertian; and shrunken and brassy, sometimes with retraction
of haemoglobin from the outer part of the corpuscle, in the aestivo-
autumnal.

7. Crescentic Bodies. — Crescents and bodies of the crescentic phase appear
only in infections with the aestivo-autumnal parasite.

8. •pigmented Leucocytes. — Most abundant during and shortly after the
paroxysm, they usually disappear during the period of apyrexia in quartan
and tertian infections, whereas it is not uncommon to find them in all
periods of aestivo-autumnal infections.

The Intimate Strdctdee of the Malarial Parasite

The first systematic study of the finer structure of the malarial parasite
was made by Celli and Guamieri (1888-89). This was followed by similar
investigations by Grassi and Feletti, Eomanowsky, Sacharoff, Mannaberg,
Antolisei, and Bastianelli and Bignami. The small size and the but slightly
differentiated appearance of most forms of the parasite, and the difficulty of
obtaining clear differential stainings, obscure the insight into their intimate
structure.

Little detail of structure can be made out in unstained specimens. The
substance of the parasite presents in general a homogenous, colorless, hya-
line appearance. In the amoeboid hyaline bodies of the quartan and tertian
parasites, particularly in the larger forms, an area of variable size in the
centre, or more frequently exeentrically placed, may sometimes be differ-
entiated by its clear, pale appearance from the more refractive outer zone.

514 MALuVIlIA

This area corresponds to the unstained structure interpreted by many
observers as the nucleus in stained specimens. Occasionally two or more
such clear spaces can be seen. Sometimes in the larger amoeboid and the
mature forms a finely granular appearance of the protoplasm can be detected.
It is particularly characteristic of the aestivo-autumnal parasite that the
young intracorpuscular hyaline bodies show, when at rest, a clear space
surrounded by a ring of protoplasm, usually thin and delicate on one side
and thicker on the other. This clear space appears unstained on stained
specimens. The mature forms in which the pigment has collected into one
or more clumps appear uniform in structure in fresh specimens, or may per-
haps present a slightly granular appearance. Within the spores, especially
distinctly in those of the quartan parasite, a bright body can often be dis-
tinguished, which represents the nucleus or a nucleiform material.

The methods for staining the parasites are described under " Diagnosis,"
(page 139, Vol. I, " Syst. Tract. M." [Loomis], 1897). These methods
are useful, not only for the study of the finer structure, but also for the ready
detection of the unpigmented young hyaline forms, particularly of the
aestivo-autumnal parasites, which may, vvithout very careful observation,
escape recognition on fresh specimens, whereas the presence of pigment at
once attracts attention in the fresh specimens to the other parasitic forms.
On suitably stained specimens the intracorpuscular young hyaline bodies
show a stained outer part, an unstained, usually excentrically placed, in-
ternal part, and one or more deeply stained round or elongated particles
situated, as a rule, near the border of the stained and unstained parts. The
constant unstained part is not to be confounded with vacuoles which may
occasionally be present. There have been various interpretations of the struc-
tures thus differentiated. Celli and Guarnieri designated the stained part as
ectoplasm and the unstained part as endoplasm. The deeply staining parti-
cles they interpreted as the beginning differentiation of a nucleus, which they
thought they could recognize in larger forms as a definite, stained or pale
body within the endoplasm. Grassi and Feletti do not recognize a dirision of
the protopla.'^m into ectaplasm and endoplasm, and in this they are followed
by most observers. The clear unstained part they interpret as a relatively
large, vesicular nucleus, and the deeply staining particles as nucleoli from
which may proceed a delicate reticulum of chromatin connecting them
with the nuclear membrane which they assume to exist. The rest of the
bladder-like nucleus is filled with clear nuclear juice. Although not all of
these detjiils in the structure of the nucleus, such as the membrane and the
reticulum, have been observed by subsequent investigators, Grassi and
Feletti's interpretation of the unstained part as a nucleus and of the deeply
staining particle as a nucleolus or a concentration of nuclear chromatin has

MALARIA 515

been adopted by Celli and Sanfeliee, Komaiiowsky, SaiharofT, aud Maiiiia-
berg, and has been widely accepted.

Bastianelli and Bignami, while not denying that this interpretation is
applicable to the quartan and tertian amoebae, adopt a different view as to
the structure of the aestivo-autumnal amoebae, which they have studied
with great care. They differentiate in the latter an outer colored, chromatic
cytoplasm in the form of a stained ring, usually thicker on one side, and an
inner uncolored, achromatic cytoplasm, which is all of the clear part en-
closed by the ring. The deeply staining chromatic particle they find in the
chromatic and not in the achromatic cytoplasm. Often there are two par-
ticles, each at opposite points in the ring. This particle is the only repre-
sentative of nuclear material in the parasite, and they interpret it as ful-
filling the functions of a nucleus. They consider that the rapidity of
development and multiplication of these aestivo-autumnal parasites prevents
the formation of a definite nucleus in a resting stage, such as is described for
the quartan and tertian forms.

According to Grassi and Feletti and Romanowsky, the nucleus and nu-
cleolus can be found in all stages of the regular cycle of development of the
parasite. The nucleus divides directly — or, according to Romanowsky, by
karyokinesis — to form multiple nuclei just before sporulation, each nucleus
then entering into the structure of a spore.

The evidence, however, is in favor of the view that at a certain stage of
development the nucleus and the nucleolus disappear as differentiated struc-
tures, the latter to reappear in multiple form shortly before sporulation.
Mannaberg was the first to demonstrate this clearly in his studies of the
structure of the tertian parasite. He observed that as the amoebid bodies
approach their mature form, and then become the presegmenting bodies,
the deeply staining particle (nucleolus) disappears, and later the clear,
previously unstained part (nucleus) stains diffusely, so that there is in this
stage no definite differentiation of structure in the parasite, although the
outer part, as a rule, stains more deeply than the central part. He, however,
speaks of the outer part, which contains pigment granules, as the " plasma
part," and the inner part, into which the pigment does not penetrate, as the
" nuclear part." He attributes the deeper and more diffused staining of the
parasite in this stage to the solution of nuclear chromatin into the proto-
plasm. The first evidence of sporulation on stained specimeiLs is furnished
by the appearance of numerous small, deeply staining granules of chromatin
in the periphery of the protoplasm. These are the forming nucleoli, which
increase in size and around each the general protoplasmic sul)stance, during
the process of segmentation, divides, so that each segment or spore is a cell
composed of a nucleiform, deeply staining body surrounded by its pro-

516 MAT^\RIA

to plasm ic envelope. In the quartan and tertian spores a clear unstained
part later is usually difTcrentiatpd around the ehrcunatin granule, and the
nucleus now resembles that seen in the young amoeboid hyaline bodies with-
in the red corpuscle.

BiU^tianelli and Bignami likewise demonstrated the disappearance of the
deeply staining nucleiform body in the forms of the aestivo-autumnal para-
site containing collected pigment (presegmenting bodies), and soon after-
ward the appearance of diffuse staining in the previously achromatic cyto-
plasm, so that in this stage no sharp differentiation of structure can be made
out within the parasite, which is richer in chromatic material than before
the disappearance of the nucleiform body. The first sign of sporulation is
the formation of multiple nucleiform chromatin granules in the periphery
and the development of spores proceeds in the manner already described,
save that the aestivo-autumnal spores are composed only of a deeply stain-
ing nucleiform body immediately surrounded by cytoplasm. The presence
of the small, clear, unstained part, which with the chromatin particle is
interpreted as the nucleus, often seen in the tertian and quartan spores, is
rarely observed in the aestivo-autumnal spores.

It is evident from this description that the spores of the malarial parasite
possess a definite structure, a most important feature being the presence of
a deeply staining body which serves the function of a nucleus. The recogni-
tion of this structure renders it possible to distinguish from genuine spores
the various pseudospores which have been at times erroneously interpreted
as phases of reproduction of the parasite, and which belong to the categorj' of
degenerative forms. Although Antolisei has described a double contour,
which he interprets as a membrane, about the spores, this observation has
not been confirmed, and the spores are to be regarded as naked, thus belong-
ing to the class of gv'mnospores. Some have objected to the designation of
these segments as spores, but this nomenclature is in accordance with that
employed by zoologists for similar bodies formed in a like manner in certain
other unicellular organisms.

It is evident from the preceding description that investigators are not
wholly agreed as to what structure in the malarial parasite shall be called
the nucleus, some applying this name to an unstained part containing the
deeply staining chromatin particle, others regarding the chromatin granule
itself as the only representative of the nucleus. There is, however, general
agreement that this deeply staining particle or body iS an essential constituent
of the nucleus, and that the presence of a nucleus or of a nucleiform body in
the parasite has been demonstrated. This demonstration fulfills the impor-
tant biological condition that something performing the functions of a
nucleus belongs to every cell capable of reproduction, and it has served to

MALARIA 517

remove any lingering doubt which may have been entertained as to the recog-
nition of these bodies as parasitic organisms

It is interesting to note that during the regular cycle of development there
is a continual increase in the amount of staining or chromatic substance
from the small hyaline body to the sporulating bodies, and that the cell
becomes multinucleated just before segmentation occurs. As the chromatic
substance is to be regarded as endowed with especial functional activity,
these changes are highly significant.

The mature crescents, as a rule, stain feebly and diffusely, or often only
at the poles, and perhaps also along the margin. Near the middle one or
two deeply stained granules, often covered up by the pigment, may be present,
but they are not constant. Mannaberg finds often a narrow stained band in
which are two or more deeply stained granules, stretching across the middle
of the crescent. Bastianelli and Bignami find that the young developing
bodies of the crescentic phase stain diffusely and less intensely than the
bodies with a central block of pigment which develop into segmenting forms.
Whereas in the forms of the parasite which develop into sporulating bodies
there is a continual increase in the chromatic substance as the bodies con-
tinue to develop, in the development of the semilunar bodies there is no
correspondingly large increase of staining substance. With rare exceptions
these observers found no chromatin granules in these developing crescentic
bodies, nor did they ever find in any body of this group those changes of
structure, such as the appearance of several chromatin granules, which indi-
cate sporulation.

Laveran, Celli and Guarnieri, and, with especial emphasis, Mannaberg,
consider that the crescents are enveloped in a double contoured membrane.
A number of other observers have also adopted this view. We do not con-
sider that any definite membrane, which can be regarded as a part of the
parasite itself, has been satisfactorily demonstrated around the crescents or
around any form of the malarial parasite. A double contour can sometimes,
but not regularly, be seen in the periphery of the crescents, but this alone
cannot be considered as proof of the existence of a membrane. The manner
in which little hyaline pieces (pseudo-gemmation) can sometimes be seen
to form at the margin of the crescentic bodies speaks against the presence of
an actual membrane.

THE MALABIAL PIGMENT

The question as to the origin of the malarial pigment, which was so long
discussed without conclusive result before the discovery of the malarial
parasite, has been definitely settled by this discovery. The pigment is
formed by the parasite out of the haemoglobin of the blood corpuscles by

518 MALARIA

what may be regarded at; a process of digestion. The pigment occurs in the
form of little jn'anulcs, which may be fine or coarse, and of distinct rods
and spicules, which may be as much as 1 fi long. Such rods often present a
certain superficial resemblance to deeply stained bacilli. The pigment
may occur in the form of extremely fine dust-like particles not easy to detect.
It may be fused into black blocks. The color varies from a yellowish brown
or rusty, reddish brown to black. Laveran speaks of fire red and even light
blue pijzmcnt, and Rosciibach observed a greenish hue of the pigment. The
malarial pigment is somewhat loosely ranked by pathologists among the
melanin pigments. The differences in the characters of the pigment be-
longing to the different varieties of the malarial parasite have already been
sufficiently described. The deposition of the pigment in the various organs
will be described under the " Pathological Anatomy " (page 83, Vol. I,
" Syst. Pract. M." [Loomis], 1898).

Since the examinations of malarial pigment by Meckel and by Frerichs
it has been known that concentrated sulphuric acid and hydrochloric acid
do not alter it, and that it disappears upon the addition of strong alkalies
and of chloride of lime. Kiener observed that the pigment is dissolved
by ammonium sulphide.

The demonstration of the origin of the malarial pigment from the blood
coloring matter at once raised the question whether, like many pigments of
haematogenous origin, it contains iron demonstrable by our microchemical
tests. A statement by Perls as long ago as 1867, that pigments in the spleen
of intermittent fever respond to the test for iron, has given rise to much con-
fusion. It is not W'holly clear that Perls examined the malarial pigment,
but, if he did, there can be no doubt that he mistook for the true malarial
pigment other pigments which are abundantly present in certain organs of
those dead of malaria, and which respond to the chemical tests for iron
(liaemosiderin). It has been shown by Neumann, Bignami, Stieda, Dock,
and others that the pigment formed directly by the malarial parasite does
not contain iron in a combination which will respond to our ordinary micro-
chemical tests for this element. This, of course, does not prove that it may
not contain iron in some combination, such as that in haemoglobin, which
cannot be demonstrated by our microchemical reactions. As has been
pointed out by the writers named, the organs of those dead of malaria,
particularly the spleen, the liver, and the bone marrow, contain a large
amount of haemosiderin, the presence of which is doubtless to be explained
by the extensive destruction of red blood corpuscles in malaria. There is no
evidence that haemosiderin is formed directly by the malarial parasite.
Marchiafava (1889), however, has advanced the hypethesis that the black
pigment may he formed not only within the malarial parasites, but also

MALARIA 519

within the leucocytes out ol' red corpuscles altered by the action of tlie para-
site. He thus explains the intense melanosis of the spleen, liver, and bone
marrow in certain aestivo-autuninal pernicious infections where the para-
sites appear only slightly pigmented. Bignami " comes also to the conclu-
sion, from his e.xtensive examinations of malanotic organs in malaria, that
the black pigment without niicrochemical iron reaction may have this
double origin, being formed either within the malarial parasite without an
intermediate haemosiderin stage or within cells out of haemosderin derived
from destroyed red corpuscles. The objection to this conclusion of Big-
nami is that haemosiderin is found in the liver, spleen, and bone marrow
very commonly in anaemias, but that the black pigment, without micro-
chemical iron reaction, which characterizes malarial infections, does not
appear under these conditions. It is possible that the malarial parasite may
produce some chemical change in the substance of the red blood corpuscle
which permits the transformation of the specifically altered haemoglobin
into black malarial pigment within certain cells of the body. This, how-
ever, is a pure hypothesis.

PHAGOCYTISM

The presence of malarial pigment in leucocytes and other cells has long
been known. Since the observation of phagocytic phenomena in malaria by
Laveran, Marchiafava and Celli, and MetchnikofF, important studies of this
subject have been made, especially by Guamieri, Golgi, Bastianelli, and
Marchiafava and Bignami." These investigations have shown that pliaga-
cytosis is a common and important phenomenon in malaria, although there is
much difference of opinion as to the interpretation of some of the observed
facts. Some assign to the phagocytes no higher role than that of scavengers
charged with the collection and removal of the pigment and debris resulting
from the activities of the malarial parasites and from the death and disin-
tegration of the parasites themselves. The amount of slag which is produced
in severe cases of malaria in the form of pigment, dead and disintegrating
red blood corpuscles, and degenerated and broken up parasites is so large
that even this ofBce of scavengers becomes an important one. But Metchni-
koff, Golgi, and some others believe that the phagocytes devour large num-
bers of intact, healthy parasites in certain phases of their development, and
that in this contest between cell and parasite is to be found the most im-
portant agency for the defence of the body. The arguments for and against

" Bullettino della Reale Accademia Medica di Roma, Anno XIX, fasc. II,
p. 230, 1S93.

"Especially valuable are the articles of Golgi, II fagocitismo nell' infezione
malarica, Riforma Medica, 1S88, and of Bastianelli, I leucociti nell' infezione
malarica. Bull, della R. Accademia Medica di Roma, 1892.

520 MAI^ARIA

this latter conception are essentially similar to those which are adduced as
to the pliapopytic theory in bacterial infections, the main difficulty being to
determine to what extent fully active and virulent parasites are taken up
and destroyed by phagocytes, and, even admitting the occurrence of this
mode of disposal of the parasites, whether or not it is the most essential
and the predominant factor in their destruction. That malarial parasites,
as well as bacteria, may perish in the blood plasma without incorporation
within cells cannot be doubted, as we have direct observations demonstrat-
ing this.

The cells which assume the functions of phagocytes in malaria are the
leucocytes, the endothelial cells of the walls of the blood vessels, and large
cells, found especially in the spleen, the bone marrow, and the liver, and
called by MetchnikotT " macrophages." Of the leucoc)'tes the large mononu-
clear, the polymorphouuclear, and the transitional forms act as phagocytes.
The small lymphocytes and the eosinophils have never been observed to con-
tain pigment or debris in malaria. Of the leucocytes it is the large mononu-
clear forms which are the most active and important phagocytes within the
body in malaria, but, as has been pointed out by Thayer and Hewetson, the
polymorphonuclear leucocytes are the ones which can be observed to be
active in the fresh blood during examination under the microscope. It is the
latter which pick up the pigment and the extracorpuscular and degenerated
parasites, and which attack the flagellated bodies in the fresh blood with-
drawTi from the body, so that there may be a notable difference between the
blood examined inunediately after its withdrawal from the body and that
examined at a later period as regards the number of polymorphonuclear
leucocytes containing foreign elements. Endothelial cells containing pig-
ment, parasites, or fragments of parasites or of red corpuscles are rarely
seen in the circulating blood withdrawn for microscopical examination ; but
the study of microscopical sections of organs of those dead of malarial in-
fections shows that the endothelial cells lining the capillaries and small
blood vessels, especially those of the spleen, bone marrow, and liver, in cer-
tain cases also of the brain, intestine, and other parts, manifests extensive
phagocytic activities. So too the macrophages, although they have repeatedly
been found in the circulating blood, arc met with chiefly in the splenic
blood and in the microscopical examination of organs of those dead of
malaria. These macrophages, which may attain an enormous size and are
frequently destitute of nuclei, and therefore necrotic, are mononuclear cells
derived probably in part from mononuclear leucocytes and certain fixed
cells of the pulp of the spleen and bone marrow. Their contents may be
varied, consisting sometimes within one cell of pigment, intact or degen-
erated parasites, and red blood corpuscles and entire smaller phagocytes.

MALARIA 521

Dock has counted as many as twenty parasites within one phagocyte in the
spleen. Under " Patholosjical Anatomy" (page S3. Vol. I, " Syst. Pract.
M." [Loomis], 1897),. will be described the appearances of these various
phagoc}'tes as seen in sections of the different organs of the body.

The foreign elements which are found within these phagocytes in malaria
are — (1) malarial pigment; (2) yellowish or reddish-yellow pigment de-
rived directly from disintegrated red corpuscles (haemosiderin) ; (3) red
corpuscles, sometimes intact, but usually more or less altered and frag-
mented; (4) malarial parasites, either free or enclosed within red corpuscles,
which are usually altered, such parasites appearing sometimes intact, often
degenerated and fragmented; (5) particles which are probably often derived
from the disintegration of parasites, but which do not present appearances
sufficiently characteristic to enable one to determine their origin. It has
already been mentioned that a phagocyte may be enclosed by a macrophage.
Leucocytes either with or without pigment may be thus enclosed. As phago-
cytes and other cells often degenerate and become necrotic and disintegrated
in malaria, it is evident that from this source may be derived material for
inclusion within living cells.

First in order of frequency are phagocytes containing malarial pigment.
In the examination of malarial blood obtained from the peripheral circula-
tion the only form of phagocyte which is to be seen with any frequency in
the perfectly fresh specimen is the melaniferous leucocj'te. Leucocytes con-
taining clearly recognizable parasites are rarely, if ever, seen in the freshly
drawn specimen of peripheral blood. Macrophages containing definite para-
sitic forms may occasionally be found in this situation. Both mononuclear
and poljTuorphonuclear leucocytes may contain the pigment, but in the
perfectly fresh specimen the former preponderate. The pigment is found
most frequently in the form of blocks and coarse granules, corresponding
to that set free by the process of sporulation, but sometimes the pigment
within the leucocytes is in fine rods and grains, such as belong to the earlier
stages of development of the parasite. The inference is a probable one that
in the latter case the leucoc}i;e may have enclosed the parasite.

As has already been stated, in the fresh blood removed from the body and
examined for a while under the microscope the poh-morphonuclear leuco-
cytes can be seen to engulf pigment and certain parasitic forms — viz., extra-
corpuscular forms, especially degenerated and fragmented forms, segmenting
form and spores, and altered red corpuscles — and especially do they attack
the flagellate bodies, as has been demonstrated by Thayer and Hewetson.
Such enclosed parasitic forms, with the exception of the spores, can be seen
rapidly to become indistinct and unrecognizable within the leucoc)i;es.
36

522 MAIoARIA

From tlic oxaniinution of llic frcsli circulating blood alone one obtains a
very inadequate conception of the extent and nature of the phagocytic proc-
esses in malaria. A fuller idea of these processes can be derived from the
study of blood witlidrawn by puncture of the spleen, where phagocytic
phenomena are far more active than in the circulating blood; but it is
especially in the microscopical examination of the organs of those who have
succumbed to a malarial attack that tlie best opportunity is ofTorded to learn
the extent of phagocytosis in malaria. Here one finds abundantly leucocytes,
endothelial cells, and macrophages containing pigment, parasitic forms and
altered red blood corpuscles.

I'arasites in their later stages of development, especially when they are
free, are frequently taken up by phagocytes — in their early stages rarely,
unless they have become extracorpuscular or the corpuscle containing them
is degenerated. Sporulating forms, and somewhat less frequently forms
with collected pigment (presegmenting bodies), are the ones most commonly
found in a recognizable condition within the phagocytes. It is stated by
Bastianelli and Bignami that the bodies with pigment blocks (presegment-
ing) are found most frequently within macrophages, and sporulating forms
within polymorphonuclear leucocytes. Pigmented amoebae they found
rarely, and rod blood corpuscles containing unpigmented amoebae very
rarely, within phagocytes. Bastianelli gives the following as the order of
frequency in which the various parasitic elements? are found within phago-
cytes: (1) pigment; (2) sporulating forms and spores; (3) red corpuscles,
normal or decolorized, containing sporulating fonus or bodies with central
pigment blocks; (4) brassy and decolorized red corpuscles containing plas-
modia (hyaline bodies in the amoeboid stage) ; (5) free bodies with central
jiigment clumps; (G) more rarely free amoebae or red corpuscles of normal
appearance containing parasites in the amoeboid stage. According to the
observations of the writer, free bodies with central pigment clumps occupy
a higher place in this scale than that assigned to them by Bastianelli.
Crescents enclosed in phagocytes may be found even in the circulating blood.
The various bodies within phagocytes often lie in an area surrounded by a
clear zone like a vacuole.

Golgi (1887-88) discovered that phagocytosis occurs in quartan and ter-
tian infections with a definite periodicity which stands in relation to certain
phases in the cyclical develo]niient of the parasite, and therefore to certain
periods of malarial fever. This is readily understood when one considers
that it is especially the free pigment and the mature and segmenting para-
sites and the degenerative forms which are taken up by phagocytes. The
pigment is liberated by the process of sporulation which, as has already been
explained, occurs shortly before and during the early stages of tlie paroxysm.

MALAEIA 523

Corresponding witli this, Golgi found that pigmented leucocytes are present
in the circulation during the paroxysm and for a short time afterward, and
that they disappear from the circulation during tlie apyrexia. This perio-
dicity in the appearance of melaniferous leucocytes and of other phagocytes
can be observed regularly in quartan and tertian infections. There are fre-
quently indications of it also in aestivo-auliininc' infections, but on account
of the irregularities in the cyclical development of Haematozoon falciparum,
of the prolonged period of sporulation, of the frequent occurrence of multiple
groups of parasites, and of the presence at all periods of degenerated red
corpuscles, this periodicity in the occurrence of phagocytosis is often ob-
scured or is not manifest at all. Pigmented leucocytes may be found in
many cases of aestivo-autumnal infection during all periods of the disease,
although they are more nmnerous during the paroxysm and shortly after-
ward. In the severe prolonged cases they are generally abundant, and they
may persist in the circulation for several days after cure is effected. As
long as crescents are present pigmented leucocytes may be found.

Parasites which, to all appearances, are normal are found within phago-
cytic cells. What is the fate of such enclosed parasites? That many de-
generate and die cannot be questioned, for these degenerative alterations
can be directly observed in progress under the microscope in examining
fresh blood, and in studying malarial blood and tissues one frequently en-
counters evidences of this fate of the parasites. It is claimed, however, by
Marchiafava, Bignami and Bastianelli that enclosed spores, although pre-
vented from further development, may survive for a long time within leuco-
cytes and other cells, and that such latent spores may after an indefinite
period be set free and cause by their development a relapse of the fever.

Attention has already been called to Golgi's belief that tlie aestivo-
autumnal parasite may, and to a considerable extent does, develop within
the leucocytes and endothelial cells of internal organs, in ordinary cases
chiefly of the spleen and bone marrow. He adduces a number of considera-
tions in support of tliis view, but the objective evidence he and his pupil,
A. Monti, find in the detection of the frequent presence of this parasite,
apparently intact and in all stages of development, within these cells. In
opposition to Golgi, however, it is claimed by ilarchiafava, Bignami and
Bastianelli that early phases of development of the parasite are rarely seen
within the cells, and that, therefore, the much more commonly enclosed late
phases cannot have developed within the cells from 30ung parasites. Golgi
also brings to his support the observation, made by all who have studied the
Eubject, that many of the cells containing parasites degenerate and die, as is
made evident especially by the loss of their nuclei. He interprets this as
meaning that in the conflict between cell and parasite the latter often comes

524 MAIARIA

off thfi virtor. Furtlior invostigatioiis arc needed to determine to what
extent Golgi's doctrine as to the intercellular residence and development ot
Haematozoon falciparum is correct. Certainly the ^eatly preponderating
number of intact aestivo-autmunal parasites observed in examining the
organs of tliose dead of pernicious malaria are found within free red blood
corpuscles in the vessels of internal organs.

The theory of Metchnikoff that the essential factor in the resistance of the
body to the malarial parasite resides in the activities of phagocytes is opposed
by many considerations. The most important factors in determining the
gravity and the course of a malarial infection are the degree and quality of
virulence possessed by the parasite, on the one hand, and the resistance of
the individual receiving the parasite, on the other hand. There is no evidence
that phagocytic functions are in abeyance in severe and pernicious cases of
malaria. On the contrary, we find here often enormous numbers of parasitic
enclosures within phagocytes. There is no proof that spontaneous recoveries
from malaria are associated with an increase of phagocytic activity. Inas-
much as phagocytes regularly attack degenerated and fragmented parasites,
and as we know that such degenerations occur frequently within parasites
free in the plasma, it is permissible to suppose that many of the parasitic
forms found within phagocytes were already impaired in their vitality before
they were engulfed by cells. After the administration of quinine, which
directly injures the malarial parasite, a distinct increase in the number of
phagocytes has been often observed. Certainly quinine does not stimulate
the leucocytes to swallow the parasites. Here the increase in the phagocytes
must be attributed to the increase in the number of damaged parasites.

There is evidence that the blood plasma may exert a parasiticidal effect
upon the malarial organism, as well as upon other protozoa (Faggioli),
when the parasite has escaped from the protective covering of the red blood
corpuscle. The period wlien the largest number of malarial parasites are
destroyed is that of sporulation and of free spores, and it is during this phase
of the life history of the parasite that quinine acts most effectively. We
may, at least provisionally, adopt a theory to explain natural resistance to
the malarial parasite similar to that which many accept regarding resistance
to bacteria — viz. that the parasites are destroyed by parasiticidal substances
contained both in the plasma and within leucocytes and other phagocytic
cells. The substances injurious to the parasite are in the last analysis fur-
nished to the plasma by the cells, and are in a more concentrated or potent
form within the cells than in the fluids. This theory assigns to the phago-
cj^tes a higher role than that of mere scavengers. They are endowed in
especial degree with the power of destroying the parasite, but this power is
shared by the plasma.

MALARIA 525

PATHOGENESIS

The discovery of tlie malarial parasite has placed within our reach the
means of solving many problems concerning malaria which we could not
formerly even attack with any hope of success. Already we have attained a
satisfactory understanding of not a few previously unexplained manifesta-
tions of malaria, and other formerly obscure malarial phenomena have been
brought at least within the range of our comprehension. Much still remains
to be elucidated, but we cannot doubt that further studies will continue to
throw fresh light upon what remains obscure.

In the description of the symptoms and lesions of malaria attention will
frequently be called to their relations to the parasite, and in this connection
only certain salient points, relating more particularly to pathogenic proper-
ties of the parasite, require consideration.

The mere presence of the malarial parasite in the body is not sufficient to
cause symptoms. The organisms must have multiplied to a certain point
before their presence is manifested by recognizable symptoms. The bearing
of this fact upon certain malarial phenomena, more particularly upon the
varying periods of incubation as determined by experimental inoculations
of malarial blood and upon fevers with long intervals, will be considered in
the clinical part of this article.

It may be stated as a general rule, which was first formulated by Golgi,
that the larger the number of organisms present in the body the more severe
are the manifestations of the disease; but the number of the organisms is
by no means the only factor which determines the gravity of the disease.
The variety of parasite which is concerned in the infection is a factor of
fundamental importance. The quartan variety produces the mildest attacks,
the tertian is more virulent than the quartan, and the aestivo-autumnal
variety is the most virulent of all, and is the one which is almost exclusively
associated with the pernicious attacks. These variations in virulence are
best explained upon the assumption that the malarial organism produces
toxic substances of varying virulence according to the variety of parasite.
There is also clinical evidence that one and the same variety may vary in
virulence, so that, for example, some aestivo-autumnal parasites are more
virulent than others.

In seeking an explanation of the varying clinical characters of malarial
infections we have to reckon not only with the number, the varieties, and the
virulence of the parasites, but also with several other factors, such as pre-
disposing conditions on the part of the individual infected, the occurrence
of multiple groups of the parasite, the distribution of the organisms in in-
ternal parts, the circulatory and other anatomical disturbances induced by
the parasites.

526 MALARIA

Periodicity is the most striliing clinical characteristic of malarial fevers,
and the explanation of this phenomenon has exercised the minds of pyretolo-
gists from ancient times. It is true that intermittenee is not limited to
fevers of malarial origin, but regularity of rhythm in the occurrence of
the paroxysms is especially characteristic of malaria. One of the most
interesting additions to our knowledge resulting from the discovery of the
niiilarial parasite is the demonstration by Golgi, which has been abundantly
confirmed, that this rhythm in the malarial paroxysms corresponds to a
rhythm in the development of successive generations of the parasite.

The onset of each paroxysm corresponds to the ripening and sporulation
of a generation of parasites and the setting free of a new brood." Exactly
what the connection is between this act of sporulation, with the liberation
of a fresh brood of young parasites, and the cause of the febrile paroxysm,
is not definitely kno^vn. It was at first suggested by Golgi (1887) that the
paroxysm is due to the invasion of the red blood corpuscles by the new
group of parasites, but it was shown by Antolisei (1890) that the paroxysm
depends rather upon the act of segmentation than upon the invasion of the
blood corpuscles by a new generation of organisms, for quinine, administered
before a paroxysm in sufficient quantity, may, by destroying the fresh brood,
completely prevent the invasion of the red corpuscles, but it cannot prevent
the segmentation and the impending paroxysm. The view is now widely
held, and seems plausible, that in the act of sporulation and of liberation
of the spores chemical poisons are set free, and that these poisons, by their
action on the nervous centres concerned in the production of fever, cause the

^ The old idea that the periodicity of malarial fevers depends upon the period-
ical production in the blood of a materia peccans is thus confirmed. It is
interesting in this connection to note the line of argument presented by
Griesinger in his admirable and suggestive article on the malarial diseases
(Virchow's Handb. d. spec. Path. u. Therap., Bd. II, Abth. 2, 2te Auflage, p. 41,
Erlangen, 1S64) : The cause of the periodicity of the fever cannot, therefore, be
referred to the disposition of the nervous system to rhythmical vital actions, as
many have formerly done, but it must, at least according to our present although
very incomplete knowledge concerning the causes of heat, be attributed to some-
thing periodically occurring in the blood, which is connected with the increased
production of heat. It has been formerly conceived that a certain substance, a
materia peccatxs, appears periodically in the blood and incites the febrile heat
and reaction: this material requires for its production and complete development
sometimes longer, sometimes shorter, periods, and herein lies the cause of the
rhythm of the fever As an explanatory hypothesis this conception accom-
plishes more than the later attempts at explanation The continuous

morbid process which causes the poisoning incites periodically changes in nutri-
tion or in the blood which arouse the nervous apparatus to abnormal manifes-
tations.

MALAEIA 527

febrile paroxysms. This toxic theory of malaria has been elaborated espe-
cially by Baccelli.

The fact that the malarial parasite resides in, feeds upon, and destroys
the red blood corpuscles furnishes an entirely satisfactory explanation of
two of the most characteristic and important manifestations of malaria —
the melanaemia and the anaemia. The malarial pigment, for wliich we
formerly had no adequate explanation, is formed as an undigested residue
within tlie body of the parasite by metabolic processes directly out of the
haemoglobin of the infected red blood corpuscle. Various stages of the
formation of the pigment within the parasite can be seen. The liberation
of tliis pigment, its inclusion by phagocytes, its deposition in various internal
organs, liave all been described, and will be further considered under the
"Pathological Anatomy "(page 83, Vol. I, " Syst. Pract. M." [Loomis],
1897). The relations of the biological characters of the parasite to malarial
anaemias and to haemoglobinuria will be fully considered in the anatomical
and clinical parts of this article (pages 93, 116, 125, and 130, Vol. I, " Syst.
Pract. M." [Loomis], 1897).

The ways in which the red blood corpuscles may be altered by the action
of the malarial parasite are various. The extent of these changes varies
with the variety and the virulence of the parasite. They are least in quartan
infections, greatest in the aestivo-autumual. The infected blood corpuscle
may appear otherwise normal. It may be swollen or shrunken or variously
deformed. It may divide into two or more pieces. It may be partly or com-
pletely decolorized, or the haemoglobin may separate from the stroma and
be dissolved in the plasma, or may be concentrated around the parasite.
Especial significance in the aestivo-autumnal infections attaches to that
alteration in the corpuscle which has been repeatedly referred to as the brassy
change, on account of the resemblance in the color of the shrunken corpuscles
to brass, sometimes compared also to copper or old gold. Xor are the cor-
puscles which are actually infected by the parasite the only ones which may
be altered. Uninfected corpuscles may also be changed in appearance, and
may be destroyed, especially in cases of haemoglobinuria.

These changes in the red blood corpuscles, wliich must be regarded as
degenerative and destructive cannot be brought wholly into parallelism with
the development of the malarial pigment. In fact, the most profound lesions
and the greatest destruction of the red corpuscles occur in infections with the
aestivo-autumnal parasite, which is characterized by the small amount or
even the entire absence of pigment. To explain many of these chantres we
must have recourse again to the theory that toxic substances are produced
by the parasite and directly damage the blood corpuscles.

528 MALABIA

These alterations in the red hlood corpuscles not only explain the malarial
anaemias and the haemoglobinuria with their concomitant symptoms and
lesions, and the accumulation of malarial and other pigments in certain
organs, but they are utilized, although less conclusively, to explain certain
other malarial phenomena. We know from physiological observations that
the physical integrity of the red blood corpuscles is an important condition
in the maintenance of their circulation within the blood current. It is
reasonable to suppose that corpuscles as profoundly altered as are many of
those infected with the malarial parasite will circulate with difficultj-, and
will tend to accumulate in certain situations wliere local conditions of the
circulation favor the lodgement of foreign particles which get into the circu-
lation. Many writers, therefore, attribute to these alterations in the physical
properties of the infected red blood corpuscles the accumulation of the para-
sites within the vessels of certain internal organs, more particularly the
spleen, the bone marrow, the liver, and the brain, and they explain the absence
of such accumulation in quartan infections by the comparatively slight lesions
of the infected corpuscles, and the large accumulation in tertian, and still
more in aestivo-autumnal, infections by the more serious damage inflicted
upon the infected red corpuscles by the varieties of the parasite causing these
latter infections. Doubtless these factors — changes in the infected red cor-
puscles and local conditions of the circulation — are important in determining
the localization of the parasites in certain internal parts, but with our present
knowledge we cannot explain the van-ing distribution of the parasites ob-
served in different cases exclusively by their aid, any more than we can
adopt a similar explanation for the localization of the microorganisms in
other infections.

The localization of the parasites in some cases, more particularly in aestivo-
autumnal infections, within definite vascular areas of internal organs stands
in relation to corresponding symptoms and lesions. The comatose and the
choleriform types of pernicious malaria are associated with an accumulation,
which may be enormous, of the parasites in the capillaries and small vessels
of the brain and of the stomach and intestine respectively. Other special
localizations of tJie parasites will be mentioned in the subsequent part of this
article. In these cases capillaries and otlier small bloodvessels may be partly
or completely plugged with parasites, chiefly within red blood corpuscles.
Swollen, degenerated, and desquamated endothelial cells, pigment, macro-
phages, and other phagocytes contribute to this occlusion of the vessels.
Genuine thrombi also occur.

Serious disturbances of the circulation must result from such extensive
plugging of the vessels. It is not easy to determine how far these mechanical
disturbances of the circulation are responsible for svTnptoms and lesions

MALARIA 529

with which they are associated. Marchiafava and Bignami and others regard
them as the essential cause of tlie grave nervous symptoms in comatose
pernicious fever, and of other symptoms and of lesions. Many years ago
Frerichs likewise attached much importance in the causation of cerebral
symptoms to accumulations of pigment and the formation of coagula within
the cerebral vessels. It appears, howevei, to +he writer that, aside from
certain general pathological considerations and analogies with similar con-
ditions in other diseases, this mechanical explanation is inadequate, and that
here too the toxic products of the parasite are operative. The promptness
with which the grave cerebral symptoms may subside after administration of
quinine is not easilj' reconcilable with the theory that they are due to plug-
ging of the vessels.

Even the focal necroses which are common in the liver in pernicious cases,
and may occur in the spleen, the kidneys, and elsewhere, are best interpreted
as due to the toxic products of the parasite, rather than as the result, as is
claimed for the liver by Guarnieri, of plugging of the bloodvessels. These
necroses do not differ from those observed in diphtheria, typhoid fever, and
streptococcus and other infections, and that they may be purely toxic in
origin has been demonstrated by Welch and Flexner.*"

The capillary hemorrhages which have been observed in the brain in the
comatose form of pernicious fever, and which may occur elsewhere, may be
referred to the hyperaemia and stasis resulting from plugging of the vessels.
The interesting fact has been observed that in these capillary haemorrhages
the extravasated red corpuscles are without parasites, while the neighboring
bloodvessels are filled with red corpuscles containing parasites. The ex-
planation of this which is given by Marchiafava and Bignami and adopted by
others is that the corpuscles containing parasites on account of their greater
adhesiveness stick to the walls of the vessels and thus are prevented from
escaping. The writer offers another explanation as the more probable. The
examination of these small haemorrhages shows that they are the result of
diapedesis, and not of actual rupture of the vessels (rhexis). It is not diffi-
cult to comprehend that red corpuscles altered by the invasion of parasites
would not participate in the process of diapedesis, whereas it is not easy to
understand why they should not escape from ruptured vessels.

It is evident from what has been said that, while occlusion of vessels and
consequent disturbances of the circulation are common in severe malarial
affections, and are doubtless of importance in causing some of the lesions
and svTiiptoms, the more important and characteristic symptoms and lesions
are, in the opinion of the writer, with our present knowledge, better explained

" The Johns Hopkins Hospital Bulletin, March, 1892.

530 MAI^RIA

by the toxic tlieor}- of the pathogenic action of the malarial parasite than hy
any mcclianical theories whicii have yet been offered.

Wo have, however, no positive demonstration of the existence of specific
niahirial toxins. The investigations as to the toxicity of the urine of
malarial patients will be described on page 123 (Vol. I, " Syst. Pract. M."
[Loomis], 18!)7). They have not led to any positive results as to the detec-
tion of specific malarial poisons.

It is a very old conception that tlie febrile reaction of the malarial par-
oxysm is conservative in tb.e sense that this response of the body to the
presence of pyogenic agents in some way aids in the elimination or destruc-
tion of injurious .substances. This conception is not altogether without
support from tlie parasitological study of malaria. The fever begins at the
time of the birth of a new generation of parasites. These young organisms
before they have entered the red blood corpuscles are, of all phases of develop-
ment of the parasite, in the most vulnerable condition, as has been shown
by investigations of the action of quinine. That a large number of them
perish during the febrile paroxysm seems to be demonstrated, at least in
quartan and tertian infections, by the contrast between the number of
sporulating forms and the number of succeeding infected corpuscles. Espe-
cially suggestive of increased potency of parasiticidal agencies during the
febrile paroxysm are cases, especially of quartan or tertian infection, in
which, after a sharp paroxysm, tlie symptoms and the parasites disappear,
perhaps permanently, but often to return after a long interval as a recrudes-
cence of the fever (page 121, Vol. I, " Syst. Pract. M." [Loomis], 189;).

SIMILAR HAEMATOZOA IN THE LOWER ANIMALS

Great interest attaches to the presence in the blood of certain lower
animals of protozoan parasites closely resembling the malarial parasite.
Attention was first called to this resemblance by Danilewsky (1885-86),
who described more fully certain forms which were previously known, and
added the discovery of new forms, especially that of haematozoa in birds
which bear close resemblance to the human malarial parasite. Since Dani-
lewsky's first publications there have been a number of investigations on this
subject by Kruse, Celli and Sanfelice, Grassi and Feletti, Laveran, Labbe,
and others.

In the blood of frogs, turtles, lizards, and some other cold-blooded animals
haematozoa presenting some points of resemblance to the malarial parasite
are not uncommon. Of these the best studied and most interesting is
Drepanidium ranarum (Lankester), identical with Gaule's "Wiirmchen,"
in the blood of frogs. It is, however, certain haematozoa in birds which
bear such close resemblance to the malarial parasite that their identity with

MALARIA 531

the latter has been assumed by Danilewsky and Grassi and Feletti, who speak
of the existence of malaria and of malarial parasites in these animals. Most
of the observations thus far reported have come from Russia and Italy, but
the parasites have been found in birds also in Germany and France, and
recently in the United States.

In birds thus infected have been fuund forms similar to those of the
malarial parasite in man — viz. unpigmented and pigmented hyaline bodies
(which, however, in distinction from similar bodies in man, manifest little
or no amoeboid movement), sporulating forms, crescents, and flagellated
bodies. The bird's haematozoa are also parasites of the red blood corpuscles,
from which they produce black pigment: they pass through the same stages
of development as the latter, and the same diversity of views exists as to the
origin and significance of the crescents and flagellated bodies. The name
Haemopkoteus was introduced by Kruse to designate these so-called mala-
rial parasites of birds, and various other names have also been suggested.
Grassi and Feletti adopt the same names and the same classification for these
parasite of birds as for the human parasites (page 487). There are differ-
ences between the haematozoa found in different species of birds, and in the
same species apparently different varieties of the parasite have been observed,
but there are at present no definite classification and no certainty as to the
number of varieties which may exist.

Although these haematozoa of birds evidently belong to the same class of
organisms as the malarial parasite, there are several rea.sons which indicate
that they are not identical with the latter. They present certain morpho-
logical and physiological differences which it would lead too far here to
describe. Although found thus far chiefly in birds from malarial regions,
it is not proven that they may not exist in birds elsewhere. The inoculation
of uninfected birds with the blood of birds containing the parasites ha-s been,
in a large preponderance of the experiments, unsuccessful in the result.
The inoculation of birds with blood from human beings affected with ma-
laria, and the inoculation of human beings with the blood of birds containing
the haematozoa, have been uniformly without positive result (Di Mattel).
Large doses of quinine have no influence upon the parasites in birds. The
presence of the haematozoa in birds is usually without recognizable disturb-
ance of the health of the birds, although it may cause a chronic or an acute
affection. While, then, we must admit a close relationship between certain
haematozoa of birds and the human malarial parasite, the existing evidence
is opposed to their identification.

SO-CALLED PARASITIC BODIES IN EPITHELIOMA'

Under the microscope are specimens of carcinoma which show various
intracellular formations apparently identical with some, at least, of the
bodies which a number of recent observers have described as sporozoa or
similar parasites. There are also sections of an epithelioma of the penis,
made from pieces which had been placed immediately after removal in
Fleming's solution, which are particularly rich in these intracellular bodies.
These bodies correspond in appearance and behavior with coloring agents to
many of those described by Sjobring and by Siegenbeck van Heukelom.
Most of them appear as round or irregular masses, sharply differentiated
from the protoplasm of the cancer cell enclosing them by a higher refraction
index and by deeper staining with eosin and safranin. They vary in size
from minute globules to masses which occupy the greater part of the cell.
They occasionally lie in a vacuole within the cell. They sometimes contain
one or more particles which stain deeply with haematoxylin. Round or
irregular particles, staining deeply with haematoxylin, are sometimes found
within cancer cells presenting normal nuclei. Some of the inclosed bodies
are pale and do not stain deeply with any of the dyes employed, but are more
or less sharply differentiated from the surrounding protoplasm. These pale
bodies are usually about the size of leucocytes, or somewhat smaller, and fre-
quently contain nuclear masses resembling fragmented nuclei. It is not easy
to give an accurate description of all the various bodies or formations which
may be found in the cells of an epithelioma more or less sharply differentiated
from the surrounding protoplasm.

These and similar enclosures in cancer cells must be familiar to all who
have made a careful study of epithelioma and, while their nature cannot
always be satisfactorily determined, it is entirely premature and unwarranted,
on any evidence as yet brought forward, to regard them as sporozoa of other
forms of parasites.

Many of these bodies so far as flat celled epithelioma is concerned, can be
explained, (1) as masses of keratine, a part of the protoplasm having under-
gone in a circumscribed area the keratine metamorphosis, while the rest
remain granular ; (2) as irregular masses of eleidin or kerato-hyalin ; (3) as

' Report of remarks before the Johns Hopkins Hospital Medical Society, Balti-
more, October 6, 1890.
Johns Hopkins Hosp. Bull., Bait, 1889-90, 1, 97-98.

532

PARASITIC BODIES IN EPITHELIOMA 533

included leucocytes undergoing degenerative changes, with or without frag-
mentation of nuclei; (4) as scattered nuclear fragments derived from the
preceding.

Just as epithelioma is essentially an atypical growth of epithelium, so it
is not surprising to find various atypical metamorphoses of the epithelial
cells, such as partial transformation of the cell protoplasm into kerato-hyaline
and into keratine.

THE PARASITE OF CANCER'

Dr. Gaylord lias lirought before us something more than the mere descrip-
tion of the so-called cell enclosures observed in hardened specimens of cancer.
Of the enclosures hitherto described in preserved material the only ones
which present anything like a definite organization and which, it seems to me,
have not been altogether satisfactorily explained are the bodies first accu-
rately described by Thoraa and Sjobring, and subsequently noted by most
of those who have studied the subject. These bodies in English and Amer-
ican writings are often desigiiated without much propriety as " Plimmer's
bodies." No conclusive evidence that these bodies, still less that any other
of the various enclosures, are parasites, has been furnished, and it now
seems evident that no further progress in the search for parasites is likely
to be made by the examination of hardened material with our present
methods.

Under these circumstances it is important to turn to the examination of
fresh material and to make attempts to cultivate parasitic organisms, pro-
vided such exist in cancer and other malignant tumors. This direction of
study has therefore been followed in recent years by several investigators,
and it is especially his results along these lines which Dr. Gaylord has re-
ported. As regards artificial cultures, it is certain tliat no forms of bacteria
demonstrable by existing methods are directly concerned in the causation
of cancer, and, notwithstanding the stronger claims made in behalf of
Blastomycetes, I am glad to learn that Dr. Gaylord rejects these claims and
takes a position in this regard opposed to that of Sanfelice, Roncali,
Plimmer, Leopold, and others. He interprets as protozoa tiie bodies which
he regards as parasites.

Leaving out of consideration the occasional and accidental presents of
cultivable bacteria and yeasts in cancer, I question whether what is called
by Dr. Gaylord and other investigators as the cultivation of protozoa or of
sporozoa from cancers should be so designated, and it does not appear that
secondary cultures carried on from generation to generation have in any
instance been secured.

' Remarks on a paper entitled, The Parasite of Cancer with Demonstrations,
by Harvey R. Gaylord, before the Johns Hopkins Hospital Medical Society,
Baltimore, April 15, 1901.

Johns Hopkins Hosp. Bull., Bait., 1901, XII, 295-296.

634

PARASITE OF CANCER 535

There is not much agreement among different observers either in the
description or the interpretation of the various bodies regarded by tliem as
parasites to be seen in fresh cancerous material or fluids, or in such material
kept free from bacterial contamination, whether mixed with some cultural
fluid or not. Dr. Gaylord lays especial emphasis upon the presence in can-
cers and other conditions of homogeneous, yellowish, spherical bodies re-
sembling droplets of fat but without the usual reactions for fat, and he
considers that he finds evidences of multiplication of these bodies and of tlieir
passing through a definite cycle of development which he describes. He is,
I trust, prepared for a considerable degree of skepticism following this
announcement of his results, and it is desirable that this should be the atti-
tude of mind until we are in possession of more evidence than has as yet
been furnished in favor of the parasitic hypothesis. It is, however, incum-
bent upon pathologists to make a careful study of all that can be seen in
the microscopic examination of fresh, macerated, and preserved cancerous
material, and whatever else may be the outcome of such studies, they will
have furthered our knowledge of cellular degenerations and metamorplioses.
Unless there are those present who on the basis of such study are prepared to
discuss Dr. Gaylord's findings, it does not seem to me worth while to discuss
them in detail.

Dr. Gaylord has presented an instance of multiple nodules in the lungs
of an adenocarcinomatous nature following the intravenous injection of
cancerous ascitic fluid. With this exception and one or two more doubtful
cases his experimental results, so far as the reproduction of malignant
tumors is concerned, are, like those of other investigators in the same line,
nearative.

EXHIBITION OF ANIMAL PARASITES'

These parasites were collected from domestic animals in Baltimore, during
the previous two years as opportunity offered, no attempt being made to
have the collection complete. The interest in animal parasites has been
overshadowed of late years by the study of the pathogenic bacteria, but
nevertheless the entozoa are of great interest and importance and deserve
our careful attention.

1. From the horse : "

Spirojjtera megastoma (or FUaria megastoma) . The stomachs show the
honey-combed submucous tumors, with ulcerated mucosa, containing the
large-mouthed maw-worms. This parasite is not very rare in the horses of
this region, but in none of the cases in which it was found, was there evi-
dence that it had materially damaged the usefulness of the animal.

Strongylus armatus. Here are several specimens, gross and microscopical,
of verminous aneurism of the anterior mesenteric artery. The presence
of the palisade worms in the bloodvessels causes interesting histological
changes. This parasite with the resulting aneurisms is common in horses
of this region. In one instance it had caused fatal colic.

Gastrophilus equi. Here is a stomach, the mucous membrane of which
near the cardia is completely covered with bots.

2. From the cow :

Actinomyces bovis. Although this is a vegetable parasite, the opportunity
is taken to show a nmnber of specimens of actinomycotic tumors from the
jaws and other parts of the cow. On account of the absence of any satisfac-
tory laws regulating the inspection of meat in this state, the number of
cattle affected with actinomyces brought to Baltimore and slaughtered here
for the market is unusually large and there is rarely any diflieulty in pro-
curing specimens of this disease. Attempts have been made to cultivate the
organisms according to the directions given by Bostrom but without success.
No instance in which the actinomyces has been found in human beings has
been recorded.

Cystirercus taeniae mediocariellatae. This parasite was found once in the
heart-muscle of a cow.

Strongylus micrurus. A nimiber of cases of verminous bronchitis and
pneumonia in calves due to this parasite have been observed and here are
microscopical sections of the lungs so affected.

Filiaria labiaio-papiUosa (Alessandrini). This worm was found free on
the peritoneal surface of a cow without causing any apparent injury.

' Report of remarks before the Johns Hopkins Hospital Medical Society, Balti-
more, March 17, 1890.
Johns Hopkins Hosp. Bull., Bait., 1S90, I, 72-73.

536

EXHIBITION OF ANIMAL PARASITES 537

3. From the sheep :

Taenia expansa. This parasite was found in the small intestine. It is
quite common.

Stronrjylus contortus. The parasite was found in large numbers in the
stomach of several sheep which had died at Druid Hill Park without other
apparent cause of death.

4. From the hog :

Echinococcus. Echinococci were found in several hogs which had been
born and reared in the neighborhood of Baltimore, but this parasite is not
common in this region. Sections of the liver are shown illustrating every
stage of development of this bladder worm from cysts smaller than apea up
to cysts as large as an orange. Here are specimens of the taenia echinococ-
cus produced by feeding the cystic worms to a dog.

Cysticercus cellulosae. The pork measles has been found in only a few
instances.

Echinarhynchus gigas. This worm is common in the swine of this region
and appears to be common throughout the United States. The ulcerated
and necrotic patches in the inner wall of the small intestine caused by the
attachment of the thorn-headed worm, bear some resemblance to the necrotic
foci resulting from hog cholera. In only one instance had the gut been
actually perforated by this worm.

Trico-cephalus crenaius. This parasite was very common in the caecum.

Ascaris suilla, believed by many to be identical with Ascaris lumbri-
coides. It was not ven,' often met with. In one case the small intestine for
a distance of 40 cm. was found packed full of ascarides, but there were no
evidences of intestinal obstruction and it is questionable whether this accu-
mulation of the worms, so as apparently to obstruct the gut, is not a post-
mortem occurrence.

Sclerostoma pin-guicola (VerriU), believed to be identical with Stephan-
urus denafus (Diesing), although this identity is not absolutely certain.
This interesting worm was found in the abdominal adipose tissue and in the
liver. The presence and mode of migration of this parasite in the liver of
swine have not hitherto been described. Sclerostoma pinguicola was found
in the livers of eleven swine, and, while not very frequent, cannot be con-
sidered a raritv' in this situation. It is found, often in large numbers,
in the main trunk and branches of the portal vein, which then usually con-
tain parietal or occluding thrombi in which the worms are imbedded. The
real habitat of the worm is, however the connective tissue around the portal
vessels. In this tissue it burrows its way, producing inflammatory masses
of new connective tissue rich in leucoc}i;es. On section of the liver, nodules
and bands with sinous cavities containing a brownish or reddish white puru-
lent fluid are observed. Similar nodules are also visible projecting on the
surface of the liver. In these sinous cavities the parasite may be found, or
it may be absent, having made its way to other parts. The worm finds its
way into the portal vessels by ulceration from the peri-portdl tissues through
the walls of the vessels, and in several instances the worm could be demon-
strated partly without the vein. Before actual penetration into the vein
there occurs a bulging inward of the vessel wall on which forms a thrombus
composed primarily of blood platelets. One of the most interesting his-
37

538 EXHIBITION OF ANIMAL PARASITES

tological changes produced by the invasion of this parasite into the liver is
an extensive new growth of the mucous glands in the walls of the bile ducts.
This new growth occurs in the areas of newly formed connective tissue in
the neighborhood of the parasites. Actual adenomatous formations of un-
doubted parasitic origin are produced in this way. The same alteration has
been recently described and pictured by S'chaper in connection with disto-
matosis of the liver (" Deutsche Zeitschrift fiir Thiermedicin," Bd. VI,
p. 1). On section of the worms, as found in the liver, leucocytes with well
stained nuclei, resembling those in the fluid of the cavities containing the
worms, can be seen in the intestinal canal of the worm, but whether this can
be interpreted as evidence that the pus cells produced by the presence of the
worm actually serve as its food is uncertain. Sometimes the lesions of the
liver, which have been described were extensive, the surface and interior of
the organ presenting a large number of parasitic foci, and it would seem as
if such an extent of the disease must be injurious but no cases were observed
in which the death of the animal coidd l>e attributed to the presence of
Sclerostoma pinguicola. The parasite as found in the liver and as found iu
the well known foci in the abdominal fat tissue is identical. Here are instan-
ces in which the main trunk of the portal vein as it enters the liver is com-
pletely occluded by a thrombus containing the sclerostomata.

Strongyhis paradoxus. This strongvde is extremely frequent in the bron-
chi of the swine in this region. Its presence was found to be the direct
cause of death in three pigs. In these cases the trachea and bronchi con-
tained an almost incredible numlier of strongyies, so that on sections of
the lung, tlie medium-sized and small bronclii appeared tilled with worms.
Strongylus paradoxus is usually associated witli some bronchitis and often
with broncho-pneumonia, but it may be present, even in large numbers,
without either bronchitis or pneumonia. In fact in one of the fatal cases
in which the strongyles appeared to fill the medium-sized and small bronchi
and were present in enormous numbers in the trachea and large bronchi
there was no trace of pneumonia and scarcely any bronchitis. The animals
suffered from extreme dyspnoea and the heart pulsated so violently as to be
visible at a distance and to communicate its motion to the entire thorax. At
the autopsy the right ventricle was hypertrophied. The favorite habitat of
the worms when present only in moderate number is in the bronclii in the pos-
terior part of tlie caudal lobes, and sometimes their numl>er is so small that
considerable searching is required to detect them. There is usually a little
muco-pus in the thrombi where the strongyles are lodged even when there is
no general bronchitis. The adjacent lung parenchyma is often emphysem-
atous or on the other hand it may be simply atelectatic or it may be the seat
of a broncho-pneumonia. Frequently there is a broncho-pneumonia of the
ventral lobes when the worms are to be found only in the posterior parts of
the caudal lobes. The broncho-pneumonia associated with Strongijhw; para-
doxus appears as a brownish or grayish red consolidation in which the
individual lobules and lobulettes can Ije felt and seen as nodules. The
affected part is not much swollen and there is generally no pleuritic exuda-
tion. On microscopical section the air cells contain leucocytes, epithelioid
cells, sometimes fibrin and red blood corpuscles and frequently ova of the
strongyles. These ova are often partly or completely enclosed within giant

EXHIBITION OF ANIMAL PARASITES 539

cells By a combination of Weig^ert's fibrin stain and picrocarmine very
beautiful pictures in which the ova are stained blue and the cells red and
yellow with picrocarmine can be obtained. A very instructive lesson in
embryology is furnished by the ease with which all stages of development of
the ova from the simple cell up to the developed embryo worm can be fol-
lowed in these preparations.

5. From the dog:

Taenia cucurnerina. This is by far the most common tape-worm of the
dogs used for experiment in the laboratorv", being found in sixty per cent of
these animals.

Taenia serrafa. Here are specimens produced by feeding dogs Cysticen
pisiforin.es from the rabbit.

Taenia ecliinococcus was found only in dogs artificially fed with the echi-
nococcus from the hog.

Eustrongylus gigas. Here is a specimen of this worm, 95 cm. long, found
free in the peritoneal cavity of a dog. It has been found three times in this
situation in dogs used for experiment in the laboratory.

Strongylu-s of dochmius irigonocephalus (Uncinaria trigonocephala).
This parasite was found in the small intestine in seventy per cent of the
dogs used in the laboratory, a much larger proportion than has hitherto
been observed. The head of the wonu was often found imbedded in the
mucous membrane and surrounded by a small extravasation of the blood.
Sometimes scanty, it was, in many cases, found in large numbers. Positive
e%adence that the parasite was the cause of anaemia in the animals could not
be found. It was occasionally met with in the stomach as well as in the small
intestine.

Tricocephalus depressiusculu.s. This worm appears to be a constant inhab-
itant of the dog's caecum.

Ascari^ marginata (doubtless a variety of Ascaris mystax). This para-
site was found in only a few cases. It was found both in the stomach and in
the small intestine.

FUiaria immiiis. It was not met with in any of the dogs used in the
pathological laboratory and is not common in this region. It, however,
occurs here and it has been observed occasionally in the biological laboratory
of the Johns Hopkins University.

6. From the rabbit:

Coccidium oviforme. This parasite was present in one-third of the rabbits
used for experiment in the laboratory. Coccidia are also common in the
intestines of rabbits. There are small, opaque, grayish white patches, sug-
gesting somewhat a superficial necrosis, on the surface of the mucous mem-
brane of the small and large intestine. These patches contain large numbers
of coccidia, often enclosed in epithelial cells.

Cysticercus pisiformis. It is common in the peritoneal cavity. Here are
specimens which illustrate the nodules and scars caused by the migration of
this parasite through the rabbit's liver.

7. From the rat:

Cysticercus fasciolaris. It was found in the liver.

540 EXHIBITION OP ANIMAL PARASITES

8. From the cat:

Taenia drassicollis. This worm was found in the intestines.

No instance of Distoma in the animals examined was discovered and in
general distomatosis of domestic animals appears to be rare in this region.
Through the kindness of Professor Brooks, I am in possession of a number
of living water snails, many of which are infested with cercaria and living
specimens of those interesting forms in the life history of Distoma are exhib-
ited under the microscope. These snails were obtained in the neighborhood
of Baltimore, so that opportunity for infection with distomata is present
here.

INTESTINAL AND HEPATIC ACTINOMYCOSIS, ASSOCIATED
WITH LEUKAEMIA'

I. Abstract of Clinical History by Thomas S. Latimer

History. — W. H. Thomas, colored male, aged 21, single, a day-laborer,
was admitted to the City Hospital, Baltimore, November 17, 1895. The
patient claimed to have always been well until the previous eight months,
during which several attacks simulating appendicitis, but without operative
treatment, occurred. On admission he complained of headache, loss of
appetite and obstinate constipation, with frequent nose bleed, an irregular
fever, slight chills and sweats, not requiring continuous taking to bed.

Examination. — The patient was anaemic. There was slight enlargement
of the axillary and post cervical lymphatic glands. The chest examination
was negative except for a feeble heart-beat. The pulse was 120 per minute,
weak and easily compressible. On abdominal examination, no tenderness or
lump in the region of the appendix was made out. Upon repeated examina-
tion, the spleen could not be felt. His liver, however, was found greatly
enlarged, extending well below the margin of the ribs, felt smooth and firm
and was somewhat tender on palpation. No fluctuation could be foimd.
Because of a tentative diagnosis of deep seated hepatic abscess, the liver was
aspirated in several places but without result. No microscopical examina-
tion of the small particles that were found clinging to the aspirator was
made. Blood examination showed red blood cells, 3,200,000, white blood
cells, 24(),000. A differential white blood count showed :

Polymorpho-nuclear neutrophilic leucocytes 58 per cent.

Polymorpho-nuclear neutrophilic leucocytes 5 " "

Large mononuclear and transitional leucocytes 4 " "

Small mononuclear leucocytes 3 "

Myelocytic leucocytes 30 " "

The haemoglobin was 25 per cent. No malarial parasites were found.

Subseqtient Course. — The patient had an irregular morning and evening
temperature that varied between 97.6° and 104° F. respectively. Tlie
patient only suffered discomfort when lying on the right side or during

' Report of a pathological specimen.
In; A Case of Intestinal and Hepatic Actinomycosis in Man, Associated with
Leukaemia, by Thomas S. Latimer, Baltimore.

Tr. Ass. Am. Physicians, Phila., 1896, XI, 332-335.

541

542 INTESTINAL AND HEPATIC ACTINOMYCOSIS

manipulation of the liver. The liver coiitiuued to increase steadily and uni-
formly in size, with no localized area of tenderness, fluctuation or enlarge-
ment. The patient became unable to lie on the right side. He was uncom-
fortable after eating and his bowels continued constipated. At first a sliglit
general anasarca developed, which rapidly increased, together with an
ascites, so that respiration became considerably embarrassed. The dyspnoea
was greater than was fairly to be accounted for by the interference with the
movements of the diaphragm. The ascites was tapped several times to re-
lieve the dyspnoea. Oedema of the lungs greatly increased the dyspnoea.
There was no intestinal disturbance except a tendency to constipation with-
out increase of pain on defecation. Any disease of the appendix was com-
pletely masked by the condition of the liver, ascites and oedema of the
abdominal wall. In spite of all treatment, the patient's strength steadily
diminished until February 10, 1896, when he died, apparently from asthenia.

Diagnosis. — Myelogenous leukaemia with enlarged liver due to diffuse
leukaemic infiltration. No suspicion of actinomycosis was entertained.

Autopsy (by N. G. Keirle and John Rurah). — Autopsy about five hours
after death; body that of a medium sized man; with general anasarca;
oedema greater on the left side of the body, the face and arms especially. Skin
pitted on pressure everywhere ; the abdomen much distended with fluid ;
thin watery fluid ran from the nose and mouth. The muscles were pale and
bloodless. The abdomen contained a large quantity of pale, straw-colored
fluid ; there were numerous adhesions ; both the parietal and visceral layers
of the peritoneum generally thickened; intestines bound together by peri-
toneal adhesions ; omentum very adherent and without fat. Liver extended
some 10 cm. below the margin of the ribs. Along the costal margin to 7 cm.
of the median line was a dense, firm mass of organized inflammatory tissue
3 cm. in thickness. At the lower part of the same, pus escaped, on cutting
out the mass from a cavity that could not be well determined, as it was all
closed in by thick walls of inflammatory tissue. Just below the liver about
25 c. c. of greenish pus escaped from an abscess at that point. Spleen was
slightly enlarged; weight 350 gm; surface bluish gray; capsule slightly
thickened. Kidneys were somewhat swollen (moist) with cloudy swelling.
The entire ascending colon and the hepatic half of the transverse colon
were massed in inflammatory tissue. The ascending colon, for 6 cm. in its
middle could not be removed. The appendix was involved in a mass of
inflammatory tissues just above the brim of the pelvis; bile duct, patent;
the liver weighed 3260 gm. Left pleural cavity contained 500 c. c. of pale,
yellowish fluid; no adhesions. There was no effusion on the right side;
but a few adhesions, that broke up easily, between visceral and parietal layer
of the lower lobe and the diaphragm. The right lung was pushed up to the

ASSOCIATED WITH LEUKAEMIA 543

fourth rib in front, but extended in the back to the tenth rib. The left lung
was slightly pigmented, upper lobe crepitated, was somewhat emphysema-
tous, and oozed white f rotliy fluid on section. Lower lobe did not creditate
in the lower half, and oozed a thin sanious fluid on section. Pieces sank in
water. The right lung showed changes similar in character to those existing
in tlie left lung. The heart showed no important alteration.

II. Pathological Repoet of Liter

The liver was the only part submitted to me for examination. It had been
incised, but was complete. It was preserved in alcohol.

Macroscopic Examination. — The liver presents an irregularly globular
Bhape, measuring 22 x 18 x 12 cm. The right lobe, which is much enlarged,
is occupied tliroughout nearly its whole extent by a mass measuring 12 x 16
cm. This mass extends for a short distance also in the left lobe. It extends
throughout the whole thickness of the liver, from the lower to the upper
surface, but it occupies a larger transverse area in the lower two-thirds than
in the upper third of the organ.

The inferior surface of the right lobe, with the exception of a narrow
margin of liver-substance on the right side, is entirely occupied by the new
growth, which here was apparently continuous with an abscess formation
extending downward along the ascending colon. This inferior surface and
the posterior margin of the right lobe are connected with a dense mass of
fibrous adhesions, in which are included the hepatic vessels, the right
adrenal gland, and the hepatic flexure of the colon.

The diaphragm is firmly adherent to the superior surface of the right lobe
of the liver, and has been removed with the liver. The mass of new growth
in the liver has penetrated through the liver substance on the upper surface,
but has not penetrated through the adherent and thickened diaphragm.

Upon section it is seen that a definite fibrous capsule of dense consistence
and grayish color surrounds the mass in the liver, separating it from the
surrounding brownish red parencliyma of the liver. This fibrous capsule is
complete except in certain areas on the inferior surface of the liver or of the
new growth, where the opaque, yellowish characteristic foci of the mass come
to the surface, and were evidently in connection with the subhepatic abscess.
This relation and the general topography afford presumptive evidence that
the morbid process invaded the liver from below by continuity.

Upon section the mass presents in exquisite manner the characteristic
honeycombed appearance of a chronic actinomycotic tumor. There are
spaces and interlacing trabeculae. The spaces often anastomose. They vary
in shape and size on section, some being round, others oval, others more or
less cylindrical. They contain a soft yellowish white purulent material,

544 INTESTINAIv AND HEPATIC ACTINOMYCOSIS

which can be squeezed out readily, and in which can be detected abundantly
the small yellowish granules of the colonies of actinomyces. The immediate
margins of the spaces are of an opaque, yellowish white, necrotic appear-
ance. The spaces vary from 1 to 6 or 8 mm. in diameter.

The trabeculae are in general broad and interlacing and of firm consistence
and translucent gray color, like fibrous or granulation tissue.

Microscopic Examination. — For tlie study of the histological structure,
staining with haematoxylin and eosin was used ; for the details of the struc-
ture of the parasite. Gram's, Weigert's, and Mallory's stains were found most
serviceable.

The microscopical sections show interlacing bands of fibrillated connective
tissue, rich in long fusiform cells. Between these fibrous bands there are
dense accumulations of cells. In the immediate neighborhood of the actino-
myces the cells are closely packed together and there is little or no basement
substance. These cells are predominately polymorphonuclear leucocytes;
in other words, the parasitic colonies lie for the most part in purulent foci.
Outside the areas of actual pus there is granulation tissue in varj'ing stages
of formation, from a tissue composed almost exclusively of granulation cells
and leucocytes to a tissue rich in basement-substance and with elongated
cells. In the fibrous trabeculae are bloodvessels with thick muscular walls
and containing an excess of leucocytes, among which are many mononuclear
forms. Adjacent to the liver parenchyma the fibrous tissue is dense and con-
tains numerous rows of compressed liver cells, presenting the appearance of
the so-called newly formed bile ducts. Here and there are mucous glands
derived from those in the walls of the bile ducts, but now without evident
connection with bile ducts, and apparently hypertrophied and proliferating
so as to simulate adenomata. The capillaries of the liver contain an excess
of leucocytes, mononuclear cells predominating.

The colonies of actinomyces are rarely single, more frequently they are
conglomerated into irregular masses, which may be 1 to 2 mm. in diameter.
These colonies in general present a central, looser part of tangled fine fila-
ments and slender rods, with, at times, deeply staining coccus-like bodies,
and a more densely woven ring of fine filaments nearer the periphery, from
which the filamentous branching threads radiate outward. These radiating
threads often extend out among the surrounding pus cells and are often
devoid of any bulbous swelhngs or club-like extremities.

It is not found easy to demonstrate satisfactorily the clubs which are
frequently found at the extremities of the threads in cases of actinomycosis.
The stain recommended by Mallory is most suitable for this demonstration.
By this stain there could be demonstrated around some, although not around
most, colonies a deeply stained red, almost homogeneous, peripheral zone.

ASSOCIATED WITH LEUKAEMIA 545

into which the blue threads could be traced. This red margin clearly be-
longed to the parasite and not to the surrounding cells, from which it was
often separated by a narrow space. The out«r surface of this red border was
often somewhat irregular and indented, and in general the impression was
gained that this outer zone, which stained by Mallory's method deeply red,
consisted of the coalesced material which composes the club-like swellings
at the extremities of the threads in most cases of actinomycosis. I am in-
clined to interpret the failure to demonstrated sharply defined clubs in this
case, and the appearance of a diffuse, homogeneous, peripheral substance,
with the staining reactions of the clubs, to postmortem changes. That the
clubs may become indistinct or even disappear in consequence of postmortem
changes has been demonstrated by Weigert.

But only some of the colonies showed this homogeneous marginal zone.
Many were entirely devoid of such a zone or of any suggestion of clubs. It is
now well known that actiuomyces colonies are often devoid of characteristic
club-like swellings. In this case, as in that reported by Mallory, there are
numerous bacilli belonging to the actinomyces, scattered among the cells
independently of the colonies. Clumps of streptococci were also observed in
small number, so that there was mixed infection with actinomyces and
streptococcus.

The mass in the liver, therefore, presents macroscopic-ally and micro-
scopically the typical structure of an actinomycotic tumor. As has already
been stated, the evidence is that the parasite gained access to the liver and
generated the new growth at the inferior surface of the organ. The process
gradually extended so as to invade most of the right lobe and a part of the
left lobe of the liver.

Although I have not had the opportunity to examine other parts from
this case, there can be little or no doubt, in the light of the clinical history
and the observations made at the autopsy, and in similar cases, that the
portal of entry of the parasite was the intestine, and in all probability the
starting point was actinomycotic appendicitis (possibly colitis), whence the
morbid process extended upward in the tissues along the ascending colon
to the right hypochondrium, and invaded tbe liver at its lower surface.

PREVENTIVE
MEDICINE

MODES OF INFECTION '

Mr. President and Gentlemen, Fellow-Members of the Medico-Chirwr-
gical Society. — When honored by the invitation to deliver the Annual Ad-
dress before this Society, it seemed to me appropriate to select a subject
relating to that department of medicine in which the most important dis-
coveries have been made in recent times. The far reaching advances in our
knowledge of the causation of infectious diseases have opened up new fields
of view in so many and in so various directions, that I have been somewhat
in doubt as to what phase of the subject it would be most profitable for us
to consider on the present occasion.

The time has gone by when much profit is to be derived from the discus-
sion of that very general and hackneyed theme, the germ theory of disease;
for the doctrine thus expressed is no longer a theory, and there is, doubtless,
no one competent to form an opinion on the subject who does not believe
that certain infectious diseases are caused by microorganisms, and that it is
a logical inference that the other diseases of this class are produced by para-
sitic organisms — although there may be differences of opinion as to how
far this doctrine has been proven for individual diseases.

I have thought that it might be of interest to pass in review certain funda-
mental ideas concerning infectious diseases, and to note how far these ideas
have been modified or expanded by recent discoveries.

ilany of these ideas are by no means of recent origin, for from the earliest
times onward much attention has been devoted to the investigation of epi-
demic diseases, and particularly of tlieir causation. The conceptions of
contagium and of miasm are almost as old as the history of medicine itself.
Ancient writers have recorded their belief in the existence of infected locali-
ties, and in the conveyance of epidemic diseases by means of the drinking
water and of the air. Individual predisposition to infection, as well as pre-
disposition according to time and to place, are not modem ideas, as is shown
by such historical terms as genius epidcmicus, constitutio pestilens. The
science of epidemiology is much older than that of bacteriology, and has
taught us much concerning the causation and development of infectious
diseases.

The question arises : Has our knowledge concerning the origin and spread
of infectious diseases been widened and has it become more exact since the

' Annual address delivered before the Medical and Chirurgical Faculty of
Maryland, Baltimore, April 27, 1887.
Tr. M. and Chir. Fac. Maryland, Bait., 18S7, 67-87.

549

550 MODES OF INFECTION

discovery of the living eontagium of many of these diseases? While grant-
ing the vast scientific importance of this discovery, it is in itself only the
confirmaton of the faith of far-seeing minds of past generations. The mere
demonstration of that which was previously a reasonable supposition does
not offer a new point of view.

It is proper for us to inquire whether the investigation of the micro-
organisms causing infectious diseases, and the study of the characteristics
and life histories of these parasites, of the media and conditions of tlieir
growth and of the means of their destruction, have added materially to the
knowledge which was already afforded us by the epidemiological study of
these diseases. Have we thereby gained a clearer conception of such terms
as miasm, eontagium, and miasmatic eontagium ? Have we a deeper insight
into the conditions under which a virus is transmitted from an infected to a
healthy person, and of the conditions of infection through the air, the drink-
ing water and other media ? Can we form any more definite ideas of what is
meant by individual predisposition to an infectious disease and by such
terms as predisposition in time and in place?

Even if we were obliged to answer all of these questions in the negative,
not one particle would be detracted from the importance of further pursuit of
bacteriological studies, for experience has sliowm that nothing is more short
sighted tlian to estimate the value of scientific discoveries according to their
immediate practical utility. And, moreover, the questions which I have
raised relate to only a few out of many practical aspects of these studies;
but if, as I believe to be true, it can be shown that light has been shed upon
some of the most interesting and obscure problems concerning infectious
diseases, by the .studies of the living organisms causing these diseases, then it
is apparent that the results of these studies are of more immediate interest
and of interest to a much wider circle than would otherwise be the case.

Our knowledge in the directions indicated is but fragmentary. The title
" Modes of Infection " under wliich I wish to gatlier together some of these
fragments has been selected as a convenient one to cover most of the thoughts
which I desire to present to you. The intention, however, is not to consider
exhaustively all possible modes of infection, but chiefly to dwell upon such
points relating to the causation of infectious diseases as have been most
illuminated by recent investigations, particularly in bacteriology.

There is now tolerable unanimity of opinion as to the meaning attached
to the terms infections and infectious diseases. Most recent authorities
understand by infection the condition produced by the entrance and multi-
plication of pathogenic microorganisms within the body. An infectious
disease is one wliich is caused by the invasion and reproduction within the
body of pathogenic microorganisms. To define an infectious agent as a

MODES OF INFECTION 551

specific poison capable of indefinite multiplication is only to express ob-
scurely the idea just conveyed, for we know and can conceive of no poison
capable of indefinite multiplication except a living organism. The analogies
formerly drawn from the fermentation and the putrefaction of organic sub-
stances, and still preserved in the designation zymotic diseases, have lost all
force as an opposing argument since it ha= betjj shown that these processes
are produced by living organisms. In the absence of any other probable, I
may say even conceivable, hypothesis, to refuse to accept the doctrine of a
coniagium vivum as applicable to all infectious diseases because it has been
demonstrated only for certain of these diseases, is about as reasonable as to
reject the law omnis cellula e cellida because this has not been proven for
every cell or every species of cell.

We should be by no means justified to substitute in the foregoing defini-
tion of infection instead of pathogenic microorganisms, bacteria or fissure
fungi. It is true that most of the infectious agents with which we have
become acquainted are bacteria, but the malarial parasite is a notable excep-
tion to this. There are grounds for believing that the specific organisms of
some of the infectious diseases may belong to low forms of animal or vege-
table life other than the bacteria. Our means for demonstrating the pres-
ence of bacteria are comparatively satisfactory, but this cannot be said of
most of tlie other protozoa, and it is perhaps in consequence of this imper-
fection of our methods of investigation that so many infectious diseases have
resisted successfully our efforts to discover their efficient causes.

It is gratifying, after so much strife, to be able to record this agreement
of opinion as to the definitian of infection and of infectious diseases in
general. It is customary to classify infectious diseases etiologically into
contagious, miasmatic, and miasmatic contagious diseases. As to the signifi-
cance of these terms, and particularly as to the real nature of the so-called
miasmatic contagious diseases, tliere exists great confusion. As the epitliets
miasmatic, contagious, and miasmatic contagious meet us upon every hand
in our investigations of infectious diseases, as they relate to conceptions
which lie at the very foundation of our knowledge of the subject, it is mani-
festly of the utmost importance that their meaning shoiild, if possible, be
rendered clear and precise. I question, however, whether these terms any
longer suffice for the classification of infectious diseases, although, as Petten-
kofer has said, the ideas contagium and miasm are so bred into our flesh
and blood that we would as soon think of parting with them as with one of
our limbs even after it had become useless.

Originally the distinction between contagium and miasm was sharply
defined. There are two attributes which essentially characterize the ordinary
conception of contagium, viz. multiplication within the diseased body, and

552 MODES OF INFECTION

capability of transmission from tlie diseased to tlie healthy body. The latter
attribute implies, of course, the elimination of the contiigious principle in
an active state from the diseased body. On the other hand a miasm is pro-
duced outside of the body. According to the belief of many writers it does
not multiply within the body, and all agree that it is not eliminated from
the body in a condition capable of producing infection. Especial emphasis
in framing these distinctions was laid, in the case of a contagious disease,
upon the origin of the virus within the body (endogenous), and in the case
of a miasmatic disease, outside of the body (exogenous). These ideas con-
cerning contagium and miasm answered well enough for the typically con-
tagious diseases such as syphilis and the exanthematous fevers, and for the
typically miasmatic disease, malaria. But confusion began during the mid-
dle third of the present century when the origin and spread of Asiatic
cholera were carefully studied. It was found impossible to classify this
disease under either of the two existing divisions. It has in common with
the contagious diseases the characteristic that persons affected with cholera
may convey the disease to localities previously free from it, and may prove
the starting points of wide spread epidemics. Cases sometimes occur of
which the only natural interpretation is that they have originated from conta-
gion. On the other hand, in infected localities the disease often develops in
those who have never seen a cholera patient, much less come into contact
with one, while those in attendance upon such patients as a rule are no more
liable to the disease than others living in the same locality. Similar observa-
tions were made with reference to typhoid fever.

There arose the contest, not yet ended, between the contagionists who
held that these diseases are to be ranked as contagious, and the localists who
regarded them as miasmatic in origin, and to explain certain peculiarities
introduced the new conception of a portable miasm. The majority, how-
ever, sought refuge under a new cover. The class of miasmatic contagious
diseases was formed, and in this amalgamated group were placed cholera,
typhoid fever, yellow fever, and several other infectious diseases not con-
veniently classified elsewhere.

Various meanings have been and still are attached to the term miasmatic
contagious diseases. Some understand by a miasmatic contagious disease
one which is propagated sometimes by a contagium and sometimes by a
miasm — that is, sometimes by a virus produced within the diseased body,
and sometimes by a virus produced out-'^ide of the body. Others hold the
opinion that for the production of cholera, typhoid fever, and other diseases
of this class, two viruses or microorganisms are necessary, one derived from
a person affected with the disease, and the otlier derived from the soil, or at
least from some external source. But the view which has gained the most

MODES OF INFECTION 553

adherents, and which is the prevalent one at the present time, is that a
patient with typhoid fever or with cholera throws off from his body a poison,
a microorganism, which at the time of its discharge is not capable of pro-
ducing the disease, but which under favorable circumstances undergoes out-
side of the body some unknown metamorphosis by which it acquires this
power. This last view is the one which is accepted in most of the text books
on medicine pubUslied within recent years in this coimtry and in Europe,
and I presume that it embodies the belief on the subject of most practitioners
of medicine.

One of my main objects in the present address is to direct your attention
to what seem to me weak points in this hypothesis, and to endeavor to ex-
plain in a more natural and satisfactory manner the peculiarities of the so-
called miasmatic contagious diseases, at least so far as two leading represen-
tatives of this group, viz. cholera and typhoid fever, are concerned. The
discovery of the microorganisms which are in all probability to be regarded
as the specific causes of cholera and of typhoid fever, and the investigation
of their properties, should have led, it might be supposed, to a general re-
vision of the widely accepted doctrine of miasmatic contagious diseases; but
this has not been the case — at least among clinical writers, who apparently
see no reason why the actually discovered germs, as well as those previously
surmised, may not undergo the assumed matamorphosis outside of the body
which renders them capable of infection. This is still the reasoning of
Liebermeister in his work on " Infectious Diseases," published in 1885, in
which he accepts the cholera and the tj-phoid bacilli as the agents of infection.

Let us now examine in detail the arguments which are brought forward
in support of the miasmatic contagious doctrine as previously defined.

In the first place, it is urged that a metamorphosis such as is assumed to
occur in the agents of infection after their elimination from the body of a
cholera or a typhoid fever patient, has its analogy in the well known in-
stances of alternation of generation ; and usually the ordinary tape-worm is
cited, the ova of which, as is well known, first develop into cysticerci, and only
these, when swallowed, are capable of giving rise to mature tape-worms.

The argument by analogy, however, instead of supporting the miasmatic
contagious hypothesis, is directly opposed to it. In the class of organisms
to which the typhoid and the cholera germs belong, no instance is known of
any organism after its discharge from the body acquiring infectious proper-
ties which it did not previously possess, or of its undergoing any transforma-
tion at all resembling that assumed to occur. On the other hand, we know
of some pathogenic organisms which are rendered more virulent by their
passage through the body of an animal susceptible of the disease; and, in
general, bacteriologists are inclined to regard as especially potent bacteria
38

554 MODES OF INFECTION

which are fresh from the bodies of infected animals. Where it is aimed to
produce intoxication by means of ptomaines, as can be done by cultures of
the typhoid and of the cholera bacilli, then it is true that old cultures, as
would naturally be supposed, are the most effective ; but there is no reason
to believe that ptomaine intoxication plays any role in the primary infection
with the typhoid or the cholera germs; or, if it did, where are the ptomaines
likely to be more abundant than in fresh typhoid and cholera stools?

Before we knew as much as we now do about the properties of bacteria,
the transformation hypothesis now under criticism could be advanced with
some show of reason ; but at present our information upon this and similar
points is by no means scanty, and in the absence of any pertinent analogy
for such an occurrence, the assumption seems entirely imwarrantable that
the specific organisms of cholera or of typhoid fever acquire new or in-
creased virulence after their removal from the body. Inoculation experi-
ments upon animals witli the cholera spirilla lend no support to this
assumption.

In the second place, it is urged in support of the miasmatic contagious
theory that the ispecific germs of these diseases cannot be eliminated from the
body in a condition capable of causing infection ; otherwise those who are in
proximity to the patients must frequently become infected, as in cases of
smallpox or of typhus fever. This is, evidently, the argument which has the
greatest weight. It is to explain the absence, or at least the infrequency of
any direct communication of cholera and of typhoid fever from one person
to another, that the hypothesis under consideration was constructed.

It is, of course, apparent that the specific germs of cholera and of typhoid
fever must be discharged from the body in a very different way and must
have very different properties from those of the contagium of smallpox and
similar diseases. It is because our ideas of what characterizes a contagium
are derived from our observations of such highly contagious diseases as
smallpox or scarlet fever that we are loath to admit that cholera or typhoid
fever patients emit anything which can be called an active contagium. I
believe, also, that not a little of the difficulty of this admission conies from
the popular notion that a source of active contagion must necessarily infect
the surrounding atmosphere, as is the case with a smallpox patient.

It is, however, possible to reconcile the fact that the discharges of cholera
and of typhoid fever patients contain a contagium, and that, too, in an
active form, with the infrequency with which these diseases are communi-
cated in a manner which is ordinarily understood as contagious.

Let us take for example cholera, and consider in the light of recently
ascertained facts what conditions must be fulfilled in order that the disease
niaY be contracted directly from a patient. It is to be borne in mind that the

MODES OF INFECTION 555

cholera germ is discharged from the body only in the faeces, and very excep-
tionally in the vomitus. It is not present in the urine, nor in the breath,
nor in the sputum, nor is it thrown off from the surface of the body. These
are well established facts, so that we can conclude that the only danger
of direct infection from a cholera patient is by means of the stools. It
is necessary, however, to come into actual contact with the stools in order
to become thus infected. It has been proven by exact and very interest-
ing experiments of Naegeli and Buchner that bacteria are never lifted by
currents of air from the surface of fluids or from moist surfaces in gen-
eral. One could remain in a room containing any quantity of cholera
stools swarming with cholera spirilla and tliere would be no danger of infec-
tion with cholera through the air. Bacteria are conveyed into the air only
when they are in a dry condition, and the cholera organism is quickly des-
troyed by drying. So far as cholera is concerned, there is therefore no basis
for the prevalent belief that the atmosphere becomes infected for a certain
distance around substances containing an active contagium, although this
belief is justified as regards certain other species of contagia.

But it does not suffice for infection merely to have come into contact with
cholera stools ; portions of the stools must actually be swallowed. There is
every reason to believe that infection with cholera takes place only through
the reception of the virus directly into the alimentary canal, and not through
subcutaneous inoculation or through the respiratory organs.

If this last condition be fulfilled and portions of cholera stools be actually
swallowed, even then in any given case the chances are probably at least three
to one that no infection would follow; for cholera spirilla are destroyed by
the acid of the gastric juice, and it is a matter of experience that only a
minority of those exposed to the specific cause actually contract the disease.
These considerations show how worthless are the isolated experiments of
those foolhardy individuals who have voluntarily swallowed cholera dejecta
and cultures of the cholera spirilla. Whatever had been the outcome of these
few experiments, no positive conclusions could be drawn from them. A
negative result, for reasons already given, was to be expected; a positive
result would prove nothing, for the experiments were all made in districts
already infected with cholera, and it would have been impossible to decide
whether the infection had taken place in a natural way or as the result of the
experiment. The conditions were of course entirely different in the instance
of the doctor in Koch's laboratorj- who contracted cholera as a result of care-
less handling of cultures of cholera spirilla, for there was at the time no
cholera in Germany and no other possible source of infection than the
cultures.

556 MODES OF INFECTION

Enough has been said to show what difficulties attend the direct com-
munication of the disease by a cholera patient. It is perfectly explicable
why direct contagion is so infrequent notwithstanding the fact that cholera
stools contain the contagion in an active form, indeed sometimes almost as
a pure culture. There is no necessity to resort to any such artificial, compli-
cated and unsupported hypothesis as the miasmatic contagious doctrine in
the sense at present under consideration.

But any satisfactory esphmation the specific cause of cholera must account
for occasional instances of transmission of the disease by contagion. I do
not propose to discuss here in detail that most vexed question. Is cholera
contagious? but I believe that he who denies absolutely the contagiousness
of the disease must shut his eye to plain facts. There are instances, and
of course they are to be sought not in regions where cholera is epidemic but
where sporadic cases occur, where the only natural interpretation is in favor
of direct contagion.

Now the miasmatic contagious hypothesis has no room for these contagious
cases, whereas there is no difficulty in accounting for occasional instances of
contagion according to the view, which I believe to be an established fact,
that the cholera stools contain the active cholera virus. Indeed, such in-
stances of contagion are to be expected, although least frequently of course
among doctors and nurses, whose comparative immunitj' is usually cited to
prove the non existence of any active contagium eliminated by a cholera
patient. Doctors and nurses are the most likely to see that the cholera stools
are properly disinfected, and also to disinfect their hands or other parts of
their persons which may have become soiled by the dejecta. On the other
hand, among ignorant persons living in cramped and unclean quarters the
chances of direct contagion are much more favorable. It is probable that the
statements in books relating to the frequency of cases of cholera caused by
contagion are misleading, for such cases are least likely to come under the
observation of those who contribute most largely to medical literature,
namely, physicians with practice in hospitals and among the well-to-do
classes living under good hygienic surroundings.

There is a general agreement upon the point that the epidemic spread of
cholera cannot be accounted for by direct contagion. It is generally admit-
ted that the specific agent of infection, derived from the dejecta of a cholera
patient, may under favorable conditions multiply outside of the body, in the
ground, upon vegetables and elsewhere. We are to seek the chief sources of
infection in cholera epidemics in the drinking water, the food, the ground,
in actual contact with substances coutaining the specific germs. A discus-
sion of these various external sources of infection, notwithstanding the
great interest and importance of the subject, is not pertinent to my present

MODES OF IXFECTIOX 557

argument, which is to show not only that it is not necessary to deny the
existence of an active coutagium in the fresh cholera stools, but that there is
every reason to believe that such contagium is actually present.

I have selected cholera for the purpose of showing the falseness of the mias-
matic contagious theor}' as expounded by Liebermeister and others, partly
because our knowledge concerning its etiology has become much more
exact since Koch's discovery of its specific germ, and partly because this
disease has been eenerally regarded as the main support of this theory.
Indeed, the hypothesis of the transformation or ripening of germs after
they leave the body was constructed especially to account for the phenomena
of Asiatic cholera. Tht arguments which I have present«d apply equally to
typhoid fever, another important member of the miasmatic contagious group
of diseases. Here, too, the specific virus is eliminated from the body, as a
rule, only in the faeces. There exist the same reasons in the one as in the
other disease why infection is likely to take place only exceptionally in the
form of direct contagion. It is not necessary to go over the same ground
with typhoid fever which we have already traversed with cholera, for as
regards the point now under consideration the evidence is of the same char-
acter for both diseases.

Our information is at present wholly insufficient to enable us to form any
positive opinion as to the mode of elimination of the specific virus of yellow
fever.

I have attempted, gentlemen, to make it probable that a patient with
chelera or with typhoid fever emits a contagium in just as active a state as a
patient with smallpox or with scarlet fever. We cannot explain the difference
in frequency with which the two sets of diseases are propagated by direct
contagion by assuming that only in the latter diseases is the virus eliminated
in a condition capable of producing infection. The relative frequency with
which infectious diseases are communicated by direct contagion depends, I
believe, first of all, upon the channels through which the virus is eliminated
from the body.

It may be stated as a broad proposition that every infectious disease can by
artificial means be transmitted from an individual affected with the disease
to another individual susceptible of the disease. This is only the natural
inference from the fact that each infectious disease has its specific virus in
the shape of a microorganism which is present and multiplies in the bodies
of those affected with the disease. Although there is no evidence that under
natural conditions malaria is ever transmitted from one person to another,
still it is possible to accomplish this artificially, as has been proven by the
experiments of such trustworthy obseners as Gerhardt and Marchiafava
and Celli, who inoculated successfully, with blood from malarious patients,
persons who were entirely free from malaria.

558 MODES OF INFECTION

Strictly speaking, therefore, in every infectious disease there is a conta-
gium, but we should fall into grave errors if we drew our conclusions as to the
natural modes of infection from the results of artificial inoculations, as is
illustrated by the example of malaria.

To explain why, under natural conditions, some diseases, such as the ex-
anthematous fevers, are usually transmitted by contagion ; other diseases,
such as typhoid fever and cholera, only infrequently, and other diseases,
such as malaria, never by contagion, it is necessary, I repeat, to consider the
channels by which the virus is eliminated, if at all, from the body.

If, as in the case of malaria, the virus is not discharged at all from the
body, tlien of course there is no possibility, under the conditions of nature,
of the communication of the disease from one person to another. If, as in
the case of cholera and of typhoid fever, the virus is discharged only by way
of the faeces, then contagion is possible, but it is not hkely to occur with
ordinary care and with ordinary cleanliness. If, as in the case of scarlet
fever, measles and smallpox, the virus is eliminated from the skin and ad-
heres to thin scales of epidermis which can be readily transported through
the air, then contagion is likely to be a common occurrence.

I do not wish to be understood as implying that the mode of elimination
of a virus is the sole factor in determining the degree of contagion of a dis-
ease. There are, of course, other important factors, such as the degree of
resistance offered by the virus to drying, the chances of its being conveyed
into the air, its quantity, etc., as well as the degree of susceptibility which
exists on the part of those exposed and the portal through which the virus
must enter in order to cause infection.

I trust, gentlemen, that this will be found a more rational, fruitful and
satisfactory way of regarding the infectious diseases than to wander among
the mazes of miasmatic, contagious, and miasmatic contagious diseases, and
to imagine that in some diseases the virus is eliminated in a potent state,
and in other diseases in a state requiring some subsequent transformation
to make it potent.

It is unfortunate that our positive knowledge concerning the mode of
elimination from the body of the specific poisons of the various infectious
diseases is still very incomplete. Only for those diseases whose special
agents of infection have been discovered is our information exact upon this
point. For some other diseases we have good grounds for forming an opinion,
while in the case of several infectious diseases, such as relapsing fever, we
arc quite in the dark on the subject.

It may not be out of place to call your attention to certain points which
bear upon this question. The experiments of Wyssokowiisch, made in the
Hygienic Laboratory of Gottingen, and published not quite a year ago, have
shown that nonpathogenic bacteria injected into the blood of animals in a

MODES OF INFECTION 559

few hours disappear from the blood and are deposited in certain organs,
especially the liver, the spleen, and the marrow of the bones, whence they
also disappear, as a rule, in a short time. They are not eliminated by the
urine or by any other excretion. He found that microorganisms in general
are discharged by the urine only when they form some local lesion in the
kidney or some part of the urinary tract. He found, likewise, that organisms
injected into the blood are not discharged by the intestine unless they first
cause some lesion of the alimentary canal. Similar facts were determined
regarding secretions from other mucous membranes. The experiments of
Wyssokowitsch warrant the following statements:

The specific germs of infectious diseases can be and, in cases of recovery,
doubtless often are, destroyed within the body.

Contrary to what many have believed, the kidneys and the intestines
cannot be regarded as important means of freeing the body from micro-
organisms which have gained access to the blood.

When the specific microorganisms of an infectious disease are found in
the urine or in the faeces, it may be inferred that the genito-urinary appara-
tus and the alimentary tract respectively are the seat of some lesion produced
by these organisms.

These experiments justify also the inference, in itself probable enough,
that the specific viruses of infectious diseases are discharged from those free
surfaces which are themselves the seats of the characteristic lesions of the
disease, as for instance from the respiratory tract in pulmonary tubercu-
losis, lobar pneumonia, whooping cough, diphtheria; from the skin, in scar-
let fever, measles, smallpox, typhus fever, erysipelas; from the intestines,
in typhoid fever, cholera ; from the urethra or vagina in gonorrhoea, syphilis.
For several diseases, however, we have no satisfactory data for determining
in what manner the special poison is eliminated. This is true, for instance,
of cerebrospinal fever and relapsing fever.

We are ignorant as to whether microorganisms may be eliminated by
the breath, although it is a common notion that this occurs. In view of the
experiments already cited, which show the difficulty with wliich micro-
organisms are detached from moist surfaces by currents of air, it seems im-
probable that organisms can be conveyed from the body by the breath. Of
course, if the organisms were momentarily set free by acts of coughing, th.en
they might be carried on by the respiratory current, but it is at least very
questionable whether in ordinary breathing particulate substances can be
thus transmitted.

We have up to this point, gentlemen, considered only the diseased body
and its fresh excreta as the source of infection, and we have reached the
conclusion that in every infectious disease there is a contagium, but that
whether or not the disease is likely to be propagated as a contagious one

560 MODES OF INFECTION

depends upon various circumstances, among which the mode of elimination
of the contagium from the body is of the utmost importance.

A question of great interest, as well as of practical importance, is whether
or not any given infectious agent finds conditions outside of the body favor-
able for its prolonged existence. This question is not identical with that of
tlie reproduction of the special virus outside of the body. The importance of
the latter point has been somewhat exaggerated in discussions relating to the
etiology of infectious diseases. Special agents of infection may be widely
distributed wathout their finding conditions favorable to reproduction out-
side of the animal body. Thus tlie bacillus of tuberculosis appears to be
almost as widely spread throughout nature as the organisms which cause
suppuration, and yet the tubercle bacillus can find only exceptionally the
conditions of temperature and of nutriment which permit its multiplication
outside of the body, whereas the pus organisms doubtless find abundant
opportunities for their development on various substances outside of the
body.

The mere facts of the mde distribution of certain infectious microorgan-
isms and of frequent infection from external sources do not justify us in
drawing conclusions as to the capability of growth of tlie organisms as
saprophytes. This is a point which can be positively decided only by a
knowledge of the life history and properties of the different infectious
organisms.

So far as our present knowledge reaches, it is only such infectious micro-
organisms as form spores which are capable, under natural conditions, of
prolonged existence outside of the body without reproduction. These spores
can resist high temperatures, drying, and various other agencies which are
destructive to the ordinary vegetative cells. Thus we can explain why, for
instance, infection with the tubercle bacillus can take place from external
sources, while infection with gonorrhoea always requires contact with fresh
gonorrhoea! secretion, although in neither instance does the special virus
reproduce itself outside of the animal body, except under such artificial
conditions as we can produce in our laboratories.

The question as to the reproduction of infectious microorganisms outride
of the body, although it has not all of tlie significance sometimes attaclied
to it, is nevertheless one of much interest. It is from this point of view that
infectious microorganisms are often classified by bacteriologists. Thus there
are microorganisms which find only within the animal body the conditions
suitable for their growth and development. Such organisms are called
obligatory parasites. Examples are the parasitic organisms of syphilis,
gonorrhoea, tuberculosis, and doubtless of smallpox, measles, scarlet fever,
etc. Other infectious microorganisms are capable of growing under natural

MODES OF INFECTIOX 561

conditions both -within the body and outside of the body, as in the soil. Such
infectious agents are called by bacteriologists potential parasites. In the
case of some of the potential parasites their natural home seems to be the
animal body, as appears to be true, at least in most localities, of cholera
spirilla and typhoid fever bacilli ; while in other cases the natural habitat of
the organism is the soil, whence it makes occasional excursions into the
animal body. The malarial parasite conforms to the latter type. The growth
of microorganisms outside of the body is spoken of as saprophytic.

In the case of typhoid fever there is no a priori objection to supposing
that its parasite may grow in situations where it has not been introduced by
any human being. The weight of evidence seems certainly opposed to such
a supposition ; still Murchison and other authorities have contended for the
so-called spontaneous origin of typhoid fever in some eases, and the question
can be settled only by a careful analysis of epidemiological facts, in the in-
terpretation of which there inhere, as is well known, important sources of
error.

Of the utmost importance in the elucidation of the spread of many of the
infectious diseases, particularly of cholera and of tj-phoid fever, is the in-
vestigation of the conditions favorable to the existence and growth of para-
sitic microorganisms in the soil, the drinking water, upon vegetables and
other substances outside of the body, as well as of the means by whith infec-
tion occurs from these external sources. These subjects, which pertain to
public hygiene, can be touched upon only very briefly upon this occasion.

More attention has been paid to the influence of the soil and of the drink-
ing water in the propagation of epidemic diseases than to any other of the
factors named. Under the brilliant leadership of Pettenkofer a school of
hygienists has developed who lay emphasis almost exclusively upon the soil
in this matter, and are imwilling to admit that epidemic infection takes
place through the drinking water.

We owe to this school valuable researches as to the physical conditions of
the soil which favor the development into an epidemic of such diseases as
cholera and typhoid fever, as well as to conditions hostile to such develop-
ment. Among the conditions favorable to an epidemic may be mentioned
a certain degree of porosity of the soil, a certain amount of moisture, and
some impregnation with decomposing animal and vegetable material. But
notwithstanding these painstaking investigations, which are much more
extensive than this brief notice would indicate, it must be admitted that
they have left us considerably in the dark as to how we are to regard the
soil as concerned in the propagation of infectious diseases. There has been
no actual demonstration of the infectious microorganisms of cholera and
of typhoid fever in the soil, or of their multiplication there, and, above all,

562 MODES OF INFECTION"

no satisfactory explanation as to the means by which infectious agents are
transported from the soil to the animal body.

To the medical profession in this country and in England it is not com-
prehensible how there can still be distinguished authorities who deny that
epidemics of typhoid fever or of cholera are ever attributable to drinking
water. Yet in Germany there are hygienists who are not only quite posi-
tiveh', but even somewhat violently opposed to what tliey call tlie drinking
water hypothesis. It is doubtless true that we are often too ready to accuse
the drinking water in an outbreak of typhoid fever ; but if medical evidence
is worth anything, there can be no reasonable doubt that many epidemics
of typhoid fever have been due to contamination of the drinking water
with the typhoid virus.

The experiments of Meade Bolton have revealed tlie important fact that
most pathogenic microorganisms do not multiply in water sufficiently pure
ever to be used for drinking purposes. Not only do the pathogenic bacteria
not multiply in drinking water, but, if they do not contain spores, most of
them are destroyed in drinking water in a short time, varying from a few
hours to several days, according to the species and the quantity of bacteria.
These experiments have been hailed by the Munich school of hygienists as
opposed to the view that epidemic infection can take place through the
drinking water, but they need not be so interpreted, nor are they so inter-
preted by Bolton.

These experiments make it necessary to suppose that a single infection
of the drinking water with infectious organisms would not suffice for an
epidemic lasting more than a few days. To keep up a long continued epi-
demic by means of contaminated drinking water, there must be some com-
munication between the water and some focus in which the disease producing
organisms are present in large number or are multiplying. This is in
harmony with the fact that repeatedly in epidemics traceable to the water,
communications have been proven to exist between the water and cess pools,
drains, privies, or other possible foci of infection. In considering water as
a source of infection, one must remember that this can occur not only by
drinking, but also by the use of the water in cooking, and in washing dishes
subsequently used to contain food.

As is well known, there have been several epidemics of typhoid fever in
which the source of infection has been traced to the milk. Although in
these instances it was believed that the milk was itself infected by the addi-
tion of contaminated water, nevertheless it is well to note that in one im-
portant particular milk differs from water in its behavior toward pathogenic
microorganisms. Milk is an excellent nutritive medium for nearly all of
these organisms. The t}'phoid and the cholera .spirilla grow in milk rapidly

MODES OF INFECTION 563

and abundantly, without producing any alteration in the external appearance
of the milk. Inasmuch as certainty of infection depends, in the case of many
diseases, upon the number of organisms which enter the body, it is apparent
that this property imparts a particularly dangerous character to infected
milk.

As regards the means of transportation by which the agents of infection
are conveyed from external objects to the body, the most important is be-
lieved to be the air by those who lay the most stress upon the influence of the
soil in the spread of epidemic diseases. It seems probable, however, that too
big a role has hitherto been assigned to the air as a carrier of contagion. The
fact has already been mentioned that currents of air are incapable of lifting
bacteria from moist surfaces; and Naegeli has shown, also, that if bacteria
be dried with their natural gelatinous envelopes or from albuminous sub-
stances, they are in much tlie same physical condition as insects attached to
a surface by mucilage, and cannot be carried away by the air unless they are
first converted into a dust-like powder. If it be furthermore considered that
some bacteria are destroyed by complete desiccation, it is evident that these
facts compel us to restrict witliin much narrower limits than most writers
have done, the importance of the air in the transportation of agents of in-
fection. Still there remains evidence enough that the virus of some diseases,
notable of malaria, and probably of yellow fever, may be, and often is, con-
veyed through the atmosphere. As infection through the air is something
which we have no means of combating, it is encouraging to learn that this
resistless fate has a narrower sway than we had been led to believe.

There are many grounds for supposing that the chief means of infection
are by actual contact, in one way or another, with the agents of infection.
The conviction of the truth of this statement is borne in almost irresistibly
upon one who has engaged extensively in the cultivation of microorganisms.
I have kept for weeks at a time, side by side in a sterilized dish to which
filtered air had free access, two watch glasses, one containing a culture of
the typhoid bacilli in beef tea, the other containing simply sterilized beef tea.
During this time, notwithstanding its close proximity to the typhoid culture,
the beef tea in the second glass remained perfectly pure, without a trace of
contamination from its neighbor. Many illustrations of the same principle
might be drawn from the work of a bacteriological laboratory. We study
the exposed cultures of such pathogenic organisms as anthrax bacilli, cholera
spirilla, glanders bacilli, and run no risk of infection from these so long as
we do not come into contact wdth the cultures.

There is one observation which we sometimes make in our laboratories in
summer — to our discomfiture — which, although it may seem trivial, is not
without its practical bearings. This is the readiness with which micro-

564 MODES OF INFECTION

organisms may be disseminated by flies and other insects. Upon the so-
called plate cultures we can sometimes trace the devious wanderings of an
insect by the colonies of microorganisms which it has planted in its course.
The application of tliis experience to a possible means of transportation of
the special organisms of infectious disease is too apparent to need further
elucidation.

I shall not weary you by attempting to elaborate in all of its details the
doctrine that one of the chief means of infection is by contact. There are
thousands of ways in which we can inadvertently come into contact with
sources of infection. , This teaches us that it is an error to construct ex-
clusive theories of infection, such as are expressed by the terms " soil hy-
pothesis," " drinking water hypothesis," etc.

There is one lesson, however, which has come from the epidemiological
study of the relations of the soil and of the drinking water to infectious
diseases, and that is the immense importance of the proper disposal of the
refuse matter around human habitations and the supply of pure drinking
water. The eflicacy of a good system of drainage or of sewerage in prevent-
ing the development of many epidemic diseases is probably to be sought, not
in the purifying of the ground so that pathogenic organisms cannot grow
there, but in affording means by which these orgapisms, contained in human
excreta and other substances, are readily carried away. The discussion of
these points relates to sanitary science, and does not belong to my theme,
but I cannot refrain from a brief allusion to the subject on account of its
great practical importance.

What can be more instructive, as well as more encouraging, than to wit-
ness the manner in which Asiatic cholera, during its present journey, has
failed to secure any foothold in those European cities which are characterized
by cleanliness and proper sanitary arrangements, although it has been re-
peatedly introduced into such cities? These cities have secured their im-
munity, not by spasmodic precautionary efforts after the entrance of tlie
disease, but at the price of systematic, vigilant and intelligent exertions
during what may be termed the time of peace. Without wishing to pose as
an alarmist, I believe that with the announcement of the appearance of
Asiatic cholera upon this continent, the time has come to emphasize the fact
that the only enlightened and civilized public policy is to be prepared at all
times and in all places to meet the enemy.

Of the various factors entering into the causation of infectious diseases
none is more obscure than that designated predisposition, and yet this is a
factor witli which we must undoubtedly reckon. This mysterious predis-
position to certain infectious diseases plays, perhaps, even a greater role with
us, at the present time, than it did with our forefathers in medicine, who
wrote so much concerning constitutio epidemica.

MODES OF INFECTION 565

It cannot be said that the increase in our knowledge concerning the specific
causes of infectious diseases has illuminated to any great extent what is
meant by predisposition, and still a few glimmers of Light have been sent into
this dark corner by recent bacteriological investigations.

Mention has already been made of the fact that the cholera spirilla are
destroyed by the acid gastrc juice, so that we a-e warranted in regarding all
conditions which neutralize the acidity of the gastric juice as affording pre-
disposition to this disease.

Perhaps the most positive addition to our knowledge in this direction has
been the demonstration of the importance of preexisting diseases or lesions
of structure in affording ready means of ingress and suitable conditions for
the lodgment and growth of pathogenic microorganisms within the body.
In this connection attention may be called to the experiments of Wyssoko-
witsch and of Prudden, which show the necessity of previous alterations of
structure in the cardiac valves before they are adapted for the lodgment and
development of the microorganisms which cause ulcerative endocarditis.
Grawitz has shown that the bacteria of suppuration may be injected in large
quantity into the healthy peritoneal cavity without doing any damage, but
that they set up suppurative peritonitis if they meet there woimded tissues,
stagnating fluids, or so-called dead spaces from which they are not readily
absorbed.

Especially instructive in this light is the study of the manifold compli-
cations which attend scarlet fever, typhoid fever, and other diseases which
are accompanied by necroses and ulcerations of the mucous membranes of
the throat, intestine, and other parts with which microorganisms are
normally in contact. While it has been shovm that most of these micro-
organisms are harmless, there are not infrequently among them some which
are pathogenic, such as the cosmopolitan bacteria of suppuration. The
superficial necroses and ulcerations of the mucous membranes in scarlet fever
and typhoid fever afford means of ingress for these bacteria, which often find
within the body foci of least resistance resulting from the existing diseases.
We are therefore not surprised to learn that many of the complications of
these diseases are produced by the staphylococci and streptococci of suppu-
ration, or that there are frequently found in these diseases in the tissues and
fluids bacteria, particularly micrococci, which have nothing to do with the
specific cause of the primary disease, although often enough mistaken for it
by hasty observers.

Time will not permit me to elaborate the ideas here touched upon.
Enough has been said to show that we need not despair of gaining some
definite conception as to the nature of predisposition and immunity to dis-
ease, but we must not forget that our positive knowledge at present touches

566 MODES OF INFECTION

only the outlying boundaries of the subject. We do not even know why dif-
ferent species of animals behave differently toward infectious agents — why,
for instance, house mice resist tlie deadly glanders bacilli, while the more
hardy field mice readily succumb — still less can we account for differences
in susceptibilty of individuals of the same species.

It is easy enough to construct plausible theories of predisposition and of
immunitj', and such theories have their scientific uses ; but we must remem-
ber that we have gained no explanation of the facts when we base our theories
upon such popular phrases as struggle for existence between cells and bac-
teria, or fitness of the soil for the growth of bacteria, etc. Even tlie more
tangible phagocytic doctrine of Metschnikoff cannot be said to have materi-
ally advanced our knowledge as yet, or to have met with much support in
facts.

Before leaving this subject it may be well to say that possibly we are at
present in the habit of assigning too great importance to predisposition as
a factor in the causation of infectious diseases. It is such a convenient refuge
that we are tempted to bury in its obscurity many etiological facts which we
cannot readily explain. While I would not by any means ignore the impor-
tance of hereditary predisposition to tuberculosis. Is it not probable tliat
cases are often included in this category which do not belong tliere ? When
we think of the especial dangers of infection to which the offspring of tuber-
culous parents are exposed from their youth upward, of the likelihood that a
child will follow an occupation which has favored the development of phtliisis
in a parent, and of the frequency with which the concurrence of the disease in
ancestor and descendant is mere coincidence, it is apparent that we are in
danger of assigning to heredity a larger part in the causation of tuberculosis
than it deserves.

It must be admitted that the instances in which we have been able by exper-
iments upon aniaials of the same species to demonstrate different degrees
of predisposition toward infectious agents are not very striking or very
numerous.

And now, gentlemen, I bring to conclusion this imperfect survey of some
points relating to the etiology of infectious diseases. We are only upon the
threshold of a deeper insight into the nature of a class of diseases which liave
been more devastating to the human race than any upheavals of nature or
any wars. They have left their imprint upon political, the social and the
intellectual history of the world. One need not be of a very sanguine tem-
perament to hope that our steadily increasing knowledge will bear fruit, not
only, as in the past, in the prevention of these diseases, but also in a rational
system of casual therapeutics.

CONSIDERATIONS CONCEENING SOME EXTERNAL SOURCES

OF INFECTION IN THEIR BEARING ON

PREVENTIVE MEDICINE'

No department of medicine has been cultivated in recent years with such
zeal and with such fruitful results as that relating to the causes of infectious
diseases. The most important of these results for preventive medicine and
for the welfare of mankind is the knowledge that a large proportion of the
causes of sickness and death are removable.

It is evident that efforts to preserve health will be most intelligently and
effectually applied when they are based upon an accurate and full knowledge
of the agencies which cause disease. Public and private hygiene, however,
cannot and fortunately has not waited for the full light of that day, whose
dawn has only begun to appear, when we shall have a clear insight into the
causation of preventable diseases. Cleanliness and comfort demand that
means shall be taken to render pure the ground on which we live, the air
which we breathe, and the water and food with which we are supplied, and
we must meet these needs without waiting to learn just what relation in-
fectious agents bear to the earth, air, water and food.

It is a fortunate circumstance that modern sanitation has been controlled
so largely by the belief in the dependence of endemic and epidemic diseases
upon organic impurities in the soil and in the water. Incomplete and even
erroneous in many respects as are the views which have prevailed concerning
the origin and spread of epidemic diseases by the decomposition of organic
substances, the sanitary measures which have been directed toward the re-
moval of filth have achieved great conquests in limiting the development and
extension of many infectious diseases. The benefits which one common-
wealth of this country has derived from the intelligent employment of public
sanitar}' measures were clearly and forcibly presented before this Association
last year by Dr. Walcott in his admirable address in State Medicine.

While nothing should be said or need be said to lessen the importance of
cleanliness for public health, it is important to bear in mind that hygienic
cleanliness and aesthetic cleanliness are not identical. In water, which
meets the most severe chemical tests of purity, typhoid bacilli have been
found. On the other hand, the air in the Berlin sewers, which certainly

' An address in State Medicine delivered before the American Medical Asso-
ciation, Newport, R. I., June 28, 1889.

Maryland M. J., Bait, 1889, XXI, 201-208; 226-234.

567

5G8 EXTERNAL SOURCES OF INFECTION

does not meet the most modest demands of aesthetic cleanliness, has been
found to be nearly or quite free from bacteria.

It needs only to be stated to be generally admitted that the scientific basis
of preventive medicine must be the accurate knowledge of the causative
agents of preventable diseases, a knowledge which can be derived only from
a careful study of all the properties of these agents, the modes of their recep-
tion and of their elimination by the body, the circumstances which favor and
those which retard or prevent their development and spread, their behavior
in the various substances which surround us or which we take into our
bodies, and the sources of infection, not only those which laboratory experi-
ments show to be possible, but those which are actually operative.

So long as we were unacquainted with the living organisms causing in-
fection, the means at our disposal for studying the etiology of infectious dis-
eases were limited to the observation of all of the circumstances which we
could determine regarding the origin and spread of these diseases. We
could only infer what might be the properties of the infectious agents from
the study of phenomena often obscure and difficult of interpretation.
Chiefly by this method of investigation the science of epidemiologj' has been
built up. It has established facts and laws no less of practical than of scien-
tific importance. But it has left unsolved many problems, and has filled
gaps with speculations. Admitted epidemiological facts are often open
to various interpretations.

We are evidently at a great advantage when we can study the epidemiologi-
cal facts with a knowledge of the substances which actually cause infection,
and this we are now enabled to do for a limited number of the infectious
diseases. This new method of research, which thus far has been mainly
bacteriological, has aided us not so much by simplifying the problems of
etiology, which still remain complicated enough, as by affording greater
accuracy to the results.

It is my aim in this address to consider some results of the modern studies
of pathogenic microorganisms in their bearing upon preventive medicine,
more particularly upon the sources of infection. It is, of course, impossible
within the limits of the address to attempt a complete survey of this impor-
tant field. Time will permit the presentation of only some of the salient
points.

Infectious diseases are those which are caused by the multiplication within
the body of pathogenic microorganisms.

It has always been recognized that some infectious diseases, such as the
exanthematous fevers, are conveyed directly from the sick to tlie healthy. It
is not disputed that in these evidently contagious diseases the infectious
germ is discharged from the body in a state capable at once of giving rise to
infection.

BEAEIXG ON" PREVENTIVE MEDICINE 569

In a second group of infectious diseases, of which malaria is the type, the
infected individual neither transmits the disease to another person nor, so
far as we know, is capable of infecting a locality. Here there is reason to
believe that the infectious germ is not thrown off in a living state from the
body, but is destroyed within the body. In this group the origin of infection
under natural conditions is always outside of +be body.

In a third group there is still dispute whether the disease can be trans-
mitted directly from person to person, but all are agreed that the infected
individual can infect a locality. It is especially fortunate that the bacteria
which cause cholera and typhoid fever, the two most important representa-
tives of this group of so-called miasmatic-contagious diseases, have been dis-
covered and isolated in pure culture. These are the diseases about whose
origin and epidemic extension there has been the greatest controversy. They,
above all other diseases, have given the impulse to public sanitation during
the last half century. The degree of success with which their extension in
a community is prevented is an important gauge of the excellence of the
local sanitarv" arrangements. A clear comprehension of the origin and
spread of these diseases signifies the solution of many of the most vexed and
important problems of epidemiology and of state hygiene.

It is difficult to understand how those who accept the discovery that the
bacteria causing typhoid fever and cholera have been found and cultivated
from the stools of patient? affected with these diseases, can doubt that these
patients are possible sources of contagion or can entertain the view once so
widely prevalent that the infectious germs of these diseases are discharged
from the body in a condition incapable of producing immediate infection.
In an address delivered on another occasion I have endeavored to present
the considerations which reconcile the comparative infrequency of direct
contagion for these diseases with the belief in the elimination of the causative
germs in an active state from the body, and have there pointed out several
well known factors which determine the frequency of conveyance of an in-
fectious disease by contagion. There are reasons, some of them very obvious,
whj' diseases in which the infectious substances are operative only when
received into the digestive tract, and are discharged usually only with the
feces, are less likely to be transmitted by immediate contagion than those
diseases in which the virus is thrown off from the skin on epidermal scales.

But the field of operation of direct contagion for these so-called miasmatic-
contagious diseases is at most a restricted one and the chief sources of infec-
tion are outside of the body from which primarily the infectious germs may
have been derived. It is to these external sources of infection, which
are of such importance in public hygiene, that I wish especially to direct
attention.
39

570 EXTERNAL SOURCES OP INFECTION

A full comprehension of the sources of infection is, to be obtained only
by a detailed study of the etiology of the individual infectious diseases, but
this is, of course, impossible within the limits of an address. It may, how-
ever, be useful to present some of the facts which have a general bearing upon
the subject. Let us consider, then, from the point of view of modern bacte-
riological studies, what role, in harboring or transporting infectious agents,
may be played by those substances or media with which we necessarily come
mto intimate contact, such as the air, thq ground, the water and our food.

It is universally admitted that many infectious agents may be transported
by the air, but the extent of danger from this source has often been exag-
gerated. It is a popular error to suppose that most of the minute particles
of dust in the air either are or contain living organisms. The methods for
determining the number and kind of bacteria and fungi in the air are now
fairly satisfactory, altliough by no means perfect. These have shown that
while the number of living bacteria and fungi in the atmosphere in and
around human habitations cannot be considered small, still it is greatly
inferior to that in the ground or in most waters. Unlike fungus spores,
bacteria do not seem to occur to any extent in the air as single detached
particles, which would then necessarily be extremely minute, but rather in
clumps or attached to particles of dust of relatively large size. As a result
in a perfectly quiet atmosphere these comparatively heavj- particles which
contain bacteria rapidly settle to the ground or upon underlying objects
and are easily filtered out by passing the air through porous substances such
as cotton wool or sand. Rain washes down a large number of bacteria from
the air. That the air bacteria are derived from the ground or objects upon
it is shown by their total absence, as a rule, from sea air at a distance from
land, this distance naturally varying with the direction and strength of the
wind.

A fact of capital importance in understanding the relations of bacteria to
the air, and one of great significance for preventive medicine, is the impossi-
bility of currents of air detaching bacteria from moist surfaces. Substances
containing pathogenic bacteria, as, for instance, sputum containing tubercle
bacilli or excreta holding typhoid bacilli, cannot, therefore, infect the air
unless these substances first become drj' and converted into a fine powder.
We are able to understand why the expired breath is free from bacteria and
cannot convey infection, except as little particles may be mechanically de-
tached by acts of coughing, sneezing or hawking. Those bacteria, the vitality
of which is rapidly destroyed by complete desiccation, such as those of Asiatic
cholera, evidently are not likely to be transported as infectious agents by
the air, if we except such occasional occurrences as their conveyance for a
short distance in spray.

BEARING ON PREVENTIVE MEDICINE 571

The only pathogenic bacteria which hitlierto have been found in the air
are tlie pus organisms, including the streptococcus found by Prudden in a
series of cases of diphtheria, and tubercle bacilli, but no far reaching con-
clusions can be drawn from the failure to find other infectious organisms
when we consider the imperfection of our methods and the small number of
observations directed to this point. The evidence in other ways is conclusive
that many infectious agents — and here the malarial germ should be promi-
nently mentioned — can be and often are conveyed by the air. While we
are inclined to restrict within narrower limits than has been customary the
danger of infection through the air, we must recognize that this still remains
an important source of infection for many diseases. All those, however,
who have worked practically with the cultivation of microorganisms have
come to regard contact with infected substances as more dangerous than
exposure to the air, and the same lesson may be learned from the metliods
which modem surgeons have foimd best adapted to prevent the infection of
wounds with the cosmopolitan bacteria which cause suppuration.

"We are not, of course, to suppose that infectious germs floating in the
form of dust in the atmosphere are dangerous, only from the possibility of
our drawing them in with the breath. Such germs may be deposited on sub-
stances with which we readily come into contact, or they may fall on articles
of food where they may find conditions suitable for their reproduction,
which cannot occur when they are suspended in the air in consequence of the
lack of moisture.

From the facts which have been mentioned concerning the relations of
bacteria to the air, what points of view present themselves to guide us in pre-
venting infection through this channel? Surely something more than that
this purpose is accomplished simply by abolishing foul odors.

Certain indications are so plain as to need only to be mentioned in this
connection, such as the disinfection and removal, as far as possible, of all
infected substances, an indication wliich applies equally to all channels of
infection and which it is much easier to mention than it is to describe how
it shall be realized. But there are two indications which apply especially to
the prevention of the transportation of disease germs by the air. One is
the necessity of guarding, so far as practicable, against the dessication, when
exposed to the air, of substances which contain infectious germs not de-
stroyed by drying, and another is free ventilation.

For no disease is the importance of the first of these indications so evident
and so weU established as for tuberculosis, the most devastating of all infec-
tious diseases. Against this disease, formidable as it may seem to cope with
it, the courageous crusade of preventive medicine has begun and is destined
to continue.

572 EXTERNAL SOURCES OF INFECTION

It is now jjenerally recognized that the principal, although not the sole,
sources of tuherculous infection are the sputum of individuals affected with
pulmonary tuberculosis and the milk of tuberculous cows. Comet, who has
made a laborious and most instructive experimental study of the modes and
dangers of infection from tuljcrculous sputum, has also elaborated the
practical measures which should be adopted to diminish or annihilate these
dangers. These measures have been so recently and so widely published in
medical journals, and so clearly presented before a section of this association,
that I mention them only to call the attention of practitioners of medicine
to their importance and to emphasize the fact that they are based chiefly
upon the principle that infectious substances of such nature as tuberculous
sputum should not be allowed to become dry and converted into dust when
exposed to the air.

By means of free ventilation, disease-producing microorganisms which
may be present in the air of rooms are carried away and distributed so far
apart that the chance of infection from this source is removed or reduced
to a minimum. It is a well established clinical observation that the distance
through which the specific microbes of such diseases as smallpox or scarla-
tina are likely to be carried from the patient by the air, in such concentration
as to cause infection, is small, usually not more than a few feet, but increases
by crowding of patients and absence of free ventilation. The well known
experiences in the prophylaxis and treatment of typhus fever are a forcible
illustration of the value of free ventilation.

It is, of course, not to be understood that by ventilation we accomplish
the disinfection of a house or apartment. Ventilation is only an adjunct of
such disinfection which, as already mentioned, is of first importance. Time
will not permit, nor is it in the plan of this address, to discuss the details
of such questions as house disinfection, but I may be permitted to say that
the methods for disinfecting apartments have been worked out on a satis-
factory experimental basis and shf^uld be known, at least by all public health
officers. Whether it be pertinent to this occasion or not, I cannot forbear to
add my protest to that of others against placing reliance upon any method
hitherto employed of disinfecting houses or apartments by fumigation.
And I would, furthermore, call attention to the lack in most cities of this
country of public disinfecting establishments such as are in use, with ex-
cellent results, in many cities of Europe, and which are indispensable for
the thorough and convenient disinfection of clothing, bedding, carpets, cur-
tains, etc.

After this short digression let us pass from the consideration of the air
as a carrier of infection to another important external source of infection,
namely, the ground. That the prevalence of many infectious diseases de-

BEARING OX PEEVENTIVE MEDICINE 573

pends upon conditions pertaining to the soil cannot be questioned, but the
nature and the extent of this influence have been and are the subjects of lively
discussion. The epidemiological school, led by Pettenkofer, assigns, as is
well known, to the ground the chief and even a specific and indispensable
influence in the spread of many epidemic diseases, particularly cholera and
typhoid fever. The statistics, studies and speculations of epidemiologists
which have related to this subject probably surpass in number and extent
those concerning any other epidemiological factor. The exclusive ground
hypothesis has become an ingenious and carefully elaborated doctrine with
those who believe that such diseases as cholera and tj-phoid fever can never
be transmitted by contagion. These authorities cling to this doctrine with
a tenacity which indicates that on it depends the survival of the exclusively
locaUstic dogma of these diseases.

To all who have not held aloof from modern bacteriological investisrations
it must be clear tliat views which have widely prevailed concerning the rela-
tions of many infectious germs to the,soil require revision. The question is
still a difficult and perplexing one, but on some hitherto obscure or misunder-
stood points these investigations have shed light, and from the same source
we may expect further important contributions to a comprehension of the
relations of the ground to the development of infectious diseases.

The ground, unlike the air, is the resting or the breeding place of a vast
number of species of microorganisms, including some which are pathogenic.
Instead of a few bacteria or fungi in a liter, as vrith the air, we find in most
specimens of earth thousands and often himdreds of thousands of micro-
organisms in a cubic centimeter. Fraenkel found the virgin soil almost as
rich in bacteria and fungi as that around human habitations.

This vast richness in microorganisms belongs, however, only to the super-
ficial layers of the earth. Where the ground has not been greatly disturbed
by human hands there is, as a rule, about three to five feet below the surface
an abrupt diminution in the number of living organisms, and at the depth
where the sub-soil water usually lies, bacteria and fungi have nearly or en-
tirely disappeared. Fraenkel, who first observed this sudden diminution in
the number of microorganisms at a certain level beneath the surface, explains
this singular fact by the formation at this level of that sticky accumulation
of fine particles consisting largely of bacteria, which forms the efficient
layer in large sand filters for water. Of course the number of bacteria and
the depth to which they penetrate will vary somewhat with the character,
especially the porosity, of the soil and its treatment, but the important fact
that all, or nearly all, of the bacteria and fungi are retained in the ground
above the level of the sub-soil water will doubtless hold true for most .situa-
tions.

574 EXTERNAL SOURCES OF INFECTION

The conditions are not favorable for the multiplication of bacteria in the
depth of the ground, as is shown by the fact that in specimens of earth brought
to the surface from a depth of a few feet, the bacteria which are at first pres-
ent rapidly multiply. What all of the conditions are which prevent the re-
production of bacteria in the deep soil has not been ascertained, but the fact
necessitates similar precautions in the bacteriological examination of the
soil as in that of water.

We have but meagre information as to the kinds of bacteria present in
the ground in comparison with their vast number. Many of those which
have been isolated and studied in pure culture possess but little interest for
us so far as we know. To some of the microorganisms in the soil appears to
be assigned the role of reducing or of oxidizing highly organized substances
to the simple forms required for the nutrition of plants. We are in the habit
of considering so much the injurious bacteria that it is pleasant to contem-
plate this beneficent function so essential to the preservation of life on this
globe.

Among the pathogenic bacteria which have their natural home in the
soil the most widely distributed are the bacilli of malignant oedema and those
of tetanus. I have found some garden earth in Baltimore extremely rich in
tetanus bacilli, so that the inoculation of animals in the laboratorj' with
small bits of this earth rarely fails to produce tetanus. In infected localities
the anthrax bacillus and, in two instances, the typhoid bacillus, so far as it
was passible to identify it, have been discovered in the earth. There is
reason to believe that other germs infectious to human beings may have
their abiding place in the ground; certainly no one doubts that the malarial
germ lives there. As the malarial germ has been shown to be an organism
entirely different from the bacteria and the fungi, we cannot apply directly
to its behavior in the soil and its transportation by the air, facts which have
been ascertained only for the latter .species of microorganisms, and the
same precautions must be observed for other diseases with whose agents of
infection we are not acquainted, as, for instance, yellow fever.

In view of the facility with which infectious germs derived from human
beings or animals may gain access to the soil, it becomes a matter of great
importance to determine how far such germs find in the soil conditions
favorable for their preservation or their growth. We have, as is well known,
a number of epidemiological observations bearing upon this subject, but
with few exceptions these can be variously interpreted and it is not my
purpose to discuss them. The more exact bacteriological methods can, of
course, be applied only to the comparatively small number of infectious dis-
eases, the causative germs of which have been isolated and cultivated, and
those methods hitherto have been applied to this question only imperfectly.

BEAEING ON PEEVENTIVE MEDICINE 575

We cannot regard the soil as a definite and unvarying substance in its
chemical, physical and biological properties. What has been found true of
one kind of soil may not be so of another. Moreover, we cannot in our ex-
periments bring together all of the conditions in nature wliich may have a
bearing on the behavior of specific microorganisms in the soil. We must,
therefore, be cautious in coming to positive conclusions on this point on the
basis of experiments, especially those with negative result. With these
cautions kept constantly in mind the question, however, is one eminently
open to experimental study.

The experiments which have thus far been made to determine the behavior
of infectious microorganisms in the ground have related especially to the
bacilli of anthrax, of t\"phoid fever and of cholera, and fortunately these are
the diseases about whose relations to the ground there has been the most
discussion and concerning which we are most eager to acquire definite in-
formation.

As regards anthrax bacilli, it has been determined that in ordinary garden
or field earth they do not multiply, but in earth contaminated by blood,
urine or feces their reproduction can occur. They can grow on various
vegetable substrata. There is no reason to doubt, therefore, that the anthrax
bacilli can find in or on the ground suitable conditions for their multiplica-
tion, although such conditions are not everywhere present. For durable
infection of the soil with anthrax bacilli, it is, however, more important that
these bacilli should find there suitable conditions for the formation of spores,
than that they should be able simply to multiply. The vegetative forms of
anthrax bacilli would not, as a rule, be able to survive for a great length of
time the hostile influences which they are likely to encounter in the ground,
such as insuiBcient or exhausted moisture and the attacks of saprophytic
organisms. On the other hand, against these injurious influences the anthrax
spores have great resistance. In the superficial layers of the ground the
anthrax bacilli may often find those conditions of moisture, of temperature,
of oxygen supply and of insufficient food, which we know are most favorable
for the development of their spores ; indeed Soyka has shown that the ground
presents often these conditions better than our culture media. A circum-
stance discovered by Feltz, which, however, needs confirmation, is, if true,
of not little significance. He finds that anthrax bacilli may undergo a pro-
gressive diminution in virulence in the soil. If this should be true likewise
of other infectious microorganisms, we should be able to account in some
instances for the variable degree of virulence which clinical observation in-
dicates that certain agents of infection acquire.

So far as anthrax bacilli are concerned, we may conclude, therefore, that
the ground occasionally offers suitable conditions for their reproduction.

576 EXTERNAL SOURCES OF INFECTION

but what is of greater importance, it offers especially favorable conditions
for their long continued preservation in the form of spores. I must forego
here the further consideration of the special circumstances inherent in the
soil which control the origin and spread of epidemics of anthrax in cattle,
although many interesting investigations have been directed to this subject.

Of greater interest to physicians is the behavior of typhoid and of cholera
bacteria in the ground. As has already been intimated the ground is re-
garded by Pettenkofer and his school as the principal breeding place of these
microorganisms outside the body. This view, however, is not supported by
bacteriological investigations. Inasmuch as the cholera and typhoid bacilli
may multiply on various vegetable substrata and substances derived from
animals at temperatures often present in the ground, it is evident that here
and there conditions may be present for their growth in the ground, but this
growth is likely to be soon interrupted by the invasion of ordinary saprophy-
tic organisms and other harmful influences. The typhoid bacilli are more
hardy in resisting these invaders than are the cholera bacteria, which easily
succumb, but even for the former, so far as our present knowledge extends,
the ground can rarely serve as a favorable breeding place.

It is not, however, necessary that these organisms should multiply in
order to infect for a considerable time the ground; it is sufficient if their
vitality is preserved. As to this latter point, the reports of different investi-
gators are not altogether concordant. Such excellent observers as Koch,
Kitasato and Uffelmann found that the cholera bacteria, when added to feces
or a mixture of feces and urine, rapidly diminished in number and at tlie
end of three or four days at the most, had wholly disappeared. In a mixture
of the intestinal contents from a cholera corpse with earth and water Koch
found many cholera bacteria at the end of three days, but none at tlie end of
five days. On the other hand, Gruber reports the detection of cholera bacteria
in dejecta fifteen days old. The weight of bacteriological evidence, there-
fore, is opposed to the supposition that the bacteria of Asiatic cholera pre-
serve their vitality for any considerable time in the ground or in the excreta.

With respect to the bacilli which cause typhoid fever, it has been sho\vn
by Uffelmann that these may live in feces, mixture of feces and urine, and
mixture of garden earth, feces and urine for at least four or five montlis,
and doubtless longer, although they may die at the end of a shorter period.
He also finds that under these apparently unfavorable conditions some
multiplication of the bacilli may occur, although not to any considerable
extent. G rancher and Deschamps found that typhoid bacilli may live in
the soil for at least five months and a half. Unlike the cholera bacteria,
therefore, the typhoid bacilli may exist for months at least in the ground
and in fecal matter, holding their own against the growth of multitudes of

BEARING ON PREVENTIVE MEDICINE 677

saprophytes. This difference in the behavior of cholera and of typhoid
germs is in harmony with clinical experience.

As regards other infectious bacteria than those which have been considered
I shall only mention that tubercle bacilli, although incapable of multiplica-
tion under the ordinary conditions of nature on+side of the body, may pre-
serve their vitahty for a long period in the ground, on account of their
resistant character, and, furthermore, that the pyogenic cocci, on account
of their considerably resistant nature and-their modest demands in the way
of nutriment, can be preserved and sometimes probably grow in the ground.
Indeed Staphylococcus pyogenes aureus has been found in the earth by
Liibbert.

The conclusion which we may draw from the observations mentioned is
that, in general, the soil is not a good breeding place for most of the infec-
tious bacteria with which we are acquainted, but that it can retain for a long
time with unimpaired vitality those which produce ispores or which offer
considerable resistance to injurious agencies, such as anthrax bacilli, typhoid
bacilli, tubercle bacilli and the pyogenic cocci.

In order to become infected with bacteria in or on the ground, these bacteria
must in some way be introduced into the body and we must, therefore, now
attempt to determine how bacteria may be transported to us from the ground.
So various and intricate are the possibilities for this transportation that it
is hopeless to attempt to specify them all.

There occurs to us first the possibility of the conveyance of infectious
microorganisms from the soil by means of currents of air, a mode of carrying
infection which ha5 already been considered. Here I shall only repeat that
the wind can remore bacteria from the ground only when the surface is dry
and presents particles of dust, and that the sole, and perhaps the chief, danger
is not that we may inhale the infected dust.

Manifold are the ways in which we may be brought into contact with in-
fectious bacteria in the ground, either directly or by means of vegetables to
which particles of earth are attached, by the intervention of domestic
animals, by the medium of flies or other insects, and in a variety of other
ways, more or less apparent.

An important, doubtless for some diseases the most important, medium
of transportation of bacteria from an infected soil is the water which we
drink or use for domestic purposes. From what has been said it is evidently
not the sub-soil water which is dangerous, for infections like other bacteria
cannot generally reach this in a living state, but the danger is from the
surface water and from that which trickle? through the upper layers of the
ground, as well as from that which escapes from defective drains, gutters,
cess-pools, privy vaults and wrongly constructed sewers or improper dis-

578 EXTERNAL SOURCES OF INFECTION

posal of sewerage. I shall have something to say presently of water as a
source of infection, and shall not further elaborate here the dangers of in-
fection of drinking water through contaminated soil, dangers which, especi-
ally as regards typhoid fever, are widely appreciated in this country, even if
often imperfectly counteracted.

A point which has been much discussed and one of interest is, whether
bacteria which are in the depth of the ground can come to the surface. Two
agencies especially have been considered by some as capable of transporting
bacteria from the depth to the surface. One is ascending currents of air in
the ground and the other is the capillarity of fluids in the minute pores of
the ground. The first of these suspected agencies must be unquestionably
rejected in view of the fact that even a few inches of sand is sufBcient to
filter all of the bacteria out of the air, even when it is in much more rapid
motion than can occur within the ground. Moreover, that degree of dryness
which is essential for the detachment of bacteria by air-currents is not
likely to be present much below the surface of the groimd. The experiments
which have been made to determine to what extent bacteria may be carried
upward by the capillarity of fluids in the ground have not yielded harmo-
nious results, but the weight of evidence is opposed to the belief that this is a
factor of any considerable importance for this purpose.

From what has been said concerning the growth of pathogenic bacteria in
the soil we shall not be inclined to attribute to the multiplication and the
motility of these organisms much influence in changing their places in the
ground.

The somewhat sensational role assigned by Pasteur to earthworms of
bringing bacteria to the surface cannot be wholly ignored and has received
support from observations of Bollinger regarding anthrax, but it is question-
able whether much importance is to be attached to this agency.

Regarding the depth to which typhoid bacilli may penetrate in the soil,
the experiments of Grancher and Deschamps shows that at the end of five
weeks they may reach a depth of 16 to 20 inches below the surface. As Hoff-
mann has demonstrated the extraordinary slowness with which fluids and
fine particles penetrate the soil, it is probable that in the course of time a
greater depth than this may be reached. Indeed, Mace claims to have found
in the neighborhood of a well suspected of infection, typhoid bacilli, to-
gether with ordinary intestinal bacteria, at a depth of at least 6^ feet below
the surface. There are a number of instances recorded in wliich there is
good reason to believe that turning up the soil and cleaning out privies or
dung-heaps in which typhoid stools have been thrown, have given rise to
typhoid fever, even after the infectious excreta have remained there a year
or more.

BEARING ON PREVEXTIVE MEDICINE 579

It cannot be said that bacteriological investigations have as yet shed much
light upon a factor which plays a great role in epidemiologj', namely, pre-
disposition to infection from the ground, according to locality and time, and
this deficiency receives constant and vehement emphasis from the localistic
school of epidemiologists. We can, however, readily understand that varying
conditions, such as temperature, moisture, porosity, quality of soil, may
exert a controlling influence in determining the behavior of infectious
germs in the soil and the facility of their transportation to human beings or
animals. As regards that much-discussed question, the significance of varia-
tions in the height of the sub-soil water, in relation to the prevalence of
certain epidemic diseases, particularly cholera and typhoid fever, we now
know that this cannot depend upon the presence of bacteria in the sub-soil
water itself or in the capillary layers immediately above it. It has been
plausibly suggested that with the sinking of the sub-soil water fluids from
infected cess-pools, privy vaults, and other localities may more readily be
drawn into wells or other sources of water supply, and that by the same
cause the surface of the ground becomes dry so that dust particles may be
lifted by the wind. Other more or less plausible explanations have also
been offered, but it must be confessed that our positive information on the
point is meagre. There can, however, be little doubt that this significance
of the variations in sub-soil water is apparent only for certain localities and
has been considerably exaggerated and often misunderstood. It is not,
however, pertinent to my theme to discuss this or other purely epidemiological
observations concerning the relations of the ground to the spread of epidemic
diseases, interesting and important as are many of these observations.

Before leaving the subject of the ground as a source of infection, permit
me to indicate briefly some conclusions which may be drawn from what has
been said as to the principles which should guide us in preventing infection
directly or indirectly from the ground.

First in importance is to keep infectious substances so far as possible from
the ground. This implies the early disinfection or destruction of such sub-
stances as t3-phoid and cholera excreta and tuberculous sputum.

Second. The ground should be rendered so far as practicable unsuitable
for the continued existence of infected germs. This, at least for some dis-
eases, is accomplished by a proper system of drainage, which, moreover, for
other reasons possesses hygienic importance.

Third. Means should be provided to prevent waste products from getting
into the ground around human habitations or from gaining access to water
used for drinking or domestic purposes. In cities this can be accomphshed
only by a properly constructed system of sewers. The system of storing
waste products in cess-pools whence they are to be occasionally removed

580 EXTERNAL SOURCES OF INFECTION

cannot be approved on hygienic grounds. There are conditions in which
the disposal of waste products in deep wells only used for this purpose and
whence these products can filter into the deep layers of the ground may be
permissible, but this can never be considered an ideal method of getting rid
of excrementitious substances, and is wholly wrong in regions where wells
are used for drinking water. But I am trespassing with these remarks upon
a province which does not belong to me, but rather to practical sanitarians
and engineers. I shall only add that the advantage gained by preventing
organic waste from soaking into the ground is not so much that the ground
i.s thereby rendered better adapted for the existence of infectious micro-
organisms, but is due rather to the fact that this waste is likely to contain
infectious germs.

Finally, in cities, good pavements, absence of unnecessary disturbance of
the soil, cleanliness of the .streets, and laying of dust by sprinkling are not
only conducive to comfort, but are sometimes hygienically important in pre-
venting infection from the ground and dust.

In passing from the consideration of the ground to that of water, one
feels that he now has to do with a possible source of infection against which
in this country and in England he is at liberty to make any accusation he
chooses without fear of contradiction. There is reason to believe that such
accusation has been repeatedly made without any proof of misdemeanor on
the part of the water. It is not, therefore, with any desire to awaken further
the medical or the public conscience that I wish to say a few words concern-
ing the behavior of bacteria in water and the dangers of infection from this
source. That such dangers are very real must be apparent when we consider
the universal employment of water and its exposure to contamination from
all kinds of sources.

Ordinary water, as is well known, contains bacteria in large number. Not
a few species of bacteria can multiply rapidly and to a large amount even
in distilled water. These are the so-called water-bacteria, and like most of
the microorganisms found in ordinary drinking water are perfectly harmless
saprophytes. What we wish to know is, how pathogenic microorganisms
conduct themselves in water. Can they grow or be preserved for any length
of time in a living condition in water? As regards the multiplication of
pathogenic bacteria in water the results of different experimenters do not
altogether agree. Wiereas Bolton failed to find any gro^rth, but rather a
progressive diminution in the number of pathogenic bacteria planted in
sterilized water. WolfPhiigpl and Ricdel ob>ierved a limited reproduction of
such bacteria, including tho.'^e of typiioid fever and cholera. This ditTcrence
is due, probably, to the methods of experimentation employed. According
to Kraus, these latter bacteria diminish rapidly in numljcr in unsterilized

BEAEING ON PREVENTIVE MEDICINE 581

spring or well water kept at a low temperature. The?e experiments indicate
that water, even when contaminated with more organic impurities than are
likely ever to be present in drinking water, is not a favorable breeding place
for pathogenic bacteria. Still it is to be remembered that these laboratory
experiments do not reproduce exactly all of the conditions in nature, and it
may happen that in some nook or cranny or vegetable deposit at the side of
a well or stream some pathogenic bacteria may find suitable conditions for
their multiplication.

But as has been repeatedly emphasized in this address it is not necessary
that pathogenic bacteria should actually multiply in a medium in order to
render it infectious. It is suiEcient if their life and virulence are not de-
stroyed in a very short time. As to this important point Bolton found that
in sterilized water typhoid bacilli may preserve their vitality for over three
months and cholera bacteria for 8 to 14 days, while Wolffhiigel and Eiedel
preserved the latter in water for about 80 days. Under natural conditions,
however, these organisms are exposed to the over growth of the water
bacteria so that Kraus found in unsterilized water kept at a temperature of
10.5° C. (50.9°F.) the typhoid bacilli no longer demonstrable after 7 days,
and the cholera bacteria after 2 days. The conditions in Kraus's experiments
were as unfavorable as possible for the continued existence of these patho-
genic bacteria, more unfavorable than those often present at the season of
prevalence of cholera and typhoid fever, nevertheless I do not see that they
justify the conclusions of Kraus as to the slight probability of drinking
water ever conveying infection with the germs of typhoid fever and cholera.
To render such a conclusion probable it would be necessary to demonstrate
a much shorter preservation than even Kraus himself found. In judging
this question it should not be overlooked that infection of drinking water
with the typhoid or the cholera germs is not so often the result of throwing
typhoid or cholera stools directly into the source of water supply as it is the
consequence of leaky drains, cess-pools, privy-vaults or infected soil, so that
there may be continued or repeated accessions of infected material to the
water.

In view of the facts presented, there is no sufficient reason, therefore, from
a bacteriological point of view, of rejecting the transmissibility of t}'phoid
fever and cholera by the medium of the drinking water. This conclusion
seems irresistible when we call to mind that Koch once found the cholera
bacteria in large number in the water of a tank in India, and that the typhoid
bacilli have been repeatedly found in drinking water of localities where
typhoid fever existed. Nor do I see how it is possible to interpret certain
epidemiological facts in any other way than by assuming that these diseases
can be contracted from infected drinking water, although I know that there

582 EXTERNAL SOUKCES OF INFECTION

are still high authorities who obstinately refuse to aecept this interpretation
of the facts.

In this connection it may be mentioned that pathogenic bacteria may
preserve their vitality longer in ice than in unsterilized drinking water.
Thus Prudden found typhoid bacilli still alive which had been contained
in ice for 103 days.

When we come to consider the ways in which water may become infected
with pathogenic microorganisms we recognize at once a distinction in this
respect between surface water and sub-soil water. Whereas tlie sub-soil
water may be regarded under ordinary circumstances and in most places as
germ-free, the surface water, such as that in rivers, and streams, is exposed
to all manner of infection from the ground, the air, and the admission of
waste substances. Unfortunately in the ordinary way of obtaining sub-soil
water for drinking purposes by means of dug wells this distinction is obliter-
ated, for the water which enters these wells free from bacteria is converted
into a surface water often exposed, by the situation of the well, to more
dangerous contamination than other surface waters used for drinking pur-
poses.

Now let us turn our attention as we have done with other sources of in-
fection to a brief outline of certain general principles which may help us in
avoiding infection from the water.

We shall in the first place avoid so far as possible the water suspected of
infection, especially with the germs of such disease as typhoid fever and
cholera. When it is necessary to use this suspected water it should be boiled.

As regards the ^-ital question of water supply, it may be stated as a general
principle that no hygienic guarantee can be given for the purity of surface
water which has not been subjected to a proper system of filtration, or for
the purity of spring or well water fed from tlie sub-soil unless such water is
protected from the possibility of infection through the upper layers of the
soil or from the air. This is not saying that water which meets certain
chemical and biological tests and which is so situated that the opportunities
for its contamination appear to be absent or reduced to a minimum is not
admissible for the supply of drinking water, but the possibility of infection
can be removed only by the fulfillment of the condition named, and upon
these conditions the hj-gienic purist will always insist.

Unfortunately we have at present no domestic filters which are satisfactory
and most of the^e in common use are worse tlian none, as they soon furnish
a filtrate richer in bacteria than the original water. The only effective
method of water-filtration for the general supply is by means of large sand
filters such as are in use with excellent results in Berlin and some other
cities. These require skilled attention. I cannot on this occasion discuss

BEARING ON PREVENTIVE MEDICINE 583

the construction or working of these filters but would refer those who are
interested to the full and careful investigations of the Berlin filters by
Wolifhiigcl and by Plagge and Proskauer.

What is accomplished by these artificial .sand filters is accomplished under
natural conditions, also by the ground, which furnishes a sub-soil water free
from microorganisms, and to obtain pure water vo have only to devise means
by which this sub-soil water may be secured without the chance of contamina-
tion. Just as the water, which has passed through the sand filters, is col-
lected in suitable reservoirs and is distributed in pipes, which do not admit
contamination from without, so by means of properly constructed artesian
or driven wells we may secure the naturally filtered sub-soil water with the
same freedom from the chances of infection.

It is well to bear in mind that no biological or chemical tests of water can
replace those measures which have been mentioned as necessary to secure
purity of water supply. These tests are of value only when applied with
proper precautions and with due consideration of the special circumstances
of each case for which they are employed. There has been much profitless
discussion as to whether greater significance is to be attached to the chemical
or to the bacteriological examination of water. Each has its own special
field of application and in this the one cannot replace the other method.
The bacteriological examination has for hygienic purposes the specific agents
of infection in the form of microorganisms, as has already been done for
cholera bacteria and typhoid bacilli, but this is a comparatively rare result
and does not at present afford a wide field of application for this method.
The significance of the bacteriological test is to be based more frequently
upon the fact that it concerns itself with the same class of microorganisms
to which some of the recognized and doubtless many of the undiscovered in-
fectious agents belong and from the behavior of which in some respects con-
clusions can be drawn as to the behavior of the pathogenic organisms. Thus
the bacteriological test is the only one which enables us to judge correctly
of the efficacy of those methods of filtration of surface water and of con-
struction of wells which insure purit}' of water supply. The points of view
from which we can estimate correctly according to our present knowledge
the relative merits and fields of application of the chemical and of the bacte-
riological methods of water examination have been clearly indicated by
Plagge and Proskauer and by Wolffhiigel. The theme is one beyond the
limits or the scope of this discourse and I have referred to its chiefly to em-
phasize the fact that we cannot rely upon chemical or bacteriological tests of
water to the exclusion of those protective measures which have been men-
tioned, although I do not intend to imply that each of these tests when
properly employed does not afford important information and is not of great
value in many eases.

581 EXTERNAL SOURCES OF INFECTION

I have already taxed so largely your time and patience that I must pass
over with brief mention the food as a source of infection. Unlike those
external sources of infection which we have hitherto considered, many
articles of food afford an excellent nutritive medium for the growth of a
number of species of pathogenic microorganisms, and in many instances
this growth may be abundant without appreciable change in the appearance
or taste of the food.

When we consider in how large degree the certainty and the severity of
infection with many kinds of pathogenic microorganisms depend upon the
number of such organisms received into the body, we can appreciate that
the danger of infection from food which contains a mass of growing patho-
genic bacteria may be much greater than that resulting from the reception
of infected water or air, media in which infected organisms are rarely
present in other than a very dilute condition. The entrance into the body
of a single infectious bacterium with the inspired air is, at least in the
case of many, many diseases, not likely to cause infection, but let this
bacterium fall upon some article of food, as for instance milk, where it
can multiply in a short time at a favorable temperature many thousand
fold, and evidently the chances of infection become vastly increased.

Among the various agencies by which infectious organisms may gain
access to the food may be mentioned the deposition of dust conveyed by
the air, earth adhering to vegetables, water used in mixing with or in the
preparation of food, in cleaning dishes, clothes, etc., and contact in mani-
fold other ways with infected substances.

Fortunately a very large part of our food is sterilized in the process of
cooking shortly before it is partaken, so that the danger of infection from
this source is greatly diminished and comes into consideration only for un-
cooked or partly cooked food and for food, which, although it may have been
thoroughly sterilized, is allowed to stand considerable time before it is used.
Milk, in consequence of its extensive use in an unsterilized state and of the
excellent nutritive conditions which it presents to many pathogenic bacteria,
should be emphasized as especially liable to convey certain kinds of infection,
a fact supported not less by bacteriological than by clinical observations.
Ilesse found that also a large number of ordinary articles of food prepared
in the kitchen in the usual way for the table and then sterilized afford a
good medium for the growth and preservation of typhoid and cholera
bacteria, frequently without appreciable change in the appearance of the
food.

Upon solid articles of food bacteria may multiply in separate colonies, so
that it may readily happen that only one or two of those who partake of the
food eat the infected part, whereas with infected liquids, such as milk, the

BEARING ON PREVENTIVE MEDICINE 585

infection is more liiicly to be transmitted to a larger number of those who are
exposed.

In another important particular the food differs from the other sources
of infection which we have considered. Not only the growth of infectious
bacteria, but also that of bacteria incapable of multiplication within the
body, may give rise in milk and other kinds of food to various ptomaines,
products of fennentation and other injurious substances which when ingested
are likely to cause more or less severe intoxication or to render the alimentary
tract more susceptible to the invasion and multiplication of genuinely in-
fectious organisms.

It is plain that the liability to infection from food will vary according to
locality and season. In some places and among some races the proportion of
uncooked food used is much greater than in other places and among other
races. In general, in summer and in autumn, the quantity of fruit and food
ingested in the raw state is greater than at other seasons, and during the
summer and autumn there is also greater danger from the transportation
of disease germs from the ground in the form of dust and the amount of
liquids imbibed is greater. The elements of predisposition, according to
place and time upon which epidemiologists are so fond of laying stress, are
not, therefore, absent from the source of infection now under consideration.

I have thus far spoken only of the secondary infection of. food by patho-
genic microorganisms, but, as is well known, the substances used for food
may be primarily infected. Chief in importance in the latter category are
the various entozoa and other parasites which infest animals slaughtered for
food. The dangers to mankind resulting from the diseases of animals form
a separate theme, which would require more time and .space than this address
affords for their proper consideration. I shall content myself on this occasion
with only a brief reference to infection from the milk and flesh of tuberculous
cattle.

It has been abundantly demonstrated by numerous experiments that the
milk from tuberculous cows is capable when ingested of causing tubercu-
losis. How serious is the danger may be seen from the statistics of Bollinger
who found with cows affected with extensive tuberculosis the milk infectious
in 80 per cent of the cases, in cows with moderate tuberculosis the milk in-
fectious in 66 per cent of the cases and in cows with slight tuberculosis the
milk infectious in 33 per cent of the cases. Dilution of the infected milk
with other milk or with water, diminished or in sufficient degree it removed
the danger of infection. From statistics furnished me by Mr. A. W. Clement,
V. S., it appears that the number of tuberculous cows in Baltimore which are
slaughtered is not less than 3 to 4 per cent. Among some breeds of cattle
tuberculosis is known to be much more prevalent than this.
40

586 EXTERNAL SOURCES OF INFECTION

There is no evidence that the meat of tuberculous cattle contains tubercle
bacilli in sufficient number to convey infection, unless it be very exceptionally.
Nevertheless one will not \\nllin(rly consume meat from an animal known to
be tuberculous. This instructive repugnance, as well as tlie possibility
of postmortem infection of the meat with tubercle bacilli in dressing the
animal seem good grounds for discarding sucli meat. The question, however
as to the rejection of meat of tuberculous animals has important economic
bearings and has not been entirely settled. As to the rejection of the milk
from such animals, however, there can be no difference of opinion, although
this is a point not easily controlled.

The practical measure to adopt in order to avoid infection from the food
are for the most part sufficiently obvious. Still it is not to be expected that
every possibility of infection from this source will be avoided. It is difficult
to discuss the matters considered in this address without seeming to pose as
an alarmist. But it is the superficial and the half knowledge of these subjects
which is most likely to exaggerate the dangers. While one will not under
ordinary circumstances refrain from eating raw fruit or food which has not
been thoroughly sterilized or from using unboiled or natural waters in the
fear that he may swallow typhoid or cholera bacteria, still in a locality in-
fected with cholera typhoid fever he will, if wise, not allow himself the same
freedom in these respects. Cow's milk, unless its source can be carefully
controlled, should when used as an habitual article of diet as with infants,
be boiled or the mixed milk of a number of cows should be selected, but this
latter measure offers less protection than the former.

In most places in this country we are sadly lacking in good sanitary in-
spection of the food, especially of the animal food, offered for sale. One
cannot visit the slaughter house in Berlin or in Munich, and doubtless
similar ones are to be found elsewhere, and watch the intelligent and skilled
inspection of the slaughtered animals without being impressed with our
deficiency in this respect. In large cities an essential condition for the
efficient sanitary inspection of animal food is that there should be only a
few places, and preferably only one place, where animals are permitted to
be slaughtered. Skilled veterinarians should be selected for much of the
work of inspection.

It may rciusonably be asked that the national government which has already
spent so much money for the extermination of such diseases as pleuro-
pneumonia and hog cholera, which are not known to endanger the health of
mankind, should turn its attention also to means for eradicating tuberculosis
from cattle, which is scourge not only to the economic interests of farmers
and dairymen, but also to the health of Iiumaii beings.

BEARING ON PREVENTIVE MEDICINE 587

Without any pretension to having done more in this address than to sketch
here and tliere a few principles derived from bact«riological researches con-
cerning only some of the most widely distributed external sources of in-
fection, I trust that enough has been said to show the folly of any exclusive
dogma as to modes of infection. The ways of infection, even in one and
the same disease, are manifold and various, and can never be resolved into
exclusive hypothesis, ,such as the drinking water hypothesis, the ground
hypothesis, etc.

It follows, therefore, that it is not by sanitary improvements in one direc-
tion only that we can control the spread of preventable epidemic diseases.
In one situation improvements in the supply of drinking water check the
prevalence of typhoid fever, in another place .similar measures show no such
influence ; or, again, in one city the introduction of a good system of sewer-
age diminishes epidemic diseases, and in another no similar result follows.
AVe should, therefore, aim to secure so far as possible good sanitary arrange-
ments in all directions and in all respects.

It has also been rendered evident in what has been said that infectious
agents differ markedly from each other in their behavior, so that while public
sanitation aims at those measures which are found to be most widely bene-
ficial, it should not forget that each infectious disease is as much a separate
problem in its prophylaxis as in its symptomatology, etiology and treatment.
It will not aim to combat cholera with the means foimd best adapted to
scarlet fever, but it will adapt preventive measures as directly to the specific
end in view as possible.

In presenting to you the results of researches, chiefly bacteriological, con-
cerning the scientific basis of preventive medicine, I hope to escape the
accusation of one-sidedness and narrowness by the statement that I do not for
a moment intend to imply that the bacteriological method is our only source
of accurate knowledge on the subjects which have been considered. My aim
is accomplished if I have succeeded in making clear that this method has
established facts which aid in a clearer conception of the causes of some im-
portant infectious diseases, in a better understanding of the sources and
dangers of infection, and in a more efficient selection and application of
sanitary measures.

If this science of only a few years' growth has furnished already acquisi-
tions to knowledge so important, so far reaching, may we not look forward
with assurance to the solution of many dark problems in the domain of in-
fectious diseases, problems the solution of which may yield to preventive
medicine a future of usefulness and success which we cannot now foresee.

SANITATION IN RELATION TO THE POOR'

The sanitary condition of the poor is a matter which concerns not the poor
alone, but the whole community. There is abundant evidence to show that
the health of a city is iniluenced in a large measure by the condition of the
abodes, the habits and the surroundings of the poor. The removal, so far
as practicable, of unsanitary conditions attendant upon poverty is not a
philanthropic undertaking only, but it is a duty which states and cities owe
to all of the citizens.

There are several reasons why it seems proper and desirable to bring before
this Charity Organization Society a question which is so largely one of the
state and municipal policy.

The charity organizations of this country have become one of the powerful
agencies for influencing and directing public sentiment, and consequently
civic action, in such matters as public sanitation.

These organizations, moreover, are interested, not only in the immediate
alleviation of distress due to poverty, but also in searching after the under-
lying conditions and in basing remedial measures so far as possible upon
these conditions. There can be no complete study, no adequate solution, of
the social question witliout a knowledge of the influence of unhygienic con-
ditions upon the physical, ment^il and moral state of the poor, as well as
of the effect of poverty in producing these conditions.

A third reason why it is desirable to introduce this subject here, is that
it is in the power of individuals doing the work of this organization to diffuse
some sanitary knowledge among the poor. The results of such individual
effort may not be great as compared with what may and should be done by
public agencies, but they will do some good, especially in the direction of
domestic hygiene, a subject of which women can be excellent teachers.

Sanitation among the poor in this threefold relation to public hygiene, to
the social problem and to the individual work of this organization is of
course a theme far beyond the limits assigned to me upon this occasion. I
shall be able to touch upon only a few of the salient points.

The two circumstances which have had the most potent influence in the
development of modern sanitary science have been the occurrence of great
epidemics of disease, especially of cholera, and also in this country of yellow

"An address delivered before the Charity Organization Society of Baltimore,
November 14, 1892.
Bait., 1892, 14 p., 8°.
688

SANITATION IN EELATION TO THE POOR 589

fever, and the belief in the dependence of tliose diseases usually called
zj'motic or infectious upon filth.

If the public cannot be awakened in any other way to the correction of
glaring sanitary defects than by an outbreak of cholera, then such a visitation
is not an unmixed evil, for in a few years more lives will probably be saved
by the removal of well known causes of preventable disease than are destroyed
by the cholera, and the chances of a renewal of the epidemic will be lessened,
if not wholly abolished.

Hamburg has been warned time and again by sanitarians of the danger
of using unfiltered Elbe water for drinking purposes, but it has required the
sacrifice within the space of a few weeks of eight thousand lives and untold
misery for this warning to be heeded.

It is fortunate that public sanitary measures have been controlled so
largely by the belief that most infectious diseases depend upon filth. In
this belief the main purpose of public sanitary efforts has been to render pure
the water we drink, the air we breath, the food we eat and the .soil upon
which we live.

Within the last dozen years we have acquired definite knowledge of the
causes of some of the most important infectious diseases and we now know
that these diseases are not generated by filth in so direct a manner as was
once supposed. We may drink contaminated water, breath impure air and
live on a polluted soil without getting typhoid or typhus fever, or diphtheria
or scarlet fever or other infectious disease. These influences may be and
doubtless are deleterious to health, but unless the specific germs of disease
have been introduced, they do not produce well defined diseases.

Many of these disease germs, however, are widely distributed and there
is good reason to believe that such unhygienic conditions as those mentioned
afford to many the best opportunities for multiplication and for conveyance
to the human body.

If we render difficult or impossible the contamination of our water, air,
food and soil, with ordinary impurities which may not in themselves be
demonstrably harmful, we make difficult or impossible their contamination-
with the germs of many diseases.

We are thus enabled to understand how there may be serious sanitary
defects in a place without such an injurious iofluence upon health as to
attract much attention. Nevertheless, these defects are a constant menace
to the health of the inhabitants. The demonstration of sewage contamination
in the sources of supply of drinking water is significant, not because the ad-
mixture with sewage is in itself dangerous, but because it indicates that the
gates are open for the entrance into the water of the germs of typhoid fever
or of cholera, if these germs are present in the sewage. It is true that cholera,

590 SANITATION IN RELATION TO THE POOR

for instance, might be introduced into such a place and by a fortunate chance
the germs of the disease not gain entrance to the soil or to the water so as to
produce an epidemic, but is it not foolish and short sighted to leave the
lives and happiness of thousands dependent upon such a chance when we
know what measures are necessary in order to reduce the chance to a mini-
mum, if not to eliminate it altogether? The most ordinary prudence de-
mauds that the open gates be closed. One of the most instructive lessons of
the visitations of Asiatic cholera in Europe since 1884 has been the failure
of this disease to gain a foot-hold when introduced into cities with irreproach-
able water supply and sewage disposal.

That there are serious sanitarj' defects in Baltimore, is well known.
Attention has been called repeatedly to most of tliem by the health officers
of the city and by others. The annual reports of the health department have
for many years recommended the abolition of the present primitive methods
of disposal of excreta and house-wastes. Dr. Robe in his report for 1890
says : " It is impossible to find language capable of expressing in its entiretj'
the filthiness and dangers to life and health by which we are surrounded so
long as the present privy system is maintained," and Dr. McShane, the
present Commissioner of Health endorses these views and says : " Nothing
of greater importance can be suggested than the adoption of some means for
the proper removal and disposal of household and other sewage."

The present health commissioner and others have recently called public
attention to serious sewage contamination of the sources of water supply of
Lake Roland, which affords drinking water to a large part of the city.

Notwithstanding these notorious violations of sanitary principles, this
city appears to be reasonably healthy. Indeed during the latter half of the
decade 1880-90 the death rate of Baltimore as officially given out. reached a
point which has been regarded as the ideal of perfection for modern cities,
so that the mayor in his message in 1887 claimed for Baltimore " a lower rate
of mortality than prevails in any city in Europe or America." I deem it,
however, proper to say, that during this decade the official death rate was
computed upon the basis of a gross exaggeration of the population, and was
therefore smaller than the true death rate. At the beginning of the decade,
in the Report of the Health Department for 1880, the estimat<'d population
was 61,483 in excess of the U. S. Census for the census year 1879-80, and at
the end of the decade in 1888 and 1889 the estimated population was 65,904
in excess of the U. S. Census for 1890 and 44,916 in excess of the police census
for 1890. In accounting for the apparently great increase in the death rate
in 1890 as compared with 1889 — an increase from 17.4 per 1000 in 1889 to
22.41 in 1890 — the commissioner of health in his report for 1890 says,
" Inasmuch as the estimated population on which the calculation of the

SANITATION" IX RELATIOX TO THE POOR 591

mortality rate was based was nearly 50,000 too high, the increase in the death
rate is only partly an actual increase."

In calling attention to the serious errors in the official death rates of this
city during the period mentioned, I would not be understood as basing
the plea for sanitary reforms upon an alarming mortality in this city. While
there is nothing alarming in the death rate of this as compared with other
cities, I believe that we have now sufficient experience as to the beneficial
effects of sanitary reforms to justify the prediction that, as regards infant
mortality and certain infectious diseases, the mortality in this city could be
materially reduced by the introduction of such improvements in public sani-
tation as belong to a well managed modern city. The teaching of experience
is direct and uniform in this regard.

I have already endeavored to point out tliat serious sanitary defects,
although for a time they may not appear to injure the health of those exposed
to them, become a standing menace to health upon the approach of certain
epidemic diseases.

But I do not consider it necessary to base the argument for sanitary im-
provements exclusively upon their demonstrable influence on public health,
manifest as their influence often is. Such things as pure drinking water,
well paved and clean streets, and well drained soil are conducive to comfort
and happiness and to the commercial welfare of a city. They exert in this
way a direct influence upon prosperity and an indirect influence upon health,
not appreciable by any mortality statistics, but clear enough to the experience
of individuals and of the community.

This matter of public sanitation is one purely of municipal administra-
tion. I suppose that those who have the power to initiate and carry out
measures necessary to secure to us a water supply free from danger of con-
tamination, a civilized system of disposal of sewage, well paved and clean
streets, good drainage, freedom from pollution of our water courses and
harbor, removal of dwellings which cannot be made fit for human habitation,
conceive that their personal and political interests lie in quite different
directions, and for this indifference the apathy of the general public is largely
responsible.

Recommendations of health officials, reports of special commissions, ad-
dresses to tax payers' associations, are unheeded.

Great as are the cost and the practical difficulties in executing municipal
engineering works, they have been successfully surmounted by cities less
favorably placed as to natural advantages and pecuniary resources than is
this city.

Mr. Andrew D. White makes a strong statement when he says that, " With-
out the slightest exaggeration we may assert that, "n-ith a few exceptions, the

592 SANITATION IN RELATION TO THE POOR

city governments in the United States are the worst in Christendom, the
most expensive, the most inefficient and the most corrupt," but so high an
authority in sanitary matters as Dr. John S. Billings says that this state-
ment " is true .so far as municipal engineering work is concerned with regard
to several of the largest cities in this country." I cannot forbear from quot-
ing in this connection a passage from Mr. Joseph Cliamberlain's article in
the last number of the " Forum " on " Municipal Institutions in America
and England." After showing that the expenditures for local purposes in
the city of Boston are largely in excess of those in the City of Birmingham,
England, he says : " The leading idea of the English system may be said to
be that of a joint stock or cooperative enterprise in which every citizen is a
shareholder and of which tlie dividends are receivable in the improved health
and the increase in the comfort and happiness of the community. The
members of the council are tlie directors in this great business, and their fees
consist in the confidence and the gratitude of those among whom they live.
In no other undertaking whether philanthropic or commercial, are the re-
turns more speedy, more manifest or more beneficial. To give a .single illus-
tration the reforms in Birmingham carried out in a few years reduced the
death rat£ from 26.8 per 1000 in 1874 to 19 in 1888. In other words the
initiation of the unpaid members of the council and their supervision of
the loyal and assiduous labors of the paid officials have been the means of
saving the lives of more than 3000 persons in a single year ; and inasmuch
as for a single death many ca^es of illness not actually fatal may be reckoned,
it is easy to see what a mass of human suffering has been lightened and how
much misery has been prevented."

In view of Mr. Cliamberlain's description of municipal administration in
Birmingham it is interesting to note that the Special Commission appointed
in 1889 bv Mayor Davidson to examine all the departments of the city
government of Baltimore and to make such recommendations as they deem
appropriate, recommended the appointment of unpaid commissions of citi-
zens to be at the head of several departments of the citj' government, such as
the Board of Health, tlie Board of Public Works and the Board of City
Charities.

It has seemed to me necessary to say at least these few words regarding
the relation of public health to municipal government, in order that we may
be under no illusion as to what can be accomplished for sanitary reform in
the condition of the poor outside of public agencies. I realize fully that what
is needed in tliis matter is active work. Interested observers and critics we
have in abundance, but the active workers for reform are few. Our dis-
satisfaction with tlie intruments at our disposal should of course make us
try to get better ones, but in the meantime we can accomplish much with
those which we already have, and it is the part of practical wisdom to take

SANITATION IN RELATION TO THE TOOK 593

hold of these instruments and apply them to the best use possible under the
circumstances. Our health ofBcials are often well aware of the vices of the
system under which they are obliged to work and I believe that they will
welcome any coojjeration and assistance which public spirited citizens and
organizations are able to render them. Under our existing political condi-
tions, experience seems to show that more can be accomplished by the quiet,
intelligent and well directed efforts of individuals and of such organizations
as societies for city improvement, which do not directly antagonize tliose
wlio wield political power, and which receive the approval of the general
public, than by spasmodic political movements for reform.

Of the problems more directly relating to sanitation among the poor in
its bearing upon public health, the medical relief of the poor is the most
amply, even if not the most judiciously, provided for. The medical treat-
ment of the poor is to a very large extent gratuitously assumed by the medi-
cal profession. In this respect physicians perform an amount of unpaid
labor without any parallel in other professions or business. So great are
the abuses of medical charities that these have been described as the greatest
pauperizing agency now in existence. This subject has been so often dis-
cussed and has been so frequently presented before Charity Organization
Societies, that I shall not dwell upon it. Great benefit has been derived
from the cooperation in some cities of Charitj' Organization Societies in
investigating the circumstance of patients applying for gratuitous medical
relief in hospitals and dispensaries, and a more extended and perfect system
of such cooperation might be usefully inaugurated in this city.

There is one need which is 80 urgent in this city that public attention
should be forcibly directed to it and that is a hospital for infectious diseases.
Dr. Eohe, when he was commissioner of health, in 1890 urgently recom-
mended the construction of such a hospital, and his successor has em-
phatically endorsed this recommendation. At present no hospital in the city
wiU undertake to receive cases of scarlet fever, diphtheria or smallpox.
When one considers the necessity of prompt isolation of these cases in order
to prevent their epidemic distribution and of our helplessness in this regard in
the emergency of a visitation of cholera or yellow fever, it is clear that this
is a matter which should receive immediate attention.

A public establishment for disinfecting by steam is scarcely less important
and is now provided in most large cities which can lay any claim to decent
sanitation. Among the most important results of the discover}' and study
of the specific germs which cause infectious diseases, has been the develop-
ment of the methods necessarj' to destroy these germs outside of the body
when their presence is suspected in such substances as clothing, bed linen,
household furniture, etc. Some methods of disinfection which were formerly
and are still sometimes relied upon, are now known to be inefficacious.

594 SANITATION IN RELATION TO THE POOR

There is now universal agreement of opinion tliat heat is the most powerful
and useful disinfectant ajjent. Every large city should be supplied with a
public establishment for disinfecting by steam, with which it would be well
to combine a crematory for burning articles which cannot be disinfected or
are not worth disinfecting. The disinfection of rooms, furniture, bedding,
etc., should be intrusted to a corps of men who are trained for the purpose.

The housing of the poor is a sanitarj' problem which offers the greatest
difficulties, but there are few sanitary questions which have received more
intelligent discussion and treatment from philanthropic and practical men
and women.

In all efforts to benefit the poor, but especially here, we have to distinguish
two classes of the poor, between which the lines cannot be sharply drawn.
In one class are those who earn small wages, to whom the struggle for exist-
ence is hard, who manage to preserve decency and self-respect, and in the
other class are the failures of life, the criminal, the drunkard, the tramp and
the loafer and also a few who have been temporarily forced by adverse circum-
stances to this low level, but who are capable of rising.

For the first class, it seems to have been demonstrated that healthful
dwellings can be furnished at a price within their ability to pay, and that
these yield a fair return on the investment. Over the construction of these
dwellings and tenement houses, the health officials should exercise a rigid
sanitary supervision to insure their proper supply with water, air and light
and to control the arrangements for drainage and disposal of excreta.

Of the second class of the very poor, Mr. Theodore Thomson in his paper
on " The Housing of the Poorer Classes," read before the Seventh Inter-
national Congress of Hygiene and Demography in London says : " Some-
thing else will have to be done with the lowest class of all. Of these it may
be said that were they to-morrow housed in a palace, they would in ten davs
make it a pig isty. For them remedies are required other than those needful
for the class immediately above them. No doubt they will, despite them-
selves, to some extent be benefited by sanitary arrangements in their dwell-
ings, by demolition of unhealthy areas, by improved lodging houses under
existing laws. But so long as there is an insanitary building left, they will
go to it, for they do not admire sanitation. They will avoid all model dwell-
ings for they do not wish to be cleanly and orderly as there prescribed by
rule, and they will destroy and fill with filth any interior that becomes theirs.
It is to be hoped that the benefits of education will ctTect some improvement
in the members of thi^s class, but it must be a long time before these benefits
create any appreciable effect. Private effort, such as the noble work of Miss
Octavia Hill and others, is one of the means to which one may look with hope.
Possibly registration of the worst cla.ss of houses with frequent and -itringent
supervision of the habits of the inmates, may be useful. Suih supervision

SANITATION IN EELATION TO THE POOR 595

would not be pleasant to the inmates, Init it is perhaps desirable that life
should not be made too pleasant for this class of society, most of whom
deserve no sj-mpathy other than that which one bestows on the victims of
heredity."

Mr. Alfred White, who is to speak to us this evening, in his paper on this
subject at the Conference of Charities and Corrections in 1885, believes that
the class of people who prefer squalor and darkness to decency and light,
who need moral reformation before they can be properly moved into better
surroundings, is a small minority of the laboring class here as compared
with London.

.Something must be done for this apparently hopeless class ; if not for their
own sake, at least for the sake of the rest of the community. If their exist-
ence among us is inevitable, they at any rate should not be permitted to
occupy abodes unfit for human iiabitation, which endanger the health of
their neighbors and of the whole community and which may become the
breeding places of pestilence. I believe that such houses if they cannot be
made decently healthful, and some cannot, should be demolished. What is
to become of the inmates ? I reply that some will move elsewhere, and that
is well, some will be forced to lead more decent lives, and tliat is also well,
and some will go to the almshouse. It is better and in the long run cheaper
for the city to take care of this remnant in the almshouse than to permit them
to live as they now do.

Between ISTi) and 1890 in the city of Dublin 2556 unsanitary houses have
been cleared of tenants and closed. More than one-half have been completely
removed and the other half have been extensively repaired and rendered
habitable. This is one of the great sanitary reforms which have been carried
out in that city by Sir Charles Cameron during the past twelve years, and
which have led to the almost complete extinction of t>-])hus fever and to
other most gratifying results in the improvement of public health.

The impression is a general one that the working classes are better houses
in Baltimore than in most large eastern cities, and I think that this is cor-
rect. According to the 10th census (the returns of 11th census on this point
are not yet available) the average number of persons to a dwelling was in
Baltimore G.o-t, in Philadelphia 5.79, in Boston 8.26, in Cincinnati 9.11,
and in New York 16.37. This means that with us the great majority of the
families of the working classes have each a separate house. There are,
however, in this city instances in which several families are crowded into
houses intended originally for a single family, and this condition is of course
worse than that of a well constructed tenement house intended for many
families. How common these instances are is not known, and it is much to be
desired that trustworthy data should be collected concerning the housing of
the poor in this city. An important and useful work might be done if this

596 SANITATION IN RELATION TO THE POOR

Cliarity Organization Society, or some other public agency, or even some
individual, had the inclination and the means to put to work a body of
volunteer ,«anitary inspectors who should do for this city what a corps of
similar inspectors under Mr. Dwight I'orter has done in the investigation
of tenement house districts in Boston. Mr. Porter was assisted by certain
students from the Institute of Technolog}'. They received the hearty co-
operation of the official board of health.

The most important means at the disposal of departments of public health
for the prevention, detection and removal of unsanitary conditions, is a
body of efficient sanitary inspectors acting under suitable sanitary laws. In
some cities such inspection is carried out with admirable system. It requires
intelligence, tact and special training on the part of the inspectors. We are
sadly deficient as regards the inspection of slaughter houses, animal food,
milk and dairies. The services of one or more skilled veterinarians are need-
ful for much of this work and they cannot act efficiently without better laws
regulating these matters than we now have. The number of sanitary in-
spectors now employed by our board of health seems to me too small to per-
form efficiently the work which should be done.

We have thus far considered the sanitary state of the poor more especially
in its relation to the rest of the community. I hope that it is apparent that
merely from a mercenary and commercial point of view it is for the interest
of the community to take care of the health of the poor. Philanthropy
assumes a totally different aspect in the eyes of the world when it is able to
demonstrate that it pays to keep the people healthy. " The health of the
people is the wealtli of the state." This may be a sordid and mercenary way
of looking at the question, but it is the way which has enabled reformers to
convince mankind of the necesisity of public sanitary measures. It is esti-
mated, and of course such an estimate can be only a rough one, that nearly
100,000 deaths occur annually in this country from preventable causes.
For each death there are of course several cases of illness not fatal, due to
preventable causes. One can form from such a statement some idea of the
enormous loss in money and productive labor which we suffer from prevent-
able causes of illness and death.

The influence of unsanitary conditions upon the health, the character and
the morals of the poor is manifestly an important question in sociology. A
good deal has been written upon it, but mostly in a vague and indefinite way.
The subject has not received the scientific investigation which it deserves
and many of the c.\i.sting data are untrustworthy.

The death rate is stated to be from two to three times greater among the
very poor than among those better situated. But it is not only as to the
influence of unsanitary conditions upon the health, but upon the whole

SANITATION IN RELATION TO TEE POOR 597

physical, mental and moral constitution of those subjected to them, that we
wish information.

It is of course self-evident that insufficient and wretched food, filthy sur-
roundings, close and impure air and overcrowding must effect not only the
health but also the habits and morals of those subjected to such an environ-
ment. Is any moral regeneration possible under such circumstances? Is
not the first step a regeneration of the physical environment ?

The picture has been drawn of the man of the alley who comes home from
his work. After stumbling over the filthy refuse heap in front of the house,
he enters a dingy and repulsive abode in which the air is close and depressing.
The small room is crowded and it is pervaded with offensive odors. The food
is scanty and ill cooked. Near by is a capacious room, relatively clean, where
conversation and excitement may be found, where to him everj-thing is bright
and alluring and where for a few coppers he can get something which for a
time .stimulates him and makes him forget his misery. The wonder is not
so much that one man reels home drunk and a brute, but that for every such
one there are not a dozen. It is not difficult to comprehend the reply which
was made by such a man to the clergjnian who remonstrated with him. " If
you were to come and live and sleep here, you, sir, would drink whiskey too."

The immorality which must necessarily ensue from bestial over-crowding
has been depicted often enough.

But it is not so much these gross and flagrant vices which spring from
unwholesome living that I wish to emphasize at present. These are the
themes of sermons and tracts and are well known. These vices belong in a
large part to a class of the poor which many believe to be irreclaimable.

The class best worth helping are the industrious, hard-working wage
earners, struggling to make a decent living, who possess a fair degree of
intelligence and preserve their self-respect.

Whether many of these shall keep their heads above the water or shall sink
to the submerged class, depends I believe in larger measure upon their sani-
tary surroundings than is generally supposed. Many of these worthy people
live under very unfavorable hygienic conditions which can be remedied.
Many are ignorant of the simplest rules of health. They suffer often a
gradual physical deterioration not amounting to actual illness. Their minds
and characters suffer with the body. Many of these poor people become
intemperate, not usually, as many temperance reformers seem to think, be-
cause they deliberately choose to be drunkards, but as a natural result of the
circumstances under which they are forced to live. It is useless to appeal to
the self-control of these individuals and to leave them breathing a polluted
atmosphere in unwholesome houses with scanty and bad food.

It has become more and more evident that the great work of charity in
the future is to consist, not so much in almsgiving, as in efforts to educate

598 SA^^TATION" IN RELATION TO THE POOR

the poor, to strengthen their characters, to lift them up physically,
mentally and morally. A fundamental part of this uplifting must be an
improvement in the sanitary conditions in the abodes of the poor and in-
struction in domestic hygiene. I have little confidence in the remedial
efficacy of measures which do not include this fundamental work.

I believe that the worker* in this and similar organizations wlio visit the
houses of tlie poor, can do much good in carrying to them the simpler lessons
in domestic hygiene as to such matters as ventilation, cooking, household
cleanliness, etc. They can also make clear the necessity of certain simple
precautions, such as boiling the water and the milk, to be exercised at the
approacli of certain epidemic diseases, such as cholera and typhoid fever.

This implies that these workers themselves possess the requisite informa-
tion. Sanitiiry science is less of an intuitive nature than many seem to
suppose. Knowledge of it is to be gained by reading good books on the sub-
ject, by demonstrations and by lectures, and I venture to suggest that it
might be well for this organization to make some provision for ib> workers
in the way of instruction in sanitation. Although my theme has been sani-
tation among the poor, it is not to be understood that the ricli do not also
suffer their full ,'^hare from sins of ignorance and neglect in matters of health.

In conclusion I would say that in emphasizing the importance of sanitary
reform, I do not for a moment suppose that this is the only agency to be used
in elevating the condition of the poor. Tliere are other motives to work and
other agencies to be employed which occupy a much loftier plane than those
which I have treated.

Still less do I suppose that even perfect sanitation would be a panacea
for the evils attendant upon poverty. The roots of these evils lie far beneath
the surface. It may be that tliey are inseparable from existing conditions of
society and from the present industrial system and that nothing short of a
social revolution can wholly remove them.

But we need not wait for a reconstruction of society and tlie introduction
of some scheme which we would now call Utopian in order to bring relief.
How many generations will pass before this radical relief will come, if it
come at all, no one can tell. Our present duty i* to make use of the best
instrumentalities a\ailable and among those which promise the surest and
quickest and happiest results is sanitary improvement. I would therefore
earnestly commend to tlie attention of those engaged in the great and rapidly
developing work of our modern organized and associated charities the im-
portance of including in tliis work efforts to improve the sanitary surround-
ings of the poor and to educate the poor in matters pertaining to health.

ASIATIC CHOLEEA IN ITS RELATIONS TO SANITARY

REFORMS '

Since the appearance of Asiatic cholera in Europe last summer, and
especially since its arrival in the harbor of New York last autumn, and its
persistence in Europe during the winter, an unusual degree of public interest
in sanitary matters has been awakened tliroughout this countr}'. This is
due mainly to the popular apprehension lest this most dreaded of epidemic
diseases should gain a foot-hold in this countr}' during the coming summer
and autumn.

Unwonted attention is given to public health administration. The
national government provides additional legislation regarding quarantine.
There is a general cry for cleaner streets, removal of public nuisances, and
more efficient sanitary inspection. The character of the water supply is
scrutinized. Measures, often more vigorous than wise, are taken to remedy
sanitary defects of long growth. Hospitals for infectious diseases and
modern disinfecting plants are demanded. .Committees and conferences of
citizens and of various civic organizations are formed. Magazines and news-
papers are lending their aid, often most efficiently, toward education of the
public and measures for improved sanitation. The public is readier to
listen than at ordinary times.

A similar awakening of public interest in sanitation has attended the
approach of cholera in tlie past. However near or remote one mav consider
a visitation of cholera, whether or not one may approve of much which is
-written on this subject at present, and of some of the measures urged for
the prevention of tliis disease, anyone interested in sanitary improvements
must welcome the increased attention given to this subject and the laro-er
opportunity to secure some permanent additions to our sanitary resources.
This feeling may be tempered by the fear that now as in the past excitement
and sudden emergencies may lead to hasty and inconsiderate measures and
foolish and wasteful expenditure of money, but this makes it all the more
desirable to take advantage of the opportunity and to try to direct thought
and action into the right channels.

In this way surely some good can be done. Knowledge of the simpler
principles of hygiene can be more widely diffused among the people. The
sanitary sense, even of the more enlightened, can be further cultivated. The

'Pop. Health Mag., Wash., 1893-94, I.

599

GOO ASIATIC CHOLERA

inhabitants of cities may be lud to take some active personal interest in the
sanitary condition of their towns. Sanitary defects can be brought into
clearer light and to some extent remedied. Public health administration can
be aided and improved. Possibly a hospital for infectious diseases, a public
disinfecting establishment, even some important work in municipal engi-
neering, improved methods of registration of vital statistics or better sani-
tary legislation can be secured.

Some knowledge of the nature and mode of distribution of infectious dis-
eases must be useful to those interested in questions of public health, and,
although each infectious disease presents its owti peculiar problems there is
none which can teach more important and helpful lessons in sanitation than
cholera, and there is none which has had so profound an influence upon the
development of modern hygiene.

Cliolera is to us of the nineteenth century the chief reminder of the great
pestilences of former centuries which have disappeared from civilized lands.
These great pestilences were attributed for the most part to causes beyond
human control, such as the anger of an offended Deity or some mysterious
epidemic constitution of the atmosphere. The careful study of the mode of
spread of epidemic cholera has given the early impulse and chief support
to the doctrine, which is the mainspring of modern sanitation, that the
causes of many infectious diseases are preventable. There is no disease
about which so much has been written as concerning Asiatic cholera, the mere
list of titles of books and articles on this subject occupying one hundred
and forty-eight pages in the great Index Catalogue of the library of the
surgeon-general's office.

Althougli cholera has existed in parts of India probably from time
immemorial, it was not until the year 1817 that it spread over India, and in
the following six years over a largo part of Asia. The second cholera pan-
demic began in 1826, but not until 1831 did it reach for the first time western
Europe, and in 1832, Canada and the United States. Each pandemic of
cholera has lasted for several years, during which the disease has travelled
over most of tlie inhabited regions of the globe, only a few remote countries,
such as the islands of the Pacific ocean and Australia, having thus far
escaped. According to tlie usual reckoning the present is the sixth of the
great pandemics of cholera.

The sixty-two years which have passed since the first appearance of Asiatic
cholera in western Europe have witnessed the most important developments
of modern hygiene. It is interesting to note to what extent sanitary iscience
and sanitary works have been influenced by the occurrence and the study
of this disease.

AND SANITARY EEFORMS' 601

It was under the direct impressions of the first terrihle visitation of
cholera that in England the office of Registrar General was established and
William Farr was appointed to fill it. We owe to this office and to the work
of this man the ap])lication of statistics to public health. As has been said
by Dr. Parkes, an English hygienist, " It is impossible for any nation, or for
any government, to remain indifferent when in figures which admit of no
denial, the national amount of health and happiness, or disease and suffer-
ing, is determined. Tlie establishment of the Registrar General's office in
1838, and the commencement of the system of accurately recording births
and deaths, will hereafter be found to be, as far as the happiness of the
people is concerned, one of the most important events of our time. We owe
a nation's gratitude especially to liim to whose sagacity the chief fruits of
the inquiry are due, William Farr."

The English have taken the foremost place in the art of formulating laws
for the protection of health and in the organization of the machinery for
public health administration, which is entirely of modern growth as a
separate department of government. In 1833 the dread of cholera led to an
act of Parliament, empowering the privy council to take certain preventive
measures against the spread of the disease, and every extensive visitation of
cholera has been followed by activity in the passing of fresh sanitary acts.
During the discussion in Parliament in 1875 on the Public Health Act, the
most complete code of sanitary law in existence, Disraeli said : " The public
health is the foundation on which repose the happiness of the people and the
power of a country. The care of the public health is the first duty of a
statesman."

A decisive part in the development of the doctrine that certain infectious
diseases are propagated chiefly through impure drinking water and con-
taminated soil is traceable to the investigations concerning the mode of
spread of cholera. Tlie celebrated instance of the Broad street pump in
London, in 1854, furnished conclusive evidence that the cholera poison may
be conveyed by the drinking water. A distinguished modem hygienist has
said, " The Broad street pump has played not only a decisive role in the
cholera question, but it has furnished also the most important impulse for
the development of a new era in the department of public hygiene."

That pioneer and master of modern hygiene, Max von Pettenkofer, bases
to a large extent his views as to the agency of contaminated soil in the spread
of certain infectious diseases, upon forty years' study of the relations of the
soil to the distribution of cholera.

These views widely held as to the propagation of some infectious diseases
by the drinking water and by the soil, and based so largely up)on the study of
cholera, have been not of theoretical interest only, but they have influenced
41

602 ASIATIC CHOLERA

profoundly the practical measures which liavc heen undertaken to preserve
and promote the health of the people.

Cholera has destroyed millions of human lives, but it has been the means
of saving millions more. It has been one of the levers of progress in modem
sanitation. The same measures which are needed to protect a city against
occasional epidemics of cholera are needed at all times to protect it against
other infectious diseases, such as typhoid fever, which are spread in a similar
manner, and which, although they do not come with the terrible impetuosity
of cholera, steadily do their deadly work, and in the course of time destroy
among us far more lives than cholera. These measures for the sanitary
welfare of the people should be provided independently of the danger of
cholera, but it has often happened that governments and citizens are not
aroused by tlie common, but preventable, causes of death to undertake sani-
tary works, the necessity for which is evident enough to sanitarians. Unfortu-
nately, they have required sometimes the violent impressions of an outburst
of cholera to stir them to undertake these long-needed sanitary improve-
ments. Witness at this moment Naples, Marseilles, and Hamburg, which are
spending millions of dollars for destruction of insanitary quarters, for bet-
ter sewage disposal, for improved water supply. But think of the thousands
of lives destroyed, the panic, the commercial depression, the untold misery
through which tliese cities have passed before the warning was heeded.

When we consider the properties of the infectious agent of cholera and
the facts established concerning the mode of spread of the disea.se, it is not
difficulty to understand why cholera should have had so large an influence
upon the hist«rical development of modern sanitary science and art, and why
measures which are useful in preventing the invasion and propagation of tliis
disease are applicable also to typhoid fever and some other infectious dis-
eases. There have been and still are conflicting views <is t-o some points in
the causation of cholera, but as to many points there is substantial unani-
mity of opinion.

Asiatic cholera is an infectious disease. By an infectious disease is meant
one which is produced by a specific microorganism in the body. Whether
or not an infectious disease is contagious, that is, communicable from person
to person, depends upon the properties of the causative microorganism, and
especially upon the manner in which this orpuiism is usuallv eliminated
from the body and must he received in order to cause infection, ^\^len, as
is the case witli cliolcra, tlic infectious germs arc disihargod, .solely or chieflv,
by the intestine, and must be taken in by the mouth in order to cause tlie
disease, it is evident that the disease is not likely to be conveyed directly
from the sick to the healthv.

AND SANITAEY REFORMS 603

The species of bacterium which is always associated with Asiatic cholera,
and which there is the best reason for believing to be the cause of the disease,
is usually called the comma bacillus of Koch, from its shape and the name
of its discoverer.

The recognition of this bacillus is the only absolutely positive means of
diagnosis of Asiatic cholera. After the establishment of an epidemic mis-
takes in diagnosis are not likely to occur, and if they do, they are of little
consequence, but it is important that a bacteriological examination should
be made in the earliest suspected cases, in order that suitable preventive
measures may be taken.

One of the most important properties of the cholera germ is that it is
killed in a short time by complete drying. Bacteria float in the air with
particles of dust only wdien they have been desiccated. Currents of air are
incapable, under ordinary circumstances, of lifting bacteria from moist .sur-
faces. The inference is therefore justifiable that the germs of cholera are
not disseminated through the atmosphere, and that we cannot contract the
disease by taking the germs in with the air which we breathe. This inference,
which is a most comforting one, is supported by observations of the mode
of distribution of the disease and is manifestly of great practical importance
as regards the care and prevention of cases of cholera. The cholera patient
is not a -source of danger to tliose in proximity in the same way that a
smallpox or scarlet fever patient is. Neither the patient nor his discharges
infect the surrounding air. The inhumanity wath which those seized with
cholera are sometimes treated by the public is based upon groundless ideas
as to the real sources of danger.

The cholera germs must be taken in by the mouth and swallowed in order
to produce the disease in human beings. In other words, the principal
sources of infection are the drink and food, sometimes the hands or other
objects contaminated with cholera spirilla and brought into contact with the
mouth.

But even if the cholera germs in this way gain entrance to the stomach,
there are many chances that they will not produce the disease. They are
weakened or killed by acids, and the acidity of the normal juices of the
stomach is an obstacle to their passage in a living and virulent condition
into the intestine, which is the only part of the body where they can multiply
and flourish. Tliis teaches the importance of a healthy stomach in cholera
times, and the danger of indiscretions in diet or in other ways, which impair
the functions of this organ. We can understand why during epidemics of
cholera there is often a marked increase in the number of case? a day or two
after the carousing of a popular holiday or a Continental Sunday.

604 ASIATIC CHOLERA

Aside from the condition of the stomach there appears to Ix; a marked
difference in individual susceptibility to cholera. A large number of persons
do not contract the disease even when exposed to its causes. Some develop
only a slight or moderate diarrhoea, wliich would not ordinarily attract
attention, although cholera spirilla may be present abundantly in the in-
testinal discharges. Others are carried off in a few hours by the most malig-
nant type of the disease. To what e.xtent the*e differences depend upon
variations in susceptibility, or to variations in the virulence of the cholera
germs, or to other causes, is not definitely known, but we know enough to
indicate tliat among our prophylactic measures should be included such a.s
tend to produce and to preserve individual resistance to the disease so far as
this is within our control.

It is well known that the largest proportion of the victims of epidemic
cholera is among the crowded poor living under insanitary conditions.
Hence it is plain that improvements in the abodes and the conditions of
living of this class will do much to lessen the chances of an epidemic of
cholera. Every large city has its dangerous spots, which may become breed-
ing places of infectious diseases, and the thorough overhauling and cleaning
up, often indeed the destruction, of these places are an important part of
municipal sanitation.

It has already been mentioned that the cholera germs multiply only or
chiefly in the intestinal tract and that they are discharged with the intestinal
contents, sometimes with tlie vomit. They are never eliminated with the
breath or from the surface of the body. The real danger from a cholera
patient to other persons is in his discharges and in objects soiled with these
discharges. With ordinar}' care and in decent conditions of living the
chances of any part of these discharges being received directly into the
alimentary tract of those in the immediate neighborhood of the patient are
so slight that cholera is not ordinarily regarded as contagious. In properly
conducted cholera hospitals inst.uices of such contagion are very infrequent,
but in the crowded homes of the poor such instances are not so uncommon,
so that in every large epidemic of cholera a certain number of cases, par-
ticularly in the so-called house epidemics, are attributable to contagion in
the sense in which this term is ordinarily used.

The thorough disinfection of the discharges of cholera patients and of
objects soiled by them is obviously of the first importance. The cheape«t and
most generally applicable and efficient of the disinfectants for the discharges
are milk of lime and chloride of lime of good quality. One of the great
obstacles to checking the spread of the disease in this way is the occurrence
of mild cases, which are not recognized as cholera, but which are capable of
distributing the germs.

AND SANITARY REFORIIS 605

Outside of the endemic home of cholera, in southern Bengal, Asiatic cholera
is always to be referred to the importation of the cholera germs, although
often the exact time and mode of entrance cannot be traced. Human beings
and their effects are the chief carriers of these germs. Restraint of human
intercourse with infected localities has naturally been regarded as a chief
measure of protection. The achievements of quarantine in keeping out
cholera have been relatively to its vexations, hardships, cruelties, and inter-
ference with commerce so small that many distinguished sanitarians would
discard it altogether. As we are situated in this country it would doubtless
be unwise to relinquish quarantine, but all the good which can be accom-
plished by quarantine can be attained by scientific and humane methods,
which should be uniform and under unrestricted national control.

The public should realize tliat quarantine is at best an imcertain and often
inefficient protection against cholera, and that far greater safety is to be
sought in measures which render the city or locality unsuitable for the
multiplication and distribution of the germs of the disease. All great
epidemics of cholera are referable to infection of the locality. One of the
fundamental facts in the epidemiology of cholera is that the disease has
been introduced time and again into certain places without spreading,
whereas at other times or in otlier places the introduction of a single case
has been the starting point of a terrible epidemic. There are cities which are
naturally immime against the epidemic spread of cholera; there are other
cities which have made themselves virtually cholera-proof. It is this pre-
disposition in time and in place which has been and is still the subject of
much of the controversial literature regarding cholera.

We do not know the nature of all of the local and seasonal factors con-
cerned in the causation of epidemics of cholera, but concerning some we have
sufiBcient information to indicate the line of action to be pursued in en-
deavoring to make a place unsuitable for the spread of the disease. From
what has already been said in this article it is clear that the susceptibility
of a place to cholera must depend in very large measure upon the facility
with which the discharges of cholera from a patient can get into the soil and
into the sources of supply of the drinking water. In other words, the charac-
ters of the drainage, of the disposal of sewage and of the water supply will
often decide the fate of a city when cholera has been introduced. The evidence
that some of the great epidemics of cholera and especially of the explosive
outbursts of the disease are due to infection of the water supply seems con-
clusive. The recent epidemic in Hamburg will be cited hereafter as a classi-
cal example of a drinking water epidemic.

The lesson to be learned from experience seems clear enough. A city can
make itself nearly if not wholly immune against cholera. This requires

GOG ASIATIC CHOLERA A>rD SANITARY REFORMS

imicli time, money, and inttflliKenre. It demands the aid of skilled sanitary
knowledge. The problems of municipai sanitation must be appreciated by
intelligent public opinion, but they can be solved only by those who have
special knowledge and who are trained for the purpose. The necessity of
calling in the assistance of skillful sanitary e.xperts for the work of municipal
sanitation is one of the most important objects of education of the public in
sanitary matters. As soon as there is a demand for those possessed of the
requisite training, there will be no lack of the supply.

The problems of protection of a city against cholera are essentially the
problems of municipal sanitation in general. They relate to such matters
as the protection of the water supply against contamination ; to the proper
disposal of sewage; to good drainage; to cleanliness of streets; to improve-
ment or removal of insanitary quarters; to thorough sanitary inspection; to
the provision of public disinfecting establishments, public bathing places,
and hospitals for infectious diseases ; to education of the public in hygiene ;
to the employment of sanitary experts. If the apprehension of an invasion
of Asiatic cholera and the consequent interest in sanitary matters should
prove the incentive to sanitary reforms, there will result permanent increase
in happiness and health and the prevention of other infectious diseases,
which, although less dreaded because they are more familiar, are in reality
more serious and constant objects of concern than cholera.

THE RELATION OF SEWAGE DISPOSAL TO PUBLIC HEALTH'

I am somewhat perplexed how to treat the subject assigned to me, for,
although it is a very broad one, its various parts have been so parcelled out
that those who are to follow will take up most of the points which would
naturally fall within my theme.

The basis of modern sanitation is the recognition of the fact that certain
diseases, particularly those called infectious, are preventable. So familiar is
this conception, that it is difficult to realize that it is essentially of modern
origin. While it is true that in all ages there have been enlightened physi-
cians to whom this conception of the preventability of disease was not entirely
foreign, nevertheless the prevailing opinion in ancient and medieval times
referred the origin of epidemic diseases to such supposed causes as the anger
of an offended Deity, the influence of the planets and comets, poisoning of
wells by the Jews, some mysterious epidemic constitution of the atmosphere,
etc. Under the control of such ideas, it is clear that public and private sani-
tation could not develop. Certain great public works of antiquity to which
we must attach hygienic value, such as the momumental aqueducts and
drains of ancient Eome, were undertaken for public convenience and not
with any clear appreciation of their relations to public health.

The doctrine of the preventability of infectious diseases was first estab-
lished upon a firm basis by the collection and analysis of vital statistics.
This great contribution to preventive medicine we owe to the establishment
of the Registrar General's Office in England, in 1838, concerning which an
English hygienist has justly said : " It is impossible for any nation or
for any government to remain indifferent when in figures which admit of no
denial the national amount of health and happiness, or disease and suffering,
is determined. The establishment of the Registrar General's Office in 1838,
and the commencement of the system of accurately recording births and
deaths, wiU hereafter be found to be, as far as the happiness of the people
is concerned, one of the most important events of our time."

The impetus which led to this systematic collection and study of vital
statistics, as well as to other great sanitary reforms, was the invasion of

' Remarks made before the Joint Meeting of the Medical and Chirurgical
Faculty of Maryland and the Maryland Public Health Association, to discuss
the Sewage Disposal of Baltimore, Baltimore, November 19, 1897.

Maryland M. J., Bait., 1897-98, XXXVIII, 199-204.

607

608 SEWAGE DISPOSAL AND PUBLIC HEALTH

Asiatic cholera for tlie first time into Western Europe in 1831. The careful
study of the mode of spread of this pestilence led to the clear recognition of the
fact that it is a preventable disease, and it was soon discovered that the same
conception is applicable to typhus fever, typhoid fever and many other infec-
tious diseases. Cholera has destroyed millions of human lives, but it has
been the indirect means of saving millions more.

The visitation of great epidemic diseases, such as cholera and yellow fever,
has been one of the levers of progress in modern sanitation. Although we
have constantly with us diseases, notably typhoid fever, which teach the
same lessons and are as jireventable as cholera, it has often required the
violent impressions of the outburst of some rapidly spreading and strange
pestilence to stir a community to undertake sanitary improvements, whose
necessity has been long pointed out by sanitarians. We in Baltimore can,
if we choose, wait to receive such a violent lesson, but it is the part of wisdom
and prudence to profit by the same lesson which existing circumstances
teach no less distinctly, even if with less impetuosity.

It is fortunate that those who instituted the first public sanitary measures
did not wait to find a thoroughly scientific basis for them. Even in this day
with our greatly extended knowledge of the causation and mode of spread
of infectious diseases, there are many proved measures for preventing the
development and spread of disease, for which we cannot give an entirely
satisfactory scientific explanation. We must utilize the results both of
practical experience and of scientific investigation in determining the charac-
ter and the eflFicacy of sanitary procedures.

The early English sanitarians based their practical sanitary measures
upon a belief in the efficacy of cleanliness in preventing the development
and extension of infectious diseases, and they directed their effort* espe-
cially to securing pure .soil to live upon, pure air to breathe, pure water to
drink, and pure food to eat. While modern bacteriology- has taught us the
particular impurities in our environment most to be dreaded and conse-
quently better means to guard against them, this programme of the early
sanitarians remains to this day the broadest and most satisfactory basis of
preventive medicine.

While the great media of our environment, soil, water, air, and food, are
so intimately a^ssociated in their sanitary relations, that impurities of one
are likely to afreet others, my theme on this occasion relates especially to the
dangers of pollution of the soil.

The soil is the ])lace to which sooner or lat<>r all organic matter returns.
From it conies all life and to it all life returns. " Dust thou art, and unto
dust shalt thou return," embodies a profound scientific truth. The soil is
the greatest laboratory in the world. It is there through the agency of

SEWAGE DISPOSAL AND PUBLIC HEALTH 609

microscopic organisms that organic matter derived from plants and animals
is decomposed and converted finally into the simple inorganic substances
which make the food of plants. The plants again build up these simple
mineral constituents into the complex organic materials of their bodies, which
make the food of animals. In this continual circulation of matter, agencies
at work in the soil play an indispensable part, a part so essential that if this
link in the chain should drop out all life ujwn this globe would cease in a
comparatively short time.

It is through these agencies, which are chiefly living microorganisms
present everywhere in the superficial soil, that the soil is able to dispose of
organic matter which it receives and thus continually to purify itself. Upon
tliis principle is based the method of disposal of sewage by irrigation and
filtration through the soil. But there is a limit to the capacity of soil to con-
vert organic material into a harmless state and if this limit is exceeded we
have a polluted soil. There are likewise various circumstances, which cannot
be considered here, which influence the rapidity and extent of this process of
self-purification. For example, when the organic material is not received
upon the superficial layers of the soil, but leaks out, as through cesspools, into
the deeper layers, the process of purification is much slower and less efHca-
cious. In this way tlie soil may become contaminated to great depths and
may bring serious injury to people living upon it. There are various artifi-
cial conditions, such as pavements, which render much of the ground in cities
incapable of doing the work of virgin soil in transforming organic waste.

What are the dangers of such contamination of the soil? Some of
these dangers we can point out with reasonable certainty ; others, which we
have reason to believe exist in view of certain benefits which regularly follow
purification of the soil, we understand at present either very imperfectly or
not at all.

Pettenkofer has called especial attention to the fact that the air in the lower
parts of our houses is derived in no small part from air drawn from the
ground, unless the special construction of the cellars prevents this. If this
ground air comes from a polluted soil, it contains foul gases, the precise
influence of which upon the health of the inhabitants it has not yet been
found possible to determine, but there is reason to believe that it may be
injurious, and certainly it must be regarded as offensive. That such air
uuder certain circumstances may contain disease-producing microorganisms
is highly probable. Wlien the soil has become saturated with illuminating
gas derived from leaky or broken gas pipes, the air of houses in the neighbor-
hood may become so contaminated with gas drawn in from the soil, that
serious poisoning of the inhabitants may result, as has repeatedly been
observed.

610 SEWAGE DISPOSAL AND PUBLIC HEALTH

The view is widely held that serious roiitaniiiiation of the soil is injurious
to the health of those livini^ upon it, independently of the actual presence iu
such soil of the specific germs of disease. Exposure to such influences is
thought to be capable of impairing mental and physical vigor and in general
of lowering resistance to disease. Among the various factors which deter-
mine the higher death rate in many crowded and insanitary localities, pol-
lution of the ground is doubtless one of importance.

It is, however, more especially in the presence of the specific microorgan-
isms which cause infectious diseases, that we have to seek the chief dangers
from contamination of the soil with human and animal excreta and house-
hold waste. Without proper methods of disposal of sewage abundant oppor-
tunities are afforded for the escape of such pathogenic microorganisms into
the soil.

The fate of isuch organisms after they have reached the soil is various. It
has been demonstrated that the bacilli of tuberculosis and of typhoid fever
may survive months, perhaps even years, and that those of cholera may per-
sist for weeks in the soil. Whereas in virgin soil they do not find requisite
food for their multiplication, the bacilli of typhoid fever may actually mul-
tiply in soil contaminated with organic material.

Having once reached the soil, these disease-producing germs may be con-
veyed to us in manifold ways. An important medium of transportation of
bacteria from an infected soil is the water which we drink or use for domestic
purposes. Our chief interest here in Baltimore in the contamination of drink-
ing water from the soil relates not to our own soil, save in the occasional
use of wells, especially in the recently annexed districts, but relates to that
bordering on the streams and reservoirs from which we receive our naturally
excellent drinking water. It is, therefore, not necessary to dwell upon this
point on this occasion.

Among the various other ways by which harmful bacteria may reach us
from contaminated ground it will suffice to specify tlieir conveyance attached
to particles of dust in the air, their transportation by flies and other insects,
and by domestic animals, their presence upon vegetables, especially those
eaten uncooked, and our own direct contact with the soil. It is evident that
the possibilities of infection from soil contaminated with disease germs are
numerous and often intricate.

The list of disea.ses whose causation has been shown to stiind under certain
conditions in more or less direct relation to contamination of the ground
with their specific germs is a long one. Among the more important may be
mentioned malaria, typhoid fever, cholera, yellow fever, dysentery, tul)ercu-
losis and the summer diarrhoeas of infants. Experience teaches, unmistak-
ably, that contamination of the soil with organic refuse favors the develop-

SEWAGE DISPOSAL AXD PUBLIC HEALTH 611

ment and spread of such diseases as these, and that drainage and purification
of the soil by proper systems of sewerage are among the most effective
measures for their prevention.

■ No more instructive illustration of the value of modern methods of public
sanitation can be found than the inability of Asiatic cholera to secure a
foothold during the last two European epidemics in clean cities with proper
sewerage and water supply and its ravages in notoriously filthy or insanitary
cities, such as Toulon, Marseilles, Naples and formerly Hamburg. The
public should realize that quarantine is an extremely vexatious, expensive,
uncertain, means of protection, and that far greater safety can be secured by
measures which render a city unsuitable for the multiplication and distri-
bution of the germs of epidemic diseases. A city can make itself cholera-
proof by well understood sanitar)' measures.

Insanitary conditions, to adopt a metaphor employed by Pettenkofer,
represent the powder and the germs of cholera or tj"phoid fever sparks. It
is wiser to keep no powder of this sort than to engage in frenzied and often
futile efforts to drive away the sparks which, if they reach the powder, will
cause a destructive explosion.

Although the nature of the relationship between the conditions of the
ground and the prevalence of tuberculosis is not well understood, practical
experience has shown that many localities have secured, by good drainage of
the soil, great reduction in the mortality from this most deadly scourge of
the human race, a reduction amounting in some places to nearly fifty per cent
of the former death rate. Similar measures in Berlin and elsewhere have
notably lowered the mortality among infants, particularly from summer
diarrhoea.

I call your attention to these various charts hung upon the wall which
illustrate some of the beneficial results which have been secured by purifica-
tion of the soil through proper systems of sewerage. The charts speak for
themselves.

Upon this one the black column represents the average number of deaths
from typhoid fever in 313 cities without sewers and the next column, less
than one-quarter of the first in height, shows the deaths in 39 cities with
efiicient sewers.

This second chart shows on the left side the deaths from typhoid fever to
each 10,000 inhabitants in each of a series of cities with good sewers and a
general water supply, and upon the right side the deaths from the same
cause in cities without sewers or ver}' imperfectly sewered. You will observe
that the average in the first series is 2.4 and in the second is 10, with many
cities lower than the average in the first series, notably Munich, Dantzic,

G12 SEWAGE DISPOSAL AND PUBLIC HEALTH

Vienna and FriUikforl, and many liigher tlian the average in the second series,
notably several Italian cities.

Especially instructive is the next chart, which shows the experience of
Munich durinfT the frradual improvement of an orioinally hi;,'hly contami-
nated soil. During the first period represented, when the inhabitants drank
water from wells and the excreta were stored in ordinary privy vaults, the
death rate from typhoid fever was 24.2 per 10,000 inhabitants. When the
city required the cementing of the vaults, the death rate fell to 16.6. The
remaining three lines show the successive reductions in the death rates with
the gradual extension of the sewerage system, until in 1884 the deaths from
this fever were reduced to 1.4 per 10,000, and in 1888 to 1 per 10,000 inhab-
itants. By systematic and intelligently directed sanitary improvements tlie
cities of Munich and Vienna have been converted from hot-beds of typhoid
fever to places from which this disease has been practically eradicated. All
of the money which they have expended in carrying out these great sanitary
reforms has been repaid a hundredfold in the increased health, happiness
and productive capacity of the inhabitants and in the increa-sed value of
property.

The same results can be secured by Baltimore and other cities, as is demon-
strated by this chart, which shows for Dantzic, Breslau. Frankfort, Berlin,
Vienna, Bnissels, London, Xew York. Boston, Brooklyn, and other cities the
deaths from typhoid fever to each 10,000 inhabitants before, during and
since the introduction of sewerage aJid general water supply. You will ob-
serve that the experience has been everywhere the same, lowering of the death
rate to a quarter, a sixth, an eighth, a twelfth, even a twentieth, of the former
rate.

This red line represents the mortality from typhoid fever in Baltimore.
It is the official mortality from this disease. The actual mortality is con-
siderably higher, for, as Dr. Osier hiis pointed out, doubtless most of the
deaths in this city returned to tlie Health Department as from malarial fever
and from typho-malarial fever are in reality due to typhoid fever. The death
rate from typhoid fever in this city, as he ha.s shown, is that which belongs
to an unsewered city with general water supply, and it can he confidently
predicted that the introduction of efficient sewerage and the protection of the
sources of our water supply will reduce this mortality to the low rate of well
sewered and well watered cities.

The reduction in typhoid fever shown by the charts cannot be attributed
wholly to the introduction of good sewers. In many instances it has been
due mainly to the introduction of a general supply. of pure drinking water.
Authorities have differed as to the relative value of sewerage and of water
supply in influencing the prevalence of typhoid fever. We need not pause

SEWAGE DISPOSAL AND PUBLIC HEALTH 613

here to discuss this matter. Both factors are important, tlie drinking water
usually the more important. But it is suffic'ient for our purj)ose to show
that purification of the ground by proper disposal of sewage is one of the
factors in determining a reduction in the occurrence of typhoid fever and
other diseases.

It is by no means an easy matter in all cases to assign to each one of the
various recognized elements which go to make up an entire system of satis-
factory municipal sanitation its due share in the beneficial result, for it
rarely happens that one is introduced by itself alone, and the harmonious
working of the whole system is often necessary to secure the best results from
the individual factors, such as pure water supply, efficient sewerage, good
drainage, cleanliness of streets, improvement or removal of insanitary quar-
ters, thorough sanitary inspection of dairies and food-stuffs, public disinfec-
ting establishments, hospitals for infectious diseases, municipal laboratories,
etc. In some instances, however, the conditions have been such as to furnish
conclusive demonstration of the separate influence of the introduction of
effective sewerage upon the death rate from typhoid fever. This is notably
true of Dantzic and Stockholm, as is illustrated by these charts. In the
former city a high death rate from typhoid fever persisted after a good
general water supply, but after the introduction of the system of sewerage
it fell from nearly 10 per 10,000 to 1.5. You will observe in tliis striking
chart how in the city of Stockholm the mortality from typhoid fever fell,
pari pas.fu, with the gradual extension of the sewerage system, reaching in
1887 the low figure of 1.7 per 10,000.

Much more evidence might be adduced, if it were necessary, to show the
beneficial influence of good sewerage upon the health of a community, but
enough has already been said to demonstrate the hygienic importance of
proper disposal of sewage. Indeed it might seem unnecessary to dwell upon
these matters upon which sanitarians are agreed, were it not that public
indifference to this subject indicates lamentable ignorance, although for two
generations the gospel of public sanitation has been preached to this city by
its health officers and others. Trite and wearisome as the tale may be,
it is one which must be told and retold and we cannot choose but hear until
the end desired is attained.

But it is not necessary or even desirable to rest the argument for an efficient
sewerage system exclusively upon its effects on public health, important as
these are. Quite apart from the large saving of human life, the proper dis-
posal of excreta, household waste, water and garbage contributes so much
to the comforts, conveniences and even decencies of living and so essential a
part of such disposal in large cities is a good system of drains and sewers,
that it is positively uncirilized for a modern ci*^- to be deprived of the

614 SEWAGE DISPOSAL AND PUBLIC HEALTH

advantages of fucIi a system. The conditions in this respect here in Balti-
more with its leaky and overflowing surface drains, with its utterly insuffi-
cient storm water drains, witli one-twentieth of its area, exclusive of streets
and parks, occupied by privy pits and cesspools, permitting often overflow
and leakage into the ground and cellars, with arrangements by which sew-
age and garbage are allowed to befoul the streams and the harlxir basin, are
obnoxious in the extreme. That greater damage to health and property has
not been the result of these primitive conditions is due in large part to the
natural salubrity of the city and the configuration and character of the
ground.

ilr. Mendes Cohen, in a published address delivered before the Taxpayers'
Association of Baltimore about six years ago, pointed out ven,' clearly and
forcibly the injury to property caused by the defective drainage of this city
and he showed how the rental value of property would be so much enhanced
by the introduction of good drainage that a large share of the necessary cost
of the improvements would be thereby covered. Dr. Fulton will tell you this
evening something about the loss in money due to sickness and death entailed
by the present conditions and the estimated pecuniary gain which can reason-
ably be expected to follow the establishment of a good system of sewers. But
who can estimate the suspense, the suffering, the grief, the despair caused by
the unnecessary sickness and sacrifice of life through neglect of the plainest
laws of sanitation ?

The immediate occasion of our assembling this evening upon the call of
the physicians and sanitarians of this state is the consideration of the
recently published Eeport of the Sewerage Commission of the City of Balti-
more, of which an abstract has been presented to you by Dr. McShane.
Those who are to follow me will discuss the details of this Eeport. It seems
to me to be an admirable document, supplying as it does the necessary data,
based upon a careful and scientific investigation of the problems involved,
to enable the reader to form an intelligent judgment upon tlie subject. It
would be a great misfortune if the citv' of Baltimore should not take advan-
tage of this opportunity to come to some definite solution of this problem
which must be solved sooner or later and which becomes more complicated
the longer it is deferred. It behooves our citizens and above all our legis-
lators to give earnest heed to this matter and to see to it that this Report does
not remain as fruitless in practical results as did its predecessors.

EELATIONS OF LABOEATORIES TO PUBLIC HEALTH '

Mr. President and Members of the American Pujlic Health Association:
I am very glad of the opportunity of appearing before you, and desire to
say a few words with reference to the general subject of the relations of
laboratories to public health. A laboratory is a workshop where those, who
are suitably trained, have charge of the work which is done, where they have
the proper supply of material and adequate means for carrying out the study
of such material. Such laboratories may be used for different purposes.
Some of them we may regard as private laboratories; some as purely investi-
gating laboratories; others are intended for purposes of instructiou, and
still others are mainly to make available to the general public the results of
scientific work by the conduct of certain technical procedures. Laboratories
in one form or another have existed from the earliest times. We must
suppose that Aristotle had something in the nature of a laboratory, and
although we know very little definitely about the remarkable Alexandrian
period in medicine and science, it is clear that laboratories must have existed
then. But public laboratories, which were freely opened for purposes of
instruction and investigation, are modern. With the exception of the ana-
tomical laboratory, which has existed in some form since the fifteenth cen-
tury, laboratories, as now understood, are the creation of the present century.

It is usually stated that the first laboratory in a modern sense was the
chemical laboratory founded by von Liebig in 1823. This is not strictly
correct as a physiological laboratory was established by Purkinje in Breslau
in 1824. It nevertheless remains true that Liebig's laboratory had the
greatest influence upon the subsequent development of laboratories through-
out the world, and to this day our chemical laboratories are the best sup-
ported and best equipped laboratories which we possess. I shall not
att-empt to trace the evolution of laboratories up to the present time. But
it is of interest to note the very recent development of laboratories devoted
to the study of hygiene.

The first laboratory of hygiene was started by von Pettenkofer in ifunich
and opened for students and investigators in 1878. It is rather surprising
that the existence of public hygienic laboratories goes back only to that

' Report of an address delivered before American Public Health Association,
Minneapolis, Minn., October 31, 1899.
Am. Pub. Health Ass. Rep., 1899, Columbus, 1900, XXV, 460-465.

615

616 LABORATORIEIS AND PUBLIC HEALTH

quite recent jwriod, and those of 30U, who are familiar with the outcome of
the foundation of that remarkahle laboratory in Munich, know that it wad
one which included all departments of hyj^iene in the broadest sense — the
physical side, the chemical side, the bacteriological side of hygiene, all rep-
resented there by separate departments with the respective directors of these
departments. What inestimable benefits it has brought to the city of
JIuuich ! In this laboratory were investigated the great problems relating
to the disposal of sewage, the public water supply, the factors concerned in
the prevalence of epidemic diseases, and more especially of cholera and
typhoid fever. The well-known doctrine as to the relation of typhoid fever
to ground-water was promulgated and thoroughly discussed. The result has
been of inestimable value to the inhabitants of that city — a city which was
once the very hotbed of typhoid fever, and which, at the present day, is prac-
tically free from it, so that 1 have heard von Ziemssen say that he has found
it extremely difficult to give practical demonstrations to medical students
of the lesions of this disease. The great work of von Pettenkofer and
his coadjutors cannot be expressed in dollars and cents.

A great impulse to the foundation of hygienic laboratories came about this
period from the epochal discoveries in bacteriology. It was then that Koch
introduced his remarkably simple methods for the isolation and study of
bacteria of certa.Ln infectious diseases. The stimulus from these great dis-
coveries led to the very rapid foundation of hygienic laboratories in connei'-
tion with universities, so that within a few years nearly all of the great univer-
sities in Germany were provided witJi such lalx>ratories. Ajiother factor which
has exerted a great influence in the development of hygiene has been the
occurrence of epidemic diseases, more particularly such diseases as cholera,
and in this country also yellow fever, and possibly it may turn out in the
East that the plague may have a similar influence upon public sanitation
there. Devastating as tho^e diseases have been, it is a question whether the
final outcome has not been on the whole to the advantage of the human race,
because it does often seem as if it required the violent impressions of such
pestilences to stir tlie people up to an appreciation of the needs of sanitation
which are realized by sanitarians themselves, but who find it very hard to
bring these matters to the attention of the public in a forcible way. As the
result then of the very natural development of laboratories in general, of the
developments in bacteriology and of the lessons of epidemic diseases, we have
witnessed during the last twenty years the rapid foundation of hygienic lab-
oratories connected particularly with universities, and with boards of health,
both municii)al and state. It is more particularly with reference to the latter
laboratories, connected with nniiiicipal and state boards of health, that we
are especially interested.

LABORATORIES AND PUBLIC HEALTH 617

It will be appropriate to say a few words with reference to the development
and organization of such laboratories, tlie important results which have been
achieved and the prospects which we can reasonably expect from their work.
These laboratories, as you already know, have been founded in large number
in this country, and, in fact, the development of laboratories connected with
boards of health is one which is peculiarly American. The appreciation of
the need of such laboratories, o.f what can be accomplished by them and of
the benefits which the general public derive from them, has been greater
in this country than elsewhere. We have led in this particular direction.
The work of these municipal and state laboratories should in the first place,
be put in charge of those who are especially trained in modern methods in
bacteriolog}', in chemistrj-, in hygiene and in patholog}'. These are very often
the younger men who have had opportunities for these special lines of study.
Such laboratories are, in a few instances, well supported, better supported
than the laboratories in connection with universities. The kinds of work
undertaken in these laboratories relate more particularly to practical prob-
lems concerned in the diagnosis, prevention and cure of disease ; whereas the
broader biological aspects are more properly considered in laboratories which
belong to colleges and universities. But it has been difficult indeed for med-
ical colleges and universities to supply suitable laboratories. They are
expensive, and comparatively few of the educational institutions of this
country are supplied with anything which is worthy of the name of a hygienic
laboratory. I think one could count upon the fingers of one hand the lab-
oratories connected with medical colleges or universities in this country
which are appropriately called hygienic laboratories, not that hygiene is not
represented in a larger proportion than that, but suitably equipped hygienic
laboratories exist in small number in this country. This, of course, is to be
very much regretted, and it is to be hoped that the influence of this Associ-
ation may be such as to lead to a greater appreciation of the need of such
laboratories in connection with our teaching bodies, because I think that such
hygienic laboratories in connection with universities should work out prob-
lems that are different from those which interest municipal and state boards
of health.

Let us consider for a moment some of the results obtained from such lab-
oratories. As you all know, one of their main purposes is to assist physicians
in making exact diagnoses of certain diseases. Their greatest triumphs are
in relation to diphtheria, in the recognition of the cases of genuine diph-
theria, on the one hand, and in seeing to it that specific treatment by anti-
toxin is properly carried out. But their field of usefulness is by no means
limited to diphtheria, but extends to the diagnosis of other diseases, such as
42

618 LABORATORIES AND PUBLIC HEALTH

tuberculosis, typhoid fever and malaria. While often tuberculosis is readily
recognized by the physician, once in a while cases occur in which the physi-
cian must be in doubt as to the diagnosis, and he should be able to call to his
aid those who are working in these laboratories for the purpose of enabling
him to make a correct diagnosis. The diagnosis of fevers, such as typhoid
and malarial fever, offers an important field of usefulness for these lalxjra-
tories, particularly in the south. In the recent war we are told that the diag-
nosis of typhoid fever was made with great reluctance, and that physicians
often made a diagnosis of malarial fever in many cases of genuine typhoid
fever. We have means at our disposal for the accurate diagnosis of these two
diseases. The diagnosis of typhoid fever can frequently be made with the
Widal reaction, and it looks now as if there w-ere to be other methods added
which will enable us to make a diagnosis at an earlier stage of the disease
than where the Widal reaction is applicable or in cases where this reaction
fails. Especially to be desired is the establishment of laboratories available
for the diagnosis of malaria in the regions wjiere malaria prevails, particu-
larly the severe forms of the affection. Nothing should be called malaria un-
less the malaria] parasite is present, and an exact diagnosis of the disease can
be made by samples of blood properly collected. With a little instruction the
physician should be able to send these specimens in sucli a way that a report
could be returned within a short time as t« the existence of malaria. Wlien
we consider tlie practical importance of these two diseases in this country,
and the fact that typhoid fever is preventable and that the recent discoveries
regarding the relation of the mosquito to the spread of malaria offer pros-
pect* of eradicating malaria, the importance of extending in the direction
indicated the work of municipal and state laboratories is apparent.

Then, there is the chance of one of the greater devastating epidemics
making its appearance. The municipal and state boards of health can make
early diagnoses. Thus if Asiatic cholera should make its appearance, effec-
tive measures of prevention can now be taken at the onset, for it is important
to recognize the first case of the disease before it can gain a foothold. The
experience during the last cholera epidemic in Germany was that when the
first cases were recognized and immediate measures were taken to check the
spread of the disease, those mea.«urcs were very effective. But where the
disease was allowed to gain a foothold, it was difficult to put an end to tlie
epidemic. Suppose the plague should make its appearance in this country ;
if tlie city or state is provided with a suitable laboratory, with well trained
piiysicians, the first case or two sliould be recognized and etTective measures
of prevention should be taken, so that tliese laboratories should stand as au
effective defence between us and the outbreak of this great pestilence. It is

LABORATORIES AND PUBLIC HEALTH 619

not clear that the.se laboratories can be so useful with reference to the diag-
nosis of yellow fever, because we have not exact methods, still they can be
heljiful in many directions with reference to this disease.

These laboratories can carry on original investigations and important
practical work with reference to water supplies, to the disposal of sewage,
to examinations of food, of milk, etc. All of these aro subjects which properly
pertain to some aspects of the work of lalioratories, but I shall not attempt to
consider them now. The foundation of such laboratories has had a very im-
portant stimulating influence upon boards of health, both local and state.
It has introduced a scientific spirit into the work ; it has brought into con-
nection with executive officers the younger men who are full of enthusiasm
with reference to studies along these lines, and I think that we may say that
the general tone of boards of health has been elevated and stimulated by the
foundation of laboratories of this character.

It is to be deplored that our National Government has had so little share
in this important movement in public hygiene. This Association has advo-
cated a plan by which the various states may secure aid from the National
Government for the support of public laboratories of hygiene analogous to
that in operation in the case of Agricultural Experiment Stations, and it
seems to me very desirable that this or some similar plan should be adopted.
Then we are all agreed that our government should have a central sanitary
organization in connection with which a laboratory of public hygiene should
be established. We can now appeal as never before to the furtherance there-
by of commercial interests, a motive which seems to be more efficacious with
our legislators than the lives and health of human beings, possibly even more
than the welfare of cattle.

JIany of you know that the workers in these laboratories have come to-
gether on this occasion in unusual numbers, largely through the very excel-
lent work of our public-spirited member. Dr. Wyatt Johnston. These
workers have been brought together here with a view to organizing a Labora-
torj' Committee or Section of this Association. A few years ago a somewhat
similar meeting of bacteriologists was held under the auspices of the Water
Committee of this Association in New York, and we all felt at that time that
it would be fortunate if we could have a permanent organization composed
of such men as were there assembled. In fact, the idea of organizing the
working bacteriologists and allied chemists into a biochemical section has
been in the air for some time, and the outcome seems to be the best form of
organization, viz. : one which will bring these experts into this Association.
What we propose to do is to bring them as a group here and have them
become members of the Association. There are many questions which are

620 LABORATORIES AND PUBLIC HEALTH

very technical, relating to methods of procedure, etc., which it would not be
at all appropriate to bring before the general body of the Association, such
as chemical examinations of water, classification of water bacteria, eto., etc.
It is proposed, therefore, that this relatively small group of members of this
Association shall constitute a sub-group — call it what you like. I do not
think Laboratory Committee is a dosignativo term, in that it does not express
exactly the scope of the work. However, matters of detail can be readily
settled by a conference committee. The idea is that we should be called a
section of this Association, which shall assemble here at the same time tliat
the general Association comes together, but that the meetings of the smaller
body or section shall take place on the day preceding the meeting of the
general Association, and, if possible, their special work should be completed
then. If any work remains over, provision should be made for finishing
it without conflicting with the sessions of the general body. Subjects of
special interest only to the practical worker should be discussed before the
meeting of the section, and members of this section having papers of general
interest should present them before the Association. The details of organ-
izing such a section can be worked out later. It is clear to us, however, that
none should be eligible to membership in the section who do not become like-
wise members of the American Public Health Association. That is our
understanding, and we ask no special autonomy other than that we shall
come together in connection with your meeting by such an arrangement as
will be mutually advantageous, increasing your membership in quantity and
quality, bringing certain kinds of members whom, I am sure, you will all be
glad to welcome here to add to the usefulness of the Association. It will be
of advantage to bacteriologists to come into close contact with the practical
work of this Association, and to this Association to receive these workers.

DUTIES OF A HOSPITAL TO THE PUBLIC HEALTH '

It is a well known fact that there are no social, no industrial, no economic
problems which are not related to problems of health. The better conditions
of living, housing, working conditions in factories, pure food, a better supply
of drinking water, all these great questions, social, industrial and economic,
are bound up with the problems of public health. The humanitarian move-
ment has been one of the great agencies in promoting the better health move-
ment. There have been two great means by which interest in public health
and the movement for the promotion of the health of the community have
been advanced. One has been the new humanity', the otlier has been the
advance in knowledge. I regret to say that I believe the impulse has been
stronger, on the whole, from those interested in the humanitarian movement
than it has been from my own profession. Anyone who is informed as to
the influences which are operative in tlie last century, from 1830 to 1850,
which initiated the modern public health movement and culminated in the
passage of tlie public health act in 1848 in England, knows that it was less
a movement on the part of the medical profession than it was on tlie part
of philanthropists. Those interested in the conditions of the laboring
classes and informed as to the steps taken for the prevention of disease, know
that it was the human impulse more tlian any other which started tlie modern
public health movement — at least, the governmental activities, and the
recognition that the care of the health of the people is an important func-
tion of government.

But, after all, that impulse alone would not liave been sufficient. It is of
vital importance that health activities should be based upon accurate knowl-
edge of the cause and of the spread of disease. At the period (1848) of
which I am speaking, they knew little about how such diseases as typhoid
fever and cholera were spread. Public hygiene was a blundering affair then.
Efforts costing vast sums of money v, ere misdirected and wasted. However,
one idea dominated at that time, which was in many ways a fortunate one
at that stage; this idea was the relation of disease to conditions of filth. It
was known that one disease, typhus fever, especially bore a relation to filth,
and through the application of this knowledge typhus fever was checked.

' Report ot an address delivered before the National Conference of Charities
and Correction, Baltimore, May 14, 1915.

Proc. Nat. Confer. Char., Bait., 1915, 309-218.

621

622 HOSPITAL AND PUBLIC HEALTH

Until its recent appearance in eastern Europe typhus fever was practically
exterminated from civilized countries. But the new knowledge came with
the discovery of the causjition of the class of disease of the greatest signifi-
cance to mankind, the infectious diseases.

We could have no more striking example of the health-saving, the life-
saving knowledge which comes from penetration into the cause of disease,
deeper insight into the manner in which disease is spread, than the vast
benefits which have come from the discoveries of Pasteur and Koch and
the work carried on by tlicm and those following them. These discoveries
initiated a movement in medicine which gave a new face to things, so that
we think of modern medicine as something quite different from the medi-
cine of the past. We think of it oft^^n as Ijeing more different than we are
justified in doing. The truth is that there has been no change in the real
aims of medicine from the beginning. From the days of antiquity, the
aim of the pliysician has always been to cure and to prevent disease. It is
precisely that consistency of purpose wliich gives such interest to the
future of medicine, no matter how futile the efforts of the past may have
been nor how long men wandered in ignorance and darkness.

But tlicre came to us a new liglit, and with it a new power. The physi-
cian acquired a control over the spread of many of the infectious diseases
and in tlie case of some a new power in the treatment of disease wliich
rendered his mission a far more significant one for the world than it had
ever been before. It is now possible to control great pestilences. We be-
lieve even in the possibility of the complete eradication of such pestilences.
Only the other day I attended a conference in New York where the possi-
bility of taking up the complete extermination of yellow fever was considered.
It is possible that will be initiated. Anyway, the problem seems a soluble
one, and the work undertaken in tliat direction full of promise. This advance
in medicine was not merely in relation to this class of diseases but it affected
all branches of medicine. It stimulated investigation, so that the physicijui
can do far more in all classes of diseases than was possible in the past. There-
fore medicine makes an appeal to the community, it makes an appeal to the
goveniment, for support, it makes an appeal to public spirited philan-
thropists, wliich it never could have done in the past. Far-sighted, public
spirited philanthropists who appreciate the possibilities of further explora-
tion in this field have enabled medicine to undertake investigations, and it
is above all important that we should acquire further knowledge as to the
causation of disease.

I have no doubt that we arc today directing our efforts in the wrong way,
as I have said they were doing sixty and seventy years ago. I have no doubt
we are spending millions of money fruitlessly, wastefully, as compared with

HOSPITAL AND PUBLIC HEALTH 623

what the possibilities might be if we had a more exact knowledge of the
causation and propagation of disease. Consider for a moment the vast sums
formerly wasted in eiforts to control yellow fever by quarantine, and how
simple the problem became when we learned that yellow fever can be spread
only in one way, by the bite of a particular species of mosquito.

There are a great variety of agencies concerned in the promotion of public
health, prevention of disease, and the treatment of disease. While the theme
assigned to me relates to one particular agency in this warfare upon disease —
the hospit-al — I must say at least a word about two others of most importance,
namely, the governmental agencies, public health boards, commissioners and
officials, simply to emphasize the importance of better organization and bet-
ter support of our pubLic health officials and boards. Among our chief
needs I would mention, in the first place, larger appropriations ; in the
second place, better trained experts; and, in the third place, taking the work
out of politics. I am not going to elaborate on these, but I hardly like to
speak before an audience of this kind without at least referring to the im-
portance of better support and organization of our boards of health, and the
great need of opportunities for the better training of experts in that field.
The selection of a commissioner of health is of course, a matter in which
the whole community is interested. The entire country should be looked
over in order to find the best man for the position — not simply the one who
can easily be found in the community.

One other agency I should at least like to refer to, and that is the public
health nurse. One of the contributions of the hospital to public health work
has been the trained nur.«e. We are familiar with the incalculable advan-
tages which come from the introduction of the system of visiting nurses.
They should be extended into larger use and there should be a more special-
ized training for the public health nurse. It is of the greatest importance
that her activities should extend to the rural districts. One of the striking
circumstances of the modern public health movement is the limited advantage
which rural communities have derived from this new knowledge.

As regards the relation of the hospital to health, there is no activity of
the hospital that is not related to health directly or indirectly. I shall speak
somewhat disconnectedly on certain points, I think, because it is quite im-
practicable in the time available to present the subject in a comprehensive
and systematic manner. First, as regards certain types of hospitals. We
have the general hospital and various kinds of special hospitals. There is
one of these special hospitals, the tuberculosis hospital, which has had such
influence and which brings so important lessons that I would like to refer
to it. I do not propose to discuss the importance of the hospital in the tuber-
culosis crusade, as that would lead too far. Suffice it to say that it has the

624 HOSPITAL AND PUBLIC HEALTH

very first place. The tuberculosis hospital has two functions which it is
important to bear in mind. One is the educational function. The benefit
of residence in a tuberculosis hospital to a consumptive is not measured
solely by improvement in liis health. So far as tlie community is concerned,
it is measured also by the education of the patient in methods of right living.
There has probably been no influence which has had larger effect in stirring
up the public mind as regards many of the problems of the public health
than the tuberculosis crusade. It has taught people the value of fresh air;
it has emphasized the importance of proper conditions in the household and
in the factory, because tuberculosis is a disease which is spread by the imme-
diate environment — in houses, workshops or factories. The lessons which
have reached tlie public, largely through the work of our tuberculosis hospi-
tals and sanatoria, have been of inestimable value in tlieir effects upon public
heahh.

I would like to point out in this connection, familiar as it is, that just as
ill the case of tuberculosis, so in nearly all the efforts to control infectious
diseases there are incidental benefits which are often not foreseen but which
in many instances equal, if not exceed, the actual effect upon the control
of the particular disease in question. Take, for instance, the control of
typhoid fever, with the consequent insistence upon a pure water supply,
pure food, and certain conditions relating to the spread of disease from
person to person, using the military to clean up unsanitary morasses and
swamps around human habitations and rendering large areas fertile and
suitable for cultivation. One might go on and point out benefits often far in
excess of the actual results which are immediately in view when tlie attack
is first made.

The tuberculosis dispensary is something very different from the ordinary
dispensary. It is perfectly obvious that it would be absurd to conduct a
tuberculosis dispensary as most dispensaries were conducted before the great
movement initiated by our chairman, Dr. Cabot, came into use. by having
the patient simply come to tlie dispensary, receive a dose of medicine, and
then go away. The idea of following tJie patient to the home, of instruction
in the home, not only of the patient but of all in proximity to him — all that
conception, whicli, thanks to Dr. Cabot, is now so familiar in the work of a
dispensary, although so imperfectly attained in many cases — is exemplified
in a striking way by the tubcrculosi-; dispensary.

There are many other special hospitals for the eye, ear, throat, and child-
ren's diseases. I have only one remark to make in regard to these. It is a
pity that these hospitals have developed to such a large extent as independent,
detached hospitals, often unsuitably located, and out of touch with the
general hospital movement. I ciuinot pause to consider why this has been.

HOSPITAL AND PUBLIC HEALTH 625

It is mainly because the movement started about a century ago and became
active about sixty or seventy years ago, and those who were interested in tliese
branches were not welcome in general hospitals and were more or less com-
pelled to go to one side to establish these special institutions. It is un-
fortunate, and it is very important tliat in future we should do all we can to
remedy this condition, and when a new hospital of tliis kind is founded it is
probable that it sliould be in connection with a general hospital. Referring
to tlie three special hospitals we have been so fortunate as to secure in con-
nection with the Johns Hopkins Hospital, they are far more useful inistitu-
tions and do a far larger service to the conmiunity by virtue of the fact tliat
they are on the grounds of the hospital and in intimate association with the
Johns Hopkins Hospital — in fact, administered by that hospital.

I cannot pause to discuss the development of the modern hospital, but it
is something very different from the hospital of the old days. One of tlie
most significant developments in medicine, and therefore in public health,
has been the development of the modern general hospital. This has come
about largely through increased knowledge of the methods of study and
diagnosis and treatment of disease. It has come about also to some extent
through a more correct view as tc the function of the hospital in education
and in the treatment of patients. These new conceptions are responsible
for a situation where the patient profits by the resources of modern medicine
and of education in sanitarv' ways of living to an extent quite impossible in
private practice. The best that can be done with existing knowledge for the
treatment and relief of disease is to be found now in tlie well equipped and
well organized general hospital.

For whom are these benefits available? In all the American hospitals
where the rich and the poor are both admitted they are available for the
very rich and the very poor. On the whole I think the poor derive the great-
est advantage. The rich formerly did so, and still, I think, to a considerable
extent, share the opportimities of medical discoveries in the treatment of
their diseases. But tliere is a large middle class which at present is not
adequately provided for. I see that that is a subject for a paper in the pro-
gram of the Conference. I was not fortunate enough to hear the paper, but
the very title shows an appreciation of tlie situation. One of the urgent
needs is to supply adequate accommodations in the best of our general
hospitals for all classes of the community. Whether tliey shall be provided
for in inexpensive private rooms or whether by more attractive arrange-
ment in public wards, so as to make the accommodation more acceptable,
I am not prepared to say. Although I am talking on these subjects, I am not
a hospital physician and am not in practice and have not that intimate
personal contact with the .subject that would make my opinion as to the
best solution of a problem of this character of particular value.

626 HOSPITAL AND PUBLIC HEALTH

Why is it that hospitals oiler these superior advantii^es in the treatment
and care of disease? It is because they are well equipped and organized and
because there is a whole staff of assistants. The study of modern disease re-
quires all sorts of examinations by new methods that are in many cases
intricate. Sometimes it is doubtful whether tlic knowledge so derived is
applicable to the case in hand, but whatever sheds light upon the extent and
character of disease must eventually be found of advantage to the patient.
In many cases the private physician is enabled to bring to bear upon his
patient all of these resources essential to the accurate diagnosis and treat-
ment of disease. The hospital reaches only a relatively small fraction of
the entire community — I do not know how many. It has been said that not
more than one-tenth of the sick are cared for in hospitals. The opportunities
are inadequate at present for meeting this great need. It is possible that the
private physicians may be enabled in some way or other to liave at their
disposal such advantages as exist at present almost solely in hospitals.

Some think that the solution is going to be the eventual disappearance of
the private practitioner as we know him today. Some think the profession
is to be socialized. Steps in that direction have already been taken in Den-
mark and other Scandinavian countries where the doctors are paid by the
state, and it is interesting to learn the results of those experiences. But I
think it would be a pity to have the whole practice of medicine institution-
alized. There was something so fine about the best type of family doctor
in the old days. My father was a country doctor and I know something of
the life and what it meant to patients so that I cannot help feeling that every
effort ought to be made to rescue this situation. A recognition of it is, of
course, the first step. How it is to be met I do not know. I have read tliat in
Fall River the physicians have arranged for coordinated effort in their labora-
tories which results in conditions similar to those which exist in hospitals.
I desire to call your attention to the situation witliout attempting mvself
to suggest a solution ; but there is this contrast today as between the organ-
ized, well equipped hospital and the opportunities there afforded for tlie
treatment of disease, and the situation in priviite practice. As regards the
services rendered by the hospital, the side of it with which I am most familiar
is the educational one. The primary purpo-^e — and it must remain the
primary purpose, is the care of the patient. Nothing can be done in a hospi-
tal which in any way can be of possible injury to the patient. The argument
is so familiar that perhapvs it hardly needs prcsentiition, that the use of tlie
hospital for educational purposes really is for the benefit of the patient. If
this can be demonstrated, then we shall be convinced that a hospital which
serves not merely a humanitarian purpose, but educational ami scientific
purposes as well, is doing a far more iniiwrtant and larger work than the

HOSPITAL AND PUBLIC HEALTH 637

hospital which has nothing more to do than to care for the patient. We must
bring this to tlie attention of the public at every suitable opportunity.

The medical school and hospital in the past have developed abroad sepa-
rately, and the real problems of medical education in this country are the
result of that divergent development. We know now that it is important
to bring them together. They never should have developed apart. But the
difficulties are greater tlian one might imagine. The medical school must
have satisfactory relations to a hospital. It is fortunate if the university
or medical school has its hospital, as we liave at the Johns Hopkins. But
as the future of medical education really depends upon its connection with
a hospital, I should consider the future of medical education dark indeed,
in this country, if we were to build hospitals without the university assum-
ing the administration of them. The important thing is for the trustees of
privately endowed institutions to feel that they are doing the best for the
hospital in making it freely available for medical teaching. This superior
kind of hospital is to a large extent at present in this country the well en-
dowed private hospital, but our municipal and state-supported hospitals are
beginning to awake. It is important, and it is a requirement of modern
sanitation, that tliese facilities should be supplied. When I sj>eak of the
educational side of the hospital, I have in mind not merely opportunities for
training doctors and nurses, but for the training of patients as well. Take,
for example, the movement for the early recognition of cancer — the impor-
tance of the public being instructed that sores that do not heal up should
have the physician's attention, that early operation for cancer is usually
successful and the results of delay lamentable — the result of which has been
an organized effort to bring this knowledge home. Do we make use of our
knowledge as we should with patients coming to the dispensary? There are
the same opportunities for bringing lessons home as to right conditions of
living, health, and prevention of disease as are exemplified in the case of
tuberculosis.

There is the scientific work of a hospital. Definite knowledge, of course,
is the most obvious result of the work of those engaged in hospital activities,
but the spirit of investigation has a value so great for the workers that I do
not believe it can be overestimated. It is incumbent upon mimieipal and
state-supported hospitals to make provision whereby the staff, especially the
young men, may be stimulated by laboratory opportunities. The equipment
can be relatively modest, but there should be opfwrtunities which make them
see that medicine is something more than a trade. I would emphasize that
the value of the investigating spirit is not to be measured by making dis-
coveries in science. The spirit of investigation is a stimulus to a real pleas-
ure in work, to better work and better care of patients, and unless the workers
have it, their task becomes merely routine.

628 HOSPITAL AND PUBLIC HEALTH

I want to say a word about autopsies. Podmorlem examination is not
my theme, but it is through the knowledj:fe derived from them that many of
the jireat advances in medicine have come. Tliere is every reason why they
should be characterized as a matter of routine. Dr. Brookings, who has
done so much at the Wasliington University Medical School has said : " I
would not care to put myself in the hands of a physician who, if I should die,
did not want an autopsy and did not want to face the results." The matter
is of sufficient importance, I tliink, to bring to the attention of an audience
of this character.

I have only touched here and there upon my subject. In conclusion, I
would like to add just one thought. It is of the utmost importance that
hospitals should be more linked together with all the agencies which are con-
cerned with public health work. Dr. Cabot has done immense service in
waking us up on tlie question of dispensaries. It is a wonder we could have
slept ,so long. The new era that has been ushered in by social service work
is certain to see the dispensary brought into closer relations with other
agencies concerned in all its fields of activity. I think there is room for a
better organization, a better coordination, a more effective cooperation of the
hospital with the boards of health. I happen to be a member of a state
board of health, and know that we see ways in which tlie hospitals could be
more cooperative than they are at present with all kinds of charity and relief
organizations. The hospitals that take this form are to be, not the only
agency, but I tliink a primary one in the promotion of public health.

OPENING REMARKS BY THE PRESIDENT OF THE SECTION ON
PATHOLOGY AND BACTERIOLOGY OF TUBERCULOSIS '

I esteem it a high honor and privilege in behalf of my American colleagues
to extend a most cordial welcome to all in attendance upon this first section
of the Sixth International Congress on Tuberculosis, and especially to those
who have come from foreign countries to participate in our proceedings. We
are indeed fortunate in the presence of so many distinguished investigators
whose papers and discussions enrich our program and give assurance tliat
this Congress will not pass without substantial contributions to our knowl-
edge of tuberculosis.

It will not be deemed invidious if I express the special gratification which
we all feel in having with us, as an active participant in the work of this
Section, his Excellency, Professor Koch, the illustrious discoverer of the
tubercle bacillus, who must rejoice to witness, in such a gathering as this,
the evidences of the far-reaching and inestimable benefits to mankind which
have come from this discovery, and the promise of greater benefits in store.
We appreciate most highly the participation of so many eminent colleagues
from France, who have cooperated so generously and so effectively in our
efforts toward the success of this Congress. We welcome warmly our kindred
in speech and in blood from Great Britain and her possessions and with equal
cordiality our fellow-workers from Germany and Austria-Hungary, from
Holland and the Scandinavian countries, from Spain, Russia and other
European countries, from Japan and the Orient, and from our sister repub-
lics of Central and South America.

Every effort has been made to assure the truly international character of
this Congi'ess, and a glance at our program will indicate that this result has
been secured. Over seventy per cent of the papers on the program of Section
I are contributed by participants from foreign countries — a gratifying re-
sult made possible by a certain measure of self-restraint on the part of
American workers, who are prepared to furnish papers, if the time permitted.

A word concerning the construction of the program of this Section may be
of interest. After consultation with other officers of the Section I determined
that, instead of selecting themes for discussion and inviting referees and

' Remarks made before the First Section of the Sixth International Congress
of Tuberculosis, Washington, D. C, September 28, 1908.
Tr. VI Internat. Cong. Tuberc, Phila., 1908, I, Sect. I, 2-4.

629

C'^0 OPENING REMARKS

co-referees in accordaiuc willi the umimI i ustom, I would acc'ept papers
voluntarily submitted and then arran^rc tlicni in groups with the expecta-
tion that the result Wduld lie inueli the same, and that the more importajit
and larger themes would thus he presented by those actually engaged in
tlicir study and whose interest was for the time concentrated upon the sub-
jects* presented by them. By thus grouping the titlc,= of papers voluntarily
submitted, the larger topics, such as the biology and chemistry of the tuben-le
bacUlus, the channels and sources of infection, the specific tuberculin reac-
tions, immunity, the relations of human and bovine tuberculosis, will be
presented in a satisfactory and authoritative manner.

In view of the crowded condition of our program I must remind tlie
readers and discussers of the necessity of strict enforcement of the rules,
that the time allotted for referees and co-referees is not to exceed fifteen
minutes, for readers of papers ten minutes, and for participants in the dis-
cussions five minutes ; and especially I would urge the importance of handing
to the Secretary of the Section the written remarks in discussion before the
close of each meeting in order to secure their appearance in the " Transac-
tions."

The main significance of the International Congresses of Tuberculosis
has been in the past, and will continue to be, on the side of prevention of the
dLsease. As has been said, tuberculosis is indeed the disease of the people,
in a truer and larger sense than can be affinned of any other malady. From
the discovery of the tubercle bacillus, and the study of its properties, and of
the sources and modes of infection, there has come a new message of hope to
suffering humanity, so full of untold blessing that the peoples of the earth
have been aroused to its significance, and in all civilized countries there has
been inaugurated what is appropriately called the crusade against tubercu-
losis. Already in certain places the application of intelligent measures of
prevention, based upon a new knowledge, has achieved results so full of
promise that the hopes of even the most enthusiastic no longer seem so
extravagant as they may once have appeared. Nowhere has the existing
knowledge been applied to the prevention of tuberculosis save in part and
inadequately, but the achievements of even this imperfect application are
sullicicnt to in,spire the world to tlie search for fuller knowledge, and to
better directed and more efficient effort^s toward prevention. The crusade
against tuberculosis is truly a battle of the people, by the people, and for
the people. It is not a doctors' fight merely, but all the forces of society-
economic, social, moral, legislative, administrative, philanthropic— must be
enlisted in this contest.

The benefits to the eoniiuunity which result from success in the prevention
of disease extend, as a rule, far beyond the mere control of the particular

BY THE PRESIDENT OF THE SECTION 631

disease in question, incalculable as this benefit may be. As regards tubercu-
losis, it has become increasingly apparent that successful prevention will be
attended by improved conditions of living, of work, and of play ; in a word,
by a general social betterment of the people. It is this aspect of the crusade
which has very properly stimulated the interest of phihuithropists, social
workers, and statesmen.

When we contemplate the popular interest and enthusiasm which have
already been aroused in the campaign against tuberculosis, the readiness to
institute preventive measures, the large pecuniary resources which are
available, and the great expenditure of money and of energy already made
or in the process of making, we must be impressed witli the importance of
making sure that our measures of prevention are really based upon accurate
and full knowledge of the mode of spread of the disease, and are so applied
as to yield the best results, in tlie most economical way, most surely and
most quickly. The campaign must rest upon a sound scientific basis, and
must be conducted along correct scientific lines. This scientific foundation
is supplied mainly by the knowledge furnished by investigation of the sub-
jects represented in this first section of the Congress, namely, the pathology
and bacteriology of tuberculosis. Other sections of the Congress may seem
to be concerned more directly with the marshalling of the forces, with the
conduct of the assault, with the stirring of the martial spirit, and the appeal
to arms, but ours is the division which must supply the ammunition and the
weapons and the strategy of the campaign.

While our existing knowledge of tuberculosis already furnishes the basis
for vigorous and intelligent measures of prevention against tuberculosis, it
must be conceded that there are many important open problems awaiting
further investigation, and that there is still much diversity of opinion re-
garding the point* essential to the proper conduct of tlie campaign. We may
confidently anticipate that the proceedings of this section will contribute
sometliing of value towards the elucidation of some of these problems and
toward a closer agreement of authoritative opinion. They will be, I trust,
a source of pleasure and of profit to all in attendance.

WHAT MAY BE EXPECTED FROM MORE EFFECTIVE APPLI-
CATION OF PREVENTIVE MEASURES AGAINST
TUBERCULOSIS'

j¥r. Chairman, Ladies and Gentlemen: To those who have so long pleaded
the cause of public health in this country, often, it seemed to deaf ears, this
occasion must be a source of great encouragement and inspiration. The
interest manifested by this large audience, the presence as presiding officer
of one of our most distinguished citizens, the stirring addresses of the
Governor and other speakers, and the participation of so many eminent in
public life, in philanthropic effort, and in medicine and sanitation, are indi-
cations of a great awakening in behalf of the health of the people of this state.

This awakening has come mainly through interest in that disease which
may truly be called " the disease of the people." No other disease merits
this designation in equal measure with tuberculosis, which carries off one-
third of those who die at a time of life which should be that of the greatest
productive energy. The people have recognized their true foe in tubercu-
losis, and are stirring to the combat throughout the civilized world.

It may be asked why it is necessary to arouse the public regarding the
prevention of tuberculosis more than concerning other preventable diseases.
Many triumphs of preventive medicine have been achieved without the great
upheaval of popular interest. The necessity of enlisting the active interest
and support of the public in the campaign against tuberculosis is due not
solely to the extent of the ravages of this disease, enormous as these are, but
to the fact that the prevention of tuberculosis is a social and economical
problem as well as a medical one, and that therefore not only medical and
sanitary measures but also other forces of the community — legislative, ad-
ministrative, philanthropic, educational — must cooperate in the struggle.
An important aspect of the crusade against this disease is that success in the
struggle signifies also social betterment, enlightenment in ways of healthy
living and working and intelligent interest and education in individual and
public hygiene in general.

• Report of an address delivered before a Public Meeting under the auspices
of the State Charities Aid Association in cooperation with the State Department
of Health, in behalf of a State Campaign for the Prevention of Tuberculosis,
Albany, N. Y., January 27, 1908.

Albany M. Ann., 1908, XXIX, 256-262.
632

MEASURES AGAINST TUBERCULOSIS 633

The thought wliicli comes first to my mind, as I have witnessed the enthu-
siasm and interest manifested by this large meeting, is how such energies
and forces as have been aroused and are ready to be moved can be so
directed and applied as to secure in the most effective manner the best
results. It is of fundamental importance to secure the cooperation and co-
ordination of all the necessary agencies and to proceed along well defined,
systematic lines.

Since the discover}- of the tubercle bacillus by Koch in 1882 it has been
known that tuberculosis is a preventable disease, and experience has demon-
strated that in the initial stage it is curable in the majority of cases. With-
out the aid of experimentation upon animals this greatest discovery in the
domain of bacteriology could not have been made.

It is in my judgment a conservative statement that at least one-half of
the existing sickness and mortality from tuberculosis could be prevented
within the next two decades by the application of rational and entirely
practicable measures, and I believe that we can look forward to a much larger
success. You can be assured that the expenditure of money and of well
directed energ}' in this cause will lead to a very considerable saving of human
life, and that in no other direction will money expended for sanitary reform
yield equally important results to the community.

The essential elements in the solution of the problem of prevention of
tuberculosis are clear understanding of the modes of conveyance of the dis-
ease, well considered, practicable measures of prevention based upon this
knowledge, the application of these preventive measures under the direction
of skilled sanitary officers, and adequate resources for their application.

The justification for the statement that the death rate from tuberculosis
mav be cut in two is based upon the fact that the saving knowledge which we
possess regarding this disease is at present only most inadequately and im-
perfectlv applied in prevention, and that even this inadequate application
has brought about a notable decline in the mortality from tuberculosis in
many communities, and it would appear, precisely in those places where pre-
ventive measures have been most effectively employed.

In Prussia the death rate from tuberculosis has diminished about forty
per cent in the last twenty years. In Sweden there has been a similar reduc-
tion. Particularly significant is a like diminution in New York City, which
oSers unusually difficult problems in consequence of the tenement house
conditions and the resulting density of the population and of certain other
unfavorable factors. The Health Department of New York City, largely
through the admirable work of Dr. Biggs, has achieved a triumph in this
reo-ard which has attracted the attention of sanitarians throughout the world.
43

634 MEASUEES AGAINST TUBERCULOSIS

In England the decline in the death rate from tuberculosis began long before
the discovery of the tubercle bacillus and has continued to the present time,
but in this countrj- there have been throughout this period special hospitals
for consumptives and intelligent public sanitation.

Permit me to indicate very briefly what I conceive to be tlie more im-
portant agencies necessary for the control of tuberculosis.

1. A leading role in the campaign against any infectious disease is the
notification of the disease to the health authorities, and in my judgment
this should be recognized as an essential feature in the administrative con-
trol of tuberculosis. New York City deserves the credit of having demon-
strated the feasibility and the practical benefits of the notification and regis-
tration of tuberculosis. In the light of this actual experience of the workings
of the system little weight can be given to most of the arguments which have
been and are still urged against its adoption, and I am pleased to hear from
Dr. Porter that an effort is to be made to secure a state law along similar
lines.

2. Mr. Choate, in his opening remarks, touched upon the importance of
early diagnosis of tiiberculosis. An important aid to this end, which is
indeed of the utmost significance, is the establishment of laboratories main-
tained by municipal and state boards of health and freely at the service of
physicians.

There are at least three classes of institutions which are of primary
importance.

3. First in importance for the treatment of tuberculosis are sanatoria.
This country owes a great debt to Dr. Trudeau, the pioneer in the establish-
ment of sanatoria for tuberculosis in America and the leader in the crusade
against this disease. While I consider that hospitals for advanced cases of
tuberculosis are more important than sanatoria in the prevention of the
spread of tuberculosis, still the latter institutions are also valuable for this
purpose in accomplishing the arrest of the disease in those who would other-
wise become possible sources of infection and especially in their educational
influence extending far beyond the actual inmates. Here the great lesson
is most effectively taught that by proper disposal of his expectoration and
certain simple precautions the consumptive may render himself entirely
iiarmless as a source of infection to others.

In Germany today some twenty-five thousand patients in the early stages
of tuberculosis are treated in sanatoria, a number equal to about one-fourtli
of the total deaths from this disease. Sanatoria on such a scale and fre-
quented by patients to such an extent must rank among important prevent-
ive agencies.

MEASURES AGAINST TUBERCULOSIS 635

4. Hospitals for the isolation of advanced cases of tuberculosis are given
by Koch the first position among the agencies for checking the spread of the
disease, and their importance is especially emphasized also by Dr. BiggS.
These hospitals unlike the sanatoria, receive the patients who are most
dangerous to otliers and are responsible largely for the spread of the disease.
Eviery populous community should be provided wii,h one or more hospitals
for patients in the advanced stages of tuberculosis, and every effort should
be made to secure the transfer to the hospital of such patients, when they
cannot be suitably cared for in their homes. Much more should be done than
is now customary to make tlicse hospitals attractive to these patients and
their friends. One of tlie greatest difficulties in the crusade against tuber-
culosis at the present time, especially in this country, is the utterly inade-
quate provision for these hospitals. There is also difficulty, even where the
hospitals exist, in inducing patients to enter them in sufficient numbers.

Under present conditions only a relatively small number, in this country
not more than 4 per cent at best, of tuberculosis patients are cared for either
in sanatoria or in hospitals. It is evident that through some other agency
the largest number of consumptives must be reached. This is now being
accomplished more and more effectively and in constantly increasing measure
by the special tuberculosis dispensarj'. This is or should be an institution
in many respects different from what is ordinarily understood by a dis-
pensary. The German conception of this institution is expressed by the
designation " information and aid station." The French idea is also that
of an antituberculosis bureau, forming a centre for the enlightenment of tlie
public, for hygienic education, for the discovery of centres of tuberculous
infection in households and workshops, for the instruction of patients in the
precautions necessary to prevent spread of the disease, for the improvement
of living and working conditions, for medical care and kindred purposes.
Visiting nurses and health inspectors constitute an essential part of tlie
machinery of these tuberculosis dispensaries, wliich we must rank among the
most important and effective ag^encies in the campaign.

Time forbids more than the mere mention of such recognized preventive
measures as the disinfection of rooms vacated by consiunptives througli death
or removal, enforcement of laws and regulations against expectoration in
public places, protection of food, especially the milk supply, by suitable laws
and their enforcement, sanitary inspection of factories, workshops, lodging
houses, etc., destruction of tuberculous sputum and the education of con-
sumptives, of the public and of school children in the elementary facts re-
garding the origin and spread of tuberculosis, and in ways of healthful
living.

636 MEASURES AGAINST TUBERCULOSIS

Scarcely less important than measures, like tlie foregoing, specifically
directed against tuberculosis, are all conditions which make for the improve-
ment of the (Iwelliiiijs and working; places of the poorer classes. Air, light,
and food are as inijioriant for the prevention as for the cure of tuberculosis.
Parks, playgrounds, in a word all measures to improve the health of the
people, operate in a very direct way in increasing resistance to tuberculosis
and in lessening chances of infection. There is reason to believe that no
small part in the diminution of the amount of tuberculosis has been due to
improvement in the general conditions of living.

Tlic specific measures against tuberculosis must be carried out by the health
officials and especial emphasis must be placed upon the need of a larger
number of well trained sanitary experts in the work of our state and munici-
pal boards of health and of larger resources at their disposal. Upon them
must fall the main part of the work in the campaign against tuberculosis.
With some notable exceptions our city and state boards of health are far
behind in efficiency similar boards in England and Germany. The need of
special training for the successful conduct of public health work is most
inadequately appreciated by the general public and, it is to be feared, even
by the medical professions in this country.

Progress in the struggle against tuberculosis is largely a question of ways
and means. I have enumerated some of the more important agencies needed
for the control of this disease not with the intention of outlining a pro-
gramme, but to indicate how inadequately at present preventive measures
are in operation and thereby to substantiate the opinion that wider and more
effective application of these measures would yield correspondingly better
results. Much larger funds are needed than are now available, but it can
be confidently predicted that the returns in the saving of human life and in
increase of happiness and of productiveness will be out of all proportion to
the pecuniary outlay.

What New York accomplishes in this world-wide movement against tuber-
culosis and the way she accomplishes it have a significance not limited by
the boundaries of this Empire State. An especial incentive to prompt action
is the opportunity which will be presented next September of demonstrating
to the world at the International Congress of Tuberculosis what this state
has done and is doing in the most stupendous struggle against disease ever
undertaken by man.

CONSIDERATIONS RELATING TO THE CONTROL OF
TUBERCULOSIS '

The people have been aroused as never before in this combat against the
most devastating disease of mankind. They have recognized that it is a
disease of the whole people, and as in no other battle the question arises,
How can the forces which have been aroused be directed into those channels
which will yield the best results in the shortest time and the most economic
way? In other words, what course of action should be taken in order to
secure domination of this terrible disease? All these various agencies, of
wliich the campaign is composed, must, of course, be brought into action,
but the foundation of our work re-ts upon our exact knowledge of the nature
of the disease. Our exact knowledge of the mode of origin and spread of the
disease is only about twent}--five or twenty-seven years old. It was not until
the fact was thoroughly established that the disease was due to a micro-
organism that we could undertake intelligent measures of prevention. We
had to learn much more as to the nature of the germ, the conditions under
which the disease was acquired and how it spread. It may now be stated
tliat while all of these problems have not yet been solved, we have an amoxuit
of information which enables us to state positively that if practical measures
based upon this exact scientific knowledge are properly applied, the amount
of tuberculosis can be reduced to a relatively small figure. It woidd be most
hazardous to prophesy how soon that will be, but it is safe to say that in less
than one generation the mortality from tuberculosis will be cut in two if
we apply the knowledge we already possess.

I cannot, of course, at tliis time attempt to state in any detail what should
be the program of prevention, but it may not be out of place to run over a
few of the leading measures in this program. As a consideration of first
importance, I would place the registration of all cases of tuberculosis, at
least in the larger cities. I know objections have been raised to this, and
these have come not a little from the members of our profession ; but in reply
to tho?e objections we can say that these laws have already been applied and
successfully carried out in certain cities. That, I think, is a sufficient answer
to those objections. It is fundamental, in this campaign, that there should

' Report of an address delivered before the National Association for the Study
and Prevention of Tuberculosis, Washington, D. C. May 14, 1909.
Nat. Ass. Study & Prev. Tuberc, Tr., Phila., 1909, V, 34-36.

637

638 CONTROL OF TUBERCULOSIS

be notififation and registration. We should know of the existence of the
disease ; where it is and how much there is of it. There should be everywhere
also means at the disposal of the physician for the prompt and accurate diag-
nosis of the disease, because the sooner it is recognized, the better the results,
in both prevention and treatment. We now come to institutional treatment,
of wliich there should be a number of types, and each of these has its part to
play in this preventive campaign. The first of these in importance is the
sanatorium for the treatment of the early cases. One of the greatest blessings
to mankind has been the establishment of these sanatoria, where patients
with tuberculosis in its earlier stages can be cured. There is no agency which
makes so strong an humanitarian appeal as the sanatorium, and it takes the
very first place in the preventive campaign against tuberculosis.

Another kind of institution is the hospital for advanced cases, and this
leads me to the central point of what I have to say. In Scotland and Ireland,
as well as in England and Wales, and especially in Germany, there has been
a notable reduction in tlie death rate from tuberculosis. Now, of course,
it must be evident to you that if we can put our finger upon precisely the
factor or factors which are responsible for this reduction in the niortiility
of tuberculosis, we have there the agency or agencies which we should bring
into operation immediately. It is not so easy to say exactly what has been
responsible for this progressive diminution in the amount of tuberculosis,
and it would lead altogether too far if I should attempt to bring before you
the various opinions on this subject, but I would like to state what is the
conclusion of the highest authorities on this subject, men who have studied
this matter very fully, such as Koch in Germany, and Arthur Newsholme,
the best vital statistician in English^peaking countries. Both of these
authorities are of the opinion that tlie factor that has done the most is what
is called institutional segregation. That means the isolation of patients
with tuberculosis so far as is possible, in institutions. That should be
emphasized today as the central feature of the campaign against tuberculosis,
and the great need in this country is a supply of suitable hospitals for these
cases of advanced tuberculosis. That does not make the same appeal as does
the establishment of sanatoria. You have two patients, one hopelesslv ill.
the other a young man in the early stages of the disease. It is the latter that
makes the strongest humanitarian appeal. Hence, we can leave to a much
larger extent the establishment of these sanatoria to private philanthropy,
while it is to the legislature and public health boards that we must look for
the segregation of the more advanced cases. By that we will doubtless gain
more than by any other single factor. Further than this, I believe the time
has come when we should emphasize the importance of institutional segrega-
tion as the most important factor in reducing the incidence of the disease;

COXTROL OF TTJBERCTJLOSIS 639

and in dealing witli patients who are a serious menace to the community
and who cannot or will not be taught to take proper safeguards against the
infection of their fellow-men, I think that the health authorities should be
empowered to place them in proper institutions.

Another agency that should be considered ir this connection is the dis-
pensary for tuberculosis. It is there that many of these patients first apply
for treatment, and it is there that the plans of this campaign are more or
less centralized. However, I cannot elaborate further on these points.
These institutions, their establishment and maintenance, cost money, but
the amount of money which is expended, in proportion to the return, is most
trifling. The returns to the community are out of all proportion to the sum
required. It has been estimated that it would increase by only about 50
per cent the cost of the dependent poor already provided for by the state.
Fewer would have to be provided for than are provided for now in the insane
hospitals. When you estimate how prevalent tuberculosis is today, and
how great a loss it entails upon the community, who could hesitate to go
before our legislatures, with this great force of public sentiment behind us,
and demand that they shall carry out a program which rests upon exact
knowledge, and which will yield returns beyond all conception as to their
final value to mankind.

The proper housing of the poor and the establishment of playgrounds are
incidental to the problem under discussion, but do not represent the central
idea. The prophylaxis of tuberculosis makes such a strong appeal to the
community because everything connected with it leads to better conditions ;
but all diseases are similar in that respect. The *ame holds true in regard
to the prevention of typhoid fever and malaria. All these factors are of
importance, and we can use everyone to the greatest advantage, but never-
theless we should make it clear to the public that there are a few definite
agencies which should first be emphasized as the central ideas of our program,
and which give the greatest promise of return.

THE SIGNIFICANCE OF THE GREAT FREQUENCY OF TUBER-
CULOUS INFECTION IN EARLY LIFE FOR PRE-
VENTION OF THE DISEASE'

Permit me, in behalf of the members of the Association, to extend a wel-
come to all our guests; also to express our gratification at this opportunity
of meeting in the city of Denver. The custom of the Association as a national
organization has been to meet in the citj- of Washington. There has been
only one exception to this rule in the past, namely the meeting held in 1908
in the city of Chicago, for which there were special reasons. This meeting,
therefore, marks a departure from our precedents, but one, which, I think is
to be welcomed. I believe the influence of the Association will be extended
by meeting occasionally, say once in three or four years, outside of the city
of Washington. While it is important to preserve the national character of
the Association, it is likewise important to extend the influence of the Asso-
ciation and its benefits by occasional meetings in different parts of the
country.

With peculiar satisfaction I express our pleasure in meeting in this city,
which has been so actively identified with the anti-tuberculosis movement.
We shall certainly feel well repaid if this meeting is a help in any way to
the great cause in which we are engaged, and I am confident that the Asso-
ciation itself will derive great advantage from meeting in this place. We
have experienced already enough of hospitality and of the excellent arrange-
ments for our meeting to justify me in expressing even now our thanks to
the committee of arrangements and to all who have coo])erated with them.

Since our last meeting, my predecessor in this office. Dr. Edward G.
Janeway, has passed away, and it is fitting that we should pay our tribute to
the memory of this great physician, who enjoyed to an unusual degree the
confidence and esteem of all his colleagues, and was one of the most influ-
ential and useful men who have adorned the profession of medicine in
America. His remarkable powers as a diagnostician, which to some seemed
almost intuitive, rested upon long years of training, the first fifteen vears of
his professional life being devoted largely to that combination of work in the

' President's address delivered before the Seventh Annual Meeting of the
National Association for the Study and Prevention of Tuberculosis. Denver, Col.,
Juno 20, 1911.

Nat. Ass. Study & Prev. Tuberc, Tr., Phila., 1911, VII, 17-28.
640

FREQUENT TUBERCULOSIS IN EARLY LIFE 641

deadhouse with close observation in the hospital wards which has been the
basis of the diagnostic skill of so many famous physicians.

Dr. Janeway was interested greatly in the subject of tuberculosis and in
the movement to which we are committed. Dr. Knopf has kindly furnished
me with data which I hope he will embody in an a- tide pointing out many
of the specific contributions of Dr. Janeway to the subject of tuberculosis.
He and Dr. Austin Flint, the elder, were among the tirst in this country to
recognize the significance of Koch's discovery in 1888 of the tubercle bacillus.
Even shortly before that he published a paper on the contagiousness of pul-
monary tuberculosis. It is rather difficult to trace all the contributions of
Dr. Janeway through his published writings. For this purpose it is neces-
sary to go through the reports of societies, and especially the discussions in
societies. lie made a large number of reports to the New York Pathological
Society. Without exhaustive search I have counted not less than seventy
published contributions of Dr. Janeway, a record which, while not prolific,
is certainly not sterile, when one considers the value of his papers.

The great work of the New York City Board of Health in initiating the
municipal control of tuberculosis, with which a former president of the Asso-
ciation, Dr. Hermann Biggs, has been so actively identified, received from
the beginning the active and influential support and advice of Dr. Janeway.
He was prominent in the work of the Committee on Prevention of Tubercu-
losis of the Charity Organization Society of the City of New York, and of that
of the New York State Charities Aid Association. He was much sought for
as a member of committees, for the voice of no medical man carried greater
weight with the public.

I shall ask the audience to rise in respect to tlie memory of Dr. Janeway.

Shortly after our meeting last year, early in May, there died Robert Koch,
to whose great discoveries is due the movement against tuberculosis which
was the occasion for the organization of this Association and to which our
presence here today is due.

The name of Robert Koch is immortal in the history of medicine. He was
endowed with the divine genius for scientific discovery, and was undoubtedly
one of the greatest benefactors of his kind who has ever lived. We have only
begun to reap the benefits to be derived from his discoveries. Generation
after generation will continue to glean the harvest.

The real significance of Koch's work is that he gave us the key which
enables us to unlock the secrets of that class of diseases, the infectious, which
are of the greatest racial and social significance to mankind, whereby medi-
cine, and especially preventive medicine has been revolutionized, iledicine
has come into relation with the problems of societj' in a way never before

642 FREQUENT TUBERCULOSIS IN EARLY LIFE

approached, and has a part to play of the hij^hcst significauce for liumaii
welfare.

The greatest of Koch's discoveries is that of the tubercle bacillus, an-
nounced in 1<S82, not quite three decades a^o. Not even Koch himself, far
less others, could foresee all the beneficial results which would flow from this
discovery, nor can we realize it all today.

Koch's interest in the subject of tuberculosis was paramount. He not
only introduced the methods which enable us to learn the mode of origin and
spread of tliis disease, but he continued, for over thirty years, a leader in
investigation in this field. It is rare that man opens the path and at the
same time enters in and reaps such a rich harvest as Koch did.

Koch's discovery and study of tuberculin, while at first arousing hopes
destined to disappointment, have proved to be of vast significance, not merely
in their practical bearings, but in elucidating many problems connected with
tuberculosis and other infections. I need in this connection only to remind
you of the interest which now attaches to the subject of hypersusceptibility
or anaphylaxis of which the tuberculin reaction is an example.

Koch's pronouncement on the question of the relation of human to bovine
tuberculosis, bitterly contested as it has been, has been of great service in
advancing our knowledge of a subject of great practical as well as scientific
importance. It may be doubted whether a voice less powerful than his could
have arrested the attention of investigators and have led to such numerous
and valuable investigations as those which are now bringing the opinions of
scientific students into fair agreement as to the extent and character of the
dangers to human beings from bovine tuberculosis.

We recall with especial gratification Professor Koch's visit to this country
and his participation in the International Congress on Tuberculosis in
Washington in 1908, to which he gave such luster.

I would like to add a word about another important contributor to our
knowledge of tuberculosis who has passed away more recently, namely, Pro-
fessor Arloing, of Lyons, France. I speak of him particularly on account of
the charming impression which he made upon all who met and heard him at
the International Congress on Tuberculosis in Washington. He was one of
that agreeable and important group of French colleagues who honored us by
their presence, and I feel that you would wish me to pay at least this tribute
of a few words to the memory of one for whom we came to have great admi-
ration, almost, I may say, affection, on account of his delightful personality.
He is a real loss to the cause of tuberculosis, and especially to that in France.
It is significant that in the city of Lyons, where he worked, in contrast with
so many of the French cities, there has been a decided decline in the inci-
dence and niortalitv from tuberculosis.

FOR PREVENTION OF THE DISEASE G4;3

The Association has reason to feel much gratification at the work which
it has done in the six years since it was started. While the general aims of
the Association have been clear from the first, there has been no attempt to
formulate a definite program. The effort has been to further the propaganda
against tuberculosis in a national way, and to direct our energies in channels,
which, for the time being, seemed most promising, so far as the resources of
the Association permitted. The effort has been to stir up general interest in
the subject, and especially to aid and encourage local organized movements.
When we consider the large number of associations against tuberculosis
which have started during these years, numbering now, I believe, nearly five
hundred, many in afiiliation with our national body, and initiated through its
efforts ; when we regard the good that has been done by our traveling exhibits,
going from place to place, accompanied with lecturers, and usually associated
with public meetings stimulating the interest of physicians and the general
public wherever they go ; when we note the specific contributions in the
Transactions of the Association, and the stimulating influences of our meet-
ings, it is evident that the relatively small amount of money which we have
had at our disposal has accomplished an immense amount of good. We have
received generous contributions from individuals, and we have reason to be
especially grateful to the Russell Sage Foundation, without whose generous
aid our work would have been seriously curtailed.

We can look forward most hopefully to the continued and enlarged activi-
ties of this Association. You will all wish me, I am sure, in this connection
to express our appreciation and thanks to our very energetic and able execu-
tive secretar}'. Dr. Farrand, who is really the one so largely responsible for
it all, working with singular unselfishness, devotion, intelligence, and sym-
pathy in this great cause.

There are so many topics which I should like to bring before the Associa-
tion that I am somewhat embarrassed at attempting a selection. I should
like to say a word, at least, with reference to the scientific basis of the cam-
paign against tuberculosis. It is, of course, self-evident that rational and
effective measures of prevention against any infectious disease must be based
upon as exact knowledge as possible concerning the modes of origin and of
propagation of that disease, and it is because we have at least a measure and
a saving measure of such knowledge relating to tuberculosis that we are
engaged in the campaign, which is so full of hope, but no one would pretend
that there are not before us many unsolved problems. No one would claim
that our preventive measures could not be more effective, more economically
concentrated, more intelligently directed if a good many of these problems
were solved. Did we know more precisely, for instance, the paths of infee-

6-1-i FREQUENT TUBERCULOSIS IN EARLY LIFE

tion ; did wo know the full signififance of the almost universal infection with
tubercle bacilli, at least in certain strata of the community, in the early
years of life did we know, in a word, a great deal more concerning the origin
and spread and nature of the disease, we would certainly be better armed to
fight this enemy. We should, therefore, always in this Association keep in
mind the importance of having the scientific side represented, as is now done
in our pathological and clinical sections, and our sociological brethren,
whom we are glad to have with us, must hear with us at times in the presenta-
tion of subjects of somewliat special and technical interest, which they may
not feel bear directly and immediately upon the campaign. On the other
hand, tlie scientific members must welcome all the aid wliich tliose engaged in
great social reforms can render. It is here in this Association, as it is in the
whole movement, that all the forces of society must be coordinated, and the
Association is fortunate in having secured the coliesion of all who are inter-
interested in the subject of tuberculosis, whatever may be the special line of
interest and activity.

The important subject of the portals of entry and paths of infection for
the tubercle bacillus is to be treated by Dr. Ophiils, the chairman of the
Pathological Section.

I have referred to the work which has been done to determine the share of
tubercle bacilli of bovine origin in causing human tuberculosis. There is
now general agreement of opinion that bovine haeilli are negligible as a
cause of pulmonary consumption, the only question left open being the
possibility of the transformation of the bovine into the human type by pro-
longed survival in the human host, a view for which, at present, there is
very little satisfactory evidence. When one considers that most of the
cases of open tulierculosis, which are the chief source of danger in spread-
ing tlie disease, are pulmonary infections, it is apparent that a good share
of Koch's contention upon this subject has been substantiated.

There is no doubt, however, that Koch gave a somewhat misleading im-
pression, and underestimated the risks of infection from bovine sources.
Such infection plays a role by no means negligible in the tuberculosis of
infancy and childhood, particularly in the scrofulous infections of lymphatic
glands and of other parts, which are so common at that period of life. Our
prophylactic niea.sures, therefore, should not neglect the dangers of tubercu-
losis infection from milk, although these dangers are far exceeded by the
risks from human sources.

The most important contributions which have been made in recent years to
the genesis and pathology of tuberculosis are those concerned with the study
of tuberculosis infection in infancy and childhood, and the interpretation of

FOR PREVEXTIOlSr OF THE DISEASE 645

the bearings of such infection upon the manifestations of the disease, partic-
ularly upon pulmonary consumption, in later life. I wish more particularly
to call your attention to some of the results of these investigations.

The first thorough investigation of the frequency of tuberculosis infection
in human beings was made by Xiigeli and published in 1900. He found
that 97 per cent of adults examined at autopsy in Ziirich showed either
active latent, or healed tuberculosis ; in other words, that infection with the
tubercle bacillus is practically universal by the time adult life is reached.
That is, of course, not equivalent to saying that ever}' one has or has had the
disease, tuberculosis. It signifies merely that in the class examined prac-
tically every one had received into the body tubercle bacilli, and that these
had left their rec-ord beliind. XageU's observations startling as they seem,
have been confirmed by similar methods elsewhere, notably by Burckhardt in
Dresden.

Further studies have shown that in the great majority of cases this almost
universal infection with tubercle bacilli in the classes examined dates from
before the fourteenth year of age. This conclusion is based partly upon
autopsies, especially of those tested during life with tuberculin, and partly
upon the results of the testing of large numbers of infants and children for
the tuberculin reaction by the harmless cutaneous and puncture methods.
There is every reason to believe that a positive result of these delicate tests
is certain evidence of an existing or healed tuberculous infection.

By means of data of this character it has been demonstrated by Hamburger
and Monti that about 95 per cent of all the children in the Vienna hospitals
are already tuberculous by the time they reach the twelfth to the thirteenth
year of life. Similar results have been obtained in Prague, and it is probable
that they hold true for children of the poorer classes in other large cities.
While the percentage is doubtless considerably smaller for children of the
well-to-do and in smaller towns and country places, the significance of the
figures cited is scarcely diminished thereby, for it is especially to the poorer
classes that our measures of prevention in the control of tuberculosis as a
racial problem must be directed.

In considering this question of the frequency of tuberculosis we must, as
already mentioned, keep clear in our minds the distinction between tubercu-
losis as a cause of death and tuberculosis as found, often only after long
and patient search, as an accessory lesion in the inactive, latent, or healed
forms. Regarded from this point of view, it is important to note that in
the first weeks of life tuberculosis in any form and the positive tuberculin
reaction are extremely uncommon. During the second half of the first year
of life the number of cases increa.ses, and in the second year they are no
longer uncommon, and when the infection is found at this period, it is

646 FREQUENT TUBERCULOSIS IN EARLY LIFE

usually as the cause of death, most frequently as a tuberculous meningitis
or acute miliary tuberculosis. After this period, up to the age of puberty,
while the percentage of cases increases year by year, reaching over 90 per
cent by this time, the infection appears more and more frequently as an
inactive or healed lesion, fatal tuberculosis being relatively uncommon.

As has long been known, pulmonary consumption is rare in the first
decade and a half of life, the prevailing forms of tuberculosis in the earlier
years being tuberculous meningitis and acute miliary tuberculosis, and after
the third or fourth years chronic lymphatic disease and affections of the bones
and joints. It is not, however, justifiable to infer from the prevalence of
these types that the primary infection has been through the alimentary
canal, as in the vast majority of cases of tuberculosis in infancy and child-
hood there exists tuberculosis of the bronchial lymphnodes, usually associated
with a focus in the lungs.

In the light of these facts we must concede that von Behring was right in
his statement that in the great majority of instances pulmonary consump-
tion develops in an individual who has previously been infected with the
tubercle bacillus, although he was in error in his view that the primary
infection usually dates from the first year of life and is derived from the
milk of tuberculous cows.

Much light has been thrown upon the significance of this startling fre-
quency of primary tuberculous infection in early life, as regards its bearing
upon the genesis of pulmonary phthisis, by the study of the influence of
an existing tuberculoisis upon renewed infection with the tubercle bacilli.

Koch, in his first study of tuberculin, observed that a tuberculous guinea
pig behaves differently from a normal one when reinfected with tubercle
bacilli. In tlie former the reaction is immediate and is followed by a local
necrosis, ending in complete healing of the site of reinfection, unless the dose
of bacilli be too large. This observation comparatively neglected by subse-
quent experimenters, has been made the starting point in the last few years
of interesting experimental studies by Romer and Joseph, Hamburger, and
others. That a measure of protection may be afforded by previous inocula-
tions with tubercle bacilli was demonstrated experimentally by Trudeau in
]890.

On account of the high degree of susceptibility of guinea pigs it requires
special methods of inoculation and small doses of tubercle bacilli to demon-
strate readily the protective influence of an existing tuberculous infection of
limited extent to reinfection, but such demonstration has been conclusively
brought by Romer and by Hamburger. Particularly impressive and con-
vincing are Romer's experiments with the tuberculous reinfection of sheep,
which closely resemble man in their sensitiveness to tuberculin. These

FOR PREVENTION OF THE DISEASF) 647

animals may be rendered by a localized tuberculosis completely insusceptible
to the subsequent intravenous injection of quantities of bacilli which kill the
control animals in a few weeks with generalized tuberculosis.

The condition which is present in these animals as the result of a localized
tuberculous infection is tliat designated by von Pi-quet as allergy, and is
characterized at once by inmiunity and by hypersusceptibility, the former
being manifest upon the introduction of small or moderate doses of tubercle
bacilli, which are readily disposed of, and the latter by the death of the
animal or rapid development of the disease when the doses are excessive. In
both instances the reaction follows speedily the reinfection.

There would appear to be also significant differences in the character of
the tuberculous lesions according as these are the result of a primary in-
fection or of a reinfection. It has long been known that ulcerative pulmo-
nary tuberculosis is rarely produced experimentally in animals, and the
usual assumption has been that they are but little susceptible to this form
of tuberculosis, so common in human beings, but this cannot be the com-
plete explanation. In 1894 Prudden demonstrated to the Association of
American Physicians genuine pulmonary phthisis in tuberculous rabbits
subjected to secondary intratracheal streptococcus inoculations. Concur-
rent or mixed infections, however, are not necessary, as it has been shown
by von Behring and others that phthisis can be induced by renewed inocula-
tions with tubercle bacilli in animals already tul)erculous. Reinfections from
without are not absolutely necessary, provided there exist the proper ratio
between the degree of resistance of the animal and the number and virulence
of the bacilli. Given this condition, a single inoculation, even in guinea
pigs, has been known to produce a progressive chronic tuberculosis, resem-
bling phthisis in man, but here it may well be that there are repeated auto-
inoculations, such as are assumed to occur in man in chronic progressive
tuberculosis.

There is abundant evidence that human beings, as well as animals, are
protected by slight or limited tuberculous infections, dating in the former,
as has been stated, usually from childhood, against the effects of renewed
inoculation witli tubercle bacilli botli from without the body and from
within. It is by virtue of tlie alteration or allergy effected by the primary
tuberculous infection that the subsequent entrance of tubercle bacilli from
without or their distribution from the primary focus to other parts of the
body leaves no record behind in the majority of cases, for it is impossible to
suppose that the two or three old scars or foci of tuberculous infection usually
found represent the only penetrations of bacilli into the body during the life
time of the individual.

Gratifying as is the recognition of the protective value of an existing tuber-
culous focus of limited extent, we must keep in view that there is another

648 FREQUEXT TUBERCFLOSIS IX EARLY LIFE

side to the shield, and that it is precisely upon the basis of the altered reac-
tion resulting from a primarj- infection tiiat pulmonary consumption de-
velops. Here there are doubtless many factors concerned which require
further clinical, anatomical, and experimental study before we shall reach
a satisfactory understanding of the pathogenesis of pulmonary plithisis.

We are in the dark as to the relative frequency in the causation of pulmo-
nary consumption of auto-inoculations from existing tuberculous foci or of
reinfections from without, but in view of the difficulty of tracing sources of
infection in individual cases it is important to learn that it is not necessary
to have recourse to extraneous infections, and my own belief is that in many
instances pulmonary consimiption results from auto-inoculations from pre-
viously inactive or latent foci of tuberculosis in the lungs or bronchial glands,
possibly in other parts of the body.

Furthermore, we lack precise information concerning the causes which
determine the occurrence of pulmonary consumption as the result of rein-
fections. It is probable that in some instances the explanation is to be
found in the massive doses of bacilli received into the lungs, or in their
repeated introduction at shore intervals of time, but it seems difficult for
many cases to dispense with the doctrine that the resistance of the individual
is lowered as the result of unfavorable conditions of health and of living.
There still remains room for appealing to the various factors which have so
often been presented as influencing the disposition of the individual to
tuberculosis.

Another question requiring investigation is. Whether immunity persists
after complete disappearance of all tubercle bacilli from the body, and if so,
how long? In view of the difficulty of making sure that there are no living
bacilli in the body, the question is not easy to settle, but the evidence seems
to be in favor of a return of susceptibility within a certain period after com-
plete recovery.

Although analogies in medicine are dangerous, there is mucli which is
suggestive in that which has often been drawn in recent years between tuber-
culosis and syphilis. In both diseases an existing infection affords protection
from reinfections, and both are characterized by a remarkable "' Umstim-
mung " of the system of allergy, whereby primary infections pursue a course
different from the later manifestations of the disease, which in both affec-
tions are marked by extensive caseous masses, with a greater tendency to
liquefy and form cavities in tuberculosis than in syphilis. According to this
analogy, pulmonary consumption would correspond to the late or tertiary
lesions of syphilis. I do not think, however, that we are justified in pressing
this analogy too far.

It hardly needs to be emphasized that the facts which I have briefly
sketched have important bearings upon methods of prevention of tubercu-

FOR PREVENTION OF THE DISEASE 649

losis, and must be taken into consideration in formulating the plan of cam-
paign.

Perhaps the most important lesson is the necessity of protecting infants
and children from infection with tubercle bacilli, so far as possible. It may
perhaps have occurred to you that if, in so meny instances, the primary
tuberculous infection dating from early life be, as it has been called, a
" beneficent vaccination," we should not be overanxious to prevent it. In
reply to this arcrument it may be stated, in the first place, that experience
indicates that we hardly need concern ourselves with this matter of securing
protection. We are not likely to escape, if we would, the minimal tubercu-
lous infections. " Am Ende bekommt jeder ein bischen Tuberkulose," as
the old German physician said many years ago. The preventive vaccinations
will take care of themselves.

On the other hand, as I have mentioned, the forms of tuberculosis which
appear in the first two or three years of life are predominantly fatal forms,
and not innocuous vaccination and these surely we should do all in our
power to prevent. Furthermore, there is much in support of the view that
the ultimate fate of the individual as regards progressive tuberculosis, it
may be later in life, depends largely upon the extent of the primary infec-
tion, which is itself related to the ntunber and virulence of the bacilli re-
ceived into the body.

In the light of our newer knowledge there is abundant reason for the ever-
increasing emphasis placed upon the importance of attacking the problem
of tuberculosis in the early years of life. The key note is the segregation of
patients with open tuberculosis, that is, in the main, the consumptive, so that
they will not be the means of spreading the infection to other members of
the family, especially the children. In France much is done in the way of
removal of children from homes where there is a consumptive member, but
while this procedure is effective, and perhaps can be employed oftener in
this country than is now customarj-, it is not likely to be widely applicable
with us. The. results of constructing tenements especially adapted for the
home treatment of consumptives must await further trial before we are
warranted in drawing conclusions as to the efficacy of this interesting experi-
ment. Our main reliance, as has been so often urged before this Associa-
tion, must be upon hospitals designed for the reception of advanced or open
cases of tuberculosis, and it would appear that there is no other measure of
equal importance in lessening the spread of the disease.

A further deduction from the newer views as to the pathogenesis of pulmo-
nary consumption is the importance of preventing reinfections, whether
extraneous or autogenous, and of maintaining and increasing the resistance
to the effects of such reinfections. Here come into consideration not only
44

.650 FREQUENT TUBERCULOSIS IN EARLY LIFE

the hospitals for the care of tuberculous patients, but all those procedurts
for the after care of those who are able to resume work, but are so likely to
relapse after return to previous conditions of living and work. Working
farms and colonies for the tuberculous have an important place in the com-
paign against the disease.

I believe that no mistake is made in preaching the gospel of hygiene to
increase resistance to tuberculosis. Even if it should appear that undue
emphasis is laid upon measures of general hygiene as a special feature of
the anti-tuberculosis crusade — and I do not believe that such is the case —
the incidental benefits in furthering the cause of individual and public
hygiene and tlie general improvement of the health of the people, derived
from this part of the campaign, have been of incalculable value. It has
been, above all, the movement against tuberculosis which has taught people
the value to health of fresh air, of proper and sufficient food, of exercise and
play, of well ventilated and sanitary' homes and workshops, of shorter work-
ing hours, of a living wage, and other social reforms.

There has been in the last half century, and especially since the discovery
of the tubercle bacillus, a notable, steadily increasing diminution in the
amount of tuberculosis. The fact that this decline is not universal, and
that where it has occurred it has been in varying degrees in different places,
indicates conclusively that special causes have been operative in bringing
it about. I believe that it can be shown that the reduction stands in rela-
tion to the character and efficiency of the activities directed against the dis-
ease, although there may be difficulty in assigning to each factor in these
activities its precise share in the result. As is well known, Koch and
Newsholme, after careful analyses of these factors, have reached the con-
clusion that the segregation of consumptives in hospitals far outweighs in
preventive value all others.

The results wliich have already been obtained and the greater ones which
we can reasonably expect to follow, both in the control of tuberculosis and
in the improvement of the health and efficiency of the people, are full of
encouragement to press forward with increasing zeal in the greatest task
ever attempted in the domain of preventive medicine. As tuberculosis is a
disease of society, it must be met by a combination of all the forces of society,
and we may be assured that such combined efforts, intelligently directed
and based upon accurate knowledge, will bring direct and indirect benefits
to mankind far outweighing all tlie money and time and energy expended.

CONTROL OF BOVINE TUBERCULOSIS'

It is clear that there are certain matters which are established; there are
others which are very much in dispute ; and still others which we must regard
as hardly approached as yet. It depends a good deal upon where we lay the
emphasis. We may agree on some body of facts, and still lay emphasis more
upon one than upon the other feature, and we may reach somewhat different
conclusions without disagreeing as to the facts.

It is true that Koch in his address in London certainly left the impression
by the conclusion drawn from his own words that there was practically no
danger whatever of infection from bovine sources. It is true also, and the
point has been emphasized in this country, that Koch did not add very
material new facts. Dr. Theobald Smith, one of the most careful workers
on the subject, had previously pointed out the rather subtle morphological
and biological differences between the human voice and bovine types. He
also noticed (it was known before) that it was difficult to inoculate success-
fully calves or cattle with tubercle bacilli from human sources. With char-
acteristic caution, however, he did not venture to draw the conclusion that
because calves are insusceptible, relatively to human tuberculosis, we should
infer that human beings are insusceptible to bovine tubercle bacilli. That
was the difference mainly between Theobald Smith's and Koch's presentation
of the subject. Koch drew that inference without basis of facts. It is also
true that Professor Koch at the Washington Congress somewhat shifted the
position he had previously taken. He took the position that, in the campaign
against tuberculosis, pulmonary consumption is the main factor to be con-
sidered. I think he stated that eleven-twelfths of the deaths from tubercu-
losis in human beings were traceable to pulmonarv' tuberculosis; that the
other forms of tuberculosis — the glandular, the surgical forms of tuberculosis
— were not open cases ; that is, they did not figure as an important factor in
the spread of disease: therefore, those who are interested in tuberculosis as
a problem with reference to the extermination of the disease might almost
neglect the dangers from bovine tuberculosis; that it was upon pulmonary

' Report of remarks on a paper of Mazyck P. Ravenel made before the National
Association for the Study and Prevention of Tuberculosis, Denver, Col., June 21,
1911.

Nat. Ass. Study & Prev. Tuberc, Tr., Phila., 1911, VII, 367-370; 374.

651

653 CONTROL OF BOVINE TUBERCULOSIS

tuberculosis we should concentrate our attention, and that there was little or
no evidence of infection from bovine tuberculosis, or that bovine infection
played no particular role in it. Dr. Park, af3 you know, has come to the same
conclusion at which Dr. Ravenel has arrived with reference to the role
played by the bovine bacillus in the causation of phthisis. There have been
a few cases in which it is claimed the bovine tubercle bacillus has been found
in phthisis, chiefly in the sputum. I know that Professor Koch considered
that tlie most important thing, at present, was further investigation on that
subject. He called attention to certain important sources of error, in butter
and milk, where the bovine tubercle bacillus was present. One might readilv
have in the sputum the presence of the bovine tubercle bacillus accidentally,
and, at the same time, playing no part whatever in the disease process in the
lung; therefore, it requires much more than mere demonstration of the
tubercle bacillus of bovine type in the sputum of consumptives before one
could draw the inference that it was really causing the disease in the lung.
I happen to have had the good fortune to spend an hour with Professor
Koch, in the Institute for Infectious Diseases, a year before he died, after
he had returned to Berlin from America and I found him engaged almost
exclusively in the study of this subject. He must have collected a good deal
of material and new facts. I have heard nothing about any prospect of these
being published. He showed me figures and charts, all in confirmation of
his previous position, that the bovine tubercle bacillus played no part in the
production of pulmonary tuberculosis ; that is on the assumption that there
is no transformation of the bovine into the human type. Of course there is
the point at issue. Koch believed there was no such transformation. That
is the opinion very cautiously expressed by Dr. Theobald Smith, and I do
feel that his position on anything relating to this question is almost the most
authoritative one in the world; and he thinks that the evidence is, to say the
least, very inconclusive ; that here is a point for further work, and research
along this line ought to be followed out. There have been a few scattered
observations. An attempt has been made to determine whether or not the
bovine tubercle bacillus is transformed into the human type in human beings,
namely, by studying those light necrophilic warts so commonly seen on the
hands of butchers, to try to find out whether they contained the bovine type
of tubercle bacilli. There is nothing easier than to get such material on
which to work. These warts remain on the hands of butchers for a consider-
able time, and if one could get the history of a number of years, and has a
chance of using that material, the results of such investigations might be
valunhle. I think it ought to be had in great abundance in Chicago. We
ninst have oj)j)ortunities of studying these warts and seeing whether we get

CONTROL OF BOVINE TUBERCULOSIS 653

a transformation of this type of bacillus. One investigator has come to the
conclusion from considerable clinical examination that there was such a
transformation of the tubercle bacillus, with apparent preservation of viru-
lence, indicating that the bovine type was due to the fact that the animal
had spontaneous infection from another source. Thit case has been analyzed
and the proof found inconclusive. These are more or less, I think, facts on
which there can be general agreement. I myself am disinclined to the view
which Dr. Ravenel favors as to the transformation of type. One should be
open-minded on the subject and consider it still sab judice. There are so
many sources of error which we have to consider in connection with this work.
If you have inoculated a cow with the human type of tubercle bacillus, what
appears to be a transformation, as indicated by the production of a general-
ized tuberculosis in the calf, is really the result of your experimental inocu-
lation, and not the result of spontaneous infection. That is a difficult matter
to control. Mr. Stiles has stated most impressively his views on this subject,
giving us a series of fatal cases, making a very notable percentage, to say the
least, of fatal cases of tuberculosis in human beings, chiefly in children. If
you let these cases nm they will doubtless play an important role in the
spread of the disease from person to person, and they are of significance from
every point of view, particularly from a humanitarian standpoint.

Shall we do anything to check that large mortality? I think one can
accept all the facts which Koch himself admitted at Washington, and still
maintain that it is of importance to recognize that there is a serious danger
from the infection of human beings from the milk of tuberculous cattle, and
that while human sources are far more important in the spread of the disease,
we should not by any means neglect the other. The character of evidence
which Mr. Stiles has brought forward here is one deserving of every respect,
and more especially by physicians, who do not have to discuss some of these
more subtle laboratory points. Koch himself realized tliat in his London
address he took the position that there was verv' little evidence of primary
alimentary infection. There are extraordinary differences as to the incidence
of tuberculosis according to locality. To bring that into exact relation with
the milk supply has been difficult. While the experience of Edinburgh which
Jlr. Stiles has presented is very important and apparently conclusive on the
points he has brought before us, still in Kiel and in Vienna they claim they
have scarcely any primary intestinal tuberculosis, and, of course, we are
informed by Kitasato that in Japan, where milk in not used, and where there
is little or no tuberculosis among cattle, they have the same tyi^es of glandu-
lar and bone and joint tuberculosis, and we can exclude positively the milk.
These statistics we find are interested somewhat differently. However, the

654 CONTROL OF BOVINE TUBERCULOSIS

liigh percentage of deaths nientioiied by Mr. Stiles teaches us the great im-
portance of such clinical facts as he has brought before us, so that my opinion
is that we are justified in insisting upon a better control of the purity of the
milk in our cities. It is the great sanitary problem of today. It is a great
white river, and it is just as much a river as the water flowing through our
cities, but it is much more diiBcult to keep pure this great white river of
milk. It is just as important, nevertheless, and the most urgent problem
before our municipal health authorities today is the protection of the milk
supply.

I will say that there is little or no value attached to the method of differen-
tial diagnosis which Detre advised.

CHILD WELFARE '

Mr. President, Ladles and Gentlemen. — I may perhaps be permitted, as a

resident of this city, to reinforce the words of welcome which have already
been expressed, and I know that I speak in behalf of my fellow citizens, who
are also present, these words of welcome, to the members of this Association,
to the guests and others who have been so good as to come here. We wish
especially to express our gratitude to his Eminence, the Cardinal; to his
Excellency, Ambassador Jusserand, who has brought us these kind messages
from France; and to Professor Fisher, who has made himself an inspiring
leader of the great movement for the improvement of public health in this
country ; and I would like especially to impress the note of welcome to my
old master and teacher and friend of these many years. Professor Jacobi, of
New York.

We are very glad, indeed, to have this first meeting of an Association, which
I believe imtiat«s one of the most important campaigns in preventive medi-
cine in this country, in this city, partly, perhaps, because there is no city
which needs the influence and benefits which will come from the work of this
Association more than the City of Baltimore ; partly, -also, because we have
a certain measure of loyal pride in the fact that that great tuberculosis asso-
ciation. The Xational Association for the Study and Prevention of Tuber-
culosis— which, I judge, the name of this Association has followed — had its
first meeting in this city, and in connection with it was an exhibition which
Dr. Fulton devised and which has turned out to be one of the most interest-
ing and important factors in the whole crusade against tuberculosis. And
I trust that there is a future of lasting usefulness and power before this
Association equal to that which has been demonstrated to have been the
outcome of the work accomplished already in these few years by the Tuber-
culosis Association.

There is, of course, no need of my saying anything more than has already
been said as to the fundamental importance of the subject of infant mor-
tality. Statistics are tiresome for most people, but, trite as it may be, it
certainly is enough to arrest one's attention, no matter how busy he may be,
to learn that in the state of Maryland over one-fifth of all the deaths of all
ages occur under one year of age; that one-third of all the deaths occur

' Report of an address delivered before the American Association for the
Study and Prevention of Infant Mortality, Baltimore, November 9, 1910.
Tr. Am. Ass. Study & Prev. Inf. Mortal., Bait., 1910, I, 51-56.

655

656 CHILD WELFARE

under five years of age. The rate is a little higher in this state in conse-
quence of our negro population than in some other parts of our country.
In the registration area of this country the deaths under one year of age are
a little less than one-fifth of all deaths at all ages, and about one-third under
five years of age. In the first three months of life, one-ninth of all the deaths
occur. Such figures as these are enough, of course, to indicate the funda-
mental importance of this subject.

When one inquires into the leading causes of death during this period
one finds that the greater number are operative in the first months of life.
Some of these are sometimes spoken of as unavoidable, but, as Dr. Jacobi
has said, most of them are not. We do not think, however, that the crusade
in the prevention of infant mortality will yield the quickest results if directed
against those causes which to some seem vuiavoidable — such causes as pre-
mature births, congenital defects, hereditary taints, accidents at birth,
causes of that kind. It is more especially against another set of causes of
infant mortality, namely, the so-called diarrhoeal and digestive disorders,
the acute respiratory diseases, bronchitis and pneumonia and the infections
that the campaign shoiild be directed. Probably the infections play a very
important part in the digestive disorders, and tuberculosis we know plays a
by no means unimportant part in the deaths during the first year of life.
During this period, especially in nurslings the infectious diseases which we
associate with childJiood are less common than after the first year of life.
Whooping cough and measles occur, but scarlet fever is uncommon and this
is especially true among those that are nursed at the breast. This is in
itself suggestive; it shows that the infant receives from the mother a certain
measure of protection against diseases toward which she is herself immune.
There are many reasons why the cow's milk can never be an entirely satis-
factory substitute for the mother's milk, and one reason is that the protective
substances in the cow's milk — admirable a.s they may be for protecting the
calf against the diseases of cattle — do not protect the infant against the
diseases of the human being. We have the most satisfactory experimental
evidences that the milk contains immune substances which have been gen-
erated in the body of the mother, and see how important it is that she should
transmit these protective substances to the offspring at this period of life
when the offspring is attempting to adjust itself to these new conditions and
is exposed to all these changes. This kind of protection is needed particu-
larly in the class of disea.ses which I have specified, the acute respiratory
and diarrhoeal infections and the infections which are most preventable.
Professor Fisher has made interesting investigations, which he himself
would not consider to be anj'thing anytliing more than approximate, but
they are certainly suggestive as to what is the ratio of prcventabilily of these
various diseases of childhood and infancy. At least 60 jter cent of this class

CHILD WELFARE 657

of diseases is preventable, and readily preventable, by the application of
knowledge already in our possession. With further additions to knowledge,
the ratio of preventability would be still further increased, but at present
we probably are within entirely safe bounds to say that 60 per cent of the
deaths of infant* in the first year of life due to the causes which I have
mentioned could be prevented.

It will be tlie purpose of this Association to point out in considerable
detail what the causes of tliese preventable diseases are and the measures
which are to be taken for prevention. One cannot have the most cursory
reference to the subject of infant mortality without having at once brought
to one's attention the fundamental importance of material nursing in pre-
serving the life of the infant. That will be repeated over and over again. I
think that those in the audience who are familiar with the subject only in
the families of the well-to-do can hardly realize the risks in artificial feeding.
It is not because artificial feeding is not possible. It is possible we all know,
but it requires an amount of care and education on the part of those entrusted
with it which is not to be expected in the families of the poor. It is not
surjjrising to hear that the deaths are at least 15 to 1 among the artificially
fed, as compared with those fed at the breast.

Our time for keeping you here has passed, but before closing I would like
to point out what I conceive to be certain of the useful functions of this
Association. Of course, one of the most important is the education of the
public, the enlightenment of the public. The responsibility is with j'ou;
it is with me; it is with the public. When one is told that the application
of knowledge which we now possess in an entirely practicable manner will
lead to the saving of 12.t,000 lives yearly among these infants, is that not
enough to stir one to activity ? In this country at least — in any democratic
country — the public must be enlightened, otherwise we cannot secure from
our legislatures the necessary laws and the necessary funds, resources for
carrying out these preventive measures. I regard, therefore, the stirring up
of the public, the enlightenment of the public, as one of the most important
functions of the Association. It should stimulate better sanitary organiza-
tion and administration in the country all along the line. It should lend its
whole force toward the organization of a National Health Department, which
movement has been so forcibly presented to us by Professor Fisher tonight.
We should all be familiar with the character of the opposition to the move-
ment. I do not propose to discuss it, but it is based upon misconception
and it is ba?ed upon ignorance, and sometimes, I think, it is based upon
intentional misrepresentation, as has been pointed out, putting personal in-
terests and commercial interests above the interests of health and life. This
Association, therefore, should stand, for a strengthening of the activities
of the Federal Government in public health work. That department will

658 CHILD WELFARE

surely have a Department of Child Hygiene. We have had demonstrated to
us in New York City how much good can be accomplished by the creation
in a Department of Health of a division of Child Hygiene. They have taken
the lead there in this regard as so often and to such a great extent in public
health work.

The question of registration of births is at the bottom of this whole move-
ment. I hope those who are here will be able to be present when Dr. Wilbur
reads his paper on this subject tomorrow night. Then you will learn that
we are creeping in the dark until we have an accurate and tolerably full
registration of births. There must be a pressure brought to bear upon the
medical profession, who are woefully lacking in the performance of their
duty in this matter, and I simply mention that it is a matter of very first
importance to be considered in the activities of this Association to see that
our country is no longer in the scandalous and disgraceful condition in which
it is today as regards an accurate recording of births. It would be the topic
of an entire lecture to make clear to you exactly why we should have an
accurate registration of births. Until there is such a registration one cannot
tell what the rate of infant mortality is, the ratio of deaths of infants under
1 year of age per thousand living. One can only guess at it. One cannot
define the rate of infant mortality at all in this country today. One esti-
mates it is something like one-seventh; in New York perhaps one-seventh
of those born die in the first year of life.

Another very important activity will be the correlation of all the various
agencies that are acting separately. The various public and private agencies
should be all brought together in order to secure the best results, because
they will often be working at cross purposes otherwise. This is specified as
one of the very important activities of the Association, and it is indeed to
be very much emphasized.

Then I hope the Association will stimulate investigation in this field. We
have by no means the amount of knowledge which is to be desired. It is a
big and significant fact that the campaign for the prevention of infant
mortality has been long delayed in this direction. One reason is, I think,
that we have not such tangible, accurate or precise knowledge of the many
causes of infantile diseases that we have aliout some other diseases. Take,
for instance, yellow fever, typhoid, malaria. IIow relatively definite our
knowledge is of the etiology. There are a great many problems connected
with this entire subject, which must be solved before we can go ahead with
as full knowledge as is to be desired.

I think also one of the important purposes of the Association must be to
fomiulate a definite program of preventive measures. When one goes over
all the jiossible factors and influences concerned, one will find that one is
brought to problems of poverty, of ignorance, of dirt, of insanitation, of in-

CHILD WELFAEE 659

dustrial conditions, etc., and one is confused to know exactly where to take
hold in order to secure in the shortest time the best results. I hope one of
the purposes of this Association will be to formulate as definite a program
as possible as to where and how efforts should be concentrated in order to
secure the best results in the shortest time and 'n the most economical way.

These are what I conceive to be among the important functions of this
Association. What one may expect from the direct benefit in the saving of
liuman life would, of course, justify all efforts; but I am very fond of dwell-
ing upon the indirect benefits which come from all these movements. " In-
fant mortality is the most sensitive index of social welfare " ; it takes hold
of the very foundations of society. Its prevention means improvement in
the homes, improvement in the mothers, and improvement in the social con-
ditions, the industrial conditions and the sanitary conditions in general.
This, as Professor Fisher lias pointed out, is sufficient answer to those near-
sighted persons who think they are extremely philosophical in this matter
when they argue that we are interfering with natural selection. News-
hoLme, who is the greatest student of this whole subject, at least from a
statistical point of view, says the high rate of infant mortality brings about
conditions which make for national degeneracy and infirmity, and I believe
firmly that this is true. Those who plead that our preventive efforts are in-
terfering with the natural selection of the individual are pleading virtually
for the retention of what are the most unfortunate social conditions. They
are pleading that the woman shall continue to work in factories to the end
of her pregnancy. They are pleading for continuance of the intolerable
social conditions. I think we can look forward, even if this Association
meets only a part of its expectations of what it is going to accomplish in
this country, to a great future of usefulness, both of direct and indirect
benefit.

Let me urge upon you the importance of studying the exhibit. I have
not myself had the opportunity to do so yet, but I know that that exhibit has
been brought together with great sacrifice of time and thought and energy
on the part especially of the Chairman of the Committee, Dr. Price, Secre-
tary of the State Board of Health. We are particularly indebted to Dr.
Schereschewsky of the Public Health and Marine Hospital Service, who
has been of invaluable assistance in helping us to get together this exhibit.
We are also indebted to Dr. Wilbur, head of the Vital Statistics Department,
Bureau of the Census, and to many others, who have been so good as to send
exhibits. No such exhibit has ever been brought together before. It will be,
I think, the most distinctive and instructive feature of this meeting, and I
believe it will be an example to those who are engaged in similar movements
elsewhere and that they will recognize this feature as their strongest means
of reaching efficiently the general public.

INSTITUTE OF HYGIENE'

At a conference ' on training for public health service held at the offices
of the General Education Board in New York on October IG, 1914, dis-
cussion seemed to develop substantial agreement on tlie following points:
(1) That a fundamental need in tlie public health service in this country at
the present time is of men adequately trained for the work; (2) that a dis-
tinct contribution toward meeting this need could be made by establishing
at some convenient place a school of public health of high standard; (3) that
such an institution, while maintaining its separate identity, should in the
interest both of economy and of efficiency be closely affiliated with a imiver-
sity and its medical school; (4) that the nucleus of this school of public
health should he an institute of hygiene.

Mr. Eose and Dr. Welch were asked to formulate a plan for such an insti-
tute of hygiene and in compliance with this request offer the following
report, which is designed to set forth the scope and general character of the
organization of the institute and the service which it should render in train-
ing in hygiene, preventive medicine and public health and in the advance-
ment of these subjects. If desired, the report can be supplemented by a
detailed statement of organization, plan of building, budget and courses of
instruction.

I. Public Health and Hygiene in England and in Germany

The origins of the modern public hefilth movement and of the cultivation
of hygiene as an independent science may be found especially in the passage
of the Public Health Act in Englanii in 1848 and in the establishment of tlie
first hygienic institute by von Pettenkofer in ilunich in 1865. The great<^t
stimulus to further development came from the discoveries relating to the
causation and the mode of spread of the infectious diseases and the conse-

' William H. Welch and Mr. Wickliffe Rose.

The following report, prepared by Dr. William H. Welch and Mr. Wickliffe
Rose, was presented to the Trustees at their meeting, January 12. 1916. The
Rockefeller Foundation Annual Report, (The Rockefeller Foundation, 61 Broad-
way, New York), 1916, p. 415-427.

' Dr. A. C. Abbott, Dr. Hermann M. Biggs, Dr. Simon Flexner. Mr. Jerome D.
Greene, Dr. Victor G. Heiser, Dr. Edwin O. Jordan, Mr. Starr J. Murphy. Dr. Wm.
H. Park. Mr. Wickliffe Rose, Dr. M. J. Rosenau, Dr. Theobald Smith, Dr. George
C. Whipple, Dr. C. E. A. Winslow, Dr. Wm. H. Welch. Prof. D. D. Jackson, Dr.
F. Cleveland, Dr. W'allace Buttrick, Dr. E. C. Sage and Dr. Abraham Flexner.
660

INSTITUTE OF HYGIENE GGl

queut vastly increased power to control these diseases. It is instructive for the
present purpose to note the different conceptions and directions of develop-
ment in this field in the two countries. In Germany every university has it-s
department or institute of hygiene, conducted by a professor and corps of
assistants, where the subject is presented broadly in all its varied as])Octs,
students are taught by lectures, laboratory courses and field work, and the
science is advanced by research. In England, on the other hand, the impor-
tant hygienic laboratories are few and mostly governmental or independent.
For training the emphasis is laid upon public health administration, in which
respect Great Britain leads the world. Those desiring to qualify as medical
officers of health must possess the diploma in public health, obtained by
passing an examination after at least nine mouths of specal preparation, most
frequently under a qualified medical officer of health and in a hospital for
infectious diseases. It seems obvious that lessons are to be learned from both
the German and the English systems, and that the ideal plan will give due
weight to both the scientific and the practical aspects of hygiene and public
health.

II. The Situation and Needs ix Ameiuca

In this country we are woefully lacking both in laboratories of hygiene and
in opportunities for training in public health worli. Three or four medical
schools have hygienic laboratories, but none is complete, and adequately
equipped and supported. Still other schools attempt something in the way
of instruction in this subject, but it is all inadequate and unsatisfactory.

The need for supplying these deficiencies is at present the most urgent one
in medical education and in public health work, and is recognized on all sides.
The cry comes loudest from public health officials, social workers and others
interested in public health administration, national, state, municipal and
rural, who realize the lack of trained leaders and trained workers in all grades
of the service. Here with the rapidly growing appreciation of efficient public
health organization new and promising careers of useful service are opening
for those who are qualified by ability, character and training. Scarcely less
important is it for medical students and physicians who engage in practice
to be well grounded in the principles of hygiene and of preventive medicine.
Furthermore, the advancement of knowledge in this field, the cultivation of
hygiene as a science, is one of the great needs of this country and should be a
fundamental aim of an institute of hygiene.

III. Variods Classes to be Trained

The first and in many respects the most important class of person.s who
will seek to be trained in a school of public health are those who expect to
devote their lives to health work in some of its branches. These will aim to

662 INSTITUTE OF HYGIENE

become for the most part public health officials or to be engaged in some
capacity in public health service, but some may become teachers or be con-
nected with institutions or find other opportunities for a career in the ever
widening field of sanitation. It is of the first importance to consider and to
supply the needs for the education of the prospective public health officials.
Without attempting an exhaustive analysis, the following classification
will suffice to indicate the various tv'pes of officers or experts required in public
health administration :

1. Higher administrative officials, as commissioners of health and health
officers in cities and districts, and division or bureau chiefs in the larger
state and city departments of health.

2. Health officers in towns, villages and rural communities.

3. Higher technical officials or experts, as statisticians, sanitary engineers,
chemists, bacteriologists, diagnosticians, epidemiologists, etc.

4. Inspectors of various kinds, as school, sanitary, food, factory, etc.
inspectors.

5. Public health nurses.

With this class may be included those preparing to enter the Public Health
Service of the federal government.

An institute or school of hygiene should furnish suitable training for all
of these, and while courses adapted for special needs will be supplied, it does
not seem desirable to conceive of such an institute as constituted primarily to
provide training for higher or lower grades of service so much as to furnish
opportunities for a good general education in all branches of hygiene.

While it is hardly possible to over estimate the importance of providing
opportunities for the training of those who are to become public health
officials, the need here is at present so acute that there is some danger of
overlooking the conception of hygiene as a science and art which is much
broader than its application to public health administration. Hygiene in-
cludes much more than state medicine. It is not necessary to consider here
the distinction sometimes made, especially in this country, between hygiene
and sanitation. In this report the term " hygiene " is used to include both,
that is, the whole body of knowledge and its application relating to the
preservation and im]irovcnient of health of individuals and of the community
and to the prevention of disease.

With this broad conception it is obvious that the educational and scientific
opportunities of an institute of hygiene should not be limited to the use of
those who intend to become specialists in public health work and sliould cover
a wider field than that of state medicine or sanitation.

It is of the utmost importance that education in the principles of hygiene
should be available for students and graduates in medicine who are to engage

INSTITUTE OF HYGIENE 663

in the practice of their profession. With the present crowded medical cur-
riculum obligatory courses in hygiene for undergraduate students of medi-
cine must necessarily be restricted, but with the tendency toward greater
freedom of election of medical studies there is the need and opportunity to
provide more extensive optional courses in hygien?. There is a wide field
for tlie establishment of graduate courses in hygiene for physicians. Even
in Great Britain, where the character of training is designed almost wholly
for public health officials, many who intend to become medical practitioners
secure the diploma in public health. The mission of the practising physician
is in many respects changing, and there can be no doubt that a year or more
of graduate work in hygiene would be eagerly sought by many physicians and
and would greatly increase their capacity of useful service to their patients
and to the community, if the proper opportunity for such work were provided.

Sanitary engineering has become a specialized profession, and the institute
of hygiene should combine with tlie engineering school in supplying the
requisite training.

The public health nurse, both as a part of the public health service and
independently of such connection, is destined to play a role of increasing
importance in the improvement of conditions of health living and working
and in the control of infectious and industrial diseases in this country. The
institute of hygiene should cooperate with schools and organizations for
training nurses in meeting the need for a supply of trained public health
nurses.

When one considers the many points of contact between the modern social
welfare movement and the public health movement, and to what an extent
social and economic factors enter into questions of public health it is clear
that an institute of hygiene must take full cognizance of such factors and that
students of social science should profit by certain opportunities in the insti-
tute, as well as students of hygiene by training in social science and social
work.

An important class to be provided for in an institute of hygiene will be
those engaged in special advanced work in some branch of the subject and in
original investigations of hygienic problems. A main function of the insti-
tute should be the development of the spirit of investigation and the advance-
ment of knowledge, upon which intelligent public health administration and
individual hygiene are absolutely dependent. It will be especially from this
class of advanced workers and investigators and from the group of assistants
in the institute that the teachers and the authorities and experts in hygiene
will be recruited for service in different fields of activity and the standards
of the profession of hygiene and of public health will be elevated.

6G4 INSTITUTE OF HYGIENE

IV. Field to be Covered

The field covered by the terms " hygiene," " sanitary science," " public
health," " preventive medicine " is so broad and varied that it is hardly pos-
sible w-itliin a brief compass to indicate all of the subjects here included.
Strictly speaking the territory embraces a group of sciences or the application
of various underlying sciences. Unity is to be found rather in the end to be
accomplished — the preservation and the improvement of health — than in the
means essential to this end. It is the focussing upon this definite purpose
which gives coherence to the organized body of knowledge embraced under
the designations " hygiene " and " sanitation," and makes important its
study and cultivation as a professional pursuit.

Although the practitioner should have knowledge of hygiene and of the
means of preventing disease and has abundant opportunity in the practice
of his calling to apply this knowledge, and the public health worker, if he is
to prevent disease, must have a knowledge of the origin, mode of spread and
diagnosis of disease, still it is becoming increasingly clear that public health
work constitutes a distinct profession, and the wider recognition of this fact
will be an important result of the creation of institutes or schools of hygiene.

The wide scope of the professional training required for the well equipped
public health worker is sufficiently indicated by the mere enumeration of the
more important subjects to which more or less attention must be given in an
institute of hygiene, at least so far as their scientific groundwork in relation
to sanitation i,s required. Such subjects are vital statistics ; epidemiology or
the causation, spread and prevention of transmissible diseases, including
tuberculosis and the venereal diseases ; diagnosis of infectious diseases ; indus-
trial hygiene ; sanitary parasitolog}', including bacteriology and immunology ;
sanitary chemistry; sanitary engineering; hospital construction and admini-
stration ; housing, ventilation, heating, lighting; disinfection ; the hygiene of
air, soil, water and climate ; water supplies and sewage disposal ; infant mor-
tality and child hygiene ; hygiene of schools ; mental hygiene ; heredity and
eugenics ; social hygiene ; personal hygiene ; diet and nutrition ; rural, farm
and dairy hygiene; milk supply; food and drug adulterations; nuisances;
public health administration and organization, sanitary laws and codes; quar-
antine and immigration; tropical hygiene; relation of animal diseases to
human diseases ; public education in healthy living; social service work ; sani-
tary surveys.

V. Agency Eequired to Perform this Function^

The central, essential and main agency required to meet the needs which
have been indicated is an institute of hygiene, housed in its own building,
provided with the requisite laboratories and facilities and with its own staff

INSTITUTE OF HYGIENE 665

of teachers giving their entire time to the work of teaching and investigating.
Given such a central institute it is easy to add to the curriculum, when
found necessary, certain courses which are now given, or could readily be
supplied by various existing departments of the medical school, the engineer-
insr school or other faculties of the university. The mere assem6ling of such
courses does not constitute a school of hygiene. The great need of the
countrj' today in the promotion of public health is the establishment of well
equipped and adequately supperted institutes or laboratories of hygiene,
where the science of hygiene in its various branches is fruitfully cultivated
and advanced and opportunities are afforded for thorough training in both
the science and the art. It would be a misfortune if this broader conception
of the fundamental agency required for the advancement of hygienic knowl-
edge and hygienic education should be obscured tlirough efforts directed
solely towards meeting in the readiest way existing emergencies in public
health service.

1. Relation to a Medical School. — The profession of the sanitarian or
public health worker not being identical with that of the practitioner of
medicine, the institute of hygiene, as the essential part of a school of hygiene,
should have an independent existence and should not be regarded merely as
a department of a medical school. But the medical school offers much which
the institute of hygiene wiU require either as preliminary training or in
course and which it will not care to duplicate. In the interest of economy
and efficiency, therefore, the school of hygiene should be closely related to a
medical school of high standard in such way that the facilities of each should
be open to the students of both.

It is likewise important for study and training in preventive medicine that
the institute should have access to the facihties of a good general teaching
hospital, as well as to various special hospitals. The need of opportunities
for observation and study of patients in an infectious disease hospital is of
course obvious.

2. Connection with a University. — To perform to best of advantage its
function, the institute should be a part of a university. The medical school
has found such connection to be a practical necessity. The institute of hy-
giene would draw even more heavily upon certain schools or departments of
the university, as those of engineering and of sociolo,g}-. In additon to having
at its disposal the facilities of the universit}-, the institute would iind the
stimulating and sustaining scientific spirit and ideals of the university an
indispensable asset.

3. Separate Identifij.—V^hile intimately related to the university and its
medical school, the institute of hygiene should be established on its own

45

666 INSTITUTE OF HYGIENE

foundation, and should preserve and emphasize its own identity as a separate
institution devoted exclusively to the science and the service of health; it
sliould have its own building, and its own corps of instructors with adequate
provision for teaching and research.

While it is not difficult to bring together on paper a group of courses
selected from the several schools and departments of the university and by
the addition of a few new courses make a presentable prospectus of a school
of public health, this is not the conception of such a school or institute as we
believe will best fulfill the functions of developing the science and art of
hj-giene and of training for this new profession. If the institute is to make
itself felt as a constructive force it must have in it a group of scientiiic inves-
tigators and teachers whose absorl)ing interest is in developing the science
of hygiene and applying it to the conservation of health.

While the concentration of work here advocated involves some duplication
of equipment, this is not as large as might be supposed and in view of the
great advantages, does not constitute a serious objection. The institute must
have its own chemical laboratory; it would be inconvenient and unsatisfac-
tory in the extreme to attempt to use chemical laboratories devoted mainly
to other purposes for the many important studies in sanitary chemistry. The
principle microbiological laboratory of a medical school could without detri-
ment be transferred to the institute of hygiene, although provision must exist
for bacteriological work in the pathological laboratory, as well as in the hos-
pital. Most of the other physical equipment of the institute would involve
little duplication.

4. Organization and Departments. — At least in the beginning there should
be a director of the institute, who will also be the head of one of the main
divisions. Eventually the heads of these divisions may constitute a group or
faculty with coordinate powers in directing the policy and affairs of the
institute.

It is possible to indicate only in outline and in a general way the principal
departments or divisions of an institute of hygiene, as details of organization
and division of work should be left to the staff of teachers whose interests and
qualifications will very with the tadividuals.

a. Chemical Division. — The applications of chemistry to sanitary science
and art are extremely important and varied, and already highly developed.

b. Biological Division. — Here there would be a number of subdivisions, as
bacteriolog)', protozoology, medical zoology.

c. Engineering or Physical Dirision. — A part of this can best be provided
for in the engineering school, but the institute should provide opportunities
for the study of certain hygienic problems requiring the application of
physical science.

INSTITUTE OF HYGIENE 667

d. Statistical Division. — While the various questions connected with the
collection and study of vital statistics constitute the most important subject
in this field, there are other important applications of statistical science to
hygiene.

e. Division of General Hygiene and Preventive Medicine. — Under this
broad head may be included epidemiology, industrial hygiene, the principles
of public health administration and other subjects not embraced under the
previous captions.

The foregoing classification is not designed to be either final or exhaustive
and is manifestly reduced to its simplest terms.

If qualified men can be found there should be three or four teachers of the
rank of full professors, but in their absence it would be better to select even
for some of the important divisions younger men of great promise with the
grade of assistant professors or of associates. In addition to these probably
at least eight or ten assistants at moderate salaries would be required.

As already stated, the institute once established on its own foundation
will draw upon the medical school, tlie engineering school and other depart-
ments of the university for courses of instruction which it will not care to
provide on its own grounds, and it will itself cooperate in furnishing instruc-
tion to students in other departments.

5. Field \Vorh. — Hygienic excursions to inspect water filtration plants,
sewage disposal systems, methods of heating and ventilation and for kindred
purposes constitute a f aluable part of practical sanitary training. The most
important training in the field, however, will be provided by establishing
working relations with state and municipal departments of health and with
the United States Public Health Service. This arrangement will provide
for giving to the students practical experience in every department of public
health work. The ^students may in this way become acquainted under
favorable conditions with the methods of handling the health problems of
the large city as well as those of the rural community. There will be oppor-
tunity for participating in the work of sanitary sun'eys. Cooperation with
the Federal Public Health Service will give good opportimity for experience
in quarantine work and in sanitary and epidemiological work on a large
scale. Such relations will be mutually helpful. The states and cities will
reap the benefit of intelligent and scientifically trained workers who wiU
enter the service as real workers in all fields of its activities. The institute
and its students in turn will have the benefit of this practical experience.

6. Museum. — An important feature of the institute will be a good
hygienic museum, which will contain models, charts, preparations, and other
material which can be gradually brought together. This will serve not only
for demonstrative teaching, but also for the education of the public. The

668 INSTITUTE OF HYGIENE

influence and usefulness of the institute will be extended by popular lectures,
conferences and extension courses.

7. Special Courses. — The institute should provide for the needs of those
already engaged in health work, who desire to pursue short courses or to do
advanced work in special branches.

8. Requirements for Admission; Certificates and Degrees. — The details
regarding the conditions for admission to the institute may be left to future
consideration, but it should be stated that while the majority of candidates
for diplomas and degrees will doubtless be graduates in medicine, these
distinctions should not be limited to physicians. The institute should be
ready to receive and to reward with its diplomas and degrees all who come
with a satisfactory preliminary education and pursue the required training,
which need not be rigidly uniform for all matriculates. Even those who
may not meet the requirements for matriculation and become candidates for
the degree may find opportunity to pursue special courses of study. It has
been abundantly demonstrated that the profession of public health work can
be successfully followed by sanitarians whose principal training has been
sanitary engineering, sanitary chemistry and sanitary biology.

9. Influence of the Institute. — The benefits to be expected from the estab-
lislmient of such an institute as that proposed are not to be measured solely
by the number of students trained within its walls. The institute can supply
only a relatively small number of those who desire to enter upon public
health service. The far-reaching influence of the institute should be felt in
the advancement of the science and the improvement of the practice of
public health, in establishing higher standards and better methods of profes-
sional education in this field, in stimulating the foundation of similar insti-
tutes in other parts of the country, in supplying teachers and in cooperating
with schools of a simpler character designed for briefer technical training
which should be established in each state in connection jointly with boards
of health and medical schools.

THE SCHOOL OF HYGIEXE AND PUBLIC HEALTH AT THE
JOHNS HOPKINS UNIVERSITY '

Our president, with a self-denial which I might appreciate, has intrusted
to me the agreeable function of announcing upon this occasion one of the
most important and gratifying gifts ever bestowed upon this university, a
benefaction likewise of national interest. This is the provision of funds by
the Eockefeller Foundation for the purpose of establishing in connection
with the Johns Hopkins University a school of hygiene and public health.
This action of the Foundation was conununicated to the trustees of the
university onlj' today shortly before these exercises. It is hardly necessary
to add that the trustees have acted promptly in accepting this generous gift
and have already taken the first steps toward organization of the new school
in selecting Dr. Howell as the head of the physiological division of the Insti-
tute of Hygiene and to cooperate in the work of organization and develop-
ment, and in appointing me as director.

It is expected that the school will be opened in October, 1917, as it is esti-
mated that a year will be required for the planning, construction and equip-
ment of the building and the gathering together of the staff of teachers.
The necessary funds for construction, equipment, maintenance and expenses
of the school will be provided by the Eockefeller Foundation.

When we consider the revolutionary discoveries of the last forty years in
our knowledge of the causes and means of prevention of diseases, the great
progress in the science and art of public health and the incalculable benefits
to the community in the application of this knowledge, we can all realize
the beneficent service rendered to this great cause by this latest gift of the
Eockefeller Foundation, which has already contributed so largely to the
advancement of medical science and education. Not only this university, but
also this city and state and the whole country owe a great debt of gratitude
to the Foundation for the provision thus made of improved opportunities
for training in preventive medicine and public health work and for cultiva-
tion of the sciences which find application in public and personal hygiene.

It is naturally most gratifying to us that Baltimore and the Johns Hop-
kins University have been selected for the location of the new school of

' Report of remarks made at the Commencement Exercises of the Johns
Hopkins University, June 13, 1916.

Johns Hopkins Univ. Circ, Bait., 1916, XXXV, No. 7, 9-13.

669

670 SCHOOL OF HYGIENE AND PUBLIC HEALTH

hygiene and public health. Our city, in its situation, its relations to the
south and other parts of the countrj', its proximity to the national capital,
and its opportunities for study and work in the field of preventable diseases,
is favorably located for such a school. I think that I may say that determin-
ing considerations have been the advantages arising from close association of
the school with the medical school, the hospital, the school of engineering
and other departments of the Johns Hopkins University, and it is for these
reasons especially that the decision reached by the Foundation after pro-
longed and careful study of the situation in different parts of the country
is so gratifj'ing to us. The wider extension of the influence and usefulness
of the university, the possibilities of greater service to this city and state and
to the country at large about to be opened by the new school, should materi-
ally strengthen the position of the Johns Hopkins University and aid in
securing much-needed support in the development of other departments.

While the detailed plans of organization of the school of hygiene and
public health will be worked out and announced later, a few points may here
be touched upon.

Inasmuch as the profession of the sanitarian and worker in public health,
although closely connected, is not identical with that of the practitioner of
medicine; the school of hj-giene and public health, while working in coopera-
tion with the medical school, as well as with the school of engineering, will
have an independent existence under the university coordinate with these
schools. Opportunities in each will be available to students of the other
schools.

The central and principal feature of the school will be an institute of
hygiene housed in its own building, provided with the requisite laboratories
and facilities and with its own staff of teachers giving their entire time to the
work of teaching and investigating.

There will be here laboratories of sanitary chemistry of physiology as
appUed to hj-giene — a most important although much neglected subject —
of bacteriologv' and protozoology, and provision for epidemiology, industrial
hygiene, vital statistics, a museum, librar}', etc. Additional facilities for
instruction and research will be supplied by the medical and the engineering
schools, tlie hospitals, especially the newly opened wards for infectious dis-
eases of the Harriet Lane Home for Invalid Children, and other departments
of the university, which will be aided in undertaking the new work.

It is anticipated that mutually helpful relations will be established with
our municipal and state departments of health, assurance of which has been
given by our public-spirited Mayor and other autliorities, and with the
Federal public health service, whereby opportunities will be afforded for field

AT THE JOHNS' HOPKINS UNIVERSITY 671

work and other practical experience in various branches of public health
work.

Especially advantageous will be the relations with the International
Health Commission of the Eockefeller Foundation, which is engaged in the
study and control not only of hook-worm, but alsj of malaria, yellow fever
and other tropical diseases, which will receive due attention in the work of
the Institute.

It is intended that the school shall furnish opportunities of a high order
for the cultivation of the various sciences which find application in hygiene,
sanitation and preventive medicine, and for the training of medical students,
engineers, chemists, biologists and others properly prepared who wish to be
grounded in the principles of these subjects, and above all for the training
of those who desire to fit themselves for careers in public health work in its
various branches — that most attractive profession for those qualified to
practise it. The most urgent need at the present time is provision for the
scientific training of prospective health officials and for supplementary and
advanced courses for those already engaged in sanitary work. Suitable
recognition of the satisfactory completion of work in the school will be
given by the bestowal of certificates and degrees.

Directions in which it may be expected that the usefulness of the school
of hygiene and public health will l)e extended are cooperative efforts with
our training school for nurses and other agencies in the training of public
health nurses, who have become such important agents in voluntary and
public health work, and in the education of the public by exhibits, lectures
and other means to a better application and imderstanding of the signifi-
cance and needs of public and personal hygiene.

The dreams which many of us in the medical faculty have long cherished
are now about to be realized. The opportunity which this great benefaction
places in the hands of the Johns Hopkins University is most inspiring. It
is comparable to that presented to the universitj' at its beginning for the
promotion of higher education, and later to the medical school and the
hospital for advancement of the standards and methods of medical educa-
tion. The responsibilities devolving upon the university in this new under-
taking, entrusted to it with such high hopes, are commensurate with the
splendid opportunities. May we not confidently anticipate that in this new
field the results will be in keeping with the achievements of the university in
the other fields it has cultivated so successfully ?

EEMAEKS AT OPENING OP MEDICAL CONFERENCE OF RED

CROSS SOCIETIES'

I esteem it a very great privilege to speak on behalf of my colleagues who
are delegates to this Conference. I think it is not going too far to say that
the entire medical profession of America and, indeed, all those who are
interested in the prevention of disease and in the promotion of public health,
would be glad to express their appreciation to the Committee of Red Cross
Societies for having called together this Conference. Especially, I think all
present will agree that we are indebted to Mr. Davison, who has again added
to the very great service he has rendered in leading the American Red Cross
during the war, by looking to the future, and for having conceived the idea
that the great forces, resources, energies and thoughts which have been
called into action by the Red Cross during the war, should continue to
operate for the benefit of mankind.

How quickly we who have been interested in these questions have re-
sponded to this invitation ! How warmly we have welcomed this great
opportunity, carrying with it an equally great responsibility ! I think that
those of us who have often felt that we have been preaching to deaf ears the
gospel of health have come here feeling actual joy that at last such great
forces as are embodied in the Red Cross Associations are to be strengthened
and expanded into a world-wide organization, for the promotion of health
and the prevention of disease. We are confident that there are great possi-
bilities of good in the application of this knowledge to the welfare of man-
kind.

It is a subject for congratulation that the minds of men have been
awakened to the possibilities of improving the health and welfare of mankind
through the control of disease, and it is a matter of the utmost gratification
that these objects are to be attained through the Red Cross whose organiza-
tions are to be continued, strengthened and expanded for the good of man-
kind.

We who have been joined together in close association during this war in
fighting the common enemy, an enemy of civilization, are to continue in

' Report of remarks as Presiding OfBcer at the Second General Session of the
Medical Conference, held at the invitation of the Committee of Red Cross
Societies. Cannes, France, April 1, 1919.

Proc. Med. Conf., Cannes, France, 1919, 24-25.
672

MEDICAL CONFERENCE OF EED CROSS 673

closer bonds of friendship, because we are joined together not to forge
weapons of destruction, but united to consider what we can contribute for
the heaUng of the nations. There are assembled in Paris delegates to con-
sider the formation of a League of Nations. We are assembled here to confer
upon the formation of a League of Health. An 1 1 venture to say tliat what
we negotiate here will signify to mankind fully as much as the result of the
deliberations in Paris.

I believe that we are contributing to the good and welfare of mankind by
the creation of this League of Health under the Associated Red Cross
Societies of the World, quite as much as will be contributed by the League
of Nations under whose sanction, if not under whose direction, I trust we
shall be permitted to act. We, therefore, pledge the loyalty of our delegates
from America to this Committee of Red Cross Societies, and we wish at the
same time to express our pleasure at being associated with our colleagues
from France, England, Italy, and Japan, in this great movement.

SCOPE OF THE PROPOSED HEALTH ACTmTIES OF THE
LEAGUE OF EED CROSS SOCIETIES '

In our deliberations upon the general plan and purposes of a central
health organization under the associated national Red Cross Societies, there
are certain points which it seems to me important for us to bear in mind.

The first consideration is the importance of starting the new work along
the right lines. A broad, comprehensive and detailed program will doubtless
eventually be developed, but this must be a matter of gro'W'th, determined
by the results of experience and by the available resources. We cannot pre-
cisely define or foresee these lines of future development, although I believe
that we are all agreed that their possibilities are of incalculable importance
for the welfare of mankind. Our more immediate task is to make recom-
mendations concerning the initial steps which should be taken, trusting that
time will indicate the paths which subsequently may be followed to greatest
advantage. The future developments are obviously dependent in no small
measure upon the successful initiation of the plan upon relatively simple
lines.

In the second place, we should keep in mind that we have been called
together to confer upon what an association or league of Red Cross Societies
can wisely undertake in the promotion of health and the prevention of dis-
ease among the peoples of the world. While present conditions do not per-
mit this league to assume a completely international character, it is permis-
sible to look forward to tlie time wlien it will possess this character, but even
under existing circumstances, we should not lose sight of tlie fact that our
recommendations should concern themselves with the activities of an organ-
ization representative of many countries of the world.

Inasmuch as the central organization will operate mainly through the
various constituent national societies, and upon their invitation, it is clear
that a primary and main purpose of this organization will be to strengthen
and develop existing Red Cross Societies, aiding them to enter upon these
new and promising fields of work, and also to create such societies where tliey
do not now exist.

' Report of remarks as Presiding Officer at the Fourth General Session ot the
Medical Conference, Cannes, France, April 3, 1919.
Proc. Med. Conf., Cannes, France, 1919, 50-51.
674

SCOPE OF PEOPOSED HEALTH ACTIVITIES 675

It should require little argument to show that the lied Cross in entering
upon the field of preventing human misery caused by disease and suffering, is
not diverting from its great work of relief, but is rather following a natural
and logical path of development; for preventable disease is a continuing
calamity, and its control is the best kind of rtMef, which will render unneces-
sary many of the large expenditures and appeals assumed by the Eed Cross
in the past.

Although public health administration is in the main a governmental
function, we all know how helpful in manifold ways are voluntary organiza-
tions, such as those concerned with tuberculosis, with child hygiene, with
mental hygiene, with venereal diseases, etc., in educating and organizing
public opinion, in carrying on demonstrations, in influencing beneficially
sanitary legislation and administration and in promoting in various otlier
ways modern health movement. The Eed Cross will not supplant any of
these agencies, governmental or voluntary, but rather will aid them and
help to coordinate their activities.

It cannot fail to be a source of the utmost gratification to all interested in
the betterment of health and the prevention of disease that the Eed Cross,
with its uuequaled influence and power, and its record of magnificent work
in fields of activity of the greatest importance is to continue its labor in
times of peace for the future welfare of the world. That these activities will
be guided by the voice of science is indicated by the character of the Con-
ference which we have been summoned to attend.

One of the important functions of the central health bureau of the asso-
ciated Eed Cross Societies will be to collect and distribute for the informa-
tion and education of the public, the best available knowledge concerning
hygiene and methods of preventing disease. A survey of the incidence and
distribution of diesase, and the general health conditions in the different
countries with the methods of control adopted would be an extremely helpful
and much-needed contribution.

Tlie modern health movement started in England less than a century ago
with such a survey, which indicated clearly that there were controllable
factors determining the prevalence of disease in certain localities, and under
certain conditions of living and of working. As a result, there developed in
England a practice of local pubUc health administration in which this
country still leads the world. Besides England, each of the countries repre-
sented in this conference has something of value to contribute. France, the
country of Pasteur, so worthily represented at this Conference by his suc-
cessor and our President, Dr. Eoux, and his colleagues, has been a leader in
scientific discovery, and has given us such men unmatched in tlie power of
orderly thinking and clear expression. We owe to Italy studies of malaria

676 SCOPE OF PROPOSED HEALTH ACTIVITIES

and methods for its control, of the greatest importance in sanitation, and it
is gratifying to find in attendance on this Conference those who have made
these great contributions. I had tlie opportunity four years ago of becoming
personally acquainted with the fruitful activities of scientific investigation
in Japan, in her admirable institutes. I think that America, largely through
the efforts of Dr. Biggs, may claim to have had a leading share in the appli-
cation of scientific discoveries in public health organization and adminis-
tration, and especially in the organization and development of public health
diagnostic laboratories, which we regard as a central feature of our sanitary
methods. I cite these instances merely to illustrate the benefits which may
be expected from a central health organization, such as that contemplated
under the Red Cross, in which the sanitarians and methods of the leading
civilized countries are represented.

ERRATA

L. F. T. 1

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Location of Error

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61

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64

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276

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298

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486

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677

()78

s

ERRATA

Page

Location of Error

Correction

•

540

L. F. T.

2

" (trassicollis "

should

read

crassiroUix

543

L. F. T.

3

" creditate "

should

read

crepitate

551

L. F. B.

17

" deflnitian "

should

read

definition

575

L. F. T.

IS an

id other pages " feces

" should

read

faeces

576

L. F. B.

1

" fecal "

should

read

faecal

577

L. F. B.

16

" remore "

should

read

remove

586

L. F. B.

21

" cholera typhoid "

should

read

cholera or typhoid

595

L. F. B.

13

" houses "

should

read

housed

648

L. F. T.

18

" shore "

should

read

short

653

L. F. B.

1

" interested "

should

read

interpreted

658

L. F. B.

1

" insanitation "

should

read

unsanitation

663

L. F. T.

19

" health "

should

read

healthy

666

L. F. B.

9

" very "

should

read

vary

670

L. F. B.

12

" chemistry "

should

read

chemistry,

l?1)

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