Anemia and resuscitation : an experimental and clinical research

Front matter

Hibrarp

ANEMIA AND RESUSCITATION

Open Knowledge Commons

Preface

In presenting the material of this book for publication it gives me pleasure to express my many obligations to my associates. Although the problems originated in my clinic, and the experiments were planned by me, their accomplishment was made possible by the diligent labors of my associates. Part of the subject matter was presented before the College of Physicians, Philadelphia, in 1908 as the Mutter Lecture for that year under the title "Surgical Anemia and Resuscitation."

To Dr. D. H. Dolley's untiring efforts, for which appreciation has already been expressed in "Hemorrhage and Transfusion," is due the large accumulation of data on cerebral anemia.

In the research on anemia of the voluntary muscles I am indebted for the preliminary work to Dr. Lawrence Pomeroy, and for the later work to Dr. A. M. Tweedie. The research on anemia of the intestines was also in charge of Dr. Tweedie, Dr. H. G. Sloan conducting the experiments on certain phases of this important work. The neurocytologic work in this research, as well as some of the later work on cerebral anemia, was done by Dr. J. B. Austin. The drawings illustrating the changes in the brain cells in gangrene of the intestine were made by Miss Armenouhie H. Tashjian.

vii viii PREFACE

To Dr. Charles S. White, of Washington, D. C, are due my thanks for permission to use the three illustrations showing the relationship of the thoracic viscera, and also to "Surgery, Gynecology, and Obstetrics" for the blocks for the same.

To Dr. F. W. Hitchings I wish to express my especial appreciation for his tireless labor and enthusiasm in the arduous task of compiling the various tables, abstracting the literature, arranging the experimental data, and assembling all of the material into book form.

The final revision of the text was made by my editor, Miss Amy Rowland.

G. W. C.

Contents

PAGE

INTRODUCTION 3

Chapter I

ANEMIA OF THE CENTRAL NERVOUS SYSTEM. EXPERI- MENTAL OBSERVATIONS 5-54

Introductiox 5

The Blood Supply of the Brain : General Considerations 6

The General Effects of Complete Anemia of the Central Nervous System as Seen in Dogs Resuscitated

after Relative Death 8

Technique of Experiments lo

Recovery Results 13

Special Phenomena following Resuscitation . . 20 Comparison of the Author's Results with the Results

of Others 28

Protocols of Ten Selected Experiments ... 31 Table I — Time of the Respiratory and Circulatory

Changes 50

Table II — Ten Cases in Which the Total xA.nemia

Lasted Seven and One-Half or More Minutes . ■ 51 Table III — The Course of the Blood-Pressure after

Resuscitation 52

Table IV — The Time of Return of the Reflexes after

Restoration of the Circulation 53 ix

CONTENTS

Chapter II Page

ANEMIA OF THE CENTRAL NERVOUS SYSTEM: CLINICAL OBSERVATIONS. CEREBRAL ANEMIA THROUGH LIGATION OF THE COMMON CAROTID ARTERIES . 55-72

General Considerations 55

Analysis from the Literature of Five Hundred Cases

OF Ligation of the Common Carotid Artery . . 57 The Author's Cases of Temporary Simultaneous Closure of Both Common Carotid Arteries . . 64 Technique of Ligation of the Common Carotid Artery

AND Its Branches 65

Chapter III

ANEMIA OF VOLUNTARY MUSCLES: EXPERIMENTAL OBSERVATIONS— ANEMIA OF THE POSTERIOR EX- TREMITY OF DOGS 73-107

Protocols of Forty-Three Experiments .... 75

Table — The Results Obtained by Causing Anemia of the Hind Legs of Dogs for Varied Durations of Time 106

Chapter IV

ANEMIA OF VOLUNTARY MUSCLES : CLINICAL OBSERVA- TIONS—OCCLUSION OF THE ABDOMINAL AORTA IN MAN 108-122

Chapter V

ANEMIA OF VOLUNTARY MUSCLES : CLINICAL OBSERVA- TIONS—ANEMIA OF THE LOWER EXTREMITIES IN MAN THROUGH LIGATION OF THE MAIN ARTERIAL TRUNKS . 123-13^

Ligation of the Common Iliac Artery 125

Ligation of the External Iliac Artery .... 126

CONTENTS XI

PAGE

Ligation of the Common Femoral Artery .... 127 Ligation of the External Femoral Artery . . . 130 General Recapitulation 132

Chapter VI

ANEMIA OF VOLUNTARY MUSCLES : CLINICAL OBSERVA- TIONS—ISCHEMIC PARALYSIS 133-143

Case in Which Pressure on the Muscles Apparently Played an Important Part I33

Case in Which Embolism of the Brachial Artery Was the Only Etiologic Factor I35

Case in Which Marked Muscular Contracture Followed Contusion of the Leg; Spontaneous Recovery 130

Case of Ischemic Contracture in Which Pressure Was Probably an Important Etiologic Factor but in Which Marked Relief Followed Freeing of Nerve Trunks from Pressure by Cicatricial Tissue . . 140

Case in Which Bandaging for Uncomplicated Pott's Fracture Was Followed by Gangrene, Necessitating Amputation 141

- Case in Which Beginning Gangrene of the Hand

Followed Prolonged Application of a Tight Sleeve 142

Chapter VII

CERTAIN CLINICAL APPLICATIONS FROM THE FOUR PREVIOUS CHAPTERS. LOCAL GANGRENE FROM ANEMIA OF THE EXTERNAL SOFT PARTS OF THE BODY . 144-149

Anemia in Lesions of the Spinal Cord .... 140

Saline Infusions ; . . . . 148

Flap Tension and Suture Tension I49 xii CONTENTS

Chapter VIII Page

ANEMIA OF THE SMALL INTESTINE: EXPERIMENTAL OBSERVATIONS. INTERFERENCE WITH THE CIR- CULATION OF LOOPS OF SMALL INTESTINE OF DOGS FOR DIFFERENT LENGTHS OF TIME UNDER DIFFERENT CONDITIONS i5o-i94

Experiments in Which a Loop of Small Intestine ■with Its Blood Vessels Was Ligated en Masse with Tape, the Tape being Removed Before the Abdomen Was Closed 152

Experiments in Which a Loop of Small Intestine Was Ligated, a Lateral Anastomosis Having Been Previously ^vlade to Isolate the Loop, and the Tape Removed Before Closing the Abdomen . . . 162

Experiments in Which a Lateral Anastomosis Was Made, a Loop of Intestine Ligated, and the Tape Left in Place After the Abdomen Was Closed . 164

Experiments in Which a Lateral Anastomosis Was Made, a Loop of Intestine Ligated, and the Loop Excised at the End of the Period of Anemia Before Closing the Abdomen 166

Experiments in Which a Lateral Anastomosis Was Made, a Loop of Intestine Ligated, a Drainage Tube Inserted Into the Loop, and the Abdomen Closed 168

Experiments in Which a Lateral Anastomosis Was Made, a Loop of Intestine Ligated, and the Loop Allowed to Project Through the Abdominal Wound -. . 172

Experiments in Which There Was Partial Occlusion of the Blood-Supply of a Loop of Intestine by Ligation of the Corresponding Arteries and Veins, in the ^Mesentery 174

Control Experiment 176

Tabulation of the Experiments on Intestinal Anemia 177 Summary of Experiments on Intestinal Anemia . . 178

CONTENTS Xiii

PAGE

The Injection into the Intestinal Tract and Perito- • NEAL Cavity of Dogs of Juice from Loops of Small Intestine Previously Rendered Ischemic for Varying Periods of Time 179

Injection into the Peritoneal Cavity .... 180 Injection into the Lumen of the Intestine . . . 183

Injection Intravenously 186

Injection Intraperitoneally of Intestinal Juice from a

Dead Dog 188

Injection of Sterilized Intestinal Extract (i) Intravenously and (2) Intraperitoneally .... 189 Injection into Dogs of Intestinal Extract from Gangrenous Intestine of Dogs, or of Extract from Intestine of Dead Dogs 190

CHAPTER IX ANEMIA OF THE KIDNEYS AND SPLEEN . . 195-219 Experiments in Which the Renal Artery Alone Was

Clamped 199

Experiments in Which Both the Renal Artery and

Renal Vein Were Clamped 207

Anemia of the Kidney of Dogs from Which One

Kidney Had Previously Been Removed . . .211

Summary of All Experiments 212

Anemia of the Spleen 214

CHAPTER X RESUSCITATION OF THE BODY AS A WHOLE . . 220-240 General Considerations 220

Resuscitation of the Respiratory Apparatus . . . 221

Artificial Respiration 221

Schafer's Table Showing the Relative Efficiency of

Methods of Giving Artificial Respiration . . . 223

Methods Commonly in Use 226

XIV CONTENTS

Chapter XI Page

RESUSCITATION OF THE BODY AS A WHOLE (Continued) 241-249

The Author's Method of Resuscitation .... 244

Chapter XII General Recapitulation . . . . . . 250-251

Local Anemia 250

Resuscitation 251

INDEX 299

LIST OF ILLUSTRATIONS

FIG. PAGE

I. Normal Small Intestine of a Dog (high magnification) 151

II. Normal Small Intestine of a Dog (low magnification) 151.

III. Anemia of the Intestine. Duration of anemia four

hours (high magnification) 157

IV. Anemia of the Intestine. Duration of anemia four

hours (low magnification) 157

V. Anemia of the Intestine. Duration of anemia six

hours (high magnification) 160

VI. Anemia of the Intestine. Duration of anemia six

hours (low magnification) 160

VII. Cortex from Normal Dog. Brain cell changes produced by toxemia due to anemia of the small intestines of a dog. Facing page 190

VIII. Cortex from Toxemic Dog. Brain cell changes produced by toxemia due to anemia of the small intestines of a dog. Facing page 190

IX. Cerebellum from Normal Dog. Brain cell changes produced by toxemia due to anemia of the small intestines of a dog. Facing page .... . 192

X. Cerebellum From Toxemic Dog, Brain cell changes produced by toxemia due to anemia of the small intestines of a dog. Facing page 192

XI. Anemia of the Kidney. Duration of anemia seven

hours (low magnification) 206

XII. Anemia of the Kidney. Duration of anemia eight

hours (low magnification) . . -. . . . 206

XV xvi LIST OF ILLUSTRATIONS

FIG. PAGE

XIII. Longitudinal Frozen Section^ Showing Relation of

THE Heart to the Diaphragm 235

XIV. The Thoracic Viscera as Seen from the Front^ the

Ribs and the Sternum Intact ..... 236

XV. The Thoracic Viscera as Seen from the Front^ the Viscera Being Exposed by Removal of the Ribs and Sternum 237

XVI, Method of Giving Adrenalin by Injecting it Directly INTO A Stream of Normal Saline Solution 244

Introduction

The following studies of anemia as it affects the body as a whole or its component parts have been made in an endeavor to solve practical clinical problems which both the surgeon and the internist often confront.

In regard to the resuscitation of the body as a whole, the fact has not been sufficiently appreciated that the greatest and most essential difficulty is to overcome the anemia of the brain. In apparent death from drowning, from gas poisoning, from electric shock, or from any of the many other causes of suspended animation, the organ which most quickly succumbs beyond the power of reanimation is the brain rather than the heart. Since continued normal action of the heart and lungs is dependent on the activity of the brain, the presence or absence, as well as the degree and duration of anemia of the latter organ, decides the possibility of resuscitation.

The field for the study of local anemia is very large. Among the commonest examples of causes of local anemia may be mentioned embolism and thrombosis, the too tight application of bandages and other apparatus, localized pressure from the weight of the body in unconscious patients, twisted pedicles of tumors and organs, too tight packing of wounds, and incarcerations and strangulations of intestines. New problems in local anemia have been presented in the last few years, largely through the work of Carrel in transplanting organs or even extremities from one individual to another. Successful organ transplantation presupposes knowledge of

4 INTRODUCTION

the power of any given organ to resist anemia while the operation is being performed.

KuHabko's brilliant work in making the heart continue to beat after its removal from the body, supplemented by the work of Hill, Batelli, d'Halluin, and others abroad, and of Stewart and his associates in this country, paved the way to further study of the automaticity of action of that organ. Attempts to resuscitate the body as a whole by massage of the heart, by artificial respiration, or by the injection of saline or other solutions into the circulation were the natural sequence of their results.

The experiments from the author's laboratory which are presented in this book are a continuation of those on surgical shock, in which it was shown for the first time that the blood pressure of a decapitated dog could be maintained for hours by means of the slow, continuous infusion of normal saline solution and adrenalin. This again led naturally to the use of the adrenalin-saline intravascular infusion combined with rhythmic pressure on the chest as a means of resuscitation, a method which, so far as is known, was first demonstrated by the author before the Cleveland Medical Society at Western Reserve University Medical College.

In this monograph, as in some of those already published, it has seemed best to publish the experiments in considerable detail. The labor and expense of producing them have been great, and their publication may save other workers unnecessary repetition.

Chapter I

ANEMIA OF THE CENTRAL NERVOUS SYSTEM. EXPERIMENTAL

OBSERVATIONS.

INTRODUCTION

For a number of eminently practical as well as scientific reasons it is important to know the effects of total or partial anemia of the brain. For example, in the course of operation or as the result of injury the surgeon may be compelled to choose between ligating the common carotid artery or taking other hazards. It would assist him in making an intelligent decision if he knew the effect of anemia of the brain. In operating on the brain he may be obliged to retract a portion of it, thus causing localized anemia. How long will the brain safely endure such anemia? What will be the immediate and final results if he resorts to these measures? Will intermittent retraction be safe, when continuous retraction would be certain to cause injury from local anemia? In cases of cerebral compression from fracture of the skull, from tumors, from abscesses, from edema of the brain, from hemorrhage, anemia is in many instances the most important factor.

It would be of considerable practical value to know whether or not all parts of the brain and spinal cord endure anemia equally well. Do differences exist between the resistance of the lower and higher centers, and if there are differences, are they because the one has been established earlier in the course of evolution than the other, and has become, as some one has expressed it, hardened by longer use, or is it because some portions of the brain are more delicately poised ? Which will endure anemia longer, the sight or the auditory mechanism, an eye reflex or a tendon reflex, the emotional or the motor mechanism? Will a given amount of anemia abolish the memory and yet leave the motor mechanism intact? Among the medullary centers is the respiratory or the vasomotor, the cardio-accelerator or the cardio-inhibitory the more resistant to anemia?

In the following pages an attempt has been made to throw light on these various questions. The importance and the difficulty of the subject must be the excuse for presenting so large a mass of data in detail as well as in summary.

THE BLOOD SUPPLY OF THE BRAIN: GENERAL CONSIDERATIONS

In the course of evolution, the brain, more than any other organ in the body, has been evolved in such a way as to have a constant supply of blood under even pressure. The brain can expand but the skull cannot expand under the influence of increased blood-pressure. Consequently, unless there were a protective mechanism which would afford a constant margin of safety against over-expansion, cerebral anemia due to pressure of the brain against the skull would be produced. Such a mechanism is provided by the water-bed of cerebral fluid on which the brain rests, and by the large venous sinuses.

When the brain expands or when it shrinks in volume the cerebral fluid, which connects directly with the spinal fluid, ebbs and flows. At the same time the blood in the large venous sinuses is forced out or in. Under ordinary conditions this prevents undue pressure on the brain, but, as a protection against cerebral anemia, another mechanism has been evolved, viz., the elevation of the arterial blood-pressure through stimulation of the vasomotor mechanism by anemia.

Aside from the volume factor of safety, the importance of the brain being abundantly supplied with blood is emphasized by the provision of a large artery, the common carotid, on each side of the neck. Moreover, each artery is well protected by being deeply buried under strong muscles and fasciae, and is so placed as to be easily defended in case of attack on the individual. In addition to the great carotids there are also the vertebral arteries, which could scarcely be torn except by such an injury as would sever the head from the body. A still further addition to this quadruple supply is the small amount which passes through the arteries of the spinal cord.

Besides such adequate protection against cerebral anemia, provision for equalization of intracerebral pressure is necessary. This is secured by that wonderful adaptive arrangement at the base of the brain, the circle of Willis, by means of which blood is simultaneously received and delivered from the above-mentioned sources. Under normal circumstances the distribution is under even pressure although the halves of the brain may not receive exactly the same amounts of blood. Under certain other circumstances, however, such as fighting, in unusual exertion of one part of the body, in certain positions of the neck and head, and when one side of the neck is subjected to direct pressure, there may be inequality of pressure in the supplying arteries, but, subject to the laws of physics, the inequality must be largely eliminated in the circle of Willis and hence in the brain. The fact that cerebral arteries are straight and numerous and do not anastomose freely has an important and direct bearing. Closure of an artery between the heart and the circle of Willis is a very different matter from closure of one between the circle of Willis and the cerebral tissue.

To summarize the anatomical points which have a direct bearing on cerebral anemia : ( i ) Provision is made for cerebral expansion and contraction within the skull; (2) there is a blood-pressure-raising mechanism with which to combat anemia; (3) the four major arteries are placed in the most favorable positions for both active and passive protection against injury; (4) these arteries empty into a circular receiving vessel at the base of the brain which equalizes the pressure and from which an even start is made for the passage of the blood through the straight non-anastomosing arterial trees to every part of the cerebral tissue.

THE GENERAL EFFECTS OF COMPLETE ANEMIA OF THE CENTRAL NERVOUS SYSTEM AS SEEN IN DOGS RESUSCITATED AFTER RELATIVE DEATH

The method employed by the majority of investigators has been that of occlusion, either of the cerebral vessels or of the aorta at various levels. The objection to this method, which is frankly acknowledged, is that the factor of collateral circulation cannot be entirely eliminated, even in the most favorable animal, the cat. Further, the brain and the spinal cord have been investigated separately, a procedure which must make a vast difference, not in determining the relative viability of the various centers, but in fixing the limit of anemia, admitting of a complete recovery of the animal. Stewart says : "Division of the cord in the upper dorsal region (III to VI dorsal vertebrae), if done before fairly complete recovery of the cerebral centers, is followed by collapse, dilatation of the pupil, cessation of respiration, cardiac failure, and death. The integrity of the spinal centers is necessary for the resuscitation of the cerebral centers."

Other methods of investigation employed, such as artificial circulation through the decapitated head, and the introduction of emboH, preclude the possibility of recovery studies. Within the last decade, with the more or less successful attempts at resuscitation of the heart, contributions to the subject of anemia of the whole central nervous system have been made by several observers, notably Prus and Batelli.

The author's study of brain anemia was the sequence of work on the resuscitation of animals killed by anesthetics and asphyxia, which may be briefly summarized as follows : By means of a centripetal infusion of salt solution into an artery together with the simultaneous injection into the stream of one or two cubic centimeters of 1-1,000 adrenalin chlorid, the simultaneous employment of vigorous artificial respiration and rhythmic pressure on the thorax over the heart, the animal may, within certain limits, be resuscitated. For as long as five minutes after total cessation of function resuscitation is usually successful; for as long as from five to ten minutes there are more failures; while after ten minutes the chances of success are progressively less. As will be seen later, this method is uniformly successful within the limits which are compatible with viability of the central nervous system. The method is necessarily self-limited, for, in the case of a heart which is losing its irritability owing to lapse of time, dilatation may occur from the infusion before the beat is inaugurated. Even in dogs with rigid chest walls compression of the chest has proved satisfactory. In periods under five minutes but little compression is necessary. Direct cardiac massage is, therefore, not essential.

The primary purpose being to determine the period of anemia which the central nervous system can endure with subsequent recovery, the method offers the advantage that no operative procedure is necessary except the small incision for inserting the infusion cannula. The author's results are lo SURGICAL ANEMIA AND RESUSCITATION

based, first, on a series of thirty unselected dogs, resuscitated after the lapse of various periods of time, in all but five of which the subsequent course of events was not disturbed. These five were killed after different times for the purpose of histologic examination. Secondly, the series of sixty experiments on dogs, previously reported in the paper on resuscitation, was drawn upon for data pertaining to this work. In the latter experiments blood-pressure and respiratory tracings were made.

Technique

For the recovery experiments, with one exception, the dogs were killed with chloroform. While open to objection on account of the paralyzing effect on the nervous system, and non-elimination of the chloroform until after the resuscitation, this method was adopted in imitation of the condition most likely to afford opportunity for resuscitative measures in failure of the heart in the course of surgical operations. All procedures were done with the customary aseptic precautions. The infusion cannula was inserted into the axillary artery.

In order to estimate in some measure the effect of the anesthesia on the subsequent recovery of the dogs, two experiments were done in which the dog was anesthetized in the usual way to the point of respiratory failure and was then resuscitated by artificial respiration without cessation of the circulation being permitted. The first dog showed full return to intelligence in sixteen minutes. The second one took ether like an alcoholic patient, it being forced for ten minutes before struggling ceased. However, in twenty minutes after recurrence of the respiration, the animal walked about and showed return of function, though extremely "groggy."

The period of total anemia was estimated to start from the moment when the first heart sound ceased to be audible

ANEMIA OF THE CENTRAL NERVOUS SYSTEM II

with the stethoscope, this sound sometimes persisting for several minutes after the failure of blood-pressure as recorded upon the drum and the disappearance of the carotid or femoral pulse and the second sound. While this is only the statement of a well-known fact, attention is called to it, because very possibly in some experiments it made the stated period of anemia shorter than it actually was, the circulation being too feeble to reach the brain, although the first heart sound was still audible. In some cases on account of the heart sounds becoming fainter, it was impossible to record the actual moment of failure. In these a leeway of at least one-half minute was allowed from the last distinct sound to the recorded cessation. From the time of starting the chloroform to respiratory failure there was an average of two and three-fourths minutes, with a minimum of fifty seconds and a maximum of seven and five-twelfths minutes. (See Table I, page 50.)

The cessation of respiration and the final failure of the heart were synchronous in five cases; from which the intervening time varied up to six and three-fourths minutes, with an average of one minute and fifty-seven seconds. From a study of the tracings of the first series it was found that the blood-pressure was at the base line during a longer average time than the latter half of this period. It is probable, therefore, that during this period the cerebral circulation was reduced nearly to the vanishing point, and while a small amount of blood goes a long way in the brain, Leonard Hill saying, "It is obvious that the cortex can be kept from death for hours by the merest dribble of blood," this marked anemia of several minutes' duration had an effect which was apparent in that the cases with prolonged partial anemia did not recover as readily as did the average dog subjected to total anemia of equal duration. It is worthy of note that in the dog showing the maximum recovery period, which was one and one-third minutes above the time of the second best result, only twentytwo seconds intervened between respiratory and cardiac failure.

In five out of the twenty-nine animals killed by chloroform there was a brief spontaneous recurrence of the heart sounds, occurring from twenty seconds to one and one-half minutes after they had entirely ceased, and accompanied in two instances by two or three faint respiratory efforts. In only one instance was the carotid pulse palpable. As the total duration of anemia cannot be exactly classified, both the absolute and practical duration will be given. The time spent in resuscitation is included in the period of total anemia.

While it seems reasonable to suppose that centripetal arterial infusion of salt solution aided by indirect massage of the heart would hardly reach the brain to any extent during a period of administration of from one to three minutes, and, further, as if it did there would be very little blood in the salt solution, the question was put to the test of experiment. In a dog which had been dead for twelve minutes a solution of methylene blue was infused into the axillary artery, and the usual procedures, with the exception of adrenalin injection, were carried out for double the average time. No indication of its having reached even the bulbar centers was found. This is in contradistinction to direct massage, which, according to d'Halluin, effects a veritable artificial circulation, which is sufficient to reanimate and maintain bulbar activity. Study of the tables of Prus shows that as a result of direct massage respiration returned in twenty-nine out of thirty-five experiments in one series, though there was no return of effective heart beat, and, in seven cases, reflexes and muscular movements reappeared.

The definition of the end of the period of total cessation of the circulation was, however, sharp, the resumption of function on the part of the heart being abrupt and visible as well as palpable. After a few initial heart sounds blood-pressure rose rapidly, often within ten seconds, to as much as 200 mm. of mercury or over, this rise being due to the adrenalin.

Recovery Results (Tables I and II, pages 50 and 51.) Permanent and complete recovery was obtained after five minutes, six minutes,^ six minutes and ten seconds, six minutes and fifteen seconds,^ and seven minutes and thirty sec-' onds of total cessation of the circulation. That is, one dog out of twelve with total cessation of circulation between the periods of seven minutes and eight and one-half minutes recovered, whereas only one out of seven between the periods of five minutes and six and one-half minutes died apparently as a direct result of the anemia. Complete recovery was presumptive in another dog after cessation of circulation for seven minutes and thirty seconds. One dog of the second series, after cessation for five minutes and thirty seconds, was killed after twenty-four hours for the purpose of histological examination. As compared with the others of the same degree his condition assured a probable recovery. The asphyxiated dog, after cessation for five minutes and forty-five seconds, was killed on the fourth day. A second animal of the first series, after seven minutes' cessation, was killed on the third day.

Our experience showed no intermediate condition uncomplicated by accidental organic lesion ; in other words, no slow decline to death. The demarcation between recovery and death was sharp. In practically all the experiments the crisis was reached in from twelve to twenty-four hours. Then

^ Recurrence of heart sounds interjected for thirty seconds ; practical time, six minutes and thirty seconds.

^ Recurrence of heart sounds for one minute and twenty seconds ; practical time, six minutes and thirty-five seconds.

death ensued quickly, or else distinct improvements of nervous functions began shortly, continuing more or less rapidly until complete restoration, though the convalescent period lasted in two dogs four and six weeks respectively.

From his studies on the effect of different degrees of anemia produced by occlusions, Leonard Hill says : "The degree of anemia required to produce dementia is separated by the narrowest line from that which produces coma and death of the respiratory center. There are either no symptoms or death in a few hours." Our results accord with this statement. Up to a certain point, not to be exactly limited, but, roughly, six minutes, the after-effects are not marked, and the second, third, or fourth day brings complete recovery. For example, one dog (Experirnent lo), after four minutes and ten seconds' cessation of circulation in less than one hour showed entire return of intelligence, which was evinced partly in well-defined efforts to escape from the laboratory; while another, after six minutes and ten seconds (Experiment 29), showed general return of function within twenty-four hours. Beyond the six-minute limit, however, there is a great deal of after-effect, which increases disproportionately with the increase in the duration of the period of anemia, in some instances reaching a state in which the animal is little more than a cardio-respiratory mechanism.

Beyond this limit recovery is altogether uncertain, but our experiments indicate that the stage of depression is tided over, and that recovery will be complete eventuall}^ though the narrowness of the escape is shown by the degeneration of a certain number of neurons in the recovered dogs, whose brains were studied by the Marchi method. This does not exclude the possibility of a partial recovery with a permanent localized after-effect, such as the paralysis of one foreleg, a result described by Stewart in two animals which, however, were under observation only seven and nine days, respectively. In our dog, which recovered after anemia of the maximum duration, the degeneration predominated in the pyramidal fasciculus. The distinction here has reference to the ability of the whole organism to maintain any life. The viability of the vital centers, as well as of other centers, is considerably above that of the brain as a whole, as the recovery-results prove, and the immediate outcome must depend on the maintenance of the interrelation and association of all brain centers, cortical and subcortical. Stewart says that, when exposed to adverse influences, the synapse proves the weak link in the nervous chain.