MEDICAL DEPARTMENT, UNITED STATES ARMY

SURGERY IN WORLD WAR 11

THE PHYSIOLOGIC EFFECTS

OF WOUNDS

By

THE BOARD FOR THE STUDY OF THE SEVERELY WOUNDED

North African-Mediterranean Theater of Operations

OFFICE OF THE SURGEON GENERAL

DEPARTMENT OF THE ARMY

WASHINGTON D. C., 7952
The volumes comprising the history it the Medical Department of the U. S. Army

in World War II are divided into two series: (i) The Administrative and Operational

series which constitutes part of the general series of the history of the U. S. Army in

World War II, published under the direction of the Office of the Chief of Military History,

and (2) the Professional, or clinical and technical series, published as The Medical Department of the United States Army under the direction of the Office of The Surgeon

General. Both series are being prepared by the Historical Unit, Army Medical Service.

This volume is one of number of surgical volumes to be published in the latter series.

Major General George E. Armstrong, The Surgeon General

Advisory Editorial Board

Brig. Gen. Albert G. Love, U. S. A. (Ret.), Chairman

Map Gen. Paul R. Hawley, U. S. A. (Ret.)

Brig. Gen. Stanhope Bayne-Jones, A. U. S. (Ret.)

Brig. Gen. Malcolm C. Grow, U. S. A. F. (Ret.)

Brig. Gen. Raymond A. Kelser, U. S. A. (Ret.)

Brig. Gen. Paul I. Robinson, U. S. A.

Col. Joseph H. McNinch, MC, U. S. A.

Michael E. DeBakey, M. D.

Morris Fishbein, M. D.

J. Ben Robinson, D. D. S.

Richard H. Shryock, Ph. D.

Lewis H. Weed, M. D.

Editors of Surgical Volumes

Fred W. Rankin, M. D.

Michael E. DeBakey, M. D.

Colonel Calvin H. Goddard, MC, A.U.S., Editor in Chief

For sale by the Superintendent of Documents, U. S. Government Printing Office

Washington 25, D. C. Price $3.50 (Buckram)
THE MEDICAL DEPARTMENT OF THE UNITED STATES ARMY

The Physiologic Effects of Wounds

By

The Board for the Study of the Severely Wounded

North African-Mediterranean Theater of Operations

Members

Henry K. Beecher, M. D.

Formerly Lt. Colonel, MC, A. U. S.

Fiorindo A. Simeone, M, D.

Formerly Colonel, MC, A. U. S.

Charles H. Burnett, M. D.

Formerly Major, MC, A. U. S.

Louis D. Smith, Ph. D.

Formerly Captain, SnC, A. U. S.

Seymour L. Shapiro

Formerly Captain, SnC, A. U. S.

Eugene R. Sullivan, M. D.

Formerly Lt. Colonel, MC, A. U. S.

Tracy B. Mallory, M. D.*

Formerly Lt. Colonel, MC, A. U. S.

Chairman

Deceased

Report of the Board edited by Henry K. Beecher.

This volume was prepared by the Historical Division, Army Medical Library, under the

direction of Colonel Joseph H. McNinch, MC, U. S. A., Editor in Chief; Associate Editor,

Sylvia Gottwerth.
THE

BOARD

FOR

THE

STUDY

OF

THE

SEVERELY WOUNDED.

Left

to

right:

Lt.

Col.

(later

Colonel)

Fiorindo A.

Simeone,

Capt.

(later

Major)

Charles

H.

Burnett,

Capt.

Louis

D.

Smith,

Capt.

Seymour

L.

Shapiro,

Lt.

Col.

Henry

K.

Beecher,

Maj.

(later

Lt.

Colonel)

Eugene

R.

Sullivan,

Lt.

Col.

Tracy

B.

Mallory.

Monghidora,

Italy,

1944.
Foreword

Severe surgical shock following trauma is not commonly encountered in

the medical practice of any group during peacetime. When it occurs it is the

result of unexpected accident, and adequate provision for careful study has

seldom been available. Consequently, although considerable noteworthy experimental work had been done on shock in animals since World War I,

little opportunity has existed to study this serious condition in man. When

the United States entered World War II, much information required for

handling battle casualties with serious injuries was not available. The need

for whole-blood replacement for resuscitation was incompletely understood.

The significance of blood volumes, infection, continuing hemorrhage, the

anatomic location of the injury, and the limitations of analgesic and anesthetic

agents was not fully appreciated although all these subjects had been understood in seemingly adequate manner.

The brunt of this lack of information and training in U. S. Forces was

carried by the Medical Service of the North African and later the Mediterranean Theater. Until June 1944, when their forward medical service was

organized to study the severely wounded, they were the only theaters with

sizable numbers of ground troops steadily in contact with the enemy. For

nearly years they experienced battle casualties at rates almost continuously

above 50 per 1,000 per annum, and for nearly 10 months of this period

their battle casualties were above 100 per 1,000 per annum. The ingenuity,

resourcefulness, and thoroughness with which Medical Department personnel

performed under these trying circumstances are exemplified by the work

of the individuals of the MTO Board for the Study of the Severely Wounded

and the progressive steps taken by them to initiate their studies without

special provision or support.

The Board’s studies on human casualties under battle conditions contributed much information of immediate practical value for the handling

of wounded as well as pointed the way for many basic studies required for
VI

the future. The data were accumulated under the rigors of field conditions,

at times under fire, and the work was often begun in the shock tents few

minutes after wounded subject fell. This research was unique for American

Forces during World War II and provided information on the resuscitation

and treatment of the severely wounded that cannot be procured from any

other source. Aside from its significance as contribution to medical knowledge, this report must stand as tribute to the men who showed that it

could be done.

GEORGE E. ARMSTRONG

Major General, U. S. Army

The Surgeon General
Preface

On September 1944, the Commanding General, North African Theater

of Operations, appointed Medical Board to Study the Treatment of the

Severely Wounded, his action following by only two days recommendation

by the Surgeon of that theater that such board be appointed. Appendix

includes the Surgeon’s communication and the order appointing the Board,

together with data concerning its organization and operation.

Each of the authors of this volume was member of the Board as formally

established. Before that time several of us had been interested individually

in various aspects of the physiologic and pathologic changes in the severely

wounded, and the chapters of this volume include our observations both as

members of the Board and as individual investigators. The background against

which the study was undertaken is described fully in the Introduction.

At the time this study began, our attention was focused in considerable

part on anuria in the wounded. This interest continued, but it early became

apparent that to limit ourselves to the study of anuria was undesirable and

actually impossible. Thus at the end of the work we have found, almost

inevitably, that what we have is kind of physiologic atlas of the severely

wounded. In producing it we have followed the trend that medicine as

whole has taken: Probably there are few new things to be learned in studies

of gross morphology, but certainly much remains to be found in the domain

of function. So too it may be with the wounds of battle. They have already

been accurately described in terms of structural loss, but there are great

deficiencies in our knowledge of the effects of wounds on the function of

organs. If this study has contributed in useful way toward filling these

gaps, our effort will have been justified.

The several chapters of this volume have been written by the member

or members of the Board responsible for those particular phases of the investigation. The aim has been to present factual observations, with minimum

of essential supplementary remarks to orient the reader. We have, there-
fore, in most instances deliberately avoided detailed discussion of the data.

Many of the findings were provocative to us, and we hope they will be to

others; in any event the mass of data accumulated in this battlefront study

provides basis for contemplation and further work. From these data the

reader who may differ with our views can construct his own and perhaps

more accurate interpretations and conclusions.

For those who have not had similar experience, it may be difficult to

judge which things caused trouble during the course of the work and which

were not important. Of real importance were the winds that blew some

tents down, split others, upset stoves, knocked bottles off shelves, and stirred

up endless clouds of dust that swirled around our hilltop at Monghidoro

and invaded the laboratory. The rain and mud were unpleasant but not of

real consequence until the dampness began to interfere with the spectrophotometer. When we were up in the Apennines, water froze and the cold

at night caused solutions to alter and saturated solutions to crystallize out.

Troublesome as these things were, they were overcome either by waiting

until the environmental conditions had improved, or by the ingenuity of our

technicians.

Supplies and equipment needed for our studies were for the most part

delivered promptly and'in adequate quantity but occasionally delays in arrival

of items influenced the progress of our observations. In only two instances

was absence of supplies of material consequence. We never succeeded in

obtaining equipment to make desired oxygen determinations, and materials

for renal clearance studies arrived so late that only few cases could be studied.

Although the spectacular “artificial moonlight” produced by great floodlights reflected from clouds lighted up the out-of-doors at night and was

much used in the months of the Northern Apennines Campaign, we never

escaped from the necessity of working in blacked-out tents, and in poorly

lighted tents it was easy to overlook cyanosis or icterus.

The major consideration at all times was that our studies must not delay

or otherwise interfere with the treatment of the wounded soldier. The necessity of not interfering with the therapy due the wounded man was important.

The patient’s good came first; it was trying but necessary sometimes to let

observations go, knowing that an unfortunate shortcoming would be present

in the case under study. During periods of heavy action, when the cases

best suited for study were coming in, the man covering the shock tent needed all the maneuvering skill of combat pilot to keep out of the way of those
IX

responsible for the care of the wounded man. At times he failed, all of us

failed, to get the observations needed for completeness.

Sometimes patient would be accessible to us for only few hours and

then would be evacuated to the rear, never to be seen again. Most of the

patients were followed into the postoperative period, but some were evacuated at, for our purposes, their most enlightening stage, or sometimes, because

of the tactical situation, we were obliged to move forward or back and

leave them.

We realize that those accustomed to working in the atmosphere of leisure

and with the laboratory facilities of peacetime can find much to criticize here. We

had to get what we could when we could, and record it “on the go.” Our

observations are published as recorded at the time and without later attempt

to identify and compare individual cases in all the various aspects of the

study. It will be readily appreciated that identical data could not be obtained

on all cases. We present the results without apology. Moreover, we believe

that what we were able to do indicates the soundness of our attempt to study

the wounded in the line of combat where they fell.

Finally, we are bound to acknowledge the extraordinary spirit of the

newly wounded, those with whom we dealt. They did all they could to help

us in this work.

HENRY K. BEECHER, M.D. (Formerly Consultant in Resuscitation and Anesthesia, North

African-Mediterranean Theater of

Operations)

Boston, Massachusetts

23 February 1952

Contents

Page

FOREWORD

PREFACE vii

INTRODUCTION

Chapter

INTERNAL STATE OF SEVERELY WOUNDED MEN ON ENTRY

TO THE MOST FORWARD HOSPITAL 21

II LIVER FUNCTION IN THE SEVERELY WOUNDED 75

III RENAL FUNCTION IN THE SEVERELY WOUNDED 90

IV DIAGNOSIS OF LOWER NEPHRON NEPHROSIS RESULTING

FROM TRAUMA AND SHOCK (“SHOCK KIDNEY”): CLINICOPATHOLOGIC CORRELATION no

CLINICAL, PHYSIOLOGIC, AND BIOCHEMIC CORRELATION IN

LOWER NEPHRON NEPHROSIS 121

VI TREATMENT OF LOWER NEPHRON NEPHROSIS 184

VII EFFECT OF ALKALIS IN TREATMENT OF TRAUMATIC SHOCK 194

VIII PIGMENT MOBILIZATION IN SEVERELY WOUNDED MEN 201

IX PATHOLOGY OF THE KIDNEY IN TRAUMATIC SHOCK ...

224

SULFONAMIDES IN RELATION TO “SHOCK KIDNEY” ....

249

XI THE CRUSH SYNDROME IN BATTLE CASUALTIES 255

XII GENERAL PATHOLOGY OF TRAUMATIC SHOCK 283

Appendixes

ORGANIZATION AND OPERATION OF THE BOARD FOR THE

STUDY OF THE SEVERELY WOUNDED 307

THE FIELD LABORATORY 315

BIOCHEMIC METHODS 323

SURVEY OF CASE RECORDS 359

INDEX 369

The Physiologic Effects of Wounds

Introduction

report is spread that there is, in some country or other, giant as big as

mountain; and men presently fall to hot disputing concerning the precise length

of his nose, the breadth of his thumb, and other particulars, and anathematize

each other for heterodoxy of belief concerning them. In the midst of all, if some

bold sceptic ventures to hint doubt as to the existence of this giant, all are

ready to join against him, and tear him to pieces.—Attributed to Voltaire

Shock—the Background

Although warriors have died of their wounds from the beginning of time,

the first scientific approach to an analysis of how and why they die was

made during World War I. In that war the wound surgeon lifted his eyes

from the shattered limb to inquire with some degree of precision about the

nature of the processes that wound may initiate in the body as whole.

Because, even if the limb were amputated and every organ of the body was

sound, death was likely to occur as the terminal event of profound disturbance known as wound shock.

World War revealed wound shock as complex problem. Its nature

was not solved nor were sufficient observational data accumulated to permit

clear identification and subsequent analysis. Certain pre-existing hypotheses

(vasomotor exhaustion, acapnia, adrenal exhaustion) were discredited, but

other concepts inadequately supported by facts (traumatic toxemia, the distinction between shock and hemorrhage) were substituted. These concepts

centered on wound shock as an entity not accounted for by hemorrhage,

infection, brain injury, blast, asphyxia of cardiorespiratory origin, fat embolism, or any other clearly demonstrable lethal effect of trauma. World War

thus recognized problem of shock but left it wrapped in mystery.

At the end of World War the so-called shock problem was transferred

to the experimental laboratories of medical science. Attempts were made to

resolve it by physiologic and chemical techniques under wide variety of

experimentally induced circumstances. As the methods of initiating experimental shock were multiplied, the term itself became broadened, so that it
THE PHYSIOLOGIC EFFECTS OF WOUNDS

included number of processes that appeared to have one feature in common

—a reduced effective volume flow of blood with inadequacy of the peripheral

circulation and resulting tissue asphyxia. In the clinic as well as the laboratory, shock became separated from wounds, and “medical shock,” “obstetrical

shock,” “burn shock,” “shock due to infection,” and other types were

described as entities. So-called shock became synonymous with the process of

dying from almost any cause unless death was practically instantaneous or, as

Henderson stated, “unless one is burned alive.” The phrase, “the problems of

shocks,” was used by Mann to describe this confusion of definition.

In the welter of animal experimentation during and after World War

there were certain findings pertinent to the original problem. Bayliss and

Cannon had imitated wound shock by crushing and lacerating the thigh

muscles of anesthetized animals. This was supposed to produce destruction

of tissue but not very great extravasation of blood. Failure to measure

the factor of blood and fluid loss in the local area of trauma (and, as shown

later, failure to recognize the superimposed clostridial infection) enabled

Cannon and other experimenters to propose that toxic products of tissue

disintegration were absorbed into the general circulation, causing what was

termed traumatic toxemia. Parsons, Parsons and Phemister, and Blalock

measured the local blood and fluid loss in traumatized legs by precise methods

and showed that it was far greater than had been suspected and quite

sufficient to account for the reduction in blood volume observed.

It was thus made clear that estimation of the amount of hemorrhage

in an injured man must include the blood extravasated into the tissues as

well as that poured on the ground or caught by the dressings. It was also

found necessary to consider the blood volume that remained in circulation

Henderson, Y.: Fundamentals of asphyxia. J.A.M.A. 101: 261-266, July 22, 1933.

Mann, F. C.; In Bulletin on Shock, minutes of third meeting of Subcommittee on Shock, Division of

Medical Sciences, National Research Council, 18 May 1942, p. 117.

Bayliss, W. M., and Cannon, W. B.; Sections IV, V, and VI in Report VIII, Traumatic Toxaemia as

Factor in Shock, Special Report Series, No. 26, Medical Research Committee. London, H. M. Stationery

Office, 1919.

Cannon, W. B.: Traumatic Shock. New York, D. Appleton and Co., 1923.

Parsons, E.: Experimental shock and hemorrhage. Tr. A. Resid. ex-Resid. Physicians, Mayo Clin.

(1929) 10: 106-108, 1930.

Parsons, E., and Phemister, D. B.: Haemorrhage and “shock” in traumatized limbs; experimental

study. Surg., Gynec. Obst. 51: 196-207, Aug. 1930.

Blalock, A.: Experimental shock; the cause of the low blood pressure produced by muscle injury.

Arch. Surg. 20: 959-996, June 1930.
INTRODUCTION

in terms of plasma and red cells, for the proportionate loss of these elements

varied under different circumstances. The phenomena of hemoconcentration

and hemodilution were thus made understandable. Nevertheless certain investigators insisted on using the physical state of the blood to define shock

as an entity, and confusion was introduced by proponents of the thesis that

shock could not exist unless hemoconcentration was present.

In critical review of the shock problem in 1942, Wiggers commented

that contributions to the literature on shock appeared to be directed toward

the support of one or another favored theory. Experimental conditions, he

stated, had not been carefully evaluated and conclusions, rather than facts,

were emphasized. “Beneficial effects,” Wiggers said, “are claimed for various

forms of therapy in instances in which it was never shown that the subjects

were in state of shock which would have proved fatal without treatment.”

Obvious loss of blood (hemorrhage), or plasma (burns), or water and

electrolytes (dehydration), or all elements (trauma) were generally accepted

as clearly recognized initiating factors in shock. Beyond these, however, experimenters continued to search for other mechanisms by which the volume

of blood returned to the heart might be reduced. Belief in generalized

increase in capillary permeability, concept introduced with “traumatic

toxemia,” held sway for years, and many investigators insisted that this, and

only this, accounted for the “true” shock that had been witnessed in World

War I.

Analysis of the course of events in progressive circulatory failure was

pressed in the attempt to identify and define phase-line that ushered in

what was called an “irreversible” state. It had been claimed in World War

that the seriously wounded could be resuscitated by appropriate measures

if their condition was attributable to hemorrhage alone, but that if profound

shock had been superimposed on hemorrhage or had appeared independently

of hemorrhage, all measures, including blood transfusion, were futile. The

term “irreversible” was used by some with specific reference to the function

of tissues or the closely linked processes of intermediary metabolism. It was

used in this sense by the Subcommittee on Shock of the National Research

Wiggers, C. J.: The present status of the shock problem. Physiol. Rev. 22; 74-123, Jan. 1942.

Subcommittee on Shock, Committee on Surgery, Division of Medical Sciences, National Research

Council: Shock, p. xxi (Preface). In National Research Council, Division of Medical Sciences.

Burns, Shock, Wound Healing and Vascular Injuries. Military Surgical Manuals, vol. V. Philadelphia,

W. B. Saunders, 1943.

956507 0—52
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Council: the process of shock brings about certain changes in the

function of the tissues which, after time, become irreversible.”

By others the term “irreversible” was applied to the dynamics of the circulatory system itself. It was held that at some point in the deterioration of

the organism in shock the circulatory failure became irreversible and the

subject displayed this change by becoming nonreactive to transfusion. “Apparently,” as Wiggers 10 wrote, “at certain stage an adequate circulation

cannot be restored by merely filling the system as one does an automobile

radiator.” The same writer expressed his surprise at “how well tissues or

organs withstand very low rate of blood flow before they cease to function

or are unable to revive.”

Thus the assumption was made that at one moment restoration of blood

volume could stay the progress of death, but in the next moment it would

be unable to do so. It seemed reasonable to believe that if this phase-line

could be identified by experiment and an analysis be made of the physiologic processes then in motion, corrective measures might suggest themselves.

But even under precisely controlled laboratory experimentation, minor variations in conditions may determine whether the animal lives or dies. Subtle

differences in environmental temperature, anesthetic agents, age, and previous nutritional state of the subject, as well as other conditioning factors

make it difficult to halt the cinema of life at particular frame where one

may say: Up to this point continuing life is possible—beyond this, death is

inevitable. If difficult in precise experimentation, identification of the onset

of irreversible shock becomes impossible when one is confronted by the

results of the random trauma sustained by soldiers under combat conditions.

Although the diagnosis of “irreversible shock” appeared with some frequency

on the clinical records in World War II, it was merely pretentious way of

indicating that the man had died of lethal wound.

This, then, was the background of our knowledge of wound shock when

World War II began. It was entered with the concept that (i) plasma to

restore the bulk of the blood in the intravascular space and (2) sodium chloride

solution for dehydration and electrolyte depletion of the interstitial space were

therapeutic measures adequate to the purpose of adjusting homeostasis in

wounded man. As the war progressed, this concept changed. It soon became clear that much precise information about the physiologic state of wounded 10 See footnote 8.
INTRODUCTION

man was wanting, and efforts toward this end culminated in establishment

of the Board for the Study of the Severely Wounded in the Mediterranean

Theater of Operations. The chronology of events leading to better understanding of the disturbed physiology of the severely wounded and their management in World War II may be traced through several phases, beginning

with the preliminary one of planning for the treatment of shock.

iS/lanagement of Severely Wounded in World War II

Preliminary Planning for Treatment of Shock

The first problem encountered in the combat area was the need for

whole blood transfusion, for while plasma was in plentiful supply, it proved

inadequate for the purposes envisioned. An extract from “Report on the

Activities of the Surgical Section of the 77th Evacuation Hospital,” dated

10 December 1942, provides baseline for review of the planning for the

treatment of shock in World War II. This unit shipped from England with

Torch Forces and entered on the landing at Oran.

The W.I.A. [wounded in action] had for the most part either succumbed to or

recovered from any existing shock before we saw them. However, later traumatic cases

came to us in shock and some of the early cases were found to be in need of whole blood

transfusions. There was plenty of reconstituted blood plasma available. However, some

cases, particularly those with large blood loss, were in dire need of whole blood. We had

no transfusion sets, although such are readily available in the United States, no sodium

citrate, no sterile distilled water, and no blood donors. Transfusion bottles were borrowed

from the British, sodium citrate was purchased from French pharmacy, water still

appeared from some unexplained source, our enlisted men who had been working long

hours volunteered as donors, and whole blood transfusions were given. It would seem that

there is grave need of provision for whole blood at the locality and time of definitive

treatment.

The initial decision to rely on plasma rather than blood transfusion for

the resuscitation of the wounded appears to have been based in part on the

view held in the Office of The Surgeon General of the Army, and in part

on the opinion of the eminent civilian investigators summoned by the National Research Council to act as advisers to the Armed Forces. The Committee on Transfusions first met on 31 May 1940. The Army representative

made the following statement: “If the theaters of operations are mostly

outside the United States the Army would likely discourage the use pf
THE PHYSIOLOGIC EFFECTS OF WOUNDS

blood banks. If war should come closer they might want to use blood that

could be transported by airplane or specially devised refrigeration. In more

distant places where blood could not be collected locally, plasma, either plain

or dried, would have to be used.” The representative of the Navy also favored

“dried blood” (plasma).

The following is quoted from report of the meeting submitted to the

Chairman of the Committee on Surgery, National Research Council, under

date of 24 July 1940:

The greater part of the day was devoted to consideration of whole blood and blood

plasma and blood serum transfusions. The consensus of opinion was that the greatest

emphasis should be placed on the use of blood plasma for the following reasons; (1) Most

instances of shock are associated with hemoconcentration and given quantity of plasma

is more effective than an equal quantity of whole blood in treatment; (2) blood plasma

is approximately as effective in the treatment of hemorrhage as is whole blood; (3) the

difficulties of preservability and transportability of plasma are considerably less than those

of whole blood; and (4) matching and typing are not necessary when pooled plasma

(suppression of iso-agglutinins) is used.

The last two reasons given may have been concessions to the position

taken by the representatives of the Army and Navy; the first two, however,

appear to reflect the prevailing concept of wound shock held by experts at

that time. The efficacy of blood in the treatment of hemorrhage had been

established in World War I. In small quantities it had been preserved and

transported considerable distances, even up to regimental aid posts. It had

been recorded that “in cases of profound shock accompanied by loss of blood,

excellent results are obtained from direct blood transfusion.”11 Robertson 12

had cast doubt on the efficacy of various fluids used as “substitutes” for blood

in World War (gum acacia, gelatin) and called attention to the fact that

their beneficial effects were often slight. “The only means available of increasing the oxygen-carrying power of the blood is the addition of new red blood

cells,” he had said. “This constitutes the unique value of blood transfusion.”

Whole blood transfusion also had become universally employed in surgery

in civil life.

It is of real interest, therefore, to inquire into the process of reasoning

11 Fraser, J., and Cowell, E. M.: clinical study of the blood pressure in wound conditions. Report

II, sec. i, Special Report Series, No. 25, Medical Research Committee. London, H. M. Stationery Office,

1919, p. 49-71.

Robertson, O. H.: Memorandum on blood transfusion. Report IV, Special Report Series, No. 25,

Medical Research Committee. London, H. M. Stationery Office, 1919, p. 143-180.
INTRODUCTION

that led the Committee on Transfusions of the National Research Council

to take the position that “most instances of shock are associated with hemoconcentration and given quantity of plasma is more effective than an equal

quantity of whole blood in treatment.” This concept can be traced back to

observations on the wounded made in World War by Cannon, Fraser,

and Hooper 13

who reported that counts of red cells in blood taken from

the capillary bed were high, particularly when compared with those of venous

blood. This also was keystone in the establishment of shock as an entity

distinct from hemorrhage and led to the widely accepted hypothesis of

generalized increase in capillary permeability. “Hemoconcentration was found

to furnish practical means for differentiating shock from hemorrhage, but

the enormous potential value of this sign was not comprehended by the

members of the Special Committee on Wound Shock nor has it been sensed

by physicians during the 20 years since that time,” wrote Moon 14 in 1938. The manual on shock (1943), prepared under the auspices of the Committee on Surgery of the Division of Medical Sciences of the National Research Council, also set forth this erroneous concept.

The other statement of the Committee on Transfusions, namely, that

“blood plasma is approximately as effective in the treatment of hemorrhage

as is whole blood,” appears to have found origin in conclusions drawn from

laboratory experiments that were purposely designed so that the number of

variables could be rigidly limited. Transference of these conclusions to

situation that introduced number of additional variables was an error of

human reasoning. An example may be found in the widely quoted experiments of Rous and Wilson 10

(1918). These authors made precise determination of the limits within which plasma may replace the loss of whole blood

in acute hemorrhage induced in rabbits. In summarizing the results of their

experiments these authors stated that “however desirable transfusion may be,

it is not essential to recovery from even the severest acute hemorrhage, if

13 Cannon, W. B.; Fraser, J., and Hooper, A. N.: Some alterations in the distribution and character

of the blood. Report II, sec. 2, Special Report Series, No. 25, Medical Research Committee. London, H. M.

Stationery Office, 1919, p. 72-84. 14 Moon, V. H.: Shock and Related Capillary Phenomena. New York, Oxford University Press, 1938. 15 National Research Council, Division of Medical Sciences. Burns, Shock, Wound Healing and

Vascular Injuries, prepared under the auspices of the Committee on Surgery of the Division of Medical

Sciences of the National Research Council. Military Surgical Manuals, vol. V. Philadelphia, W. B. Saunders

Co., 1943.

14 Rous, P., and Wilson, G. W.: Fluid substitutes for transfusion after hemorrhage. J.A.M.A. 70:

219-222, Jan. 26,1918.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

only the blood bulk can be restored in other ways.” The conclusion drawn

from this and subsequent observations by others 17 led to formulation of the

statement by the Committee on Transfusions. The brief description of

rabbit in which up to three-fourths of the blood volume, as measured by the

hemoglobin depletion, had been withdrawn and replaced by plasma contains one phrase that is significant; “The least exertion would cause the

animal to pant heavily.”

Presumably the rabbit had no semblance of wound other than the

needle puncture. Substitute for the rabbit housed quietly in its cage wounded

soldier picked up by litter bearers and transported by ambulance, who has

in addition an extensive and painful wound with continuing extravasation

of blood and plasma into adjacent tissues. Then add sedation, roentgenographic examination, anesthesia, and surgical operation with further loss

of blood. It is obvious that the introduction of these and other variables,

purposely and of necessity excluded from the original experiments, may

completely negate the conclusion. Both errors, the association of wound shock

with hemoconcentration and the estimation regarding the effectiveness of

blood plasma, are understandable in view of the paucity of observations made

in World War concerning the disturbed physiology of wounded men.

Restoration of the blood bulk in the intravascular space by infusion of

colloid solution that might be expected to stay within the confines of the semipermeable membrane of the capillary walls was envisioned during World

War I. This was projection of the Starling 18

concept elaborated by Scott 19

in 1916. Tests were made of the properties of soluble starch, dextrin, gelatin,

and gum arabic, and preparations of the latter were given extensive field tests,

particularly by the British, guided by the basic experiments of Bayliss. 20

The advent of human plasma, as result of the development of methods

that enabled it to be preserved and packaged in desiccated form, appeared

to provide final answer to the problem of the restoration of blood bulk by

infusion. The treatment of shock and hemorrhage was thus reduced to the

simple terms of the exchange of fluid between the intravascular space and

17 Bayliss, (see footnote 20) for example, had shown that “more than one-half of the blood in the cat

can be replaced by gum solutions with satisfactory results.” 18 Starling, E. H.: On the absorption of fluids from the connective tissue spaces. J. Physiol. 19: 312-326,

May 1896.

19

Scott, F. H.: The mechanism of fluid absorption from tissue spaces. J. Physiol. 50: 157-167, Feb. 1916. 20 Bayliss, W. M.: Intravenous injections to replace blood. Report I, Special Report Series, No. 25,

Medical Research Committee. London, H. M. Stationery Office, 1919, p. 11-41.
INTRODUCTION

the interstitial space under clearly defined physicochemical laws. Extension

of this same reasoning led to the proposal that because the serum albumin

fraction of the blood as prepared by Cohn21 packaged high proportion

of the total colloid osmotic activity of the serum in small liquid volume, it

was peculiarly appropriate to military needs. It was postulated that the interstitial fluid compartment would provide the necessary diluent unless the

patient were badly dehydrated.

This oversimplified physicochemical approach, which was an extension

of the World War quest of Bayliss aided by the availability of refined

and human-derived preparations, not only failed to take into account the

variables described, but also placed undue emphasis on single physicochemical property of the blood; namely, the osmotic activity of the plasma

proteins. Not only was the important function of the red cells as oxygen

carriers ignored, but also their contribution to the total blood mass under

abnormal circumstances. Both the magnitude of the initial loss of whole

blood occasioned by wounding and the significance of continuing seepage

of blood and its fluid components into the tissue spaces were underestimated.

And finally, an effort to restore and maintain blood bulk based on colloid

preparations, either derived from human proteins or otherwise, presupposes

space bounded by semipermeable membrane—not one in which large

areas of the membrane may have been rendered freely permeable by the direct

effects of trauma.

Evolution of Knowledge During World War II

The evolution of the management of the seriously wounded during World

War II may be divided into three phases for purposes of description, although

it is apparent that as phases they are not pencilled with the clarity observed

in phase-lines on tactical map. first phase may be recognized in which

efforts to identify the gross nature of the problems and devise immediate

solutions predominate. Cobwebs of theory and hypothesis were swept away

by simple observations and precise definitions. This was followed by phase

during which all efforts centered on the development and perfection of the

practical art of resuscitation. In the final phase systematic and precise meas21 Cohn, Edwin J. Memorandum on the preparation of normal human serum albumin. Report No. i,

Subcommittee on Blood Substitutes, Division of Medical Sciences, National Research Council (acting for

Committee on Medical Research, Office of Scientific Research and Development), February 1942.
10 THE PHYSIOLOGIC EFFECTS OF WOUNDS

urements were made that for the first time described the actual physiologic

state of the wounded man as it was observed on the field of battle.

search among the records of World War II for novel and challenging

hypotheses regarding the nature of shock is likely to prove disappointing.

The very abundance of facts and experience discouraged “hot disputing” and

debate. And yet from this experience emerged certain concepts that, when

fully grasped, will be found no less significant because they appear simple

and direct.

First Phase: Identification of the Problem

Although in retrospect the North African Campaign was but brief

curtain raiser for the sustained action that was to come later, it stands historically as period in which the major problems of the management of

the wounded were clearly identified. The campaign was over before many

needs of the military organization could be met, but the foundation for future

action was secured.

The Surgical Consultant, North African Theater of Operations (U. S. A.),

reported for duty in Algiers on March 1943. His first official report, submitted under date of 24 March 1943, following period of temporary duty

in II Corps on the southern Tunisian front, was Memorandum on whole

blood transfusion. Further data were collected and formal report on whole

blood transfusion was made to the Theater Surgeon, NATOUSA, on 16 April

1943. The following conclusions and recommendations were made.

Conclusions

a. There is need for whole blood transfusion in the treatment of significant proportion of the wounded. Plasma is not an adequate substitute in these cases.

b. Adequate and conventional safeguards that govern blood transfusion are difficult

or impossible to attain in forward echelons.

c. The British Base Transfusion Unit has demonstrated the feasibility of supplying

large amounts of whole blood to the combat area.

Recommendation

That central laboratory be established in NATOUSA to provide whole blood, intravenous solutions, distilled water, and plasma.

The Italian Campaign had progressed to the establishment of the Anzio

Beachhead before the distribution of preserved blood from central laboratory
INTRODUCTION

was realized. In the meantime, however, the evacuation hospitals and later

the field hospitals employed for forward emergency surgery were encouraged

to establish their own blood banks with supplies requisitioned for that purpose.

Following this decision on therapy, the next important question that faced

the Surgical Consultant in southern Tunisia in March and April 1943 was

whether casualties were dying of irreversible shock—in fact, whether wound

shock, unassociated with hemorrhage and other clear results of trauma, existed

as an important problem in World War II. It was obvious that precise definition was necessary if this question was to be answered, for, as was noted

in the Report of the Surgical Consultant dated July 1943:

In Field Medical Records, Case Reports, and Death Reports, as well as in verbal

discussions among Medical Officers, the term “shock” is used with vague definition or

quite commonly with no definition whatsoever. In the case reports of battle casualties dying

in the forward area, “shock” or “irreversible shock” is almost invariably recorded as

secondary cause of death. This is true whether the wounded man had lethal craniocerebral wound, an overwhelming peritonitis, fulminating gas gangrene infection, or simply

died of uncontrollable hemorrhage.

Circulatory failures from peritonitis, bacterial infection, intrathoracic injury, burns, and injury to the central nervous system were placed in separate

categories. All other forms of circulatory failure which arise within few

hours as result of wounding were considered as “wound shock.” 22 study

was undertaken that covered the course of the evacuation of some 1,263

casualties from the battalion areas through the evacuation hospitals. No record

could be found of death from wound shock under terms of the restricted

definition, in which hemorrhage could be excluded as the important factor.

The conclusions drawn from this study as well as from direct observation of

large numbers of wounded were expressed as follows: 23

Under conditions that prevailed in the management of battle casualties between 20

and 25 March in the sampling area of II Corps, wound shock was not cause of death.

This does not imply that wound shock did not occur among the survivors, but if so it

appears that remedial treatment was adequate.

22 The Battle ofEl Alamein (October and November 1942) was one of the first occasions on which blood

and blood substitutes were used on large scale for the resuscitation of battle casualties in forward medical

units. Report No. 1, Medical Research Section, GHQ, MEF, by Lt. Col. W. C. Wilson, RAMC, described the

condition of the wounded with special reference to wound shock and its treatment. The necessity for the

restricted definition of wound shock was presented with great clarity. 23 Report of Surgical Consultant, Office of the Surgeon, Headquarters, North African Theater of Operations, U.S.A., July 1943. (Appendix B, 1;Par. B, 2.)
12 THE PHYSIOLOGIC EFFECTS OF WOUNDS

“Irreversible” wound shock does not appear to be problem of pressing significance.

The problem of shock as observed in the Tunisian Campaign centered in the application of accepted means of treatment, rather than in the need for additional methods of

management.

Second Phase: Development of Resuscitation

The second phase in the advancement of understanding of the management of the seriously wounded was development and perfection of the practical art of resuscitation. The many experienced surgeons of the Theater

contributed to and shared the responsibilities of Theater-wide educational

program. Special acknowledgment is made of the contributions of Colonel

Howard Snyder, Surgical Consultant to II Corps and subsequently to Fifth

Army, and of Lt. Colonel Henry K. Beecher, assigned to AFHQ as Consultant in Resuscitation and Anesthesia and working on temporary duty in

the forward installations. Simple and direct observations made while actually

caring for battle casualties confirmed the conclusions of the Tunisian Campaign and led to the complete discard of the confused theories of traumatic

shock that had been elaborated from the experience of World War I.

highly significant product of the development of the art of resuscitation

was merging of consideration of shock with consideration of the implications

of the wound. Historically, wound surgery has been linked with the prevention and treatment of infection, and, as matter of fact, in the less

seriously wounded this function of surgery still is predominant. In World

War II this concept was modified, as it was not applicable to the many

desperately wounded casualties that came under surgical management. It was

no longer valid to hold that seriously wounded man could be resuscitated

solely by measures directed toward restoring blood volume, and that when

this was accomplished wound surgery could be undertaken, depending only

on the time necessary for prevention of infection. Wound surgery under these

circumstances assumed the new position of being in itself the climax of

resuscitation. General recognition of the principle that procedures commonly

grouped as “resuscitative” are but integral steps in the management of

situation that must be viewed as whole, and that wound surgery may in

itself be the most potent act of resuscitation, stands as basic achievement

of military surgery in World War II.

This concept was glimpsed in the Tunisian Campaign and led to the
INTRODUCTION

following comment in the official report of the Surgical Consultant dated

July 1943:

Resuscitation comes to be regarded as sub-specialty of military surgery and as such

becomes goal in itself. One central fact must be kept in mind and, although it appears

obvious, it is often overlooked both in theory and practice. wounded man is resuscitated

not only to save life but to prepare him for necessary surgery.

This divorce of surgeon from shock is disquieting outgrowth of the war that cannot

be too strongly condemned. Resuscitation in every case being prepared for operation is an

integral part of the surgical management of trauma and must “remain so if optimal results

are to be achieved.

The concept was more fully developed during the Italian Campaign by

Lt. Colonel Henry K. Beecher24 who presented the following broad definition of resuscitation that includes operation as an essential component:

The enemy has produced the worst wound he could, and its consequences are cumulative—dehydration increased by unusual fluid loss in sweat and vomitus, continuing

hemorrhage or plasma loss, pain making rest impossible, increasing emotional exhaustion,

developing infection—these and other factors are set in operation by the initial wound.

Their progress in the seriously wounded is to be checked in most cases only by surgery

or by death. Resuscitative measures give temporary stay and make successful surgery

possible in the severely wounded; but in most cases true release from the consequences of

the wound is effected only by surgery. Surgery is not only the goal but is itself part of

resuscitation in the broad sense. Any other view is likely to lead to unfortunate separation

between the activities of the “shock team” and those of the surgical team. Care of the

wounded man must be continuous and supervision uninterrupted.

This concept now appears obvious, and in fact is principle soon grasped

by the practical worker in the field. It is likely to be overlooked when conclusions are drawn from laboratory experiments purposely designed to isolate

and test the efficacy of single therapeutic measures.

The establishment of wound surgery as inseparable from the management

of wound shock had many practical applications. It was strong consideration

in the placement of the surgical hospital for treatment of the severely wounded

alongside the divisional clearing station, as was determined in Sicily, short

litter carry placed the casualty in the hands of competent surgical team

equipped not only for resuscitation in the conventional sense but for the

major procedures of surgery. It led to the close observation of wounded

man’s response to blood replacement therapy. If the response was transient

24 Beecher, H. K.: Preparation of battle casualties for surgery. Ann. Surg. 121: 769-797, June 1945.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

or unsatisfactory, it was not judged that his shock was “irreversible” or that

he displayed “negative reaction” because of widespread capillary damage,

or that it was futile to try “to repair the damage done by prolonged oxygen

want.” It was assumed that either continuing hemorrhage or spreading infection was present, or that dead limb required amputation or dead tissue

called for excision; operation was immediately undertaken with continuing

transfusions to support the patient’s condition.

Another practical result was that resuscitative measures carried out in the

field, forward of surgical hospital, came to be regarded as temporary and

designed only to preserve life during transportation. They thus became both

qualitatively and quantitatively different from those combined with surgery.

It was necessary to rely on plasma as the chief measure to support the patient

during transport, but plasma was used in minimal amounts without intent

to restore the blood volume flow to normal level. The dangers of the

overuse of plasma became apparent. Resuscitation within the hospital included

use of additional plasma, whole blood, ancillary measures, such as bronchoscopy, oxygen therapy, and nerve block to relieve pain or to restore respiratory

effectiveness if crippled by the wound, and initial wound surgery.

Third Phase: Documentation by Scientific Evidence

By the summer of 1944 it was evident that although nearly two years of

experience had enabled the Theater to develop the procedures of resuscitation

to high peak of effectiveness, this was largely an accomplishment of the

practical art and remained to considerable extent undocumented by scientific evidence. If left in this status at the end of World War II, it would

tend to be forgotten, as are many other practical lessons that emerge from

the experience of war. Even the validity of the experience would be open

to question. Bayliss, 20

toward the end of World War I, had written: “On

the whole it is remarkable that so little positive evidence is forthcoming as

to the superiority of blood transfusions. Statements are made on the basis of

general impressions, rather than on convincing proof. In the nature of the

case, such proof would be difficult to provide.” The question was often asked

whether the experience in Italy was really accepted at face value and whether the precepts that had been formulated would be transferred to the conflict in

the Pacific and to civilian needs.

25 See footnote 20
INTRODUCTION

EARLY STUDIES

Some data of precise nature had been obtained, but they were of fragmentary nature, Lt. Colonel John D. Stewart, member of the Consulting

Surgical Staff of the Surgeon, NATOUSA, while on temporary duty with

the Fifth Army in December 1943, made arrangements with the Commanding Officer of the 2d Medical Laboratory, with the concurrence and support

of the Surgeon, Fifth Army, to conduct clinical study of the freshly

wounded. small mobile laboratory was set up at the 3d Platoon of the

nth Field Hospital on 20 January 1944. This platoon was situated near the

36th Divisional Clearing Station, northeast of Mignano, about seven miles

behind the front. The objective was to study by formal biochemic methods

certain aspects of shock, hemorrhage, and dehydration,

preliminary report was submitted under date of 17 March 1944. Observations had been made on some 35 badly wounded patients immediately after

admission, usually within 12 hours after wounding. final report of this

study, extended to include 100 desperately wounded observed during the first

months of 1944, was submitted on January 1945.26 The data indicated

(1) absence of hemoconcentration in shock, (2) reduction of blood volume

in shock, (3) greater reduction of red-cell concentration than of plasma protein concentration early after wounding, (4) lowering of both red-cell and

plasma protein concentration later, and (5) frequency of later dehydration.

During approximately the same period (n February through June 1944)

the Consultant in Anesthesia and Resuscitation, NATOUSA, and Captain

Charles H. Burnett carried out an extensive study 27 on the wounded at the

94th Evacuation Hospital, observing 557 cases on the Cassino Front (Mignano) and 2,296 cases on the Anzio Beachhead. In the latter site the position

of the evacuation hospital bore the same relation to the front as field

hospital. While the greatest significance of this contribution lay in formulating procedure for the clinical management of resuscitation in the seriously

wounded, in 37 of the most severely wounded fairly extensive laboratory observations were made. These confirmed the absence of hemoconcentration.

Starting in March 1944 in field hospital platoon, Captain Joseph J, Lalich,

26 Stewart, J. D.: Observations on the severely wounded in forward field hospitals of the Fifth Army,

with special reference to wound shock. Report to the Surgeon, Mediterranean Theater of Operations, U.S.A.,

Jan. 1945. Also, J.A.M.A. 133: 216-219, Jan. 25, 1947. 27 Beecher, H. K., and Burnett, C. H.: Field experience in use of blood and blood substitutes (plasma,

albumin) in seriously wounded men. M. Bull. North African Theat. Op. (no. 1) 2: 2-7, July 1944.
16 THE PHYSIOLOGIC EFFECTS OF WOUNDS

2d Auxiliary Surgical Group, carried out series of hematocrit and plasma

protein determinations by the copper sulfate method. His findings, like those

of the other workers, were quickly made available to forward surgeons and

were submitted as formal report on 12 November 1944. Attention was called

to the low hematocrit readings obtained from to days after initial surgery

despite the very liberal use of blood transfusions in resuscitation. This was

phenomenon that was exciting interest in the general hospitals in Peninsular

Base Section. For the success of the vigorous program of reparative wound

surgery that was being formulated, it was found necessary to provide for the

liberal use of whole blood transfusion at the base.

There was need, however, for far more comprehensive study. In the

opinion of the Medical Research Committee of the Theater there was little

doubt that the impetus of the tremendous program undertaken to provide

so-called “substitutes” for blood in World War II would be projected into

the postwar period. It might be revived with any threat of future war.

It was essential, therefore, that the so-called impressions derived from experience be documented by hard, cold facts about the condition of freshly

(wounded man. To this end, everything about seriously wounded soldier

that could be observed and recorded by precise measurement should be ascertained and recorded. The collection of data needed to be extended to sufficient number of casualties to make the findings conclusive.

ESTABLISHMENT OF BOARD FOR THE STUDY OF THE SEVERELY WOUNDED

The summer of 1944 in Italy was period of readjustment to meet the

over-all strategy of the war in Europe. Between mid-June and the end of July

more than division week was withdrawn from the forces to train and

stage for Operation Anvil, the attack in southern France executed on 15

August. Pursuit of the enemy to the north had brought the Allied armies

up against the “Gothic Line,” an elaborate defense system in the northern

Apennines. Then on 10 September general offensive was launched to break

through into the Po Valley. As it became apparent that the Medical Service

was to face renewed heavy flow of casualties, the Medical Research Committee sponsored certain fact-finding tasks that required concentrated and

carefully organized effort for accomplishment. One of these was further

analysis of the state of the seriously wounded.

More information was urgently needed regarding the problem of anuria.
INTRODUCTION 17

Kidney damage associated with crushing injuries sustained in air raids had

been described as component of the “crush syndrome” by Bywaters et al.28

early

in the war. Identification of damaged kidney function as component of injury in the soldier seriously wounded by flying missiles on the battlefield came

slowly, but experience had already suggested that it either was being overlooked or was subject to misinterpretation. Identification was slow because first

of all it requires the coordinated effort of wide variety of expert skills in the

forward area to rescue desperately wounded soldiers and keep them alive until

such time as suppression of kidney function manifests itself. This involves the

activity of the entire medical department from the company aid-man in the

field to the surgical team and nursing staff in mobile hospital. When

gravely wounded man dies within 48 hours of being hit, the chances are that

any suppression of kidney function will pass unrecognized.

In the N, R. C. Conference on Shock held on December 1943, Dr. Donald

D. Van Slyke had presented communication on the “Effect of Shock on the

Kidney.” The concept was developed that the peripheral vascular constriction

that compensated for deficit in the volume of circulating blood in shock may

practically stop the blood flow through the kidneys. Urinary excretion stops,

and prolonged ischemia may be followed by permanent suppression of renal

function. Although presented as hypothesis, this concept. brought fresh

point of view to clinical problem that was beginning to be identified in the

field. Under date of 16 February 1944, letter, from which the following extract is quoted, was addressed to Dr. Van Slyke by the Surgical Consultant.

By excellent forward surgery and the liberal use of whole blood transfusion as well

as plasma, we are saving lives but also keeping certain men alive temporarily only to

display the type of kidney damage you describe. This has been either complete anuria with

death, or in one case fall of urinary output to 200 cc. with ultimate recovery of kidney

function. As you suggest, this phenomenon is not unique to the “crush” syndrome but

may occur in any wounded man who experiences long period of greatly reduced volume

flow.

Delay in the identification of the problem of anuria in battle casualties was

not solely matter of organization or preoccupation with more pressing problems. Recognition of anuria depended on close check of fluid intake and

output, items that are difficult to secure even in well-run civilian hospitals.

28 Bywaters, E. G. L.; Delory, G. E.; Rimington, C., and Smiles, J.: Myohaemoglobin in urine of air

raid casualties with crushing injury. Biochem. J. 35; 1164-1168, 1941.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chemical tests for azotemia were not available in the mobile hospitals. The

terminal event of pulmonary edema from forcing fluids in order to correct

supposed dehydration was subject to misinterpretation as manifestation of

blast injury or other result of direct trauma to the lungs.

Even when suppression of urinary excretion was recognized, other causes

than the specific effects of the injury required exclusion. In the earlier phases

of the war medical officers were alerted to the effects of sulfonamide administration on the kidney. Early in 1944 the widespread usage of sulfonamides was

still making it difficult to clarify the problem of posttraumatic anuria. This

was referred to in the Annual Report of the Surgical Consultant (1943) as

follows: “Kidney damage is probably the most frequent and easily overlooked

sequel of shock and is manifested by anuria or reduced urinary output. Information relative to renal damage produced by decreased volume flow of blood

is particularly desired because of close linkage with policies on sulfonamide

therapy.”

Even more important, however, was the use of blood transfusion in resuscitation. The question arose again and again how often blood transfusion itself

might be responsible for kidney damage. To interpret posttraumatic anuria,

blood given in transfusion must meet rigid specifications. It must be compatible both in type and iso-agglutinin titer. It must be collected and stored in

closed system to avoid contamination. When supplied in bulk in military operation, frequent checks must be made for free hemoglobin content both at the

bank, in the forward hospital, and by examination of the recipients’ plasma

after transfusion.

With the increased use of transfusion in the forward area and the distribution of preserved whole blood from the central laboratory in Naples, the identification of posttraumatic anuria became tangled with that of “transfusion

kidney.” Informal requests came from Anzio Beachhead for distribution of

Type blood for massive transfusions in this type of recipient. The policy of

issuing only Type blood in which the iso-agglutinins had been titered was adhered to. Blood with titer 1:64 or above was labeled “for O-Type recipients

only”; that with weaker iso-agglutinin titer was considered suitable for universal use. The problems of poorly preserved or contaminated blood encountered

elsewhere in the field during World War II were not encountered in the U. S.

Army, Mediterranean Theater.
INTRODUCTION

The basic conditions outlined above had been established in Italy by late

summer in 1944. The medical department personnel were expert from long

experience; penicillin had replaced sulfonamides in the treatment of the seriously wounded; the Theater blood bank was issuing liberal supply of whole

blood that met the required specifications. The total situation, both military

and medical, was thus favorable for an intensive study of the seriously wounded

soldier. To this end, the Theater Surgeon recommended on September 1944

that Board to Study the Treatment of the Severely Wounded be appointed

by the Commanding General, NATOUSA. Such board was established on

September 1944 and it is the report of this Board which is presented in this

volume. In retrospect, it is doubtful that this particular effort would have been

feasible at an earlier date; even if undertaken it probably would not have been

as productive, for reasons that have been presented.

Selection of the personnel of this Board was matter of vital importance,

and the recommendations of his Medical Research Committee were generously

accepted by the Theater Surgeon. It was essential that medical officers be selected who were skilled in the techniques of clinical investigation that can be

utilized without harm or discomfort to seriously injured patients. Different

phases of the study required precise and critical observations in the laboratory,

in the ward tents, and in the operating tent. It was essential that the members

of the Board be familiar with the subjects to be studied—seriously wounded

soldiers. Those finally selected had long experience in identification of the

complex sequelae of wounds, and those in charge of the clinical aspects were

experts in the practical art of resuscitation. Further, and most important, all

had become expert in the art of overcoming, rather than being frustrated by,

the retarding element of “friction” ever present in huge military undertaking.

It is of more than passing interest to note that the minutes of the first meeting of the Committee on Transfusions of the National Research Council, already referred to, contain the suggestion “that group of men be allowed to

work in the Army, freed from any of the obligations of Army officers, who

would study cases of shock as investigators. This would give opportunity to

observe shock on big scale, an opportunity to get an insight into the nature

of shock.” This was on 31 May 1940. In May 1945, as the Germans in northern

Italy capitulated and brought the task of the Board to conclusion, this objective had been accomplished—not precisely as visualized, but effectively. The

956507 0—52
20 THE PHYSIOLOGIC EFFECTS OF WOUNDS

members of the Board were in no way “freed from any of the obligations of

Army officers,” but were, on the contrary, selected because they were competent to assume the highest privilege accorded officers—the freedom of individuarjudgment and action. They were not group that merely worked in the

Army”; they were of the Army.

EDWARD D. CHURCHILL, M.D.

(Formedy Colonel, MC, A.U.S., Surgical

Consultant, North African-Mediterranean

Theater of Operations)
CHAPTER

Internal State of Severely

Wounded Men on Entry to the Most

Forward Hospital

The effects on the human body of the destructive forces of warfare have

been described many times in terms of organic damage and tissue loss. Our

concern was rather with the internal state of the severely wounded man. Gross

tissue damage is obvious, or becomes obvious on surgical exploration, but our

purpose during the first phase of this investigation was to describe the latent

consequences of the wound as revealed in impairment of organic function and

in abnormalities of the blood and the urine. These initial studies were made

shortly after the patient entered the most forward field or evacuation hospital,

before either vigorous resuscitative measures or operation had yet been undertaken. The physiologic studies were continued, whenever possible, throughout

the patient’s course. Other aspects of the investigation as whole relate to diagnosis, treatment, and pathology of the severely wounded.

The very severely wounded (“nontransportable patients”) were those selected for study. They were the most critically wounded or injured battle casualties to reach forward hospital alive. With few exceptions, chiefly cases of

injury, the casualties studied were from the “wounded in action” group. The

cases are listed in Appendix D.

AR 40—1025, Sec V, par 79a, 12 Dec 44, sub: Definition [of injury]. “The term ‘injury’ is used

here in its broad sense to include such conditions as fractures, wounds, sprains, strains, dislocations, concussions, and compressions, commonly thought of as ‘accidents’ .”

ASF Manual 807, 25 Oct 44, Glossary. “Casualty (Personnel). soldier who is rendered unavailable

for service as result of disease, injury, or enemy action .”

AR 40-1025, Sec II, par 26, 12 Dec 44, sub: [Definition of] WIA (wounded in action) cases.

“The term will include wounds or injuries incurred as direct result of hostile act of military enemy.

It will not include injuries accidentally incurred while in combat, or those incurred on purely training

flights or missions.”
THE PHYSIOLOGIC EFFECTS OF WOUNDS 22

Table 1.—Time from Wounding to Surgery, Mediterranean

Theater of Operations

In all, 186 casualties were examined in the most forward hospitals by members of the Board. From previous studies made in the Theater, it was estimated

that of 10,073 battle casualties in the area to reach forward hospitals alive during the period of the study, between 201 and 252 were seriously wounded.

Hence the 186 studied here may be considered an adequate sample of the severely wounded in the Theater. One hundred and eight of these 186 casualties

were seen at the time of admission and were studied rather completely (including blood chemistry and urine analyses) at that time. Account was taken

of the nature and type of the wound, and also of the evacuation time, including the distance to be covered and the character of the terrain, since delay

along the evacuation trail, the reaction of the patient to his wound, and his

response to subsequent management all influence the factors under study and

increase the significance of the laboratory data.

In addition to the data obtained as background material, the initial studies

included determination of blood loss, of plasma protein and hemoglobin levels,

analysis of other biochemic changes encountered, initial kidney function studies, and study of liver function in the newly wounded man.

It will be observed in the tables and charts of this and following chapters

that different groups and varying numbers of patients have been drawn from

the total for consideration in given instances. This has been done because it

was often found in comparing two or more factors that records were incomplete for the specific comparison in question and had to be omitted. As reAverage Time in Hours

Source and Period

of

Collection

Number

of

Wounded

Wounding

to

Battalion

Aid Station

Battalion

Aid Station

to Collecting

Company

Collecting

Company to

Clearing

Station

North of Florence, Italy (September 1944 to March 1945) 100 2.68 2.95 1.98

Loiano, Italy (April 1945) 47 4.65 1.43 0.93

Via Reggio, Italy (March and

April 1945) 44 4.59 0.84 0.99
INTERNAL STATE ON ENTRY TO HOSPITAL 23

Table i.—Time from Wounding to Surgery, Mediterranean

Theater of Operations—Continued

suit comparatively small numbers of cases are presented in some instances. No

attempt has been made to keep the number of cases uniform in any of the

various phases of the study; rather we have presented all the data that were

complete for any one phase. This method was considered desirable because of

the nature of the study and the exigencies under which it was carried out.

In the tables throughout the study the standard error of the mean is shown

whenever the data were sufficient to warrant this method of statistical

treatment.

Initial Studies

Time from Wounding to Hospital

Entry and Surgery

Although some of the casualties were wounded near the forward hospitals,

the majority had to be transported some distance, often over mountainous terrain, by litter carry or motor transport. Since the time required to transport

patient from the place of wounding to the most forward hospital may greatly

influence his condition on arrival, some indication of the length of this period

in the Mediterranean Theater of Operations is given in Table 1, which shows

the average progress of three groups of casualties along the evacuation route.

The first group consists of 100 men selected at random from those in our study

Average Time in Hours

Source and Period

of

Collection

Number

of

Wounded

Clearing

Station to

Forward

Hospital

Forward

Hospital

Entry to

Operation

Total Time

from

Wounding to

Surgery

North of Florence, Italy (September 1944to March 1945) 100 1.41 5.38 14.40

Loiano, Italy (April 1945) 47 0.56 8.28 15.85

Via Reggio, Italy (March and

April 1945) 44 0.60 5.13 12.15
FORWARD HOSPITAL in Italy after rain {above). In evacuation by jeep, as shown

below, plasma could be administered during the trip, even over rough roads, but the terrain

in Italy often made all types of evacuation difficult and affected the condition of the patient

on his arrival at forward hospital.
INTERNAL STATE ON ENTRY TO HOSPITAL

who were wounded during relatively quiet period in the fall, winter, and

spring of 1944-45. The other two groups represent men who were severely

wounded during offensives in the spring of 1945. In the third locale cited, it

was contended by those concerned that, considering the circumstances, evacuation had been effected rapidly. The table also shows the average time from hospital admission to surgery and the total time from wounding to surgery in the

three groups.

Type and Location of Wounds

For various correlations throughout the study wounds are grouped according to their type, or location, or both. Many patients incurred multiple wounds,

some multiple major wounds. For certain purposes two broad classifications of

type were utilized: peripheral and nonperipheral, and this terminology will

be used whenever pertinent. Nonperipheral wounds were defined as those involving the major body cavities (the abdomen, the thorax, and the interior of

the skull); all others were considered as peripheral. Crush cases are excluded

in some of the correlations because they were studied separately.

In the following classification the severe wounds only are considered, since

they were pertinent to the study. Thus in the patients with multiple severe

wounds some wounds were listed as the principal major ones; no attempt was

made to record minor wounds, such as fracture of phalanx, for example. In

general, the types of wounds found in our patients were as follows:

Severe peripheral wounds were present in 116 patients, constituting

major injury in 81 instances. Nearly all were wounds of the extremities. Thirty-three patients had peripheral wounds without fracture, 16 of which were the patient’s major wound. Fifty-three of 70

patients had major peripheral wounds with fracture, and 13 had traumatic amputation of an extremity. In 10 of these 66, major wound

was also listed in another category. Three patients among those with

peripheral wounds had injury to the spinal cord.

Of the severe nonperipheral wounds, 34 patients had thoracic

wounds (a major wound in 30 instances) and 56 patients had intraabdominal wounds, major wound in 50 instances. An additional 21

patients had combined thoraco-abdominal wounds and patients had

separate wounds of the chest and abdomen. Of the total abdominal

wounds, there were 25 wounds of the liver, 20 wounds of the kidney
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

2.—Relationship of

Pain

to

Major

Wound in

215

Patients

(Data

Taken

from

Study on Pain

in

Men

Wounded

in

Battle

*)

Further

Average

Time

from

Total

Dose

Latest

Dose

Time

since

Pain

(degree

Pain

Relief

Type

of

Wound

Number

of

Patients

Age

Wounding

of

Morphine

of

Morphine

latest Morphine

and

number of

patients

in

Therapy Wanted

yrs.

hrs.,

average

mg.,

average

mg.,

average

hrs.,

average each

group)

(number

of

patients)

Compound Fractures of

Long

Bones

50

24.8

±0.9

12.5±1.3

27.0±1.5 (1

pt.

none)

22.6

7.0±0.8

19

none 12

slight moderate 12

severe

11

yes

39

no

Extensive Soft-tissue

Wounds

....

50

24.5±1.

11.3±1.4

27.0±2.7 (11

pts.

none)

19.5

7.2±0.6

19

none 15

slight moderate severe

yes

41

no

Penetrating Wounds

of

Thorax

50

24.

±0.8

9.8±1.0

25.0±1.8 (11

pts.

none)

21.2

6.

±0.6

15

none 18

slight 11

moderate severe

10

yes

40

no

Penetrating Wounds

of

Abdomen

50

22.7

±0.6

7.2

±0.7

29-0±2.2 (5

pts.

none)

25.0

4.

±0.7

none slight 14

moderate 24severe

yes

23

no

Penetrating Wounds

of

Cerebrum

15

25.

±1.4

7.9±1.4

19.8 ±4.2 (8

pts.

none)

19.8

6.

±1.5

none slight moderate severe

yes

14

no

See

footnote

4,

text.

Patients who

did

not

receive

morphine are

not

included

in

the

averages.
INTERNAL STATE ON ENTRY TO HOSPITAL 27

(treated by nephrectomy in instances), and in case it was not

known whether kidney or liver wound had been present. Wounds

of the urinary tract involving the bladder or structures above it occurred in patients. Ten patients with nonperipheral wounds had

multiple major wounds.

Crush injuries were found in nine patients, and there was only one

case of head injury.

Clinical Condition of Patients on Arrival

at the Most Forward Hospital

Pain

The frequency and severity of pain in different types of wounds had been

extensively studied under similar conditions and on the same types of patients

shortly before the Board was organized and the study was therefore not repeated on these 186 patients. Part of the data obtained in the early study is

shown in Table 2. The incidence of severe pain was surprisingly low. The data

showed that severe pain was not to be accounted for on the basis of the patients’ having received less morphine or having received it earlier than patients

who reported little or no pain. It was also pointed out that three factors are

chiefly important in the distress of the wounded: pain, mental distress, and

thirst. In the severely wounded patient in good general condition, the first

two factors are important. In the man in shock, thirst is the main and often

the only cause of evident distress, but it may be extreme.

Shoc\ Grading of Shoc\.—The view sometimes has been taken that shock is

either present or absent in given case and that to try to distinguish between

degrees of shock is futile. In this study, however, it was found instructive to separate the patients arbitrarily into four categories; namely, those with “no

shock,” “slight shock,” “moderate shock,” and “severe shock.” This was done

on the basis of the criteria listed in Table which in turn were based on preliminary observation of large numbers of battle casualties by members of the

Board. patient was assigned to particular category if he exhibited the maBeecher, H. K.: Pain in men wounded in battle. Ann. Surg. 123: 96-105, January 1946; also

Bull. U. S. Army M. Dept. 5: 445-454, April 1946.
28 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

3.—Grading of

Shock* Skin

Degree

of

Shock

Blood

Pressure (approx.)

Pulse

Quality

Temperature

Color

Circulation (response to

pressure, blanching)

Thirst

Mental

State

None

Normal

Normal

Normal

Normal

Normal

Normal

Clear

and

distressed.

Slight

Decreased 20%

or

less

Normal

Cool

Pale

Definite slowing

Normal

Clear

and

distressed.

Moderate

Decreased 20

to

40%

Definite decrease in

volume

Cool

Pale

Definite slowing

Definite

Clear

and

some apathy

unless

stimulated.

Severe

Decreased 40%

to

non- recordable

Weak to

imperceptible

Cold

Ashen to

cyanotic (mot- tling)

Very sluggish

Severe

Apathetic

to

comatose;

little

distress except

thirst.

It

will

be

observed

that

sweating, nausea, and

vomiting are

not

included,

than

they

are

to

shock.

The

pulse

rate

can

be

influenced

by

too

many unimalthough

these

criteriawere frequently referredto

in

World

War

reports.

In

portant

factors

to

have

value

in

estimating

degree

of

shock;

pulse

quality,

howthe

Board’s

experience

they

were found

to

be

uncommon and

of

no

value

in

ever,

is

important.

The

last

three

columns

of

the

table

include

items

not

estimating

the

extent

of

shock.

They

are

probably more

closely

related to

ordinarily

considered

in

evaluating

patient’s

condition;

since

we

found

them

psychologic

factors, to

the

nature of

the

wound,

or

to

reactionto

morphine

useful,

they

are included.
INTERNAL STATE ON ENTRY TO HOSPITAL

jority of criteria for that category as opposed to another. These signs were inadequate, of course, for management of case, for comprehensive appraisal

of the patient’s condition must include not only an accurate concept of his

present state but also shrewd estimate of his probable course in the immediate future.

On the basis of this arbitrary classification the 186 patients under study

were evaluated as to the degree of shock they had at the time of their admission to the hospital. In three of them the degree of shock could not be ascertained. Those 78 patients who were not seen on admission by any member of

the Board were classified by the Board on the basis of the available clinical

data and on discussion with medical officers who had seen them on admission.

In the 108 patients who had been observed on admission by some member of

the Board the degree of shock was probably more uniformly classified. Table

shows the clinical evaluation of shock and its distribution in these 108 patients

as well as in the entire series. It is apparent that the distribution remained

about the same when the 108 were separated from the entire group. Since the

percentages were essentially unchanged when the magnitude of the cases was

roughly doubled, it was assumed that the size of the sample 108 cases was

adequate.

Table 4.—Classification and Distribution of Shock

Relationship to Time from Wounding.—Examination of the records of 167 of the entire group of severely wounded men under study on whom these data

Degree of Shock

All Patients

Patients Seen on

Admission by

Members of Board

Number

Percent

of

Total

Number

Percent

of

Total

None 34 18.3 20 18.5

Slight 37 20.0 27 25.0

Moderate 55 29-5 34 31.5

Severe 57 30.6 26 24.1

Unclassified 1.6 0.9

Total 186 100.0 108 100.0
Table

6.—Wound

Composition in

Each

Shock

Category 12

Patients

Major

Wound

Composition

Degree

of

Shock

Number

of

Patients

Pene- trated Abdomen

Pene- trated Chest

Lacerated Soft Tissue

Traumatic Amputation of

Extremity

CompoundFracture of

Long

Bones

Miscellaneous Wounds

and

Injuries

Cases

Concomitant of

Injuries

NonePercentage

....

24

29%

4%

21%

8%

4% *(8%)

Crush 29%

Abdominal

wound

and

compound, comminuted

fracture

of

humerus

case.

SlightPercentage

....

24

29%

13%

21%

8%

13%

CrushPenetrated face

Compound, comminuted

fracture

of

sacrumFractured vertebra

17%

[•Abdominal wound

and

penetrating

chest

wound

case.

Moderate Percentage

....

36

Abdominal

wound

and

penetrating

chest

wound—

cases.

Abdominal

wound

and

compound, comminuted

fracture

of

both

bones

of

leg

case. Abdominal

wound

and

compound, comminuted

fracture

of

humerus

case.

36%

22%

14%

17%

11%M9%)

Chest

wound

and

compound,

comminuted

fracture

of

arm bones

case.

Soft-tissue

wound

and

fractured

skull

case. Traumatic

amputation

and

compound,

comminuted

fracture

of

bones

of

other

leg

case.

SeverePercentage

....

37

10 27%

14%

8%

24%

22% *(24%)

CrushFractured pelvis

5%

Abdominal

wound

and

penetrating

chest

wound

cases.

Chest

wound and

compound,

comminuted

fracture

of

humerous

case.

Chest

wound

and

compound,

comminuted

fracture

of

ilium—

case.

Includes some

ca

Petcentages mar ses in

which ced

with

aster surgical

ampu

isk

include

th tation

was undertaken

early.

compound

fractures

listed

under

concomitant

injuries.
INTERNAL STATE ON ENTRY TO HOSPITAL 31

were complete failed to show any correlation between the time from wounding

until examination (clinical appraisal and blood analysis) and the presence or

severity of shock (Table 5). The time elapsed in each of the four groups was

approximately the same. There was, however, striking correlation between severity of shock and blood loss, as will be shown later.

Table 5.—Relationship of Degree of Shock on Hospital Entry to Time

from Wounding—167 Cases

Relationship to Wound.—Table indicates the wound composition of 121

patients in each shock category. It merits some comment. If the two types of

serious extremity wounds—traumatic amputation of extremities and compound

fractures of long bones—are combined (the two are often very similar as to

blood loss), it can readily be seen from Table that the incidence of such

wounds rose progressively in each category of increasing severity of shock. In

the section on Blood Loss it will be shown that the greatest loss of hemoglobin

occurred when the wound involved compound fracture of the long bones or

Table 7,—Incidence of Combined Cases of Serious Extremity Wounds

(Major or Concomitant Injury) in each Shock Category

Degree of Shock

Number

of

Cases

Average Time from

Wounding

to Hospital Entry

Hours

None 29 6.7 ±0.9

Slight 36 7.6±0.8

Moderate 52 6.4±0.5

Severe 50 6.9±0.7

Degree of Shock

Number

of

Cases

Incidence ofTraumatic Amputation

or Compound Fracture of Long Bones

Percent ofallsuch cases in each shock group, Table

None 16.6

Slight 20.8

Moderate 14 38.9

Severe 18 48.6
THE PHYSIOLOGIC EFFECTS OF WOUNDS

SEVERELY WOUNDED MAN receives treatment in the forward area.

traumatic amputation of an extremity. Since most patients having such wounds

were in severe shock, one can generalize with probability of accuracy and say

that it is the wounds that are associated with great hemorrhage that cause severe shock. Reasons for laboring this rather obvious point will be discussed

later.

In contrast to the rising incidence of severe extremity wounds in progressive shock categories, the percentage of penetrated abdomens, although rather

high, shows no such consistent rise. In the severe-shock group, abdominal

wounds are definitely less often cause of the poor condition of the patient

than are the combined extremity wounds. (Incidentally, this evidence does not

support the view that clostridial infection plays an important part in producing

shock in general.)

The question might be raised as to whether the relative importance of ab-
INTERNAL STATE ON ENTRY TO HOSPITAL 33

dominal wounds as cause of shock has heretofore been exaggerated. The poor

prognosis often encountered in patients with abdominal wounds probably has

great deal to do with the apprehension felt in the presence of such lesions.

The concealed hemorrhage or concealed contamination often present in these

cases may lead to subsequent profound shock. So, while on the average abdominal wounds were not as often cause of severe shock on hospital entry

as were serious extremity wounds, the impossibility of accurate preoperative

appraisal of the abdominal wound makes it difficult to exaggerate its potentialities.

Shock will be discussed in each of the following sections of this chapter and

an attempt will be made to correlate degree of shock with the data under discussion whenever possible.

Cardiovascular System

Electrocardiographic Observations.—Prior to organization of the Board, 58 electrocardiographic records were made on 30 patients in severe shock and

after recovery. Since the observations were made on the same type of patients

as those studied by the Board and under similar circumstances, electrocardiograms were not made on the Board’s cases. The results of that study are summarized here. In 10 patients (one-third of that series) the blood pressure could

not be measured on hospital entry. In the other two-thirds the degree of circulatory collapse was somewhat less severe, but even so the systolic blood pressures ranged from 60 to 70 millimeters of mercury and the diastolic from 20 to

40 millimeters.

Definite abnormalities of the electrocardiograms were observed in of the

30 patients. The most striking feature was the normal character of the findings

in the remaining twenty-five. In of the patients with abnormal findings,

the electrocardiograms showed striking but transient inversion of the wave

in lead 1. In patient with an intrathoracic injury there was shift from

marked right-axis deviation back to normal following operation. The electrocardiogram in the fourth patient showed bizarre QRS complexes of low voltage, and in the fifth showed evidence of an unusual degree of temporary cardiac irritability with paroxysmal fibrillation and ventricular tachycardia.

Burnett, C. H.; Bland, E. F„ and Beecher, H. K.: Electrocardiograms in traumatic shock in man

J. Clin. Investigation 24; 687-690, September 1945.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 34

This electrocardiographic evidence of abnormality is of some interest but

difficult to explain. In no instance were there clinical signs of cardiac weakness, such as abnormal accentuation of the pulmonary second sound, basal rales,

gallop rhythm, or congestion of the cervical veins or of the liver. As stated, the

majority of the electrocardiographic findings were within normal limits. Several patients in the series were in severe shock, having low blood pressure for

period of hours with no effect upon the electrocardiogram. It may be significant that in both patients with transient inversion of the wave in lead 1, the

wound involved the left side of the chest, although so far as could be determined by roentgenographic examination and clinical findings at the time of

operation, the heart and pericardium escaped injury. Furthermore, the transient nature of the inversion was more in accord with temporary functional

disturbance (possible hypoxia) than with lasting tissue injury.

Pulse Rate.—The pulse rates of the patients in the present study were considered in relationship to shock and no significant difference was found between the four categories (Table 8). The pulse rates considered were those

taken as close as possible to the time the condition of the patient was evaluated. When the pulse was imperceptible at the time of initial examination, the

first recordable rate was used unless the record showed evidence that the patient was well on the way to resuscitation.

Table 8.—Relationship of Degree of Shock to Pulse Rate—106 Cases

The finding that the average as well as the minimum and maximum pulse

rates were about the same in all degrees of shock was surprising. There are two

possible explanations for this: i. The tachycardia in the lesser degrees of shock

may have been due in part to excitement. 2. In some cases the elevation of the

pulse rate (and the vasoconstriction accompanying it) may have been adequate

to ward off the signs of shock. It is interesting that even patients judged to be

Degree of Shock

Pulse Rate

None

(13 cases)

Slight

(24 cases)

Moderate

(34 cases)

Severe

(35 cases)

Minimum

Maximum

Average

70

140

103±7.2

88

150

111 ±3.4

80

160

113±3.6

60

144

116±3.3
INTERNAL STATE ON ENTRY TO HOSPITAL 35

in severe shock can have pulse rate as low as 60 beats per minute. Of greater

significance than the actual rate of the pulse is its volume, which often was

decreased so much in severe shock that the pulse could no longer be felt.

Blood Pressure.—Blood pressures were analyzed in only those 70 cases out

of the 186 in which they had been recorded at the time the patient’s condition

was evaluated. The volume of the circulating blood was also determined in

these 70 patients. There was no significant fall in the average systolic blood

pressure except in those in moderate or severe shock (Table 9). It will be shown

that these patients with considerable shock had lost on the average 33.6 percent of their calculated normal blood volume and nearly 50 percent of the total

circulating hemoglobin. In those with severe shock, the systolic blood pressure

fell rapidly, the average being 49 millimeters of mercury. This group had lost

approximately half the normal blood volume (see Table 22). There was, however, progressive drop in the average diastolic blood pressure with increasing

degrees of shock (Table 9). The average diastolic blood pressure of the patients in severe shock was half that of the patients in moderate shock. As severity of shock increased, there was significant and progressive decline in the

pulse pressure (Table 9). This confirmed the clinical observation that the volume of the pulse was closely correlated with the degree of shock.

Table 9.—Relationship of Degree of Shock to Blood Pressure—70 Cases

“Irreversible” Cha?iges in the Cardiovascular System.—Everyone who has

treated many patients for shock has encountered some who fail to respond to

the transfusion of blood deemed adequate under ordinary circumstances, and

this is often attributed to “irreversible” changes that have presumably taken

place during prolonged hypotension, ischemia, and anoxia. This problem is

956507 0—52

Degree of Shock

Systolic Blood Pressure

mm. Hg

Diastolic Blood Pressure

mm. Hg

Pulse Pressure

mm. Hg

Lowest Highest Average Lowest Highest Average Lowest Highest Average

None (13 cases) 108 150 126±11.9 64 80 75 ±1.5 30 80 52 ±4.1

Slight (20 cases) 90 140 109±3.0 40 86 66±2.7 28 80 44±2.7

Moderate (21 cases) .... 30 136 95 ±4.9 20 90 58±3.5 10 56 36±2.8

Severe (16 cases) *0 80 49±7.6 *0 68 ±5.8 *0 58 24 ±4.7

When the values were unmeasurable (2 cases) they were considered to be 0.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

further discussed in the section on Blood Loss. In most instances, adequate explanation can be found for the failure of patients in shock to respond to blood

transfusion; some common examples are concealed and continuing hemorrhage, hemothorax, irritant contamination of the peritoneum, peritonitis, clostridial myositis, and fat emboli. Four cases from our series are illustrative.

CASE REPORTS

Case 77.—A patient with severe thoraco-abdominal wound was received at forward

hospital in severe shock 814 hours after he was wounded. Resuscitative measures were

continued for nearly hours. During that time he received only 1,500 cc. of whole blood.

His condition failed to improve and he was operated upon but did not survive the

operation.

Necropsy showed massive collapse of the right lung with plug of mucus in the right

main bronchus. The lower lobe of the left lung was collapsed and about one-third of the

left upper lobe was atelectatic. There was gross dilatation of the right ventricle of the

heart. On histologic examination minimal evidence of fat embolism in the pulmonary

vessels was found but considered of no clinical significance.

Comment.—There was adequate cause for this patient’s failure to respond

to resuscitation. More aggressive measures should have been taken, including

bronchoscopy and the use of more blood in less time. There should have been

more concern when no improvement occurred during the first hours after

the patient’s admission to the hospital.

Case 45.—A patient with severe abdominal wound was admitted to forward hospital in severe shock hours after wounding. During the next hours, units (600 cc.

total volume) of plasma and liter of whole blood were transfused. The blood pressure

during that time changed from imperceptible to 90 millimeters of mercury systolic and

70 diastolic. An additional unit of plasma was administered and an infusion of 500 cc.

of 2-percent solution of sodium bicarbonate was given intravenously. Although this was

the optimum time for surgery, operation was delayed and hours later the blood pressure

was again unmeasurable. It was restored to 86 millimeters of mercury systolic and 60

diastolic after transfusion of liter of whole blood, and operation was performed which

lasted hours.

At operation the abdominal cavity was found to be “full of blood.” The blood pressure

and pulse rate were unmeasurable during much of the operation. The patient never

regained consciousness and died 3% hours after the end of the operation. Necropsy showed

perforation of the inferior vena cava. There was histologic evidence of minimal fat embolism in the pulmonary vessels, probably of no clinical significance.

Comment.—The recurrent hypotension in this patient was probably due to

continued extraperitoneal and intraperitoneal hemorrhage. Operation should
INTERNAL STATE ON ENTRY TO HOSPITAL 37

have been performed while he was responding well to resuscitative measures

during the first hours after admission to the hospital.

Case 100.—This patient had multiple wounds involving both arms, the left thigh, and

the face. There were compound fractures of the left humerus, radius, and ulna, and of

the right ulna. There was also transection of the right femoral artery with vascular

insufficiency in the leg. He was admitted in severe shock to forward hospital 3% hours

after wounding, and within 90 minutes he received 300 cc. (total volume) of plasma and

liters of whole blood. He showed general improvement but his blood pressure was still

only 80 millimeters of mercury systolic and 50 diastolic. His pulse rate was 144 beats per

minute. Three hours after admission his blood pressure was 90 millimeters of mercury

systolic and 58 diastolic. Operation was delayed for additional hours. At no time during

operation did the recorded blood pressure fall below 85 millimeters of mercury systolic.

The patient had received total of 4,500 cc. of whole blood before, during, and immediately after operation.

Ten hours after operation the patient’s blood pressure was low and he looked pale

and “anemic.” transfusion was started, but an hour later he suddenly died. Ten minutes

earlier he had carried on an intelligent conversation. Pulmonary embolus was suspected

but at necropsy no cause could be found for the sudden death. Microscopically, moderately severe grade of fat embolism was found in the lungs.

Comment.—The question was raised whether the 5- or 6-hour period of

hypotension in this patient could have caused irreversible changes in the

cardiovascular system so that it simply “gave out” when it did. This cannot be

answered with certainty. The fat embolism in retrospect appears to be the more

important consideration.

Case 120.—This patient had simple penetrating wound of the thigh caused by shell

fragment. The femoral artery below the origin of the profunda femoris was severed.

During evacuation the patient had received units (1,200 cc. total volume) of plasma and

when he reached the evacuation hospital, about hours after wounding, he must have

appeared in good condition for no resuscitation was deemed necessary. At operation, performed 4V2 hours after admission, the femoral artery, vein, and nerve were found to be

completely transected. The vessels were ligated and the foreign body was removed.

At the conclusion of the operation, the systolic blood pressure was only 70 millimeters

of mercury and remained between 70 and 60 throughout the day. Despite- this the patient

appeared to have good color and his skin was not cold. Transfusion of liter of whole

blood did not improve the blood pressure. The right leg looked as though it would not

survive. Anuria developed and the patient died 48 hours after operation. Necropsy revealed

nothing to account for the postoperative hypotension. There was no concealed hemorrhage

and no evidence of clostridial myositis in the involved extremity. There was no histologic

evidence of fat embolism.

Comment.—This patient probably had lost more blood than was realized.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Resuscitation

Before admission of the patients in this study to forward hospital, resuscitative efforts had been limited chiefly to control of pain and hemorrhage

and to administration of blood plasma. Relatively little whole blood was given.

The 108 patients seen by us on admission had received, on the average, units

of plasma before the first blood sample was taken. Plasma administration was

distributed in this group as follows:

Thus 69 percent (74) of these patients had received two units (600 cc.) or less

of blood plasma before or shortly after arrival at the most forward hospital.

Twenty-seven of the 108 patients received transfusions of whole blood prior to

withdrawal of the first blood specimen for laboratory analysis. Three of these,

or percent, had received whole blood in an aid station before admission to

forward hospital. The blood transfusions were distributed as follows:

The following tabulation summarizes the average quantities of blood and of blood plasma used in resuscitating 157 of the very seriously wounded patients in our series (the 108 referred to above and 49 others on whom we had clinical notes):

Blood plasma preoperatively (average of 122 cases) 3.08 units Blood plasma during operation (average of 10 cases) 1.68 units

Whole blood preoperatively (average of 127 cases) M50 cc

Whole blood during operation (average of 95 cases) 1,160 cc.

unit 250 cc. of normal plasma diluted to 300 cubic centimeters.

Number of Patients

22

Units of Plasma

none

Number of Patients Units of Plasma

2K

17

13

12 11

Number of Patients

13

10

Units of Blood
INTERNAL STATE ON ENTRY TO HOSPITAL 39

In round numbers, our average patient in this series had just over units (total

volume) of blood plasma and blood transfusions (total of about 2,500 cc. of

whole blood) to support him from the time of wounding until his operation

was completed. It is interesting to observe that plasma was used during surgery

in only 10 of these 157 patients.

The information concerning the cases referred to here was drawn from the

shock tents of most of the hospitals of the Fifth Army and represents broad

sample of current practice in Italy over the last year of the European War.

Essentially the same type of case had been studied by two of us earlier at

Anzio. In that series the average patient received 1,537 cc whole blood

(three transfusions) to prepare him for and carry him through surgery. These

three transfusions contrast with the five referred to above. notable difference

between the Anzio study and Mediterranean Theater practice in general was

in the time elapsed from hospital entry to start of surgery. In the Anzio study

this averaged hours, 21 minutes. Reference to an earlier part of this section

on Time from Wounding to Hospital Entry and Surgery will show that over

the Fifth Army Area as whole, the average time from hospital entry to surgery varied from hours to hours. Two differing views as to the correct

preparation of wounded men for surgery are represented in these figures: the

extended, and the rapid. The extended required five transfusions of whole

blood; the rapid, three. This has been discussed in previous publication.

Plasma Protein Concentration and Hematocrit Values

On Admission to Forward Hospital

The concentration of protein in the plasma and the blood hematocrit value

(both calculated from specific gravities measured by the copper sulfate

method give clue to the shifts that have taken place between the blood

stream and the tissues as well as to blood loss from the body. When considered

’Beecher, H. K., and Burnett, C. H.: Field experience in use of blood and blood substitutes

(plasma, albumin) in seriously wounded men. M. Bull. North African Theat. Op. (no. i) 2; 2-7, July

1944.

‘Beecher, H. K.: Preparation of battle casualties for surgery. Ann. Surg. 121: 769-792, June 1945.

‘Phillips, R. A.; Van Slyke, D. D.; Dole, V. P.; Emerson, K., Jr.; Hamilton, P. B., and Archibald, R. M.: Copper sulfate method for measuring specific gravities of whole blood and plasma. BUMED

News Letter, U. S. Navy, vol. 1, June 25, 1943.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 40

with quantitative measurements of whole-blood loss, fairly accurate picture

of one consequence of the wound can be obtained. The plasma protein and hematocrit levels were determined in our patients shortly after their admission to

the most forward hospital, before resuscitation, anesthetization, or operation

had been undertaken.

Relationship to Type of Wound

In Table 10 the relationship of the average plasma protein concentration

and the average hematocrit value to the type of wound is shown for 50 patients who, prior to study, had received only unit (300 cc.) of blood plasma

or less than unit (in some instances no plasma had been administered). The

patients whose wounds were peripheral are grouped and compared with those

having nonperipheral wounds; crush cases are not included.

From the table it may be seen that there is no decided difference between

the plasma protein levels of patients with peripheral and those with nonperipheral wounds. On the other hand the hematocrit values were significantly

higher in the latter group which is consistent with the hemoconcentration

sometimes found in such patients. There was also less loss of hemoglobin (as

will be discussed in the section on Blood Loss) in those patients with intraabdominal and thoraco-abdominal wounds than in those having severe wounds

of the extremities. Maintenance of more nearly normal blood volume in patients with such nonperipheral wounds doubtless reduces the need and tendency for blood dilution, although this factor alone would not account for the

hemoconcentration when it is found in such cases.

Table 10.—Relationship of Plasma Protein Concentration and Hematocrit

Value on Admission to Type of Wound in Patients who had

Received Unit or Less of Plasma

Type ofWound

(Exclusive of crush)

Average Plasma

Protein Concentration

Gm.per 100 cc.

{normal; 6.5)

Average Hematocrit

Value

cc. cells in 100 cc.

{normal; 47)

Peripheral (2 cases) 6.2 ±0.1 37.4±1.0 Nonperipheral 6.5±0.1 42.0± 1.0

(Abdominal, thoracic, and thoraco-abdominal)

(2 cases)
INTERNAL STATE ON ENTRY TO HOSPITAL

Relationship to Blood Loss

When average plasma protein concentrations and average hematocrit values

in patients with peripheral and nonperipheral wounds are compared with loss

of blood volume (39 cases), it may be seen from Table 11 that the hematocrit

values were significantly lower in all patients who had lost more than 30 percent of their calculated normal blood volume. The hematocrit level of 36 is

23.4 percent below the normal of 47 (Wintrobe method).

In the case of the plasma proteins, however, even when there was loss of

30 percent or more of the normal blood volume, the average concentration was

6.1 Gm. per 100 cc. (only 6.1 percent below the normal of 6.5). In other words,

the hematocrit level fell proportionately about four times as much as that of

the plasma proteins. The blood appears to have been diluted by protein-rich

fluid (6.1 Gm. per 100 cc. of blood). The evidence is too meager to justify much

speculation here. However, as pointed out by Evans, 10

the axial stream of corpuscles is surrounded by plasma envelope. This varies in thickness and total

volume, depending upon certain hydraulic principles. It might be possible that the

alterations in the circulation caused by the loss of 30 percent or more of the normal

volume of blood (slowing of the peripheral circulation, for example) resulted

in dragging an appreciable volume of plasma with normal protein content into

Table ii.—Relationship of Plasma Protein Concentration, Hematocrit

Value, and Type of Wound to Blood Loss in Patients who had

Received Unit or Less of Plasma

10 Evans, Robley: Personal communication.

Blood Volume Loss of Less than 30 Percent Loss of 30 Percent or More

Non- All Non- All

Type of Wound Peripheral peripheral Types Peripheral peripheral Types

(Exclusive ofcrush)

(10 cases) (17 cases) (27 cases) (8 cases) (4 cases) (12 cases)

Average Plasma Protein Concentration 6.4 ±0.1 6.5 ±0.1 6.5 ±0.1 6.0 ±0.1 6.4 6.1 ±0.1

(Gm. per 100 cc.)

Average Hematocrit Value 39.0±1,7 43.0±1.0 41.5 ±1.0 35.0±1.3 37.8 36.0±1.1

(cc. cells in 100 cc.)

Abdominal, thoracic, and thoraco-abdominal.

Determinations made on hospital admission.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

the circulating blood. Or it might be possible that protein was brought into the

circulation from the liver.

Influence of Plasma Therapy

The influence of previous administration of blood plasma upon the concentration of plasma protein and the hematocrit value was considered, and the

findings in different types of wounds are shown in Table 12 and Charts and

2. Only three of the patients had had blood transfusions; these will be ignored.

It is clear from the table and charts that plasma therapy did not influence the

plasma protein level, but it did have an important effect on the hematocrit

level.

The plasma protein concentration and hematocrit value were also analyzed

in regard to shock, the data being broken down into two categories in which

“no shock” and “slight shock” were grouped together, as were “moderate

shock” and “severe shock.” No important differences were found between the

two categories.

Table 12.—Effect of Plasma Therapy on Average Plasma Protein and

Hematocrit Admission Levels in 89 Patients with Various Types of Wounds

Plasma Time from

Type of Wound Number Units of Protein Hematocrit Value Wounding

(Crush of Plasma Concentration to Determination

excluded) Cases Received

Gm. per 100 cc. cc. cells in 100 cc. hours

25 to 6.2 ±0.1 37.4±1.0 8.5 ±1.2 Peripheral .... 17 to 5.9±0.1 3l.9±1.5 *8.1 ±1.5

13 to 6.1 ±0.1 *28.6±1.9 9.8±1.2

Total 55 to 6.1 ±0.1 33.7 ±0.9 8.7 ±0.7

11 to 6.6 ±0.2 44.1 ±1.8 6.3 ±1.4 Abdominal.... to 6.7 ±0.3 40.2 ±4.3 7.8 ±3.1

to 11 6.1 *32.2 *12.2

Total 19 to 11 6.6 ±0.1 41.6±1.9 6.8±1.3

Thoracic to 6.5 ±0.2 40.0±1.2 7.9±2.6

to 6.6 ±0.2 35.4±1.8 7.2 ±1.7

Total 15 to 6.5 ±0.1 7.8 ±1.2 7.6±1.4

No determination made in one case. (Determinations made on hospital admission.)
INTERNAL STATE ON ENTRY TO HOSPITAL 43

CHART i. Influence of plasma therapy

on plasma protein and hematocrit levels in

peripheral wounds

CHART 2. Influence of plasma therapy

on plasma protein and hematocrit levels in

abdominal wounds

Relationship to Shock

Plasma protein and hematocrit levels were also studied in relation to the

clinical condition of about ioo badly wounded patients (crush cases excluded)

on admission to the forward hospital. The fall in average plasma protein concentration is probably significant as the cases are grouped in Table 13 and

Chart 3; the fall in hematocrit value is definitely significant. There was no

evidence of hemoconcentration. When the patients were grouped according to

Table 13.—Plasma Protein and Hematocrit Levels on Admission

in Relation to Shock*

Degree of Shock None Slight Moderate Severe All Cases

Average Plasma Protein

Concentration

(Gm. per 100 cc.)

Average Hematocrit Value

(cc. cells in 100 cc.)

6.6±0.1

(15 cases)

42.5 1.7

(15 cases)

6.4±0.1

(26 cases)

38.4±1.5

(26 cases)

6.2 ±0.1

(34 cases)

34.6±1.0

(33 cases)

6.0±0.1

(2 cases)

31.5 1.5

(24 cases)

6.3±0.1

(100 cases)

36.1±0.8

(98 cases)

All types of wounds, exclusive of crush cases.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 44

Table 14—PlasmaProtein and Hematocrit Levels on Admission in Relation

to Shock in Patients with Abdominal Wounds

CHART 3. Plasma protein and hematocrit

levels in relation to shock—all types of

wounds

location of the major wound, there was no significant fall in the concentration

of plasma protein in those with peripheral wounds in relation to the degree of

shock. The findings in patients with abdominal wounds showed up differently

(Table 14). In the group with minimal shock, the plasma protein concentration may possibly be accounted for by weeping of the irritated peritoneal surfaces, fluid being released which contained less protein than the plasma. As

shock became moderate or severe, probably due to greater blood loss, the

plasma protein concentration fell to figure like that for extremity wounds,

with hemodilution overcoming the effects of exudation. These data indicate

that the plasma protein and hematocrit values can vary independently.

Degree of Shock None—Slight Moderate—Severe

Average Plasma Protein Concentration 6.9±0.1 6.1 ±0.2

(Gm, per 100 cc.) (10 cases) (9 cases)

Average Hematocrit Value 47.0± 1.6 34.9±1.8

(cc. cells in 100 cc.) (10 cases) (8 cases)

Average Hours after Wounding 7.0±1.5 11.6

(10 cases) (9 cases)
INTERNAL STATE ON ENTRY TO HOSPITAL 45

Blood Loss

Volume and Hemoglobin

The quantity of blood wounded man can lose and yet recover has generally been underestimated. One indication that this is so was the fact, well

shown in the prolonged campaigns of the Mediterranean Theater, that robust

young soldiers tolerated surgery well, long before the blood volume or even

the blood pressure had been restored to normal. Actually the concept of restoration of the patient in shock to normal prior to surgery is based upon false

premise. Full organic restoration probably requires days to achieve. good response of young wounded man to treatment is by no means admissible evidence that his circulatory system has been restored to normal; it is evidence

of the existence of safety factors in human physiology. These points have been

discussed elsewhere. 11

In the belief that measurement of the blood loss that had been sustained by

these severely wounded men by the time of their arrival at forward hospital

would clarify the matter of the importance of whole blood for the wounded,

such study was carried out. The direct relationship between quantity of blood

lost and degree of shock had long been recognized, but further evidence of this

relationship was desirable in view of the ever-recurring suggestions that the

cause of shock is mysterious and to be explained by the presence of toxins in

the body or by the breakdown of some vague but vital force.

The blood volume and the hemoglobin concentration were determined in

67 patients 12 shortly after their arrival at the most forward hospital (which in

most instances was field hospital). The blood volume loss and the total

hemoglobin loss, expressed as percentages of calculated normal for each patient, were then determined on the basis of these findings. Normal blood volume was considered to be 8.5 percent of the body weight, after Gregersen.

(See Appendix for the method used.) Peters 13 has commented on the loss

of the dye T-1824 from the blood stream. Such loss of dye would of course

11 See footnote 8. Also see section on Resuscitation in volume on general surgery of the series: The

Medical Department of the United States Army. To be published.

15 The blood studies were actually made in yi cases (see Table 15), but one case was discarded

because of probable technical error and three others are excluded from the present discussion since they

represent types not common to the group; namely, two crush injuries (Cases 93 and 124) and head

injury (Case A-7). 13 Peters, J. P.: Role of sodium in production of edema. New England J. Med. 239: 353-362, Sept. 2,

1948.
46 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 15.—Initial Blood Changes in 71 Severely Wounded Men

Case of crush injury,

(0): Not measurable.

Blood

Blood Volume Deviation

from Normal

Circulating

Hemoglobin

Pressure

at Time of

Blood

Degree

of

Shock

Blood

Sugar

Time

after

Woundpercent

Hemoglobin

Present

Hemoglobin

Case

No.

Volume

Determination

ing

From

Observed

Value

By

Correction

Deviation

from Normal by Cor

rection

mm. Hg mg. per

100 cc. hours grams percent

53 80/40 Moderate 106 -10.6 -22.9 -22.9 689.2 -37.8

83 130/70 Slight 53i 13.1 -3.3 -0.8 941.1 -16.1

91 108/78 None 2H -26.0 -37.7 -37.7 464.3 -52.9

>93 (0) Severe 14'A -11.7 -34.0 -30.3 1,203.8 +2.6

100 80/50

150/80

-28.4

-21.3

-69.0

-36.9

-65.0 551.3

702.8

-76.6

102 None -29.1 -39.0

107 80/50 Moderate 374 -20.7 -78.6 -68.9 419.2 -77.6

108 58/0 Severe 372 -25.5 -38.9 -30.0 341.9 -64.1

110 (0)

120/80

y. -35.7

-2.7

-37.6

-7,1

-37.6

-7.1

553.5

851.8

-47.4

111 Slight 157 14 -5.1

113 94/58 ....do.. 149 -14.9 -20.2 -20.2 573.1 -28.2

122 50/30 Severe 87 -34.4 -55.0 -48.2 632.3 -58.4

124 120/64 None 10 15.3 -2.8 -2.8 1,012.5 -1.6

125 72/58 Severe 125 23 -21.3 -33.0 -29.1 562.2 -52.7

126 100/60 Moderate 183 2h -30.9 -32.3 -32.3 666.6 -44.4

127 90/40 Slight 11 -39.8 -59.4 -44.2 331.2 -65.9

128 110/80 ....do.... 184 6'A +6.2 -49.8 -32.6 837.8 -39.8 129 120/64 Moderate 191 -21.7 -30.9 -21.7 485.6 -44.2

130 60/20 Severe 272 -31.3 -51.6 -40.5 410.9 -62.0 131 40/20 ..do.... 177 IK -29.8 -43.6 -39.0 477.5 -54.3

134 120/76 None 15 -7.8 -11.3 -7.8 1,098.9 -3.8

139 (0) Severe -19.3 -75.7 -23.3 491.0 -54.5 140 100/60 Slight 141 16.8 -1.1 -1.1 1,002.2 -5.8

141 100/60 ....do.... 131 -20.2 -25.5 -25.5 648.5 -39.1 142 110/70 Moderate 210 6% -25.7 -31.9 -27.0 521.3 -43.0

143 80/54 ....do.... 203 +3.4 -13.9 1.8 790.8 -24.0

144 90/62 Slight 12 +8.8 -6.7 -1.5 542,8 —36.6 145 100/50 ....do.... -8.4 -15.7 -12.1 785.0 -30.7 147 80/48 Severe 165 13 -6.5 -24.1 -14.3 510.4 -42.7 148 74/20 Moderate 175 12 -5.2 -24.8 -14.9 493.2 -45.8 149 48/? Severe 115 17 -2.3 -31.3 -9.8 693.3 -32.7

A-1 116/60 Slight 155 2H -9.3 -17.4 -14.0 967.2 -22.6

A-2 114/62 ....do.... 170 4A -2.3 -2.3 -2.3 922.0 -9.6 A-3 136/90 Moderate 185 5.4 +2.9 +2.9 896.6 -8.3 A-4 132/72 None 93 4H -8.2 -8.2 -8.2 639.0 -31.1 A-5 120/86 Slight 106 -25.3 -25.3 -25.3 604.4 -35.6 A-6 118/64 Moderate 208 -24.2 -29.8 -24.2 479.7 -38.4
INTERNAL STATE ON ENTRY TO HOSPITAL 47

Table 15.—Initial Blood Changes in 71 Severely Wounded Men—

Continued

Case of head injury.

Probable technical error in this case.

(0): Not measurable.

Case

No.

Blood

Pressure

at Time of

Blood

Volume

Determination

mm. Hg

Degree

of

Shock

Blood

Sugar

mg. per

100 cc.

Time

after

Wounding

hours

Blood Volume Deviation

from Normal

percent

Circu

Hemo

Hemoglobin

Present

grams

lating

globin

Hemoglobin

Deviation

from Normal by Correction

percent

From

Observed

Value

By

Correction

!A-7 (0) 315 A. -31.6 -31.6 -31.6 540.6 -47.0

A-8 108/70 Slight 10 -14.8 -14.8 -14.8 667.4 -23.3

A-9 112/70 Moderate 1V2 -25.9 -35.0 -25.9 449.9 -49.1

A-10 108/74 Slight 11 -3.7 -3.7 -3.7 842.5 -28.4

A-l 110/76 ....do.... 79 -29.9 -33.4 -29.9 716.4 -37.4

A-12 104/70 Moderate 164 -11.3 -20.4 -20.4 676.2 -35.6

A-13 150/70 None 121 18 -18.4 -18.4 -18.4 555.0 -36.2

A-14 100/80 Moderate 93 -32.6 -40.2 -32.6 522.7 -50.3

A-l 104/70 ....do.... 143 -29.2 -44.4 -29.2 488.3 -53.5

A-16 130/70 None 139 -8.2 -10.5 -8.2 895.8 -12.2

A-l 140/60 Slight 201 -41.5 -63.9 -49.0 411.6 -69.1

A-18 30/20 Moderate 134 8H -42.7 -46.6 -42.7 398.4 -61.7

A-19 116/78 None 167 -31.9 -31.9 -31.9 579-3 -42.5

A-20 92/50 Slight 145 13 -34.1 -37.9 -34.1 429-1 -56.6

A-2 68/50 Severe 234 4H -46.7 -71.0 -54.8 240.4 -83.8

A-22 140/80 None 110 IX -2.8 -2.8 -2.8 1,200.6 11.5

A-2 128/80 ....do.... 127 4A 17.0 17.0 17.0 1,120.7 13.3

A-24 110/70 ...

.do.... 140 4'A -0.3 -10.3 -10.3 832.5 -6.4

A-2 126/80 Slight 140 -18.7 -22.3 -18.7 923.5 -15.1

A-26 110/70 ....do.... 196 -7.4 -7.4 -7.4 711.6 -23.1

A-2 114/80 None 125 5H +32.7 +32.7 +32.7 1,170.6 +48.4

A-28 64/20 Severe 218 6H -9.2 -28.0 -9.2 522.7 -38.7

A-29 80/38 ....do.... 382 -28.2 -54.9 -37.1 407.0 -63.6

A-30 88/40 Moderate 198 -31.8 -54.1 -40.7 378.7 -66.7

A-31 80/52 ....do.... 180 10 -10.2 -17.8 -10.2 778.8 -26.9

A-32 80/40 ....do.... 115 -25.4 -37.9 -29.5 549.8 -46.8

A-3 90/50 ....do.... 175 -2.9 -28.4 -25.3 585.5 -40.6

A-34 80/68 Severe 125 26H 12.8 -16.6 -8.2 952.8 -19.0

A-3 86/66 Moderate 159 -37.5 -41.9 -37.5 415.2 -55.1

A-3 108/88 ....do.... 163 20 -34.1 -38.6 -38.6 388.1 -56.8

A-37 120/68 ....do.... 136 -41.6 -52.4 -52.4 418.2 -62.4

A-38 (0) Severe 133 -24.6 -58.3 -48.7 482.2 -66.1

A-39 124/72 None 184 -7.1 -7.1 -7.1 786.4 -20.5

A-40 100/64 Slight 126 +3.5 +3.5 +3.5 899.4 -5.5
48 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 16—Blood Changes in 69 Severely Wounded Men Classified

According to Degree of Shock

A. No Shock—12 Patients

give falsely high value for blood volume. Our blood-loss values were estimated by difference, difference between an average normal blood volume (8.5

percent of body weight) and the value found. Therefore the losses we report

are lower than the fact; they are minimal rather than maximal.

To compensate for the effect on his blood volume of the blood and plasma

received by the patient, certain corrections were applied to our blood volume

determinations. The majority of patients had received some plasma prior to

hospital admission and few had received whole blood. Although blood volume determinations were made as soon after hospital admission as possible,

resuscitative procedures had likewise been initiated. Actually, in most cases,

determinations and resuscitation proceeded concurrently. Two methods of

correcting blood volume findings were therefore utilized: Correction and

Correction B.

Correction was the subtraction of the total quantity of blood and

blood plasma received by the patient from the time of wounding until

Blood Volume and Total Hemoglobin Determinations

Percent deviation from normal Blood

Pressure Time

after

Wounding

at Time of Blood

Case

No,

Blood Volume Hemoglobin Blood

Volume

Sugar

Determina- mg. per

From By Correction From By Correction tion hours 100 cc.

Ob- Observed served mm. Hg

Value Value

91 -26.0 -37.7 -37.7 -43.1 -52.9 -52.9 108/78 2H 102 -21.3 -36.9 -29.1 -31.1 -39.0 -39.0 150/80 3H

•124 15.3 -2.8 -2.8 14.7 -1.6 -1.6 120/64 10H

134 -7.8 -11.3 -7.8 -3.8 -3.8 -3.8 120/76 15M

A-4 -8.2 -8.2 -8.2 -31.1 -31.1 -31.1 132/72 4M 93

A-13 -18.4 -18.4 -18.4 -36.2 -36.2 -36.2 150/70 ISH 121

A-16 -8.2 -10.5 -8.2 -12,2 -12.2 -12.2 130/70 Ya. 139

A-19 -31.9 -31.9 -31.9 -42.5 -42.5 -42.5 116/78 8H 167

A-22 -2.8 -2.8 -2.8 11.5 11.5 11.5 140/80 l'A no A-23 17.0 17.0 17.0 13.3 13.3 13.3 128/80 4'A 127

A-24 -0.3 -10.3 -10.3 +4.1 -6.4 -6.4 110/70 4A 140

A-39 -7.1 -7.1 -7.1 -20.5 -20.5 -20.5 124/72 184

Case of crush injury.
INTERNAL STATE ON ENTRY TO HOSPITAL 49

Table 16. Blood Changes in 69 Severely Wounded Men Classified

According to Degree of Shock

B. Slight Shock—20 Patients

completion of the test.

Correction was the subtraction of only the quantity of blood and

plasma received from the time of the patient’s hospital admission until

completion of the test.

Correction was applied for the purpose of correlating the patient’s

clinical condition on arrival at the hospital with the amount of blood (the percentage of his estimated normal blood volume) that he had actually lost due to

his wounds, regardless of the amount that may have been replaced. Correction

was for correlation between the patient’s clinical condition on arrival and

the blood deficit existing at that time. The same corrections were applied in

calculating the total hemoglobin loss. However, in the case of hemoglobin

Case

No.

Blood Volume and Total Hemoglobin Determinations

Percent deviation from normal Blood

Pressure

at Time of

Blood

Volume

Determination

mm. Hg

Time

after

Wounding

hours

Blood

Sugar

mg. per

100 cc.

Blood Volume Hemoglobin

From

Observed

Value

By Correction From

Observed

Value

By Correction

83 13.1 -3.3 -0.8 -3.9 -16.1 -16.1 130/70

111 -2.7 -7.1 -7.1 -5.1 -5.1 -5.1 120/80 14H 157

113 -14.9 -20.2 -20.2 -23.4 -28.2 -28.2 94/58 3H 149

127 -39.8 -59.4 -44.2 -63.1 -65.9 -65.9 90/40 11

128 +6.2 -49.8 -32.6 -9.7 -39.8 -39.8 110/80 6H 184

140 16.8 -1.1 -1.1 11.7 -5.8 -5.8 100/60 4H 141

141 -20.2 -25.5 -25.5 -34.7 -39.1 -39.1 100/60 131

144 +8.8 -6.7 -1.5 -30.0 -36.6 -36.6 90/62 12X 145 -8.4 -15.7 -12.1 -27.8 -30.7 -30.7 100/50 A-l -9.3 -17.4 -14.0 -17.8 -22.6 -22.6 116/60 2H 155

A-2 -2.3 -2.3 -2.3 -9.6 -9.6 -9.6 114/62 4H 170

A-5 -25.3 -25.3 -25.3 35.6 -35.6 -35.6 120/86 106

A-8 -14.8 -14.8 -14.8 -23.3 -23.3 -23.3 108/70 10

A-10 -3.7 -3.7 -3.7 -28.4 -28.4 -28.4 108/74 11H A-l -29-9 -33.4 -29.9 -37.4 -37.4 -37.4 110/76 79

A-17 -41.5 -63.9 -49.0 -61.6 -69.1 -69.1 140/60 201

A-20 -34.1 -37.9 -34.1 -56.6 -56.6 56.6 92/50 13X 145

A-2 -18.7 -22.3 -18.7 -15.1 -15.1 -15.1 126/80 3H 140

A-2 -7.4 -7.4 -7.4 -23.1 -23.1 -23.1 110/70 196

A-40 +3.5 +3.5 +3.5 -5.5 -5.5 -5.5 100/64 Vi 126
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 16. Blood Changes in 69 Severely Wounded Men Classified

According to Degree of Shock

C. Moderate Shock—21 Patients

there was essential agreement between calculation and calculation because, with rare exceptions, whole blood had not been administered before the patient reached the most forward hospital.

Tables 15 through 22 show blood and hemoglobin loss in relation to other findings for patients individually and by groups. The loss is given as the percentage difference between calculated normal and the observed value, or be- tween the calculated normal and the observed value modified by Corrections

and B. For blood all three determinations are shown. For hemoglobin only the estimated loss derived by Correction is shown. It will be noted that few entries (shown as plus values in the tables) seem to indicate that the blood volume was greater than normal despite loss of blood. Several factors, indiCase

No.

Blood Volume and Total Hemoglobin Determinations

Percent deviationfrom normal Blood

Pressure

at Time of

Blood

Volume

Determination

mm. Hg

Time

after

Wounding

hours

Blood

Sugar

mg. per

100 cc.

Blood Volume Hemoglobin

From

Observed

Value

By Correction From

Observed

Value

By Correction

53 -10.6 -22.9 -22.9 -29.6 -37.8 -37.8 80/40 107 -20.7 -78.6 -68.9 -49.5 -77.6 -77.6 80/50 374 126 -30.9 -32.3 -32.3 -43.0 -44.4 -44.4 100/60 2H 183 129 -21.7 -30.9 -21.7 -44.2 -44.2 -44.2 120/64 191 142 -25.7 -31.9 -27.0 -41.9 -43.0 -43.0 110/70 6H 210

143 +3.4 -13.9 1.8 -22.5 -24.0 -24.0 80/54 203 148 -5.2 -24.8 -14.9 -39-6 -45.8 -45.8 74/20 12 175 A-3 +5.4 +2.9 +2.9 -5.8 -8.3 -8.3 136/90 185 A-6 -24.2 -298 -24.2 -38.4 -38.4 -38.4 118/64 208 A-9 -25.9 -35.0 -25.9 -49.1 -49.1 -49.1 112/70 7A A-12 -11.3 -20.4 -20.4 -23.5 -35.6 -35.6 104/70 2H 164

A-14 -32.6 -40.2 -32.6 -50.3 -50.3 -50.3 100/80 5M 93 A-15 -29.2 -44.4 -29.2 -53.5 -53.5 -53.5 104/70 143 A-18 -42.7 -46.6 -42.7 -61.7 -61.7 -61.7 30/20 SH 134 A-30 -31.8 -54.1 -40.7 -57.8 -66.7 -66.7 88/40 5M 198

A-31 -10.2 -17.8 -10.2 -26.9 -26.9 -26.9 80/52 10 180 A-32 -25.4 -37.9 -29.5 -42.6 -46.8 -46.8 80/40 7A 115 A-3 -2.9 -28.4 -25.3 -21.7 -40.6 -40.6 90/50 175 A-3 -37.5 -41.9 -37.5 -55.1 -55.1 -55.1 86/66 159 A-36 -34.1 -38.6 -38.6 -56.8 -56.8 -56.8 108/88 20 163 A-3 -41.6 -52.4 -52.4 -62.4 -62.4 -62.4 120/68 136
INTERNAL STATE ON ENTRY TO HOSPITAL

Table 16. Blood Changes in 69 Severely Wounded Men Classified

According to Degree of Shock

D. Severe Shock—16 Patients

vidually or collectively, might have brought about this apparent discrepancy:

i. In the case of uncorrected entries, blood and plasma administered may have

been in excess of blood loss. 2. Entries are from calculations based upon an

average normal which may have been too low for some patients. 3. There may

have been errors in technique in blood volume determination.

Relationship of Blood Lpss to Type of Wound

Fifty-nine of the patients listed in Tables 15 and 16 suffered primarily from

single major wound (abdominal, chest, or peripheral) and could therefore

be more readily studied as to the relationship of blood loss to type of wound.

956507 0—52

Blood Volume and Total Hemoglobin Determinations

Percent deviationfrom normal Blood

Pressure Time

after

Case WoundNo.

Blood Volume Hemoglobin

at Time of

Blood

Volume

Blood

Sugar

From

ObBy Correction FromObBy Correction

Determination

ing

hours

mg. per

100 cc.

served

Value

served

Value

mm. Hg

93 -11.7 -34.0 -30.3 12.0 +2.6 +2.6 (0) 4H 100 -28.4 -69.0 -65.0 -44.1 -76.6 -76.6 80/50 4'A 108 -25.5 -38.9 -30.0 -61.8 -64.1 -64.1 58/0 372

110 -35.7 -37.6 -37.6 -45.7 -47.4 -47.4 (0)

122 -34.4 -55.0 -48.2 -45.9 -58.4 -58.4 50/30 87

125 -21.3 -33.0 -29.1 -44.9 -52.7 -52.7 72/58 23 125

130 -31.3 -51.6 -40.5 -51.6 -62.0 -62.0 60/20 272

131 -29.8 -43.6 -39.0 -45.1 -54.3 -54.3 40/20 177

139 -19.3 -75.7 -23.3 -50.5 -70.7 -54.5 (0)

147 -6.5 -24.1 -14.3 -37.5 -42.7 -42.7 80/48 165

149 -2.3 -31.3 -9.8 -26.1 -32.7 -32.7 48/? 17 115

A-21 -46.7 -71.0 -54.8 -75.6 -83.8 -83.8 68/50 4Yx 234

A-28 -9.2 -28.0 -9.2 -38.7 -38.7 -38.7 64/20 6H 218

A-2 -28.2 -54.9 -37.1 -54.7 -63.6 —63.6 80/38 3H 382 A-34 12.8 -16.6 -8.2 (0) -19.0 -19.0 80/68 26H 125

A-38 -24.6 -58.3 -48.7 -42.0 -66.1 -66.1 (0) 133

Blood sugar was determined in another patient in

found to be 216 mg. per 100 cc. of blood.

Case of crush injury.

(0): Not measurable.

severe shock (Case 112) 11 hours after wounding and
THE PHYSIOLOGIC EFFECTS OF WOUNDS 52

Chart 4. Blood Volume Loss in Relation to Location

of Wound

The findings in these 59 patients, and in others who had combined thoracoabdominal wounds, are presented in Tables 17 and 18, and in Charts and 5.

The huge standard errors present in several instances indicate the wide variations in the results found. From the table it would appear that loss of blood

volume was greatest in the patients with peripheral wounds (Table 17). However the number of cases was small, the variability in the data was wide, and

the true state of affairs possibly was masked by dilution of the blood volume

after wounding by movement of fluid from the tissues to the blood stream.

The data on hemoglobin loss are probably more revealing. There is significantly greater loss of hemoglobin in men with peripheral wounds than in

those with abdominal wounds (Table 18) and in this case the situation is not
INTERNAL STATE ON ENTRY TO HOSPITAL 53

Chart 5. Hemoglobin Loss in Relation to Location of

Wound

obscured by the factor of hemodilution. This difference is in agreement with

the previous finding that more patients with compound fractures of long bones

Table 17.—Relationship of Blood Volume Loss to Type of Wound

Type of Wound Number of

Cases

AverageBlood Volume Loss

Percent of calculated normal

From Observed Value By Correction By Correction

Peripheral 32 20.8±3.0 34.2 ±3.2 28.2 ±3.1

Abdominal 13 7.6±3.6 21.3±6.2 16.4±5.5

Thoracic 14 17.9±2.6 28.6±4.6 21.4±2.3

Thoraco-abdominal 6.6±6.8 13.7±5.5 10.3±6.2

Total 65 16.2±1.9 28.5 ±2.5 22.7 ±2.1

All determinations before operation and anesthesia.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 54

Table 18.—Relationship of Hemoglobin Loss to Type of Wound

or traumatic amputations were in severe shock than were those with abdominal wounds (Tables and 7). Data on the comparison of blood loss in the

two types of serious extremity wounds are scanty but are presented for what

they are worth, Table 19. The blood loss in patients with compound fractures was greater than it was in those with traumatic amputation, probably

because of the greater tissue damage usually found in the former.

Table 19.—Loss of Blood Volume and Total Hemoglobin in 31 Patients

with Severe Extremity Wounds

Table 20 shows the average blood volume and hemoglobin losses in 40 patients with all types of wounds who had received either none or small amounts

of plasma but in no instance more than unit before the determinations were

made. The losses here are less than those shown in Tables 17 and 18 because

the group includes fewer of the patients in severe shock. Again greater average loss of hemoglobin than of blood volume is shown. This is explained by

Average HemoglobinLoss

Type of Wound Number of

Cases

Percent of calculated normal

From Observed Value By Correction

Peripheral

Abdominal

Thoracic

Thoraco-abdominal

32

13

14

40.0±3.4

17.3±6.0

34.4±3.2

20.3 ±6.5

46.0±3.1

24.0±6.4

37.8±3.2

23.6±6.3

Total 65 32.5 ±2.5 37.8±2.6

All determinations before operation and anesthesia.

Type of Wound No Fracture Compound Fracture Traumatic

Amputation

Average Blood Volume Loss

(By Correction A)

Average Hemoglobin Loss

(By Correction B)

21.9±8.1

(7 cases)

32.8±7.0

(7 cases)

40.8±4.2

(19 cases)

5I.6±4.2

(19 cases)

27.0±3.2

(5 cases)

43.0±3.9

(5 cases)

Percent of calculated normal.
INTERNAL STATE ON ENTRY TO HOSPITAL 55

hemodilution which normally takes place after blood loss. Red blood cells are

not replaced appreciably during the interval from wounding to arrival at

forward hospital except by transfusion.

Table 20.—Loss of Blood Volume and Total Hemoglobin in 40 Patients

whohad Received Unit or Less of Plasma

Relationship to Type of Wound

Relationship of Blood Loss to Time from Wounding

There was no important average increase in blood volume loss or in hemoglobin loss with increased time elapsing between wounding and hospital entry

(Table 21). However, those men who were suffering from continuing blood

loss were probably given priority of evacuation. Somewhat greater blood losses

were usually found in those who arrived at the hospital soon after wounding

than in those who were brought in later.

Table 21.—Relationship of Blood Loss to Time from Wounding in 67 Cases

(All Types of Wounds)

Type of Wound Number of

Cases

Average Blood Volume

Loss

(By Correction A)

Percent of calculated

normal

Average Hemoglobin

Loss

(By Correction B)

Percent of calculated

normal

Peripheral 18 23-9±3.9 38.0±4.3 All Other 22 5.2 ±2.9 22.5 ±3.8

Total 40 19-1 ±2.4 29.5±3.1

All determinations before operation and anesthesia.

Time from Wounding

Hours

Number of

Cases

AverageBlood Volume

Loss

(By Correction A)

Percent of calculated

normal

Average Hemoglobin

Loss

(By Correction B)

Percent of calculated

normal

None to 41 29.0 37.5

to 12 17 31.9 42.3 13 and Over 24.7 35.8
56 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Relationship of Blood Loss to Degree of Shock

It is well known that individuals do not respond alike to given blood loss;

even previously healthy, normal young soldiers vary greatly in their response.

This fact, together with the inexactness inherent in any clinical appraisal of the

degree of shock plus the errors of the experimental method used, might have

tended to obscure real relationship between shock and blood loss. However

this relationship was so striking that, even with the relatively small number of

cases, the positive correlation of blood loss to the severity of shock was statistically significant (Table 22 and Chart 6).

Table 22. Relationship of Blood Loss to Degree of Shock in 67 Cases

(All Types of Wounds)

The degree of wound shock as we saw it in men injured in battle precisely paralleled the quantity of blood actually lost. Conversely, recovery from

shock resulted promptly from administration of whole blood. Although we

made intensive search at the bedside of thousands of wounded men throughout

the shock tents in Italy, we never found clear case of “irreversible shock,”

mentioned so frequently in the literature. It is true that there were wounded

men in whom the loss of blood was so rapid and so great that it was impossible

to transfuse them with blood fast enough to save their lives. (For example, we

were unable, in the case of the soldier who had both thighs blown off by

shell burst just outside our door at Anzio to get blood into him fast enough

to save his life; he died in very few minutes.) Nor were we able to resuscitate patients who had had inadequate circulation in the central nervous system

Number

Average Blood Loss

Percent of calculated normal

Degree of Shock of

Cases From Observed Value By Correction

Volume Hemoglobin Volume Hemoglobin

None 11 10.5db4.1 17.4±6.4 14.4±4.9 20.0±6.7

Slight 20 11.2±6.5 25.0±4.4 20.7 ±4.1 29.7 ±4.2

Moderate .... 21 21.7±3.1 4l.7±3.3 34.3±3.7 46.1 ±3.3

Severe 15 22.0±3.9 44.3 ±4.3 45.9±4.6 55.5 ±4.5
INTERNAL STATE ON ENTRY TO HOSPITAL 57

Chart 6. Relationship of Blood Loss to Degree of Shock

so long that nearly all centers except the respiratory appeared to be dead; we

were not able to overcome death of organs or of nervous tissue by resuscitative

effort. But we believe that application of the term “irreversible shock” to either

type of case is to use definition that has no place at the bedside, however

interesting it may be as concept, and that may do real harm by providing an

excuse for limiting resuscitative effort.

In short, if “irreversible shock” in the accepted sense was present, we missed

it. If toxins caused any of the shock we saw, with the exception of that due to

overwhelming and clinically apparent bacterial infections, we failed to recognize it. The shock we saw was caused by loss of blood (or of fractions of the

blood). It was relieved by administration of whole blood.

From our data it may be said that, in general, when third of the blood

volume is lost, clinical shock of more than slight degree will result, and when

half is lost, severe shock will result. It was also shown that in individual cases

as much as 75 percent of the blood could be lost and the patient survive.

Cases A-17, A-21, A-29, A-37, A-38, 127, and 139 are examples of severe

blood loss and survival. The greatest blood volume losses found were 78.6 percent in Case 107 and 75.7 percent in Case 139 (Table 16, and D). Both de-
58 THE PHYSIOLOGIC EFFECTS OF WOUNDS

terminations were obtained by Correction A. Shock was moderate in the first

case and severe in the second. The greatest loss of total hemoglobin found was

83.8 percent in Case —21 (Table 16, D). This patient had serious extremity

wounds and was in severe shock.

Our data also indicated that, on arrival at the hospital, generally the deficiency in total hemoglobin was greater than the deficiency in blood volume.

This is understandable in view of the well-known mechanism for replenishing

blood volume at the expense of tissue fluid. On the other hand, once the readily

available reserves of hemoglobin have been called into action, no mechanism

is available to replace them rapidly; consequently it would be expected that

greater deficiencies would be found in the total hemoglobin.

There was no correlation between passage of time and the degree of shock

encountered, in that the elapsed time was the same in each of the four categories of no shock, slight, moderate, and severe shock. This does not say that

continuing hemorrhage, for example, is not related to degree of shock; certainly it is, but the important factor in the development of shock is the character of the wound, particularly as it indicates the quantity of blood lost, not

the passage of time per se.

We have tried various ways of handling the data on shock. Some investigators have attempted to separate the effects of blood loss alone from the effects supposedly accounted for by “sympathico-adrenal activity.” Practically,

this is impossible. Moreover, the validity of any such separation even if possible

must be questioned. For example there is the matter of increased glycogenolysis

in shock. Following all the recent advances in knowledge of carbohydrate

metabolism, it seems to be too great simplification to hang the explanation

on the rather shaky peg of “sympathico-adrenal activity,” so we take refuge in

our purpose of merely stating our findings, with little conjecture, and leaving

to future study the search for their significance.

One great consequence of blood loss is the intense vasoconstriction, the

shrinkage of the capacity of the vascular bed to accommodate the decreased

blood volume. Contraction of the spleen probably plays relatively small role

in compensating for the blood lost in battle. Other body adjustments to blood

loss do, however, take place, such as the entry of fluid into the blood vessels in

an attempt at compensation. The greatest extravascular store of readily available fluid in the body is that in the extracellular space. Dehydration and oligemia may make quite early demands, not only on this extracellular but also

on the intracellular supply.
INTERNAL STATE ON ENTRY TO HOSPITAL 59

Biochemic Changes Encountered

The clinical appearance of the newly wounded man, as well as his subsequent course, offers abundant evidence that profound changes have occurred

in his internal state by the time he is admitted to hospital. To be reported

here are chiefly the changes found in the blood although certain urinary findings also are recorded. These changes are significant not only because they reveal the problem at hand, but also because they offer some basis for reasonable

therapy. Several factors influence the presence or extent of the abnormalities

found. These are discussed in the following sections.

Blood Chemistry Findings

Relationship to Location of Wound.—No significant relationship was found

between the location or type of the wound and the plasma nonprotein nitrogen, creatinine, uric acid, phosphorus, or magnesium (See Table 24, page 60).

Average values for serum sodium, plasma chlorides, and plasma carbon-dioxide

combining power also were determined and likewise failed to show any significant relationship to the type of wound.

Relationship to Delay in Hospital Arrival.—With increased passage of time

following wounding, the average plasma nonprotein nitrogen level rose (Table

23). This upward swing of the nonprotein nitrogen offers basis for some interTable 23.—Relationship of Plasma Nonprotein Nitrogen Level to Time

from Wounding in 92 Patients with all Types of Wounds

Time from

Wounding

hours

Average Nonprotein

Nitrogen

mg. per 100 cc.

Type of Wound

Percent

of

Cases

Peripheral 48

to (48 cases) 34.2±1.1 Abdominal and thoraco-abdominal. 33

19

Peripheral 73

to 13 (26 cases) 4l.2dbl.7 Abdominal and thoraco-abdominal. 12

Thoracic 15

Peripheral 67

13 or More (18 cases) 46.3±3.2 Abdominal 22

11

Averages based on determinations made before operation and anesthesia.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

—Biochemic 24.

Findings in

Relation to

Type

and Locationof

Wound

Type

of

Wound

Nonprotein Nitrogen

Creatinine

NPN

Uric

Acid

Phosphorus

Magnesium

mg.

per

100

cc.

mg.

per

100

cc.

Creatinine 10

mg.

per

100

cc.

mg.

per

100

cc.

mg.

per

100

cc.

Peripheral (Without

fracture)

39.0±3.7 (11

cases)

1.7db0.1(11

cases)

2.6±0.20 (11

cases)

5.0 (5

cases)

4.5±0.65 (6

cases)

2.3 (5

cases)

Peripheral (With

fracture)

4l.0±1.8 (32

cases)

1.6±0.10(31

cases)

2.7±0.13 (31

cases)

4.4±0.50 (19

cases)

4.9±0.50 (24

cases)

2.3±0.13 (20

cases)

Peripheral (With

traumatic

amputation)

47.0±4.3 (6

cases)

1.5

±0.30 (6

cases)

3.7±0.65 (6

cases)

5.5 (2

cases)

4.9 (4

cases)

2.0 (3

cases)

Abdominal

34.0±2.2 (19

cases)

1.4±0.1(19

cases)

2.7±0.12 (19

cases)

4.9±0.59 (16

cases)

3.9±0.30 (17

cases)

2.0±0.10 (16

cases)

Thoraco-abdominal

38.0±3.1 (7

cases)

1.5±0.28 (7

cases)

3.0±0.37 (7

cases)

6.1 (5

cases)

4.5±0.55 (7

cases)

2.0 (5

cases)

Kidney

Injury

35.0±2.9 (9

cases)

1.5±0.25 (9

cases)

2.6±0.29 (9

cases)

6.5±0.99 (6

cases)

4.0±0.50 (9

cases)

2.0±0.12 (7

cases)

Liver

Injury

37.0±3.0 (10

cases)

1.3±0.10 (10

cases)

3.0±0.23 (10

cases)

5.8±0.98 (6

cases)

3.9±0.40 (9

cases)

2.0±0.10 (6

cases)

Thoracic

36.0±2.5 (14

cases)

1.3±0.15 (14

cases)

2.9±0.26 (14

cases)

4.1

±0.63 (8

cases)

4.2

±0.28 (13

cases)

1.9±0.10 (11

cases)

Averages

basedon

determinations made

before

operation

and

anesthesia.

With

and

without kidney

and

liver

injury.
INTERNAL STATE ON ENTRY TO HOSPITAL 61

esting speculation, out of place here, but one might ask in passing: Is this rise reflection of decreased renal blood flow? Does this rise mean that renal impairment is initiated by the wound and continues, with accumulation of nonprotein nitrogenous waste products Does this presumed malfunction set the stage

for later trouble with the kidneys? The plasma creatinine level did not rise

significantly with the passage of time preceding hospital entry, nor did that of

uric acid, phosphorus, or magnesium (Table 25). Also no correlation was

found between passage of time and levels of plasma chlorides, serum sodium,

or plasma carbon-dioxide combining power.

Table 25.—Relationship of Several Plasma Constituents* to Time from

Wounding

Relationship to Clinical Condition.—The interesting relationships of the

plasma nonprotein nitrogen, creatinine, phosphorus, and magnesium to the

degree of shock are shown in Table 26. Statistically significant rises occurred

for nonprotein nitrogen, phosphorus, creatinine, and magnesium in progressive categories from “no shock” to “severe shock,” with the chief difference

occurring between the moderate- and severe-shock groups. The rise in uric acid

was not statistically significant. When these substances were compared with

blood loss, the same positive correlation was found for the nonprotein nitrogen,

creatinine, phosphorus, and magnesium, as would be expected. Again the correlation in the case of uric acid was not significant. These comparisons are

shown in Table 27; blood loss was divided into five categories from no loss to

loss of more than 40 percent of the calculated normal blood volume.

Data relevant to acid-base balance are presented in Tables 28 and 29 and

Chart 7. An acidosis was present in those patients with severe shock and is

Time from Wounding

hours

Creatinine

mg. per 100 cc.

Uric Acid

mg. per 100 cc.

Phosphorus

mg. per 100 cc.

Magnesium

mg. per 100 cc.

to 1.3±0.1 4.5 ±0.4 4.4±0.3 2.1 ±0.1

(50 cases) (38 cases) (49 cases) (41 cases)

to 13 1.6±0.1 4.7 ±0.5 4.8±0.3 2.1 ±0.1

(26 cases) (15 cases) (19 cases) (15 cases)

13 to 24 1.7 ±0.2 5.9±0.7 4.2 ±0.5 1.8±0.1

(19 cases) (7 cases) (11 cases) (9 cases)

Averages based on determinations made before operation and anesthesia.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

—Biochemic 27.

Findings* in

Relationto

Blood

Loss

Table

26.

—Biochemic Findings*in

Relation to

Shock

Degree

of

Shock

Nonprotein Nitrogen mg.

per

100

cc.

Creatinine mg.

per

100

cc.

NPN Creatinine 10

Uric

Acid

mg.

per

100

cc.

Phosphorus mg.

per

100

cc.

Magnesium mg.

per

100

cc.

No

Shock Slight

Shock Moderate

Shock

Severe

Shock

34.0±1.5 (18

cases) 35.0±1,8 (24cases) 37.0±1.6 (32cases) 44,0±2.1 (24cases)

l.0±0.05 (18

cases) 1.3

±0.09 (24

cases) 1.4±0.08 (32cases) 2.

±0.

15

(23

cases)

3.3

±0,12 (18

cases) 2.9±0.

17

(24

cases) 2.8

±0.1 (32

cases) 2.

±0.15 (23

cases)

4.0

±0.62 (10

cases) 4.

±0.41 (16

cases) 4.8

±0.6 (17

cases) 5.2

±0.56 (16

cases)

3.3

±0,24 (14

cases) 3.8

±0.18 (20

cases) 4.3

±0.23 (24

cases) 5.8±0.52 (21cases)

1.7±0,05(11

cases) 1.9

±0.06 (17

cases) 2.0

±0.09 (20

cases) 2.

±0.16 (16

cases)

Averages

basedon

determinations made

before

operation

and

anesthesia.

Blood

Volume

Loss

(By

Correction

A)

Nonprotein Nitrogen

Creatinine

NPN

Uric

Acid

Phosphorus

Magnesium

Percent of

calculated

normal

mg.

per

100

cc.

mg.

per

100

cc.

Creatinine 10

mg.

per

100

cc.

mg.

per

100

cc.

mg.

per

100

cc.

to to

15

15

to

25

25

to

40

Over

40

31.0±3. (9

cases) 36.0±2.4 (9cases) 37.0±2,3 (12

cases) 38.0±2.3 (19cases) 41.0±2.2 (18cases)

1.0±0.07(9

cases) 1.

±0.05 (9

cases) 1.3

±0.14 (12

cases) 1.7±0. 18

(19

cases) 1.8±0.13 (18cases)

3.1

±0.19 (6

cases) 3.2

±0.20 (9

cases) 3.0

±0.17 (12

cases) 2.6

±0.17 (19

cases) 2.5

±0,18 (18

cases)

4.4

±0.76 (6

cases) 4.8

±0.73 (9

cases) 3.9

±0.42 (9

cases) 5.0±0.53 (16

cases) 4.8

±0.60 (16

cases)

3.2

±0.34 (8

cases) 3.7

±0.

18

(9

cases) 4.0±0.28 (12

cases) 4.2

±0.33 (17

cases) 5.

±0.58 (18

cases)

1.8

±0.07 (8

cases) 1.9±0.07(9cases) 1.8

±0.08 (I

cases) 2.1

±0.10 (17

cases) 2.4±0. 18

(18

cases)

Averages

based on

determinations made

before

operation

and

anesthesia.
63 INTERNAL STATE ON ENTRY TO HOSPITAL

CHART 7. Plasma electrolytes (on hospital

admission) in relation to shock

reflected in the carbon-dioxide combining power. significant fall of carbondioxide combining power was correlated with shock (Table 28). Evidence that

these low values are due to metabolic acidosis will be presented in the discussion of azotemia in Chapter IV. Plasma chlorides were uniformly normal

in all shock categories (Table 28); likewise, urinary chlorides were essentially

normal although they showed wide variations in concentration (Table 29).

There was, then, no evidence of salt deprivation on hospital entry. Phosphates,

although significantly higher in terms of total anions in those in severe shock

than in those with no clinical evidence of shock, could have had little effect on

the acid-base balance. Plasma proteins are not included in Table 28, but they

showed insufficient variation in terms of electrolyte concentration to have affected acid-base balance.

The plasma was examined for lactic acid in patients shortly after they

were wounded. The findings were compared with those in normal, active
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

28.

—Plasma

Electrolyteson

Admission in

Relation to

Shock

Average

Electrolytes mEq./L.

All

Cases

No

Shock

Slight

Shock

Moderate

Shock

Severe

Shock

Carbon-dioxide

Combining

Power

25.3±0.5

7.9

1.0

26.1

±0.7

26.1

±0.9

22.1

±0.9

(93

cases)

(13

cases)

(22

cases)

(3

cases)

(2

cases)

Chlorides

100.5±0.6

102.0±3.0

101.0±0.7

100.0±0.5

99.5

±0.9

(9

cases)

(13

cases)

(24

cases)

(33

cases)

(24

cases)

Phosphates

3.0±0.2

2.2

±0.3

2.5±0.2

2.9±0.3

4.0±0.5

(78

cases)

(13

cases)

(20

cases)

(2

cases)

(20

cases)

Magnesium

1.8±0.07

1.4±0.05

1.6±0.06

1.8±0.10

2.2

±0.16

(64

cases)

(11

cases)

(18

cases)

(19

cases)

(16

cases)

Sodium

**

144.3(15

cases)

142.1 (6

cases)

147.1 (4

cases)

144.7 (5

cases)

Crush cases

not

included.

**

On

bloodserum.

mEq./L

=milliequi

valent

levels.
65 INTERNAL STATE ON ENTRY TO HOSPITAL

Table 29.—Preoperative Urinary Findings in Relation to Shock

soldiers and in 10 bed patients convalescing from severe wounds. The results

are recorded in Table 30. They show twofold increase in the concentration

of lactic acid in the wounded when compared with normal, active soldiers and

with convalescent bed patients.

Table 30.—Concentration of Lactic Acid in Plasma in Severely Wounded

Subjects and Controls

Average Average Sodium No Sodium

Chlorides Received since since

Degree of Shock Average pH

mg. per 100 cc.

Wounding Wounding

as NaCl grams number of cases

No Shock 6.3±0.2 1,128± 185 1.0

(7 cases) (5 cases) (4 cases)

Slight Shock 5.7=h0.1 945±l69 0.8

(6 cases) (8 cases) (5 cases)

Moderate Shock ....

5.7 ±0.1 423±185 3.7

(6 cases) (5 cases) (4 cases)

Severe Shock 5.7 ±0.2 704±24l 3.2 None

(7 cases) (5 cases) (7 cases)

All Cases ....

5.9±0.1 819d-105 2.2

(26 cases) (2 cases) (20 cases)

Note; Specific gravity of urine: 1.027 ±0.001 (26 cases).

10 grams of sodium citrate furnish 2.3 grams of sodium. 10 grams of sodium bicarbonate furnish 2.7 grams ofsodium.

Subjects

Lactic Acid Concentration in the Plasma

mg. per 100 cc.

Minimum Maximum Average

Normal Controls (7 active soldiers)

Wounded Examined to 19 Hours (average 10

17 24 21

hours) after Wounding

(5 cases)

Patients in third to fifth Week of Convalescence

29 46 38

from War Wounds

(10 cases)

14 21 16
66 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 31.

—Average Plasma

Bilirubin and

Hemoglobin

Levels in

Patients with

Various

Types of

Table 32.

—Average Plasma

Bilirubin and

Hemoglobin Levelsin

Relation

to

Time

from

Wounding Wounds

Type

Intra- abdominal

Thoraco- abdominal

Peripheral

of Wound

Liver

Kidney

Thoracic

WithFracture

WithoutFracture

Van

den

Bergh

Index

(mg.

of

bilirubin per

100

cc.)

0.36±0.04 (9

cases)

0.42

±0.07 (8

cases)

0.43

±0.1 (15

cases)

0.39±0.04 (7

cases)

0.58±0.07 (15

cases)

0.57±0.05 (36

cases)

0.49±0.12 (6

cases)

Plasma

Hemoglobin (mg.

per

100

cc.)

10.7±1.4(10

cases)

12.8±2.3(8

cases)

10.1 ±1.8 (15

cases)

12.7 ±2.2 (7

cases)

10.1 ±1.6 (15

eases)

10.9±1.1 (42

cases)

11.3

±2.9 (10

cases)

Time

from

Wounding

until

Blood

Sample

Drawn

hours

Van

den

Bergh

Index

mg.

of

bilirubin per

100

cc.

Plasma

Hemoglobin mg.

per

100

cc.

to

0.45

±0.05

11.4±0.9

(47

cases)

(48

cases)

to

12

0.64±0.07

9.4±1.4

(2

cases)

(27

cases)

13

to

24

0.69±0.07

11.1 ±2.1

(13

cases)

(18

cases)
INTERNAL STATE ON ENTRY TO HOSPITAL

Plasma Bilirubin (van den Bergh Index)

and Plasma Hemoglobin Levels

Relationship to Type of Wound.—On comparison of the type of wound with

the plasma bilirubin and hemoglobin, no impressive relationships were found

(Table 31).

Relationship to Time from Wounding.—The van den Bergh index rose

significantly with increases in time from wounding to examination (Table 32).

This may have been due to the absorption of breakdown products from hematomas, and to impaired liver function (see Chapter II). The situation was

simpler at this time (when most of these patients had not yet been transfused

with blood) than it would be later when large volumes of blood had been

given which might tend to elevate the bilirubin level. The plasma hemoglobin level appeared to rise with the passage of time, but this was not significant so far as the data at hand are concerned.

Relationship to Clinical Condition.—There was no clear relationship between degree of shock and the plasma bilirubin or hemoglobin levels (Table

33). However, when the bilirubin level was compared with the blood loss

(Correction A), significant relationship seemed to emerge, although the

values were all at rather low level (Table 34). Presumably the rise is to be

accounted for by hemolysis of blood in damaged tissues, followed by absorption into the blood stream. There was no apparent correlation of blood loss

with plasma hemoglobin levels.

Table 33.—Average Plasma Bilirubin and Hemoglobin Levels in Relation

to Degree of Shock*

Averages based on determinations made before operation and anesthesia. Crush cases not included.

956507 0—52

Degree of Shock

Van den Bergh Index

mg. ofbilirubinper 100 cc.

Plasma Hemoglobin

mg. per 100 cc.

None 0.43 dbO.08 12.1 ±1.8

(11 cases) (14 cases)

Slight 0.68±0.10 11.3±1.6 (23 cases) (2 cases)

Moderate 0.54±0.06 10.8±1.4

(27 cases) (33 cases)

Severe 0.47 ±0.05 8.8±0.9

(21 cases) (24 cases)
68 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 34,—Average Plasma Bilirubin and Hemoglobin Levels in Relation

to Blood Loss*

Table 35.—Average Plasma Glucose Levels in Severely Wounded Men

A. Relationship to Degree of Shock

B. Relationship to Blood Loss

C. Relationship to Time from Wounding

Blood Loss

(By Correction A)

Percent of calculated

normal

None to 5% to 15% 15 to 25% 25 to 40% Over 40%

Plasma Bilirubin

(mg. per 100 cc.)

Plasma Hemoglobin

(mg. per 100 cc.)

0.31 ±0.07

(6 cases)

15.5 ±2.6

(7 cases)

0.56±0.10

(8 cases)

11.2±3.6

(8 cases)

0.50±0.10

(10 cases)

9.8±2.0

(11 cases)

0.52 ±0.05

(20 cases)

14.3±1.6

(20 cases)

0.64±0.11

(18 cases)

10.0±1.2

(18 cases)

Averages based on determinations made before operation and anesthesia. Crush cases not included.

Degree of Shock None Slight Moderate Severe

Glucose Level 134±9 149±9 178±13 202 ±26

(mg. per 100 cc.) (9 cases) (14 cases) (19 cases) (13 cases)

Blood Loss

(By Correction A)

Percent of calculated

normal

None to to 15 16 to 25 26 to 40 Over 40

Glucose Level

(mg. per 100 cc.)

143±12

(6 cases)

159±15

(7 cases)

153±7

(9 cases)

177±18

(17 cases)

194±23

(15 cases)

Time from Wounding None to Hours to 12 Hours 13 to 24 Hours

Glucose Level

(mg. per 100 cc.)

182±13

(36 cases)

161 ±10

(13 cases)

144±7

(8 cases)

Normal: from 80 to 90 mg. per 100 cc. of plasma.
INTERNAL STATE ON ENTRY TO HOSPITAL 69

Chart 8. Plasma Glucose Levels

Blood Sugar

The blood-sugar level was determined in 57 severely wounded men as they

arrived at the forward hospital and was found to be above normal in all of

them (Table 35 and Chart 8). Normal by the method used was considered

to be from 80 to 90 mg. per 100 cc. of plasma. Some of the men had received
THE PHYSIOLOGIC EFFECTS OF WOUNDS

plasma but none had had significant quantity of whole blood before the determination was made. The blood-sugar level appeared to rise significantly both

with increased blood loss and with increased severity of shock (Table 35

and B). The glucose level may fall with the passage of time following wounding, but our data were not extensive enough to demonstrate this (Table 35 C).

Presumably the elevation in blood-sugar level was due to mobilization of liver

glycogen following adrenal activity and probably reflected the emotional and

physical stress the men had experienced.

Table 36.—Urine Tests for Creatine in 32 Patients

Case No.

Preoperative

Specimens

Postoperative

Specimens Degree

of

Shock

Patient’s

Outcome Comment

Positive Negative Positive Negative

89

101

102

106

107

108 Anuria, high azotemia.

109

110

111

112

113

117

118

120

121

123 Oliguria, high azotemia.

124

125

12 Oliguria.

127

129

130 Severe Lived Oliguria, high azotemia.

131 ....do.... Died Oliguria, high azotemia.

133 High azotemia.

A-l

A-2

A-3

A-4

A-5

A-6 NPN tn 60.

A-16 NPN to 63. A-40 Slight ....do....

Total 37 16 L:21

D;ll

Anuria; urinary output of less than 100 cc. daily; oliguria: 24-hour urinary output of 100-600 cc. for at least

day in the posttraumatic period; high azotemia: plasma nonprotein nitrogen over 65 mg. per 100 cc.
INTERNAL STATE ON ENTRY TO HOSPITAL

Urinary Findings

Acid-Base Relationship.—Sodium in the urine was measured in too few

cases for reliable averages. Most of the values found were within the normal

range. Magnesium, like phosphates on the acid side, was increased but not

sufficiently so to affect total acid-base equilibrium. Urinary pH and specific

gravity indicate that these men had essentially normal renal function at the

time they were wounded, in that they could make both an acid and concentrated urine. The acid-base relationship will be discussed further in Chapter III.

Creatinuria.—The appearance of creatine in the urine of adult males is

abnormal. On the assumption that there might be some abnormality in the

metabolism of creatine and creatinine in shock, the urine was examined for

creatine in 32 patients (Table 36). In all, 69 urine specimens were tested;

the results are summarized in Table 37. Creatine was found in the urines

of 26 of the 32 patients. It was present in out of 15 of the patients examined preoperatively, and in 20 out of 29 patients whose urines were examined postoperatively. In 13 of the 32 patients urine tests yielded only positive results, in 11 patients only negative, and in the remaining 9, different specimens tested yielded both positive and negative results.

With one exception (Case 121) all patients who died showed creatinuria

at one time or another. It was also present in approximately half the patients

who survived. In relation to shock, 14 of 18 patients who had been in moderate

or severe shock showed creatinuria. This tendency for creatine to be excreted

in the urine in cases of moderate and severe shock and in fatal cases might

indicate that it is the result of metabolic changes which accompany shock.

Table 37. Summary of Results in 69 Urine Specimens Tested for Creatine

Source Positive Negative

(44 specimens) (25 specimens)

Preoperative

Postoperative 37 16

From Patients with No Shock or Slight Shock 18 11

From Patients with Moderate or Severe Shock 26 14

From Patients Who subsequently Died 20

From Patients Who Lived 24 18
THE PHYSIOLOGIC EFFECTS OF WOUNDS 72

Liver Function in the Newly Wounded Nlan

As will be discussed in Chapter II, the only direct laboratory test of liver

function carried out here was that of the bromsulfalein excretion. The van den

Bergh index and uric acid levels have also been considered as being in part at

least related to liver function.

Bromsulfalein Retention

On Arrival at the Most Forward Hospital.—In 59 severely wounded patients the average bromsulfalein retention on forward hospital arrival was

12.4 1.2 percent (standard error of the mean) 45 minutes after mg. of dye

per Kg. of body weight had been injected intravenously. This is well above the

normal of 1.0 0.1 percent (as established in control group of 45 subjects),

and above our arbitrarily chosen upper limit of normal of percent (see

Chapter II).

Relationship to Time from Wounding.—There was no difference between

the average bromsulfalein retention in 29 men examined within the first

hours after wounding (14.4 ±1.8 percent) and in 19 men examined after the

first hours (13.1 1.6 percent).

Relationship to Location of Wound.—In 22 patients with serious extremity

wounds there was 13.3 2.3-percent average retention, and in 18 patients with

abdominal wounds there was an average of 14.7 2.1-percent retention—no

difference. In men with penetrating chest wounds, however, the average retention was only 7.0 ±1.8 percent, which is significantly lower than that found

in the other groups.

Relationship to Shoc\.—In 57 patients separated into the shock categories

(no shock, slight, moderate, and severe shock) no significant correlation with

bromsulfalein excretion could be found; neither was there any correlation with

blood volume or hemoglobin loss.

Relationship to Plasma Administration.—Curiously enough, there was

great increase in average bromsulfalein retention percent) in 25 men who had had one or two units of plasma, over the average retention

(8.0±2.0 percent) in 15 men who had had none. Three or more units of

plasma did not increase the effect beyond that produced by one or two units.

The effect was transient and disappeared between the first and second day

following operation.
INTERNAL STATE ON ENTRY TO HOSPITAL 73

Plasma Bilirubin and Uric Acid

The bilirubin and uric acid concentrations in the blood have been discussed

earlier in this chapter in relation to other factors studied.

SUMMARY

In the past, battle wounds have been described chiefly in terms of organic

damage or tissue loss. The purpose of this chapter has been to describe, shortly

after the soldier arrived at the forward hospital, the latent consequences of his

wounds as they influenced organic function and produced changes in blood

volume and chemistry, and abnormalities in the urine. These matters were

studied, before vigorous resuscitative efforts had yet been made, in 108 patients.

Altogether, 186 patients were studied in the course of the work carried out by

the Board for the Study of the Severely Wounded.

In considering patients who had received not more than one unit of plasma,

or none at all, it was observed that the hematocrit level was higher in those

with abdominal wounds than it was in those with peripheral wounds, but even

in the patients with abdominal wounds the average hematocrit values were

somewhat below normal. While severe hemoconcentration can occur in cases

of burns, crush, and abdominal wounds, this was infrequent in our series and

was by no means general characteristic of shock as we saw it.

When the patients who had received little or no plasma or blood therapy

at the time of first examination were divided into two groups, depending upon

whether more or less than 30 percent of the blood volume had been lost,

puzzling situation was apparent: the average concentration of protein in the

plasma in the more severely bled-out group was 6.1 grams per 100 cubic centimeters. This is 6.1 percent below normal. On the other hand, the average

hematocrit value in this same group had fallen to 36 from the normal of 47,

reduction of 23.4 percent. The hematocrit level thus fell about four times as

much as that of the plasma proteins. One implication of this is that the blood

had been diluted with protein-rich fluid. Its possible source is discussed.

Evidence is presented that the plasma protein level was not influenced by

plasma therapy, although the hematocrit level was. There was sharp fall in

hematocrit value with increasing severity of shock. Other examples of the

independent variation of these two factors are given.

It is shown that men can lose about 75 percent of their blood and yet re-
74 THE PHYSIOLOGIC EFFECTS OF WOUNDS

cover—more than had been generally supposed. Blood loss in various types of

wounds is discussed. Data presented show that there was quantitative relationship between loss of blood volume or hemoglobin and the degree of shock

met clinically. This supports the view that the major cause of the shock we

encountered was hemorrhage.

No important differences in blood volume or hemoglobin loss were encountered with the passage of time from wounding to examination. This was

possibly to be accounted for by the high priority and consequent rapid evacuation given to patients with bleeding wounds.

The clinical condition of the newly wounded man offers abundant evidence that his internal state has been profoundly altered by the time he enters

forward hospital. In addition to the matters already mentioned, this was

studied in terms of nitrogenous waste products, electrolytes, bilirubin, and

blood sugar. In general, these substances were found not to be influenced by

the location of the wound. The plasma nonprotein nitrogen level rose rather

strikingly with delay following wounding. The full significance of this is not

clear, but it offers grounds for some interesting speculation. Examination of the

four shock categories in sequence from “no shock” to “severe shock” shows significant rises in nonprotein nitrogen, creatinine, phosphorus, and magnesium.

Acidosis was present in the patients in severe shock. They showed considerable fall in carbon-dioxide combining power as compared with that of

patients with no clinical evidence of shock. The acidosis appeared to be of the

“metabolic” type.

No evidence of salt deprivation was found on hospital entry. Examination

of the admission urine specimen with regard to hydrogen ion concentration

and specific gravity indicated that the men studied had essentially normal

renal function at the time they were wounded.

The van den Bergh index rose significantly with increasing time from

wounding to examination. This is discussed briefly. No clear relationship of

shock to bilirubin or plasma hemoglobin levels was found. The blood-sugar

level was found to be above normal. It was particularly high in the patients

with severe shock.

Definite depression of liver function, as measured by bromsulfalein retention, was found on hospital arrival. We found no correlation between liver

function and the degree of shock. The administration of one or two units of

plasma appeared to impair liver function still further. This was transitory

effect and was not increased by giving three or four units of plasma.
CHAPTER II

Liver Function in the

Severely Wounded

Methods

The only specific laboratory test of liver function used in this study was

that of bromsulfalein excretion, although the van den Bergh index and uric

acid levels were also considered in conjunction with liver activity. The test was

selected because of facilities available and on the basis of experience of the

group studying infectious hepatitis in the Mediterranean Theater of Operations.

Procedures

The standard procedure for the determination of bromsulfalein dye retention, using the Hynson, Westcott and Dunning Comparator Block, was

abandoned for the following reasons: Various degrees of hemolysis in the samples of plasma would result in readings that indicated as much as 5-percent

retention when no bromsulfalein was present. Therefore low-retention figures

could not be accurately determined, as results were often not reproducible to

within 5-percent retention. Furthermore the method was time-consuming.

The test was set up on the Coleman Junior Spectrophotometer Model No. 6,

using 1: dilution of plasma, and reading the color of the alkalinized bromsulfalein at 575 millimicrons. Five milligrams of bromsulfalein dye per kilogram of body weight were injected intravenously and 45 minutes later blood

sample was drawn from different vein. In brief, the procedure (fully described in Appendix C) was as follows:

1. To cc. of plasma in cuvette were added cc. of 0.9-percent solution

of sodium chloride. These ingredients were well mixed and the spectrophotometer

was set to read 100-percent transmission at 575 millimicrons.

2. Three drops of 10-percent solution of sodium hydroxide were added to

the same tube; the tube was inverted once and was read in the spectrophotometer.
76 THE PHYSIOLOGIC EFFECTS OF WOUNDS

3. The transmission percentage was observed and the percentage of dye

retention recorded from the standard curve.

Standards of Normal and Abnormal Function (Controls)

In order to establish standard of liver function that would be normal for

our particular subjects who were all combat soldiers, 50 apparently healthy

men on active duty in the combat zone were selected at random as control

group. The men selected were hospital personnel, ranging in age from 19 to

45 years, the average age being twenty-nine. Forty-five minutes after injection

of bromsulfalein, 45, or 90 percent of the subjects, had less than 3-percent retention of the dye, with an average retention of i.o±o.i percent (standard

error of the mean) for the group.

Five subjects, or 10 percent of the group, had more than 3-percent retention of the dye after 45 minutes, as shown in Table 38. It seems reasonable

that the first three (Subjects A, B, and C) and possibly all five of these men

may be considered to have had abnormal liver function of some degree, since

the percentage of dye retention persisting after 45 minutes was “abnormally”

high for this group. In any case, since 90 percent of men with apparently

normal liver function had less than 3-percent bromsulfalein retention 45 minTable 38.—High Retention of Bromsulfalein in Subjects* of Control

Group

Subject

Percentage of Retention

after 45 Minutes

Comments

First Test Second Test

(1 month later)

16.0 4.0 Improvement indicates that impaired function was present at time of first test.

3.5 4.3 Subject had had jaundice /i years previously.

Palpable liver, fingers below costal margin on inspiration. Liver disease present.

15.2 15.6 Persistent high retention. Liver definitely

abnormal.

7.2 3.9 Possibly abnormal function. 5.8 7.6 Weight of subject 105 Kg. Possibly abnormal

liver function.

None of these subjects had any definite clinical symptoms of poor liver function.
LIVER FUNCTION IN THE WOUNDED 77

utes after mg. per Kg. of body weight were injected, we arbitrarily chose

3-percent dye retention as the upper limit of normal.

Liver Function in Severely Wounded Patients

on Entry to the ISLost Forward Hospital

The average severely wounded battle casualty showed considerable impairment of liver function as measured by bromsulfalein retention on hospital

entry. The average dye retention in 59 severely wounded patients was 12.4 percent±i.2 percent, which is well above the arbitrary normal limit of percent.

This finding was considered in connection with several factors. As in the entire

study, the number of patients on whom various combinations of findings are

shown represent the maximum number available for that particular comparison.

Relationship to Time from Wounding

Forty-eight patients were divided into two groups according to whether

liver function was measured (a) within the first hours following wounding

or (b) more than hours after wounding. The average percentage of dye retention was found to be: for (a), 14.4=!=1.8 percent (29 patients); for (b),

13. ±i.6 percent (19 patients). It was therefore concluded that there was no

relationship between time from wounding and bromsulfalein retention.

Relationship to Location of Major Wound

Twenty-two patients with severe extremity wounds had an average retention of i3,3±2.3 percent; 18 patients with abdominal wounds i4.7±2.i percent, and 11 patients with chest wounds 7.o±i.8 percent. If conclusion may

be drawn from this small number of patients, those with chest wounds appeared to have significantly less dye retention than those with wounds of the

extremities or of the abdomen. Patients with direct injury to the liver had

somewhat higher average retention (18.4 percent) than those with abdominal

wounds without direct liver injury (14.7 percent). However there was such

wide spread in the data, particularly in the patients with direct liver damage,

that the difference between the two groups cannot be considered significant.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chart 9. Comparison of Degree of Shock, Blood Loss,

and Liver Function

Relationship to Shock and Blood Loss

Whether liver malfunction increases with the presence and severity of

shock was considered. Bromsulfalein retention was measured in 57 patients

classified according to degree of initial shock, and the mean values are shown

in Table 39. The test was made, on the average, from to hours after wounding. No significant increase in bromsulfalein retention was found with increased severity of shock; in fact dye retention was just as high in the patients

without shock as it was in those with slight or moderate degrees of shock.

Although slight increase in retention is shown for patients in severe shock,

there was considerable spread in the bromsulfalein data, as indicated by the

large standard errors of the mean, and this increase is not significant. It is

possible that larger series might have shown some correlation with severe

shock. As might be expected, there was also no correlation of bromsulfalein

retention with blood volume loss or total hemoglobin loss (Table 40). Chart

compares this lack of correlation with the high correlation between degree of

shock and blood loss (volume and hemoglobin) which was brought out in

Chapter I.

Liver function was clearly impaired in these severely wounded patients. It
LIVER FUNCTION IN THE WOUNDED 79

Table 39.—Bromsulfalein Retention and Shock

was just as much affected in those without shock as it was in those with severe

shock. Shock therefore was evidently not the key to this condition. The

great deterioration of the circulation found with increasing degrees of shock

did not appear to strain liver function measurably insofar as can be judged

from these data. The main cause of the impaired function must be sought

elsewhere.

Before it is assumed from these findings, however, that there was no more

impairment of liver function in those patients who had severe shock than in

patients without shock, the question should be raised as to whether the degree

of liver impairment could be masked by the given dose of bromsulfalein in

patient who, for example, had lost 50 percent of his normal blood volume. In this

instance the given dose of dye would be abnormally concentrated, since it

would be less diluted in the abnormally small volume of blood present. PerTable 40.—Bromsulfalein Retention and Blood Loss

Time from BromNumber Wounding to sulfalein

Degree of Shock of Test Retention

Patients

hours percent

None 10 5.9±1.5 11.6±2.3

Slight 17 6.0± 1.8 11.9±2.2

Moderate 17 6.5±0.6 11.1 ±2.7

Severe 13 8.1 ±1.7 13.5±1.7

Known in only 11 cases.

Number

of

Patients

HemoglobinLoss

(By Correction A*)

percent of calculated norfnal

Average

Bromsulfalein

Retention

percent

Number

of

Patients

Blood Volume Loss

(By Correction A*)

percent of calculated normal

Average

Bromsulfalein

Retention

percent

II to 12.2 ±3.2 22 to 25 I1.1 ±1.9

17 26 to 45 11.2 ±2.1 18 26 to 45 13.8±2.3

22 Over 45 14.3±2.1 12 Over 45 14.8±3.3

Observed value less all blood or

termination.

plasma administered from time of wounding to completion of the de-
THE PHYSIOLOGIC EFFECTS OF WOUNDS

haps an impaired liver would be able to excrete greater absolute quantity of

such unusually concentrated dye (unusually concentrated because of the abnormally small total volume of blood diluting it) than it would if the usual

dilution of the dye had occurred. If so, this conceivably could mask liver impairment. Moreover, if normal circulation is preserved longer in the liver than

it is in other organs, then good excretion of the dye might occur even in the

presence of abundant blood loss and severe clinical shock. While it seems unlikely that these factors could account for the apparent masking of liver impairment as consequence of severe shock, they must be considered.

Effect of Blood Plasma Therapy on Liver Function

There seemed to be significant increase in bromsulfalein retention following administration of one or two units (250-500 cc. total volume) of plasma

(Table 41). However, there was no further increase after administration of

Table 41.—Effect of Blood Plasma Therapy on Bromsulfalein Retention

three or more units. Whole blood, on the other hand, showed an opposite

effect. At the time these bromsulfalein determinations were made, only negligible quantities of whole blood had been transfused. By the first day following

operation, large quantities of blood, up to several liters in given cases, had

been transfused, yet dye retention was less than it had been on the patients’

hospital entry. The whole picture is puzzling and one would like to see more

data. If the increase in dye retention following administration of plasma was

real effect, it was transient one, and if real, might it have been due to the

preservative used in the plasma, or to the foreign protein in pooled plasma?

Average Bromsulfalein Retention

percent

No Plasma

Administered

Plasma Administered

units*

or or more

On Admission 8.0±2.0

(15 cases)

14.0±2.0

(2 cases)

13.7±2.0

(16 cases)

First Postoperative Day 7.2 ±2.2

(10 cases)

9.7±2.1

(16 cases)

6.6±1.7

(7 cases)

unit =300 cc. total volume.
LIVER FUNCTION IN THE WOUNDED 81

Chart io. Bromsulfalein Retention and Patients’

Outcome

Postoperative Course and Liver Function

In Table 42 liver function is considered in relation to the patient’s outcome. Average bromsulfalein retention, measured during the preoperative

period and the first postoperative days, is shown for those who lived and

those who, either in the period covered or subsequently, died, as well as those

who at this time or later developed “high azotemia.” The first group, showing

bromsulfalein retention in those who lived, is the only one in which the data

can be considered in any satisfactory quantitative sense (Chart 10). Not only

are the cases relatively few in the other groups, but since death had not occurred nor had uremia or high azotemia appeared in many instances until

considerably later than the time interval covered by this table, the high bromsulfalein retentions of those who died in the first four or five days are masked

by patients whose values were normal at this time but later became abnormal.

The data shown in Table 42 are given, however, because they do show qualitatively typical trend.

In this study “high azotemia” was defined as plasma nonprotein nitrogen level of 65 mg. per

100 cc. or higher at any time in the posttraumatic period.
82 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 42.—Bromsulfalein Retention and Patients’ Outcome

So many factors influence the bilirubin and uric acid levels in the plasma

that there is little point in discussing them in detail here; however, Tables 43

Table 43.—Plasma Uric Acid Levels in Relation to Patients’ Course

and 44, Charts and 12 are presented to show the trend of these substances

in the postoperative course of patients. One must assume that the transfused blood had considerable influence.

Average Bromsulfalein Retention Preoperative

Postoperative Day

percent Period

First Second Third and Fourth

Nonfatal Cases 12.6dhl .4 8.6±1.4 6.1±1.1 6.6± 1.2

(45 cases) (40 cases) (32 cases) (15 cases)

Fatal Cases

Death from all Causes 11.8±2.7 18.0±2.9 22.1 ±4.4 1.5 ±7.4

(9 cases) (12 cases) (8 cases) (8 cases)

Uremic Deaths only 12.5±1.4 12.2±2.3 17.4±5.2 29.4±6.8 (4 cases) (5 cases) (7 cases) (7 cases)

High Azotemia Cases .... 12.9±2.3 15.1 ±3.8 17.0±3.5 21.9±5.7

(Includes uremic deaths) (8 cases) (9 cases) (12 cases) (11 cases)

Average Uric Acid Levels (mg. per 100 cc.)

Patients

Preoperative

Postoperative Day

First Second Third or Later

All Patients 5.0±0.3 6.6±0.7 6.6±1.1 8.1±1.5

(55 cases) (19 cases) (17 cases) (14 cases)

Good Postoperative Course 4.4±0.3 4.7 ±0.7 4.5 ±0.7 3.3±0.4

(Does not include high azotemia or fatalities)

Postoperative Course not

(39 cases) (9 cases) (9 cases) (8 cases)

Good 6.5±0.7 8.2±1.0 10.7±1.9 12.2±1.6 (Includes high azotemia and

fatalities)

(14 cases) (10 cases) (6 cases) (8 cases)
LIVER FUNCTION IN THE WOUNDED «3

Table

—Plasma 44.

Bilirubin

Levelsin

Relationto

Patients’ Course

956507 0—52

Average

Plasma

Bilirubin

Levels

(ms.

per

100

cc.)

Patients

Preoperative

Postoperative Day

First

Second

Third

and

Fourth

Fifthor

Later

All

Patients

0.59±0.04

1.63±0.33

1.55±0.26

1.69±0.35

2.55±0.81

(77

cases)

(27

cases)

(29

cases)

(22

cases)

(19

cases)

Good

Postoperative Course

0.61

±0.06

1.36±0.27

1.3

±0.27

0.91

±0.1

0.84±0.24

(Does

not

include

high

azotemia or

fatalities)

(58

cases)

(17

cases)

(18

cases)

(8

cases)

(7

cases)

Postoperative Course

not

Good

0.43±0.04

2.04±0.62

1.98±0.62

2.50±0.66

2.98±

1.0

(Includes

high

azotemia

and

fatalities)

(17

cases)

(12

cases)

(9

cases)

(10

cases)

(15

cases) or

*2.22

±0.7 (14

cases)

One

value

of

13.6

omitted to

get

this

average.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chart ii. Plasma Uric Acid Levels in Relation to

Patients’ Course

Chart 12. Plasma Bilirubin Levels in Relation to

Patients’ Course
LIVER FUNCTION IN THE WOUNDED 85

Effect of Ether Anesthesia on Liver Function

It has been repeatedly stated that liver function, as measured by bromsulfalein retention, is considerably impaired by ether anesthesia. Tentatively accepting this statement, it was necessary to determine just how important this

factor might be in causing bromsulfalein retention in our patients, for many

of the patients with oliguria or anuria were not seen until after operation at

which time bromsulfalein retention was usually high. Accordingly data were

obtained on 42 patients prior to operation and again on the first day after

administration of ether anesthesia. In most of the cases the test was repeated

on the second and even on the third postoperative day. The findings in the 42

individual cases are presented in Table 45 and the averages are shown in

Table 46. It was observed that in the patients who were in grave condition following

operation, as proved by their early deaths, the average percentage of dye retention rose sharply. There were of these moribund patients; they are

grouped separately on Table 46. Presumably the failing liver function in these

cases was due to anoxia, but whatever its cause, the moribund patients reacted

so differently from the others that the findings when these are eliminated

from the total of 42 are also shown. Surely this grouping gives more accurate

picture of the effect, or lack of it, of ether on liver function. Since there was

decrease in average bromsulfalein retention following ether anesthesia in

both the entire group and the patients who survived, the point of whether or

not the moribund patients should be included need not be labored.

The failure of ether to produce an increase in bromsulfalein retention was

of considerable surprise to us, and we are at loss to explain why our findings

are the opposite of those reported by others. It must be taken into account, however, that our first postoperative examination of liver function was 24 hours

after anesthesia. The intervening time should be studied, as healthy young

soldiers may respond more quickly than average civilian patients. It may be

stated, therefore, that so far as this study is concerned, evidence of poor liver

function in patients seen for the first time postoperatively is not to be explained as an effect of ether anesthesia.

Oliguria was defined as 24-hour urinary output of 100-600 cc. for at least day in the posttraumatic period.

Anuria was defined as urinary output of less than 100 cc. in 24 hours.
86 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

—Ether 45.

Anesthesia in

Relation to

Bromsulfalein

Retentionand Plasma

Nonprotein

Nitrogen Levelsin

42

Patients

Case No.

Age yrs.

Major

Wounds

Degree of Shock

On

Admission

Duration of

Anes- thesia minutes

First

Post- operative

Day

Second

Post- operative

Day

Dye

Re- tention percent

NPN mg.

per

100

cc.

Dye

Re- tention percent

NPN mg.

per

100

cc.

Dye

Re- tention percent

NPN mg.

per

100

cc.

91

27

Traumatic

amputation, thigh

None

15

33

90

106

21

Transection,

femoral

artery

do

30

180

24

125

34

Perforating, chest;

fracture,

humerus;

gas

gangrene

Severe

15

64

150

26

89

136

130

27

Compound

comminuted

fractures,

tibia,

ilium

(with

penetrating,

chest)

27

240

49

18

60

134

33

Penetrating,

abdomen,

chest

None

10

35

50

17

12

46

139

26

Penetrating, chest;

fracture,

femur

Severe

15

53

150

36

140

23

Penetrating, abdomen

Slight

10

37

175

11

41

141

19

Penetrating,

abdomen,

chest

do

15

36

135

29

142

24

Penetrating,

chest

Moderate

26

75

29

144

32

Perforating, face

with

compound

fractures

Slight

10

33

135

24

145

41

Penetrating, arm,

thigh,

chest

do

14

43

120

13

34

148

25

Traumatic

amputation,

both

lower

Moderate

46

60

40

A-l

23

Penetrating, chest

Slight

26

210

30

A-2

21

Perforating,

abdomen

do

29

225

26

A25

Penetrating, abdomen

Moderate

27

160

22

46

60

A17

Traumatic

amputation,

foot

Slight

30

50

28

21

A-6

22

Penetrating,

abdomen

Moderate

31

38

180

34

45

30

46

A-l

Penetrating,

chest

Slight

14

27

70

29

31
87 LIVER FUNCTION IN THE WOUNDED

A-16

23

47

90

10

63

A17

21

Traumatic

amputation, lower

arm;

penetrating, abdomen

Slight

30

31

180

16

34

26

A-18

35

Traumatic

amputation,

leg

(with

fracture,

other

leg)

Moderate

40

53

120

12

69

43

A19

26

Compound

fracture,

tibia

....

None

23

42

90

17

53

36

A-20

29

Traumatic

amputation,

foot

Slight

15

30

77

27

23

A-2

21

Near

traumatic

amputation,

midthigh

Severe

58

90

58

51

A-22

21

Perforating, liver,

kidney

....

None

23

31

140

10

29

12

A-2

25

Penetrating, abdomen

do

29

145

27

26

A-2

20

Compound

fractures,

femur,

humerus

Severe

24

41

195

37

25

A-2

20

Severed

femoral

artery

do

22

44

70

34

29

A-3

20

Perforating, chest

Moderate

11

48

180

49

25

A-32

19

Penetrating, chest

do

37

100

46

A-35

25

Near

traumatic

amputation, lower

34

60

34

A-3

19

Compound

fracture,

humerus

do

36

85

29

28

A-38

19

Compound

comminuted

fracture

with

severe mangling,

lower

leg

Severe

48

215

44

40

A-40

25

Penetrating, back,

abdomen,

chest

Slight

36

182

29

26

*122

22

19

42

300

30

63

*126

23

49

110

30

51

*129

20

Penetrating wounds,

lumbar

region,

compound

comminuted

fractures

15

32

125

82

04

*131

27

Penetrating, chest,

abdomen

Severe

10

39

253

16

104

116

*143

28

Perforating, chest,

abdomen

Moderate

26

38

120

28

66

27

62

*147

23

Severe

10

47

163

20

105

*A-30

24

Severed

femoral

artery

Moderate

12

39

120

30

61

39

90

*A-36

21

Multiple

soft-tissue

wounds,

both

53

210

42

77

Patient died.
88 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 46. Effect of Ether Anesthesia on Average Bromsulfalein

Retention and Nonprotein Nitrogen Levels

SUMMARY

Liver function in the severely wounded was measured by bromsulfalein

retention. In 90 percent of 50 apparently healthy soldiers, the average bromsulfalein retention was found to be i.o±o,i percent 45 minutes after intravenous injection of mg. of the dye per Kg. of body weight. On the basis of

the findings in this control group, the upper limit of normal retention was

arbitrarily fixed at percent.

Considerable impairment of liver function was observed in the newly

wounded at the time of their arrival at most forward hospital, the average

impairment in 59 patients being (standard error of the mean) percent as measured by bromsulfalein retention. This finding has been considered

in connection with several factors:

Patients All Patients

(42 cases)

Patients

not

Moribund

(34 cases)

Moribund

Patients

Only

(8 cases)

Age of Patient (years)

Bromsulfaiein Retention on Hospital Entry

24.5 24.8±0.9 23.4

(percent)

Nonprotein Nitrogen Level

12.8 13-3±1.7 11.6

(mg. per 100 cc.) 38.6 37-7 ±1.7 42.4

Ether Anesthesia Duration (minutes) ....

Bromsulfaiein Retention, First Postoperative

Day

140.0 132.0±6.0 175.0

(percent)

Nonprotein Nitrogen Level

11.6 8.3dbl.4 25.0

(mg. per 100 cc.)

Bromsulfaiein Retention, Second Postoperative Day

47.8 39J ±3.0 76.2

(percent)

Nonprotein Nitrogen Level

7.8 6.1 ±1.2 19.8

(mg. per 100 cc.) 48.0 39.9 ±5.0 93.0

Since there is possibility that the liver plays largerrole than is now recognized in nonprotein nitrogen

levels, the effect of ether anesthesia on the plasma nonprotein nitrogen was also investigated. It has been stated

that ether anesthesia produces rise in the nonprotein nitrogen level. No evidence to substantiate this was found

in our patients, if those who are moribund are excluded. It is well-known and confirmed here that the nonprotein

nitrogen level rises rapidly in moribund patients.

Standard errors of the mean are shown for this series to indicate the spread encountered.
LIVER FUNCTION IN THE WOUNDED 89

Time from Wounding.—No relationship could be found between time

from wounding and bromsulfalein retention.

Location of Wound.—Patients with extremity wounds had the same average retention (13.3—2.3 percent) as those with abdominal wounds (14.7*2.1

percent). Curiously, those with chest wounds seemed to have less retention of

the dye (7.0* 1.8 percent) than those in the previous categories. Patients with

direct injury to the liver showed 18.4-percent average retention. It is doubtful

if this is significantly higher than that found in other abdominal wounds, since

there was considerable spread in the data.

Shoct{.—No correlation between presence or degree of shock and liver function was shown, and, as might be expected, no correlation of bromsulfalein

retention with blood-volume loss or hemoglobin loss. The great deterioration

of the circulation found in patients in the more severe shock categories does

not appear to strain liver function measurably insofar as can be judged from

these data.

Plasma. —It was surprising that one of the great stresses placed upon the

body, such as that due to shock, had little if any effect on liver function as

measured by bromsulfalein retention, yet the administration of one or two

units of blood plasma produced considerable, although transient, increase in

retention.

POSTOPERATIVE FINDINGS

Liver function during the postoperative course of the severely wounded, as

determined by bromsulfalein retention and bilirubin and uric acid levels, is

recorded.

The statement has been made repeatedly in the past that liver function as

measured by bromsulfalein retention is considerably impaired by ether anesthesia, In order properly to assess patients seen for the first time postoperatively, liver function studies were carried out in 42 patients before and after

prolonged ether anesthesia. Contrary to other reports, we found in these patients at least decrease in bromsulfalein retention postoperatively, except in

those who were moribund. There is generally sharp increase in bromsulfalein retention in patients whose condition is deteriorating rapidly.
CHAPTER III

Renal Function in the

Severely Wounded

The desirability of measuring renal function as accurately as possible in

the severely wounded was clear at the outset of the study. In the majority of

cases this was done by determination of phenolsulfonphthalein excretory capacity and by urine concentration tests, in conjunction with routine urine and

blood chemistry analyses. Mannitol and sodium para-amino hippurate did not

become available for clearance measurements until the last weeks of the Italian

campaign. Results of the phenolsulfonphthalein, urine concentration, and the

few renal clearance tests performed will be described.

Phenolsulfonphthalein Excretory Capacity

Because of practical considerations, the phenolsulfonphthalein excretion test

was made postoperatively except on one patient who had no surgery, when it

was done after transference from the shock ward, but in all cases it was some

hours after the patient had been adequately resuscitated. Fifty-seven patients

were tested, all of them within 72 hours after wounding, and some of them

were tested again after the third day in order to follow their rate of improvement. The latter group comprised 12 patients available for retesting out of 37 in whom dye excretion had been found low in the first test and patients on

whom the first tests had been made later than the third day after wounding,

but in whom the quantity of dye excreted was still low (Cases 125, 104, and

29 on Table 48).

Technique of Test.—The following technique of performing this test was

commonly employed. Six milligrams of phenolsulfonphthalein were injected

See Appendix for details of performing the test.
RENAL FUNCTION IN THE WOUNDED 91

intravenously and urine was collected 15, 30, 60, and 120 minutes later. It was

necessary to use an indwelling catheter in almost every instance to insure accurate collection. Oral intake of fluid was restricted in most patients at the time

the test was performed; therefore, in order to promote urine flow, infusion of

liter of 5-percent dextrose in isotonic saline solution, or 10-percent dextrose in

distilled water, was frequently started about 30 minutes before the dye was

injected.

Excretory Capacity in the First Days after Wounding.—The average results of the test made on 57 patients during this period, together with other

pertinent data, are shown in Table 47 and Chart 13.

The most striking finding was the difference in the average percentage of

dye excreted by the 20 patients who had not been in shock and that excreted

by the 37 who had had slight, moderate, or severe shock. At all test periods the

average excretion was normal for the group that had not been in shock. (See

also section to follow on the effect of anesthesia on these patients.) During the

first 30 minutes, the average excretion was low for the group that had been

in shock, and decreased progressively with increasing severity of initial shock.

Although standard errors of the mean are rather large, and although there are

no significant differences between the three groups with slight, moderate, or

severe initial shock, the qualitative variations are evident. After the first 30 minutes, average dye excretion became normal for all patients except the 14 who

had been in severe shock at hospital admission. In them the average excretion

was significantly less than normal even after hours.

The table shows that as phenolsulfonphthalein excretory capacity diminished,

not only did the severity of initial shock increase but also, as would be expected,

there was rise in the number of patients who had had hypotension on admission and the number who subsequently developed urinary suppression and /or high azotemia.

Effect of Anesthesia. —One might argue that the diminished ability to excrete phenolsulfonphthalein in these patients might have been largely or partially an effect of the anesthetics employed, especially ether. Our data indicate

that this is not true. Nineteen of the 20 patients shown in Table 47 and Chart 13,

who had neither initial shock nor hypotension, received ether anesthesia, either

Twenty-one of these are not included in the total series of 186 patients. They were added merely

to enlarge the series of phenolsulfonphthalein tests without attempting to do complete studies. Seventeen

of the 2i had no initial shock; slight shock, and moderate shock. Data on these additional cases were

obtained from the 8th Evacuation Hospital.
92 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

47.

—Average

Phenolsulfonphthalein Excretory

Capacity of

57

Patientswithin

72

Hours after

Wounding

Relationship to

Degree

of

Shock on

Hospital

Admission

Degree

of

Shock on

Admission

Number

of

Patients

Average

Phenolsulfonphthalein Excretion

percentage increments

Time

from Wounding

NPN

on Day

of

Test

High Azotemia

Oliguria or Anuria

Hypotension on Admission

(Total:

57)

15

minutes {min.

n.:

25)

30

minutes (min.

35)

60

minutes {min.

n.:

45)

120

minutes {min.

50)

to

Test hours

mg.

per

100

cc.

number

of

patients

number

of

patients

number

of

patients

None

20

31.6±2.47

50.

±2.

64.9±2.86

73.3

±2.82

19-05±1.55 (maximum 44)

28

±1.2

Slight

11

16.86±3.43 34.

±4.66

1.45

±5.68

6l.0±5.8

30.64

±4.54 (maximum 66)

31.18±2.04

Moderate....

12

12.75 ±2.77

33.25

±5.56

49.08

±7,

12

66.08

±7.73

31.25±3.22(maximum 46)

43.08

±4.44

11

Severe

14

966±3.42

25.22±6.42

36.38

±8.66

43.62

±9.6

37.4±3.05 (maximum 60)

47.8±4.2

14

Minimum

normals

from

Stitt.

NPN

level

of

65

mg.

per

100

cc.

or

higher

at

any

time

during

posttraumatic

period.

Oliguria:

24-hour

urinary

output

of

100-600 cc.

for

at

least

day

during

posttraumatic

period.

Anuria:

24-hour

urinary

output

of

less

than

100

cc.

Systolic

blood

pressure of

80

mm. Hg

or

less.

Includes one crush

case without

operation;

all

other

P.S.P. tests

were done

postoperatively.
RENAL FUNCTION IN THE WOUNDED 93

Chart 13. Phenolsulfonphthalein Excretory Capacity in Relation to

Initial Shock

No Shock

Slight Shock

Moderate Shock

Severe Shock

.Minima! Normal

Excretion

INCREMENTS of the percentage of phenolsulfonphthalein excreted are represented.

Findings are discussed in the text. (Minimum normal excretion from Stitt, E. R.; Clough,

P. W., and Clough, M. C.: Practical Bacteriology, Haematology, and Animal Parasitology.

9th ed. Philadelphia, Blakiston, 1938, p. 733.)

alone or with sodium pentothal, and none showed any diminution of their excretory capacity. If ether per se had any marked effect on dye excretion, it

should have been evident in this group. Moreover, the average interval between

wounding and performance of the test (and thus between operation and performance of the test) in these 20 patients was much less than it was in those

who had been in shock and there was less time in which to recover from the

effects of anesthesia had there been any. Another observation in support of the

conclusion that anesthesia did not affect the ability of the kidneys to excrete

phenolsulfonphthalein was that excretion was greatly diminished in the crush

case in which no anesthetic had been administered.

Rate of Improvement in Excretory Capacity.—The test was repeated one or

more times on 15 patients who showed low rate of excretion when first tested.

Pertinent data on each of them are given in Table 48. Thirteen of these patients recovered (3 had the syndrome of recovery diuresis to be described in
Table

48.

—Phenolsulfonphthalein Excretion and Related

Datain

15

Patientson

whom

the

Test

was

Repeated

Case No.

Time

fromWounding to

Test

Phenolsulfonphthalein Excretion percentage

increments

NPN on

Day

of

Test

Degree

of

Shock on

Admission

Hypotension on Admission

High Azotemia

Output of

Urine (ClassifiPatient’s Outcome

15 min.

30 min.

60 min.

120min.

mg.

per

100

cc.

cation)

81

39

hours days

0.3 4.0

2.0 19.0

14.0 33.0

25.0 55.0

77 56

Severe

Present

Present

Oliguria

Uneventful

recovery.

60

24

hours days days 12

days

0,3 1.0 6.0 21.0

1.3 2.0 18.0 31.0

2.0 3.0 25.0 43.0

3.5 5.0 34.0 52.0

58 108 46 33

...

.do

....

Recovery diuresis.

125

days 14days

3.0 3.0

6.0 7.0

10.0 18.0

15.0 27.0

108 65

...

.do....

Do.

104

days days 11days

23.0 5.0 42.0

33.0 9.0 56.0

47.0 14.0 69.0

57.0 30.0 78.0

44

Moderate

...

.do

....

Do.

29 29

107

23

days days

6.0 0.8

15.0 1.2

21.0 3.0

28.0 17.0

41

...

.do....

...

.do....

Normal

Death,

days

after

73

wounding.

Alkalosis,

uremia

contribu- tory.
63

24

hours days days

3.0 2.0 21.0

18.0 6.0 44.0

38.0 31.0 62.0

63-0 39.0 73.0

43 31 25

...

.do.......

.do

Absent

Oliguria

Uneventful recovery.

37

hours days

0.0 43.0

0.0

2.0

16.0

54

...

.do....

...

.do....

...

.do

....

...

.do....

Do.

56.0

69.0

79.0

36

29

days days

0.0 25.0

11.0

40.0

59.0 75.0

49 46

....

do....

...

.do

....

Present

do

Stormy

course. Probable

blood stream infection.

41.0

61.0

53

31

hours days

8.0

15.0

27.0

56.0

37 27

...

.do....

...

.do....

Absent

do....

Uneventful

recovery.

34.0

48.0

63.0

73.0

15

24

hours days

23.0 47.0

42.0

55.0 73.0

70.0

36 31

Slight

...

.do....

...

.do....

...

.do....

Do.

63.0

77.0

83

23

hours days

6.5 55.0

23.0 69.0

36.0 78.0

44.0 89.0

26 24

do....

Absent

...

.do

Normal

Do.

111

7.0 41.0

34.0 43.0

68.0

74.0

30 48

...

.do.... ....

do....

.... do....

...

.do....

Do.

days

71.0

74.0

128

30

hours days

16.0

19.0 23.0

39.0 43.0

40.0

31 39

...

.do....

...

.do....

...

.do........

do....

Do.

22.0

45.0

106

20.0

47.0 57.0 28.0

67.0

73.0 81.0

24

None

....

do....

...

.do

....

...

.do....

Do.

days

40.0

73.0 48.0

102

18.0

53-0 84.0

43

...

.do....

...

.do....

...

.do

....

...

.do....

Death, 19

days

after

wounding,

from

causes unrelated to

renal

insufficiency.

days

42.0

64.0

76.0

80

mm.

Hg

or

less,

systolic.

Patients tested

for

the

first

time

on the

fourth

or

fifth

day

after

wounding.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chapter V). One patient died with alkalosis and renal failure, and the other

died of peritonitis.

Inspection of this table shows that of 15 patients tested on the fourth or fifth

day after wounding, had normal excretion; in all excretion had been low

during the first days after wounding. Three had had moderate initial shock,

slight shock, and none. Of the patients in whom excretion was low on

the fourth or fifth day after wounding, had been tested for the first time

during this period, and are known tohave had diminished excretion during the

first days.The degree of shock on hospital admission in the patients had been

severe in 3, moderate in 3, and slight in two.

Four patients were retested between the seventh and fourteenth days. One

had normal excretion by the eleventh day; another had slightly diminished

excretion only during the first 15 minutes of the test on the eighth day, and

two who had recovery diuresis (Cases 60 and 125) still had abnormal excretion

on the twelfth and fourteenth days after wounding, respectively.

With the exception of one patient (Case 107) who died with alkalosis and

renal failure, all patients in whom excretion was low on initial tests showed improvement in excretory capacity, reflected chiefly in ability to excrete increased

quantities of dye during the first 30 minutes, although the total quantities

excreted also increased with passage of time.

The time required for phenolsulfonphthalein excretory capacity to return to

normal was well correlated with urinary output, nonprotein nitrogen retention,

and degree of initial shock and hypotension (Table 48). In general, those patients with normal output of urine or only slight suppression, with minimal

nitrogen retention, and only slight initial shock regained renal function, as

measured by phenolsulfonphthalein excretion, most rapidly.

Summary, P.S.P. Test

Phenolsulfonphthalein excretory capacity was determined during the first

days after wounding in 57 patients. The test was made after resuscitation

had been effected and, with the exception of patient who was not operated

upon, after surgery had been completed. In 20 of these patients who had had

neither initial shock nor hypotension, the average dye excretion was normal.

In the remaining 37, all of whom had been in various degrees of shock, with

hypotension occurring in 27, the average dye excretion was low, especially

during the first 30 minutes. The amount of dye cleared decreased as severity of
RENAL FUNCTION IN THE WOUNDED 97

previous shock increased. In patients who had had slight and moderate shock,

average excretion was abnormal only in the first 30 minutes; in those who had

had severe shock it was low throughout the 2-hour period.

The test was repeated one or more times between the fourth and fourteenth

postoperative days on 15 of 37 patients in whom initial excretion had been found

low. In 14 of them dye excretion returned to normal during this time. In those

patients in whom impairment was only mild, kidney function was apparently

normal by the fourth or fifth day. In patients in whom it was more severe

(e.g., in recovery diuresis) renal insufficiency, as gaged by phenolsulfonphthalein

excretory capacity, persisted much longer.

Kenal Clearance Studies

The majority of the severely wounded patients who died exhibited evidence

of renal insufficiency (see Chapter V). Histologic examination of the kidneys

of these patients showed damage predominantly in the lower nephron and

relatively little evidence of glomerular damage (see Chapter IX). The anatomic

findings immediately raised the question of how closely functional impairment

corresponded with anatomic alterations. One obvious approach to solution of

this problem was utilization of clearance methods of measuring renal function.

This was done in patients—a small series but the largest we could obtain

after the materials necessary for performance of the tests became available.

Mannitol was used for measurement of glomerular filtration rate (Cm),

sodium para-amino hippurate for effective renal plasma flow (Cpah) and maximum tubular excretory capacity (Tiupah). Analysis of these substances is discussed in Appendix C. Quantities given and rates of administration were essentially those suggested by Goldring and Chasis. Indwelling, multiple-eyed

catheters were routinely employed. The bladder was washed with 10 to 30 cc.

of isotonic salt solution at the end of each collection period, followed by 10 to

20 cc. of air to insure complete emptying.

Renal clearance findings together with other pertinent data on the 11 individual patients are shown in Table 49. Five patients were studied within the

first 31 hours after wounding, but not until resuscitation had been effected and

operation completed. One of them had had no shock, slight, moderate, and

Goldring, W., and Chasis, H.: Hypertension and Hypertensive Disease. New York, The Commonwealth Fund, 1944.
98 THE PHYSIOLOGIC EFFECTS OF WOUNDS

severe initial shock. None of them had high azotemia (a plasma nonprotein

nitrogen level of 65 mg. per 100 cc. or higher) while we observed them. Output

of urine was normal in patients; one was listed as having had oliguria for

day (Case 142), but it was slight and can be disregarded.

The remaining six patients were first studied between and 30 days after

wounding. All of them had high azotemia at some time during their course.

One had no initial shock, two moderate, and three severe shock. In three patients clearances were first measured while renal failure was severe and repeated

after recovery diuresis had taken place. fourth had had severe renal failure,

but clearance tests were not made until 30 days after wounding, by which time

he had recovery diuresis and his plasma nonprotein nitrogen was normal. The

remaining two patients died 16 hours and days, respectively, after clearance

studies were done; in both uremia was present at the time of death but in

neither was it an immediate or contributory cause of death.

Results

Charts 14 through 16, in each of which all cases are included, were constructed from mean normals406 and average values listed in Table 49. The

patients who did not have high azotemia are represented by open symbols;

the who had renal failure by solid or semi-solid symbols. For Cases 138, 150,

and 133—those with the lowest renal clearance values—only the initial observation is shown. Chart 17 shows these initial values in addition to results when

the tests were repeated on of these patients.

Glomerular Filtration Rate and Effective Plasma Flow (- —Table \CpAH

49 and Chart 14.—These were definitely below normal in one patient (Case

139) 20 hours after wounding; he was the only one of the five studied during

the early postoperative period who had had severe initial shock. In two of these

five glomerular filtration rate and effective plasma flow were in the low normal

ranges. Marked diminution of both components in the three patients (Cases

33, 138, 150) with severe renal failure is evident. There were lesser degrees of

impairment in the two in whom renal failure was only coincident in death Ibid.

Berger, E. Y.; Farber, S. J., and Earle, D. P., Jr.: Renal excretion of mannitol. Proc. Soc. Exper.

Biol. Med. 66: 62-66, Oct. 1947.

Chasis, H.; Redish, J.; Goldring, W.; Ranges, H. A., and Smith, H. W.: Use of sodium p-amino

hippurate for functional evaluation of human kidney. J. Clin. Investigation 24: 583-588, July 1945.
RENAL FUNCTION IN THE WOUNDED 99

Chart 14. Relationship between Average Effective Plasma Flow and

Glomerular Filtration Rate in Patients Without and Patients

With Renal Failure

No Shock-29 hours after wounding (Case no. 134)

Slight Shock~/9 hours after wounding (Case no. !4t).

Moderate Shock-!4 hours after wounding (Case no. 142).

Moderate Shock-3/ hours after wounding (Case no 148).

Severe Shock-20 hours after wounding (Case no. 139)

Moderate Shock ,High Azotemia -3.5 days after wounding (Cose no. /43)

Severe Shock, High Azotemia -7.75 days after wounding (Case no. 147).

No Shock, High Azotemia, Recovery Diuresis tO days after wounding (Cose no. 138).

Moderate Shock, High Azotemia, Recovery Diuresis —!4 days after wounding (Case no. 150).

Severe Shock, High Azotemia, Recovery Diuresis it days after wounding (Cose no. !33).

Severe Shock, High Azotemia, Recovery Diuresis-30 days after wounding (Case no. 125).

THE VALUES represented in this and in the succeeding two charts were obtained from

average values shown in Table 49. The diagonal line shows normal filtration fraction

(^Cm ). The solid and semisolid symbols represent patients with high azotemia and CpAH/

various degrees of renal failure; the open figures patients who at no time had azotemia.

(Cases 143 and 147), and in the one (Case 125) who had fairly well recovered

from renal failure. The tendency of glomerular filtration rate and effective

956507 0—52
100 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

49.

—Summary of

Renal

Clearance

Studies in

ii

Patients

zQ vo VM IS ft ft

Oi 4l SA K) 4k V>» vo Flow Urine

h->

Cm 00 k) 4k OS bo bo min. per cc. K) <-M 4^ periods) (all

Filtration Glomerular

vo os OJ 'vl K) SA v-n sa "J sa VO vo OS 00 min. per cc.

OS

00 v» VO 4k WM00 SAOs

'vl 00 os \j\

(C Flow Plasma Effective h) PA

min. per cc. 00 KJ 4L -vj ■“ VO K) 00

00 syi 4k Flow Blood Effective 4K

OS

VO

VO

Os OS OS OS u> vo

V>J min. per cc.

Excretory Tubular Maximal VO

'vl Os vo V>J vo os 00 Capacity 4k PAH (Tm

min. per mg.

N) 4k

VO VO OJ 00 VO

CL

pi

CL

pi

CL

Pi CLPi Time 3- 3* cr ST 3- Wounding after

(A {/>

CL

C/5

ft CL S2 Shock of Degree ft

ft *1

P>

ft

3* ft Admission on

No No No Yes Azotemia High

Test of Day on NPN

"4 OS 00 K) OS 4k *"* cc. 100 per mg. V>i

•o J_.

Cl 53' Output »-l CL Urine of

»n pi

Classification

Pi

bj bj K)

Cm K)

Ui

Vi "v|

00

K) 1,693 os 4k

Urine of Output

Test of Day on

SA K> **

CC

114 ooln 11- rt IJ. 65 Day on Pressure Blood

Csl ol ol 4k 00 K) Testof olo olo olo

50 5C ft

ft ft <5

a.

c* si »i

ft
RENAL FUNCTION IN THE WOUNDED 101

125

5.72

89

544

870

80

30

days

Yes

26

Oliguria

1,550

130 91

Do.

150

4.42 4.74

15 100

87 414

131 686

12 67

14

days 26days

Moderate

Yes

123 24

Anuria

3,350 3,000

170 100 130 70

Do,

138

3.0 5.54

64

20 431

28 676

43

10

days 26days

None

Yes

217 44

Un-known: probable oliguria

1,500 4,500

140 68 128 70

Do.

143

3.8

89

598

1.037

108

days, 14

hrs.

Moderate

Yes

57

Normal

1,986

no 60

Died

days

later.

Uremia

coincident at

death.

147

4.1

64

356

630

70

days, 18

hrs.

Severe

Yes

99

1,558

110 60

Died

16

hrs.

later.

Uremia

coincident at

death.

Mean

normal

with

standard

deviation

116± 28.6

697 135.9

1,204±255.9

77. 12.9

rs

of

body

surface;

each

134

where

effective

plasValues

in

columns

through

corrected to

1.73

square

mett

represents average values

for

to

periods

in

all

cases

except Case

ma and

blood

flow

were

determined during

period

only.

day

later. Approximate. Normals

and

standard deviations: See

footnote

in

text.
102 THE PHYSIOLOGIC EFFECTS OF WOUNDS

plasma flow each to diminish proportionately was demonstrated by the relatively

normal filtration fractions -~

in most cases.

\CpaH/

Maximum Tubular Excretory Capacity (Thipah) Table 49 and Chart 15.

There is wide variation in this measurement which may represent the actual

amount of actively functioning tubular tissue, and is hence related to the functional size of the kidneys. It was significantly low in only the three patients with

severe renal failure (Cases 133,138,150). It is of interest that the one patient with

severe initial shock, who was studied 20 hours after wounding, had low filtration rate and effective plasma flow but normal Tm (Case 139). Relating plasma

flow to maximum excretory capacity PAH-) provides substantially an ex- TmpAH

pression of the quantity of plasma cleared per unit of functionally active tubular

tissue. The diagonal line in the chart is the normal ratio. Ratios significantly

Chart 15. Relationship between Average Effective Plasma Flow and

Maximal Tubular Excretory Capacity

THE SYMBOLS for the individual cases represented are explained on Chart 14. The

diagonal line represents Variation is wide, but noteworthy perhaps is the fact that TmpAH

all but two patients had normal ratios or ratios less than normal.
RENAL FUNCTION IN THE WOUNDED

Chart i6. Relationship between Average Glomerular Filtration Rate and

Maximal Tubular Excretory Capacity

THERE IS an unexpected tendency for the ratio of to be below normal. The Tmp

symbols used for individual cases are the same as those of Charts 14 and 15.

below normal presumably indicate relative renal ischemia. It may be significant

that this ratio was normal or below normal in nine patients, and that it was

lowest in the patient tested shortly after he had recovered from severe shock

(Case 139).

Relating filtration rate to maximal tubular excretory capacity ——)

VTmpAH/

(normal ratio: the diagonal line in Chart 16) gives an expression of glomerular

function per unit of functioning tubular tissue. Ratios below normal presumably

indicate greater relative impairment of glomerular function than tubular, and

high ratios the reverse. Nine of the patients had either normal or low

ratio, fact which, if significant, is difficult to explain in view of the anatomic

lesion in this type of case.

Rate of Recovery as Gaged by Cm, Cpah, and Thipah—Table 49 and Chart

17.—Findings in three patients (Cases 133, 138, and 150) who had severe renal

failure but recovered (see discussion of recovery diuresis in Chapter V) are
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chart 17. Severe Renal Failure and Subsequent Recovery Diuresis;

Rate of Recovery (Case 133)

GLOMERULAR

FILTRATION RATE (Cm)

CUBIC CENTIMETERS PER

MINUTE PER 1.73

SQUARE METERS (AVERAGE)

EFFECTIVE

PLASMA FLOW (C PAH

CUBIC CENTIMETERS PER

MINUTE PER 1.73

SQUARE METERS (AVERAGE)

MAXIMAL TUBULAR EXCRETORY CAPACITY

(Titipah)

milligrams per minute

PER 1.73 SQUARE METERS

(AVERAGE)

NOTE (i) the relatively proportionate reduction in glomerular filtration rate, effective

plasma flow, and maximum tubular excretory capacity, and (2) similar recovery rates for

all three.

shown in Table 49 and Chart 17 (Case 133). Initial observations were made

during periods of maximum failure, subsequent ones after recovery had largely

taken place. In general, on the basis of clearance measurements, all portions of

the nephron were about equally affected; recovery likewise occurred at about an

even rate in all portions. Function was apparently completely restored in one

patient (Case 133) 49 days after wounding and partially so in another patient

26 days after wounding.

Summary, Renal Clearance

Renal clearance was measured in patients in this study. Of tested within

31 hours after wounding, findings were essentially normal in four. The fifth

patient showed significantly low rates of glomerular filtration and effective
RENAL FUNCTION IN THE WOUNDED

plasma flow, but normal maximum tubular excretory capacity. He was the only

one studied in the early postoperative period who had had severe initial shock.

Six patients in whom high azotemia (a plasma nonprotein nitrogen level of

65 mg. per 100 cc. or higher) developed were studied in various stages of renal

failure. The results suggest that in this type of renal insufficiency all portions

of the nephron suffer functional impairment, and that all portions regenerate at

about an equal rate if recovery ensues. Evidence has been presented that relative renal ischemia may exist, but the number of cases is too small for this to

be of significance.

Urine Concentration Test

Although the value of the urine concentration test was self-evident, practical

difficulties prevented our using it as measure of renal function in many cases.

Restriction of fluids during the first few postoperative days was almost always

inadvisable for the patients’ welfare. Pituitrin was therefore employed, using

the accepted method of administering 0.5 cc. of posterior pituitary extract (10

units) subcutaneously and collecting urine specimens and hours afterward.

However, many of the patients in whom we should like to have known concentrating ability were dailyreceiving considerable quantities of sodium chloride

intravenously. Since the antidiuretic hormone may be ineffective during saline

administration, there was concern that in large number of cases the pituitrin

test would be complicated by recent administration of isotonic saline solution,

but in most instances we did not feel justified in requesting that the saline solution be withheld.

compromise regimen was therefore established in which all parenteral

fluids were withheld for or hours before the pituitrin was administered whenever such restriction clearly would not be harmful in any way to the patient.

Under these conditions value for normal concentrating ability is difficult to

state; we have assumed that specific gravity of 1.025 or higher represents normal integrity of tubular reabsorptive capacity for water. Data on the 32 patients

in whom concentrating ability of the kidneys was tested in this manner during

the postoperative days indicated are shown in Table 50.

Of the 17 patients in whom we assumed there was no impairment of concentrating ability (that is, the specific gravity of one hourly specimen was 1.025

or higher) during the first week after wounding, had had moderate or severe
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

—Results 50.

of

Urine

Concentration

Tests

Employing

Pituitrin 32

Cases

Specific

Gravity of

Urine

Time

from Wounding

Other Related

Factors

Number

of

Patients

TotalPatients

to

First

Test

Degree

of

Initial

Shock

Hypotension

Oliguria

High Azotemia Developed

Days

None

Slight

Moderate

Severe

Admission

Anuria

1.02

or

Higher.

to

17

1.018 to

1.025

to

Under1.018

to

17

Total

14

17

16

32

Normal

by

the

tneth

Actual

output

unknc od

used:

hourly

specimen

of

1.025 or

higher.

>wn

in

cases, but

good

presumptive

evidence

of

oliguria.
RENAL FUNCTION IN THE WOUNDED 107

shock and hypotension on admission. In of these 17, high azotemia subsequently developed. Of the patients with slightly decreased ability to reabsorb

water from the kidney tubules (specific gravity of urine 1.018 to 1.025), had

been in moderate shock, had hypotension on admission, in oliguria or anuria

developed, and in high azotemia. In the patients with marked impairment

of concentrating ability, had had moderate or severe shock, and hypotension.

Severe and prolonged azotemia developed in of these 6; they are discussed

in the section on recovery diuresis in Chapter V.

The urine concentration test was made more than once in eight patients. In

two of them the specific gravity, which was 1.018 at the time of the first test,

rose to 1.020 two and seven days later, respectively. In one it increased from 1.017

to 1.022 in three days. One of these three patients also had high azotemia and

oliguria, and two had normal output of urine and plasma nonprotein nitrogen

level under 65 mg. per 100 cubic centimeters. The remaining five patients had

recovery diuresis, and after periods of from 14 to 40 days still were unable to

produce concentrated urine.

Although the series was small, it suggests that the concentrating ability of

the kidneys may follow somewhat the same pattern as ability to excrete phenolsulfonphthalein, mannitol, and sodium para-amino hippurate. Ability to make

concentrated urine appeared to diminish within days following shock, and

improve over period of from to days, unless renal failure was severe (recovery diuresis) in which case maximum tubularreabsorption of water remained

diminished for many days or even weeks. In two patients (Cases 125 and 133)

specific gravity remained fixed even after clearance of mannitol and sodium

para-amino hippurate had returned to normal.

COMMENT

It has been demonstrated by Lauson, Bradley, and Cournand that during

shock glomerular filtration rate and effective plasma flow are reduced. These

workers have also advanced evidence that reduction in renal blood flow is partially explained by active vasoconstriction of the renal blood vessels as well as

by reduction of arterial pressure.

Lauson, H. D.; Bradley, S. E., and Cournand, A.; Renal circulation in shock. J. Clin. Investigation

23: 381-402, May 1944.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

None of our studies were carried out while the patients were in shock. Those

performed in the first few days after trauma suggest that the impairment in

kidney function may persist for some days after shock is relieved, even though

the usually accepted signs of renal failure (suppression of urinary output, nitrogen retention) may be meager. These patients probably rapidly regain normal

kidney function.

If the initial insult, whatever it might have been, was great, the resulting

renal insufficiency was much more severe and prolonged, and in significant

proportion of cases resulted in death in uremia. few patients, however, did

recover, with gradually increasing function over period of days to weeks, as

indicated by their progress in restoration of ability to excrete phenolsulfonphthalein, improvement in the glomerular filtration rate, and by increased effective plasma flow, maximum tubular excretory capacity, and concentrating capacity of the urine.

Although the histologic picture in fatal cases might suggest selective functional impairment of the lower nephron, our studies indicated that all functional

components of the kidneys were about equally impaired. Glomerular filtration

rate and effective plasma flow were reduced in essentially proportionate degrees

in most of the patients we studied. That there may have been some relative renal

ischemia in these cases is suggested by the fact that in the few patients on whom

clearance tests were done, the ratio of PAH tended to be low. One bit of TmpAH

evidence in favor of greater relative insult in the lower nephron may be cited

from the two patients in whom ability to concentrate urine was still much impaired after clearances had returned to normal. Mannitol measures glomerular

filtration; sodium para-amino hippurate is believed to be excreted by the proximal tubules. Urine concentration takes place primarily in the distal tubule. The

question arises whether this lag in recovery of concentrating capacity is manifestation of greater relative damage to the lower nephron. The discrepancies

between the physiologic and anatomic findings could perhaps be explained by

the production in these patients of renal vascular shunts, such as Trueta and

his associates have recently demonstrated in animals. It is impossible to state

from our data whether such mechanism was operative.

Trueta, J.; Barclay, A. E.; Daniel, P. M.; Franklin, K. J., and Prichard, M. M. L.: Studies in

the Renal Circulation. Springfield, 111., Charles Thomas, 1948.
RENAL FUNCTION IN THE WOUNDED 109

SUMMARY

Renal function in the wounded man was studied by measuring phenolsulfonphthalein excretory capacity in 57 patients; glomerular filtration rate,

effective plasma flow, and maximal tubular excretory capacity of para-amino

hippuric acid in 11 patients, and urine concentration, employing pituitrin, in

32 patients. All studies were made after resuscitation had been effected, and in

all surgical cases after operation had been completed. The results were qualitatively similar and indicated that functionally all portions of the nephron were

about equally impaired for period of few to many days, depending on the

severity of the initial insult which in most patients paralleled the degree of shock

on admission. Similarly, diminished renal function, as indicated by these tests,

was associated with corresponding increases in the level of plasma nonprotein

nitrogen and with decreases in urinary output. When recovery occurred, improvement of most of these functions proceeded at about an equal rate.

These physiologic findings do not correspond with the histologic findings in

fatal cases, where the lesion was observed predominantly in the lower nephron.

The fact that ability to produce concentrated urine was impaired in few

patients long after phenolsulfonphthalein excretion, glomerular filtration rate,

effective plasma flow, and maximum tubular excretion of PAH had returned to

normal might suggest greater relative damage to the lower nephron.

CASES OF SPECIAL INTEREST IN THIS CHAPTER

P.S.P. Re-test

29 60 81 102 106 III

128

15 53 63 83 104 107 125

Renal Clearance Test

I2 134 139 i4 147

150

33 138 141 143 148
CHAPTER IV

Diagnosis of Lower Nephron

Nephrosis Resulting from Trauma

and Shock (“Shock Kidney”)

As Derived from Clinicopathologic Correlation

The clinical syndrome of renal insufficiency following traumatic shock had

not yet, to our knowledge at the time of this study, been defined in the medical

literature. In the interval preceding publication Lucke has described, from both

clinical and pathologic points of view, group of similar cases under the term

“lower nephron nephrosis.” The present study, though now no longer novel,

was done independently before his publication and therefore offers unbiased

confirmation which seems worthy of record. Since civilian practice brings so few

apposite cases under the observation of any single group of investigators, one of

our clearest obligations was to attempt definition of this syndrome.

In exploration of new syndrome the first necessity is establishment of base

of departure; that is, an apparently new combination of symptoms, signs, laboratory observations, or distinctive morphologic lesions. With widening experience,

additions to and subtractions from this combination are made until the pattern

becomes stabilized, the diagnostic importance of each feature or group of features being assessed by the frequency with which it occurs in the disease in question as compared with its infrequency in other conditions.

Since the case fatality rate of this condition was high, there is little risk of

distorting the picture by using the fatal cases to establish the base of departure.

In 38 of 60 cases in which necropsy material was available, pigment nephropathy,

Lucke, B.: Lower nephron nephrosis. Mil. Surg. 99: 371-396, November 1946.
DIAGNOSIS OF LOWER NEPHRON NEPHROSIS

the characteristic renal lesion of“shock kidney” which will be described in Chapter IX, was present. In the following discussion the symptomatology in these

cases will be presented, comparing the findings as we proceed with the control

group of 22 cases in which pigment nephropathy was proved absent at necropsy.

To determine whether diagnosis of renal injury can be established beyond reasonable doubt, the fatal cases will be further compared with nonfatal cases in

which there was evidence of kidney dysfunction.

Objective Evidence of Penal Insufficiency in Cases

of Histologically Proved Nephropathy

Oliguria and Anuria

For purposes of this study, oliguria was defined as 24-hour output of urine

greater than 100 cc. and less than 600 cc.; anuria as an output not exceeding

100 cc. per day. Urine output, known in 35 of the above-mentioned 38 patients

with the characteristic renal lesion, had been subnormal for one or more days

in all, 15 patients remaining in the oliguric and 20 reaching the anuric level.

Oliguria or anuria was present from the onset of shock in all but one case, and

in this case the delay was apparent rather than real. The initial shock had been

mild, but secondary shock of greater severity occurred after operation and was

promptly followed by anuria. The majority of patients showed progression from

oliguric to anuric levels, but occasionally anuria was present from the start. In

15 patients with clinical uremia and histologically proved nephropathy, the urine

output never declined below the oliguric level. It is worth emphasis that these

individuals, often casually referred to as “anuria cases,” may never in fact become

anuric. Unless 24-hour outputs are carefully measured, significant oliguria may

easily be missed.

Nine patients with oliguria (or anuria) failed to show significant renal

lesion at necropsy. This is not surprising, considering the variety of conditions

from which these severely wounded men suffered which would tend to lower

urine output, such as deficient blood volume, prolonged hypotension, paralytic

ileus, infection, and exudation into traumatized areas and into infected serous

cavities. In two of the nine oliguria or anuria was intermittent; in both the clinical picture was dominated by severe peritonitis.
112 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Azotemia

“High azotemia,” arbitrarily defined as nonprotein nitrogen level in the

plasma of 65 mg. per 100 cc. or higher, was found in 36 of the 38 proved nephrotic cases; in case no determination was available, and in the remaining

1, death occurred within 35 hours of injury. In this patient the nonprotein level

had already climbed to 63 mg. per 100 cc., only points below our arbitrary limit,

and there can be no reasonable doubt that this limit would have been passed

had he lived few hours longer. Like oliguria, nitrogen retention was evident

from the outset. The retention level climbed steadily, usually from 30 to 40

points day, the maximal level depending solely on the length of time elapsing

before death ensued or, in those who survived, before onset of diuresis. Nitrogen

retention, like oliguria, was also observed in the absence of renal lesion (7 instances) and is explainable on similar grounds.

Hypertension

We defined hypertension for purposes of this study as an elevation of the

systolic blood pressure to or above 135 mm. Hg and of the diastolic to 90 mm.

Hg or higher. By civilian standards these figures must seem low, but it is to be

remembered that we were dealing primarily with homogeneous group of

young men between 18 and 30 years of age who had recently suffered severe

trauma usually associated with the loss of considerable amounts of blood. By

this standard, 20 of 32 patients with the renal lesion whose blood pressures had

been recorded were judged to have significant elevations of systolic or diastolic

pressure or both. Hypertension rarely appeared within the first 48 hours; it

was frequent by 72 hours, and was the rule by 96 hours.

Of the remaining 12 patients with the characteristic renal lesion who failed

to show an elevation of blood pressure, died within days of injury and on

the third day. In only patients living beyond the 3-day period did hypertension

fail to develop. One died on the fourth, on the fifth, and on the seventh day

respectively. The last patients also had severe progressive peritonitis. It seems

reasonable to conclude that hypertension is characteristic if not constant symptom of the syndrome.

The importance of hypertension is increased when viewed from the converse

point of view. No patient in this series whose kidneys failed to show pigment
DIAGNOSIS OF LOWER NEPHRON NEPHROSIS

nephropathy at necropsy had sustained elevation of blood pressure, although

an occasional determination might have been above the arbitrary limit. It must

be remembered, however, that no cases of cerebral injury were included in our

series. In such cases hypertension secondary to increased intracranial pressure is

of course frequent.

Pigment Excretion in the Urine

As part of the routine urine examination of all patients included in this study,

the supernatant urine after centrifugation was tested with benzidine for the

presence of dissolved heme-containing pigments, which, as will be discussed

fully in Chapter VIII, were largely hemoglobin and myoglobin.

All patients with morphologic evidence of renal damage excreted benzidinepositive material in the urine. In patients (exclusive of those in whom there

was direct trauma to the urinary tract) enough pigment was excreted to make

the urine grossly red or brown. In some cases descriptions such as “dark amber”

suggest pigment element, but in the majority amber and yellow were the colors

recorded, and only the benzidine test revealed the pigment element. Pigment

excretion, furthermore, was in most instances transitory and usually disappeared

on the third or fourth day. On the other hand, pigment excretion was observed

in patients whose kidneys did not show significant lesions at necropsy.

Other Urinary Findings

Other chapters of this volume contain complete discussions of the chemical

abnormalities found in the blood and urine and theresults ofrenal function tests

performed during the course of the studies. Repetition would be pointless, especially since these factors have little diagnostic value. However, three urinary

abnormalities, determination of which lies within the realm of routine clinical

pathology, are worthy of mention since, although of limited diagnostic value,

they were constant features of the syndrome.

i. Proteinuria.—All patients with proved renal lesions showed proteinuria.

However, since proteinuria was absent in only 14 of the entire series of casualties studied and was present in 51 patients without clinical or anatomic evidence

of nephropathy, its diagnostic import is negligible.

See Appendix C, section on routine urinalyses, for technique of performing the test.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

2. Persistent Acidity.—The urine of all patients manifesting nephropathy at

necropsy was acid on initial examination. The range of pH was from 5.0 to 6.9 with an average value of 5.8. The urines of the control group ranged from 5.0

to 8.4 an average of 6.2, overlapping too much to give the figures any diagnostic value. In succeeding specimens the urine from the nephropathic group

remained persistently acid with few exceptions, occasionally even despite therapeutically-induced alkalosis.

3. Fixation of Specific Gravity.—The specific gravities of the initial specimens varied from 1.009 to 1.032, though the majority of specimens fell within

the range of 1.020 to 1.026. No significant difference was found in patients with

and without nephropathy. Diversity in these initial specimens is not surprising,

since it is probable that in many instances part of the urine may have been excreted by the kidney before the patient was wounded. With the passage of time

the specific gravity of subsequent specimens declined in the nephropathic group,

despite oliguria, and tendency to fixation between 1.010 and 1.015 became apparent inall the patients with proved renal lesions. Evidence of continued power

of urine concentration occasionally helped to distinguish cases of “extrarenal”

oliguria and azotemia from the true nephropathies.

Summary: Diagnosis of Lower Nephron Nephrosis (“ShockKidney”)

Seven phenomena have been described which are characteristic of the renal

lesion following traumatic shock. One of these, proteinuria, has no diagnostic

value because of its frequency in non-nephropathic cases. Two others, persistent

acidity of the urine and fixation of specific gravity at low level despite oliguria,

are of great interest in defining the physiologic abnormality, but proved of limited diagnostic value since therapeutic emergencies frequently prevented verification by suitable test. tetrad of findings—oliguria, azotemia, pigment excretion, and hypertension—were of practical diagnostic value.

Each of these may be present singly in patients with normal kidneys. So may

any pair. The combination of oliguria and azotemia, for instance, was found five

times; even the triad of oliguria, azotemia, and pigment excretion was found

twice in patients with morphologically normal kidneys. The complete tetrad,

however, was never found in this series in patients with normal kidneys. Barring

the complication of head injury, it was concluded that this tetrad might be

considered reliable evidence of renal damage.
DIAGNOSIS OF LOWER NEPHRON NEPHROSIS 115

Uremic Symptomatology

Subjective symptoms of the type commonly to be expected in uremia were

conspicuous primarily by their absence. In the initial stages of the disorder minor

symptoms might well have been masked by the greater discomforts of recent

trauma, surgery, and anesthesia, or been suppressed by postoperative narcosis.

As the days pass, these distractions cease to be of importance, yet again and

again statements such as “patient comfortable” and “no complaints” appeared

in the records. brief review of the usual symptoms ofrenal insufficiency, noting

their frequency in this material, is in order.

Headache.—Headache was not mentioned in any case record. Minor complaints might not have been recorded, but even so headache could not have been

conspicuous feature.

Nausea and Vomiting.—Many of our patients had abdominal wounds with

subsequent gastric and intestinal surgery complicated by various grades of peritoneal irritation. They were often treated by Wangensteen drainage, making

interpretation of gastro-intestinal symptoms difficult. Nausea appeared in three

of the crush-syndrome cases and also in three others not complicated by abdominal wounds. In only two of these was it associated with vomiting, once on the

seventh and once on the thirteenth day. Persistent hicupping was twicerecorded.

Vision.—No patient complained of visual difficulties. Eyeground examinations were recorded in nine cases. In six patients the eyes were found to be normal when examined at intervals of from to 10 days, and in three patients

were found to be abnormal. Two of the latter patients showed retinal hemorrhages on the fifth and tenth days of disease, respectively, and one showed papilledema on the ninth day.

Consciousness. —Drowsiness was the most frequent cerebral symptom and

was noted in 17 instances. Its onset was recorded as early as the second day, as

late as the ninth. Very frequently the notation was accompanied by statement

such as “patient drowsy but when aroused answers questions clearly and intelligently.” One patient was frankly disoriented, and two were irrational. In patients drowsiness progressed to stupor; in of these the condition was described

as coma. This stage seldom antedated death by many hours. Onset of coma was

recorded as early as the third and as late as the tenth day. At the time of onset,

the nonprotein nitrogen levels ranged from 89 to 305 mg. per 100 cc. of plasma.

One patient regained consciousness after lapse of hours at time when the

956507 0—52
THE PHYSIOLOGIC EFFECTS OF WOUNDS

nonprotein nitrogen level was 339 mg. per 100 cc. of plasma.

Twitekings and Convulsions. —These were very uncommon phenomena.

Twitchings were recorded in two patients, convulsions in four; one of these four

recovered. Neuromuscular irritability was noted in two other patients in whom

Chvostek’s sign developed. In both, the symptoms followed vigorous alkali

therapy.

Hyperpnea.—Dyspnea or hyperpnea was recorded on 12 occasions, with onset

ranging from the fourth to the twelfth day. In six instances it appeared approximately coincidentally with the onset of pulmonary edema and may well have

been an effect of the latter. In only few instances was respiration clearly of the

Kussmaul type.

Edema. —Evidence of edema was observed in 25 patients. It appeared as early

as the third and as late as the eleventh day, largely depending on the extent of

intravenous fluid therapy. Clinical evidence of pulmonary edema was recorded

in 12 instances. Either pulmonary or peripheral edema might appear first, and

each was observed in the absence of the other. Facial edema was noted only

times.

Nonjatal Cases

In examining the clinical records of nonfatal cases in this series to see if diagnosis of renal injury could be established beyond reasonable doubt, we were hampered by incompleteness of observation and record. The findings in 44 patients

whose records were fairly complete and who manifested or more of the

criteria described above are summarized in the accompanying table.

Three patients presented the complete tetrad of characteristic findings. Two

showed the triad of pigment excretion, azotemia, and hypertension, but in both

there was uncertainty regarding urine output during the first 48 hours after

injury. Two presented the combination of pigment excretion, oliguria, and azotemia, but blood pressure determinations at appropriate time intervals were not

recorded. In five others with the same triad, hypertension could be definitely

excluded.

Among those with combination of two principal signs, one patient showed

oliguria and hypertension, but nonprotein nitrogen was not determined and the

urine was not tested with benzidine. In one case hypertension of notable level

(170/120) and azotemia were observed, but urine output was not recorded
DIAGNOSIS OF LOWER NEPHRON NEPHROSIS

Table 51. Principal Findings in 44 Surviving Patients Suspected of Having

Renal Insufficiency

nor was the urine tested with benzidine during the first days. In Case 130,

oliguria and unimpressive azotemia of 69 mg. per 100 cc. were demonstrated,

but again the urine was not tested and no postoperative blood pressures were recorded. In another patient, azotemia and pigment excretion were present but no

elevation of blood pressure occurred, and the urine excretion for the first 24 hours

was 750 cc., which was above our arbitrary limit but nevertheless in the lower

range of normality.

Three patients presented the remaining pair of findings: pigment excretion

and oliguria. Six patients manifested only transitory oliguria without supporting

evidence of nephropathy, and 19 pigment excretion with similar lack of confirmatory findings. In the light of the above findings, let us again evaluate our

diagnostic criteria.

As in the fatal group, no patient with other evidence of renal insufficiency

failed to show pigment excretion if the urine was tested with benzidine within

the first 48 hours after injury. Nineteen patients out of the 44, however, who at

no time showed any other evidence ofrenal damage, excreted benzidine-positive

material.

Number of Patients

Findings

Pigment

Excretion Oliguria "HighAzotemia”

Hypertension

(Above 135/90)

19

present.

=not recorded, or presence uncertain.

absent.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Oliguria was demonstrated in 15 patients with or more other positive findings. In patients its presence was uncertain and in it was observed in the

absence of any other sign. In one questionable case, in which there was pigment

excretion and azotemia, oliguria was absent. Oliguria in these patients who

survived was, however, sometimes extremely transitory. Among the patients

manifesting the complete tetrad, oliguria was of only day’s duration in two

cases, and lasted only days in one. The longest duration of oliguria did not

exceed days. In none of the cases was output depressed to anuric levels; i.e.,

below 100 cc. in 24 hours.

Azotemia was observed in 15 of the 44 patients. In no instance was it the

sole finding. plasma nonprotein nitrogen concentration of 88 mg. per 100 cc.

accompanied only by pigment excretion occurred in one instance. In patients

the maximal level was below 100 mg. per 100 cc., and in the range was between 100 and 150 mg. per 100 cc. of plasma. Two desperately ill patients recovered despite nonprotein nitrogen levels of 247 and 217 mg. per 100 cc. respectively.

In patients the azotemia was of such low degree (74, 77, and 69 mg. per 100 cc.

respectively) and so transitory (lasting only and days) as to be of doubtful

significance. In the other patients it lasted from to 21 days.

Seven patients showed definite hypertension which ranged from 128/90 in

Case 54 to 180/115 in Case 138. Blood pressure was not recorded for two patients

who presented the triad of pigment excretion, oliguria, and azotemia, but did not

become elevated in five other patients presenting the same combination. The remaining two patients in this group had, respectively, azotemia of more than 17

days’ duration with maximum nonprotein nitrogen level of 247 mg. per 100 cc.,

and azotemia of over days’ duration with nonprotein nitrogen level of 140 mg.

per 100 cubic centimeters. Hypertension was never observed without other evidence of renal insufficiency. Once hypertension developed it was very persistent,

even after the nonprotein nitrogen had dropped to normal levels. The shortest

duration of hypertension observed was 12 days, and in one patient it was still

present at 22 days.

In summary, pigment excretion appeared to be constant phenomenon in

the shock kidney but was seen also in many patients who never showed evidence

of renal failure. Oliguria likewise was frequently seen in the absence of renal

failure. In positive cases it might be extremely transitory and the volume not

greatly depressed. Azotemia was constant and, except in the presence of severe

complications or in the moribund state, reliable sign of renal failure. Eleva-
DIAGNOSIS OF LOWER NEPHRON NEPHROSIS

tion of blood pressure in the absence of head injury was inconstant. When present it constituted the most important confirmatory criterion.

On these grounds it is reasonable to conclude that all seven surviving patients

manifesting hypertension did, in fact, have “shock kidney.” In six of these azotemia was proved, and in the seventh the nonprotein nitrogen level was not

recorded. Eight other patients showed azotemia supported by one or more other

criteria of renal injury. In three patients azotemia was so slight and transitory

as to be of doubtful significance. In the remainder it was of sufficient severity

or was bolstered by enough other confirmatory evidence to justify the diagnosis

of renal injury.

We conclude, then, that minimum of and possible maximum of 14

of our patients developed and survived “shock kidney.” In comparison with 38 fatal cases of histologically proved shock kidney, this indicates case fatality

rate of approximately 75 percent.

SUMMARY AND CONCLUSIONS

The clinical records of 60 patients on whom necropsy was performed were

analyzed from the standpoint of factors relating to renal function, and the findings in the group of 38 with histologically demonstrated pigment nephropathy

were compared with those of the 22 in whom this lesion was not present. It

became apparent that the clinical syndrome ofrenal insufficiency which follows

shock is remarkable chiefly for the scarcity and mildness of its symptoms. Little

that the patient complained of served to call attention to the condition. Drowsiness slowly deepening into stupor was the most common symptom, but it might

be absent almost until death. The only common sign was edema, either pulmonary or peripheral.

Laboratory and blood pressure findings provided more useful criteria. Seven

findings were present with great constancy in the nephropathic cases that appeared only sporadically or never in the control group. These were in ascending

order of diagnostic importance: proteinuria, persistent acidity of the urine, excretion of benzidine-positive material, oliguria, azotemia, fixation of specific gravity

of the urine at low level, and hypertension. It was found that the diagnosis of

nephropathy could only be made by the systematic recording of four factors in

every patient who was resuscitated from shock: (1) the total urinary output,

(2) the presence of benzidine-positive material in the urine, (3) the nonprotein
120 THE PHYSIOLOGIC EFFECTS OF WOUNDS

nitrogen level in the blood plasma, and (4) the systolic blood pressure. The

symptom complex of oliguria, pigment excretion, azotemia, and hypertension

established the diagnosis. It is probable that in some cases oliguria was too transient to be recognizable, and certain that in some cases hypertension did not

develop. If the patient survived beyond days, fixation of specific gravity and

constant acidity of the urine afforded important confirmatory evidence.

These diagnostic criteria of nephropathy were then applied in review of the

records of the nonfatal cases in the series. It was concluded that minimum of

11 and possible maximum of 14 had had pigment nephropathy. Using the

former figure, the case fatality rate is approximately 75 percent.

CASES OF SPECIAL INTEREST IN THIS CHAPTER

Nonfatal

13 44 72 109 133

27 54 81 112 138

29 60 87 125 150

37 7i 104 130

Fatal

26 52 85 108 122

12 31 55 86 116 123

22 41 65 88 117 129

24 47 66 95 118 131

49 74 97 I2 13

80 98 A-30

Crush Syndrome Fatalities

69 70 78 93 132
CHAPTER

Clinical, Physiologic, and Biochemic

Correlation in Lower Nephron

Nephrosis

The importance and frequent occurrence of renal failure in those battle casualties who were severely wounded must be emphasized. In the preceding chapter the diagnosis of posttraumatic renal insufficiency was discussed from clinicopathologic viewpoint. In this chapter an attempt will be made to present

comprehensive picture of the physiologic and biochemic features of the syndrome and their correlation with the clinical findings.

In studying these patients in whom renal insufficiency developed following

trauma we have dealt with unique group of individuals. They were nearly

all young men, and so far as was known, physiologically sound prior to wounding. They had incurred severe wounds which almost immediately began to cause

changes in their internal environment. Because of the effectiveness of resuscitation and other early treatment, the wounds and the changes produced were

not severe enough to cause early death. These men withstood operation fairly

well, largely because they had been adequately treated preoperatively, but beginning with the first day or two after operation (or after trauma, if no surgery

was done) they began to show clinical and laboratory evidence of inadequate

renal function. The renal failure progressed rapidly and in most instances the

patients either died in uremia within 10 days or then began to show signs of

improvement of renal function, such as diuresis and clearance of nonprotein

nitrogen, and subsequently recovered.

In selecting patients presumed to have diminished renal function, two main

criteria were utilized: the nonprotein nitrogen level in the blood plasma, and the

degree of urinary suppression. Much of the data presented in this chapter will

relate primarily to the patients with high azotemia, since this was constant and

generally reliable indication of renal insufficiency. In many instances the data
122 THE PHYSIOLOGIC EFFECTS OF WOUNDS

are also correlated with the degree of urinary suppression because low urinary

output provides simple and useful clinical means of recognizing many cases

of impending renal failure. Our.definitions of “high azotemia” and of oliguria

and anuria have been given, and the diagnostic features of the syndrome were

discussed in Chapter IV.

The incidence of high azotemia, oliguria, and anuria in our series is shown

in Table 52. In of the 186patients no nonprotein nitrogen determinations were

made and in 50 the urinary output was unknown. Seventy-three of 181 patients

were found to have high azotemia. Thirty-three of 136 patients had anuria for

at least 24 hours, 45 oliguria (they did not reach anuric level at any time), and

58 had normal output of urine. Of the patients with high azotemia, 27 also

had anuria and 29 oliguria.

Table 52.—Plasma Nonprotein Nitrogen Level and Urinary Output in the

Severely Wounded

Clinical features

Case Fatality

Sixty-five of the 186 patients in the total series failed to survive. Of the 65 who died, 51, or 78 percent, were among those who had high azotemia or urinary

suppression or both. The serious implication of the onset of these conditions is

well illustrated by Table 53. Of the 73 patients with high azotemia, 50, or 68 percent, died. Of 33 with anuria, 30, or 91 percent, died. This table likewise shows

Nonprotein Nitrogen Level

Urinary Output (Number of Patients)

Anuria Oliguria Normal

Output

Output

Unknown Total

With High Azotemia

Without High Azotemia ....

NPN Unknown

27 29

16

10

48 43

73

108

Total 33 45 58 50 186

Urinary output ofless than 100 cc. in 24 hours.

Urinary output of 100-600 cc. in 24 hours.

Plasma nonprotein nitrogen level of 65 mg. per 100 cc. or higher.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

forcefully the importance of uremia as primary cause of death in these patients;

it was the primary cause of 34 (68 percent) of the deaths among patients with high azotemia and of 22 (73 percent) of the deaths among patients with anuria.

Table 53.—Case Fatality Rates and Type of Death in All Patients with

Azotemia and/or Urinary Suppression

Degree of Initial Shock

The relationship of the degree of shock on admission to subsequent development ofrenal failure is shown in Table 54. When the crush cases, case of true

transfusion incompatibility, and case of sulfathiazole crystalluria in the group

without shock are excluded, it becomes evident that preponderance of patients

in whom signs of renal failure appeared were recognized as having had severe

or moderate initial shock. With the above-mentioned cases excluded, 86 percent

of the azotemia group, 73 percent of the oliguria group, and 76 percent of the

anuria group had had moderate or severe shock at the time of hospital admission. Many men may have had transient shock, even of several hours’ duration,

before hospital entry with no sign of shock on entry. Our figures therefore are

doubtless too low. It is not, however, clear that the severity of the renal lesion

is entirely determined by the degree of shock. This series includes few patients

(Cases 22, 138, and 120) who, so far as we could determine, at no time had any

appreciable degree of shock yet who subsequently manifested renal insufficiency.

Fatal Cases Role of Uremia in Fatal Cases

Number of cases

Presumptive Renal Damage Total

Cases

Number Percent

Primary Cause

of Death Contrib- Coincidental

None

or UnNumber Percent

utory known

High Azotemia 73 50 68 34 68 13

Urinary Suppression

Oliguria 45 21 47 12 57 Anuria 33 30 91 22 73

Total 78 51 65 34 67

Of the 186 patients studied, 35 were classified as dying primarily ofuremia, on of whom (Case 146) no

nonprotein nitrogen determination was made. Hence only 34 patients are included in the table.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 124

Table 54.—Relationship of Initial Shock to Development of

Renal Insufficiency

Survival Period after Wounding

The time of death after wounding was considered in 51 patients who had

renal insufficiency (Table 55). Of these 51, uremia was the cause of death in

35, contributory cause in 3, and only coincidental in 13 patients. Of the 35

patients in whom uremia was the primary cause of death, 15, or 43 percent, died

in the first days and 17, or 48.5 percent, in the second days—more than 91

percent within 10 days after wounding. Of the entire group of 51 fatalities,

94 percent (48 patients) died within the first 10 days. The significance of this

time factor will be illustrated in connection with the biochemic data and in the

Table 55. Period of Survival after Wounding in 51 Patients with

Renal Insufficiency

Classification Total

Degree of Initial Shock

of Cases Cases

None Slight Moderate Severe Unknown

By NPN Retention

High Azotemia 73 27 33

By Output

Oliguria 45 13 20

Anuria 33 16

Includes crush cases, case of transfusion incompatibility, and case of slight postoperative shock.

Includes case of sulfathiazole crystalluria, case of transfusion incompatibility, and crush cases.

Time from Wounding to Death

Days

Role of Uremia in Cause ofDeath

Primary

Number of cases

Contributory

Number of cases

Coincidental

Number of cases

to 15

to 10 17

to 15

Total 35 13
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

following chapter on therapy. Evidence will also be presented that if patients

can be carried through this 10-day critical period, they stand fair chance of

recovery. This point will be further discussed later; it emphasizes the importance

of avoiding certain therapeutic errors which can result in death, such as overloading the circulatory system by administration of too much fluid.

Type and Location of Wounds

The type and location of major wounds and injuries in patients with renal

insufficiency (as indicated by nonprotein nitrogen retention and urinary suppression) is shown in Table 56. In the former classification—the high azotemia

group—peripheral wounds with fracture and intra-abdominal wounds are of

equal frequency. In the latter, peripheral wounds predominate in the oliguria

group whereas in the anuria group intra-abdominal wounds are somewhat more

frequent. Thoracic wounds are third in all three groups. Wounds of the liver,

Table 56. Type and Location of Wounds or Injuries in Patients with

Renal Insufficiency

Type and Location of Wound

High Azotemia

Number

of cases

Oliguria

Number

of cases

Anuria

Number

of cases

Peripheral, with Fracture 32 18 11

Intra-abdominal 32 14 13

Thoracic 15 10

Peripheral, without Fracture

Thoraco-abdominal

Liver 12

Kidney UO

Urinary Tract other than Kidney

Crush

Burn

Spinal Cord Injury

Totals

Multiple Major Wounds 21 10

Single Major Wound 52 35 26

Total Cases Included 73 45- 433

Six treated by nephrectomy.

Four treated by nephrectomy.

Includes case of incompatible blood transfusion.

Includes case of incompatible blood transfusion and case of sulfathiazole crystalluria.
126 THE PHYSIOLOGIC EFFECTS OF WOUNDS

kidneys, and urinary tract occurred, but not in high percentage in any group.

Hypertension

Table 57 shows the number of patients having high azotemia who at some

time in their course also had systolic blood pressure of 135 mm. Hg or higher,

or diastolic pressure of 90 mm. Hg or higher. These figures represent the probable upper limits of normal for the age group into which our patients fell. Blood

pressures were recorded in 71 of 73 patients with high azotemia, 67 being recorded within the first days after wounding or injury, including crush injury.

Hypertension developed in 44 patients, usually during the first week. In the

few in whom it was first noted after this period, the probability is that they also

had an unobserved hypertension prior to the first determinations recorded. In

general the blood pressure rose gradually, reaching maximum between the

third and sixth days after wounding. This agrees essentially with the time of

maximum nitrogen retention in the blood.

Of the 27 patients who did not have hypertension, 20 died. Of these 20,

thirteen died within the first days after wounding, three within days, and

four between and 10 days. Of those who died within few days after wounding,

many had never really recovered from shock. It seems probable that they would

Table 57.—Incidence of Hypertension in Patients with High Azotemia

Patients Hypertension

Present

Hypertension

Absent Total

Survived

With Minimal Renal Failure 12

With Recovery Diuresis 10 10

Total 15 22

Died

Uremia Primary Cause 27 34 Uremia Contributory

Uremia Coincidental 11 12

Total 29 20 49

TOTAL 44 27 71

Not including case in which the presence or absence of hypertension was not known.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

have developed hypertension if they had lived longer, especially those in whom

the primary cause of death was uremia.

Other Clinical Findings

Edema was observed in 23 of the 73 patients with high azotemia. The edema

varied in degree, but it was usually generalized, involving all extremities and the

face. It was present in 18 patients who died. Three patients had generalized convulsions. Eyegrounds were examined in patients; showed flame-shaped

hemorrhages and small exudate. pericardial friction rub was heard in patient who died of uremia, and pericarditis was found on necropsy.

Biochemic and Physiologic Features

BLOOD

Biochemic Abnormalities

large number of blood chemistry studies were made preoperatively and

postoperatively on the 73 patients with high azotemia. It was not possible to

make daily or even regular determinations on every patient, and the number of

cases indicated in the various cells of the tables to follow is conditioned by the

available data. The plasma carbon-dioxide combining power, and the concentrations of plasma nonprotein nitrogen, chlorides, phosphate, protein, magnesium, phosphorus, creatinine, and uric acid, and of the serum sodium were determined. Average values are shown in Table 58 through and Table 59.

When more than determination of any constituent was made on any patient

during the postoperative periods specified in the tables, only the most abnormal

value was selected for inclusion in the averages.

In both tables the data are presented in two ways: (1) on the basis of survival, and (2) on the basis of the daily output of urine. These findings, together

with the changes in the urine (see Tables 75-77) to be discussed later, reflect

the typical biochemic and physiologic alterations which occurred in those of the

severely wounded patients in whom renal insufficiency developed. The data show

the changes taking place during the acute phase either to the time of death or,

in those who survived, through the recovery phase as long as we could follow

the case. Variations will be mentioned whenever they are important.
128 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

58.

—Physiologic

and Biochemic

Findings in

Patients with

High

Azotemia*

A.

Plasma

Nonprotein

Nitrogen** Average

Plasma

Nonprotein

Nitrogen

(mg.

per

100

cc.)

Classification of

Cases

Preoperative

Postoperative Period

Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

47.3

±4.8

72.8

±4.2

143.1

±9.3

182.2±17.2

175.8±29.8

127.6±23.4

(21

cases)

(31

cases)

(54

cases)

(29

cases)

(13

cases)

(10

cases)

Patients’ Outcome

Lived

41.5

±4.9

65.3

±4.1

92.8

±9.1

117.3±20.5

103.4±20.1

109.9±17.0

(8

cases)

(11

cases)

(17

cases)

(11

cases)

(8

cases)

(9

cases)

Died

—All

Causes

50.9±7.2

77.0

±6.0

166.2

±1

1.0

221.9±19.9

291.8±18.8

287

(13

cases)

(20

cases)

(37

cases)

(18

cases)

(5

cases)

(1

case)

Died

of

Uremia

36.0

80.0±7.9

190.5 ±1

1.3

258.8±12.6

291.8±18.8

287

(3

cases)

(1

cases)

(27

cases)

(14

cases)

(5

cases)

(1

case)

Died

of

other

Causes

55.4±8.9 (10

cases)

73.2

±9.5 (9

cases)

100.6±1 1.5

(10

cases)

92.8±22.7 (4

cases)

Urinary

Output

Normal

37.3

59.4±7.0

89.6±8.6

112.4±1 5.

76.0

29

(3

cases)

(5

cases)

(8

cases)

(7

cases)

(3

cases)

(1

case)

Anuria

34.5

75.6

190.4

257.1

258

155

(2

cases)

(8

cases)

(20

cases)

(12

cases)

(4

cases)

(2

cases)

Oliguria

43.0

76.5

127.9

141.2

183.6

140.4

(11

cases)

(15

cases)

(24

cases)

(10

cases)

(5

cases)

(5

cases)

Unknown

68.0 (5

cases)

69.0 (3

cases)

66.5 (2

cases)

108 (1

case)

117.5 (2

cases)

Anuria

and

Oliguria

41.7

±3.5

76.2±5.3

156.3±10.2

204.4±20.

216.7±35.2

144.6±29.7

(13

cases)

(23

cases)

(44

cases)

(22

cases)

(9

cases)

(7

cases)

Anuria,

Oliguria,

and

Unknown

49.0±5.5

75.4±4.7

152.4±10.2

204.4±20.

205.8±33.4

138.6±23.

(18

cases)

(26

cases)

(46

cases)

(22

cases)

(10

cases)

(9

cases)

through

G:

If

more than

determination had

been

made on

patient

during

the

specified

period,

the

most abnormal

valuewas used.

•*

Normal

range:

25-40

mg.

per

100

cc.

"High

azotemia”: 65

mg.

per

100

cc.

or

higher.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 129

Table

58.

—Physiologic and Biochemic

Findings in

Patientswith

High

Azotemia

B.

Plasma

Carbon-Dioxide

Combining

Power*

Classification

of

Cases

Average Plasma

Carbon-Dioxide Combining

Power

(mEq./L)

Preoperative Period

Postoperative Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

21.8

±1.3

24.9±1.3

25.6±0.9

23.6±1.5

21.4±2.

19.5

±1.5

(21

cases)

(20

cases)

(47

cases)

(23

cases)

(11

cases)

(8

cases)

Patients’ Outcome

Lived

19.3±2.0

27.4±1.5

27.7±1.

24.8±1.5

25.2

±2.3

20.3±1.4

(8

cases)

(7

cases)

(15

cases)

(7

cases)

(6

cases)

(7

cases)

Died

—All

Causes

23.3±1.7

23.6±1.8

24.6±1.

23.1

±2.1

16.

±2.

13.5

(13

cases)

(13

cases)

(32

cases)

(16

cases)

(5

cases)

(1

case)

Died

of

Uremia

24.6

24.3±2.4

23.3±1.0

20.2

±1.5

16.

±2.

13.5

(3

cases)

(8

cases)

(25

cases)

(13

cases)

(5

cases)

(1

case)

Died

of

other

Causes

22.9±2.0

22.7

±3.0

29.4±3.3

35.5

(10

cases)

(5

cases)

(7

cases)

(3

cases)

Urinary

Output

Normal

24.2

29.7

31.9±2.5

34.4±3.6

36.0

(3

cases)

(3

cases)

(8

cases)

(4

cases)

(1

case)

Anuria

26.2

23.0

23.2

20.0

19.1

22.9

(2

cases)

(6

cases)

(17

cases)

(11

cases)

(4

cases)

(2

cases)

Oliguria

20.0

24.7

25.2

23.1

20.4

18.3

(11

cases)

(1

cases)

(22

cases)

(8

cases)

(5

cases)

(4

cases)

Unknown

22.4

20.6

18.6

(5

cases)

(I

case)

(2

cases)

Anuria

and

Oliguria

21.0±1.6

24.1±1.5

24.

±0.8

21.3±1.1

19.8±1.8

19.8±1.9

(13

cases)

(17

cases)

(39

cases)

(19

cases)

(9

cases)

(6

cases)

Anuria,

Oliguria,

and

Unknown

21.4±1.4

19.9±1.6

19.5

±1.5

(18

cases)

(10

cases)

(8

cases)

Normal

range:

24-31

mEq./L
THE PHYSIOLOGIC EFFECTS OF WOUNDS 130

Table

58.

—Physiologic

and Biochemic

Findings in

Patients with

High

Azotemia

C.

Plasma

Chlorides* Average

Plasma

Chlorides

(mEq./L.)

Classification

of

Cases

Preoperative

Postoperative

Period

Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

98.8

±0.8 (21

cases)

96.8

±0.9 (31

cases)

93.7±1.6 (54

cases)

93.1±3.0 (28

cases)

91.8±6.3 (13

cases)

103.0±5.3 (10

cases)

Patients’ Outcome

Lived Died

—All

Causes

98.7

±1.3 (8

cases) 98.9±l.l (13

cases)

96.3±1.5 (11

cases) 96.9±1.4 (19cases)

96.

±2. (17

cases) 92.

±2.1 (37

cases)

94.1

±3.3 (11

cases) 92.2

±4. (18

cases)

102.7 ±7.9 (8

cases) 74.4

±3.1 (5

cases)

104.2

±5.8 (9

cases) 91.4 (I

case)

Died

of

Uremia Died

of

other

Causes

99.1 (3

cases) 98.8±1.4 (10

cases)

93.5

±1.7 (10

cases)

100.7±1.3 (9

cases)

90.7±1.9 (27

cases) 98.0±5.9 (10cases)

89.3±3.2 (14

cases) 102.2 (4

cases)

74.4±3.1 (5

cases)

91.4 (1

case)

Urinary

Output

Normal Anuria Oliguria Unknown

102.1 (3

cases) 100.0(2cases) 98.9 (1

cases) 96.2 (5

cases)

100.2 ±2.2 (5

cases) 94.4 (8cases) 96.6 (15

cases) 98.9 (3

cases)

102.7±6.8 (8

cases) 88.9 (20

cases) 94.3 (23cases) 99.4 (2

cases)

98.8±10.2 (7

cases) 90.7 (11

cases) 91.7 (10cases)

111.7 (3

cases) 76.7 (4cases) 83.5 (5cases) 133.7(I

case)

96.4 (1

case) 92.0 (2

cases) 99.8 (5cases) 125.0(2cases)

Anuria

and

Oliguria

Anuria,

Oliguria,

and

Unknown

99.1

±0.8 (13

cases) 98.3±0.8 (18cases)

95.8±1.2 (23

cases) 96.2

±1.1 (26

cases)

91.8±1.5 (43

cases) 92.2±1.5 (45cases)

91.2±2.3 (21

cases) 91.2±2.0 (21cases)

80.5

±3.4 (9

cases) 85.8

±6.1 (10

cases)

97.6±3.9 (7

cases) 103.7 ±5.9 (9

cases)

Normal

range:

97.5-104

mEq./L,
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION i3i

956507 0—52 10

Table

58.

—Physiologic and Biochemic

Findings in

Patients with

High

Azotemia

D.

Plasma

Phosphate*

Classification

of

Cases

Average

Plasma

Phosphate

(mEq./L)

Preoperative Period

Postoperative Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

3.9

±0.3

2.

±0.2

3.7±0.3

3.

±0.3

4.

±0.5

3.

±0.3

(18

cases)

(26

cases)

(45

cases)

(26

cases)

(9

cases)

(10

cases)

Patients’ Outcome

Lived

4.

±0.3

2.

±0.2

2.

±0.3

2.9±0.4

3.

±0.3

3.1

±0.3

(7

cases)

(9

cases)

(12

cases)

(10

cases)

(4

cases)

(9

cases)

Died

—All

Causes

3.6

±0.3

2.9

±0.3

4.1

±0.3

4.

±0.3

5.

±0.7

4.9

(11

cases)

(17

cases)

(33

cases)

(16

cases)

(5

cases)

(1

case)

Died

of

Uremia

3.8

2.

±0.3

4.

±0.3

4.

±0.1

5.

±0.7

4.9

(3

cases)

(10

cases)

(26

cases)

(12

cases)

(5

cases)

(1

case)

Died

of

other

Causes

3.6±0.3

3.1

±0.7

3.6±0.9

3.5

±1.0

(8

cases)

(7

cases)

(7

cases)

(4

cases)

Urinary

Output

Normal

2.9

2.1

±0.2

2.1

±0.3

2.

±0.7

2.3

(3

cases)

(5

cases)

(6

cases)

(7

cases)

(1

case)

Anuria

3.2

2.7

4.3

4.5

5.9

3.9

(2

cases)

(7

cases)

(18

cases)

(10

cases)

(4

cases)

(2

cases)

Oliguria

4.4

2.9

3.7

3.5

4.1

3.1

(9

cases)

(12

cases)

(20

cases)

(9

cases)

(4

cases)

(5

cases)

Unknown

3.9

±0.5

2.0

3.0

3.1

3.9

(4

cases)

(2

cases)

(1

case)

(1

case)

(2

cases)

Anuria

and

Oliguria

4.1

±0.3

2.9

±0.3

4.0

±0.3

4.1

±0.3

4.9±0.6

3.

±0.3

(11

cases)

(19

cases)

(38

cases)

(19

cases)

(8

cases)

(7

cases)

Anuria,

Oliguria,

and

Unknown

4.1

±0.3

2.

±0.3

4.0

±0.3

4.1

±0.3

4.

±0.5

3.

±0.3

(15

cases)

(21

cases)

(39

cases)

(19

cases)

(9

cases)

(9

cases)

Normal

range:1.04-2.0 mEq./L
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

58.

—Physiologic and Biochemic

Findings in

Patientswith

High

Azotemia

E,

Plasma

Protein*

Classification of

Cases

Average Plasma

Protein

(mEq./L.)

Preoperative Period

Postoperative

Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

14.8±0.1

15.1

±0.1

15.6±0.1

15.8

±0.2

15.8±0.3

15.8±0.3

(2

cases)

(32

cases)

(53

cases)

(31

cases)

(13

cases)

(10

cases)

Patients' Outcome

Lived

14.6±0.1

15.1

±0.2

15.1

±0.2

15.1

±0.2

16.

±0.3

16.5

±0.3

(8

cases)

(1

cases)

(17

cases)

(13

cases)

(7

cases)

(8

cases)

Died—

All

Causes

14.8±0.2

15.

±0.

15.6±0.1

16.5

±0.2

15.6±0.6

14.1

(13

cases)

(2

cases)

(36

cases)

(18

cases)

(5

cases)

(1

case)

Died

of

Uremia

13.9

15.3±0.2

15.3

±0.1

15.8±0.2

15.6±0.6

14.1

(3

cases)

(11

cases)

(27

cases)

(14

cases)

(5

cases)

(1

case)

Died

of

other

Causes

15.1

±0.1

14.8

±0.2

16.8

±0.4

18.5

±0.3

(10

cases)

(10

cases)

(9

cases)

(4

cases)

Urinary

Output

Normal

15.6

15.6±0.2

16.0±0.3

17.3±0.3

17.7

14.8

(3

cases)

(6

cases)

(8

cases)

(8

cases)

(3

cases)

(1

case)

Anuria

13.6

14.8

15.6

15.8

15.8

18.2

(2

cases)

(8

cases)

(19

cases)

(12

cases)

(4

cases)

(2

cases)

Oliguria

14.6

15.3

15.3

14.8

15.1

15.3

(11

cases)

(16

cases)

(24

cases)

(11

cases)

(4

cases)

(4

cases)

Unknown

15.1

12.6

15.6

15.8

17.0

(5

cases)

(2

cases)

(2

cases)

(1

case)

(2

cases)

Anuria

and

Oliguria

14.

±0.

15.1

±0.1

15.

±0.1

15.3±0.2

15.3±0.3

16.3

±0.3

(13

cases)

(24

cases)

(43

cases)

(23

cases)

(8

cases)

(6

cases)

Anuria,

Oliguria,

and

Unknown

14.6

±0,1

14.8

±0.1

15.3

±0.1

15.3

±0.2

15.3±0.3

16.

±0.3

(18

cases)

(26

cases)

(45

cases)

(23

cases)

(9

cases)

(8

cases)

Converted

from

Gm.

per

100

cc.

to

mEq./L.

for

purposes

of

comparison

with

electrolytes. Our

normal

range

of

plasma

protein was 6-7

Gm.

per

100

cc.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 133

Table

58.

—Physiologic and Biochemic

Findings in

Patientswith

High

Azotemia

F.

Serum

Sodium*

Classification

of

Cases

Average

Serum

Sodium

(mEq./L.)

Preoperative Period

Postoperative Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

146.3±3.7

147.5±3.7

141.3

±2.5

137.8±5.1

140.

±4.

151.7 ±5.7

(5

cases)

(6

cases)

(2

cases)

(8

cases)

(6

cases)

(7

cases)

Patients' Outcome

Lived

137.9

148.0

139.9

124.0

147.4

153.7 ±6.3

(2

cases)

(2

cases)

(3

cases)

(1

case)

(3

cases)

(6

cases)

Died

—All

Causes

151.9

147.3±5.1

141.5

±2.8

139-7 ±5.5

134.0

140.0

(3

cases)

(4

cases)

(18

cases)

(7

cases)

(3

cases)

(1

case)

Died

of

Uremia

143.3

139.5 ±2.5

139.8 ±6.

134.0

140.0

(2

cases)

(16

cases)

(6

cases)

(3

cases)

(I

case)

Died

of

other

Causes

151.9

151.3

157.8

139.1

(3

cases)

(2

cases)

(2

cases)

(1

case)

Urinary

Output

Normal

150.8

160.4

169.6

139.1

(2

cases)

(1

case)

(I

case)

(1

case)

Anuria

143.3

141.2

142.8

138.8

148.1

(2

cases)

(14

cases)

(5

cases)

(3

cases)

(2

cases)

Oliguria

137.9

148.0

137.6

124.5

136.5

148.0

(2

cases)

(2

cases)

(7

cases)

(2

cases)

(2

cases)

(3

cases)

Unknown

154.0

154.9

160.9

(1

case)

(1

case)

(2

cases)

Anuria

and

Oliguria

137.9

145.6±4.1

140.0 ±2.0

137.6±5.9

13

7.9

±4.

148.0±4.3

(2

cases)

(4

cases)

(21

cases)

(7

cases)

(5

cases)

(5

cases)

Anuria,

Oliguria,

and

Unknown

143.2

145.6±4.1

140.0±2.0

137.6±5.9

140.7 ±4.4

151.7±5.7

(3

cases)

(4

cases)

(21

cases)

(7

cases)

(6

cases)

(7

cases)

Normal

range:139-149 mEq./L.
i34 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

58.

—Physiologic and Biochemic

Findings in

Patientswith

High

Azotemia

G.

Plasma

Magnesium*

Classification

of

Cases

Average

Plasma

Magnesium

(mEq./L)

Preoperative Period

Postoperative Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

2.0

±0.1

1.4

±0.1

2.4

±0.3

2.8

±0.6

3.3

2.2

±0.3

(13

cases)

(5

cases)

(13

cases)

(9

cases)

(3

cases)

(5

cases)

Patients’ Outcome

Lived

2.2

±0.2

1.6

2.1

±0.2

1.8

2.3

2.1

±0.3

(4

cases)

(1

case)

(4

cases)

(2

cases)

(2

cases)

(4

cases)

Died

—All

Causes

2.0

±0.2

1.4

±0.2

2.6±0.4

3.2

±0.7

5.2

2.6

(9

cases)

(4

cases)

(9

cases)

(7

cases)

(1

case)

(I

case)

2.1

1.4

2.3

±0.4

3.3±1.0

5.2

2.6

(3

cases)

(2

cases)

(6

cases)

(5

cases)

(I

case)

(1

case)

Died

of

other

Causes

1.9±0.3

1.4

3.2

2.8

(6

cases)

(2

cases)

(3

cases)

(2

cases)

Urinary

Output

Normal

1.6

1.3

2.5

2.8

(3

cases)

(1

case)

(2

cases)

(2

cases)

Anuria

1.8

1.7

2.3

2.4

1.8

1.8

(2

cases)

(1

case)

(5

cases)

(4

cases)

(I

case)

(I

case)

Oliguria

2.3

1.4

2.5

3.6

5.2

2.3

(5

cases)

(3

cases)

(5

cases)

(3

cases)

(1

case)

(2

cases)

Unknown

2.3

2.8

2.3

(3

cases)

(1

case)

(2

cases)

Anuria

and

Oliguria

2.2

±0.2

1.5

±0.2

2.4

±0.4

2.9

±0.8

3.5

2.1

(7

cases)

(4

cases)

(10

cases)

(7

cases)

(2

cases)

(3

cases)

Anuria,

Oliguria,

and

Unknown

2.2

±0.1

1.5

±0.2

2.4

±0.4

2.9±0.8

3.3

2.

±0.3

(10

cases)

(4

cases)

(10

cases)

(7

cases)

(3

cases)

(5

cases)

Normal

range:

0.8-2.

mEq./L
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 135

Nitrogenous Waste Products and Phosphorus

Nonprotein Nitrogen.—Averages of nonprotein nitrogen findings are shown

in Tables 58A and 59. Although the number is small and the variation great in

some periods, giving rise to large standard errors, the data are adequate to give

fairly representative picture. Generally nitrogen retention was already significant by the first postoperative day, increased rapidly during the first 10 days,

and then began to decline. This is illustrated in Chart 18, which has been constructed from averages shown in Table 58A, “All Cases.”

Chart 18. Plasma Nonprotein Nitrogen in Patients with High Azotemia

As previously discussed, most of the fatalities occurred in the first 10

days, so the fall in nitrogen retention in the tenth through fifteenth days chiefly

represents patients who recovered. In general the nonprotein nitrogen level rose

progressively to the day of death in those patients dying primarily of uremia

(Chart 19 and Table 60). However, two patients (Cases 66 and 93) who lived

longer than 10 days after wounding (14 and 13 days respectively) had begun

to show some evidence of returning renal function. The importance of this fact

in relation to therapy cannot be too strongly emphasized: it is essential to avoid
136 THE PHYSIOLOGIC EFFECTS OF WOUNDS

any measure that might precipitate death before this spontaneous recovery can

occur.

Chart 19. Plasma Nitrogenous Waste Products and Phosphorus in

Patients who Died of Uremia

Marked qualitative differences are clear between patients in the different

categories shown in Tables 58, 59, and 60. In many instances the standard error

of the mean is large, indicating wide variation of values in the cases listed; also

the number of cases in many categories is small. Differences in degree of nitrogen
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 137

retention seem to be evident, however, (i) between those who lived and those

who died of uremia, and (2) between those with normal output of urine and

those with oliguria or anuria. The time of greatest retention is essentially in the

same periods as shown in Chart 18.

An attempt to determine whether the development of azotemia could be

correlated with the degree of initial shock was not successful. As was mentioned

previously, of the total number of patients who developed posttraumatic azotemia, oliguria, or anuria, large proportion had had severe or moderate shock

on hospital entry. few patients who had no shock or only slight initial shock

(so far as we could determine) had subsequent renal insufficiency, and the renal

failure was as severe as in those with previous moderate or severe shock. Similarly there was no evidence that nonprotein nitrogen retention was initially

greater in patients who subsequently died of uremia or who developed oliguria

or anuria than it was in those whose renal failure was less severe.

For those interested in further differences between categories of patients ancf

in day-to-day changes in the nonprotein nitrogen and other constituents of the

plasma, the detailed analyses in Tables 59 through 62 are included. The essential

trends are illustrated in the charts; minor variations are evident in the tables.

The lack of effect of ether anesthesia on nonprotein nitrogen levels was discussed

in Chapter II.

Creatinine and Urea.—In general, creatinine rose in the plasma at about the

same rate as the nonprotein nitrogen (Chart 19). Also, as with other nitrogenous

products and the electrolytes, there was no correlation between the degree of

initial shock and elevation of creatinine during the period of posttraumatic renal

failure. The plasma urea nitrogen level was determined simultaneously with

total nonprotein nitrogen and creatinine in 15 cases (Table 63). Like creatinine,

it rose approximately as the total nonprotein nitrogen rose. The relationships of

these three substances when nonprotein nitrogen was elevated are shown in the

table. The averages were obtained by using 38 determinations from larger

series on 15 patients, but including only those in which the nonprotein nitrogen

was over 100 milligrams per 100 cubic centimeters. When more than determination was included from the same patient, the samples were drawn at least

24 hours apart.

Although all waste products which make up the total nonprotein nitrogen

rose in our patients, they did not accumulate in exactly the same proportions

seen in the normal individual, if these figures represent fair sample. However,
138 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 59.—Average Plasma Nitrogenous Waste Products and Phosphorus

in High Azotemia

PREOPERATIVE PERIOD

NPN Creatinine Uric Acid Phosphorus

Classification ofCases

mg. per 100 cc. mg. per 100 cc. mg. per 100 cc. mg.per 100 cc.

Patients' Outcome

Lived 42 2.0 5.4 6.5

(8 cases) (8 cases) (5 cases) (7 cases)

Died—All Causes .... 51 2.0 5.3 5.4

(13 cases) (13 cases) (9 cases) (11 cases)

Died of Uremia .... 36 2.0 6,8 5.7

(3 cases) (3 cases) (3 cases) (3 cases)

Died of other Causes 55 2.0 4.5 5.4

(10 cases) (10 cases) (6 cases) (8 cases)

Urinary Output

Normal 37 1.2 5.0 4.3 (3 cases) (3 cases) (3 cases) (3 cases)

Anuria 35 1.7 5.7 4.8

(2 cases) (2 cases) (2 cases) (2 cases)

Oliguria 43 2.1 5.5 6.6

(11 cases) (11 cases) (6 cases) (9 cases)

FIRST POSTOPERATIVE DAY

Patients' Outcome

Lived 65 2.3 4.4 3.3

(11 cases) (11 cases) (3 cases) (9 cases) Died—All Causes .... 76 3.2 6.6 4.0

(20 cases) (20 cases) (8 cases) (16 cases)

Died of Uremia .... 77 3.5 7.4 3.8

(11 cases) (11 cases) (5 cases) (9 cases)

Died of other Causes 73 2.9 5.4 4.2

(9 cases) (9 cases) (3 cases) (7 cases)

Urinary Output

Normal 59 2.0 6.1 3.1

(5 cases) (5 cases) (2 cases) (5 cases)

Anuria 72 3.5 7.9 3.9

(8 cases) (8 cases) (3 cases) (6 cases)

Oliguria 77 2.9 5.1 4.1

(15 cases) (15 cases) (6 cases) (12 cases)
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Table 59.—Average Plasma Nitrogenous Waste Products and Phosphorus

in High Azotemia Continued

SECOND POSTOPERATIVE DAY

NPN Creatinine Uric Acid Phosphorus

Classification of Cases

mg. per 100 cc. mg. per 100 cc. mg. per 100 cc. mg. per 100 cc.

Patients’ Outcome

Lived 75 2.7 7.1 4.5

(11 cases) (10 cases) (4 cases) (6 cases)

Died—All Causes .... 118 5.0 9.0 5.3

(27 cases) (26 cases) (8 cases) (23 cases)

Died of Uremia .... 127 5.5 9.3 5.1

(20 cases) (20 cases) (7 cases) (18 cases)

Died of other Causes 91 3.4 6.7 5.9

(7 cases) (6 cases) (1 case) (5 cases)

Urinary Output

Normal 68 2.2 6.7 3.5

(5 cases) (4 cases) (1 case) (3 cases)

Anuria 125 5.6 9.2 5.0

(15 cases) (14 cases) (5 cases) (12 cases)

Oliguria 104 4.0 8.0 5.7

(16 cases) (16 cases) (6 cases) (13 cases)

THIRD POSTOPERATIVE DAY

Patients' Outcome

Lived 87 2.9 8.0 3.3

(11 cases) (10 cases) (1 case) (7 cases)

Died—All Causes .... 154 7.1 13.3 5.4

(18 cases) (18 cases) (7 cases) (15 cases)

Died of Uremia .... 159 7.4 14.4 5.6

(16 cases) (16 cases) (6 cases) (14 cases)

Died of other Causes 115 4.2 6.8 2.9

(2 cases) (2 cases) (1 case) (1 case)

Urinary Output

Normal 80 1.8 6.8 2.3

(4 cases) (4 cases) (1 case) (3 cases)

Anuria 166 7.7 10.3 5.3

(10 cases) (10 cases) (3 cases) (8 cases)

Oliguria 118 5.1 15.8 5.1

(15 cases) (14 cases) (4 cases) (11 cases)
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 59.—Average Plasma Nitrogenous Waste Products and Phosphorus

in High Azotemia Continued

FOURTH POSTOPERATIVE DAY

NPN Creatinine Uric Acid Phosphorus

Classification of Cases

mg. per 100 cc. mg. per 100 cc. mg. per 100 cc. mg. per 100 cc.

Patients' Outcome

Lived 99 3.3 15.9 4.2

(7 cases) (9 cases) (2 cases) (6 cases)

Died—All Causes .... 191 7.4 9.0 6.2

(18 cases) (18 cases) (5 cases) (17 cases)

Died of Uremia .... 224 8.9 12.3 6.9

(14 cases) (14 cases) (2 cases) (13 cases)

Died of other Causes 75 2.2 6.9 3.7

(4 cases) (4 cases) (3 cases) (4 cases)

Urinary Output

Normal 97 2.3 6.9 3.3

(4 cases) (5 cases) (3 cases) (4 cases)

Anuria 221 9.0 14.2 7.3

(12 cases) (12 cases) (3 cases) (11 cases),

Oliguria 121 4.3 13.6 4.6

(9 cases) (10 cases) (1 case) (8 cases)

FIFTH POSTOPERATIVE DAY

Patients' Outcome

Lived 106 4.4 10.5 4.3 (8 cases) (8 cases) (3 cases) (7 cases)

Died—All Causes .... 228 8.2 15.9 6.2

(11 cases) (11 cases) (4 cases) (9 cases)

Died of Uremia .... 243 8.6 18.6 6.3 (10 cases) (10 cases) (3 cases) (8 cases)

Died of other Causes 73 4.1 7.6 5.5

(1 case) (1 case) (1 case) (1 case)

Urinary Output

Normal 81 2.7 7.6 3.5

(3 cases) (3 cases) (1 case) (3 cases)

Anuria 244 8.7 14.6 5.9

(9 cases) (9 cases) (2 cases) (7 cases)

Oliguria 131 5.5 14.6 5.7

(7 cases) (7 cases) (4 cases) (6 cases)
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Table 59.—Average Plasma Nitrogenous Waste Products and Phosphorus

in High Azotemia—Continued

SIXTH POSTOPERATIVE DAY

NPN Creatinine Uric Acid Phosphorus

Classification of Cases

mg. per 100 cc. mg. per 100 cc. mg. per 100 cc. mg. per 100 cc.

Patients' Outcome

Lived 91

(5 cases)

187

3.0

(5 cases)

7.6

3.8

(4 cases)

Died—All Causes .... 16.5 6.4

(12 cases) (13 cases) (4 cases) (11 cases)

Died of Uremia .... 235 9.8 19.9 7.0

(8 cases) (9 cases) (1 case) (7 cases)

Died of other Causes 92 2.7 15.3 5.2

(4 cases) (4 cases) (3 cases) (4 cases)

Urinary Output

Normal 102 2.9 15.3 4.7

(6 cases) (6 cases) (3 cases) (6 cases)

Anuria 245 11.1 7.1

Oliguria

(5 cases)

144

(6 cases)

5.1 19.9

(4 cases)

5.7

(6 cases) (6 cases) (1 case) (5 cases)

SEVENTH POSTOPERATIVE DAY

Patients' Outcome

Lived 133 3.3 2.2 4.4

(5 cases) (5 cases) (1 case) (4 cases)

Died—All Causes .... 212 8.6 15.5 6.1

(5 cases) (5 cases) (1 case) (5 cases)

Died of Uremia .... 246 10.3 6.7

Died of other Causes

(4 cases)

76

(4 cases)

1.7 15.5

(4 cases)

3.9

(1 case) (1 case) (1 case) (1 case)

Urinary Output

Normal 111 2.1 15.5 3.7

(3 cases) (3 cases) (1 case) (2 cases)

239 9.4 (4 cases)

6.5

(4 cases) (4 cases)

Oliguria 145 5.1 2.2 4.9 (3 cases) (3 cases) (1 case) (3 cases)
THE PHYSIOLOGIC EFFECTS OF WOUNDS 142

Table 59.—Average Plasma Nitrogenous Waste Products and Phosphorus

in High Azotemia—Continued

it would appear that both creatinine and urea make up greater proportion of

the total nonprotein nitrogen in patients with severe renal failure than in the

normal individual.

Excretion of Urea and Creatinine.—In two patients who died in the first

postoperative days, 24-hour urea nitrogen and creatinine excretion was measured. The relationships of the total amounts of these substances in the urine to

plasma nonprotein nitrogen levels, urine specific gravity, and output of urine

in these two patients are shown in Table 64,

The relationship of rising plasma levels of nitrogenous waste products to low

or decreasing urinary excretion of these same substances is distinctly shown. The

fall in output and specific gravity of the urine is directly related to these changes.

Twenty-four hour specimens were examined also in two patients who had recovery diuresis and will be discussed under that subject later in this chapter. One

of these patients also showed diminished total excretion; the other was examined

after his recovery and values were essentially normal.

Phosphorus.—The characteristic retention of phosphorus in renal failure was

EIGHTH THROUGH TENTH POSTOPERATIVE DAYS

NPN Creatinine Uric Acid Phosphorus

Classification of Cases

mg.per 100 cc. mg. per 100 cc. mg. per 100 cc. mg. per 100 cc.

Patients' Outcome

Lived 103 3.5 15.0 5.3

(8 cases) (8 cases) (2 cases) (4 cases)

Died—All Causes 267 12.1 7.9

(5 cases) (5 cases) (4 cases)

Died of Uremia .... 267 12.1 7.9

(5 cases) (5 cases) (4 cases)

Urinary Output

76 1.4

(3 cases) (3 cases)

Anuria 235 12.1 16.7 8.2

(4 cases) (4 cases) (1 case) (3 cases)

176 6.4 5.8

(5 cases) (5 cases) (4 cases)
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 143

Table 60.—Average Plasma Nitrogenous Waste Products and Phosphorus

in Patients who Died of Uremia

also observed in our cases, and in general paralleled the degree of nitrogen retention (see Chart 19 and Tables 58A, 58D, 59, 60, 61, and 62). In these patients

with posttraumatic azotemia, phosphorus retention was primarily due to impaired ability to excrete that substance; whereas the hyperphosphatemia seen in

patients in shock soon after wounding was possibly due to release of phosphates

secondary to muscle damage (Chapter I). Reference to Tables 58 through 62

and to the individual case records shows that the patients with the most severe

renal damage had the greatest phosphorus retention.

Relationship of Calcium and Phosphorus. —Calcium and phosphorus determinations were made on 12 patients who had high azotemia. The well-known

reciprocal relationship of calcium and phosphorus was present in the majority

of these cases (Table 65).

Days after Wounding

NPN

mg. per 100 cc.

Creatinine

mg. per 100 cc.

Uric Acid

mg. per 100 cc.

Phosphorus

mg. per 100 cc.

First 69±10.3 3.0±0.2 4.1 4.2 ±0.47 (9 cases) (9 cases) (3 cases) (8 cases)

Second 118±11.5 4.8±0.24 7.3±1.1 4.1 ±0.28

(13 cases) (13 cases) (5 cases) (12 cases)

Third 132 ±6.2 6.3 ±0.26 12.8±2.4 5.8±0.42

(16 cases) (16 cases) (8 cases) (14 cases)

Fourth 178±5.1 8.1 ±0.47 12.9 5.9±0.36 (16 cases) (16 cases) (3 cases) (14 cases)

Fifth 245±18.9 8.9±0.53 15.0 7.1 ±0.96

(13 cases) (13 cases) (3 cases) (12 cases)

Sixth 253±13.0 9.5 ±0.70 18.4 6.9±0.22 (8 cases) (9 cases) (3 cases) (8 cases)

Seventh 234±26.3 7.8± 1.83 6.6

(4 cases) (4 cases) (3 cases)

Eighth 255 11.3 7.1

(2 cases) (2 cases) (2 cases)

Ninth 278±16.0 11.4±0.44 6.8

(5 cases) (5 cases) (3 cases)

314 11.4 7.7

(3 cases) (3 cases) (3 cases)

296 10.3 6.8

(2 cases) (2 cases) (2 cases)

Note; Data are given on this table for days post-wounding rather than days postoperative as in the preceding

table.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

6i.

—Average

Nonprotein

Nitrogen and

Electrolytes of

Plasmain

Patients in

whom

Oliguria

Developed

Plasma

Serum

Time

Determination of

Nonprotein Nitrogen mg.

per

100

cc.

CO2

Combin- ing

Power mEq./L.

Chlorides mEq./L.

Phosphate mEq./L.

Magnesium mEq./L.

Sodium mEq./L.

Preoperative

39.6±2.6

22.8±1 .4

100.2 ±0.8

3.7±0.3

2.0±0.2

138.6

(21

cases)

(19

cases)

(20

cases)

(16

cases)

(10

cases)

(3

cases)

Postoperative Days

First

59.9±5.8

25.7±1.2

98.1

±0.9

2.

±0.3

1.4

146.0

(27

cases)

(18

cases)

(26

cases)

(21

cases)

(3

cases)

(3

cases)

Second to

Fourth

99.6±1

1.4

25.3±0.8

96.4±1.7

3.2±0.3

2.4±0.4

136.8±3.3

(34

cases)

(29

cases)

(33

cases)

(26

cases)

(7

cases)

(6

cases)

Fifthto

Seventh

131.8±29.3

23.1

±1.5

92.3±2.4

3.

±0.5

3.5

124.5

(1

cases)

(8

cases)

(11

cases)

(9

cases)

(3

cases)

(2

cases)

Eighth to

Tenth

139.1±50.2

22.2

±3.0

87.4±4.3

4.1

±0,5

5.2

136.5

(7

cases)

(6

cases)

(7

cases)

(4

cases)

(I

case)

(2

cases)

Eleventh to

Fifteenth

140.4±42.tf

18.3±2.0

99.8±5.2

3.1

±0.5

2.3

151.0

(5

cases)

(4

cases)

(5

cases)

(5

cases)

(2

cases)

(2

cases)
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Table

62.

—Average

Nonprotein

Nitrogen and

Electrolytes of

Plasmain

Patients in

whom

Anuria

Developed

Time

Determination of

Plasma

Serum

Nonprotein Nitrogen mg.

per

100

cc.

CO2

Combin- ing

Power mEq./L.

Chlorides mEq./L.

Phosphate mEq./L.

Magnesium mEq./L.

Sodium mEq./L.

Preoperative

34.7

23.9

98.7

2.8

1.8

___

(3

cases)

(3

cases)

(3

cases)

(3

cases)

(2

cases)

Postoperative Days

First

5.6

±4.

23.0±3.0

95.7±2.4

2,

±0.3

1.7

143.3

(8

cases)

(6

cases)

(8

cases)

(7

cases)

(1

case)

(2

cases)

Second

to

Fourth

190.4±13.9

23.2

±1.3

88.9±2.0

4.

±0.5

2.3

±0,4

141.2 ±2.7

(20

cases)

(17

cases)

(20

cases)

(18

cases)

(5

cases)

(14

cases)

Fifth

to

Seventh

257.1±14.9

20.0±l,6

90.7±3.8

4,

±0.1

2,4±0,2

142.8±6.9

(12

cases)

(11

cases)

(11

cases)

(10

cases)

(4

cases)

(5

cases)

Eighth to

Tenth

258.0±2 1.8

19.

±2.3

76,7±4.2

5.9±0,9

1.8

138.8

(4

cases)

(4

cases)

(4

cases)

(4

cases)

(1

case)

(3

cases)

Eleventh to

Fifteenth

155.0

22.9

92.0

3.9

1.8

148.1

(2

cases)

(2

cases)

(2

cases)

(2

cases)

(I

case)

(2

cases)
146 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 63.—Relationship of Plasma Total Nonprotein Nitrogen, Urea

Nitrogen, and Creatinine in 15 Patients

Table 64.—Relationship of Urinary Nitrogenous Waste Products and

Urinary Excretion in Fatal Cases

Plasma Averages Ratios

mg. per 100 cc. Averages

Nonprotein Urea Creatinine Urea Creatinine

Nitrogen Nitrogen NPN NPN

Elevated* 193±12 137±9 7.3±0.47 0.71±0.01 0.039±0.001

Normal Value .... 33 15 1.0 0.51 .028

‘Based on 38 determinations made on 15 patients in whom N.P.N. was over 100 mg. per 100 cc.

Case 108 (Uremia primary cause of death)

Urea

Urine Urine NPN Nitrogen Creatinine Creatinine

Day Specimen was Taken Output Specific (Plasma) (Urine) (Plasma) (Urine)

cc. in Gravity mg. in Gm. in mg. in Gm. in

24 hrs. 100 cc. 24 hrs. 100 cc. 24 hrs.

Day of Operation *100 *1.032 37 *0.13 1.61 *0.20

(Postoperative)

Postoperative Day

First 185 1.014 77 0.54 3.90 0.33

Second 155 1.012 113 5.08 0.32 Third (Day of death) .... 170 6.15

Case 107 (Uremia contributory to death)

Day of Operation 60 1.028 27 1.11

(Preoperative)

Postoperative Day

First 1,560 1,017 41 7.2 1.61 1.20

Second 1,570 1.019 46 9.4 1.64 1.32 Third 1,540 1.01 10.9 1.35 Fourth. 91 4.44

Fifth 800 1.012 73 4.6 4.10 0.50 Sixth (Day of death) .... 152 5.90

•Urine specimen represents 19 hours only.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Table 65.—Relationship of Calcium and Phosphorus in 12 Patients with

High Azotemia

Uric Acid.—This substance, like phosphorus and creatinine, rose in patients

with high azotemia as the nonprotein nitrogen did, and in roughly the same

proportion while retention of both progressed with renal failure (Chart 19 and

Tables 59 and 60). Here also the number of determinations was rather small in

most categories, but the tendency for greatest retention of uric acid in those patients who had the most severe renal insufficiency will become apparent by in956307 0—52 11

Calcium Phosphorus NPN Day of Determination

Case No. mg. per 100 cc. mg. per 100 cc. mg. per 100 cc. Patient’s Outcome

(Normal: (Normal: (Normal: Postop

9-11) 1.83.5) 25-40) erative day

138 10.6 6.4 166 Recovery

10.5 6.2 162 14 diuresis.

133 9.4 4.7 108 10 Do.

9.5 5.4 101 14

60 9.9 5.0 98 Do.

93 9.0 6.0 155 *5 Death in uremia.

9.3 7.3 287 *11

37 9.0 2.1 140 Recovery-—no

oliguria.

112 8.9 4.0 67 Recovered with

minimal renal

failure.

108 8.6 5.1 77 Death in uremia.

8.4 10.9 224 **Do.

7.6 12.6 201 **

123 8.0 4.3 120 Do.

78 7.8 8.9 178 Do.

22 7.7 6.5 294 Do.

25 7.4 5.3 166 Do.

Averages for patients

with calcium of or

9.7 5.4 152

(8 determinations)

Averages for patients

with calcium of less

8.1 7.2 166

(8 determinations)

Days after crush injury. **

Days after transfusionreaction.
148 THE PHYSIOLOGIC EFFECTS OF WOUNDS

spection of the tables and from the individual case records. The elevated uric

acid seen in admission cases has been previously discussed and possible mechanisms for it mentioned in Chapter I.

Summary—Nitrogenous Waste Products

The nitrogenous waste products and phosphorus of the blood plasma all

showed progressive retention as renal insufficiency which follows shock or

trauma proceeded. In patients with high azotemia the maximum retention was

observed between the sixth and tenth postoperative days. The majority of deaths

occurred during this period also. Average values for nitrogenous waste products

fell from the tenth to the fifteenth days, representing largely patients who recovered. The few patients who died after the tenth day usually showed progressive nitrogen retention up to the day of death, but in few falling nonprotein

nitrogen level and rising urine output indicated beginning recovery even though

they subsequently died of uremia. These time factors emphasize the importance

from therapeutic standpoint of making every effort to carry the patient through

the critical first 10 days until the kidneys begin spontaneously to recover.

Acid-Base Balance

Anions

Plasma Carbon-Dioxide Combining Power and Blood pH.—The only group

with sufficient number of determinations of combining power for dependable

averages was that of “All Cases” of high azotemia from Table 58B. In these patients, initial low values were followed by rise toward normal (normal range:

24-31 mEq./L.) during the first postoperative days and subsequent gradual

fall during the next 12 days (Chart 20). breakdown of these averages according to types of cases does not yield differences which are statistically significant.

However, in general, those patients who had the most nitrogen retention, those

who died in uremia, and those with oliguria or anuria tended to have the lowest

values for carbon-dioxide combining power. Conversely, the patients with the

least nitrogen retention, those who survived and who had normal output of

urine, tended to have normal values. There was no correlation of carbon-dioxide

combining power with degree of shock after the preoperative day. The acidosis

seen in patients who were in shock when they were admitted to the hospital

was discussed in Chapter I. Evidence that low carbon-dioxide combining
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Chart 20. Plasma Carbon-Dioxide Combining Power in High Azotemia

power was result of diminished alkali reserve in these patients is only indirect.

The pH of the venous blood was measured in five patients who simultaneously had low carbon-dioxide combining power and renal failure. The results

were as follows:

From the limited number of cases in which blood pH determination was done,

and from the indirect evidence to be cited later, it seems likely that there was

metabolic acidosis in the majority of cases. If the low carbon-dioxide combining

power had been due to respiratory alkalosis, one would expect to see clinical

evidence of hyperventilation and possibly an alkaline urine, depending on the

renal function. None of our patients had either. Furthermore, in such cases the

blood pH, although probably in the normal range (7.38-7.48), would be in the

upper limits of normal. Obviously we do not have enough pH determinations

to draw any definite conclusions, and those we do have were made on venous

Case No.

69

90

Plasma CO

Combining

Power mEq./L.)

23

Blood pH

venous)

7-39

7-37

93 x6 7-3i

112 .... -. -].20 ... 7.0/j

133 21 7.32
THE PHYSIOLOGIC EFFECTS OF WOUNDS 150

Chart 21. Hydrogen-ion Concentration of Urine in High Azotemia

blood, but they support the view that most of these patients were suffering from

metabolic acidosis. This acidosis was not of the hyperchloremic type. For

further discussion, see the following sections on chlorides and sodium.

The range of the pH of the urine in patients with high azotemia gave at least

partial explanation for the acidosis; after the first postoperative day none of

the patients was able to produce urine more acid than pH of 6.0 despite an

increasingly severe acidosis. In those in whom renal failure was most severe

those who died of uremia—this abnormality was even more evident (Charts 20

and 21). The inference here is that those mechanisms responsible for acidification of the urine, such as tubular transfer of hydrogen ion, were impaired. This

subject will be discussed further in the section on Urine; average urine pH is

shown in Chart 21 and Table 76. Measurements of urinary ammonia were too

few to say whether the deficient formation of this base was also responsible for

the acidosis.

Plasma Chlorides.—The relationship of the plasma chloride level to the

severity of renal failure is shown in Chart 22 and Table 58C. The averages of

all patients with high azotemia show progressive hypochloremia through the

first 10 postoperative days and normal values after this time (normal range;
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Chart 22. Plasma Chlorides in High Azotemia

97-5' io4)- Of the patients who died in uremia, the average values show that an

extreme hypochloremia was reached by the tenth day; only one of these patients

survived longer than that day. Average values for patients who lived were only

slightly low during the period of greatest nitrogen retention. Analysis of individual case records shows that the lowest plasma chloride levels usually occurred

in those patients who died before the tenth day, and the rise in the level from

the eleventh through the fifteenth day occurred largely in those patients who

had recovery diuresis or only minimal azotemia.

Relationship ofLow Plasma Chloride Levels to Intake of Sodium Chloride.

The mechanism of the hypochloremia in these patients is not clear. Most of the

patients with low plasma chloride level were extremely ill and were taking

practically no food by mouth; hence their source of salt was almost entirely derived from that administered parenterally. In those patients who presumably

had the most severe renal lesions (those who died in uremia), there is possible

correlation between the quantity of parenteral sodium chloride given and the

plasma chloride levels (Table 66). The table shows the influence of parenteral

sodium chloride intake over period of days on the subsequent plasma chloride

level in 32 patients who died and in 19 who survived. The patients were arbi-
THE PHYSIOLOGIC EFFECTS OF WOUNDS 152

trarily divided into groups: those with plasma chloride levels of 100 milliequivalents per liter or higher, and those with levels below hundred.

Table 66.—Relationship of Parenteral Intake of Sodium Chloride for

Successive Days to Subsequent Plasma Chloride Level

Of 32 patients who died in uremia, 11 had plasma chlorides of 100 milliequivalents per liter or higher up to the time of death. All of the had received

considerable parenteral sodium chloride in the previous days. Twenty-one of the

32 had low plasma chlorides, under 100 milliequivalents per liter; 10 of these

patients had received no chlorides parenterally during the previous days, and

the remaining had received on an average considerably less salt than those in

whom plasma chloride levels were found to be normal or high. It should be

emphasized that this analysis of fatalities includes only patients who died in

uremia, that is, those in whom the maximum degree of renal impairment could

logically be expected.

Among 19 of 23 patients with high azotemia who lived, some relationship of

parenteral salt intake to low plasma chloride is also evident in the table. In addition, these patients as whole were not nearly so ill and it is likely that chloride

intake by mouth was considerable, so the total salt intake probably largely exceeded parenteral salt intake. Examination of the individual records of patients

who developed severe renal failure and yet lived (see also the section on Recovery Diuresis to follow) indicates that hypochloremia was part of the chemical

picture in most such cases, e.g., Cases 60,27,125, but that it was to an appreciable

Plasma Chloride Level and Patients’ Outcome

Number

of

Patients

Plasma Chloride Levels

mEq./L.

Parenteral NaCl in

Previous Days

grams

Average Range Average Range

Patients Died of Uremia

Plasma Chlorides 100 mEq./L. or Higher

Plasma Chlorides under 100 mEq./L

11

21

104.0

84.3

100-111

69-94

34.4

23.2

8.5-

8.5-

Patients Lived

Plasma Chlorides 100 mEq./L. or Higher

Plasma Chloridesunder 100 mEq./L 12

119.0

91.2

100-144

76-99

42.5

26.9 17.0-93.54.2-51.0

Does not include 10 patients who received no parenteral sodium chloride during the previous days.

Does not include patients who received no parenteral sodium chloride during previous days.

Does not include patients who received no parenteral sodium chloride during previous days.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 153

degree associated with the sodium chloride intake. This relationship to intake is

also brought out in conjunction with the discussion of sodium to follow.

Several exceptions to these generalizations were evident in individual cases.

With apparently adequate salt intake, the chloride level was sometimes low, even

in patients in whom there was no loss of chloride through Wangensteen drainage or vomiting. In one patient with high azotemia and with all the other clinical

features common to the syndrome of severe renal failure, the plasma chloride

levels were abnormally high (Case 133), but in this instance salt intake had been

excessive.

It is possible that the hypochloremia might have been due in part to simple

dilution of the chloride ion, since practically all of these patients had an increased

plasma volume. This will be discussed further in the section on Plasma Volume. No such connection is apparent, however, in Table 67 which shows plasma volume and plasma chloride determinations done simultaneously in 18 patients

who subsequently died of uremia. No correlation between degree of initial shock and plasma chloride level could be demonstrated.

Table 67.—Plasma Volume and Plasma Chloride Determinations in 18

Patients who Died of Uremia

Case No. Postoperative

Days

Plasma Chloride Level

mEq./L.

(normal: 97.5-104)

Plasma Volume

(% ofcalculated normal)

Decrease Increase

72 21.0

22 90

26 106 1.8

47 82 8.8

52 93 33.5

55 80 37.7

69 76 15.8

80 86 5.5

86 76 25.5

93 82 6.1

95 92 1.0

98 111 32.7

105 103 39.8

108 91 3.8

118 82 6.1

123 93 18.6

135 91 63.9 136 104 14.5
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chloride Excretion.—Total chloride excretion was measured in five patients

with high azotemia (Cases 104, 105, 107, 112, and 133). Of these, the two patients who died (Cases 105 and 107) had plasma chloride levels which were low

or falling. In both of these and in Case 112, chloride excretion was practically

nil; chloride intake was probably inadequate in each. Two of them (Cases 107

and 112, to be discussed at greater length in Chapter VII) also had an alkalosis

due to administration of excess alkali, chiefly sodium bicarbonate, in an attempt

to alkalinize the urine. Two of the three patients who lived had recovery

diuresis. Chloride excretion in one (Case 104) was essentially normal, but determinations were begun after he had actually recovered. The other patient (Case

133) had hyperchloremia, but high “threshold” for chloride excretion (see

Table 78 and Chart 26). This case will be discussed further in the section on

Recovery Diuresis.

Chloride concentration in single specimens of urine was measured in 18 patients who died of uremia. In determinations made on patients who had

normal plasma chloride levels, the average urine chloride concentration was

milliequivalents per liter. In 21 determinations on 10 patients with low

plasma levels, it averaged 54.0±7.0 milliequivalents per liter.

From these data it can, however, be concluded that in cases of renal failure

in our series the plasma chlorides in most cases tended to fall as renal failure

progressed, the degree of hypochloremia depending to some extent on salt intake. The chloride excreted in the urine was measured in too few cases to state

that the hypochloremia was not due to excessive excretion of the chloride ion.

No correlation between plasma chloride level and increased plasma volume

could be demonstrated, so the low levels, as far as can be determined from our

data, were not due to simple dilution. In addition to inadequate salt intake, there

must be other factors contributing to hypochloremia.

Plasma Phosphate.—The variations in phosphorus have been discussed in

more detail in the preceding section on nitrogenous waste products. The phosphates are mentioned here again only to indicate their relation to total acidbase balance. Reference to Table 58B-E shows that the average plasma phosphates, when converted to milliequivalents, even when elevated to twice normal

or over, constitute but small portion of the total anions; they clearly account

for only portion of the carbon dioxide displaced in those cases in which carbon- dioxide combining power is low.

Plasma Protein.—Plasma proteins have been converted to milliequivalents in
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 155

Table 58E. Inspection of these values in all categories shows remarkable constancy with very small standard errors of the mean. Although the proteins represent significant proportion of the total anions present, their importance in

terms of change in acid-base balance is negligible.

Cations

Serum Sodium.—The number of sodium analyses (Table 58F) was small

in comparison with those of anions. However, by grouping all determinations

made on patients with high azotemia between the second and tenth postoperative days (or days after trauma) some interesting facts emerge (Table 68).

Table 68.—Relationship of Serum Sodium, Plasma Chloride, and Plasma

Carbon-dioxide CombiningPower toParenteral Sodium and Chloride Intake

in High Azotemia 32 Determinations in 26 Patients

Thirty-two determinations were made on 26 patients. In instances, determinations for the same patients on different days are included, and in one

instance, determinations on different days. Twenty-four of the determinations

were among patients dying in uremia, were done on patients in whom uremia

was contributory to death, and on patient in whom uremia was coincident

with death. Five determinations were made on patients who survived, of

whom had severe renal failure. Nine of the 14 determinations which were above

139 milliequivalents per liter represent patients dying primarily of uremia;

determinations, patients in whom uremia was contributory to death; deterAverage Levels Average Intake in Previous Days

mEq./L. Total milliequivalents

Classification by SodiumLevels

Sodium

(Serum)

Chloride

(Plasma)

CO

Combining Power

(Plasma)

Extra

Sodium

Total

Sodium Chloride

Total Determinations 137.6±1.7 87,1 ±2.1 22.9±1.3 221 ±39 561 ±78 339±7l

Low Sodium

(Below 140—18 determinations)

130.6±1.2 80.7 ±2.0 22.9±1.8 187 ±56 369±65 183±54

Normal Sodium

(Above 139—14 determinations)

146.5±1.5 95.3±2.7 23.0±2.0 270±48 805 ±117 541 ±93

Calculated from percentage ofsodium or chloride present in sodium citrate, sodium bicarbonate

chloride. Extra sodium therefore represents that given as citrate or bicarbonate.

or sodium
156 THE PHYSIOLOGIC EFFECTS OF WOUNDS

minations, patients who lived but had severe renal failure, and determination

patient with slight renal failure who survived. Fifteen of the 18 determinations

below 140 milliequivalents per liter represent patients dying primarily of uremia,

patient in whom it was coincident with death, and patients who survived but

had severe renal failure.

Several facts seem evident from these data: 1. Serum sodium and plasma

chloride concentrations were related to intake of these ions, regardless of the

severity of the renal insufficiency present. 2. The acidosis, as reflected by the low

carbon-dioxide combining power, was equally severe regardless of whether the

sodium or chloride levels were normal or low. 3. The outcome was the same

in both the normal and low groups; there is no direct evidence that the diminished sodium and chloride concentrations affected the course of the syndrome.

The cause of the acidosis in these cases is not clear. If the acidosis were due

to loss of total base, one might expect lower carbon-dioxide level in the lowsodium group; if due to substitution of chloride for carbon dioxide, the plasma

chlorides should be high. As stated before, phosphates were not sufficiently elevated to account for the change entirely in terms of base equivalence. Proteins

remained constant and essentially normal. Sulfates and organic acids were not

measured; these two components might account for some of the discrepancies

evident in our data.

Plasma Magnesium.—There were too few determinations of plasma magnesium to be significant (Table 58G). Because of this, 14 determinations made

between the second and tenth postoperative days in 13 cases (two determinations

on the same patient on different days are included) were averaged and were

2.3±o.i milliequivalents per liter. The nonprotein nitrogen determinations done

simultaneously on these 13 patients averaged 164±22 mg. per 100 cubic centimeters. If these few determinations are significant, there was no evidence of

abnormal magnesium metabolism in this type of renal insufficiency.

Serum Potassium.—Determinations of this substance were made in only seven

patients (Cases 78, 80, 107, 112, 133, 135, and 138). In two of these (Cases 78 and 80) the values were 9.1 and 9.8 milliequivalents per liter respectively after several days of anuria or oliguria and justprior to death. In three (Cases 133,135,and

138) they varied between 6.2 and 7.0 milliequivalents per liter. In the remaining

two (Cases 107and 112) the values were normal (3.9 5.3).Analysis of these cases

showed that hyperpotassemia occurred only when urine volume was greatly de- creased.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 157

Serum Calcium.—This was discussed in the section on Nitrogenous Waste

Products and Phosphorus.

Summary Acid-Base Balance

From the data presented it is apparent that in lower nephron nephrosis resulting from shock or trauma, the most characteristic electrolyte abnormality

consists of progressive, fairly severe acidosis. Hypochloremia was also frequent but not constant finding, one which we have been unable to explain

adequately. Phosphate retention contributes to the acidosis. Serum cation determinations were few. Sodium concentrations followed no constant pattern. Potassium was found to be elevated at the time the patients had oliguria or anuria.

Physiologic Abnormalities

Plasma and Blood Volume

Plasma volume was determined in 23 patients at time when they had

posttraumatic renal insufficiency. The results were striking and of practical importance, for they indicated that increase in plasma volume was part of the

abnormal physiologic picture. Nineteen of these patients died and survived

through the mechanism of recovery diuresis. Average plasma volume determinations are shown in Tables 69 and 70, the former for all cases and the latter for

fatal cases. Tables 71, 72, and 73 list the individual plasma and blood volume

changes and related data on each of the 23 patients.

Relationship of Plasma Volume to Fluid Intake.—Referring first to Tables

Table 69. Average Plasma Volume Changes* in 23 Patients with Renal

Insufficiency

All Cases Increased Plasma Volume Decreased Plasma Volume

(23 Cases) (22 Cases) (1 Case)

Percent Postoperative Percent Postoperative Percent Postoperative

Change Days Change Days Change Days

43.3±5.7 6.0 ±0.7 46.2 ±5.1 6.1 ±0.7 -19.3

Percent deviation, uncorrected, from the calculated normal plasma volume.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

69 and 70, it is evident that the average plasma volume for the entire group was

increased significantly above the calculated normal after development of renal

insufficiency, the average increase for all 23 cases being 43.3—57 percent. In the

19 fatal cases the average increase was percent. The fatal cases were

further analyzed as to the quantity of intravenous fluid administered. Average

increases for the 15 patients who received an average of liter or more of fluid

intravenously daily (Group A, Table 70) were much greater than for the patients who received less than liter daily (Group B, in Table 70). Analysis of

Tables 71 and 72, from which the averages in Table 70 were computed, shows

that no patient in Group and only patient in Group had normal or

subnormal plasma volume after development of renal insufficiency. In this patient (Case 136) there is some reason to question whether deficient circulating

blood volume was adequately replaced, and hence whether he ever really recovered from shock during the days he survived after wounding. The four

patients who survived all showed increased plasma volume (Table 73).

Table 70. —Average Plasma Volume Increase* in 19 Patients with Fatal

Renal Insufficiency

Table 74 represents further analysis of all 23 cases. In 22 of them plasma

volume was found to be increased above the calculated normal when renal insufficiency developed. The one exception, patient (Case 136) who showed

subnormal plasma volume, probably had not been adequately resuscitated, as

stated above. Eighteen of the 22 patients with increases had received parenterally an average of liter or more of fluid, crystalloid or colloid, daily. In 10 of the

All Cases

(19 Cases)

Group

(15 Cases)

Group

(4 Cases)

Plasma Volume

Increase

percent

Postoperative

Days

Plasma Volume

Increase

percent

Postoperative

Days

Plasma Volume

Increase

percent

Postoperative

Days

4l.6±6.6 4.8±0.4 46.9±6.6 4.8±0.5 21.8 4.8

‘Percent increase, uncorrected, over calculated normal plasma volume.

Group A; Patients who received on the average liter or more of fluid (intravenous colloid and crystalloid)

per day.

Group B: Patients who received on the average less than liter of fluid (intravenous colloid and crystalloid)

per day.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 159

Table 71.—Plasma and Blood Volume Changes in Fatal Posttraumatic

Renal Insuffiency

Group A: Patients who Received an Average of Liter or More of

Intravenous Fluids (Crystalloid or Colloid) Daily

22 patients multiple determinations were made and of them showed progressive increases in plasma volume as renal failure became more severe. Of the

whose plasma volume did not increase further as renal failure progressed,

one (Case 69, Table 71) was in Group in which average fluid intake was high.

His plasma volume was increased approximately 23 percent over normal on both

Case

No.

Postoperative

Days

Plasma

Volume

Increase

percent

Plasma

Proteins

Gm. per 100 cc.

Hematocrit

Value

percent

Blood

Volume

Change

percent

Blood

since

Wounding

«»//*

Plasma

since

Wounding

««/Vs

7.5 36 2.2

43.9 6.8 37 21.0 2.2 3.3

26 41.5 6.9 38 21.8 4.5

47 8.7 5.3 33 4.5

33.6 4.8 35 8.8 4.5

52 5.7 36

60.1 6.2 38 33.5

55 6.4 27

95.1 6.3 25 37.7

69 6.8 70 1,5

23.5 6.3 52 13.6 1.5

5.4 47 1.5

23.5 5.1 42 15.8 1.5

80 6.5 38

10.7 7.1 38 -5.5

86 26.5 6.0 33 -0.1

6.2 39 10

61.4 6.1 32 25.5 10

95 6.5 48 10

13.4 6.6 40 -1.0 10

98 33.9 6.6 47 32.7

105 61.0 7.3 39 39.8

108 6.7 5.1 28 11

17.7 5.6 40 3.8 13

114 75,2 5.8 30 31.9

123 52.3 5.8 32 18.6 1.3

5.8 29 7.5 1,3

135 17.3 6.5 50 22.9

80.2 7.3 42 63.9

Percent deviation from the calculated normal plasma or blood volume. Minus signs indicate decreases.

unit of blood =500 cc.; unit ofplasma =300 cc. total volume.

Days after release from compression in crush injury.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 72.—Plasma and Blood Volume Changes in Fatal Posttraumatic

Renal Insufficiency

Group B: Patients who Received an Average of Less than Liter of

Intravenous Fluids (Crystalloid or Colloid) Daily

the second and ninth days after crushing injury. The other (Case 118, Table 72)

was in Group B, those with restricted fluid intake. His increased plasma volume

actually diminished although he subsequently died in uremia.

Among those who had increased plasma volumes were the four patients who

had recovery diuresis and survived. In three of them plasma volume first increased and then decreased as diuresis proceeded and nitrogenous waste products

were excreted (Table 73). The progress of the plasma volume changes in relation

to the plasma nonprotein nitrogen in these cases is shown in Chart 27. The fourth

patient (Case 150) had his first determination after diuresis had begun although

he still had severe renal failure and an increased plasma volume.

Relationship ofPlasma Volume toPlasma Protein Concentration, Hematocrit

Level, and Total Blood Volume.—The relationships of plasma volume to plasma

protein concentration, hematocrit value, and total blood volume are evident in

Tables 71, 72, and 73. There were considerable individual variations, but in general it can be stated that an expected coincident decrease in plasma protein concentration as the plasma volume rose during renal insufficiency was not usually

demonstrated. Thus of the eight patients in whom the already increased plasma

volume was known to rise, there were no significant changes in plasma protein

concentration in five (three of whom received blood between measurements);

Case

No.

Postoperative

Days

Plasma

Volume

Change

percent

Plasma

Proteins

Gm. per 100 cc.

Hematocrit

Value

percent

Blood

Volume

Change

percent

Blood

since

Wounding

units

Plasma

since

Wounding

units

22 67.9 7.1 21 13.0

93 -31.4 7.3 60 -5.7 6.2 44

22.2 6.2 39 6.1

118 34.4 6.7 41 20.7

16.3 6.6 42 6.1

136 -19.3 8.0 50 -14.5

Percent deviation from the calculated normal plasma or blood volume. Minus signs indicate decreases.

unit of blood =500 cc; unit of plasma =300 cc. total volume.

Days after release from compression in crush injury. The first determination in this case was made before

renal insufficiency developed.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Table 73.—Plasma and Blood Volume Changes in Patients with

Posttraumatic Renal Insufficiency and Subsequent Recovery Diuresis

Table 74,—Trend of Plasma Volume Changes during Posttraumatic Renal

Insufficiency in 23 Patients

there was an increase in one, and decrease in only two. Explanation for the

absence of dilution phenomenon is not evident from our data. One can only

Case

No.

Postoperative

Days

Plasma

Volume

Increase

percent

Plasma

Proteins

Gm. per

100 cc.

Hematocrit

Value

percent

Blood

Volume

Change

percent

ntravenous

Fluids

cc.

Oral

Fluids

cc.

Blood

since

Wounding

units

Plasma

since

Wounding

units

60 0.75 30.3 6.3 25 -8 3.429 5.5 10

2.5 70.1 6.5 25 20 1,000 1.435 7.5 10 6.5 73.5 6.4 24 21 625 2,386 8.5 10 11.5 31.7 6.4 38.4 13 600 3,952 13.5 10

133 13 44.3 7.6 40 25 2,518 1,750 23 10.5

16 49.8 7.4 40 32 1,583 1,416 24 12.5

27 36.1 6.1 32 26 12.5

35 7.4 5.8 36 12 26 12.5

138 30.7 6.6 40 16

29.7 6.0 40 15 1,525

10 55.6 6.6 32 20 1,650 1,160

14 11.1 8.0 40 -1.9 1,000 2,326

150 12.5 27.3 6.0 34 1.7 1,000 3,330 9.2

Percent deviation from the calculated normal plasmaor blood volume. Minus signs indicate decreases.

unit of blood 500 cc.; unit of plasma =300 cc. total volume.

Between determinations.

Approximately.

Liter or

Plasma

Volume

Results of Repeated

Determination

Patients’ Outcome

Plasma Volume

Total

Patients

more of

I.V. Fluid

Daily

Determination

Repeated

Increased

Further

Did not

Increase Lived Died

Number of patientsNumber of patientsNumber of patientsNumber of patientsNumber of patientsNumber of patients

Increased over calculated

normal 22 18 10 18

Decreased below calcuFour patients with recovery diuresis included. In them the plasma volume was

diuresis.

increased until onset of
162 THE PHYSIOLOGIC EFFECTS OF WOUNDS

postulate that in such cases plasma protein was being mobilized from protein

sources elsewhere in the body.

The hematocrit level in the eight patients in whom plasma volume increased

progressively (as shown by serial determinations) rose in one who received

blood between measurements, was unchanged in three, two of whom received

blood between measurements, and fell in four, one of whom received blood

between measurements. Although the total blood volumes were also increased,

the increments clearly were reflection of the increase in the plasma volume,

and because of the low hematocrit level in most cases, they were not as strikingly

increased as was the plasma volume.

These data indicate, then, that in posttraumatic renal failure, total circulating

plasma volume is increased. This must be due largely to the inability of the

kidneys to excrete adequate water. However, because the plasma protein concentration did not usually diminish as plasma volume increased, it is evident

that the sole explanation is not simply that hydremia exists. There would seem

to be also unexplained extrarenal factors interfering with maintenance of normal extracellular fluid volume. The practical importance of these observations

is self-evident. Administration of excessive quantities of fluids to these patients

who already have increased extracellular fluid volume can probably do nothing

toward stimulating the kidneys to excrete; it can cause fatal pulmonary edema.

Summary—Plasma and Blood Volume

Plasma volume was determined in 23 patients in whom posttraumatic renal

insufficiency developed, 19 of whom died. Averaging all 23 cases, there was an

increase over the calculated normal plasma volume of 43.3 percent, and of

41.6 percent in the fatal cases. Considering the patients individually, there was

only one in whom plasma volume was less than normal after signs of renal

impairment appeared, and there was good reason to believe that this patient

had never been adequately resuscitated from shock. Comparison of the plasma

volume with simultaneous plasma protein levels indicates that there was an increase in total circulating plasma and not simply an increase in proportion of

water in the plasma; i.e., in general, plasma protein did not decrease with increasing plasma volume. In those patients in whom serial determinations were

made, including several who had recovery diuresis, the time of maximum

ihcrease in plasma volume coincided with that of maximum azotemia, and in

those who recovered, plasma volume and plasma nonprotein nitrogen diminished at parallel rates.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 163

URINE

Specific Gravity

One of the most striking and constant physiologic abnormalities observed in

posttraumatic renal insufficiency was impairment of ability of the renal tubules

toreabsorb water. Within day or two postoperatively, those patients who developed renal impairment, almost without exception, lost the power to make

concentrated urine regardless of the amount they were excreting (Chart 23

and Tables 75 and 77). The averages in the tables and chart were calculated from

the specific gravities observed in routine specimens, usually the first morning

one. They do not, then, represent true concentration tests, but there are several

factors which indicate that the values observed, in most cases, were those of

practically maximum concentrating ability: (1) Concentration tests were done

later on patients who recovered, when it was deemed safe to do them. In these

patients, even after the retained nitrogenous products had been cleared and output had returned to normal, specific gravity remained fixed and low. (2) Many

of the specimens were taken when the output of urine was very low and hence

Chart 23. Urine Specific Gravity in Patients with High Azotemia
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 75.

—Average

Specific

Gravity of

the

Urine in

Patientswith

High

Azotemia*

Average

Specific

Gravity

Classification of

Cases

Preoperative

Postoperative Period

Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

1.026±.002

1.020±.001

1.01

±.001

1.012 ±.001

1.014±.001

1.011±.001

(11

cases)

(21

cases)

(46

cases)

(28

cases)

(13

cases)

(12

cases)

Patients' Outcome

Lived

1.026±.001

1.020±.001

1.01

±.001

1.012±.001

1.012±.002

1.011±.001

(4

cases)

(5

cases)

(15

cases)

(13

cases)

(7

cases)

(10

cases)

Died

—All

Causes

1.026±.003

1.020±.002

1.01

±.001

1.013±.001

1.016±.002

1.011

(7

cases)

(16

cases)

(31

cases)

(15

cases)

(6

cases)

(2

cases)

Died

of

Uremia

1.033

1.021 ±.002

1.014±.001

1.011±.001

1.013

1.011

(2

cases)

(9

cases)

(26

cases)

(1

cases)

(4

cases)

(2

cases)

Died

of

other

Causes

1.023 ±.003 (5

cases)

1.018±.002 (7

cases)

1.019±.002 (5

cases)

1.018±.003 (4

cases)

1.022(2

cases)

Urinary

Output

Normal

1.028

1.019

1.016±.001

1.016±.002

1.017±.004

1.007

(1

case)

(2

cases)

(7

cases)

(8

cases)

(4

cases)

(1

case)

Anuria

1.032

1.019

1.014

1.010

1.012

1.013

(1

case)

(7

cases)

(18

cases)

(10

cases)

(3

cases)

(3

cases)

Oliguria

1.026

1.021

1.016

1.012

1.013

1.011

(7

cases)

(12

cases)

(21

cases)

(10

cases)

(6

cases)

(6

cases)

Unknown

1.020(2

cases)

1.014 (2

cases)

Anuria

and

Oliguria

1.027±.002

1,020±.001

1.01

±.001

1.011±.001

1.013±.00l

1.011±.001

(8

cases)

(19

cases)

(39

cases)

(20

cases)

(9

cases)

(9

cases)

Anuria,

Oliguria,

and

Unknown

1.026±.002 (10

cases)

1.012±.001 (11

cases)

If

more

than

determination had

been

made on

patient

during

the

specified

period,

the

lowest

valuewas used.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 165

when the kidneys were theoretically concentrating urine to the maximum of

their ability. (3) In many of the patients, particularly those who died in uremia,

fluids were sharply restricted, usually to about liter day. This could be further

reason for assuming that the average urine specimen would be concentrated if the kidneys were capable of making it so; on the other hand, this argument

may be rendered untenable by the fact that plasma volume was probably increased in all cases. (4) Twenty-four hour urine specimens were collected from

five patients in whom renal failure developed. In these the specific gravity of the

total specimens showed the same trend, even though plasma nonprotein nitrogen

was rising, and in three cases total output of urine was diminishing.

It will be shown in the section on Recovery Diuresis that in those patients

who did recover, the nitrogenous waste products were cleared because of an

increasing output of urine but the urine specific gravity remained fixed at low

level. In summary, it appears from our data that in this syndrome one of the

earliest functional derangements of the kidney to occur, and probably one of the

last to disappear when recovery takes place, is the ability to concentrate the urine.

Hydrogen-Ion Concentration

The tendency of the acidity of the urine to decrease as systemic acidosis and

renal failure progress has been previously discussed (see Plasma Carbon-Dioxide

Combining Power under Acid-Base Balance, Chart 21, and Tables 76 and 77).

From our meager data on measurement of titratable acidity and ammonia of

the urine (see the section on Recovery Diuresis), it is probable that the mechanism of this failure to make very acid urine is associated with decrease in

titratable acidity and thus is similar to that seen in most types of renal failure.

Inability of the kidneys to produce urine of maximum alkalinity, if presented

with surplus of base, also seems to be feature of the syndrome (see Chapter

VII) and again is similar to the situation occasionally seen in other types of

kidney disease.

There is good evidence that acidification of the urine by active transfer of

hydrogen ions, as well as ammonia production is accomplished by the distal

Pitts, R. F.; Lotspeich, W. D.; Schiess, W. A., and Ayer, J. L.; The renal regulation of acidbase balance in man. I. The nature of the mechanism for acidifying the urine. J. Clin. Investigation

27: 48-56, January 1948. Schiess, W. A.; Ayer, J. L.; Lotspeich, W. D., and Pitts, R. F.: The renal

regulation of acid-base balance in man. II. Factors affecting the excretion of titratable acid by the normal

human subject. Ibid. 57-64.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

76.

—Average

pH

of

the Urine in

Patientswith

High

Azotemia*

Classification of

Cases

Average

pH

of

Urine

Preoperative Period

Postoperative Period

Day

2-4

Days

5-7

Days

8-10

Days

11-15 Days

ALL

CASES

5.8

±0.2

6.0

±0,1

6.2

±0.1

6.1

±0.1

6.0

±0.1

6.

±0.3

(12

cases)

(21

cases)

(43

cases)

(29

cases)

(14

cases)

(12

cases)

Patients’ Outcome

Lived

5.6±0.2

6.2

±0.3

6.6±0.2

5.2

±0.3

5.8

±0.2

6.4

±0.3

(4

cases)

(5

cases)

(15

cases)

(13

cases)

(7

cases)

(10

cases)

Died

—All

Causes

5.9±0.2

6.0

±0.1

5.9

±0.1

6.2

±0.2

6.2

±0,2

6.0

(8

cases)

(16

cases)

(28

cases)

(16

cases)

(7

cases)

(2

cases)

Died

of

Uremia

5.5

5.9

±0.2

5.9±0.

6.4

±0.3

6.4

±0.3

6.0

(2

cases)

(9

cases)

(23

cases)

(12

cases)

(5

cases)

(2

cases)

Died

of

other

Causes

6.0

±0.3

6.2

±0.2

6.1

±0.3

5.5

±0.2

5.7

(6

cases)

(7

cases)

(5

cases)

(4

cases)

(2

cases)

Urinary

Output

Normal

5.7

6.6

6.2

±0.2

5.8

±0.2

6.0

±0.2

5.9

(2

cases)

(2

cases)

(7

cases)

(8

cases)

(4

cases)

(I

case)

Anuria

5.5

5.8

5.9

6.2

6.4

6.9

(1

case)

(7

cases)

(16

cases)

(11

cases)

(4

cases)

(2

cases)

Oliguria

5.8

6.1

6.4

6.1

5.8

5.9

(7

cases)

(12

cases)

(20

cases)

(10

cases)

(6

cases)

(6

cases)

Unknown

6.1

6.9

(2

cases)

(2

cases)

Anuria

and

Oliguria

5.7±0.2

6.0

±0.1

6.2

±0.1

6.2

±0.2

6.0±0.2

6.2

±0.3

(8

cases)

(19

cases)

(36

cases)

(21

cases)

(10

cases)

(8

cases)

Anuria,

Oliguria,

and

Unknown

5.8±0.2

6.

±0,3

(10

cases)

(10

cases)

If

more

than

determination had

been

made

on

patient

during

the

specified

period,

the

lowest

valuewas used.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 167

tubular cells. This provides further correlation, perhaps, of functional with anatomic findings in patients suffering from lower nephron nephrosis following

shock or trauma.

Table 77. Average Specific Gravity and pH of Urine in Patients with

Oliguria or Anuria

Proteinuria and Pigment Excretion

As was pointed out in Chapter IV, all patients with proved renal lesions had

proteinuria, and this finding was also constant one in all patients with posttraumatic renal insufficiency. It was not, however, specific finding, for it was

absent in only 14 of the entire series of casualties studied. The relationship of

pigment excretion in the urine to posttraumatic renal insufficiency will be discussed in Chapter VIII.

Summary—Changes in the Urine

The most striking change in the urine was the fixation of specific gravity

at low levels within day or two after the onset of renal failure following shock

or trauma. This impairment of maximum reabsorptive capacity of water by the

renal tubules persisted after other evidence of kidney damage disappeared in

those patients who recovered. Inability to manufacture highly acid urine in

Time of Determination

Oliguria Anuria

pH Specific Gravity pH Specific Gravity

Preoperative 5.8±0.1 1.026±.002 5.5 1.032

(10 cases) (10 cases) (1 case) (1 case)

Postoperative Days

First 6.2 ±0.1 1.023±.001 5.8±0.2 1.019±.003

(22 cases) (22 cases) (7 cases) (7 cases)

Second to Fourth 6.4±0.2 1.0l6±.001 5.9=fc0.2 1.014±.001

(31 cases) (32 cases) (16 cases) (18 cases)

Fifth to Seventh 6.4±0,2 1.012±.001 6.2±0.3 l.OlOdc.OOl

(17 cases) (17 cases) (11 cases) (10 cases)

Eighth to Tenth 6.0±0.2 1.015±.001 6.4±0.2 1.012

(10 cases) (11 cases) (4 cases) (3 cases)

Eleventh to Fifteenth 6.0±0.2 l.Olli.OOl 6.8 1.013

(6 cases) (6 cases) (3 cases) (3 cases)
168 THE PHYSIOLOGIC EFFECTS OF WOUNDS

the presence of metabolic acidosis was also constant feature in the patients

studied.

Recovery Diuresis

The arbitrary choice of 65 mg. per 100 cc. or higher concentration of nonprotein nitrogen in the plasma as an index of renal insufficiency in this series of

cases has been discussed. Of the 73 patients included in our “high azotemia”

group, 23 (32 percent) lived. Those who survived may be further classified

according to the degree of renal impairment they exhibited: Twelve had apparently only minimal interference with renal function, with rapid return to

normal after transient nitrogen retention. We were unable to follow one patient

with nonprotein nitrogen level greater than 65 mg. per 100 cc. who lived and

so do not know what degree of renal insufficiency he ultimately had. Ten had

even greater evidence of renal impairment and their course conformed with the

syndrome we have designated as recovery diuresis.

The characteristic features of this syndrome are:

1. nonprotein nitrogen level greater than 100

milligrams per 100 cubic centimeters.

2. Oliguria or anuria, followed by substantial

diuresis resulting in clearance of nitrogenous waste products and return to normal of the electrolyte pattern,

3. Impaired ability to concentrate the urine.

4. Hypertension (systolic blood pressure above

135 millimeters of mercury; diastolic above 90).

Of the 10 patients exhibiting this syndrome, showed at least three and most

of them all four of these characteristics. The tenth patient (Case 44) was observed during period when the laboratory was not functioning, so his blood

and urine could not be examined, but clinically he displayed the characteristics

of the syndrome.

This small group of cases is of great interest and practical importance. One

would like to know why these patients recovered whereas the majority of those

with renal insufficiency died, and whether in their course or treatment there

are any clues which might lead to more effective treatment than has been found

to the present. Detailed data on few typical cases (see Charts 25 and 26),
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 169

together with pertinent clinical and physiologic findings in the group as whole,

are considered of value here. (The 10 cases were Numbers 27, 30, 43, 44, 60, 104,

I25> !33> i3 and 150-)

Clinical Features

The degree of initial shock was essentially the same for these 10 patients as

for the entire group having renal failure. Three patients had had severe shock,

moderate, slight, and no shock. As in other instances, it is entirely possible

that there may have been considerable shock in all 10, but so far as we could

determine at the time of admission, they must be classified as above.

Five of the 10 patients had multiple major wounds. The major wounds in

the entire group were: peripheral with fracture, thoracic, intra-abdominal,

and one thoraco-abdominal. One patient had contusion of the bladder. There

were no wounds of the liver or kidney.

The time of onset of oliguria in relation to wounding and operation, and the

duration of suppression of urinary output are of interest. Unfortunately the dayto-day records are not as accurate as one would like. Many of these patients were

seen in field hospitals during periods of great military activity, when the press

of work made it very difficult to make such observations. We have no record

of output of urine until the first postoperative day in any of the cases. Eight of

the 10 patients are known to have had at least day of oliguria or anuria between

the first and sixth postoperative days. Records of output of urine were not kept

for the remaining patients at the time they probably had oliguria, but questioning of ward personnel and of the patients suggested very strongly that they

too had had oliguria during this period. The duration of oliguria ranged from

to days. There followed then period of gradually increasing output of urine,

reaching in some cases or liters day. The plasma nonprotein nitrogen level

did not, as rule, begin to decrease until several days after diuresis had begun.

Because of the increase in plasma volume during the period of increasing

azotemia, it might be expected that total fluid output would exceed intake during the diuresis period. This clearly occurred in two cases (Case 60 (Chart 24)

and Case 150). In the remaining eight cases it was impossible to demonstrate

this fact from the figures available, for the records kept gave only an approximate estimate of total water balance; they did not account for water lost by

perspiration, respiration, or with the stools. Since the plasma volume returned
170 THE PHYSIOLOGIC EFFECTS OF WOUNDS

to normal and the edema subsided as diuresis proceeded, it is logical to assume

that total fluid output did exceed intake until equilibrium was reestablished.

All these patients had hypertension, by our definition. In general the blood

pressure was highest at the time of the most severe nitrogen retention and the

Chart 24. Relationship of Fluid Intake and Output in Patient with

Recovery Diuresis (Case 60)

Chart 25. Recovery diuresis occurred in this patient following an initial period of

renal insufficiency due to severe traumatic shock and great blood loss. Note: (i) Initial

period of oliguria and diminished renal function as evidenced by low phenolsulfonphthalein

excretion with fixed urine specific gravity which persisted throughout the period of observation. (2) The gradual increase in urinary output during the first week accompanied by

rising blood pressure, rising plasma nonprotein nitrogen concentration, falling carbondioxide combining power and plasma chlorides. (3) The fall in nonprotein nitrogen

occurring only several days after adequate urinary output, accompanied by improvement

of phenolsulfonphthalein excretion, rising carbon-dioxide combining power and plasma

chloride levels, and return of the blood pressure toward normal. See page iji.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Chart 25. Course of Patient with Recovery Diuresis (Case 60)
THE PHYSIOLOGIC EFFECTS OF WOUNDS 172

elevation was significant, with levels ranging from 150 to 170 mm. Hg systolic

and from 90 to no diastolic. Likewise, as diuresis proceeded and the nonprotein

nitrogen levels fell, blood pressures returned to normal. One patient was evacuated to the rear before his hypertension had subsided and we were unable to

obtain subsequent blood-pressure determinations.

Two patients (Cases 44 and 150) had generalized convulsions on the eighth

and ninth postoperative days respectively. In one, the convulsions furnished the

first clue to the attending medical officers that renal failure was present. One

of these patients also had small retinal hemorrhage in the fundus of one eye.

Eyegrounds were examined in three other patients in the group and found to

be normal. Four patients had clinical edema.

Blood Chemistry

The abnormal chemical pattern in this selected group of cases was essentially

similar to that described in the preceding section. Chart 25 represents the course

of the patient cited in Chart 24 and demonstrates the essential features seen in

all such cases.

This man, who had had period of severe initial shock, had oliguria for day.

Renal function, as measured by phenolsulfonphthalein excretion and the urine

concentration test, was greatly impaired by the first postoperative day. gradual

increase in output of urine followed. Despite diuresis, however, the nonprotein

nitrogen continued to rise for the first days—apparently because, with fixed

specific gravity of the urine, the kidneys were not at first able to clear sufficient

nitrogen. Blood pressure rose and fell approximately with the nitrogen retention.

Electrolytes followed the pattern already described but returned to normal as

renal function improved. The patient’s inability to make an acid urine in the

presence of mild acidosis is evident from study of the chart. When the patient

was evacuated on the fifteenth postoperative day,renal function was still reduced

Chart 26. There was an excessive intake of sodium chloride during the previous 10

days, which is not shown on the chart. Note: (1) The unusually high serum sodium and

plasma chloride levels. (2) relatively low urinary chloride excretion during the period

of maximum hyperchloremia and the extremely low excretion during the last days of the

observation, although significant hyperchloremia persisted. (3) The slowly falling plasma

nonprotein nitrogen level, although urinary output was over liters day during most

of the period studied. See page 773.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 173

Chart 26. Course of Patient with Recovery Diuresis (Case 133)
THE PHYSIOLOGIC EFFECTS OF WOUNDS

despite normal chemical findings in the blood. Results of blood chemistry and

urine examinations, made in eight of the nine other patients, followed essentially the same pattern.

The time of maximum nitrogen retention varied; five patients had their

highest nonprotein nitrogen level between the third and ninth days after trauma,

and the remaining four between the tenth and thirteenth days. The period of

time required for recovery of renal function varied from to 25 days.

As mentioned earlier, hypochloremia was not as prominent feature in

these patients as in those who died in uremia, but it was present to some degree

(plasma chlorides under 100 milliequivalents per liter) in five patients. One

patient (Case 133), on the other hand, following high intake of sodium

chloride, had pronounced hyperchloremia (plasma chlorides 144 milliequivalents per liter) about the time of greatest nitrogen retention (Chart 26 and

Table 79).

Plasma Volume

Four patients with recovery diuresis in whom the plasma volume was measured showed significant increase over the calculated normal. It was greatest

at the time of maximum nitrogen retention and decreased as diuresis proceeded.

Three patients (Cases 60, 133, and 138, Chart 27) were discussed in the preceding section on Plasma and Blood Volume. fourth patient (Case 150, Table

73) still had significant elevation in plasma volume when first studied on the twelfth postoperative day after diuresis had begun.

Urinary Findings

Specific Gravity.—Five patients, following administration of pituitrin, were

unable to concentrate urine above 1.015 as long as they were followed (up to

49 days postoperatively in one instance). One patient with very transient nitrogen retention could concentrate to 1.020 by the thirteenth day. Concentration

tests were not done in the other four patients, but several specimens in three

of them were uniformly dilute. In one (Case 30), two routine specimens taken

at the time of maximum nitrogen retention were 1.019 and 1.023. Twenty-four Hour Urine Analyses and Related Findings in Two Patients.

Examinations of 24-hour urine specimens were made in two patients who had

Studies made 10 months later in the United States showed normal kidney function.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

Chart 27. Plasma Volume andPlasma Nonprotein Nitrogen

Concentration in Patients with Recovery Diuresis

(Cases 60,133, and 138)

recovery diuresis. In Case 133 the collections were started just at the end of the

recovery period. Table 78 lists the findings in one of these patients (Case 104)

along with plasma determinations made on the same days. From these data

few conclusions could be drawn regarding this one patient: (1) Titratable

acidity values were rather low, considering low plasma carbon-dioxide combining power during the first days of collection. (2) Ammonia production

was normal. (3) Chloride excretion and sodium chloride intake were normal.

Plasma chloride values were normal. (4) Excretion of urea was high the first
176 THE PHYSIOLOGIC EFFECTS OF WOUNDS

day and accompanied fall in plasma nonprotein nitrogen to normal.

Table 79 and Chart 26 show comparable findings on the other patient (Case

133). Ammonia and titratable acidity determinations of the urine in this case

were not numerous enough and varied too widely to draw any conclusions

regarding acid-base regulation. Excretion of urea and creatinine was about what

would be expected in normal individual, but not sufficient to clear the retained

nitrogen rapidly. Toward the end of the 10-day period during which 24-hour urine collections were made, plasma levels of urea nitrogen and creatinine beTable 78.—Relationship of 24-HOUR Urinalyses and Plasma Biochemic

Findings in Patient with Recovery Diuresis (Case 104)

Postoperative

Days

Fluid

Intake

cc.

Parenteral

NaCl

Intake

Gm.

Urine

Output

cc.

Plasma

CO2 Combining

Power

rnEq./L.

Urine

pH

Urine

Titratable

Acidity

cc. 0.1

Urine

Ammonia

cc. 0.1

Urine

Ammonia

Titratable

Acidity

Third .... 1,060 900

Fourth 3,705 1.6 2,335 25 5.9 257 428 1.7

Fifth .... 2,100 1,590 23 5.6 199 652 3.3 33*50 1,950 5.6 302 688 2.2

Seventh 3,480 1,780 23 5.2 444 656 1.4

4,850 2,480 5.4 509 779 1.5

3,650 2,050 6.9 145 14 2.8

Tenth .... 2,790 2,100 26 6.4 69 497 7.1

3,2 50 2,890 6.5 93 594 (5.4

2,550 2,200 6.6 154 544 3.4

Thirteenth. 2,500 2,730 6.8 137 475 3.5

Plasma Plasma

Plasma Urea Urine Great- Urine

Urine Plasma NPN Nitrogen Urea inine Great- Postoperative

Days Chloride Chloride

mg. per mg. per

Nitrogen

mg. per

inine Specific

Gravity

Gm. NaCl mEq./L. 100 cc. 100 cc. Gm. 100 cc. Gm.

Third .... Ill

4.7 102 70 22.7 1.08 1.42 Fifth 3.2 101 44 27 15.4 0.80 1.30

6.9 19.2 1.80 Seventh 4.7 102 29 12.2 1.39 1.25 1.012

9.1 26.1 1.72

4.7 13.5 1.20 1.01

Tenth ....

5.9 94 29 19.9 0.94 1.48 1.012

8.1 13.5 1.33 1.010

8.4 14.5 1.25 Thirteenth. 11.7 15.4 0.80
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION

gan to fall. Clearance rates of these substances, however, were diminished during

the entire period of observation.

The relationship of serum sodium, plasma carbon-dioxide combining power,

fluid and sodium chloride intake, urinary output, and urinary excretion of

chloride in this same patient are also shown. After high intake of sodium

chloride, sodium and chloride retention developed. Plasma carbon-dioxide combining power fell, in this instance partially as result of hyperchloremia. Chloride excretion was relatively low considering the high plasma chloride level.

As the plasma chloride level fell, chloride excretion decreased to negligible

amounts during the last days, even though the plasma chloride level was still

unusually high. High serum sodium accompanied the hyperchloremia. There

is in this case evidence of high renal “threshold” for both sodium and chloride

excretion.

The course and essential features in this patient were characteristic of recovery diuresis, but he exhibited most unusual electrolyte abnormalities. Although

he had an increased plasma volume (Chart 27), there were also marked hypernatremia and hyperchloremia. An elevated serum sodium is most unusual except in the presence of dehydration, which, if the measurements of plasma

volume can be accepted, was not present in this patient. Further evidence of

inability of the renal tubules to reabsorb maximum amounts of water is seen

here in the dilute urines of total specimens in both Cases 104 and 133 during

periods of high nitrogen retention.

Renal Clearance Tests and Phenolsulfonphthalein Excretion

The results of renal clearance and phenolsulfonphthalein excretion tests in

patients with recovery diuresis were discussed in Chapter III. Briefly, in three

such patients in whom clearance measurements were made, all functional components of the kidney were diminished when first observed and gradually returned toward normal over period of several days or weeks. Similar evidence

of functional impairment and subsequent improvement was seen in three additional patients with recovery diuresis on'whom phenolsulfonphthalein excretory

capacity tests, were made.

Summary—Recovery Diuresis

Of the 23 patients with posttraumatic renal insufficiency who lived, 10 exhibited certain features which conform to the syndrome designated as recovery
7% THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

79.

—Relationship of

24-HOUR

Urinalyses and

Plasma

Biochemic

Findings in

Patient with

Recovery

Diuresis

(Case

133)

Postoperative Days

Fluid Intake cc.

Par- enteral NaCl Intake Gm.

Urine Output cc.

Blood pH (venous)

Plasma C0

Com- biningPower mEq./L.

Urine pH

Urine Titrat- able Acidity cc.

0.1

Urine Ammonia cc.

0.1

Urine Ammonia Titratable Acidity

Fourth

2,500 4,870 7,000 4.400 3.900 4,395 3,150 2,810 3,570 3,110 2,540 3,700 3.350 4.350 4.400 5,300 5.900

17 25.5 25.5 8.5 8.5 8.5 8.5 8.5 8.5

1,600 1,450 2,000 2,950 3,000 1,270 2,650 2,380 2,030 2,150 2,220 2,300 2,375 2,610 2,550 3,500

Fifth Sixth Seventh Eighth Ninth Tenth

7.32

21

Eleventh

5.7

375

1.0

Twelfth

20 21 20 20 21

Thirteenth

5.6

383

244

0.7

Fourteenth Fifteenth

6.1 6.8 8.4 8.4 8.4

461 242

528 306

1.1 1.3

Sixteenth Seventeenth

....

Eighteenth

20

Nineteenth Twentieth

16
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION i79

956507 0—52 13

Table 79.

—Relationship of

24-HOUR

Urinalyses and PlasmaBiochemic Findings in

Patient with

Recovery

Diuresis

(Case

133)

Continued

Postoperative Days

Urine Chloride Gm.

NaCl

Plasma Chloride mEq./L.

Serum Sodium mEq./L.

Plasma NPN mg.

per

100

cc.

Plasma Urea Nitrogen mg.

per

100

cc.

Urine Urea Nitrogen Gm.

Plasma Creat- inine mg.

per

100

cc.

Urine Creat- inine Gm.

Urine Specific Gravity

Tenth

134

155

108

4.34

Eleventh

6.7

19.8

1.75

1.014

Twelfth

140

170

112

92

4.87

Thirteenth

4.6

144

106

92

19.2

4.08

1.58

1.01

Fourteenth

4.6

140

178

101

81

3.96

1.73

.01

Fifteenth

3.6

142

180

100

80

14.5

3.96

1.73

1.015

Sixteenth

5.4

141

111

86

18.1

3.84

1.32

1.015

Seventeenth

....

0.12

18.3

1.32

.01

Eighteenth

0.13

129

173

102

76

16.5

2.86

1.73

1.017

Nineteenth

0.51

11.9

1.39

01

ft

Twentieth

0.70

119

97

2.37

1.01
THE PHYSIOLOGIC EFFECTS OF WOUNDS

diuresis; namely, (i) nonprotein nitrogen greater than 100 mg. per 100 cc.,

(2) oliguria or anuria followed by diuresis and fall in nonprotein nitrogen,

(3) low and fixed urinary specific gravity, and (4) hypertension. Their clinical

course and physiologic and biochemic changes were entirely similar to those

demonstrated in patients who died and were found at necropsy to have had

lower nephron nephrosis. This group of patients demonstrates, then, that recovery from this type of renal disease can occur spontaneously if the patient

survives the first critical 10 days after onset of renal failure.

SUMMARY

In earlier chapters the changes that began to occur in the internal environment soon after man had been wounded were described. The effects of these

early changes upon the kidney have been reported in this and the preceding

chapter. Following severe trauma, accompanied usually by shock, man could

be adequately resuscitated and successfully operated upon. The latent renal incompetency which might develop in this man, who had normal kidneys at the

time he was wounded, usually did not become manifest until two or three days

later. At this time there appeared signs of failure on the part of the kidneys to

withstand the initial insult, the effects of which his body had thus far resisted

with fair success.

The first clinical sign of impending renal failure usually was suppression of

urinary output. Of 73 patients with “high azotemia” (a plasma nonprotein

nitrogen concentration of 65 mg. per 100 cc. or higher at some time during

their course), 27 had anuria (urinary output of less than 100 cc. in any 24-hour period) and 29 had oliguria (output of from 100 to 600 cc. in 24-hour period).

The case fatality rate was high.Fifty patients (69 percent) of the 73 with high

azotemia died. Twenty-one (47 percent) of 45 who had oliguria, and 30 (91

percent) of 33 with anuria had fatal outcome.

Initial shock—if special types of cases such as crush injuries, reaction to

incompatible blood transfusion, and sulfathiazole crystalluria are excluded—-

was observed in large proportion of the cases. Eighty-two percent of those

who had high azotemia, and, in another category, 73 percent of those who had

oliguria and 69 percent of those who had anuria had been in moderate or severe

initial shock. These figures are undoubtedly too low, for many men probably

had been in shock before we saw them.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 181

Death occurred within 10 days after wounding in 48 (94 percent) of 51

patients who died of posttraumatic renal insufficiency. Apparently if the

wounded man can withstand this critical 10-day period, recovery of renal function begins and he may survive. In few patients there was evidence of returning renal function toward the end of their course, even though they died in

uremia. The importance of this fact cannot be overemphasized, for therapeutic error (such as overloading the circulatory system by fluid administration)

during this critical period may cause fatal outcome before natural recovery

can take place.

Hypertension (at least 135 mm. Hg systolic and at least 90 mm. Hg diastolic)

occurred in 62 percent of the patients with high azotemia, and in 79 percent

of those in this group who died in uremia. In many of the fatal cases in which

hypertension did not develop, death occurred within days after wounding.

Had these patients survived longer, probably they too would have had hypertension.

The important biochemic and physiologic abnormalities in the blood resulting from posttraumatic renal insufficiency were found to be nitrogen and

phosphorus retention, acidosis, hypochloremia, and increase in the plasma volume. These blood and plasma changes reflect rapidly diminishing renal function, as indicated by: (1) inability to concentrate the urine; (2) frequent failure

to make highly acid or alkaline urine in the presence of metabolic acidosis

or alkalosis; (3) diminished glomerular filtration rate and renal blood flow,

and (4) decreased phenolsulfonphthalein and maximum tubular excretory

capacity of para-amino hippuric acid.

Nonprotein nitrogen, urea nitrogen, creatinine, uric acid, and phosphorus

levels in the plasma rose as renal failure progressed during the first 10 days

after wounding. Most observations after this period were on patients who recovered. The level of these waste products fell between the tenth and fifteenth

days.

progressive, fairly severe acidosis was characteristic, manifested by falling

plasma carbon-dioxide combining power as renal failure advanced. Loss of

ability to make highly acid urine in most cases suggests that the acidosis was

partially to be explained by impairment of the mechanism which produces an

acid urine. few observations also indicated, as expected, an impairment of

ammonia production by the renal tubules. There was also good evidence that

removal of sodium by excretion as sodium bicarbonate was poorly accomplished
182 THE PHYSIOLOGIC EFFECTS OF WOUNDS

in those cases in which alkalosis resulted from administration of large quantities

of sodium.

Hypochloremia was severe and progressive, if all fatal cases are averaged.

Correlation of the plasma chloride level and sodium chloride intake, however,

demonstrated that the low chlorides were to some degree result of inadequate

salt intake. Serum sodium levels showed similar correlation. There was no difference in case fatality between the group with hypochloremia and those with

normal plasma chloride levels. One patient with renal failure had severe sodium

and chloride retention following high salt intake. Intake, however, does not

entirely explain variations in plasma chloride levels. No correlation with degree

of plasma volume increase was apparent, but it is suggested that some interference with water and sodium chloride equilibrium was present in addition

to the demonstrated relation to intake.

Phosphates in terms of acid equivalence, contributed toward but did not

entirely account for the acidosis. Plasma proteins, if converted to milliequivalents, were normal and constant. Sulfates and organic acids were not measured and possibly account for discrepancies in our anion determinations.

Cation determinations were few. It has already been stated that sodium

levels were partially correlated with salt intake. Magnesium was not significantly elevated in most cases. Potassium was determined in only few cases,

but the results suggest that hyperpotassemia was probably feature of the syndrome. Calcium followed reciprocal relationship with rising phosphorus levels

in the few cases in which such determinations were made.

Total plasma volume was significantly elevated in 22 of 23 patients with

posttraumatic renal insufficiency. Nineteen of these 23 died. Three patients

with severe renal failure in whom recovery diuresis developed had plasma

volume increases that reached maximum at the time of greatest nitrogen

retention and decreased after diuresis. The degree of increase of the plasma

volume was clearly related to fluid intake. The water retention appeared to be

largely result of administration of more fluid than the impaired kidneys

could excrete. Comparison of plasma volume with total blood volume indicated

that it was the plasma which was increased, rather than all elements of the

blood. The expected dilution of plasma proteins was not demonstrated in most

cases. The practical importance of this increase in plasma volume has been

mentioned.
CLINICAL, PHYSIOLOGIC, BIOCHEMIC CORRELATION 183

Ability to concentrate the urine diminished rapidly as the syndrome of

posttraumatic renal insufficiency progressed, and specific gravity became fixed

in all patients with severe degree of renal failure. In patients who recovered

it was the last of the kidney functions of those measured to return to normal.

Since urine concentration is accomplished by the distal tubular cells, whereas

mannitol, para-amino hippuric acid, and phenolsulfonphthalein reflect glomerular and proximal tubular function, the lag in recovery of water-reabsorptive capacity may point to greater relative functional impairment of the lower

nephron.

Ten patients of the 73 who had high azotemia exhibited all of the features

of severe renal failure and subsequently diuresis developed and they recovered.

The course of these patients followed pattern which has been termed the

“syndrome of recovery diuresis.” This small group re-emphasizes the importance of avoiding early fatal therapeutic errors (such as overloading the circulatory system with fluid) thereby affording the kidneys an opportunity to recover spontaneously.
CHAPTER VI

Treatment of Lower Nephron

Nephrosis

It should be stated at once that treatment of posttraumatic renal insufficiency

after the syndrome has become established is disappointing although not hopeless. Evidence has been presented that shock is one factor important in its

etiology. As soon as the patient becomes available for treatment, the shock state

can usually be corrected fairly rapidly. Primary treatment of the wounded

should therefore be directed toward prompt and adequate resuscitation of every

man in shock in order to prevent, if possible, development of serious renal insufficiency.

In presenting our experience in the management of patients with posttraumatic renal insufficiency, certain therapeutic errors to be avoided will be stressed

and the use of various drugs and procedures to stimulate renal function (most

of which are of questionable value) will be discussed.

Fluid Intake

Early in the Italian campaign fatal cases of posttraumatic renal insufficiency

began to appear. Therapy almost universally consisted of intravenous administration of large quantities of various crystalloids. Practically every known

diuretic was also employed, and attempts were frequently made to alkalinize

the urine by administering large quantities of available base by mouth or vein.

In the absence of adequate output of urine, the renal insufficiency soon became

complicated by cardiac failure as result of overloading the circulatory system.

The majority of patients so treated died rather promptly of pulmonary edema

before they had an opportunity either to die in uremia or to regain adequate

renal function.
TREATMENT OF LOWER NEPHRON NEPHROSIS 185

Early in the course of our study it was found that those patients with renal

insufficiency almost without exception had increased plasma volumes, as was

shown in Chapter V, Here then was an additional explanation for the frequency of pulmonary edema; we were dealing with patients who, as result of

renal failure, already had circulating plasma volume larger than normal. If

additional fluids were added, especially those containing sodium, water retention became more severe. The frequency of pulmonary edema and cardiac failure is therefore not surprising. The therapeutic implications of these physiologic

abnormalities are clear. Patients with this type of renal insufficiency already

have too much extracellular fluid and too large plasma volume, apparently

primarily as result of the kidney’s being unable to excrete this surplus water.

Treatment should therefore include (i) any judicious measures which might

possibly encourage the kidneys to excrete more urine, and (2) avoidance of

any measures which would further increase plasma volume and secondarily

cause cardiac embarrassment.

As was shown in the previous chapter, the critical period in the majority of

patients with renal insufficiency appeared to be the first 10 days after wounding,

when 94 percent of the total deaths occurred. Evidence has been presented that

renal function had begun to improve after this time in number of patients,

even though they subsequently died in uremia. Thus the importance of preventing an early fatal outcome resulting from too enthusiastic fluid administration

cannot be overemphasized. Unfortunately most of these patients eventually die

in uremia regardless of treatment, but by judicious use of fluids they are at

least allowed an opportunity to recover renal function spontaneously and their

chance of survival is increased.

In cases in which fluids were restricted, the incidence of pulmonary edema

was, in our considered judgment, materially lessened, even in those patients

who subsequently died primarily of renal failure. few who recovered (Cases

43,44, and 138) might have died of heart failure if quantities of fluid comparable

to those previously employed had been given.

Our recommendation on fluid intake for the average patient with oliguria

or anuria is that ordinarily not more than from 500 to 1,000 cubic centimeters

in excess of urinary output be given daily. The patients in this study were seen

in the fall, winter, and spring months when the temperature in Northern Italy

was such that extrarenal fluid losses were probably minimal. In hot weather or

when sweating is excessive this allowance should probably be increased. If
186 THE PHYSIOLOGIC EFFECTS OF WOUNDS

urinary output increases to more than liter daily, it is suggested that intake of

fluids parallel or slightly exceed output of urine until retained nitrogen is cleared.

Oral fluids, whenever their use is feasible, are preferred to parenteral ones in

order to avoid sudden augmentation of the already increased plasma volume.

Such parenteral fluids as are used should be administered slowly, and the patient

should be carefully observed for signs of pulmonary edema during infusion.

For reasons to be mentioned later under Hypertonic Solutions, the preferred

parenteral fluid is an isotonic solution of dextrose.

We have too little data on sodium to compare the level of this cation in the

serum with the sodium intake. Hence it cannot be stated whether hyponatremia

accompanied the hypochloremia, and therefore whether serious sodium depletion ever occurred. It now appears that as consequence of the practice of giving

almost no salt parenterally, hypochloremia resulted in some patients, although

the outcome in those with decreased plasma chlorides apparently was no different from that in patients with normal chlorides. In our opinion, once posttraumatic renal insufficiency has become established, the danger of producing further

edema and circulatory failure exceeds the questionable benefit to be derived

from continued attempts to replenish deficient sodium by administration of

sodium salt. We would therefore now recommend that during the oliguric and

anuric phase salt be given only in quantities sufficient to replace extrarenal salt

losses and the small quantity lost in the urine. These combined losses can only be

estimated; they probably would seldom exceed one or two grams of salt daily.

Procedures and Drugs Used to

Stimulate Kidney function

Our experience revealed no positive and sure measures capable of re-establishing kidney function after renal insufficiency had developed. The aim should

always be to avoid measures that might be harmful during the period before

Because of the water-retaining property of the cation in sodium chloride, we suggested that the

largest portion of the parenteral fluids given consist of 5- or 10-percent dextrose in distilled water. However, only the 10-percent prepared solution was available during most of the period when these studies

were being made. Although 5-percent dextrose can be made up by adding dextrose solution to distilled

water, under field conditions and the pressure of work during combat this is troublesome and was not

often done.
87 TREATMENT OF LOWER NEPHRON NEPHROSIS

the kidneys spontaneously begin to clear retained waste products. Well-known

methods of stimulating urine flow that were tried will be discussed briefly. It is

evident from the results that they were of no value, or at best of questionable

value.

Hypertonic Solutions

The advisability of giving hypertonic solutions parenterally in this syndrome

is highly debatable. They exert, at least in the presence of normal renal function, diuretic effect by (i) temporarily increasing plasma volume, and (2) by

limiting tubular reabsorption of water due to the osmotic effect of increased

concentration of solute in the distal tubules. It is clear that the first of these

actions is undesirable, since the circulating plasma volume is already increased;

the second is desirable if tubular reabsorption can be altered in the damaged

kidney.

Hypertonic saline (10-percent) solution was used in only one patient

the only one in our series with true transfusion incompatability (Case 9). There

was no observed effect on urinary output. It might be argued that early trial

of such solution would be of value in this type of renal insufficiency. If there

is no response to 500 cc. of 3-percent saline solution, further attempts at diuresis

by this method surely are contra-indicated because of the undesirable increase

in plasma volume which must result from excessive salt administration.

Either hypertonic dextrose solution or 5-percent dextrose in isotonic saline

solution was the parenteral fluid most often given to the patients we observed.

When solutions rendered hypertonic by sugar are employed, the osmotic effect

on the plasma volume must be transient, lasting only until the dextrose is metabolized. The dextrose aids in nourishing patients who, as rule, are eating

poorly or not at all. The concentration of dextrose employed in hypertonic

solution varied from 10 to 50 percent, but the 10-percent solution was the one

most often used. There was little if any evidence from extensive use of these

forms of hypertonic solutions that they influenced the output of urine.

In summary, since hypertonic solutions may dangerously increase plasma

volume, and moreover since our data indicate they are ineffective in promoting

urinary flow, isotonic solutions would seem to be preferable. If hypertonic solutions are employed, as they occasionally are in oliguria, dextrose is usually the

one of choice; limited trial of hypertonic saline solution might be indicated in

some cases.
i88 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Alcohol

The known diuretic effect of alcohol, and the suggestion that its administration might increase renal blood flow prompted rather extensive trial of this

agent. It was given to 22 patients, 20 of whom subsequently died of renal insufficiency and of whom survived through the mechanism of recovery diuresis.

Usually it was given intravenously, slowly, as 5-percent solution, the total

daily dose being from 50 to 100 cc. of 95-percent ethyl alcohol. As an alternative,

if the patient could tolerate it, from 120 to 180 cc. of whiskey were given by

mouth daily. Of the 20 patients who died, received approximately these doses

for day only, for to days, and for to days. Records are not available of the total quantities received by the patients who recovered, but it is

known that they received similar daily doses. No symptoms due to the alcohol,

other than occasional mild euphoria and drowsiness, were observed in any

patient.

In only of the 20 patients who died (Cases 41 and 52) was there significant increase in urinary output following the use of alcohol. The patients who

recovered had marked diuresis. Other patients showed no significant effects,

although occasional transitory increases of as much as 300 cc. per day in urinary

output were noted. Similar increases, however, occurred in patients with renal

insufficiency who had not been given alcohol.

Mercurial Diuretics

Mercupurin, in doses of or cc., was given to three patients who subsequently died ofrenal failure. No diuretic effect was demonstrable.

Aminophylline

No demonstrable diuresis resulted from intravenous administration of 0.24 to 0.48 Gm. of this drug to four patients who later died of renal failure.

Inorganic Ions

The use of sodium chloride has been mentioned under “Fluid Intake” and

Hypertonic Solutions.

Lauson, H. D.; Bradley, S. E. and Cournand, A.: Renal circulation in shock. J. Clin. Investigation

23: 381-402, May 1944.
TREATMENT OF LOWER NEPHRON NEPHROSIS 189

Sodium sulfate in isotonic (3.2 percent) or hypertonic (4.2 percent) solution

was given to two patients in total doses of 800 cc. and 1,000 cc. respectively.

Neither any beneficial nor harmful effects were observed. Both patients subsequently died in renal failure.

Magnesium sulfate and potassium chloride were employed on the theory

that these solutions might be effective in reducing edema of renal tubular cells

and hence perhaps promoting urinary flow. Magnesium sulfate was used in four

patients (Cases 69, 78, 93, and 95). From to Gm. were given daily (as

50-percent solution intravenously and intramuscularly) for periods of from to

days. Plasma magnesium levels, determined in two of these patients, were

7.0 milliequivalents per liter after 24 Gm. of magnesium sulfate had been administered in days in one (Case 93), and 3.8 milliequivalents per liter after

Gm. had been given in days in the other (Case 95). This second patient

received in addition 10 Gm. of potassium chloride (as 0.5-percent solution intravenously) at about the same time. No increase in output of urine was demonstrated in these patients and all four died of typical renal failure.

Although no definite symptoms of toxicity due to these cations were demonstrable in these four patients, we believe that the use of magnesium and potassium in such cases is dangerous. In the presence of renal failure, administration

of magnesium results in rapid rise in the plasma concentration of this ion.

The danger of reaching toxic levels, it is believed, outweighs any possible beneficial effects. We have no data on potassium levels reached in the one patient

who received potassium chloride. However, because this ion likewise exerts

toxic effects, in our opinion it should not be used in such cases unless serum

potassium levels are known to be normal or low. There is some evidence in

the literature to support the contention that retained potassium may play lethal

role in uremia.

Alkalis

The effect of alkalis in wounded patients will be discussed in detail in Chapter VII. Alkalis were given, usually in small doses, to many of the patients after

renal insufficiency had developed. Eleven patients who later died of uremia

were given between 10 and 20 Gm. of sodium bicarbonate per day for or more

days, yet in only two of these patients was an alkaline urine observed. The

Hoff, H. E.; Smith, P. K., and Winkler, A. W.: Cause of death in experimental anuria. J. Clin.

Investigation 20: 607-624, November 1941.
190 THE PHYSIOLOGIC EFFECTS OF WOUNDS

dangers of adding sodium to the extracellular fluid have been discussed. Further,

the main reason for giving it in renal insufficiency is to produce an alkaline

urine, the therapeutic value of which is debatable. We found no evidence that

the use of alkalis has any place in the therapy of established posttraumatic renal

insufficiency; in fact it may cause further harm.

Spinal Anesthesia

For many years, whenever anuria developed, it had been customary to suggest that spinal anesthesia be induced in the belief that the kidney failure might

perhaps be accounted for, at least in part, by reflex vascular spasm and that this

could be interrupted by spinal anesthesia. The results on the whole have been discouraging. Recent information suggests that part of the innervation of the kidney

may come from higher origins than was earlier supposed. For this reason, anesthesia to the level of the clavicle was planned. With sensory anesthesia to this

level, it is probable that vasomotor anesthesia was higher than this, since it is

produced by lower concentration of procaine hydrochloride than is required

for sensory anesthesia. Pertinent data from four cases in this study in which

this procedure was tried are summarized briefly as follows.

Case Summaries

1. (Case 4j) —In 22 hours preceding high spinal anesthesia this patient had voided

30 cc. of urine. The bladder was empty at the time anesthesia was induced.

o8oo hours—Blood pressure 128/90. 0820 —175 mg. procaine hydrochloride in cc. spinal fluid were injected

into the third lumbar interspace. Height achieved by barbotage.

0830 —Blood pressure 135/88.

0835 —Blood pressure 118/80.

0843 —Blood pressure 120/80. 0830 —Sensory anesthesia (pinprick) was present to the top of the second

rib at the sternum.

0850 —Blood pressure 112/80.

0915 —Blood pressure 118/80. Sensory anesthesia persisted at the same

level as at 0830,

0925 —Blood pressure 118/80. 0945 —Sensory anesthesia was beginning to wear off. There was no respiratory impairment at any time.

Capt. Gerald Shortz of the 2d Auxiliary Surgical Group carried out the spinal anesthesias on three

of these patients.
TREATMENT OF LOWER NEPHRON NEPHROSIS

The patient was catheterized /i hours after the spinal anesthesia had been induced.

The bladder was still empty. Conclusion: The anesthesia had no diuretic effect.

2. (Case 95) —The details concerning this case are similar to those of Case 47, except

that in this one anesthesia was obtained to about the nipple line, where it persisted for

70 minutes. The blood pressure did not fall during the period of anesthesia. Sixty-five cc.

of urine were present in the bladder just before induction of anesthesia. In the 24 hours

following induction of anesthesia there was no formation of urine; this was checked by

catheter.

3, (Case 133)—In hours preceding spinal anesthesia 65 cc. of urine had formed

and were obtained by catheter just before anesthetization.

1410 hours—180 mg. procaine hydrochloride in 10 cc. of spinal fluid were injected into the third lumbar interspace.

1415 —Anesthesia was present to the eighth cervical vertebra.

1430 —Anesthesia was present to the fourth thoracic vertebra.

1500 —Anesthesia was present to the seventh thoracic vertebra.

1515 —Anesthesia was present to the ninth thoracic vertebra.

1535 —Anesthesia was present to the second lumbar vertebra.

1600 —Anesthesia of the saddle area and legs only.

1630 —Full recovery.

2015 —85 cc. of urine were obtained by catheterization.

There was no fall of blood pressure during this test. Since 65 cc. of urine had been

formed in hours preceding anesthesia, and 85 cc. in hours following, no definite

effect could be attributed to the anesthesia.

4. (Case 138)—In 11 hours preceding spinal anesthesia, 40 cc, of urine had been

formed. The bladder was emptied of this just before anesthesia was induced. The blood

pressure remained at 120/72 throughout the test.

1500 hours—200 mg. procaine hydrochloride were dissolved in 12 cc. of spinal

fluid and injected into the third lumbar interspace.

1505 —Anesthesia was present to the eighth cervical vertebra.

1515 —Anesthesia was present to the fifth thoracic vertebra.

1535 —Anesthesia was present to the second lumbar vertebra.

1600 —Saddle and leg anesthesia only.

1650 —Complete recovery.

2100 —60 cc. of urine were obtained by catheterization.

Sixty cc. of urine were excreted in hours following induction of anesthesia

and 40 cc, had been formed in hours preceding anesthesia; hence no definite

effect of the spinal anesthesia was evident. The patient’s low point in output was

days preceding the anesthesia; in other words, steady increase in urinary

output had already begun. This patient was the only one of this group who
THE PHYSIOLOGIC EFFECTS OF WOUNDS 192

recovered. One cannot say that the spinal anesthesia either did or did not play

part in his recovery.

No definite evidence was obtained from the four patients studied that spinal

anesthesia influenced the output of urine. We had planned to try this procedure earlier, that is, soon after the onset of progressive oliguria. These plans

were interrupted by the end of the war in Italy.

Kidney Decapsulation, Sympathectomy

This was carried out in one patient (Case 129) 54 hours after initial operation, during which time the patient had voided 150cc. of urine. The right kidney

was decapsulated and periarterial sympathectomy performed. There was no

effect on urinary output, and the patient died in uremia 48 hours later, having

excreted 180cc. of urine since the second operation.

Correction of Anemia

In instances in which whole blood transfusions were indicated for the correction of severe anemia, these were given. Relatively fresh bank blood was

used to avoid possible pigment insult secondary to intravascular hemolysis of

aged cells. No benefit or detriment to the already failing kidney was observed.

Nutrition

Ideally, nutritive requirements during the acute phase of the syndrome

should be met by an adequate caloric intake, but with such foods that there will

be minimal destruction of body protein and production of urea nitrogen from

exogenous proteins. These demands would best be served by carbohydrate and

fat intake sufficient to furnish from 1,500 to 2,000 calories per day. If the patient is unable to take food by mouth, it is practically impossible to administer

enough dextrose intravenously to furnish such caloric intake and still adhere

to the more important rules of restricting fluids and prohibiting hypertonic solutions. During the acute phase of renal insufficiency one must be content with

merely furnishing the small requirement of sodium chloride as isotonic saline

solution, and with an attempt to meet caloric requirements by supplying dextrose
TREATMENT OF LOWER NEPHRON NEPHROSIS

in 5-percent solution in water in the additional small fluid allowance remaining—that is, total daily intake of500 to 1,000 cc. in excess of total urinary output.

SUMMARY

Various procedures were tried in the treatment of lower nephron nephrosis

which occurred as complication in severely wounded men. Among these were

control of fluid intake, the use of relatively fresh blood for transfusions to combat anemia, attempts to make the urine alkaline, spinal anesthesia, kidney decapsulation, and the administration of number of drugs commonly believed

to stimulate the excretion of urine. Except for evidence that avoiding excess fluid

administration reduced the incidence of early death from pulmonary edema, all

were essentially disappointing, leading to the conclusion that “the best treatment of posttraumatic renal insufficiency is its prevention.” Since shock is known

to be major factor in its development, prompt and adequate resuscitation of

every man in shock is most important.

Once renal insufficiency has developed, avoidance of the therapeutic error

of administering too much fluid and hence accentuating an already increased

plasma volume becomes of first importance. Types and quantities of fluids to

be administered during the period when renal failure is most severe (usually

the first 10 days after trauma) have been recommended. Although we employed

various drugs or procedures directed toward promoting urine flow or improving

kidney function, we met with little success in their use. These measures included

the use of hypertonic solutions, alcohol, mercurial and xanthine diuretics, and

solutions of various inorganic ions, the induction of spinal anesthesia, and decapsulation of kidney. The essential requirement appears to be that of tiding

the patient over the critical period until natural recovery of renal function begins. Dialysis procedures, which attempt to remove waste products by routes

other than the kidneys until the kidneys resume their function, offer possibilities

that were not tried in this study.

CASES OF SPECIAL INTEREST IN THIS CHAPTER

43 47 93

44 52 95 135
CHAPTER VII

Effect of Alkalis in Treatment

of Traumatic Shock

The use of alkalis has been recommended by some as an adjunct in the

treatment of the severely wounded for two reasons. First, it was proposed as

means of combatting the acidosis known to exist in shock; second, it was suggested that production of an alkaline urine might make more soluble any blood

or muscle pigments or sulfonamide crystals in the urine. Evidence will be presented here that with judicious use of alkalis it is possible to relieve metabolic

acidosis, but that in the presence of shock and the accompanying decrease in

renal function, it may be very difficult and even dangerous to attempt to produce an alkaline urine.

Any patient who receives whole blood or blood substitutes of necessity also

gets sodium citrate which is employed as an anticoagulant when the blood is

collected from the donor. Although the quantity varies slightly, we have assumed

that each unit* of blood or plasma contained Gm. of U.S.P. sodium citrate.

The quantity of alkali received by patient transfused with several liters of

blood or plasma was therefore considerable. In the patients we observed, any

additional alkali given was usually in the form of 2-percent solution of sodium

bicarbonate. This was prepared by adding sodium bicarbonate to distilled water

shortly after the water was removed from the autoclave. Although some sodium

carbonate undoubtedly resulted from this procedure, no untoward reactions

were encountered in large series of patients to whom this solution was given

intravenously. Sodium citrate, or 2.5 percent, in sterile ampules, was also employed in few instances. The sodium administered in excess of that given as

sodium chloride was calculated from the quantity present in sodium citrate or

sodium bicarbonate. This figure furnished convenient index of the total alkali

unit of blood 500 cc.; unit of plasma 300 cc. total volume.
ALKALIS IN TRAUMATIC SHOCK 95

received, since both sodium citrate and sodium bicarbonate were frequently administered.

In Table 80 the effect of increasing quantities of alkali in relation to the

degree of initial shock is shown. Those patients who received between and

Gm. of sodium (approximately from to 20 Gm. of sodium bicarbonate or

sodium citrate) still had an acid urine after 20 to 30 hours, and they showed no

remarkable rise in plasma carbon-dioxide combining power. In those who received between 5.1 and 10 Gm. of sodium the urine became alkaline only if

they had had little or no initial shock. There was significant change in preoperative and postoperative plasma carbon-dioxide combining power only in

those who had had moderate or severe shock, but their urines remained acid.

Inspection of the data on individual patients (Table 80) who received between 10.1 and 20 Gm. of sodium shows that of six who had been in moderate

or severe shock, only one was producing an alkaline urine 24 hours later and

the remaining five still had acid urines 26 to 34 hours after wounding. The two

patients with no shock and slight initial shock respectively both had highly

alkaline urines. The plasma carbon-dioxide combining power rose significantly

in five of seven patients on whom postoperative determinations were made.

These observations show rather clearly that in patients who have had severe

or moderate shock, an alkaline urine is not usually produced even after administration of large quantities of alkali, although the metabolic acidosis may be

relieved. The dangers of producing severe alkalosis in such patients, and partial explanation of their inability to form an alkaline urine become apparent

in Tables 81, 82, and 83, and Chart 28 which show the sequence of events in

three patients with moderate or severe initial shock who received large quantities of alkali. The cases are summarized as follows:

Cases of Alkalosis

Case 108 (Table 81).—This patient, who had severe shock on hospital entry, received

34 Gm. of sodium bicarbonate and 24 Gm. of sodium citrate within the first 24 hours

after admission. The plasma carbon-dioxide combining power responded to this excess

alkali by rapidly rising to 34 milliequivalents per liter, but despite this relative alkalosis the

urine did not become alkaline until the third postoperative day. The plasma chloride level

fell although scarcely any chloride was excreted in the urine. Coincident with these changes

in acid-base metabolism, the output of urine was very small, the specific gravity of the

urine fell, the plasma nonprotein level rose, and the urea nitrogen excretion was minimal.

The patient died in uremia on the third postoperative day.

956507 0—52 14
196 THE PHYSIOLOGIC EFFECTS OF WOUNDS

The

preoperative

specimens were taken

when

no

alkali,

or

very

small

quantities,

had

been

given;

the

postoperative

specimens

after

the

patients

had

received the

amount of

alkali

indicated

under

“Excess

Sodium

Intake.”

The

time

between

wounding

and

collection

of

the

postoperative

specimens

is

also

indicated.

Enough

patients

received

between

and

10

Gm.

of

sodium

to

permit

statistical

analysis; determinations

are

listed

individually

for

those

who

received

between10.1

and

20

grams. The

excess sodium

intake

in

grams

was calculated

from

the

percentage

of

sodium

in

sodium

citrate or

sodium

bicarbonate. Sodium

administered in

isotonic

saline

solution

is

not

included

in

the

data.

Table

8o.

—Relationship of

Sodium

Intake and

Degree of

Initial

Shock to

PlasmaCarbon-Dioxide

Combining Power and

pH

of

Urine

Preoperative Specimen

Postoperative Specimen

Excess

Sodium

Intake

Degree

of

Shock

on Admission

Plasma

CO2

Plasma

CO2

Hours

Hours

Gm.

Urine

pH

after

Urine

pH

after

mEq./L.

mEq./L.

Wounding

Wounding

None

or

slight

24.0±1.3

5.9

31.0

21.5

6.8±0.24

6.

±4.4

1.0

to

5.0

(6

cases)

(4

cases)

(2

cases)

(2

cases)

(7

cases)

(7

cases)

(Average

of

cases)

Moderate or

severe

24.2±1.4

5.7

26.0±2.1

32

±3.8

6.2

±0.1

31.7

±4.0

(9

cases)

(2

cas'es)

(7

cases)

(7

cases)

(10

cases)

(10

cases)

None

or

slight

24.0±1.7

5.6

24.0±1.8

27.5±3.5

7.2

±0.22

25.8±3.

5.1

to

10.0

(6

cases)

(3

cases)

(6

cases)

(6

cases)

(9

cases)

(9

cases)

(Average of

cases)

Moderate or

severe

21.3±1.7

5.9

25.5

±1.8

25.1

±1.6

6.1

±0.12

24.

±1.6

(12

cases)

(4

cases)

(8

cases)

(8

cases)

(14

cases)

(14

cases)

None

or

slight

25

26

29

7,4

29

26

5.8

33

17

8.0

15

10.1

to

S.O

(Individual cases)

19

5.9

25

34

6.7

34

Moderate or

severe

11

25

39

5.6

33

23

5.6

6.7

33

22

5.5

34

35

5.4

28

15.1

to

20.0

Moderate or

severe

15

6.1

33

26

5.5

26

(Individual cases)

26

26

24

8.1

24
ALKALIS IN TRAUMATIC SHOCK 197

Table 81.—Changes in Acid-Base Metabolism and Coincident Findings

in Patient Who Received Excess Alkali

Severe Initial Shock and Subsequent Death from Posttraumatic Renal Insufficiency

Case 112 (Table 82).—Twenty Gm. of sodium bicarbonate and 16 Gm. of sodium

citrate were administered within hours after this patient entered the hospital in severe

shock. The pH of the venous blood and the plasma carbon-dioxide combining power

promptly rose to levels indicative of moderate alkalosis, but the urine did not become

alkaline until nearly 24 hours after the alkali had been administered. Although urinary

output was normal after the first day, the plasma nonprotein nitrogen level had risen to

67 mg. per 100 cc. by the second postoperative day, when the patient was evacuated.

Plasma chloride levels fell and chloride excretion was low. Subsequent follow-up revealed

that nitrogen retention persisted for days; the status of the acid-base metabolism could

not be followed.

Case loy Table 83 and Chart 28).—This patient, admitted in moderate shock, received

35 Gm. of sodium bicarbonate and 28 Gm. of sodium citrate on the day of operation, and

15 additional grams of sodium bicarbonate early on the first postoperative day. The resulting severe and prolonged alkalosis is evident in the high plasma carbon-dioxide combining

Case 108

Parenteral Intake

Plasma Plasma Urine Urine

Period CO* Cl NaCl

Na Cl pH

mEq. mEq. mEq./L. mEq./L. Gm.

Preoperative 811 300 22 100 5.5 0.04

(18-hr. period)

PostoperativeDay

First 417 300 34 97 5.4 0.26

Second 115 75 30 96 5.4 ——

Third 23 91 7.6

Parenteral Intake Urine

Plasma Urea Urine

Period

Na Cl NPN Nitrogen Gravity Output

mEq. mEq. mg.perlOOcc. Gm. cc.

Preoperative 811 300 37 0.13 1.032 100

(18-hr. period)

Postoperative Day

First 417 300 77 0.54 1.014 185

Second 115 75 113 1.012 155

Third 170
198 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 82.—Changes in Acid-Base Metabolism and Coincident Findings in

Patient who Received Excess Alkali

Severe Initial Shock, Subsequent Nitrogen Retention, and Recovery

Table 83.—Changes in Acid-Base Metabolism and Coincident Findings in

Patient who Received Excess Alkali

Postoperative Alkalosis and Azotemia, Resulting in Death

power and blood pH. Considerable ammonium chloride was given on the fourth and fifth

postoperative days in an unsuccessful attempt to relieve the alkalosis. In this case also there

was marked lag in the production of an alkaline urine after metabolic alkalosis appeared.

By the fourth postoperative day, although severe alkalosis persisted, the patient was no

longer able to excrete an alkaline urine. Plasma chlorides fell to phenomenally low levels

Case 112

Parenteral Blood Plasma Plasma Urine Urine Plasma Urine Urine

Intake pH co Cl pH NaCl NPN Specific Output

Period (venous) Gravity

Na Cl mEqJL. mEq./L. Gm. mg. per CC,

mEq. mEq. 100 cc.

Preoperative 400 7.04 to 20 to 99 5.4 to 40 1.025 530 (21.5-hr. period) 7.45 30 6.5

Postoperative Day

First 7.45 32 86 7.1 0.43 53 1.010 2,180

Second ....

36 87 7.2 1.4 67 1.010 1,945

57

34

Case ioy

Parenteral

Intake Blood Serum Plasma Plasma Urine Urine Plasma Urine

Period pH Na CO2 Cl pH NaCl NPN Output

(venous)

Na Cl rnEq./L. mEq./L. mEq.IL. (n:7.38- Gm. mg. per CC,

tnEq. mEq. (n:l42) (n:27) (n:103) 7.48) 100 cc.

681 15 103 6.1 27 60

(18-hr. period)

Postoperative Day

324 146 160 30.2 too 5.5 to 0.3 41 1,560

7.3 Second .... 7.44 170 41 91 8.2 0.23 46 1,570

146 146 7.7 0.80 1,540

332 482 7.48 160 47 73 6.8 91 875 Fifth 245 7.52 140 43 65 5.8 0.0 73 800

60 37 56 7.3 152 200(?)
ALKALIS IN TRAUMATIC SHOCK 199

Chart 28. Effect of Alkali Administration in Fatal Case (Case 107)

SODIUM AND CHLORIDE INTAKE (PARENTERAL)

SODIUM

CHLORIDE

BLOOD pH

PLASMA OR SERUM

URINE pH

URINE CHLORIDE (NaCI)

PLASMA

NONPROTEIN NITROGEN

URINE OUTPUT

NOTE: (1) The lag in development of an alkaline urine in the presence of alkalosis and

sodium retention, and presumptive evidence of inability to excrete excess sodium, as indicated by fall in the pH of the urine after the second postoperative day; (2) the low

plasma chloride levels and negligible urinary chloride excretion; (3) rising plasma nonprotein nitrogen level and decreasing urinary output, and (4) the fixed specific gravity

of the urine.

in this patient (56 milliequivalents per liter the day before death); urinary chloride excretion was practically nil throughout his course. The plasma nonprotein nitrogen level rose,
200 THE PHYSIOLOGIC EFFECTS OF WOUNDS

and the patient died on the sixth postoperative day, with renal failure in our opinion an

important contributory factor in his death.

The low plasma chloride levels in these three cases are partly explained by the

reciprocal relationship of carbon dioxide and chloride in the plasma. That this

is not the entire explanation is evident in the fact that in two (Cases 107 and

108, Tables 81 and 83) the plasma chloride level continued to fall after the plasma

carbon-dioxide combining power had also begun to decline. Hence it would

appear that the mechanisms producing hypochloremia, frequently feature of

lower nephron nephrosis following traumatic shock (see Chapter V), were also

operative in these cases.

SUMMARY AND CONCLUSIONS

Reasons that have been advanced for using alkalis in traumatic shock are

(i) to relieve metabolic acidosis and (2) to produce an alkaline urine. We found

that large quantities of alkali are necessary to relieve acidosis when it is severe;

that is, in patients in shock. If in addition enough extra base is given to produce

an alkaline urine in these patients, the margin of safety between normal acidbase equilibrium and uncompensated alkalosis may be very small. In the event

that alkalosis does result, it may materially contribute to renal failure. Three

cases in which this may have occurred have been presented.

The mechanism of the low alkali tolerance in these patients is not clear.

The impaired ability of the kidneys to excrete excessive amounts of sodium

apparently is associated with the general impairment of renal function that

occurs in all patients suffering from shock, and continues for some time after

the shock has been relieved, as was brought out in Chapter III.

Because the evidence is so meager that an alkaline urine will prevent renal

complications in the type of patient studied here, and because of the dangers

inherent in trying to produce such urine, the use of alkalis for this purpose

is not recommended. Small quantities of alkali sufficient to relieve metabolic

acidosis, if judiciously employed, probably are advisable. The amount routinely

given with citrated whole blood or blood substitutes will in most instances be

adequate for this purpose.
CHAPTER VIII

Pigment Mobilization in Severely

Wounded Men

It was shown in Chapter IV that severely wounded men commonly excrete

heme-containing pigments, either hemoglobin or myoglobin, in the urine and

that such excretion was constantly observed in patients destined to develop the

syndrome of posttraumatic renal insufficiency. In Chapter IX the significance

of pigment excretion will be further emphasized by demonstrating that pigment

precipitation in the lower segments of the nephrons was constant feature of

the renal lesion observed in fatal cases. The importance of pigment mobilization, its transport via the plasma to the kidneys, and its excretion in the urine

was therefore obvious early in our investigations, and the present chapter will

be devoted to presentation of the available data and discussion of their significance.

Materials and Methods

We were severely handicapped by the lack of spectroscope of sufficient

sensitivity to distinguish between the closely similar spectrums of hemoglobin

and myoglobin, and even if suitable instrument had been available it is doubtful if it could have been utilized under field conditions. We resorted therefore

to use of the benzidine method, which gave color reaction strong enough

to read in Coleman Junior spectrophotometer in dilution of milligram

of benzidine-positive material per 100 cubic centimeters. The method did not,

however, permit distinction between myoglobin and hemoglobin in plasma,

so throughout this chapter the term “plasma hemoglobin” is used to indicate

the total amount of benzidine-reacting material, though in many instances

significant proportion was undoubtedly myoglobin. further small fraction of

the total was probably contributed by nonspecific oxydases, but it is improbable
202 THE PHYSIOLOGIC EFFECTS OF WOUNDS

that this was large enough to affect comparative results. Under these conditions,

results of the test were always positive for “hemoglobin,” ranging from to 12

mg, per 100 cc. in the majority of initial samples and also in samples procured

during convalescence. We therefore considered values up to 12 mg. per 100 cc.

as being within normal range.

In the urine it did prove possible to distinguish between the two pigments

within certain limits by taking advantage of the greater stability of myoglobin

in alkaline solutions. By cautiously alkalinizing the urine, hemoglobin could

be converted to alkaline hematin and precipitated while the greater portion of

the myoglobin remained in solution. Tests with known mixtures of the two

pigments showed that the separation was approximately 80-percent effective,

and analyses of normal and decolorized muscles from patients who died of the

crush syndrome provided further confirmation of the validity of the method.

When enough pigment for quantitative determination was present in urine

specimen, this method was applied. Values of “myoglobin” that were less than

20 percent of the hemoglobin present were considered negative; findings of

20 percent or more were recorded as myoglobin. Details of the methods used

will be found in Appendix C.

Determinations of plasma “hemoglobin” and of urine hemoglobin and myoglobin were made routinely upon all patients in the series from whom suitable

specimens could be obtained. In some instances high plasma values were undoubtedly due to hemolysis incurred in taking samples of blood. Great care was

used in cleaning and drying needles and syringes and in the technique of venepuncture, but needles and syringes were not paraffinized. In certain patients

injury to the kidney or other portion of the urinary tractresulted in gross hematuria, and urine hemoglobin levels in these cases were considered valueless; however, if myoglobin was discovered in such specimens, it was recorded.

Bank Blood

Since hemolysis is inevitable in stored blood, many samples of bank blood,

taken at the time the blood was given out for transfusion to our patients, were

analyzed. The plasma hemoglobin and the blood sugar levels were determined,

the latter in order to check upon the effectiveness of added dextrose as preservative, Confirmation of the serologic blood group of the bank blood was not

attempted because the triple check used in the theater blood bank was as ac-
PIGMENT MOBILIZATION 203

curate as any method we could have tried. We did, however, take the precaution of checking the blood group of the recipient whenever possible since the

“dog tags” were known to be approximately 8-percent erroneous, and since the

grouping was often too difficult for hospital technicians because of the large

quantities of group blood that some patients had already received before the

first test-specimen was obtained.

Few Rh factor determinations were made because very little typing serum

was available. All patients, however, who were conscious at the time of observation were carefully questioned regarding previous transfusion and answers

were uniformly negative. Previous sensitization was therefore improbable, and

the short duration of the period of transfusion therapy—from to days—-

made active sensitization of no importance in our problem.

Specifications of Ban\ Blood.—Blood given to patients in this study was

derived from the theater blood bank in all but two instances. All bank blood

was group and the plasma agglutinins against and cells had been determined. If these were below 1:64, the blood was labeled Universal Donor if

above this level, O-Blood, for Use in O-Recipients Only. The blood had been

drawn into sodium citrate, and dextrose had been added to give concentration

approximating 0.3 percent. Blood was stored at all times, including periods of

transportation, in refrigerators at approximately 8° Centigrade. It was never

used after the tenth day.

Analyses of Ban\ Blood.—Since all blood samples contain cells of varying

maturity, progressive hemolysis is inevitable in all stored specimens. This is

apparent in Chart 29 and Table 84 which show average plasma hemoglobin

levels at the time of transfusion in 213 samples of blood from to 10 days old.

The rate compares favorably with Gibson’s figures based on storage in A-C-D

solution. In occasional samples, usually those from to days old, considerable

hemolysis was evidenced by plasma hemoglobin levels from 100 to 300 mg. per

Case was an example of transfusion accident—A blood to an recipient. The patient was seen

in consultation at neighboring hospital and was studied for comparison only. The second patient (Case 22)

belonged to group A. He received three transfusions of bank blood in forward hospital and subsequently

was given units of group blood at general hospital. He had already given evidence ofrenal insufficiency

before the type-specific blood was administered.

Gibson, J. G., 2nd; Evans, R. D.; Aub, J. C.; Sack, T., and Peacock, W. C.: The post-transfusion

survival of preserved human erythrocytes stored as whole blood or in resuspension, after removal of

plasma, by means of two isotopes of radioactive iron. J. Clin. Investigation 26: 715-738, July 1947.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 204

Chart 29. Relationship between Free Plasma

Hemoglobin and Age of Stored

Blood—213 Samples

ioo cc. (see Charts 30, 31, and 32). The average levels in samples from to

days old, the age period of most of the blood used, were in the range from

38 to 50 milligrams per 100 cubic centimeters.

The possible effect of blood transfusions on the level of free hemoglobin

in the blood plasma of the recipients is made readily apparent by few simple

calculations. Since the average amount of free hemoglobin in the bank blood

at the time of transfusion was approximately 40 mg. per 100 cc., and 500 cc.

of blood was the amount per unit, each patient receiving unit of blood received

at the time 200 mg. of free hemoglobin. Our patients received an average of 4.2 units of blood, or 840 mg. of hemoglobin, and in the fatal cases an average of

7.3 units, or 1,460 mg. of hemoglobin was given. Seven patients received from

10 to 14 units, or 2,000 to 2,800 mg. of free hemoglobin. Assuming an average

blood volume to be 5,000 cc., such quantities of infused hemoglobin could have

resulted in plasma levels of free hemoglobin in the patients of 16 to 58 mg.
PIGMENT MOBILIZATION 205

per 100 cubic centimeters. It must not be forgotten, however, that these approximations are based on the assumption that all infused free hemoglobin would

remain in the circulating plasma. This would certainly not be true, since in

many patients significant quantities would be excreted in the urine and in all

instances some would escape with the plasma into traumatized tissues.

Table 84.—Relationship of Average Plasma Hemoglobin Level to Age of

Stored Blood—213 Analyses

Charts 30 through 33 show the relationship between hemolysis and sugar

levels in the stored blood. It is evident that most instances of extreme hemolysis

occurred in blood samples with low sugar levels. Table 85 and Chart 33 show

average sugar levels in relationship to age of the blood. The chart shows that

the sugar level was well maintained until the seventh day and dropped sharply

thereafter.

Table 85.—Relationship of Average Blood Sugar to Age of Stored Blood—-

223 Samples

Age of Stored Blood

days

Number of

Analyses

Mean Plasma

Hemoglobin

mg. per 100 cc.

Age of

Stored Blood

days

Number of

Analyses

Mean Plasma

Hemoglobin

mg. per 100 cc.

19 56 39.6±5.8 15 36.7 ±6.6 39 49.5±10 10 40±6.5 55

30 38±8 10 57

52 47.4±8 Total 213 Av.: 43.4

Number of Mean Age of Number of Mean

Age of Stored Blood Analyses Blood Sugar Stored Blood Analyses Blood Sugar

days mg. per 100 cc. days mg. per 100 cc.

256 60 289±17

15 295±33 40 266±25

11 276± 59 211

31 326±34 10 160

55 290±21 Total 223 Av.: 286
206 THE PHYSIOLOGIC EFFECTS OF WOUNDS

CHART 30. Relationship between Plasma

Hemoglobin and Blood Sugar in Blood

Stored Days—52 Samples

CHART 31. Relationship between Plasma

Hemoglobin and Blood Sugar in Blood

Stored Days

CHART 32. Relationship between Plasma

Hemoglobin and Blood Sugar in Blood

Stored Days

CHART 33. Relationship between Blood

Sugar and Age of Stored Blood—223

Samples
PIGMENT MOBILIZATION 207

Plasma Hemoglobin” Levels in Wounded M.en

The pattern of plasma “hemoglobin” (benzidine-reacting material) levels in

severely traumatized men is shown in Charts 34 through 37. In Chart 34, based

upon findings in 133 patients, the mean plasma hemoglobin level for each day

after injury is plotted. From an initial figure of 10 mg. per 100 cc., it climbs in

72 hours to 17.3 mg., then slowly falls in the course of the next 13 days to

level of mg. per 100 cc. of plasma. Chart 35 shows daily mean levels of 64 patients who had high azotemia, over half of whom died. The curve is essentially similar, though the peak is higher and is delayed 24 hours. In Chart 36 only the fatal cases with histologically proved pigment nephropathy are shown,

exclusive of crush cases. In this group the peak is sharp and high, occurring at

24 hours and attaining maximum of 36.8 mg. per 100 cubic centimeters. This

figure is still far below the generally accepted threshold level of 135 mg. per

100 cc. at which normal kidney begins to excrete hemoglobin.

The plasma bilirubin level as determined by the van den Bergh diazo test

has also been plotted on these charts, omitting cases of direct liver trauma. As

would be expected, the bilirubin curve roughly paralleled that of hemoglobin

but its peak occurred from to days later. Strict parallelism could not be expected since the bilirubin level is also affected by efficiency of liver function;

evidence of liver injury in these patients is presented in Chapters II and XII.

In considering the significance of the plasma hemoglobin levels, two possible

relationships at once come to mind: does the level depend upon the severity of

shock? or upon the quantity of blood the patient was given? The answer is

not obvious since the patients with the most severe shock usually received the most blood. Available evidence compiled from the first specimen of blood obtained for analysis is presented in Table 86. The following cases have been

excluded: all crush cases, in which benzidine-reacting pigment in the plasma

Gilligan, D. R., and Blumgart, H. L.: March hemoglobinuria; studies of clinical characteristics,

blood metabolism and mechanism, with observations on three new cases, and review of the literature.

Medicine 20: 341-395, September 1941.

Gilligan, D. R.; Altschule, M. D., and Katersky, E. M.: Studies of hemoglobinemia and hemoglobinuria produced in man by intravenous injection of hemoglobin solutions. J. Clin. Investigation 20:

177-187, March 1941.

Ottenberg, R., and Fox, C. L., Jr.: Rate of removal of hemoglobin from circulation and its renal

threshold in human beings. Am. J. Physiol. 123: 516-525, August 1938.
208 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

86.

—Mean Plasma

“Hemoglobin” Levels in

Relation to

Shock

and

Quantity of

Transfused

Blood

76

Cases Plasma

Hemoglobin Levels

Quantity

of

Blood

Received

Blood

Specimen

Drawn

Less

than

24

Hours

after

Injury

Blood

Specimen

Drawn

24-96

Hours

after

Injury

(units)

Shock

Total

Shock

Total

Minimal

Moderate-Severe

Cases

Minimal

Moderate-Severe

Cases

None

12.4

9.8 (7

cases)

11.1 (14

cases)

9.2 (5

cases)

9.2 (5

cases)

(7

cases)

to

14.0 (2

cases)

8.7 (20

cases)

9.2 (22

cases)

16.0 (10

cases)

12.4(3

cases)

15.1 (13

cases)

to

14

6.8

7.9 (3

cases)

7.5 (5

cases)

20.5

20.5 (17

cases)

(2

cases)

(17

cases)

Average

11.7(11

cases)

8.8 (30

cases)

9.6 (41

cases)

16.0 (10

cases)

17.3 (25

cases)

16.9(35

cases)

Mg.

of

benzidine-reacting material per

100

cc.

of

plasma.

Determinations basedon

first

blood

specimen

obtained

for

this

analysis.
PIGMENT MOBILIZATION 209

Chart 34. Average Levels of Plasma “Hemoglobin” and Bilirubin Related

to Time from Wounding in 133 Severely Wounded Patients

Plasma “hemoglobin”: Benzidine-positive material

may be assumed to have been predominantly myoglobin, all cases in which the

initial specimen was not obtained within days of injury, and Case 37 with

several plasma hemoglobin levels above two hundred. This figure was so completely out of line with all other cases that unique and unexplained mecha-
210 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chart 35. Average Levels of Plasma “Hemoglobin” and Bilirubin

Related to Time from Wounding in 64 Patients with High Azotemia

Plasma “hemoglobin”; Benzidine-positive material.

High azotemia: Plasma N.P.N. level of 65 mg. per too cc. or higher. Over half of these patients died.

nism of hemolysis must be assumed. Seventy-six cases were available for analysis

after these exclusions.

In compiling the table, the patients were divided into three groups: (i) those

who had received no blood transfusion prior to drawing of the first blood specimen for analysis; (2) those who had received small to moderate amounts of

blood—from to units or 500 to 1,500 cc.—and (3) recipients of large quan-
PIGMENT MOBILIZATION 211

Chart 36. Average Levels of Plasma “Hemoglobin” and

Bilirubin Related to Time from Wounding in 33

Patients with Pigment Nephropathy at Necropsy

Plasma “hemoglobin”: Benzidine-positive material. Cases 9, 41, 85, 115, 116, 132, and A-30 are

omitted.

titles of blood—from to 14 units or to liters. Shock had been estimated

in three grades of severity, and there were few patients without shock. The

956507 0—52 15
212 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chart 37. Average Levels of Plasma “Hemoglobin” and

Bilirubin Related to Time from Wounding in 107 Patients of Blood Groups or

Mean plasma hemoglobin, 56 cases, blood group

(cases 32, 45, and A-series omitted.

Mean plasma hemoglobin, 5/ cases, blood group

(cases 9,44,5! and A-series omitted.

Mean bilirubin, 56 cases, group

Mean bilirubin, 5/ cases, group

number of cases in some shock categories was so small, however, that only two

categories were utilized: (i) patients with no shock or only slight shock (the

“minimal-shock” group), and (2) patients with moderate or severe degrees of

shock. Data are shown separately for blood samples drawn within 24 hours of

injury and those taken from 24 to 96 hours after injury.

It is apparent from inspection of the table that plasma hemoglobin levels
PIGMENT MOBILIZATION 2I

during the first 24 hours after injury showed no elevation which could be attributed either to shock or to infusion of bank blood. The mean plasma hemoglobin

level for the entire group examined within 24 hours of injury was 9.6 mg. per

100 cc. of plasma, normal figure for the technique used (See Materials and

Methods). The mean for the moderate-and-severe shock group (8.8) was actually lower than the mean (11.7) of the minimal-shock group. More surprising

are comparisons based on the quantity of transfused blood. The plasma hemoglobin levels actually appear to decline from mean of 11.1 mg. per 100 cc.

in the 14 patients who had received no blood to 9.2 in 22 patients who had had

from to transfusions, and minimum level of 7.5 in the patients who had

received the largest quantities of blood—from to 14 units. These apparently

paradoxical differences are not statistically significant, but it is clear that in this

study no evidence emerged to indicate that during the first 24 hours after

injury infused hemoglobin from stored blood produced any rise in plasma

hemoglobin concentration.

In the succeeding days, from 24 to 96 hours after injury, some rise in plasma

hemoglobin was usually apparent. The average for the 35 cases in this category

was 16.9 mg. per 100 cc. of plasma. Once again no evidence was obtained that

shock per se produced any mobilization of hemoglobin. The mean of 17.3 mg.

per 100 cc. for the moderate-and-severe shock group is not appreciably greater

than the 16 mg.-figure for the minimal-shock category. In contrast to the findings in the first 24 hours, however, there does appear to be evidence that the

plasma hemoglobin level rose in proportion to the quantity of transfused blood.

It rose from mean of 9.2 mg. per 100 cc. in the patients who had received

no blood, to 15. in those who had received from to units, and to 20.5 in

the patients treated with or more transfusions. The difference between the

first and third of these means, 11.3, is more than three times the standard error

of 3.08.

In summary, the initial plasma free-hemoglobin levels of 76 wounded men

who had had various degrees of shock, and who had received from none to

14 units of bank blood before the first sample of plasma was obtained for analysis, showed no rise in plasma hemoglobin concentration within days after

injury that could be attributed to the state of shock. During the first 24 hours

after injury, the plasma hemoglobin concentration was surprisingly constant

regardless of the amount of blood the patients had received. Hemoglobin in

solution in the plasma of the infused bank blood was therefore not sufficient
THE PHYSIOLOGIC EFFECTS OF WOUNDS 214

to raise the plasma hemoglobin level of the recipient. After the first 24 hours,

plasma hemoglobin levels did rise in the majority of patients. This rise could

not be correlated with the degree of shock but did show an apparently significant correlation with the amount of transfused blood. Such delayed hemolytic

action could be due either to nonspecific, accelerated hemolysis of the infused

group red cells or to hemolysis of the recipients’ red cells from accumulation

of infused iso-agglutinins. Evidence bearing upon this possibility will be presented in the following section.

Is o-Agglutinins

Relationship to Pigment Nephropathy

In Chart 37, the mean plasma hemoglobin level of 56 patients belonging

to blood-group is compared with that of 51 patients belonging to bloodgroup O. distinct peak in the former curve on the third and fourth days after

injury is apparent. On the third day the mean level in the group was 24 mg.

of hemoglobin per 100 cc. of plasma as compared with 10 mg. per 100 cc. for

the group at the same period. The difference is large enough to indicate some

degree of hemolysis due to No reason is apparent for the rather

surprising delayed rise in plasma hemoglobin concentration in the group,

which appears on the eighth day. The precipitate character of this peak, with its

sudden rise and drop and the lack of equivalent rise in the plasma bilirubin,

suggests that this may reasonably be ascribed to inadequate sampling or technical

error.

Relationship to Lower Nephron Nephrosis

If hemolysis due to iso-agglutinins in plasma or bank blood were of importance in the pathogenesis of lower nephron nephrosis, the lesion should have

appeared with greater frequency in our patients of blood-groups A, B, and AB

than in those of group O, since all transfusions, with the two exceptions previously noted, were of blood. No evidence was obtained of any relationship

of blood group to case fatality or to development of renal insufficiency.

Blood grouping in the 186patients in the study was checked in our laboratory

in 137 instances. The distribution of blood groups among these 137 patients is
PIGMENT MOBILIZATION 215

shown in Table 87, both for all cases and for fatalities. It is evident that in both

categories the distribution approximates closely the usual figures for sample

of the American population. Equally negative evidence of any effect of blood

group is shown when the fatal cases of lower nephron nephrosis are considered. Blood group was known in 37 such cases which are shown on the table.

It is evident that the distribution again approximates that of an average population.

Table 87.—Distribution of Blood Groups (Checked) among all Patients,

those Dying from all Causes, and those Dying from Renal Failure

Hemoglobinuria and Myoglobinuria in Wounded Men

Relationship of Plasma Hemoglobin Levels to Excretion

of Hemoglobin in the Urine

Excretion of hemoglobin in the urine is dependent upon two factors: the

concentration of hemoglobin in the blood plasma and the permeability of the

glomerular filter. As has already been pointed out, only one patient, Case 37,

(crush cases excluded) showed plasma hemoglobin concentration above 135

mg. per 100 cc., the usually-accepted threshold level for hemoglobinuria. An

altered permeability of the glomeruli must therefore be assumed in all other

patients manifesting hemoglobinuria. If the increase in permeability was more

All Cases in

which Blood Group

was Checked

All Fatal Cases

in which Blood

Group was Checked

Fatal Cases with Pigment

Nephropathy in which

Blood Group was Checked

Blood Group (137 Cases) (57 Cases) (37 Cases)

Number

of

Patients

Percent

Number

of

Patients

Percent

Number

of

Patients

Percent

55 40.1 23 40.3 17 46.0

59 43.1 27 47.4 16 43.2

13 9.5 7.0 5.4

AB 10 7.3 5.3 5.4

Total patients on whom blood grouping was rechecked in our laboratory.

Blood group was not checked in of the 38 cases of proved pigment nephropathy.
216 THE PHYSIOLOGIC EFFECTS OF WOUNDS

or less constant, it might be expected that the degree of hemoglobinuria would

be influenced by the level of plasma hemoglobin. If the alteration in permeability was variable, no such relationship would be demonstrable.

The concentrations of hemoglobin in plasma and urine are compared in

Table 88 for 21 cases in which the two determinations were made upon samples

collected at approximately the same time. The possibility that the urine might

have been retained within the bladder for many hours before voiding could not

always be excluded. No evidence of correlation is present, and the Spearman

rank order coefficient of correlation (rho) is 0.03, indicating only chance relationship between the two series of figures.

Table 88.—Comparison of Hemoglobin Concentration in Plasma and Urine

in 21 Cases

Excretion of Myoglobin in the Urine

Analyses for hemoglobin and myoglobin in the urine were carried out in

42 cases in which measurable amounts of benzidine-positive material were

present. Myoglobin was positively identified in 19 cases and was the dominant

pigment in nine. (Comparison was impossible in of these because wounds

of the urinary tract made urine hemoglobin figures unreliable.) In additional

cases the test for myoglobin was positive but the proportion found was so small

(from 10 to 20 percent of the benzidine-reacting material) that the results were

classed as doubtful and were disregarded. The analyses in the remaining 15

cases were recorded as definitely negative (myoglobin from to 10 percent).

Case

No.

Plasma

"Hemoglobin”

Urine

Hemoglobin

Case

No.

Plasma

"Hemoglobin”

Urine

Hemoglobin

22.3 110.0 62 4.0 12.2

13 6.0 8.0 64 2.7 1.9

18 18.5 12.4 71 68.0 80.8

19 20.5 4.0 86 13.4 8.7

22 9.2 193.0 89 4.0 3.8

34 2.8 13.8 95 44.6 10.5

38 4.3 92.0 108 11.7 6.0

41 34.6 5.9 112 6.5 8.5

49 13.5 11.0 123 25.0 3.0

54 5.3 18.7 125 8.7 15.0

57 6.1 25.8
PIGMENT MOBILIZATION 217

The 19 positive cases are listed in Table 89 together with the degree of shock,

the concentration of myoglobin and hemoglobin in the urine, the level of

benzidine-positive material in the blood plasma, and the major clinical diagnoses.

Table 89.—Occurrence of Myoglobinuria and Correlative Findings in 19 Severely Wounded Patients

Inspection of this table reveals several points of interest. As in the case of

hemoglobinuria, it is obvious that there is no correlation between the level of

benzidine-positive material in the plasma and the amount of myoglobin excreted in the urine. For example, in Case 38 only 4.3 mg. per 100 cc. were found

Urine Plasma

Case

No.

Degree of

Shock Myoglobin Hemoglobin

BenzidinePositive

Material

Major Diagnosis

mg.per 100 cc. mg.per 100 cc. mg. per 100 cc.

Severe .... 16.0 10.3 Gas gangrene; peritonitis.

None .... 16.0 2.5 5.5 Lacerated femoral artery; anastomosis.

do 4.0 11.4 3.1 Thoracic wounds; transfusion reaction.

19 Moderate 4.0 3.5 20.5 Traumatic amputation; gas gangrene.

25 Severe .... 72.0 24.5 Abdominal wound; peritonitis.

37 Moderate 1.0 2.5 266.0 Thoracic and liver wounds.

38 Severe .... 420.0 92.0 4.3 Volvulus.

49 do 3.0 11.0 13-5 Abdominal wound.

69 None .... 588.0 0.0 37.6 Crush syndrome.

70 do 288.0 142.0 8.2 Do.

74 Slight .... 147.0 61.0 38.2 Burn.

78 do 2.5 2.1 920.0 Crush syndrome.

88 Severe .... 36.6 7.4 Abdominal and extremity wounds;

peritonitis.

89 do 1.5 3.8 4.0 Traumatic amputation.

93 do 67.0 80.0 30.0 Crush syndrome.

97 do 205.0 5.0 Abdominal wound; peritonitis.

98

126

30.0

7.0

Abdominal and cerebral wounds.

do 9.3 Thoraco-abdominal wound; peritonitis.

137 None .... 203.0 41.0 38.4 Lacerated femoral artery.

Blanks in this column indicate that wound of the urinary tract rendered the determination useless for

purposes ofcomparison.
2l8 THE PHYSIOLOGIC EFFECTS OF WOUNDS

in the plasma, while the urine contained the enormous concentration of 420 mg.

per 100 cubic centimeters. In Case 78, patient with crush syndrome, the situation was reversed. The plasma concentration was 920 mg. per 100 cc., the maximal figure of the entire series, whereas the urine contained barely enough to

measure—only 2.5 milligrams.

If the myoglobinuric cases are considered as whole, the degree of myoglobinuria shows no relationship to the severity of shock. In the “minimal-shock”

group (as previously defined), the concentrations of myoglobin in the urine

ranged from 2.5 to 588.0 mg. per 100 cubic centimeters. In the moderate-andsevere shock group, the range was from to 420 mg. per 100 cubic centimeters.

The average of seven cases in the minimal-shock group was 321 mg. in comparison with 63.7 mg. for the more severe-shock group, but with such wide

variation in the data the averages are meaningless.

Table 90.—Relationship of Muscle Necrosis to Shock

in 19 Patients with Myoglobinuria

When the nature of the major injury or lesion in these myoglobinuric cases

is taken into consideration, however, an interesting correlation does become

apparent. The cases fall readily into two groups: those with extensive necrosis

of skeletal muscle (either ischemic or infectious) and those without such muscle

necrosis. They are so listed, with the estimated degrees of shock, in Table 90.

Five of nine patients with extensive necrosis of skeletal muscles showed

minimal or no clinical evidence of shock; in those without extensive muscle

With Muscle Necrosis Without Muscle Necrosis

Case No. Degree ofShock Case No. Degree of Shock

69 None. 74 Slight.

70 Do. 37 Moderate.

Do. 98 Do.

137 Do. 126 Do.

78 Slight. 25 Severe.

19 Moderate. 38 Do.

93 Severe. 49 Do.

89 Do. 88 Do.

Do. 97 Do.

None.
PIGMENT MOBILIZATION 219

necrosis, in contrast, eight were in the moderate-and-severe shock group and

only two in the minimal-shock group. One of the latter, Case 74, with extensive

burns showed sufficient hemoconcentration to suggest more severe grade of

shock than was clinically apparent. These findings strongly suggest, on the one

hand, that myoglobin is rarely liberated in the absence of shock unless there has

been extensive necrosis of skeletal muscle, and on the other, that in the presence

of severe shock, there is some mechanism for its mobilization other than muscle

necrosis.

Relationship of Hemoglobinuria to Myoglobinuria

Attempts to correlate the variety of pigment excreted in the urine with

the type of injury or lesion provided extremely puzzling results, as may be seen

from the tabulation to follow in which cases have been classified by the predominant pigment, though many of them showed simultaneous excretion of

both pigments. Because of the frequency of multiple injuries, the same case has

often been included under more than one heading. Cases of trauma to the

urinary tract have been excluded from the hemoglobinuric but not from the

myoglobinuric category.

It is at once evident that any type of injury may be associated with either

hemoglobinuria or myoglobinuria and that in most types, except the crush syndrome and in clostridial myositis, the former is by far the more common. It

is noteworthy that in two typical crush cases no evidence of myoglobin excretion was obtained (see Chapter XI). Neither massive trauma to the extremities

nor interruption of major vessel, with consequent ischemic necrosis of muscle,

Type of injury or complication

Number

predominantly

Number

predominantly

Crush syndrome

hemoglobin myoglobin

Wounds of extremity

Major vascular interruption II

Clostridial myositis

Urinary tract injury

Liver injury

Abdominal wound II

Peritonitis

Burn

Volvulus
220 THE PHYSIOLOGIC EFFECTS OF WOUNDS

usually resulted in predominant myoglobinuria, and in two of the three patients in whom it did appear, successful arterial anastomosis had re-established

circulation of the leg before myoglobinuria was observed. In three patients (Case

70, extensive but superficial burns; Case 38, volvulus, and Case 9, mismatched

transfusion) injury of voluntary muscle can be absolutely excluded. In considering the findings, however, it must be remembered first that our test for myoglobinuria was crude and results were recorded as positive only when considerable quantities of myoglobin were present, and second that myoglobin is

rapidly excreted in the absence of renal insufficiency and the loss of single

urine specimen might cause falsely negative result.

Table 91.—Greatest Concentrations of Hemoglobin and Myoglobin

Observed in the Urine

One final comparison is of interest. In Table 91 the 12 patients showing the

highest concentrations of hemoglobin and the 12 with the highest myoglobin

concentrations are listed. As before, cases of trauma to the urinary tract have

been eliminated from the hemoglobinuric category. It is apparent from these

figures that myoglobinuria was frequently massive whereas hemoglobinuria was

rarely so when cases of direct trauma to the urinary tract are eliminated. It

is also noteworthy that four cases (Cases 38, 70, 74, and 93) appear in both

lists, suggesting that the conditions for the liberation of myoglobin and of hemoglobin may not be unrelated.

Case No.

Hemoglobinuria

mg. per 100 cc.

Case No.

Myoglobinuria

mg. per 100 cc.

22 193 69 588

70 142 38 420

109 123 70 288

110 97 205

56 110 137 203

38 92 147

71 81 25 72

93 80 93 67

61 88 37

72 58 98 30

118 38 16

128 34 16

Highest of number of determinations in each case.

Cases that appear in both columns.
PIGMENT MOBILIZATION 221

SUMMARY

The concentration of benzidine-reacting heme pigment in the blood plasma

(recorded as plasma hemoglobin) and the individual concentrations of hemoglobin and myoglobin in the urine were measured in our patients to determine

the extent of pigment mobilization. These data, together with determinations

of plasma hemoglobin in the bank blood administered to the patients, were

analyzed in an attempt to determine the mechanism of pigment mobilization

in the body and of pigment excretion by the kidney.

It was found that the bank blood used in therapy was in satisfactory state

of preservation, with an average of only 43 mg. of free hemoglobin per 100 cc.

of plasma at the moment of utilization. Even in patients who received as many

as 10 to 14 transfusions, the plasma “hemoglobin” levels of the recipients showed

in the first 24 hours no elevation which could be attributed to free hemoglobin

in the transfused blood. Comparison of the plasma hemoglobin concentrations

with the degree of shock in 76 patients showed no evidence that shock itself

induced any immediate increase in plasma hemoglobin concentration.

Twenty-four hours after injury, however, progressive rise in plasma hemoglobin began to be apparent which reached peak between 48 and 72 hours

and then slowly dropped to normal over period of weeks. This peak was

approximately twice as high (36.8 mg. per 100 cc.) in 33 cases of fatal nephropathy as in the series as whole (17.3 mg. per 100 cc.) and occurred only 24

hours after wounding. No evidence was obtained that it was higher in patients

with severe shock than in those without shock or with only minimal shock. It

was, however, significantly higher in patients who had received multiple transfusions than in those who had received no blood.

Evidence that this delayed rise in plasma hemoglobin was largely due to

iso-agglutinins was afforded by comparison of group and group recipients.

In 56 of the former, the mean plasma hemoglobin on the third day was 24 mg.

per 100 cc., whereas in sample of 51 group recipients the corresponding

level was only 10.2 milligrams. This difference was of no significance, however, in the development of pigment nephropathy as shown by the percentage

distribution of blood groups among the nephropathies, which was essentially

identical with the distribution of blood groups in the entire series of cases

studied by the Board and with an average sampling of the American population.

In 21 cases in which plasma hemoglobin levels were obtained at approxi-
222 THE PHYSIOLOGIC EFFECTS OF WOUNDS

mately the same time that the first urine specimen was voided, the concentrations of pigment in the two fluids were compared. No evidence of correlation

was found. It was concluded that the threshold of hemoglobin excretion in

wounded men must vary over wide range.

Myoglobin was positively identified in the urine of 19 patients in the series

and these cases were subjected to special scrutiny. As in the case of hemoglobin,

no correlation was found between the concentrations of benzidine-reacting pigment in the plasma and of myoglobin in the urine.

With the exception of clear-cut cases of the crush syndrome, excretion of

myoglobin could not be predicted from the nature of the patient’s injury or its

complications. It was rarely seen in wounds of the extremities, even those associated with extensive necrosis of muscle, unless they were complicated by clostridial myositis, or, as in two cases, circulation was re-established after period

of ischemia by successful arterial anastomosis. It was sometimes very severe in

patients with little or no muscle damage. When muscle damage was extensive,

the mobilization and excretion of myoglobin appeared to be independent of the

development of shock. When there was insignificant or no muscle injury, myoglobinuria was rarely found in the absence of moderate or severe shock.

Two further observations are noteworthy though their significance is not

apparent. Myoglobinuria was frequently massive, hemoglobinuria rarely so in

the absence of injury to the urinary tract. Myoglobinuria and hemoglobinuria

of significant degree frequently occurred in the same patient, suggesting common but undiscovered mechanism.

CONCLUSIONS

1. Neither the development of shock nor the therapeutic use of multiple

transfusions of group bank blood produced immediate elevation of the

plasma “hemoglobin” levels in severely wounded men.

2. The delayed rise in mean plasma “hemoglobin” for the series as whole

in the period from 24 to 96 hours was largely attributable to iso-agglutinins in

the bank blood, since it was absent in sample of 51 recipients.

3. Mean plasma “hemoglobin” concentrations were higher in the patients in

whom pigment nephrosis developed than in other wounded men but were still

far below the threshold level at which the normal kidney excretes hemoglobin.
PIGMENT MOBILIZATION 223

depression of the threshold for hemoglobin excretion must be assumed.

4. The lack of correlation between concentrations of benzidine-reacting pigment in the plasma and of hemoglobin or myoglobin in the urine suggests that

this alteration of threshold was variable.

5. The irregularity with which extensive muscle injury was followed by

myoglobinuria indicates that some factor other than necrosis of muscle cells

is involved. This factor is not shock and appears to be the maintenance or

re-establishment of the circulation in the involved muscles.

6. In small number of cases severe myoglobinuria developed in the absence of demonstrable muscle injury. The almost constant presence of moderate

or severe shock in such cases suggests the possibility of diffuse ischemic injury

of muscle which is not morphologically recognizable.

7. The fact that severe myoglobinuria and severe hemoglobinuria were often

observed in the same patient suggests the possibility of common mechanism.
CHAPTER IX

Pathology of the Kidney

in Traumatic Shock

The kidney lesion associated with the clinical syndrome ofrenal insufficiency

following resuscitation from shock is constant but not pathognomonic. Lucke,

in study of material from the Army Institute of Pathology, has shown that

similar lesion, which he has called “lower nephron nephrosis,” develops in

variety of conditions such as mismatched blood transfusion, infusion of human

hemoglobin, the crush syndrome, heat stroke, blackwater fever, thermal burns,

carbon tetrachloride poisoning, mushroom poisoning (Amanita phalloides and

sulfonamide sensitivity. The author, from his own experience, can add to the

list of etiologic agents chemical burns, anaphylactic shock following therapeutic use of antipneumococcus rabbit serum, and hemolytic reactions following

transurethral resections in which the operative field is irrigated with tap water.

Many years ago F. B. Mallory noted the lesion in an occasional patient with

hemolytic streptococcus infection. There can be little doubt that with increasing

breadth of experience many other causal agents will be brought to light.

Descriptions of the lesion in various stages may be found in innumerable

case reports under such titles as transfusion kidney, hemoglobinuric nephrosis,

interstitial nephritis, hepatorenal syndrome, and other terms, but surveys of

Luck£, B.: Lower nephron nephrosis (renal lesions of crush syndrome, of burns, transfusions, and

other conditions affecting lower segments of nephrons). Mil. Surgeon 99: 371-396, November 1946. Mallory, F. B.; Personal communication.

DeNavasquez, S.; Excretion of haemoglobin, with special reference to “transfusion” kidney. J. Path.

Bact. 51: 413-425, November 1940.

Mallory, T. B.: Hemoglobinuric nephrosis in traumatic shock. Am. J. Clin. Path. 17: 427-443,

June 1947.

Kimmelstiel, P.: Acute hematogenous interstitial nephritis. Am. J. Path. 1-4 737-761, November

1938."Helwig, F. C., and Orr, T. G.: Traumatic necrosis of liver with extensive retention of creatinine and

high grade nephrosis. Arch. Surg. 24: 136-144, January 1932.
PATHOLOGY OF THE KIDNEY 225

any considerable mass of material are few. The most notable contributions are

those of Lucke and of Bywaters and Dible in their studies of the crush syndrome. The present study is based primarily on review of material from 60

out of 63 necropsies on patients studied by the Board, but is fortified by experience gained from review of more than 150 similar nephropathies at the 15th Medical General Laboratory. The records and material from the 60 cases, correlated with the clinical and biochemic data, provided the means for surveying

the lesion in all stages of development as manifested in wounded soldiers resuscitated from shock by human plasma or whole blood transfusions.

Microscopic Pathology

The characteristic features of the lesion emphasized to greater or lesser

degree by different authors are seven: pigment casts; internal hydronephrosis;

degeneration of epithelial elements, particularly in the lower segments of the

nephrons; rupture of tubules with extrusion of their content into the stroma;

interstitial inflammation; granulomatous inflammation, and thrombophlebitis

of small intrarenal veins. Let us examine them successively.

Pigment Casts

Pigment casts, as in other forms of lower nephron nephrosis, are the most

conspicuous feature of the “shock kidney.” They were present in all cases of

proved renal insufficiency in the present series in which the survival period

was days or longer. Their absence in many of the more acute cases is an interesting feature which will be considered later.

The pigment casts were found in the distal convoluted and collecting tubules

and in the ducts of Bellini, their relative frequency in these respective locations

varying considerably from case to case. The number of nephrons involved was

difficult to estimate inroutine sections, since only portions of each nephron were

visualized. In most cases with clinically demonstrated renal insufficiency, the

proportion was obviously high but the range was wide, probably from 20 to

80 percent.

See footnote i.

®BywATERs, E. G. L., and Bible, J. H.: Renal lesion in traumatic anuria. J. Path. Bact. 4: 111-120,

January 1942.
226 THE PHYSIOLOGIC EFFECTS OF WOUNDS

The pigment, when viewed in unstained sections or sections only lightly

stained with hematoxylin, shaded from orange through orange-green to

muddy greenish-brown. It might precipitate as separate coarse globules to

microns in diameter (which are frequently mistaken on casual examination for

red blood cells); as ropes of globules, rather like strings of sausages; or as granular debris usually embedded in cast-like matrix. The staining reactions of the

pigment were not consistent. portion of it almost always showed the usual

staining reactions of hemoglobin; namely, an affinity for eosin and for the

fuchsin in the Masson trichrome, dense blue color with phosphotungstic acid

hematoxylin, and positive benzidine reaction. Another portion of the pigment,

indistinguishable in the unstained or eosin-stained preparations, failed to accept

the fuchsin in the Masson or the hematoxylin in the phosphotungstic stain, and

was benzidine-negative. Characteristic staining reactions with hematoxylin and

eosin, phosphotungstic acid hematoxylin, and Masson trichrome are illustrated

in Figures 1, 2, and 3.

Although there were some exceptions, two generalizations could be made

regarding the staining reactions of the pigment: First, the shorter the time

interval between injury and death, the greater was the proportion of pigment

which gave the staining reactions of hemoglobin. Second, the farther down the

nephron the pigment was located, the less was this tendency. Figures and

illustrate this difference in the pigment casts of the cortex and medulla. The

obvious conclusion is that with the passage of time and with the chemical

changes in the glomerular filtrate as it passed along the tubule, the original

hemoglobin-like material was altered, presumably by process of degradation

in the direction of acid hematin. This degradation never reached the point where

iron could be demonstrated with the ferrocyanide reaction. One other differential point has been noted: The hemoglobin-like pigment rarely excited significant inflammatoryreaction, whereas the altered pigment sometimes attracted

leukocytes in considerable number (Fig. 6).

Internal Hydronephrosis

Many authors have described marked dilatation of portions of the nephron

above the obstructing pigment casts. Their illustrations often show great dilatation of proximal tubules and of Bowman’s capsule. Our experience suggests

that this apparent dilatation is largely shrinkage artefact. If formalin-fixed

kidney tissue is rapidly dehydrated and embedded in paraffin, shrinkage is
PATHOLOGY OF THE KIDNEY 227

difficult to avoid. The glomeruli appear as tiny spheres occupying less than half

of the capsular space, and the diameter of the lumen of the proximal tubules

is from 50 to 70 percent of the external diameter of the tubule. If the tissue is

Zenkerized before embedding, the shrinkage is reduced and primary embedding

in Zenker-formol or in Zenker with acetic acid lessens it still further. In such

sections Bowman's capsule is rarely dilated, although some dilatation of tubules

may be apparent. still better check upon this debatable issue is provided by

the examination of frozen sections in which the factor of dehydration is excluded.

The following statements are based primarily upon the examination of frozen

sections which were prepared from almost every case in this series. No dilatation of Bowman’s capsule was observed, but tubular dilatation of moderate

but unmistakable degree was usual, with the proximal convoluted tubule the

segment most commonly involved. Dilatation was not observed before the third

day after injury, was almost constant between the third and fifth days, and

became less frequent in the cases with longer periods of survival. Dilatation of

distal convoluted tubules and upper collecting tubules, usually those situated

in the cortical rays, was less common and was ordinarily seen in the more chronic

stages from the sixth day onward. In some cases, however, dilatation was marked

in these segments and minimal or absent in the proximal tubules (Figs. and 8).

Dilatation of proximal tubules, to judge from frozen sections, correlated well

with two characteristic phenomena noted on gross examination: enlargement

of the kidney, particularly widening of the cortex, and wet surface wherever

freshly cut.

Degeneration and Regeneration of Tubular Epithelium

Degenerative changes in the epithelial cells were rare in the proximal tubules,

absent in the descending limb of Henle’s loop, usual in the ascending limb and

the distal convoluted tubule, and inconstant in the collecting tubules. The proximal tubule was usually normal except for slight to moderate dilatation. The

brush border was well maintained, the cells were not swollen, and the cytoplasmic granules were normal in size and distribution. The tubular lumens frequently contained granular nonpigmented precipitate, but this is not surprising in view of the constant albuminuria demonstrable in patients with severe

trauma and constitutes no proof of tubular injury.

In only five cases were the proximal tubules clearly abnormal. In two there
Staining Reactions of Pigment Casts

FIGURE i. Stain: Hematoxylin and eosin.

The glomerulus is normal. The distal convoluted tubules contain orange colored casts

of precipitated hemoglobin. 330

FIGURE 2. Stain: Masson trichrome. The

casts stain deep red as do red cells with this

stain. 330

FIGURE 3. Stain: Phosphotungstic acid

hematoxylin. The deep blue staining of the

pigment casts is characteristic of the reactions of hemoglobin with this stain. The

proximal convoluted tubules are dilated

and contain precipitated albumin, but the

epithelial cells show no degenerative

changes. 330
Staining Reactions of Pigment Casts

FIGURE 4. Stain: Phosphotungstic acid

hematoxylin. Renal cortex, low magnification, showing blue-staining casts in the distal convoluted tubules. The proximal tubules are uniformly slightly dilated and

contain precipitated albumin but they are

otherwise normal. 80

FIGURE 5. Stain: Phosphotungstic acid

hematoxylin. Section from the kidney pyramid of the case shown in Figure 4. This

patient died days after injury. considerable proportion of the pigment casts have

lost theirability to stain blue with the phosphotungstic acid stain. 80

FIGURE 6. Stain: Masson trichrome. Note

the acute exudation into the distal tubules

about the masses of pigment which have

begun to lose their hemoglobin-like staining reactions. 200
THE PHYSIOLOGIC EFFECTS OF WOUNDS 3°

was extensive fat vacuolation; in the two others the cells were swollen, the

brush border was obscured, and the cytoplasm filled with hyaline, presumably

albuminous droplets. Nothing in the clinical picture served to distinguish these

cases from others of the series. The infrequency of albuminous droplets in the

cells of the proximal tubules under conditions of marked albuminuria might

be interpreted as evidence of failure of resorptive function in this segment of the

nephron. Such functional paralysis would also explain the surprising fact that

only once in 200 hemoglobinuric cases was absorption of hemoglobin by the

proximal tubules observed. In one instance (Case 86) there were numerous foci

of complete coagulative necrosis of proximal tubular epithelium. The possibility

of direct traumatic injury of the kidneys could not be excluded here.

The descending limbs of Henle’s loops frequently contained considerable

amounts of orange pigment, which was not iron-positive with ferrocyanide but

accepted the fuchsin counterstain as does so-called hemofuchsin. It was sometimes weakly sudanophilic, and because of its orange-yellow color was difficult

to distinguish from fat in Sudan preparations. Since this pigment was also frequently found in cases of sudden death used as controls, we believe it to be

normal phenomenon.

The earliest and most frequent evidence of tubular degeneration appeared

in the form of fat vacuolation in the ascending limbs of Henle’s loops. The

vacuoles were extremely small, mostly from to microns; were hard to identify

in paraffin sections; were intensely red infrozen sections stained with Sudan IV;

and were not doubly refractile under polarized light. In some cases they were

found only in limited segment of the ascending limb, always the portion

closest to the corticomedullary junction; in others the process extended almost

to the apex of the pyramid, involving the entire ascending limb (Figs. and 10).

rough quantitation of the severity of this change was attempted by visual

estimation, using 1- to 4-plus scale.

Well-marked (2- to 4-plus) fat vacuolation was present in of cases in

this study in which death followed injury bv less than 48 hours, including Case

77 with survival period of only 20 hours. It was present, usually in 3- or 4-plus

grade, in 14 of the 15 cases in which death occurred between the second and

fourth days. From the fifth day onward it decreased in frequency and intensity;

it was found in only 14 of the 27 cases and in only was it above 2-plus grade.

more extensive discussion of this process will be found in Chapter XII in

connection with similar observations on other organs.
Internal Hydronephrosis

FIGURE 7. (Left) Moderate dilatation of both proximal and distal convoluted tubules is

shown in case of days’ duration. rare sulfonamidecrystal is present. Stain: Hematoxylin

and eosin. 150

FIGURE 8. (Right) Marked dilatation of the distal convoluted tubules with comparatively

slight widening of the proximal ones is apparent. Stain: Hematoxylin and eosin. 180

Staining Reactions of Fat

FIGURE 9. (Left) Stain: Sudan IV. Fat vacuolation limited to segment of the ascending

limb adjacent to the corticomedullary junction. 180

FIGURE 10. (Right) Stain: Sudan IV. Diffuse fat vacuolation of entire ascending limb of

Henle’s loop. 180
THE PHYSIOLOGIC EFFECTS OF WOUNDS 232

Occasionally on the third or fourth day, but always by the fifth, other forms

of epithelial reaction were obvious. The cells became shrunken, their nuclei

pyknotic, and they frequently lost their attachment to the basement membrane

and desquamated. At almost the same period, mitoses became apparent and

sometimes so numerous that two or three were seen in single cross-section of

tubule. These degenerative and regenerative changes were frequently limited to,

and always most severe in comparatively limited zone close to the corticomedullary junction.

Distal Convoluted Tubules.—The distal convoluted tubules in apparently

normal individuals frequently contain small granules of lipid. In some cases

of shock it was evident that the sudanophilic material was increased in amount,

but variation in the normal range makes the significance of this observation very

difficult to assess. By the fourth or fifth day after injury, degenerative and regenerative changes sometimes became apparent in the distal tubule. They were

never as marked or as widespread as in the ascending limbs, but the difference

was quantitative, not qualitative.

Collecting Tubules.—Alterations in the character of the epithelium of the

collecting tubules are difficult to recognize with certainty, since these tubules

are particularly susceptible to postmortem degeneration, including desquamation. Fat stains do not help, since lipoid degeneration rarely occurs. In wellfixed material, however, it was often evident that the cells were hyperchromatic.

Frank necrosis was rarely seen, yet mitoses were not infrequent. In other cases

reduplication of the epithelial layer was evident and sometimes, where no desquamation was apparent, sheets of epithelial cells filled the lumina of the

tubules and encircled or even invaded the pigment casts. Sometimes mitoses

were numerous in these detached or semidetached cells. In the collecting tubules,

in contrast to other segments of the nephron, the epithelial changes closely paralelled the presence of pigment casts in the affected segments.

Interstitial Inflammation

Interstitial inflammation was not noted before the third day; from the third

to the fourth day it was found in half the cases, and from the fifth day onward

it was constant phenomenon. It was first manifested as focal infiltration limited

to fairly narrow zone at the corticomedullary junction. The component cells

were predominantly lymphocytes and plasma cells, but variable proportions of

neutrophils and eosinophils were usually mingled with them (Fig. n). The
Interstitial Inflammation

FIGURE ii. Interstitial inflammatory infiltrate between tubules near the corticomedullary junction in case of days’ duration. Lymphocytes and plasma cells predominate. Stain: Hematoxylin and eosin.

300

FIGURE 12. Stain: Masson trichrome.

Low-power view of corticomedullary junction, showing interstitial edema of moderate grade and both diffuse and granulomatous inflammatory reaction. Some extruded

casts are visible. Case of days’ duration.

X80

FIGURE 13. Case of 12 days’ duration.

The formation of second zone of interstitial inflammatory reaction beneath the

capsule is shown. Stain: Masson trichrome.

150
THE PHYSIOLOGIC EFFECTS OF WOUNDS 34

Tubular Rupture

FIGURE 14. Stain: Masson trichrome. nonpigmented cast found in the process of extrusion from ruptured tubule. The cells of the tubule show pyknosis and reduplication of

nuclei. 250

infiltrate tended to be most marked in the neighborhood of the blood vessels

and also to run in strands between the straight tubules. Edema, though usually

present, was rarely conspicuous feature (Fig. 12). As days passed, the zone of

inflammatory infiltration widened and new foci appeared both in the cortex

and the medulla. In the former, they tended to be concentrated about the distal

convoluted tubules. In few of the most severe lesions, clearly-defined second

zone of inflammatory infiltration was noted in the outer millimeter of the

cortex beneath the capsule (Fig. 13).

Tubular Rupture

The distinctive phenomenon of tubular rupture was generally apparent in

any well-developed lesion from the fifth day onward. It was usually associated

with the presence of hyaline, non-pigmented casts in the affected segment,

which was most commonly the ascending limb but sometimes the distal convoluted tubule. These casts were chromophobic with hematoxylin and eosin

or phosphotungstic acid hematoxylin, but stained fairly bright green in the

Masson trichrome. In the affected segments containing the casts, portions of

the epithelial lining and of the underlying basement membrane disappeared
PATHOLOGY OF THE KIDNEY 35

without trace as if by solution. The casts at this point were frequently seen half

within the tubular remnant and half extruded into the stroma (Fig. 14).

Interstitial Granulomas

In the process of tubular rupture and cast extrusion, the advancing margin

of the cast abutting on the stromal cells was quickly surrounded by histiocytes.

With further extrusion or with complete destruction of the tubular segment,

the cast became completely surrounded by histiocytes which occasionally but

rarely fused to form giant cells (Figs. 15 and 16). The histiocytes soon invaded

the cast and appeared to break it up into comparatively small fragments. It

was possible to observe all stages from the original encapsulation to complete

disintegration, leaving focal aggregate of histiocytes with no trace of the

original cast material (Fig. 17).

Although this process unquestionably accounts for many, perhaps for most,

of the granulomatous lesions found in these kidneys, the evidence is inadequate

to prove that it was the only mechanism for their formation. Granulomas were

frequently found in the walls of veins and occasionally in the capsule of the

kidney, separated from the nearest tubule by apparently intact fibrous tissue

of considerable density. Some of these lesions were quite similar in appearance

to the Aschoff bodies ofrheumatic fever.

Hyaline masses, indistinguishable from the intratubular casts by any staining method tried, were also occasionally found in the walls of veins, even

jutting into the lumen to become the basis for thrombus formation (Fig. 18).

The question whether these represent extruded casts which have wandered

surprisingly from their original location or which have developed in situ in

some entirely different manner cannot be answered at present. It is of interest

that on only one occasion in over 200 cases studied did the author note extrusion

of pigment cast and consequent granuloma formation.

Thrombophlebitis

In considerable proportion of cases of or more days’ duration, thrombi

were readily found in the large but thin-walled veins of the corticomedullary

junction. These thrombi were attached to portion of the vein wall and they

jutted into and narrowed but almost never occluded the lumen. Beneath some

points of attachment mass of hyaline material as described in the preceding
Interstitial Granulomas

FIGURE 15. (Left) granulomatous reaction is developing around several extruded casts.

Stain: Masson trichrome. 250

FIGURE 16. (Right) Beginning collection of histiocytes about an extruded hyaline cast

and invasion of the cast by the same cells. The adjacent tubule shows mitotic figure. Stain:

Phosphotungstic acid hematoxylin. 250

FIGURE 17. (Left) Severe granulomatous inflammatory reaction between the straight

tubules. No trace of an extruded cast persists. Stain: Masson trichrome. 250

FIGURE 18. (Right) Stain: Hematoxylin and eosin. Wall of vein showing hyaline mass

resembling an extruded cast projecting into the lumen with surrounding granulomatous

reaction. 150
PATHOLOGY OF THE KIDNEY 37

paragraph was found; beneath others were well-developed granulomas with

or without traces of hyaline material. The vein walls were frequently invaded

by lymphocytes, polymorphonuclear leukocytes, or eosinophils, apparently extending from focal concentrations of the interstitial infiltrate, such concentrations being characteristically clustered about these veins.

Summary of Histologic Findings in Chronologic Sequence

The earliest change noted in the “shock kidney” was lipoid degeneration

of the ascending limbs of the loops of Henle, which usually made its appearance about 18 hours after injury, progressed in severity until the third day,

then tended to wane. Precipitation of the hemoglobin-like pigment in the distal

convoluted and collecting tubules was infrequently observed short of 24 hours

and was inconstant before 48 hours. The pigment at first stained like hemoglobin but later lost this characteristic. Moderate dilatation of the proximal

convoluted tubules was evident following the development of pigment casts.

By the third and fourth days, an interstitial inflammatory infiltrate and frank

necrobiotic changes in the cells of the ascending limbs were occasionally seen,

and from the fifth day onward both of these findings were constant. Rarely

on the third or fourth day, but usually by the fifth, tubular rupture with extrusion of nonpigmented casts was apparent, and coincidentally stromal granulomas were found in moderate numbers. From the fifth day onward, thrombophlebitis of the small veins was found in an increasing proportion of the cases.

Gross Pathology

The kidney might or might not show gross abnormalities (Figs. 19, 20, 21,

and 22). Enlargement was noted as early as the second day but was not usual

before the fourth. It tended to become more frequent and more extensive with

duration of the lesion; the largest pair of kidneys observed, 625 grams, was

found in Case 93 with the unusual survival period of 13 days. In patients with

from 7- to 10-day survival periods, kidneys weighing up to 500 grams were

usual (Figs. 20 and 21).

Enlarged kidneys were almost without exception pale, whereas kidneys of

normal size, regardless of duration of the lesion, were usually congested. On

section it became apparent that the enlargement was chiefly due to swelling
Gross Appearance of the

Crush Kidney

FIGURE 19. Kidney from Case 70. Death from crush syndrome days after injury. The

pyramids are dark in color, resembling mahogany. The kidney is normal in size and not

swollen.

FIGURE 20:

See page 239.
FIGURE 21. (Left) Kidney from Case 47 after brief fixation in Kaiserling’s fluid. The

patient died of pigment nephropathy days after wounding. The pallor of the organ is

slightly exaggerated by the fixation. The cortex is swollen and the pyramids are almost

chocolate in shade.

FIGURE 22. (Right) Left kidney from case of mismatched transfusion (Case 9) after similar

fixation in Kaiserling’s fluid. Gross appearance is identical with that of Case 47 except for

size. The enlargement of this left kidney was partly due to congenital hypoplasia of its mate.

of the cortex, which would measure from to 12 microns in thickness. The

corticomedullary junction was unusually sharp, since the cortex was pale and

the pyramids either unchanged or darker than normal. zone of intense congestion sometimes further intensified the distinction. constant finding was

the unusual wetness of the freshly cut cortical surface.

Petechial hemorrhages beneath the pelvic mucosa were the only other gross

manifestation which was at all frequent (Fig. 20). They were commonest in

cases of long duration with high grades of azotemia and are reminiscent of

similar hemorrhagic changes in advanced “decompensated’' nephrosclerosis with

renal insufficiency. They may be merely phenomenon of the uremic state.

FIGURE 20. Kidney from Case 69. Death from crush syndrome 10 days after injury. The

organ is markedly swollen. The pallor of the cortex is in striking contrast to the still dark

pyramids. Fine hemorrhages are apparent beneath the mucosa of the renal pelvis. Page 238
THE PHYSIOLOGIC EFFECTS OF WOUNDS 240

Pathogenesis

Shock

Two factors which are evidently of outstanding importance in the development of the renal lesion may appear in severely traumatized persons. One is

pigment excretion in the urine and the other is the physiologic state known as

shock. survey of the first hundred cases of pigment nephropathy studied at

the 15th Medical General Laboratory provided interesting figures regarding

the relative frequency of the lesion in different types of Army hospitals. In

base hospitals (station and general hospitals), nephropathy was found in only

percent of the necropsies, in evacuation hospitals the percentage rose to 18,

and in the field hospitals (to which only the most severely wounded, nontransportable cases were admitted) to 30 percent. Clearly pigment nephropathy

occurred in direct relation to severity of injury and, by implication, to the profundity of shock.

The cases studied by the Board offer more direct evidence. Whenever possible, clinician who was member of the Board made the examination and

recorded his impression regarding the presence and severity of shock. When

shock was recognized, it was classified as slight, moderate, or severe. In 183 cases so classified pigment nephrosis was proved at necropsy in thirty-seven.

(There were actually 38 proved cases in the Board’s entire series, but had

not been classified as to degree of shock.) Their distribution in the various

shock categories is shown in Table 92.

The decreasing frequency of renal involvement from those with marked

shock to those with lesser degrees of shock is apparent, but the six patients

Table 92.—Relationship of Proved Pigment Nephropathy to Degree of

Shock

Degree of Shock Number

of Cases

Fatal

Nephropathies Percentage

Severe 57 20 35.1

Moderate 55 12.7

Slight 37 10.8

None 34 17.6
PATHOLOGY OF THE KIDNEY 241

who were not considered to be in shock confuse the picture. This group, which

consists of Cases 9, 22, 69, 70, 120, and 132, is therefore considered in detail.

“No Shod(' Group.—Case is an example of frank transfusion accident.

Between 100 and 125 cc. of group blood had been given in error to group

recipient before characteristic reaction developed and the transfusion was

interrupted. Hemoglobinemia and hemoglobinuria were demonstrated. This

case belongs in different category and requires no further consideration.

The patient in Case 22 did not present evidence of shock at the time of entry

to the hospital hours after wounding, or at any subsequent period of observation. He belonged to blood group and received units of blood, presumably

group A, not from the theater blood bank and not checked by any member

of the Board. There was no clinical evidence of reaction to these transfusions

which were given on the fourth day of disease, only days before his death.

On the following day the nonprotein nitrogen level in the plasma was 294 mg.

per 100 cc., so the renal lesion must have antedated these transfusions. The three

early transfusions on the day of wounding were of the usual theater bank blood

and were given without incident. The Rh reaction of the patient was not determined. No etiology for hemolytic reaction was discovered, yet large amounts

of free hemoglobin, 193 mg. per 100 cc., were found in the bladder urine at

the time of necropsy.

Cases 69, 70, and 132 are examples of the crush syndrome with severe grades

of myoglobinuria. Judged by the usual clinical criteria—blood pressure, pulse,

pallor, coldness of extremities, anxiety—these patients did not impress the examiner as being in shock. Each of them, however, clearly exhibited one phenomenon which is emphasized by many students of shock: hemoconcentration,

as shown by hematocrit values of 71, 80, and 57, respectively. If shock itself was

not present, there is no doubt that closely allied physiologic abnormality was.

In Case 120 the patient was wounded in the right thigh by shell fragment

which completely transected the femoral artery, vein, and nerve. Hemorrhage

was severe and he was given 1,000 cc. of plasma en route to the hospital. On

arrival he seemed in good condition and was operated upon without further

preparation, but 1,500 cc. of whole blood were given during the operation. Immediately after operation the blood pressure was no mm. Hg systolic and 62

diastolic, but hours later it dropped to 70/40 and throughout the day the

systolic level ranged between 60 and 70 millimeters of mercury. Nevertheless

the patient’s color was good and his skin remained warm. The pathologist has
THE PHYSIOLOGIC EFFECTS OF WOUNDS 242

the temerity to suggest that in consideration of this case also shock can scarcely

be excluded.

Pigment Excretion

In Chapter IV it was shown that all patients with clinical evidence of renal

involvement following traumatic injury excreted benzidine-positive pigment in

the urine, although the amounts varied widely. In excellent correlation with this

observation is the histologic evidence of pigment precipitation in the lower

nephron segments of all patients with fatal nephropathy. These related phenomena deserve further consideration.

The Nature of the Pigment

Numerous clinical studies 010 11 have established the two pigments found in

the urine as hemoglobin and the closely related myoglobin. In histologic sections

they react identically with all methods employed (the benzidine reaction, hematoxylin and eosin, Masson’s trichrome and Mallory’s phosphotungstic acid

hematoxylin stains). It has generally been considered safe inference that the

pigment casts found in the tubules were precipitates of the same material spectroscopically identified in its soluble form in the urine, though the possibility

that they might be oxidized or otherwise chemically altered forms could not

be excluded. Harrison et al. provided spectroscopic proof that in the lesions

produced in dogs by arsine hemolysis the casts consisted predominantly of

methemoglobin. No pigments such as hemochromagen or hematin which would

be insoluble at the pH of urine were formed.

Efforts to identify myoglobin by chemical means in the kidneys of patients

who died of the crush syndrome were disappointingly unsuccessful. (See ApBywaters, E. G. L.; Delory, G. E.; Rimington, C., and Smiles, J.; Myohaemoglobin in urine of air

raid casualties with crushing injury. Biochem. J. 35: 1164—1168, November 1941. 10

Maegraith, B. G.; Havard, R. E., and Parsons, D. S.: Renal syndrome of wide distribution induced

possibly by renal anoxia. Lancet 2: 293-296, September 8, 1945.

“Minami, S.: fiber Nierenveriinderungen nach Verschiittung. Virchow’s Arch. f. path. Anat. 245:

246-267, 1923. 12 Harrison, H. E.; Bunting, H.; Ordway, N. K., and Albrink, W. S.: The pathogenesis of renal

injury produced in the dog by hemoglobin or methemoglobin. j.Exp. Med. 86: 339—356, October 1947.
PATHOLOGY OF THE KIDNEY 243

pendix for the method used.) The data are presented in the following tabulation.

It is obvious that the kidneys in the crush cases, which one might reasonably

expect to be loaded with myoglobin, did not show significantly more than those

in cases of sudden death selected as controls; actually they contained considerably less myoglobin than did the kidneys in shock cases with or without

nephropathy in which the urine never contained myoglobin. It seems probable

that this failure to recover myoglobin correlates with the fairly rapid alteration in the staining reactions of the pigment in the lower nephron segments

already described and may be attributed to chemical degradation. Under

field conditions it was impractical to attempt further identification of these

products.

Acidity of the Urine and Precipitation of

Pigment in the Tubules

One widely accepted explanation of the development of pigment nephropathy is that the pigment is precipitated from solution when the glomerular

filtrate becomes acid in reaction upon reaching the distal convoluted tubule.

It is of interest to compare the acidity of the initial pigment-containing urines

from patients in whom nephropathy was proved with those from patients with

no evidence of renal lesion other than pigment excretion. control group

in which the urine was consistently free from benzidine-positive material is

also compared in Table 93 with the two pigment-containing groups.

956507 0—52 17

Extraction of Myoglobin from Kidneys

Gm. of myoglobin

Type of case Case No. per Kg. of tissue

Control (sudden death) 0.40

0.50

Shock, no pigment casts

77

f6

bo

-fc*.

OO

Ul

Shock, pigment nephropathy 66

8o

1.3°

i-5°

0.45

Crush syndrome

OO

0.60

0.93
THE PHYSIOLOGIC EFFECTS OF WOUNDS 244

The ranges overlap widely, and the differences in the means are slight and

not significant. Acidity of the urine can be eliminated as the determining factor

in precipitation of pigment in the lower nephron. With acidity eliminated, we

are left without explanation for the phenomenon of pigment precipitation.

Presumably it is due to some change in renal physiology, particularly prone to

occur in, but not limited to shock. Possibly it is nothing more remarkable than

stagnation of the glomerular filtrate secondary to the renal ischemia which is

known to be present. Possibly it is due to increased concentration of some unknown, perhaps abnormal, metabolic product as suggested by Oliver. 13

Table 93.—Urine pH in Pigment Groups and Control Group

One is tempted to speculate upon the possibility of reciprocal relationship

between the degree of shock and pigment concentration in relation to nephropathy: When pigment excretion is great, as in the crush syndrome, some burns,

and transfusion accidents, little or no shock is necessary; when shock is severe

and prolonged, minimal pigment excretion may be required. Many of our data

would appear to support this concept, but the exceptions are too numerous and

striking to permit such conclusion.

Clinicopathologic Correlation

Any attempt to correlate form and function in the kidney is hazardous in

the extreme, but its fascination is irresistible. The first effect of shock upon the

function of the kidney is oliguria, followed quickly by retention of metabolic

products which are both nitrogenous, such as urea and creatinine, and inor13 Oliver, J.: New directions in renal morphology; method, its results and its future. Harvey Lect.

(1944-1945) 40: 102-155, 1945.

Type of Case

Number

of

Specimens

Range of pH Mean pH

Nephropathy 35 5.0 to 6.9 5.84±0.48

Pigment without Nephropathy 27 5.0 to 8.4 6.17±0.63 No Pigment or Nephropathy 39 5.2 to 8.2 6.25±0.6I
PATHOLOGY OF THE KIDNEY 45

ganic, such as phosphates. Both of these effects were manifested within few

hours of the onset of shock, whereas the first recognizable morphologic change,

the appearance of lipoid vacuoles in the ascending loops, developed about 18

hours after onset, and pigment casts appeared still later. The initial renal insufficiency is, therefore, functional rather than structural in basis. The studies of

Cournand and his associates 14have established the early onset of renal ischemia

in shock and adequately explain the initial functional changes.

Ischemia with consequent anoxemia also serves as logical explanation of

the appearance of demonstrable lipid in the parenchymal cells. As will be shown

in Chapter XII, similar phenomenon in shock was found in the liver, the

heart, and other organs in which the relationship of fatty degeneration to anoxemia has received more attention. Further knowledge of renal circulation and

of the relative susceptibility of various portions of the nephron to anoxemia is

necessary to an understanding of the localization of the changes. The hypothesis

of Trueta et al. 10that blood is shunted from the cortex into the vasa recta of the

pyramids is not satisfactory explanation, since the degenerative changes were

maximal in the very areas which, according to his theory, receive the largest

quantities of blood.

The lipoid vacuolation became more intense on the second and third days

after the onset of shock. This, however, cannot be interpreted as evidence that

the initial causative factor necessarily persisted. form of “chain reaction”

which required time for its complete development may have been inaugurated

by the initial insult.

An interesting feature of the development of the “shock kidney” is the apparent delay in the appearance of the pigmented casts. Pigment casts were

present in significant numbers in only two of the nine Board cases in which

death occurred within 48 hours of injury. Even in Cases 32 and 34, in which

death occurred between the second and third days, only traces of pigment could

be found. It is obvious from examination of the histories of this group that

none of them, with the possible exception of one (Case 34), was ever adequately

resuscitated from shock. In the case records of scores of other fatal shock cases

14 Cournand, A.; Riley, R. L.; Bradley, S. E.; Breed, E. S.; Noble, R. P.; Lauson, H. D.; Gregersen,

M. I., and Richards, D. W.: Studies of the circulation in clinical shock. Surgery 13: 964-995, June 1943. 15 Trueta, J.; Barclay, A. E.; Daniel, P.; Franklin, K. J., and Prichard, M. M. L.: Renal pathology

in the light of recent neurovascular studies. [Preliminary communication.] Lancet 2: 237-238, August 17,

1946.
246 THE PHYSIOLOGIC EFFECTS OF WOUNDS

reviewed in the Pathology Section of the 15th Medical Laboratory as controls,

unless there had been transfusion accident, pigment casts were seldom recorded when death had occurred short of 24 hours, although in one burn case

they were numerous at 14 hours. They were not seen with any regularity until

from 36 to 48 hours had elapsed since injury.

simple explanation for this phenomenon which invokes no new mechanism would be the suppression of glomerular filtration during shock, either

because of the depressed systemic blood pressure or because of specific renal

ischemia. The presence of pigment casts, therefore, may logically be considered

histologic evidence of glomerular function, either continued or at least temporarily resumed.

Functional Significance of the Pigment Casts

Although it is certain that the pigment casts play no role in the initiation

of renal insufficiency following shock, no such dogmatism is possible in defining

their possible effect in the later stages of the lesion. Controversy has hinged on

the thesis that the casts cause suppression of urine primarily by mechanical

blockage of the tubules. The morphologic evidence for this is inconclusive. It

is suggested by the high proportion of apparently blocked tubules in many cases

and by the dilatation of portions of the nephron proximal to the cast. In our

cases dilatation of moderate degree was fairly constant phenomenon from the

third day onward. It was not seen in the absence of casts, and the possibility

of mechanical block cannot be denied. The number of pigmented casts varied

widely from case to case, but their number was difficult to estimate in routine

sections and we did not use serial sections or microdissection to confirm our

impressions of the proportion of occluded nephrons. It is doubtful that they

were numerous enough to explain the almost complete urinary suppression in

certain cases. Experimental evidence that the glomeruli of nephrons whose

tubules are plugged with pigmented casts are nonfunctional was provided by

Harrison et al, 16 in the study on dogs previously cited.

It is interesting that in other forms of renal disease, chronic glomerular

nephritis and lipoid nephrosis for instance, casts form in the nephrons but are

readily swept in great numbers into the urine. In pigment nephropathy, al16 See footnote 12.
PATHOLOGY OF THE KIDNEY 47

though casts may regularly be found in the sediment, it is rare that large

numbers of them are passed.

Tubular Degeneration

The initial evidence of tubular degeneration has invariably been fat vacuoles

in the ascending limbs of Henle’s loops and less regularly in the distal convoluted tubules. This change evidently antedated and was independent of pigment precipitation, since it was frequently seen in the absence of the latter.

By the fourth and fifth days lipid tended to disappear from the tubules, but

frank necrosis and regeneration of the epithelium became evident and affected

the same segment of the nephron. These phenomena were never observed in

the shock cases in the absence of pigment precipitation, although in sulfonamide

injury to the kidney they were occasionally seen without pigment. Although

the pigment deposit appears to be sine qua non, the mechanism of its effect

is obviously indirect, since the maximal degenerative change occurred at higher

level in the nephron than did the first pigment deposits. Degeneration was most

pronounced in the ascending limbs, whereas pigment deposits began in the

distal convoluted tubules.

The functional significance of this tubular degeneration is of interest. In

lipoid nephrosis extensive tubular degeneration is associated with oliguria. It

has been suggested that the injured tubular cells permit rediffusion of the

glomerular filtrate back into the vascular system. In pigment nephropathy

tubular degeneration was constant, and such mechanism may be involved

in this syndrome as well. One point of difference between the two syndromes

should be noted, however, before accepting the hypothesis. In lipoid nephrosis

the gravity of the urine is well maintained or even concentrated above usual

limits. In pigment nephropathy fixation at low level is almost constant. This

could be readily explained by the theory of mechanical blockage, since only

few unobstructed nephrons can still function.

The focal rupture of tubules, so frequently noted from the fifth day onward,

has, in the author’s opinion, little functional significance. It is late phenomenon, whereas the entire syndrome—oliguria, azotemia, pigment excretion, and

hypertension, together with fixation of gravity—is established before it appears.

Furthermore, if actual extravasation of glomerular filtrate occurred through

these ruptures, it seems inevitable that interstitial edema would be more conspicuous feature of the histologic process.
248 THE PHYSIOLOGIC EFFECTS OF WOUNDS

SUMMARY

clinicopathologic survey of necropsy findings in 60 severely wounded

casualties provided 38 examples of lower nephron nephrosis in all stages of development. The initial change,-appearing from 18 to 24 hours after injury, was

found to be lipoid degeneration of segment of the nephron, particularly the

ascending limb of Henle’s loop, less markedly the distal convoluted tubule.

The second stage was the precipitation of pigment, either hemoglobin or myoglobin, in the distal convoluted and collecting tubules, seldom occurring short

of 24 hours after injury, more commonly between 32 and 72 hours. Moderate

dilatation of proximal and sometimes distal convoluted tubules followed pigment precipitation. Sometimes on the third, regularly on the fourth and fifth

days, necrosis and regeneration of epithelium in the ascending limbs and distal

tubules became evident, and simultaneously lymphocytes appeared between the

tubules and about the vessels. From five days onward, rupture of tubules with

herniation of their contents into the stroma and consequent granuloma formation became frequent. The last development in many cases was the formation

of nonocclusive mural thrombi in many of the small, thin-walled veins.

In clinicopathologic correlation it was shown that two factors were constant

in the nephropathy cases, inconstant in the remainder. These are (1) the excretion of benzidine-positive pigment in the urine, and (2) (with one apparent

exception) state of shock or, at least, related physiologic abnormality.

Renal insufficiency was found to antedate all structural change, but was

never progressive in the absence of demonstrable pigment nephropathy. The

effects of myoglobin and of hemoglobin precipitation upon the kidney were

indistinguishable. Our evidence does not support the hypothesis that acidity

of the urine is the factor responsible for pigment precipitation in the nephrons.

Although pigment precipitation is an essential factor in the development of

the “shock kidney,” the mechanism of its effect upon the kidney remains unexplained. The possibility that it is in part mechanical cannot be disregarded,

but the complex chain of degenerative and inflammatory phenomena demands

another explanation. Controlled experimentation will be necessary before many

of these uncertainties can be resolved.

For Cases of Special Interest in this chapter, see page 282.
CHAPTER

Sulfonamides in Relation

to “Shock Kidney”

No discussion of renal failure in the wounded of World War II would be

complete without consideration of the possible role of sulfonamide injury of the

kidneys. Two forms of this type of injury are generally recognized. One is the

purely mechanical process of crystalluria, with precipitation of the crystals in

the ureters,renal pelves, and perhaps in some instances in the collecting tubules.

The second is more complex process involving true parenchymal damage to

the kidney; it appears to be relatively independent of dosage and is believed

by many to belong in the category of hypersensitive reactions along with other

recognized sulfonamide lesions such as dermatitis, myocarditis, and pneumonitis.

The problem is difficult because this renal lesion is characteristic lower

nephron nephrosis, usually although not invariably associated with the precipitation of hemoglobin-like products in the tubules and hence indistinguishable from transfusion kidney, crush kidney, or shock kidney. With present

knowledge, distinction is impossible on the basis of renal morphology.

Sulfonamide Therapy in Battle Casualties

During the period in which the cases studied by the Board were collected,

sulfonamides were still extensively used in forward installations (aid stations,

collecting stations, and clearing stations) in the Fifth Army Area, although their

use in hospitals had greatly diminished with the arrival of large supplies of

penicillin. In the aid stations sulfonamide dressing almost universally was

applied. This might or might not be supplemented by indeterminate amounts of

sulfonamide powder dusted onto or into the wounds, and more of the drug

by mouth, the most frequent total oral dose being grams. In the field and

evacuation hospitals, sulfonamide therapy usually was stopped and penicillin sub-
250 THE PHYSIOLOGIC EFFECTS OF WOUNDS

stituted. Notable exceptions, however, were in some cases of abdominal wounds

with incipient peritonitis. Many surgeons placed from to 10 Gm. of sulfadiazine in the abdominal cavity before closing it, and some continued sulfonamide treatment by mouth for several days. There was no standard practice

since this was considered matter for individual surgical judgment.

Blood Sulfonamide Levels

Relationship to Sulfonamide Intake

Blood sulfonamide levels were determined in 50 of our patients. The tests

were made for free sulfonamide only, whereas the total of free and acetylated

blood sulfonamide would probably have been more valuable index of sulfonamide retention by the kidney. As would be expected, there seemed to be

general relationship between the blood levels of the drug and the quantity

administered, as shown in Table 94. However, the fluctuations within each

group are too great and the number of cases is too small to justify further analysis. It is noteworthy that no patient tested failed to show at least trace of

sulfonamide in the blood stream, and in two of six patients with no recorded

chemotherapy, levels of 7.0 and 10.6 mg. per 100 cc. were observed. Furthermore, characteristic sulfonamide crystals were found at necropsy in the renal

tubules in several other patients with no history of exposure to sulfonamide

Table 94.—Blood Sulfonamide Levels in 50 Patients

The maximum was actually 9.7 in one case, but this case is excluded from the average because the figure is

completely out of line and it seems certain that the patient must have received oral sulfonamide medication which

was not recorded.

Blood SulfonamideLevel

mg. per 100 cc.

Mode of Therapy Number

of Cases

Minimum Maximum Mean

Dressing only 12 0.2 2.4 1.4

Dressing and powder 0.2 5.0 1.9

Dressing, powder, and Gm. orally 12 0.2 9.7 2.5

Intraperitoneal 3.8 27.0 12.2

Continued oral 3.5 51.6 11.8

No history of therapy 0.1 10.6 3.7
SULFONAMIDES IN “SHOCK KIDNEY” 251

and no records of chemical tests for it. The only possible conclusions are that

the records were grossly unreliable so far as sulfonamide therapy was concerned,

and that, regardless of their histories, virtually all of these patients must have

received some sulfonamide therapy.

Relationship to Renal Insufficiency

The 50 patients on whom blood sulfonamide levels were determined were

classified on the basis of urinary suppression and nonprotein nitrogen level

(with or without high azotemia). In the upper two quarters of Chart 38 the

patients have been divided into those with normal urinary output and those with

oliguria. In the lower two the separation is on the basis of nitrogen retention.

Chart 38. Blood Sulfonamide Levels in 50 Patients Classified According

to Urine Output and Nitrogen Retention

Two cases in the high azotemia group are not shown on the chart. Determinations in both cases were

above 40 mg. per 100 cc., the maximal level reached being 51.6 mg. per too cubic centimeters.

956507 0—52 18
THE PHYSIOLOGIC EFFECTS OF WOUNDS 252

It is evident that blood sulfonamide levels above mg. per 100 cc. were observed

only in patients suffering from oliguria, or high azotemia, or both. Attempts

at closer analysis are disappointingly inconclusive. The average blood sulfonamide level in 36 azotemic patients was 5.7 mg. per 100 cc. as compared with

2.3 mg. per 100 cc. in the control group of 14, but again the variations are too

wide in proportion to the number of samples to warrant statistical analysis.

The mean blood sulfonamide level in 38 oliguric patients was 5.4 and in 12

without oliguria, 2.5 milligrams per 100 cubic centimeters.

The results are similar when the cases are divided, in an attempt to exclude

the influence of variation in dosage, into two groups as follows: Group A, those

patients who had external medication only, and Group B, those who received

internal medication (oral, intraperitoneal, or intravenous). Eight patients could

not be classified because of inadequate information regarding therapy. Of the

18 patients in Group A, 12 were azotemic, were not. The mean blood sulfonamide level in the former was 1.7 mg. per 100 cc., with standard error of

±1.1; of the latter 1.32 with standard error of ±0.8. Obviously the difference

is not significant. In Group B, 17 azotemic patients showed mean blood sulfonamide level of 7.8 mg. per 100 cc., with range of 0.4 to 39; and patients

with no azotemia, level of 3.7 mg. per ioo cc., with range of 0.2 to 7.8. With

range of this magnitude in such small number of cases, the calculation of

standard errors has little meaning. Similar results followed efforts to establish

any correlation of average blood sulfonamide levels with oliguria.

Very high blood sulfonamide levels (10 mg. per 100 cc. or higher) were seen

only in patients with symptoms of renal insufficiency. Nothing in this relationship serves to distinguish between cause and effect. It is obvious, however, that

with continued administration of drug eliminated almost solely by the kidney,

its level in the blood must mount with the onset of renal insufficiency. Two

cases are worthy of individual attention.

Cases in Point

Case 21.—This patient was not battle casualty. As treatment for urethral discharge,

the patient medicated himself with 12 Gm. of sulfathiazole in 24 hours. The following day

ureteral colic developed. Crystalline concretions were observed in both ureteral orifices on

cystoscopy. He was treated by pelvic lavage and had no further symptoms. It is evident that

his trouble was purely mechanical.

Case 90.—This patient was battle casualty; severe abdominal wound had resulted

in evisceration of several loops of bowel, perforation of the diaphragm, and lacerations of
SULFONAMIDES IN “SHOCK KIDNEY” 53

the liver and right kidney. The patient was in moderate shock on entry to the hospital. For

the first week postoperatively he voided adequate quantities of urine and did not show

nitrogen retention, but he was febrile. On the ninth day signs of consolidation developed

in the lower lobe of the left lung. He was given 66 Gm. of sulfadiazine between the seventh

and twelfth days.Within 24 hours the plasma nonprotein nitrogen level rose to 143 mg. per

100 cc. and later to 166 mg. per 100 cc., and the blood sulfonamide level to 51.6 mg. per

100 cc. (free sulfonamide 34.4, acetylated 17.2). Following cessation of sulfonamide therapy,

the nonprotein nitrogen level fell to 41 mg. per 100 cc. in the course of 17 days. Oliguria

did not develop during the period of nitrogen retention. It is possible that this may have

been case of sulfonamide injury of the renal parenchyma, but the relative importance of

the simultaneous spreading infection cannot be assessed.

One other line of argument must be explored before conclusion. As was

stated in the introduction, there are reasons for believing that the sulfonamide

form of lower nephron nephrosis is dependent upon hypersensitivity. One reason for this belief is the frequent association of this lesion with inflammatory

lesions of other tissues and organs; for example, dermatitis, myocarditis, interstitial pancreatitis, hepatitis, arteritis, and form of pneumonitis. In the present

series of cases, the only such associated lesion observed was pneumonitis. It is the

personal opinion of the writer (T.B.M.) that pneumonitis can occur in uremia

independently of sulfonamide treatment and that, therefore, its presence cannot be accorded great diagnostic weight.

SUMMARY

Grounds have been found for believing that the records of sulfonamide

therapy in the group of battle casualties upon which this report is based were

grossly inaccurate, but that it is reasonable assumption that few if any patients

escaped exposure to the drug. Very high blood sulfonamide levels were observed

only in patients with renal insufficiency. Except for these extreme instances, the

variation in the blood sulfonamide levels was too great in all categories studied

to yield reliable correlation between blood level and renal insufficiency. In only

two cases did clinical evidence point toward sulfonamide etiology. strong

argument against such causative mechanism was the failure to observe any

instance of other forms of sulfonamide injury such as arteritis, myocarditis,

dermatitis, hepatitis, or pancreatitis.
AN EARLY CRUSH CASE. This fresco in the Basilica of San Miniato al Monte, Florence,

Italy, by Spinello Aretino, 1387A.D., depicting construction of the Abbey at Monte Cassino,

is perhaps the earliest record of treatment of crush injury. The devil has pushed wall onto

monk who is then revived by St. Benedict, “Our ministrations were less effective.”
CHAPTER XI

The Crush Syndrome in

Battle Casualties

In preceding chapters examples of the crush syndrome have been included,

frequently with little or no distinction from the more usual types of battle

casualties. This group of cases, however, presents certain distinctive features

which require separate consideration. Moreover, though cases were reported in

the German literature among casualties of World War I, and though Bywaters

and others" have made careful clinical and biochemic studies of many civilian

casualties during the “Battle of Britain,” few thoroughly studied cases have

been recorded among the battle casualties of World War II.

In this chapter the clinical, physiologic, biochemic, and pathologic features

and the results of treatment will be discussed on the basis of nine cases, five of

which were fatal. All of the patients were crushed within stone houses typical

of the Italian countryside. (It is perhaps not coincidence that the first known

description of the syndrome came from Italy in 1908 as report of casualties

of the earthquake at Messina.) Five of the buildings in which the injuries occurred, one of them housing medical collecting company, were struck by artillery shells. Two of the casualties resulted when demolition charge exploded

and the remaining two were incurred when house about two hundred yards

from our laboratory was struck by bomb from German raider at dawn.

It was consequently possible to observe the patients virtually from the moment

of release from the rubble in which they were partially buried. All nine are

listed, together with pertinent data, in Table 95.

'Bywaters, E. G. L.: Ischemic muscle necrosis; crushing injury, traumatic edema, crush syndrome,

traumatic anuria, compression syndrome: type of injury seen in air raid casualties following burial beneath

debris. J.A.M.A. 124: 1103—1109, April 15, 1944.

Douglas, J. W. B.: Incidence of signs of renal injury following prolonged burial under debris in an

unselected series of 764 air-raid casualties admitted to hospital. Brit. J. Urol. 17: 142—147, December 1945.

Dunn, J. S.; Gillespie, M., and Niven, J. S. F.: Renal lesions in cases of crush syndrome. Lancet

2: 549—552, November 8, 1941.
256 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table

—Data 95.

Concerning Patients with

Crush

Syndrome

Case No.

A*te °/

Patient Duration of Crush

Time

from Release to

Hospital Arrival

Time

from

Release Administration to of

First

Intravenous Fluid

Parts

Affected

Operation

Time from Releaseto

Operation

Patient’s Outcome

yrs.

hrs.

hrs.

hrs.

hrs.

56

25

<6

Left

shoulder,

pelvis,

both

hips

None

Lived.

69

21

3.7

0.3

7.2

Left

arm, right

forearm,

both

thighs,

left

chest

wall.

...

do

....

Died.

70

25

3.8

0.5

9.3

Both

buttocks,

both

thighs

...

do

....

Do.

73

34

10

Back,

right

thigh,

and

leg

...

do

....

Lived.

78

19

22

14

Left

thigh,

left

forearm,

right

thigh,

and

leg.

Fasciotomy, right

leg.

96

Died.

93

32

13

13.2

Chest,

abdomen,

both

legs,

left

arm.

None

Do.

99

23

<5

10.3

Nothing

I.V.

Left

thigh,

fracture

of

right

zygoma.

Elevation of

right

zygoma.

120

Lived.

124

23

All

of

body

except

both

legs

below

knee.

None

Do.

132

22

1.5

4.8

Immediate

therapy

Left

shoulder,

neck,

scalp

laceration.

Exploration and

drainage,

neck

and

shoulder; tracheotomy.

14

Died

56

hours

after release.
THE CRUSH SYNDROME IN BATTLE CASUALTIES 57

Clinical Features

The clinical features of crush syndrome can be divided into two categories:

primary and secondary. The primary features, comprising the direct effects of

crushing injury, were common to all nine cases. The secondary features, seen

only in the five fatal cases, were the usual signs and symptoms of posttraumatic

renal insufficiency described in Chapters IV and V.

Primary Phase

Shod{.—Shock, as judged by the usual clinical criteria, was not characteristic

of the majority of our patients with the crush syndrome and was never seen

in patients observed within 10 hours of release from the compressing agents.

One patient (Case 70), for instance, looked so well when examined 30 minutes

after release that he was evacuated to the rear without treatment. He nevertheless died /. days later. Only one patient (Case 93) was in shock when first

examined and this was 13 hours after release. He had had no previous medical

attention. diagnosis of slight shock was made in Case 78 twenty hours after

release, and though diagnoses of shock were never made in Cases 69 and 132,

transitory episodes of impalpable pulse and unmeasurable blood pressure were

recorded in the case histories (at 19 hours in Case 69 and at 14 and 23 hours in

Case 132). In Case 70 and in all the surviving patients, hypotension was never

observed.

Nausea and Vomiting.—Nausea or vomiting was recorded in only three

cases, all of which terminated fatally. Nausea with hiccuping was observed in

one patient (Case 70). This occurred on the first anti second days after release

when the nonprotein nitrogen concentration was 83 to 104 mg. per 100 cc. of

plasma. Vomiting was recorded twice. One patient (Case 93) vomited while

he was still pinned down by masonry but not afterward. The second patient

(Case 78) had troublesome vomiting on the second and third days after release

from compression. On those days the nonprotein nitrogen of the plasma was

92 mg. per 100 cc, and occasionally higher.

Local Changes.—Commonly the appearance of the skin gave no indication

of the changes in the underlying muscle. In some patients, however, there were

bruises and areas of ecchymosis and lividity of the overlying skin (Fig. 23).

Immediately after release from compression the affected parts began to swell.

The swelling took place first within the fascial compartments and resembled
258 THE PHYSIOLOGIC EFFECTS OF WOUNDS

FIGURE 23. Bruising, ecchymosis, and swelling of extremity (Case 78).

the swelling of the calf muscles following interruption of the popliteal artery.

The affected areas became hard, tense, and brawny. Only later, usually after

the third day, did soft, pitting subcutaneous edema appear. Distribution of lesions

was variable. The extremities were most often involved, particularly the legs,

and the muscles of the buttock were frequently included. In one patient (Case

132) the muscles of the shoulder and neck were most affected, and edema of the

neck was so great that tracheotomy proved necessary.

During the first few days of the syndrome, the patients might have no complaints or they might complain of stiffness, soreness, aching, and tenderness in

the involved areas. Symptoms were often inversely proportional to the severity

of injury. In relatively mild lesions, pain was elicited by pressure on the affected

area; more severe lesions were insensitive to pressure. Some patients complained

of numbness of the skin of the toes and over the involved muscles. Examination revealed patchy areas of hypesthesia or anesthesia of the skin, “stocking”

type of anesthesia of the limbs, and absent reflexes. Involved muscle groups

were paralyzed or sometimes temporarily spastic. It was sometimes impossible

to feel pulsations in the arteries of the affected limbs, reminding one of the early

phase of Volkmann’s contracture. In one patient (Case 78) fasciotomy was

done for that reason. The leg was so insensitive that it was possible to perform

the operation without anesthesia.

Fractures.—Rather surprisingly, in view of the nature of the initial trauma,
THE CRUSH SYNDROME IN BATTLE CASUALTIES 259

no major fractures were observed. The only fracture recorded (of the zygoma)

could be considered only coincidental.

Secondary Phase

One patient (Case 132) died 56 hours after release from compression; the

other four lived from to 13 days after release. One died suddenly, apparently

of acute cardiac failure, the others more slowly, with progressive lethargy and

drowsiness but no typical uremic coma. Drowsiness was particularly marked in

one patient (Case 78) who had been treated with magnesium. None of the patients in this group had convulsions at any time during their illness. The mechanism of death appeared to be pulmonary edema, except in one patient (Case 93)

in whom lobar pneumonia developed on the thirteenth day shortly after the

appearance of diuresis had led to hope for his recovery.

All of the patients who died showed the usual signs and symptoms of

lower nephron nephrosis previously described (Chapters IV and V). The initial

urine specimens were deeply pigmented and reacted positively with the benzidine test; oliguria was marked and, except in Cases 69 and 93, progressive (see

Table 97). The urine, with one exception, was persistently acid and the specific

gravity was constantly low from the third day onward. The nonprotein nitrogen

level in the plasma rose progressively, and on the third or fourth day mild

hypertension developed. Details of the chemical abnormalities of the blood and

urine follow.

Physiologic and Biochemic Peattires

Blood

Blood Volume.—The blood volume was determined immediately upon arrival at the hospital in only two patients with crush injury. The first (Case 93)

was the only patient of the group thought to be in severe shock. He had lost

one-third of his total blood volume, apparently entirely in the form of plasma,

for he showed no evidence of diminution of the total hemoglobin or red-cell

mass. The hemoconcentration might have been partly responsible for the clinical picture of shock, as severe shock was generally associated with loss of circulating blood greater than one-third of the normal volume. The second patient
260 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chart 39. Hematocrit Values* in Fatal Crush Syndrome

Case No. 93

Case No. 69

Case No 78

Case No. 70

Cose No. 132

Normal: 47. Range: 42—52.

(Case 124) showed no evidence of shock clinically and no decrease was found

in the volume of circulating blood.

In three patients (Cases 69, 78, and 93) the blood volume was determined

during their course. It was abnormal in only one of them (Case 78), being

increased by about two liters 24 hours after the patient’s release from compression. During that period he had received 600 cc. of plasma (2 units), 400 cc. of

4-percent sodium bicarbonate, and 1,000 cc. of 5-percent dextrose in isotonic saline

solution intravenously. He had taken 800 cc. of liquids by mouth and had

voided 350 cc. of urine. He died days later with severe pulmonary edema. In

Case 93, the patient received no more fluid intravenously than was necessary to

correct his blood volume deficit. He died of lobar pneumonia 13 days after

release. The blood and plasma volumes in Case 69 were within normal limits

on the second and ninth days. In retrospect, from rough fluid-balance calculations, this patient was given perhaps 2,000 cc. more parenteral fluid, including

large doses of sodium bicarbonate, than optimal. The fact that severe peripheral

edema developed indicates that total body water, if not circulating blood volume,

was probably increased.
THE CRUSH SYNDROME IN BATTLE CASUALTIES 261

Chart 40, Hematocrit Values* in Nonfatal Crush Syndrome

Case No. 56

Case No- 73

Case No. 124

Case No. 99

Normal: 47. Range: 42—52.

Hematocrit Value and Plasma Proteins.—The most striking feature of the

immediate findings in the blood of patients with the crush syndrome was the

hemoconcentration in those who subsequently died. It was chiefly among these

patients with the crush syndrome that hemoconcentration was found in our

series of seriously wounded. In one patient (Case 70) the hematocrit value was

80 percent hours after his release from the crushing force. It is noteworthy

that the clinical evaluation of this man failed to reveal evidence of shock. All

of our patients with crush syndrome who died had initial hemoconcentration

(Chart 39 and Table 96). It was, however, transitory and the hematocrit value

was within normal limits by the end of the second day. None of those who

survived had hematocrit levels above normal limits (Chart 40 and Table 96).

Plasma proteins were within normal limits in six of the eight patients on

whom early determinations were made. One initial determination in patient

who lived and four determinations made in the first 24 hours after release

Normal: 47. Range: 42 to 52 percent.

Normal: 6.5. Range: to Gm. per 100 cc.
262 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 96. Hematocrit Value in Relation to Patients’ Course

Normal: 47. Range: 42-52.

from compression in fatal case were moderately elevated (Table 97). Again,

as was the case in the hematocrit values, the elevated plasma protein concentration soon returned to normal. Although our data are too few to permit of

interpretation, it is probable that consistently high plasma protein concentration in the first 24 hours is indicative of poor prognosis.

In these crush cases the initial concentration of red blood cells was relatively greater than the concentration of plasma protein, as may be seen in Chart

41. These findings suggest that with release of compression and re-establishment of circulation to the injured areas, there is prompt outpouring of plasma into

Fatal Cases

Hematocrit Value Case Hours after Case Hours after

No. No. Release cc. cells in 100 cc. cc. cells in 100 cc.

70 9.0 80.0 70 52.0 44.0

78 12.0 65.0 93 72.5 43.5

93 13.0 71.0 70 76.0 44.0

93 14.5 63.0 78 96.0 34.2

93 16.0 61.5 69 117.5 47.0

93 16.5 59.9 93 119.5 41.1

69 21.5 70.0 69 141.5 47.0

93 23.0 59.0 93 144.0 39.0

78 24.0 54.1 93 167.5 39.8

69 27.0 61.0 69 189.5 41.6

70 28.0 48.0 69 214.0 42.0

132 37.5 57.0 93 215.5 32.9

132 45.0 47.0 93 240.5 30.5

69 46.0 51.7 93 265.0 26.5

78 47.0 49.0 93 287.5 24.5

93 48.0 48.0 93 311.5 21.9

Nonfatal Cases

73 7.0 46 56 35.5 45.7

124 7.0 50 56 83.5 40.0

99 9.0 46.8 73 88.5 44.4

124 10.0 47.7 73 112.5 48.5

56 14.0 48.0 56 131.5 36.7

99 16.5 46.0 99 157.0 46.2

124 31.0 48.0 56 203.5 39.0
THE CRUSH SYNDROME IN BATTLE CASUALTIES 63

Table 97.—Plasma Protein Concentration in Relation to Patients’ Course

Fatal Cases

Nonfatal Cases

Normal: 6.5. Range: 6-7.

the affected tissues, manifested clinically by the rapid development of swelling

in the affected parts. With the loss of plasma from the circulating blood, the

concentration of the red blood cells is increased. If, as is likely, the plasma lost

into the tissues contains less protein than normal plasma, an explanation of the

early increases in the concentration of plasma proteins in some severe cases is afforded. The rapid disappearance of the hemoconcentration (and of the elevated

plasma protein level in two instances) is in part accounted for by the intravenous

administration of plasma and crystalloids, but this is not the only factor, for the

dilution occurred in the absence of intravenous therapy. The effect could be

explained by the reabsorption of extravasated plasma.

During the later stages of the syndrome in the fatal cases, the hematocrit

Case

No,

Hours after

Release

Plasma Protein

Gm. per 100 cc.

Case

No.

Hours after

Release

Plasma Protein

Gm. per 100 cc.

93 13.0 8.2 78 96.0 6.1

93 14.5 7.7 69 117.5 5.4

93 16.5 7,3 93 119.5 6.2

69 21,5 6.8 69 141.5 4.7

93 23.0 7.3 93 144.0 6.2

78 24.0 6.5 93 167.5 6.1

69 27.0 6.4 69 189.5 4.5

70 28.0 6.1 69 214.0 5.1

69 46.0 6.3 93 215.5 5.9

78 47.0 5.6 93 240.5 6.1

93 48.0 6.2 93 265.0 5.9

70 52.0 6.9 93 287.5 5.8

93 72.5 6.2 93 315.5 5.8

70 76.0 6.5

124 7,0 6.7 56 35.5 6.4

73 7.0 6.8 56 83.5 5.5

99 9.0 6.8 73 88.5 5.8

124 10.0 6.0 73 112.5 7.1

56 14.0 7.9 56 131.5 6.0

99 16.5 6.7 99 157.0 6.7

124 31.0 6.3 56 203.5 6.8
264 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chart 41. Relationship between Plasma Protein and Hematocrit Levels in

Crush Syndrome

The diagonal line indicates the locus of point representing equal dilution or concentration

of the red blood-cell mass and the plasma protein. Data on first days after injury. The line

is theoretical and obviously does not represent the relationship that would obtain if increments of crystalloid solution were added to whole blood.

value remained within low normal limits except in Cases 78 and 93 in which it

fell below 40, eventually dropping to 21.9 on the day of death in the latter case.

There was greater variability in the concentration of the plasma proteins during

the course of the disease. Two determinations in patients who survived and seven

determinations in patients who died dropped below Gm. per 100 cc., three of

them being below 5.5 (Table 97).

Plasma Nonprotein Nitrogen.—Among the patients who survived, concentration of the nonprotein nitrogen in the plasma was essentially normal throughout the course of the illness. Among those who died, it was elevated from the

start and rose progressively at an almost linear rate (Chart 42). No determinations were made in one fatal case. The concentration of phosphorus in the plasma

rose more slowly and appeared to reach its asymptote earlier.

Plasma Chlorides.—The plasma chloride concentrations were essentially

normal among the patients who survived. Among those in whom fatal crush
265 THE CRUSH SYNDROME IN BATTLE CASUALTIES

Chart 42. Plasma Nonprotein Nitrogen Concentration in Crush Syndrome*

Data on fatal and nonfatal cases. In Case 93, plotted separately on the chart, “recovery” diuresis

was well started before the patient died of pneumonia on the thirteenth day after injury.

syndrome developed, however, there was progressive drop in the concentration

of plasma chlorides except in one patient (Case 93) who developed diuresis

and showed evidence of improving renal function although he subsequently

died (Chart 43). At necropsy lower nephron nephrosis and lobar pneumonia

were demonstrated. No determinations were made in one fatal case. Concomitant with the fall in plasma chloride level, there was generally fall in the

alkali reserve of the blood as suggested by the lowering of its CO2 combining

power. These changes in plasma carbon-dioxide combining power and chloride

levels were entirely comparable to those seen in renal insufficiency following

other types of trauma (Chapter V).

Plasma Pigment —Blood specimens taken shortly after release from compression revealed abnormal quantities of free pigment in the plasma which

reacted positively to the benzidine test. Blood samples were collected in carefully dried, but not oiled, syringes and needles. With this technique, free

plasma “hemoglobin” concentration up to 15 mg. per 100 cc. was considered

within the normal range. Chart 44 shows the values obtained in the first days

after injury both in the patients who died and in those who survived. All but
266 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chart 43. Plasma Chloride Concentration* in Crush Syndrome

Normal: xoo. Range: 97.5—104. Data on fatal and nonfatal cases,

two of the determinations we were able to obtain during the first 24 hours

were above the limits accepted as normal; the exceptions were determinations

made in Case 99, nine and sixteen hours after release. Only one of the patients

showed heme concentration of over 40 mg. per 100 cubic centimeters. Data

were available on eight cases. Of particular interest, from those data, is that, like

the return of the hematocrit level and the plasma protein concentration to normal, the concentration of the free benzidine-positive substance in the plasma

tended to be within normal limits by the end of the second day. As in the case

of the hemoconcentration, then, the presence of free benzidine-positive substance in the plasma might have been missed if specimens had not been collected

soon after the patients’ release from the crushing force.

The nature of this substance, free in the plasma and giving the reaction of

heme, could not be settled. The quantities present were not large enough to

make spectroscopic analysis possible in the instrument available to us. Chemical

examination of the urine of these patients (Chapter VIII) showed that both

hemoglobin and myoglobin were excreted in large amounts, the proportions of

each varying widely from case to case. It is reasonable to assume, therefore, that both pigments were represented in the plasma as well.
THE CRUSH SYNDROME IN BATTLE CASUALTIES 267

Chart 44. Free Benzidine-Positive Substance in Plasma in Crush Syndrome*

Patients Lived

Patients Died

Data on fatal and nonfatal cases.

Urine

Gross abnormalities were found only in the urine specimens collected soon

after release from the compression force. Table 98 indicates the duration of some

of the abnormalities in the urine. It will be observed that myoglobin was not

found in the urine more than day and half after release from the crushing

force. Abnormality in the color of the urine lasted somewhat longer (up to

days), and albuminuria to significant degree was detected for as long as

days after release from the crushing influence.

Output.—None of the patients who survived the injury had any diminution

in volume of urinary output below the limits of normal. In all of those who

died (Table 99) urinary output was diminished from the start. All had oliguria.

In one instance (Case 70) anuria (an output of less than 100 cc.) was recorded

during the 24 hours beginning the day after release. Two other patients were

oliguric until the second 24-hour period, when the output dropped below 100 cc.

day. The remaining two patients (Cases 93 and 78) were oliguric but never

became anuric. In one (Case 69) diuresis had just begun to develop when he

suddenly died; in another (Case 93, Table 99) an excellent diuresis was estab956507 0—52 20
268 THE PHYSIOLOGIC EFFECTS OF WOUNDS

lished and the patient might have survived the injury had he not died of lobar

pneumonia.

Table 98,—Duration (Days) of Abnormalities in the Urine of Patients

with Crush Syndrome

Table 99.—Urinary Output in Fatal Cases of Crush Syndrome

Case No. Color

Abnormality Albumin

Benzidine-Positive Substance

Patient’s

Outcome

Hemoglobin Myoglobin

70 1.5 Died.

69 Do.

78 Do.

Do.

93 * Do.

73

56 Do.

99 (?) Do.

124 Do.

=none present.

Beyond this time the urine in this patient showed only negligible traces of albumin. **

Beyond this time only traces or faint traces of hemoglobin were recorded.

Time after Release from Compression

Urinary Output (cc. per 24 hours)

Case 69 Case 70 Case 78 Case 93 Case 132

200 50

First day after release 230 30 350 160 300

Second day after release 50 85 500 165 30

Third day after release 45 75 250 130

Fourth day after release 100 35 160 130

Fifth day after release 100 292

Sixth day after release 80 410

Seventh day after release 150 800

Eighth day after release 100 1,305

Ninth day after release 450 1,935

Tenth day after release 2,760

Eleventh day after release 4,135

Twelfth day after release 3,050

Thirteenth day after release 890
THE CRUSH SYNDROME IN BATTLE CASUALTIES 269

Color.—Yellow and straw color were considered to be the normal colors

of urine. An amber color was considered on the borderline of abnormality. All

of the patients who died had abnormal urinary color varying from red to redbrown, or mahogany to dark amber; this lasted or days. Among the patients who survived, the color varied from “ruddy” to amber; but this did not

persist longer than day.

Benzidine-?oshive Figment.—The grossly abnormal color of the urine in

patients with the crush syndrome was found to be caused by the presence of

pigment which reacted positively to the benzidine test. By the technique described in Appendix C, this pigment was thought to consist of myoglobin as

well as hemoglobin in three of the five patients who died of the crush injury.

In the fourth patient no attempt was made to distinguish between the two pigments, and in the fifth patient the benzidine test was not made on the darkamber urine. Results of the tests for myoglobin were never positive in urine

specimens obtained later than 24 to 36 hours after release from the crushing

force. Benzidine-positive substance was found later than the second day and

up to the eighth day after release, but in such small amounts that it was impossible to employ the test to distinguish between myoglobin and hemoglobin.

Qualitative spectroscopic examinations suggested the presence of myoglobin in

the specimens obtained in fatal Cases 69, 70, and 93.

Albumin.—Two of the patients who survived showed some albuminuria.

In neither case did it last more than day, and in only one (Case 56) of the

two was it of any degree of severity. All of the patients who died had marked

albuminuria. Up to or days it persisted unchanged or with increased severity.

If the patient lived longer, the degree of albuminuria then decreased, as in

Cases 69 and 93. In the latter the urine contained only faint trace of albumin

by the time the patient died of lobar pneumonia 13 days after release from

the crushing force.

Sediment.—The urinary sediment was remarkable because findings were

so scarce. In one patient who survived (Case 124), no record was made of the

examination of the organized sediment. Of the other three patients who lived,

only one (Case 73) showed casts in the urinary sediment. On the first day

after injury his urine showed occasional coarse and finely granular casts;

days later the sediment was normal. Two of the five patients who died had

no casts in the urine, although rare red blood cell and few white blood

cells were found; three did show coarse and finely granular casts in the urinary
270 THE PHYSIOLOGIC EFFECTS OF WOUNDS

sediment, but these casts were not abundant, even in centrifuged specimens.

Specific Gravity.—For the first day or two of the illness, the specific gravity

of the urine was normal in all cases. After the second to fourth days, however,

the specific gravity of the urine fell and appeared to become fixed at 1.012 to

1.013. Urine concentration tests were not done in these patients, but as in other

cases of posttraumatic renal insufficiency early impairment of ability to reabsorb water by the renal tubules is surely characteristic feature (Chapter V).

Reaction.—With one exception, the patients passed acid urine at all times

throughout the illness. This one exception (Case 69) was patient whose urine

was on the alkaline side of neutral (pH 7.2) on two occasions on the seventh

and eighth days of the illness. At all other times the urine of this patient was

acid, despite administration of sodium bicarbonate in doses thought adequate

for alkalinization of the urine (16 to 36 Gm. per 24 hours). As had been

found in the study of patients who had renal insufficiency from other causes,

alkalinization of the urine by means of administration of sodium bicarbonate

was inconsistent with safety.

Chart 45. Bromsulfalein Excretion inPatients with Fatal Crush Syndrome

Cose No. 93

Cose No. 69

Case No. 70

Case No. 78

One value in each of cases was estimated for 45-minute period, as the figures had been recorded

at 30 and 60 minutes.
THE CRUSH SYNDROME IN BATTLE CASUALTIES 271

Chart 46. Plasma Bilirubin Concentration in Crush Syndrome

(First Days)

All values in the fatal cases were above normal though still below the level at which clinical

jaundice would appear (2 mg. per 100 cc.). Values for patients who survived were within

normal limits with the exception of Case 56, plotted separately on the chart. Data on fatal

and nonfatal cases.

Liver Function

The function of the liver was tested in one of the four patients who survived and in four of the five patients who died. The examination consisted of

test of the ability of the liver to excrete bromsulfalein injected intravenously.

Dosage was calculated on the basis of milligrams of bromsulfalein per kilogram of body weight (Chapter II). By this method, retention of the dye up

to percent of the injected dose after 45 minutes was considered the upper limit

of normal. In the patient who survived the function of the liver was found to

be normal as tested by this method. In all of the patients who died liver function was found to be impaired (Chart 45). The average dye retention in the

four fatal cases was 12.77 percent, exclusive of one determination made in

Case 93, which showed 26-percent retention on the day the patient died of

lobar pneumonia.
272 THE PHYSIOLOGIC EFFECTS OF WOUNDS

The concentration of bilirubin in the plasma was increased in those patients in whom fatal crush syndrome developed and in one patient (Case 56) who

survived (Chart 46). Data were obtained on eight cases. Sufficient information

was not available to distinguish between increased production of bilirubin and

decrease in its elimination.

Pathology

The important findings at postmortem examination were confined to the

lungs, the liver, the skeletal muscles, and the kidneys.

Lungs. —All of the five fatal cases showed slight to extensive pulmonary

edema, both grossly and microscopically. The weight of the two lungs together

was recorded in four of the five fatal cases. The weights varied from 1,075 to

1,600 grams. Blood as well as edema fluid appeared on cut surfaces of the lungs

in Case 132 and, microscopically, large numbers of alveoli were packed with

red blood cells. This patient had had tracheotomy and the blood may have

been aspirated. Another patient (Case 78) was unusual in that even the visceral

pleura was edematous. Fluid poured from the cut surfaces without the necessity of compression, and the tracheobronchial tree was filled with nonbloody

fluid. In Case 93 death was due primarily to lobar pneumonia involving the left

upper lobe. Microscopically, in addition to the typical pneumonia process, some

areas showed edema with spreading pneumonic involvement.

Liver.—In view of the decreased liver function, as measured by ability to

excrete bromsulfalein and as indicated by the elevated plasma bilirubin and

the abnormally low ratio of urea nitrogen to total nonprotein nitrogen, some

histologic changes were expected in the liver. Surprisingly few were found. The

liver was microscopically normal in Case 70, and showed only scattered vacuoles

in Case 132. In Case 69 occasional mitotic figures were observed in hepatic cells,

and in Case 93, in which there had been terminally rising bilirubin concentration in the blood and terminal bromsulfalein retention of 26 percent, the

only histologic changes found were mild nuclear atypicality in the cells at the

centers of the lobules.

Skeletal Muscles.—The gross changes in the involved muscles were conspicuous. In the involved areas the normal pigment had disappeared, leaving

muscle bundles with the appearance of fish or rabbit flesh. Sometimes an entire

muscle was decolorized, more commonly only segmental areas, particularly re-
THE CRUSH SYNDROME IN BATTLE CASUALTIES 73

FIGURE 24. Decolorization in

the gastrocnemius-soleus muscle group. From necropsy in

Case 78 (see Fig. 23).

FIGURE 25. Decolorization in the left brachioradialis muscle in Case 93. Note the “fish

flesh” appearance, the sharp line of demarcation, and the distinct white band at the junction

of the depigmented and normally pigmented muscle.

gions close to major bony structures (Fig. 24). In Figure 25 (Case 93) complete depigmentation of the distal half of the forearm muscles is apparent,

whereas the proximal half is normally colored. The transition from normally

colored to depigmented areas was sharp, particularly in the cases of longer

survival, and in Case 93 (13 days’ survival) the junction was marked by

narrow white band to mm. broad (Fig. 25). In spite of the loss of color, the
74 THE PHYSIOLOGIC EFFECTS OF WOUNDS

tissue remained moist, capillary oozing appeared from cut surfaces, and no

thrombi could be discovered in any grossly visible vessels. Hemorrhage and

edema were extremely irregular in extent and intensity, absent from some

lesions, and marked in others. The gross depigmentation correlated with chemical assays showing almost complete loss of myoglobin in the affected areas

(Table 100).

Microscopic sections were available from four cases 4, 5, 10, and 13 days

respectively after injury. In the acute cases hematoxylin and eosin stains showed

relatively inconspicuous changes. Evidences of muscle-cell degeneration were,

however, present. Some cells were swollen, hyaline, and more strongly acidophilic than normal. More commonly the cells stained less intensely than

normal, cross-striations were exaggerated, occasional fractures and clefts were

present, and the sarcolemma nuclei appeared decreased in number (Fig. 26).

Though edema and hemorrhage were apparent in some areas, there was no

inflammatory reaction, either polymorphonuclear or histiocytic. With the Masson and phosphotungstic acid hematoxylin stains, the changes were far more

conspicuous. Some of the swollen hyaline fibers stained intensely red with

the Masson, or blue with the phosphotungstic stain, but the great majority

responded feebly or not at all to the specific staining reactions. In sections across

the border of depigmented area it was evident that the loss of specific staining

reaction corresponded closely with the margin of depigmentation (Fig. 27 a).

It was of interest that the cells with exaggerated cross-striations usually failed

to stain specifically.

Table ioo.—Myoglobin Content of Muscle and Kidney in Patients who

Died from Crush Syndrome

The low value was probably caused the extensive interstitial edema in this case.

Tissue

Myoglobin Content

Gm. per Kg. of Wet Tissue

Case No.

69

Case No.

70

Case No.

78

Case No.

93

Normal muscle

Depigmented muscle

Partly depigmented muscle

2.10

1.00

1.86

0.45

3.60

0.27

4.20

0.83

3.00

0.93

3.74

0.54

Kidney 0.60
THE CRUSH SYNDROME IN BATTLE CASUALTIES 75

FIGURE 26. Decolorized muscle from Case 70. The patient died days after injury. The

muscle cells, which should stain intensely with the phosphotungstic acid hematoxylin, employed stain weakly. Cross-striations are exaggerated and numerous transverse clefts have

appeared. An occasional cell has become hyalinized and lost all evidence of striation. There

is much hemorrhage into the interstitial connective tissue.

In the cases of longer duration (to and 13 days), changes were conspicuous with all staining methods but particularly with hematoxylin and eosin.

Many swollen, necrotic muscle cells had become intensely basophilic owing to

the precipitate of innumerable fine granules staining like calcium throughout

the sarcoplasm (Fig. 27 and d). In other cells the precipitate was intense in

the central portion but absent at the periphery (Fig. 28 a). Another common

type of degenerative change was coarse hydropic vacuolation which frequently

produced an appearance suggestive of vegetable cells (Fig. 27 d). Other degenerating cells showed varying degrees of infiltration with histiocytes (Figs.

27 and c). The sarcolemma nuclei in many cells showed amitotic division,

with chains of touching nuclei to 10 elements in length (Figs. 27 and 28 b).

About many of these, viable cytoplasm was present in long, slender masses suggesting regeneration of muscle cells. The interstitial connective tissue was

slightly edematous and densely infiltrated with histiocytes (Fig. 28 b). No

definite evidence of fibroblastic proliferation could be made out. Blood vessels

still remained free from thrombi or inflammatory reaction.

Kidneys.—In all but one patient (Case 70) the kidneys were enlarged at

necropsy. In three of the five fatal cases the combined weights of the two kidneys

were recorded; they were respectively 500, 550, and 625 grams. The capsules

stripped easily. In some there were ecchymoses beneath the capsule. Focal
FIGURE 27, a. Muscle from Case 70 (4 days’ survival). Phosphotungstic acid hematoxylin

stain. Section taken from partially depigmented area. In the more severely involved areas

necrotic muscle cells stain only faint brown instead of an intense purplish-blue. Even the

surviving cells stain irregularly and striations are difficult to see. The interstitial tissue is

edematous but shows little inflammatory infiltration.

b. Case 70 (see also and Fig. 26). Hematoxylin and eosin stain. At the top are three

swollen muscle cells which have lost striations. Beneath them are two necrotic cells which

have been invaded by histiocytes. At upper right and lower left are fragments of surviving

muscle which show chains of touching nuclei. Two foci of calcification are present. The

interstitial tissue shows fibrosis and inflammatory infiltration.

c. Muscle from Case 69 (10 days’ survival). Hematoxylin and eosin stain. This low-power

view shows focal calcification and vascular degeneration of muscle cells as well as chronic

inflammatory infiltration and fibrosis of tbe interstitial tissues.

d. higher magnification from the same section shown in c. Masson trichrome stain.

Coarse vascular degeneration of muscle cells producing vegetable-cell appearance is evident.

Several muscle cells no longer stain red in normal fashion and have been invaded by

histiocytes. Fibrosis and histiocytic infiltration of the interstitial tissue is apparent.
FIGURE 28, a. focus of intense calcification involving almost every muscle cell. There is

marked increase in interstitial fibrous tissue with an occasional focus of lymphocytic infiltration. Section from Case 93 (13 days’ survival).

b. Section from the same case. Hematoxylin and eosin stain. regenerating muscle cell shows

long chains of touching sarcolemma nuclei. The fibrosis and the patency of the blood vessels

are noteworthy. Partial calcification of some muscle cells at the periphery of the field is evident.

hemorrhages and fibrin deposits were commonly found beneath and on the

epithelium of the renal pelvis (see Fig. 20 in Chapter IX). When the kidneys

were cut, with one exception (Case 70), the renal parenchyma pouted through

the cut, rolling outward and forming rounded instead of sharp edge.

Characteristically, the cut surface of the parenchyma showed pallor of the

cortex and darkening of the pyramids to dark brown or mahogany color

(Figs. 19 to 22 in Chapter IX). The thickness of the cortex was normal or increased, never decreased.

The microscopic appearance of the kidneys from patients who died from

crush syndrome have been described and illustrated in Chapter IX as “lower

nephron nephrosis,’' and it will be sufficient merely to list the salient features

here.

Microscopic Features of the Kidney. —Most conspicuous was the presence of

densely pigmented casts in the distal convoluted and the collecting tubules. These

could not be distinguished in stained or unstained sections from the pigmented

casts in Case 9, known transfusion reaction. Proximal to the pigmented casts,

usually in the ascending limbs of Henle’s loops, hyaline nonpigmented casts were

numerous. In cases with survival periods of days, these hyaline casts were

frequently extruded into the stroma and formed foci for granulomatous reactions. Degenerative changes in the renal parenchyma were limited to the

lower nephron segments, usually the ascending limbs, less often the distal convoluted tubules.
278 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Glomeruli were uniformly normal except for the presence of granular precipitate in the capsular space. The proximal convoluted tubules were sometimes

moderately dilated and their lumens contained granular precipitate, but the

epithelial cells were normal and brush borders were well preserved. Interstitial

inflammatory reaction was always present at the corticomedullary junction, and

in two cases of 10 and 13 days’ duration, narrower zone of interstitial inflammatory reaction was seen beneath the capsule. In the same two cases nonocclusive

thrombi were present in some of the veins at the corticomedullary junction.

Treatment of Crush Syndrome

The results of treatment of patients with crush syndrome were disappointing. (Our ministrations were certainly less effective than those of Saint Benedict, whose successful treatment of monk crushed beneath the masonry of

wall at Monte Cassino is depicted on page 254.) In general, efforts during

the first 48 hours were directed toward correction of the hemoconcentration and

attempts at alkalinization of the urine. Subsequently the treatment was that for

renal insufficiency as described for patients with renal insufficiency from other

causes (Chapter VI).

Correction of Hemoconcentration.—Hemoconcentration was treated by administration of plasma and crystalloid solutions during the first 48 hours. Beyond this time, the degree of hemoconcentration was no longer serious problem, for reabsorption had probably begun to exceed transudation. Only two of

the nine patients received whole blood. One of the two (Case 69) received only

250 cc. of blood, administered before the hemoconcentration had been recognized. The other (Case 132) was given 1,500 cc. of whole blood when he became pulseless and no blood pressure could be determined in his extremities.

Alkalinization of the Urine.—According to By waters’*’ hypothesis, alkalinization should be started at the time the casualty is found, immediately after or

even before release from compression. This was not possible in any of our patients. The seriousness of the injury was not recognized by the aid-men. As

matter of fact, the diagnosis was not made by the medical officers until, through

an educational campaign, they had been made aware of the possibility of the

syndrome in any crush injury.

See footnote i.
THE CRUSH SYNDROME IN BATTLE CASUALTIES 279

Chart 47. Effect of Alkali Therapy in Patient with Crush Syndrome

(Case 69)

pH OF URINE

PLASMA CHLORIDES

(MILLIEQUIVALENTS PER LITER)

C0 COMBINING POWER

OF PLASMA (MILLIEQUIVALENTS PER LITER)

ALKALI INTAKE

(GRAMS NoHC0 PER DAY)

After admission to the hospital, however, all but two of the nine patients

received alkali therapy. Four of the five patients who died were treated with

alkali, one starting promptly upon admission to the hospital, one starting during the first 24-hour period after release from the crushing force, and two during the second 24-hour period. No beneficial effects were observed that could

be attributed to the alkali. As matter of fact, the most striking feature was

the failure, in the fatal cases, to succeed in alkalinizing the urine. pH of 7.2 was attained in only two specimens of urine in Case 69 (Chart 47). This patient had received larger doses of sodium bicarbonate than the other patients.

One patient in this group (Case 124) did have an alkaline urine (pH 8.4)

hours after intravenous administration of sodium bicarbonate, and it was kept

alkaline by the administration of Gm. of the bicarbonate every hours. This

patient had minimal renal lesion and survived. Administration of sodium bicarbonate was done cautiously or abandoned altogether, because of unfortunate

experiences with vigorous attempts at alkalinization in patients with renal insufficiency from other causes (Chapter VII).

Diuretics. —Alcohol was used with the hope that it would promote blood
280 THE PHYSIOLOGIC EFFECTS OF WOUNDS

flow through the kidney and serve as diuretic. It was used intravenously (total

dose; 50 to 100 cc. of 95-percent ethyl alcohol as 5-percent solution in dextrose

or isotonic saline solution), and as whiskey by mouth (60 to 180 cc. per day).

No beneficial effects were detected that could be attributed directly to the alcohol. Three of the patients were given 10-percent dextrose in distilled water

intravenously, and one received 50-percent dextrose intravenously as diuretic,

but no effect was noted in any of them that could be attributed to the medication. The failure of both alcohol and hypertonic solutions of dextrose to promote

urine flow or improve kidney function confirmed the findings in patients with

renal insufficiency from other causes (Chapter VI). Not only did concentrated

solutions fail to induce diuresis, but in three cases (Cases 70, 78, and 132) the

hypertonic dextrose solution may have hastened the onset of pulmonary edema.

Mercurial diuretics were not tried in patients with the crush syndrome.

Dehydrating Agents.—On the hypothesis that swelling and edema of the

kidney may be in part responsible for failure of function, the use of potassium

and magnesium solutions was recommended by Barker to reduce the tissue

swelling and to promote diuresis. Potassium chloride was not available to us

for clinical use, but magnesium sulfate was used intravenously and intramuscularly. It was employed in three cases (Cases 69, 78, and 93) in doses of to

Gm. daily for to days, which was sufficient to elevate the concentration of

magnesium in the blood as indicated in the two patients in whom such analyses

were made (Cases 78 and 93). In these three patients there was no definite effect

upon urinary output, and it is impossible to attribute any beneficial effect to

the use of magnesium. Undue drowsiness in Case 78 could well have been

caused by the magnesium therapy, for his serum concentration of magnesium

was 5.8 milliequivalents per liter at necropsy. The serum magnesium reached

level of 6.8 milliequivalents per liter at one stage during the course of treatment in Case 93. For the same reasons stated in Chapter VI, it is our opinion

that neither magnesium nor potassium solutions should be used in the treatment of this syndrome.

Other Measures.—Study of these nine patients taught us little as to possible

means of preventing anuria or inducing diuresis. Generally accepted methods

failed. On the hypothesis that injury to the kidney may be produced when

reabsorption of extravasated fluid takes place, pressure bandages were considered

worthy of trial and were applied in one case (Case 78) without apparent effect.

Barker, Marion H.: Personal communication.
THE CRUSH SYNDROME IN BATTLE CASUALTIES 281

In this case, however, serious extravasation into the tissues had already occurred

before the patient reached the hospital. Cold applications might prevent rapid

flooding of the kidney with large quantities of muscle-breakdown products,

inasmuch as cold is known to inhibit the flow of lymph from the periphery

into the general circulation. This therapy was not tried. Again, however, to be

effective it would have to be started immediately after release from compression, Therapeutic amputation of the involved extremities was thought to be

out of the question for the same reason.

What was learned from the patients with crush syndrome, as well as from

those with renal insufficiency from other causes, was that it is very easy to

bring about an increase in plasma volume in these patients by too vigorous

attempts at inducing diuresis with intravenous crystalloids. Once oliguria or

anuria is established, it is best to withhold fluid, allowing, preferably by mouth,

just enough fluid to compensate for loss from the gastrointestinal tract, and

for insensible loss through the skin, from the lungs, and from the sweat glands.

Under ordinary circumstances, these requirements can be met by 1,000 cc. or

less of fluid daily; more must be allowed if excessive extra-renal losses occur.

In general, patients with renal insufficiency have been found to be over-hydrated

rather than under-hydrated, and this accounts for the fact that pulmonary edema

is common cause of death.

SUMMARY AND CONCLUSIONS

laboratory and clinical study was made of nine patients who received

crushing injuries; four of the patients survived, five died. It is emphasized that

the crush syndrome develops insidiously in patients who appear well when

first seen. All patients who have suffered compression interfering with the circulation of muscle masses for periods of an hour, and perhaps even less, should

be observed carefully for development of features of the syndrome; namely,

tense swelling of the affected parts, hemoconcentration, benzidine-positive pigment (presumably myoglobin) free in the plasma and urine, and oliguria or

anuria. If examinations are not made within 24 or 48 hours, the hemoconcentration and the myoglobinuria may be missed. The volume of urinary output

should be watched closely, for significant oliguria may easily be overlooked.

The principal pathologic findings are in the compressed muscles and in the

kidneys. In the former the normal pigment, myoglobin, was rapidly mobilized
282 THE PHYSIOLOGIC EFFECTS OF WOUNDS

and absorbed, and extensive necrosis of muscle developed which tended to heal

with calcification if the patient survived week or longer. In the kidney

pigment nephropathy was found, which was indistinguishable from that which

develops following other forms of severe trauma. common terminal finding

was severe pulmonary edema.

The treatment applied to these nine cases has been described. In the presence

of oliguria or anuria, it was impossible to alkalinize the urine with doses of

sodium bicarbonate which could be administered without danger of producing

severe metabolic alkalosis. It is particularly important not to flood the circulatory system with intravenous solutions in an attempt to induce diuresis, once

oliguria or anuria have become established. When excessive fluid is administered, the patients may die of pulmonary edema before fatal uremia develops.

That recovery diuresis may develop in these cases is evidenced by two

patients in this series in whom recovery diuresis had begun before death; in

one of them it was well developed.

CASES OF SPECIAL INTEREST IN THIS CHAPTER

Fatal

69 70 78 93 132

Nonfatal

56 73 99 124

CASES OF SPECIAL INTEREST IN CHAPTER IX

Nonfatal

13 29 44 60 72 87 109 125 133 150

27 37 54 71 81 104 112 130 138

Fatal

25 47 65 85 97 117 123 A-30 12 26 49 66 86 98 118 129

22 31 52 74 88 108 120 131

24 41 55 80 95 116 122 136

Crush Syndrome

69 70 78 93 132
CHAPTER XII

General Pathology of

Traumatic Shock

To demonstrate relationship between parenchymal degenerative change

or pattern of changes and the clinical state of shock several conditions must

be satisfied. The lesions must first be sufficiently distinctive, so that there can

be no possibility of confusion with postmortem degeneration or the artefacts

of poor fixation and faulty histologic technique. Second, they must be clearly

distinguishable from the group of agonal changes seen in the tissues of any

person whose death has not been instantaneous or at least relatively rapid. Specificity of individual lesion cannot reasonably be expected, but the changes should

be demonstrable in high proportion of shock cases, absent in cases of sudden

death, and relatively infrequent in cardiac, metabolic, or cerebral deaths in

which shock-like states are comparatively uncommon. There should be demonstrable time-relationship between the onset of shock and appearance of

the lesions, and conversely between recovery from shock and their disappearance.

So far as could be ascertained, no pattern of lesions which fulfills these conditions in man has been described in the literature.

The anatomic changes associated with shock may be usefully divided into

(i) those which occur concomitantly with the state of shock and therefore

are of interest in relation to its pathogenesis and (2) those which follow shock

and therefore may be considered as its consequences. In studies of the pathology

of human shock attention has heretofore been concentrated primarily on the

former. In the present work attention is particularly devoted to the latter, but

two brief sections dealing with pulmonary edema and with fat embolism have

been included because of the extensive consideration given to them by previous

investigators.

In our own preliminary investigations, the search for possible sequelae of

Moon, V. H.: Analysis of shock. Brit. M. J. 1: 773-779, June 10, 1944.

956507 0—52 22
284 THE PHYSIOLOGIC EFFECTS OF WOUNDS

shock seemed fruitless for many months. The postmortem material of several

hundred battle casualties was vainly examined for any lesion or combination of

lesions which would fulfill the imposed conditions. The organs of patients dying

after 4, 8, or 12 hours of prolonged shock showed little evidence of histologic

change and none which could not readily be duplicated in series of non-shock

cases. When, however, the range of investigation was broadened to include

material from casualties who lived more than 18 hours after injury, and when

frozen sections stained for fat with Sudan IV were substituted for paraffin sections, fairly constant pattern was disclosed. Evidence was obtained that approximately 18 hours after shock-producing injury, fat vacuolation appears

in the parenchymal cells of the heart, liver, and kidneys. These changes increased in frequency and severity up to 96 hours after injury, then progressively

declined with longer periods of convalescence from the episode of shock, unless complicating factors, such as fat embolism or severe infection, prevented

resolution of the process.

The pancreas and adrenal were also studied in the same group of cases.

In the pancreas no lesion was recognized which appeared to correlate with

shock. In the adrenal gland series of changes was readily demonstrable: swelling of the cortex, pseudotubular degeneration, and depletion of stainable lipid,

particularly of doubly refractile lipid. Since these changes did not differ qualitatively and were less marked quantitatively than those seen in cases with infection and in other types of control material, their significance is questionable.

Only one factor, the depletion of doubly refractile lipid elements, showed

tendency to reversibility with increasing time intervals following resuscitation

from shock.

Material

The nucleus of material for this section of the study was provided by the

necropsy protocols and corresponding microscopic preparations from 60 cases

that had been studied clinically by members of the Board. As the work progressed, the importance of sepsis as complicating factor became apparent.

Additional cases were therefore selected from the files of the 15th Medical

General Laboratory in which the clinical data were sufficiently detailed to establish the diagnosis of shock and in which major sepsis could be excluded. Numerous additional examples of acute shock were included in order to cover
285 GENERAL PATHOLOGY OF TRAUMATIC SHOCK

wider time-range than was provided by the Board’s cases. In the tables to

follow, these supplementary cases have been included unless the tables are designated as “Board Cases.”

Control material was drawn both from the 15th Laboratory and from the

Army Institute of Pathology. This included several groups of cases: (1) instantaneous or sudden deaths, such as homicides and motor vehicle accidents, (2)

“medical deaths” unselected except for elimination, as far as possible, of “shocklike” states (the group included cerebral, cardiac, and infectious diseases), (3)

deaths primarily due to starvation (from necropsies done in German concentration camp), and (4) deaths from aplastic anemia. Not all organs were

available for fat stains in all of these cases; consequently the number of controls varies somewhat from one section to another. The starvation and aplastic

anemia groups were selected because of the known frequency with which fatty

vacuolation of various organs occurs under these conditions.

The majority of necropsies on the combat soldier had been performed under

field conditions by an officer of field or evacuation hospital whose experience

in pathology was often limited. (In the original 60 cases, one of the Board

members was usually present at the necropsy.) Deaths were most numerous

at times of heightened military activity when hospital staffs were overworked

in caring for the living. Necropsies were sometimes conducted in hospital operating rooms but more often in tents without benefit of flooring, heat, or adequate illumination. Scales were rarely available. The examinations and records

were inevitably incomplete. The central nervous system was rarely examined,

the intestinal tract seldom opened, and wounds of the extremities were given

but cursory attention to determine the presence or absence of gross infection,

major vascular involvement, or extensive necrosis of muscle. Blocks of representative tissues were fixed in formalin, occasionally in Zenker’s solution, and

transmitted to the Pathology Section of the 15th Medical General Laboratory

where they were sectioned and the histologic findings were reviewed by the

author.

Findings

Lungs

The Board’s cases include no examples of sudden death; hence the lungs

were never normal. Congestion was described in every case; edema in approxi-
286 THE PHYSIOLOGIC EFFECTS OF WOUNDS

mately 85 percent; atelectasis in 70 percent; fat embolism in 65 percent; intraalveolar hemorrhage in 55 percent; interstitial hemorrhage in 25 percent, and

pneumonia in 30 percent. Because two of these lesions, pulmonary edema and

fat embolism, have received considerable attention in relation to the mechanism

of shock, their significance is worth examining in more detail.

Pulmonary Edema.—Estimation of the severity of pulmonary edema is difficult from the available data in view of the large number of prosectors and the

few lung weights recorded. rough classification into three grades has been

attempted for 47 cases in which adequate information was recorded in the necropsy protocols: Grade I, little or no edema (classified as “slight”) with lung

weights probably below 800 Gm.; Grade II, moderate edema with lung weights

between 800 and 1,200 Gm.; Grade III, severe edema with lung weights from

1,200 to 1,800 grams. Fifteen cases were Grade (slight), 14 Grade II (moderate), and 18 Grade III (severe).

Several factors might influence the development of pulmonary edema in

these patients. It has been suggested that pulmonary edema is constant and

integral part of the shock mechanism. It is certainly common sequela of renal

insufficiency, from which large proportion of the patients in this series suffered. It could be due to myocardial failure and evidence will be presented later

in this chapter that myocardial degeneration actually was present in many

cases. It might be influenced by fat embolism and finally it could be brought

about, or at least intensified, by over-enthusiastic intravenous fluid therapy.

In Table 101 the degree of pulmonary edema is compared with the period

of survival in 47 shock cases. The patients dying in less than 48 hours represent

by and large the group in which resuscitation was unsuccessful. One patient

(Case 22) briefly appeared to be resuscitated only to develop two secondary

attacks of circulatory failure, in the last of which he died. These patients may

fairly be considered to have died in, perhaps of, severe and prolonged shock.

Five had minimal, moderate, and only severe edema. All had received repeated infusions of plasma and whole blood.

In the patients who survived into the third or fourth days, it is safe to assume

that shock had disappeared. In the majority of these, incipient renal insufficiency was manifest, and only one patient failed to show nephropathy at

Moon, V. H.: Shock, its mechanism and pathology. Arch. Path. 24; 642—663 (November) and 794— 813 (December), 1937.
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 287

Table i01.—Severity of Pulmonary Edema and Survival Period

in 47 Shock Cases

Board’s Cases

postmortem examination. They were oliguric or anuric, and the plasma nonprotein nitrogen had climbed to levels of 90 to 130 mg. per 100 cc., though few

or no symptoms of uremia were manifest. In nine of these cases there was

moderate or severe pulmonary edema, but since in five of them there was also

histologic evidence of myocardial degeneration, it would be impossible to assess

the relative importance of cardiac and renal factors.

The 25 patients dying from the fifth day onward have been divided into

uremic and non-uremic groups. Pulmonary edema of moderate degree was

present in 6, and of severe degree in of the 17 cases in the former group despite the fact that many of these patients were treated in consultation with clinical members of the Board and the intake of fluid was rigidly restricted. Since

there was histologic evidence of myocardial injury in only patients of this

group, the evidence points strongly to renal insufficiency as the primary cause

of the pulmonary edema. In the non-uremic group, of patients showed

moderate and only severe edema. In this group the most frequent cause of

death was peritonitis.

In summary, pulmonary edema was less frequent and less severe in patients

who were never successfully resuscitated from shock than in those patients who

Survival Period

Number of cases

Pulmonary Edema

Less than or Days

More than Days

Total Cases

48 Hours

Uremic Non-uremic

Grade

(Slight)

15

Grade II

(Moderate)

14

Grade III

(Severe)

18

Total 10 12 17 47
288 THE PHYSIOLOGIC EFFECTS OF WOUNDS

did recover from the acute stage of shock but subsequently displayed evidence

ofrenal insufficiency. Ouranatomic data offer no confirmation for the hypothesis

that loss of fluid into the alveoli is an important factor in the development of

shock.

Pulmonary Fat Embolism.—Pulmonary fat embolism is very frequent

complication of battle casualties, as the 65-percent incidence in the present group

of cases shows. Its significance is extremely difficult to assess. In the early stages

of World War 1, much attention was given to it and it was considered by some

investigators' to be an important, perhaps the most important cause of shock.

Further experience failed entirely to substantiate the hypothesis, the theories

of Bayliss and Cannon became dominant, and fat embolism was forgotten.

Frozen sections were cut and stained for fat in all of the present series of

cases in which lung tissue was available (51 cases). An attempt was made to

estimate the severity of the embolism in three grades as follows: In Grade

only an occasional droplet is seen. In Grade II droplets are fairly numerous; they

are found chiefly in large vessels or arterioles and seldom have passed into the

capillaries of the alveolar walls. In Grade Ilia considerable proportion, quarter

to half or more, of the arterioles are plugged, and in numerous areas capillaries

are filled as if by an injection mass. Systemic fat embolism of significant grade

was never found in association with Grades and II but was present in about

fifth of the cases in Grade III. Judged by experience covering several hundred

battle casualties, the author considers it improbable that Grades and II of

pulmonary fat embolism are functionally significant.

In Table 102 the grade of fat embolism is compared with the degree of

shock. It is apparent from inspection of the table that Grade III fat embolism

was present in only of the 39 cases of moderately severe or severe shock. Conversely, of 10 patients with significant fat embolism, were estimated to have

moderate or severe shock. It is evident that fat embolism is not the cause of

shock in any considerable proportion of cases. Conversely, severe pulmonary

fat embolism was always associated with shock, usually of moderate or severe

Porter, W. T.: Fat embolism, cause of shock. Boston M. S. J. 176; 248, February 15, 1917.

Great Britain. Medical Research Committee. Special Report Series, No. 26. Traumatic Toxaemia

as Factor in Shock. Oxford, His Majesty’s Stationery Office, 1919. IV. Cannon, W. B., and Bayliss, W. M.:

Note on muscle in relation to shock, p. 19—23. V. Bayliss, W. M.: Further observations on the results of

muscle injury and their treatment, p. 23—26. VI. Cannon, W. B.; Some characteristics of shock induced by

tissue injury, p. 27—32,
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 289

degree. To determine whether or not this relationship is causal would require

the study of much larger series of cases than the present one.

Table 102.—Fat Embolism and Shock in 51 Board Cases

Fat Embolism and Pulmonary Edema.—In Table 103 the grade of pulmonary fat embolism is compared with the degree of pulmonary edema. It is

obvious that there is no correlation.

Table 103.—Fat Embolism and Pulmonary Edema in 44 Board Cases

Heart

Material was available from 45 of the Board cases and 61 cases from the

supplemental series, the latter including 10 shock cases and 51 control cases.

Fat vacuolation was found in 24 of the cases from both series. This consisted

Degree of Shock

Grade of Fa

Number

Embolism

of cases

II III

Total Cases

Moderate 11

Severe 11 28

Total 17 16 10 51

Degree of Pulmonary Edema

Grade of Fat Embolism

Number of cases Total Cases

II III

Slight 14

Moderate 14

Severe 16

Total 14 14 44
THE PHYSIOLOGIC EFFECTS OF WOUNDS 290

FIGURE 29. Frozen section of myocardium stained with Sudan IV. The patient died 48 hours after shock-producing wound. Many cells are apparently filled with minute vacuoles,

from to microns in diameter, which appear as bright red granules. The affected cells are

not swollen and the nuclei appear normal. 70

of very minute vacuoles, seldom more than microns in diameter, arranged

in parallel rows between the myofibrils (Fig. 29). When present in cell, the

vacuolation was apparent throughout the cell’s entire length and breadth,

rarely segmentally or focally. It was entirely independent of the amount of

lipochrome demonstrable at the nuclear poles. The affected cell often seemed

slightly swollen in the frozen section but this change could not be recognized

with certainty in the paraffin sections. Sometimes single cells, more often

groups of from 10 to 50 adjacent fibers, were affected. Vacuolation was never

diffuse throughout the myocardium. In appearance it was strongly reminiscent of, though usually less severe than the patchy fat vacuolation seen in severe

anemia. However, no gross changes suggestive of “tigering" were ever noted.

The severity of the change, estimated by the number and size of the vacuoles

per cell and the proportion of cells involved, was roughly quantitated on zero

to 3-plus scale. The degree of involvement is compared with the survival period

in Table 104. It is evident that fat vacuolation of cardiac muscle cells was not

observed in previously healthy young men who developed shock following

trauma but failed to survive at least 18 hours. In patients manifesting shock

who lived from 18 to 96 hours, fat vacuolation of the myocardium was found
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 291

in 75 percent. With longer periods of survival the incidence dropped sharply

to 17 percent, and there were no cases of grade 3-f- severity.

Table 104.—Myocardial Fat Vacuolation in 55 Shock Cases*

Focal fat vacuolation of cardiac muscle cells has been noted frequently by

the author in cases of systemic fat embolism with embolization of the myocardial capillaries. In only two of the group under consideration was this complication present. These two men died on the fifth and sixth days after injury.

If they are excluded, the incidence of fat vacuolation in the patients surviving

more than days falls to percent.

In Table 105 the degree of shock and the severity of fat vacuolation are

compared in 14 patients among those dying within the 18- to 96-hour period

who had been examined during life by clinical member of the Board. The

number of cases is small, but increasing intensity of fat vacuolation is apparent

as shock becomes more severe.

Table 105.—Degree of Shock and Fat Vacuolation of Myocardium in 1/

Board Patients who Survived from 18 to 96 Hours

Survival Period Number of Cases

Grade of Fat

Number

Vacuolatior

of cases Percent

Positive

Less than 18 Hours 10 10

18 to 96 Hours 16 75

More than Days 29 24 17

*45 Board cases and 10 from the supplemental series.

Degree of Shock

Grade of Fat Vacuolation

Number of cases

Slight

Moderate

Severe
THE PHYSIOLOGIC EFFECTS OF WOUNDS 292

Control Cases.—A group of 51 non-shock control cases is shown in Table

106, They include number of instances of sudden death and miscellaneous

group of medical conditions. Since fat vacuolation can be produced in experimental animals by short periods of starvation/' *’

it seemed appropriate to study

some cases of starvation deaths from prison camps. And, because fatty change

in the myocardium has long been recognized as sequela of severe anemia,

series of cases of aplastic anemia was included. Analysis of the material from

the point of view of the presence or absence of peritonitis, an important factor

in relation to liver and adrenal lesions, yielded no evidence that infection was

important in the production of the myocardial changes.

Table 106.—Fat Vacuolation of Myocardium in 51 Control Cases

Summary.—Fat vacuolation of cardiac muscle fibers is pathologic process

not seen in previously healthy persons who die suddenly or who die following

shock-producing injury in period of less than 18 hours. It is found in

75 percent of individuals who have survived similar injury for periods of

18 to 96 hours, but becomes unusual in those living more than days after

injury. In small sample group the degree of fatty change appeared to parallel

the severity of shock. Though the lesion is found inconstantly in variety of

medical conditions, particularly those associated with severe grades of anoxemia,

the frequency is considerably below that observed following shock.

Dible, J. H.: Fat mobilization in starvation. J. Path. Bact. 35: 451—466, May 1932.

Dible, J. H., and Libman, J.: Further observations on fat mobilization in starvation. J. Path. Bact.

38: 269—284, May 1934.

Type of Case Number ofCases

Grade of Fat Vacuolation

Number of cases Percent

Positive

Sudden Deaths .... 15 15

Starvation Deaths 12 12

Deaths from Aplastic

Anemia ......

33

Miscellaneous

"Medical” Deaths. 15 11 27
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 93

FIGURE 30. Frozen section of liver stained with Sudan IV. The patient died 72 hours after

shock-producing wound. The illustration shows the center of lobule with some fine fat

vacuolation of all visible liver cells. 400

Liver

Fat vacuolation of the liver appears in such variety of conditions and may

be present in so many apparently normal individuals that one is often tempted

to regard it as not significant unless the amount is very great. The usual form

observed consists of vacuoles of considerable size, ranging from to 20 microns

in diameter. Such vacuoles are readily visible in paraffin sections with low

magnification (from 16- to 30-mm, objectives) inasmuch as they occupy the

full thickness of the section and appear as sharply outlined holes. Because of

their large size there are never many vacuoles in single cell.

Fat vacuolation of this type was rarely seen in shock cases, and when found

probably existed before the shock-producing injury. Extensive fat vacuolation

was nevertheless readily demonstrable in shock if sufficient time had elapsed

for its development. This form of fat vacuolation consisted almost entirely of

very fine droplets in the range from to microns in diameter (Fig. 30). Even

when the process was severe, though slightly larger droplets were found, there

was little tendency for them to fuse, and as many as 15 or 20 might be present

in single cell. The vacuolation is readily seen in paraffin sections if the 4-mm.

lens is used. Few of them extend through the thickness of the section, but two

or more layers can be seen by varying the depth of focus. Because of the small
THE PHYSIOLOGIC EFFECTS OF WOUNDS 94

size of the vacuoles, seme difficulty may be experienced in frozen sections in

distinguishing them from the normal pigment which is often slightly sudanophilic. The fat vacuoles are little larger than the pigment granules and are

rounder. Very often they show crescentic intensification of the stain on one

margin.

The affected cells in the initial stages were always centrally located in the

lobule; with increasing severity the involvement spread to the periphery. There

was little evidence of swelling of the cells and the organ as whole was not

enlarged, yellow, or greasy. For this reason it seems improbable that the

amount of fat in the liver could have been greatly increased, though check

by chemical methods would be necessary to decide this point.

The occurrence of small-droplet fat in relation to the survival period in

51 Board cases is shown in Table 107, It is evident that in shock patients surviving from 18 to 96 hours, moderate to severe fat vacuolation was an almost

constant finding. With longer survival periods, the proportion of cases with

mild or no fat vacuolation increased but instances of severe vacuolation were

still found. In reviewing the group of 31 patients who survived more than

days, it became apparent that severe fatty changes were particularly frequent

in patients with peritonitis, the only common cause of prolonged sepsis in this

series. Th is is also shown in the table.

Table 107.—Fat Vacuolation in the Liver in 51 Shock Cases,* and Influence

of Peritonitis in Patients Surviving Longer than Days

Since 26 of the 51 Board cases were complicated by peritonitis, the significance of the figures in Table 107 is open to doubt. In Table 108, which includes

28 supplementary cases from the 15th Laboratory, all cases of peritonitis or

Survival Period Number ofCases

Grade of Fat Vacuolation

Number of cases Percent

Grades

and

to 96 Hours. 20 15 90 More than Days. 31 12 48

With Peritonitis 14 71

No Major Infection 17 29

*Board cases only.
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 295

other major sepsis have been excluded. In this selected series, it is apparent

that fat vacuolation of more than minimal degree was seldom seen in shock

patients who failed to survive at least 18 hours. Of those who survived from

18 to 96 hours, 87 percent showed the presence of fat, 59 percent in moderate

or severe degree. With survival beyond 96 hours, the tendency to return to

normal is seen, the total dropping to 47 percent and that for the more severe

grades to 29 percent.

Table 108.—Centrolobular Fat Vacuolation of Liver Cells in 53 Shock

Cases Uncomplicated by Major Infection*

Control Cases.—Since fat vacuolation of the liver is such common phenomenon and can be produced by so many etiologic factors, numerous control

cases seemed necessary. Seventeen instances of sudden death were selected at

random from the laboratory files. Fifteen cases of “medical” deaths (cardiac,

cerebral, nephritic) without obvious shock-like states, 20 instances of death

from aplastic anemia, and 38 starvation deaths were included—a total of 90

control cases. The incidence of centrolobular fat vacuolation in 36 shock cases

and 90 controls is shown in Table 109.

The occurrence of moderate or severe fat vacuolation in 24 percent of the

sudden-death group is worthy of comment. This group was compiled largely

from motor-vehicle accident and homicide cases in base-section troops. The

proportion of limited-service personnel and older men was higher in such

troops than in combat organizations. Two of the men in the group studied

had been intoxicated at the time of death and had enlarged, grossly fatty livers

suggestive of chronic alcoholism. In contrast, the acute-shock group, with survival periods shorter than 18 hours, was made up almost entirely of battle

Survival Period Number

of Cases

Grade of Fat Vacuolation

Number of cases Percent

Positive

Percent

Grade

2+ or

Less than 18 Hours .... 14 11 22 8.2

18 to 96 Hours 22 87 59

More than Days 17 47 29

Includes 25 Board cases and 28 supplementary shock cases.
296 THE PHYSIOLOGIC EFFECTS OF WOUNDS

casualties, all previously healthy and vigorous young men, and therefore represents better control group than the “sudden deaths.” The relatively high

incidence (40 percent) in the miscellaneous medical deaths is not surprising

in view of the multiple etiology of fat deposit in the liver, but is still not as

high as the frequency (59 percent) in the 18- to 96-hour shock group. The

low incidence in the anemia group proved surprising in view of the known

frequency of myocardial fat vacuolation in such conditions. The starvation

cases provided most interesting contrast to the shock material. Although fat

was present in the majority of these cases, it was always manifest at the periphery,

never at the center of the lobule.

Table 109.—Centrolobular Fat Vacuolation of Liver in Shock Cases

and Controls

Summary.—Eighteen hours after shock-producing injury, fat vacuolation

was demonstrable in the liver cells at the center of the lobule in 87 percent

of 53 cases uncomplicated by major infection and was of moderate or severe

grade in 59 percent. After the fourth day it tended to disappear in cases uncomplicated by peritonitis. The incidence in the 18- to 96-hour cases was somewhat higher than in any of the control group studied.

Type of Case Number of Cases

Grade of Fat Vacuolation

Number of cases Percent

Grades

2+or

SHOCK CASES

Less than 18 Hours’

Survival 14 11 8.2

18 to 96 Hours’

Survival 22 59

CONTROLS

Sudden Deaths 17 24

Miscellaneous

"Medical” Deaths. 15 40

Deaths from Aplastic

Anemia 20 10 20

Starvation Deaths 38
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 297

Kidney

The histologic changes in the kidney following shock have been described

in detail in Chapter IX. Fat vacuolation in the ascending limb of Henle’s loop

(see Figures and 10, Chapter IX) was shown to be the first definite histologic

evidence of renal injury. In the present analysis, only this feature of the numerous renal changes which may develop will be considered. The findings in 90

cases are summarized in Table no. Supplementary shock cases, as previously

described, have been added to the Board’s cases.

Table no.—Fat Vacuolation of Ascending Limbs of Henle in 90

Shock Cases

As in the heart and liver, fat vacuolation was rarely found in shock patients

surviving less than 18 hours after injury. It was already present in 55 percent

of the 18- to 24'hour group and was evident in 85 percent of those surviving

from to days. With survival beyond that period it decreased somewhat in

frequency to 58 percent, and considerably in severity, the 2-f- and 3+ grades

dropping from 81 percent to 39 percent. In the kidney as in the heart, the

severity of fat vacuolation was uninfluenced by the presence or absence of

peritonitis.

Control Cases.—The degree of fat vacuolation in the ascending limbs in

55 control cases is shown in Table in. Fat vacuolation in the ascending limbs

of Henle’s loop is found with sufficient frequency (43 percent of the “medical”

deaths in the present group) to have led some authors to consider it normal.

Mollendorf, Wilhelm von, ed. Handbuch der mikroskopischen Anatomic des Menschen Berlin,

J. Springer, 1930. vol. VII, Part I. Harn- und Geschlechtsapparat, p. 86.

Survival Period Number

of Cases

Grade of Fat Vacuolation

Number of cases Percent

Positive

Percent

Grade

or

Less than 18 Hours .... 20 17 15

18 to 24 Hours 11 55 45

24 to 96 Hours 26 17 85 81

More than Days 33 13 58 39
298 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Its complete absence in 19 cases of sudden death and its presence in only 15

percent of 20 shock cases representing patients who died in less than 18 hours

following injury clearly indicate that it is not normal finding in healthy

young men in the 18- to 35-year age group. Dible has shown that fat rapidly

appears in this segment of the nephron in starvation experiments in rabbits.

The data on starvation deaths included in our series showed an incidence of

50 percent, with 38 percent of 2-(- or 3-f- grade. These figures are nevertheless

well below those (85 percent and 81 percent) of the 1- to 4-day shock cases

shown in Table no.

Table hi.—Fat Vacuolation of Ascending Limbs of Henle in 55

Non-Shock Control Cases

Summary.—Fat vacuolation of the ascending limbs of Henle’s loop is abnormal in men from 18 to 35 years of age. It was found in only 15 percent of

shock patients dying in less than 18 hours but was present in 85 percent of

shock patients surviving from to days after injury. From the fourth day

onward, decrease in frequency and severity was demonstrable, regardless of

whether hemoglobinuric nephrosis developed.

Adrenal

normal adrenal gland is rarely seen at necropsy by the civilian pathologist

who does not have opportunity to perform postmortem examinations upon

See footnotes and 6.

Dible, J. H., and Popjak, G.: Distribution of fatty change in kidneys and some factors influencing

its production. J. Path. Bact. 53: 133—146, July 1941.

Type ofCase Number of

Cases

Grade ofFat Vacuolation

Number of cases Percent

Positive

Percent

Grade

or

Sudden Deaths 19 19

Miscellaneous

"Medical” Deaths 14 43 22

Starvation Deaths. 12 50 38

Deaths from Aplastic

Anemia 10 25 13
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 99

persons who have died suddenly without previous disease. The adrenal gland

of the healthy young male has narrow cortex which ranges from i.o to 1.3

mm. in width. The cells are richly packed with lipid (stainable with Sudan

IV), predominantly in the fascicular layer, but numerous vacuoles are also

demonstrable in the zona glomerulosa and reticularis. Limited to the zona

reticularis are large quantities of doubly refractile lipid which serve to outline

this layer sharply when viewed with crossed Nicol prisms.

In our shock cases no medullary changes but variety of cortical changes

were observed. The amount of stainable lipid decreased and the optically active

fraction was markedly depleted. The cortex was slightly swollen and frequently

showed the pseudoacinar type of degeneration described and illustrated by

F. B. Mallory in 1914,10 more recently emphasized by Rich 11 in relation to

sepsis, and noted by Mallory and Brickley 12

in the burn victims of the Cocoanut Grove disaster. The changes observed did not differ qualitatively from

and were less severe quantitatively than those of sepsis or of such control conditions as aplastic anemia and starvation, though some degree of terminal

infection may have complicated much of this control material. Only one feature, the doubly refractile lipid depletion, showed evidence of reversibility with

recovery from shock.

In Tables 112 and 113 the stainable and the doubly refractile lipids are

compared in group of 40 shock cases free from septic complications and

control group of 18 cases of sudden death. The amount of lipid, as in other

organs, was visually estimated on zero to 3-}- scale. In this instance, however,

the maximal 3-f figure represents the normal and zero the stage of maximal

depletion.

moderate depletion of the total stainable fat is evident in the shock group

surviving from 18 to 96 hours. There is, however, no evidence of return to

normal with longer intervals of survival after recovery from shock; the process

is, in fact, much intensified in the group surviving more than days. In contrast to the stainable lipid, the doubly refractile fraction was occasionally below

the usual level in cases of sudden death (17 percent) and was depleted in

“Mallory, F. B.t Principles of Pathologic Histology. Philadelphia, W. B. Saunders, 19x4, p. 653. 11 Rich, A. R.: Peculiar type of adrenal cortical damage associated with acute infections, and its possible

relation to circulatory collapse. Bull. Johns Hopkins Hosp. 74: 1—15, January 1944. 12 Mallory, T. B., and Brickley, W. J.: Symposium on management of Cocoanut Grove burns at the

Massachusetts General Hospital; pathology, with special reference to pulmonary lesions. Ann. Surg. 117;

865—884, June 1943.

956507 0—52 24
300 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 112.—Stainable Lipids in Adrenal Cortex in 40 Shock Cases without

Infection and 18 Cases of Sudden Death

Table 113.—Doubly Refractile Lipids in Adrenal Cortex in 40 Shock Cases

without Infection and 18 Cases of Sudden Death

27 percent of shock patients dying in less than 18 hours, in one case severely

depleted. In the shock cases of 18 to 96 hours’ survival, this type of lipid was

diminished in all but one instance (92 percent of the cases) and markedly so

Type of Case Number of

Cases

Amount of Lipid

Number of cases Percent

Diminished

Percent

Greatly

Diminished

SHOCK CASES

Less than 18

Hours’ Survival. 11 11

18 to 96 Hours’

Survival ....

13 38 15

More than Days’

Survival .... 16 75 25

CONTROLS

Sudden Death 18 18

Type of Case Number of

Cases

Amount of Lipid

Number of cases Percent

Diminished

Percent

Greatly

Diminished

SHOCK CASES

Less than 18

Hours’ Survival. 11 27

18 to 96 Hours’

Survival ....

13 92 61

More than Days’

Survival .... 16 81 38

CONTROLS

Sudden Death 18 15 17
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 01

in eight cases, or 61 percent. In those patients surviving more than days,

some evidence of tendency to return to normal is shown by drop in the

percentage of severe depletion from 61 to 38 percent.

Control Material.—It was difficult to know what kind of control material

would be suitable inasmuch as most types of illness which lead to death produce similar and even more marked adrenal changes. Four groups of control

cases are listed in Table 114. It is evident that wide variety of factors affect

the storage of lipidic substances in the adrenal cortex, many of them more

profoundly than does shock.

Table 114.—Adrenal Cortical Lipids in 44 Control Cases

Summary.—Although numerous changes occur in the adrenal cortex following shock, they do not differ in character from, and are less severe than

those seen in infection and in wide variety of lethal disorders. The only factor

which was found to change abruptly 18 hours after shock-producing injury

was the amount of doubly refractile lipid in the zona reticularis. This was

diminished in 92 percent of the cases in the 18- to 96-hour group (Table 114).

This factor also was the only one in which any tendency could be established

to return toward normal with increasing time intervals following recovery

from shock.

COMMENT

The possible roles of pulmonary edema and of fat embolism in the pathogenesis of shock in men wounded in battle have been discussed in the sections

devoted to these phenomena. The pattern of parenchymal degenerative changes

Stainable Fat Doubly Refractile Lipids

Type of Case Number of

Cases Percent

Diminished

Percent

Greatly

Diminished

Percent

Diminished

Percent

Greatly

Diminished

Miscellaneous "Medical” Deaths. 14 50 22 79 29

Starvation Deaths 78 44 100 78

Deaths from Aplastic Anemia 11 82 18 91 91

Fatal Cases with Infection .... 10 100 80 100 100
02 THE PHYSIOLOGIC EFFECTS OF WOUNDS

described in the heart, liver, kidneys, and adrenals deserves further consideration as probable consequence of shock. None of the changes described are

specific for the state of shock. Fat is known to make its appearance in one or

another of these organs in response to variety of pathologic conditions such

as anoxemia, starvation, and chemical or bacterial toxic agents—and lipids

disappear from the adrenal under an even greater variety of conditions. Critical

examination of the data is therefore necessary before concluding that the observed changes were due to shock.

Errors of subjective interpretation in relying upon such vague changes as

“parenchymatous degeneration” and “cloudy swelling,” which are readily confused with postmortem degeneration and the artefacts of faulty histologic

technique, have been avoided by the use of frozen sections and fat stains;

general histologic experience indicates that there is no significant shift in the

proportion of stainable fat up to 12 hours after death. Less is known of the

behavior of doubly refractile lipids, but in the material included in this study

no evidence was discovered that this fraction of the fatty substance was affected

by postmortem degeneration within the same time limit. The observed variations from the normal are therefore vital phenomena.

Next in importance are the time relationships to shock. Table 115 shows

the percentage of all cases with abnormal fat vacuolation in the heart, liver,

and kidney, and depletion of the doubly refractile lipid in the adrenal, for

each group and for the sudden-death control group. In each of the four organs

studied no significant difference in demonstrable fat is apparent between the

sudden-death series and the shock cases in which death occurred in less than

18 hours. Abnormal changes are evident, however, in these organs in from

75 to 92 percent of shock patients who survived from 18 to 96 hours after injury.

The almost synchronous appearance of the lesions 18 hours after injury in all

four organs suggests single causative factor. The delay in appearance of the

morphologic evidence of injury in many instances until shock has been relieved

is not incompatible with causal relationship. Days and even weeks may intervene between injury and reaction with such widely varying agents as diphtheria

toxin and x-rays.

Of equal importance in establishing an etiologic relationship between shock

and the lesions which have been described is evidence of reversibility, of return

to or at least toward normal with increasing intervals after the episode of shock.

As all the necropsy material in this series necessarily derived from individuals
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 3°3

with lethal disorders, it is not surprising that complete return to normal was

not usually demonstrable. Clear evidence of tendency to reversibility is shown

in Table 116, in which the more severe grades of changes in the 18- to 96-hour group are compared with those in the group surviving days or longer. It is

noteworthy that the time interval before recovery was demonstrable was essentially the same for all four organs, the change becoming demonstrable on the

fourth day in each instance. The possible contention that the changes described

were merely agonal, like depletion of liver glycogen, is refuted by this evidence

of reversibility in large number of cases progressing to fatal outcome due

to other factors.

Table 115.—Incidence of Abnormal Fat Changes in the Heart, Liver,

Kidney, and Adrenal in Shock Cases and Control Cases

of Sudden Death

Table ii6.—Incidence of Severe Fatty Changes in Shock Cases

Though it has been repeatedly stressed that none of the changes described

can be considered pathognomonic of shock, it is not impossible that the pattern

Type of Case

Heart

percent

of cases

Liver

percent

of cases

Kidney

percent

of cases

Adrenal Gland

(Depletion of

doubly refractile

lipid)

percent of cases

SHOCK CASES

Less than 18 Hours’ Survival 22 15 27

18 to 96 Hours’ Survival 75 87 76 92

More than Days’ Survival 17 47 58 81

CONTROLS

Sudden Death 24 17

Period of Survival

Heart Liver Kidney Adrenal Gland

percent of cases percent of cases percent of cases percent of cases

18 to 96 Hours 50 59 81 61

Days or Longer .... 12 29 39 38
3°4 THE PHYSIOLOGIC EFFECTS OF WOUNDS

of changes may be. This is suggested by the data shown in Table 117. The incidence of the lesions under consideration has been compared in shock patients

surviving from 18 to 96 hours with three groups of control cases: miscellaneous group of “medical” deaths, group of aplastic anemia fatalities, and

one of starvation deaths. Only in the shock group did more than three-quarters

of the cases show involvement of all four organs.

Subsequent to making the observations upon the adrenal gland which we

have recorded, our attention was called to the investigations of Popjak 13 on the

lipids in the rat adrenal in experimental shock. He found swelling of the cortex

and marked depletion of both stainable and doubly refractile lipid. This occurred regularly 15 to 24 hours after the shock-producing crush injury, time

interval essentially the same as in our human material. In his animals restoration

to normal in 48 hours was the rule.

Table 17.—Distribution of Lesions in Control Groups Compared with

Shock Cases

We have little evidence of what the significance of these lesions may be

from the functional point of view. The renal lesion has already been discussed

in Chapter IX. No electrocardiograms were made on these patients and no determinations of adrenal cortical hormone excretion were made. In Chapter II

the results of bromsulfalein tests in shock patients were discussed. transitory

period of retention of the dye was observed, which it seems reasonable to cor13Popjak, G.: Lipids of rat adrenal in shock caused by experimental crushing injury. J. Path. Bact.

56: 485—496, October 1944.

Type of Case

Heart

percent of cases

Liver

percent of cases

Kidney

percent of cases

Adrenal Gland

percent of cases

SHOCK CASES

18 to 96 Hours’ Survival 75 87 76 92

CONTROLS

Starvation Deaths .... 50 100

Deaths from Aplastic

Anemia 33 20 25 91

Miscellaneous "Medical”

Deaths 27 40 43 79
GENERAL PATHOLOGY OF TRAUMATIC SHOCK 3°5

relate with the fatty changes in the liver which have been described. Although

no morphologic evidence of bile stasis was observed in liver sections, the possibility of hepatic as well as hemolytic factor must be borne in mind in

interpreting the elevated plasma bilirubin often noted in these patients.

SUMMARY AND CONCLUSIONS

Two morphologic phenomena which have been implicated in the pathogenesis of shock, pulmonary edema and pulmonary fat embolism, were studied

in series of fatal battle casualties. Pulmonary edema was found to be too

inconstant and too late in development to be an important factor in the initiation of shock in severely wounded men. Pulmonary fat embolism proved to be

frequent coincidental lesion. It was absent or minimal in degree in the

majority of cases, and its significance in the small remaining proportion could

not be established.

standard pattern of visceral changes was found in patients with traumatic

shock who survived minimum of 18 hours after injury. This consisted of fat

vacuolation of the heart, the central cells of the liver lobules, and the ascending

limbs of Henle’s loops in the kidney. In the adrenal gland, the doubly refractile lipid became depleted after the same time interval. In all four organs these

changes persisted for days after injury. From the fourth day onward in cases

uncomplicated by infection, tendency to return to normal could be demonstrated. The incidence of this pattern of changes proved higher in shock cases

than in variety of control material. It was concluded that they constitute

evidence of parenchymatous injury produced by shock.

APPENDIX

Organization and Operation

of the Board for the Study

of the Severely Wounded

North African (later Mediterranean) Theater of Operations, U.S.A.

ORGANIZATION

The background of events and observations leading to recognition of the

need for an organized study of the severely wounded in an active theater of

war has been described in the Introduction to this volume. The Chief Surgeon,

North African Theater of Operations, Maj. General Morrison C. Stayer,

U.S.A., discussed this problem with two members of his staff, Colonel Edward

D. Churchill, MC, Surgical Consultant, and Colonel William S. Stone, MC.

On their recommendation he initiated action from which stemmed the Board

whose work has been presented in this volume. His memorandum to the

Commanding General follows.

HEADQUARTERS

NORTH AFRICAN THEATER OF OPERATIONS

Office of the Surgeon

September 1944

SUBJECT: Appointment of Medical Board to Study theTreatment of the Severely

Wounded

TO: Quartermaster, Ordnance, G-i, G-4 and AG

1. Outstanding progress in the treatment of the wounded has been made by

the Medical Service in this theater. Many lives have been saved by this work and

many individuals that would have been hopeless wrecks, if they survived, have been

rehabilitated into normal or near normal individuals. Further progress in improving the Medical Service will depend upon proper and timely employment of the
308 THE PHYSIOLOGIC EFFECTS OF WOUNDS

skilled and experienced medical personnel present in the theater. There are several

urgent problems that should have additional study if progressive medical service is

to be maintained. On the Surgical Service, there is increasing evidence that the

recovery of some of the severely wounded is handicapped by renal lesions that complicate treatment or are sequelae of the original injury. In addition, there have been

some observations made on wounded troops that clinical condition which has been

labeled pulmonary edema is frequently encountered. Because of the above it is

considered desirable that the whole problem of resuscitation of wounded be critically

studied by competent, experienced clinicians and that the results of this work be

made available to the Medical Service of this and other theaters.

2. It is therefore requested that Board be appointed by the Commanding

General, NATOUSA, for the study of designated phases of the treatment of the

severely wounded, the Board to operate directly under the Surgeon, NATOUSA,

who will be responsible for the administration and supervision of the technical and

professional details of the Board’s work.

a. The Board will be made up of the following personnel:

MEDICAL PERSONNEL

Lt. Col. Tracy B. Mallory, O-518569—15th Medical Gen. Lab.

Lt. Col. F. A. Simeone, O-400993—Surgeon’s Office, NATOUSA

Lt. Col. H. K. Beecher, O-526881—Surgeon’s Office, NATOUSA

Major E. R, Sullivan, O-398217—6th General Hospital

Captain C. H. Burnett, O-356977—94th Evacuation Hospital

CHEMISTS

Captain S. L. Shapiro, O-509728—15th Medical Gen. Lab.

NURSES

2nd Lt. Gladys E. Maroon, N-742599—21st General Hospital

2nd Lt. Helen G. Woodman, N-741233—21st General Hospital

OFFICER Branch Immaterial (may be limited service).

One (1) Lieutenant or Captain. Request that temporary detail be made from Replacement Pool.

ENLISTED PERSONNEL Ten (10)

Sergeant—Showstack, Paul J., ASN 31297297—Medical Museum

Chemistry Technicians:

—T/4 Babb, Benjamin F., ASN 33521601—15th Med. Gen. Lab.

—T/3 Guin, Carlos F., ASN 18033517—15th Med. Gen. Lab.

General Laboratory Technician: 2nd Medical Laboratory

Clerks, Typists) Enlisted Men Qualified as drivers, tent handlers, general utilities, etc.

To be obtained on Temporary Duty from Replacement Pool.

TRANSPORTATION

Cars

personnel carrier truck

Mobile Laboratory (complete with equipment and supplies (as defined

by the Board) to be obtained from the 15th Med. Gen. Lab.)
APPENDIX 3°9

VEHICLES carrying equipment used by the Board for the Study of the Severely Wounded

pause before bomb-damaged building in Monghidoro.

TENTAGE Seven (7) Pyramidal Tents

3. Personnel involved will be on temporary duty status while assigned to

the Board and will be relieved of all other duties while so assigned. Upon completion of their work, theBoard will render report of their findings and recommendations to the Surgeon, NATOUSA. Progress reports will also be made when findings

would indicate that immediate advantage should be taken of the scientific data

obtained by the Board.

4. If requested by the Board, all Medical Installations coming under the jurisdiction of this Headquarters will, in every way possible, aid the Board in its work.

5. Medical supplies and equipment not obtainable at units where the Board

is functioning, will be furnished, as requested by the Board, from Medical depot

stocks on 90-day shipping ticket. All supplies, equipment and transportation to be

returned to proper organization or depot upon completion of temporary duty.

6. Verbal concurrence has been obtained from all other Headquarters and

units involved.

For the SURGEON:

E. STANDLEE, Colonel, MC
10 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Lt. General Jacob B. Devers, Commanding General, North African Theater

of Operations, recognizing that lives might be saved by means of such study,

gave his immediate support to the project. Only two days after the date of the

original memorandum from his Chief Surgeon, he published the following

order establishing the Medical Board to Study the Treatment of the Severely

Wounded. (This title was later commonly abbreviated to the Board for the

Study of the Severely Wounded.) The Board was made directly responsible

to the Chief Surgeon of the Theater.

HEADQUARTERS

NORTH AFRICAN THEATER OF OPERATIONS

UNITED STATES ARMY

September 1944

SUBJECT; Appointment of Medical Board to Study the Treatment of the Severely

Wounded

TO: All Concerned

1. Board of Officers, consisting of the following officers:

LT COL TRACY B. MALLORY O-518569 MC 15th Medical General

Laboratory

LT COL FIORINDO A. SIMEONE ©-400993 MC Medical Section, AFHQ LT COL HENRY K. BEECHER 0-526881 MC Medical Section, AFHQ MAJOR EUGENE R. SULLIVAN 0-398217 MC 6th Gen Hosp on T/D Med Sec, AFHQ CAPT CHARLES H. BURNETT O-356977 MC 94th Evac Hosp, Semimobile

CAPT S. L. SHAPIRO O-509728 SnC 15th Medical General

Laboratory 2nd LT GLADYS E. MAROON N—742599 ANC 21st General Hospital 2nd LT HELEN G. WOODMAN N-741233 ANC 21st General Hospital

is appointed for the study of designated phases of the treatment of the severely wounded. Officers involved will be on temporary duty status while assigned to

the Board and will be relieved of all other duties while so assigned.

2. The Board will operate directly under the Surgeon, NATOUSA, who will

be responsible for the administration and supervision of the technical and profes- sional details of the work of the Board. Upon completion of work, the Board will render report of their findings and recommendations to the Surgeon, NATOUSA.

By command of Lieutenant General DEVERS:

R. E. LINES, Captain, AGD

Asst. Adj. Gen.
APPENDIX 11

PERSONNEL AND EQUIPMENT

In addition to the members of the Board, the nucleus of which consisted

of those officers who had already been working both individually and as team

on various preliminary studies, sizable group of full-time technical and

administrative assistants was found necessary and was attached to the Board

on temporary duty. First Lieutenant William H. McMahon, INF, of the yth

Replacement Depot served for short time as administrative officer. Captain

Louis D. Smith, SnC, who had been working with the Board from the beginning, was formally assigned to the Board in December.

The two nurses originally assigned to the Board, Second Lieutenants Gladys

E. Maroon, ANC, and Helen G. Woodman, ANC, 21st General Hospital, were

succeeded by Second Lieutenants Rose C. McDonnell and Marguerite V. Cronin,

ANC, 6th General Hospital, who later were succeeded by First Lieutenants

Florence L. Giberti and Phyllis G. Madden, ANC. Also attached to the Board

were Second Lieutenant (then T/Sgt.) Louis Breslow, MAC, and Sergeant

Paul J. Showstack, 3d Medical Detachment, Museum and Medical Art Service,

the former as documentary artist and the latter as photographer.

The following enlisted laboratory technicians were assigned to duty with

the Board: T/3 Carlos F. Guin, Jr. and T/4 Benjamin F. Babb, of the 15th Medical General Laboratory; Pfc. Earl R. Zea, Pfc. George L. Williams, Pfc.

James A. Donaldson, and Pvts. Clyette S. Alligood, Donald M. Campbell, and

Walter C. Huhn, Jr., all of the 7th Replacement Depot. T/Sgt. Carl A. Sauget,

T/Sgt. Anthony N. Ashute (later replaced by T/3 Edwin A, Rooney), and

T/4 Billy D. Ashley (replacing Sgt. Guin) were later added to the enlisted

personnel. Sergeant Babb was chief medical technician.

Basic equipment available was as listed in the original memorandum from

the Chief Surgeon. Supplies and equipment not obtainable at units where the

Board was functioning were to be furnished from depot stocks on 90-day

basis. In addition, arrangements were made for continuous supply of distilled water and standard solutions, and for replacements of supplies and expendable laboratory equipment from the 15th Medical General Laboratory via

the “blood-plane” (a plane placed at the disposal of the 6713th Blood Transfusion Unit to forward blood from the base section bleeding unit to the advance

distributing unit). It was planned to set up as much laboratory equipment as

possible in tent. Since, however, some delicate apparatus might be inadequately

protected under canvas, the mobile laboratory truck of the 15th Laboratory was
12 THE PHYSIOLOGIC EFFECTS OF WOUNDS

placed at the Board’s disposal. Details of the organization and operation of the

field laboratory appear in Appendix B.

DEFINITION OF OBJECTIVES

After discussion among Board members in consultation with Colonel

Churchill and Colonel Stone, it was agreed that the major problems for investigation should be: (i) Physiologic and metabolic studies of the severely wounded;

(2) adequacy of shock resuscitation therapy; (3) possible hazards of transfusion with type blood, and (4) the mechanism of renal insufficiency following resuscitation from shock. The investigative program of the Board, although developed along diversified and varied lines, remained focused on these

primary broad objectives.

MANNER OF OPERATION

It was evident that the objectives of the study as defined could be approached

only by selection of base of operations which would meet all of several essential requirements: i. Facilities for rationing, housing, and other administrative

support of the Board. 2. Access to an adequate number of severely wounded

men. 3. Observation of the severely wounded at the earliest possible time after

wounding but under such circumstances that patients included in the study

normally would remain available for observation through the period of resuscitation (including surgery) and at least the immediate postoperative phase

of treatment. 4. Utilization of an installation in the established chain of evacuation, thereby avoiding establishment of special facilities. Obviously aid stations,

collecting stations, and clearing stations met only the second of these requirements. General hospitals failed to meet either the second or third. Forward

hospitals, i. e., either evacuation or field hospitals as employed in the combat

zone in Italy, satisfied the general requirements. The size of the research unit,

however, precluded attachment to platoon of field hospital. It was not too

great for an evacuation hospital and selection of base was thus determined.

On 19 September 1944,therefore, with equipment loaded on 2V2-ton truck,

two Command and Reconnaissance cars and the overload transported by the

“blood plane,” the personnel of the Board reported to Fifth Army Headquarters

and proceeded to the 94th Evacuation Hospital at Pratalino, few miles north

of Florence, Italy. During the greater part of the 8-month period of the study
APPENDIX

(September 1944 to May 1945) the Board remained with this hospital. For

2-month period it was attached to the 24th General Hospital, and during that

time two members of the Board alternated at platoon of the 32nd Field Hospital while another was making biochemic tests at the 8th Evacuation Hospital.

This was at the time of the push of the 10th Mountain Division, and illustrates

one method by which extensive data were obtained on casualties in several areas

during periods of maximum military activity.

system of study gradually evolved as work poured in. The hospital provided special ward tent in which all patients under study were concentrated

following operation. The Board supplied the nursing service, but primary responsibility for professional care remained in the hands of the hospital staff.

The clinical members of the Board supervised the study ward and looked over

new admissions to the hospital shock ward to select cases suitable for study.

Liaison was rapidly established with nearby field and evacuation hospitals whose

staffs kept the Board informed of cases appropriate for inclusion in the main

study. Daily trips were made by two or more members of the Board to many

of these hospitals to examine patients, record intakes and outputs, keep follow-up

notes, copy histories, pick up blood and urine specimens, and occasionally take

part in necropsies. Suitable clinical cases were abundant and the laboratory was

often hard pressed to keep up with material.

The Board functioned in close and unified manner, with all members

contributing to the whole task. Individual members assumed responsibility for

various phases of the work. Lt. Colonel Mallory, who acted as chairman of the

Board, was in charge of the pathologic aspects of the work and directed the

laboratory. He made numerous postmortem examinations, supervised others,

and from time to time took the accumulated material back to the 15th General

Laboratory for histologic study. Lt, Colonel Simeone was primarily responsible

for determinations of blood volume, as well as cardiovascular findings. Lt.

Colonel Beecher was responsible for the liver function studies, and, with Lt.

Colonel Simeone, for almost all the admission blood volume data. He was collator of the final report. Lt. Colonel Sullivan was in charge of hematologic

aspects and, with Captain Smith, made the studies of blood groups and isoagglutinins, and worked with Lt. Colonel Mallory on some of the pathologic

studies, particularly on pigment. Major Burnett carried out the kidney function

studies and directed, with Lt. Colonel Simeone, the postoperative therapy and

the collection of biochemic data. Captain Smith handled bacteriologic prob-
THE PHYSIOLOGIC EFFECTS OF WOUNDS 3M

lems. Captain Shapiro was in charge of laboratory work and collaborated in

the preparation of the biochemic data.

All medical installations within the Theater had been directed to aid the

Board in its work, and everywhere the Board met whole-hearted cooperation.

Since it was not administratively self-contained, the Board and its ancillary personnel were dependent on the various hospitals to which they were attached

for quarters, rations, standard supplies, and other administrative essentials, including transportation beyond that immediately available. (As stated previously, special supplies were obtained from the 15th General Laboratory.) In

addition, high degree of professional cooperation was essential in selecting

cases for special study and making them available for such study without interference with required treatment which remained the responsibility of the hospital staff.

DISSEMINATION OF PROGRESS REPORTS

It was recognized that observations and tentative conclusions based on the

Board’s work should be disseminated as promptly and widely as possible. This

policy would have the double advantage of making significant findings available for immediate general application and of facilitating the Board’s work as

the result of understanding and interest on the part of the medical staffs from

whom cooperative effort might be required. Therefore from time to time, findings were published in the Theater medical bulletin, discussed at medical meetings in the Theater, and circulated throughout other theaters and through The

Surgeon General’s Office by means of Essential Technical Medical Data reports.

Personal contacts, however, were probably the most rapid and effective means

for widespread dissemination of reports of the progress of the Board’s work.

For example, the 2d Auxiliary Surgical Group, attached to hospital where

the Board was working, split up in the fall of 1944 and one-half went to the

support of the Seventh Army invading Southern France. The group in the

European Theater kept in close contact with the Mediterranean group, through

which reports of the study were received and disseminated as various phases

were developed.
APPENDIX

The Field Laboratory

Establishment of field laboratory was manifestly essential to accomplishment of the program mapped out by the Board, since collection of voluminous

and complex biochemic data was fundamental to the plan of study. The laboratory supporting the study had to be mobile and readily available wherever observations were to be made on the recently and severely wounded; that is, near

the front line.

The 15th Medical General Laboratory was to serve as base of operations for

the field laboratory and thus was available for the examination of such specimens as the Board might send to it. All histologic work in fact was done at

this laboratory. In theory many other procedures required by the Board could

have been performed at the 15th Medical General Laboratory but this system

would have been totally inadequate to the need for two principal reasons: It

would not have provided immediate reports on laboratory procedures which

could aid in guiding treatment and evaluation of each patient, nor would it

have revealed findings of particular interest which might suggest and direct

special follow-up analyses. Furthermore many types of analyses, such as the

van den Bergh diazo test, and determination of blood pH, phosphorus, chlorides,

and sugar, must be performed very soon after the specimen is collected.

It was recognized, in addition, that the laboratory must not be burden on

the unit to which it might be attached and therefore it had to be self-sufficient,

not only in the performance of laboratory procedures but also with regard to its

utilities, such as electric power, heat, shelter, water supply, and disposal of

wastes. means of supply must be established which would permit the laboratory to carry only minimum essential equipment and chemicals for day-to-day

operation and to be able to count on regular and dependable replacement of

supplies and equipment from base. Some of the practical difficulties encountered in operating the laboratory have been mentioned in the Preface.

956507 0—52 25
l6 THE PHYSIOLOGIC EFFECTS OF WOUNDS

The joint considerations of mobility and self-sufficiency were reflected in

the transport and major equipment initially made available to the Board,

large mobile laboratory truck was obtained on loan from the 15th Medical

General Laboratory. In addition to reconnaissance cars and jeeps there also was

available 4-ton cargo truck. On the latter were carried adequate glassware

to take care of one day’s run of samples, size No. International Centrifuge,

two Coleman Junior Spectrophotometers, complete, Klett colorimeter, hot

plate, prescription balance with weights, drying oven, and alcohol burners.

/z-kilowatt generator, five carboys of distilled water, typewriter, and nine

pyramidal tents for the laboratory and the personnel completed the equipment,

which was loaded on 4-by-q cargo truck.

In view of the anticipated working conditions, it was considered inadvisable

to carry an analytical balance for preparation of standard solutions; therefore,

as mentioned below, arrangements were made for obtaining supply of these

solutions as needed. The needs of the study did not necessitate carrying refrigerator. vacuum pump and field autoclave were available in the mobile

laboratory truck. serviceable spectroscope was needed and was obtained later

from the University of Rome.

Assurance of continuous supply of reagents and other laboratory supplies

necessitated special arrangements. Certain common items could be obtained

from any medical unit to which the laboratory might be attached, but adequate

supplies of distilled water, standard solutions, and special reagents and apparatus

could not be obtained in this manner. Fortunately such items were readily obtainable from the 15th Medical General Laboratory which was the base of

operations for the Board. They were delivered as needed to the field laboratory by means of the carrier “blood-bank” plane which shuttled between the

General Laboratory and the forward distributing unit of the 6713th Blood

Transfusion Unit.

Shortcomings in basic physical arrangements were soon evident. The mobile

laboratory truck proved too small to provide space for more than one technician

to perform chemical analyses. The pyramidal tents were not adaptable for use

as laboratory, so ward tent was requisitioned from the 94th Evacuation

Hospital. tent of this size permitted three technicians to work comfortably

without interference and allowed systematic distribution ofreagents and equipment, thus eliminating the rehandling necessary in confined space.

Tables, working cabinet, and glassware cabinet were added. sink was
APPENDIX

made from truck gasoline tank, and water was piped from 50-gallon drum.

The sewage system was simple. All blood, plasma, urine, and solutions from

completed analyses were poured into slop pail, which was emptied into

prepared soakage pit. Water used in washing glassware ran into channels and

soaked into the ground. The tables and equipment were distributed so that all

the analytic work, the washing and drying of glassware, the storage of surplus

supplies, and the administrative and clerical work were performed in the same

tent. Blood typing and agglutination studies were made in the laboratory truck.

For the collection and submission of specimens, boxes were prepared in triplicate to contain approximately:

15 screw-cap, 22-ml. flat-bottom vials containing lithium oxalate to be used for

collection of blood specimens.

10 screw-cap, 8-ml. flat-bottom vials containing ammonium and potassium oxalate for holding blood specimens on which determinations of hematocrit value and

plasma protein concentration would be made.

corked test tubes for submission of clotted blood.

screw-cap, 250-ml. urine bottles,

12 sterile 10-ml. syringes.

sterile 30-ml. syringes.

sterile 2-ml. syringes.

10 dry 10-ml. syringes.

30 sterile 19-gage needles.

Absorbent cotton, alcohol, and rubber tubing for tourniquets.

Ampules of bromsulfalein, phenolsulfonphthalein, and sterile solution containing 100 mg. per 100 cc. of the dye T-1824 for determination of blood volume.

The specimens were required to be labelled with the patient’s name and the

date and hour the sample was taken.

Analyses

The following analyses were undertaken on the Board’s material:

Blood.—Volume, hemoglobin, hematocrit value, hydrogen ion, sugar, sulfonamides, methemoglobin, the bromsulfalein liver function test; plasma urea

nitrogen, creatinine, lactic acid, bilirubin (van den Bergh reaction), uric acid,

protein, free hemoglobin, carbon-dioxide combining power, magnesium, chlorides, phosphorus, and nonprotein nitrogen; serum sodium, calcium, and potassium.
THE TWO LABORATORY TENTS and the laboratory truck used by the Board for the

Study of the Severely Wounded, shown at Monghidoro, Italy, autumn of 1944. Later the

laboratory tents were winterized as shown.
ITALY PROVIDED VARIETY OF CLIMATE. Winter snows and spring rains mired

the laboratory truck and dampened equipment. Wherever possible the laboratory was

housed in building, but more often the work was done in tents.
20 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Urine.—Routine urinalysis, hydrogen ion, free hemoglobin, myoglobin, creatinine, creatine, ammonia, titratable acidity, chlorides, urea nitrogen, organic

acids, magnesium, bile, urobilinogen.

Tissue.—Myoglobin.

Renal Function Tests.—Phenolsulfonphthaleinexcretion, mannitol clearance,

para-amino hippuric acid clearance, and pituitrin concentration test.

Effort was made to synchronize the submission of specimens so that several

of the same tests could be performed simultaneously; immediate analyses of

single specimens were, however, made when requested.

Each technician kept notebook in which he recorded the details of the

particular determinations assigned to him. The calculations were checked, entered into the main laboratory book, and read back. After an adequate number

of cases had been completed, the laboratory data were transcribed onto five

copies of laboratory sheets and each set was stored in different place (one

copy being filed with the case record) in case storm, fire, or warfare would

spare one or more sets. Even so, the laboratory sheets of some cases were lost in

transit.

Many of the specimens submitted were irreplaceable. During the entire

course of the study, no sample was sacrificed due to breakage upon centrifugation. The No. International Centrifuge yielded results which far outweighed

the inconveniences attached to moving and servicing it. The more easily moved

table centrifuge had caused many tube breakages and was therefore not used.

The majority of the ultimate measurements made required colorimetric

readings. The Coleman Junior Spectrophotometer, powered by its own 6-volt

battery, contributed in several respects to improving the caliber of the work.

It broadened the scope of procedures that could be carried out, it reproduced

the readings accurately, and in all cases it allowed us to standardize the observations which, particularly in visual colorimetric reading of yellow, varied

among technicians. Most of the color tests, except sugar and phosphorus which

entailed comparison of easily-read blue colors, were set up for spectrophotometer

readings. The spectrophotometer sturdily resisted the stresses and strains of

repeated packing, unpacking, and moving, and no replacement of parts was

necessary during the entire study.

The initial move up to the combat line was made with emphasis on care

and protection of our supplies and equipment. Each subsequent move required

speed. For this, boxes were prepared with individual cubicles for all the reagent
APPENDIX 21

bottles. The glsssware was rolled up in blankets and these blanket rolls were

snugly wedged between the shelves of the glassware cabinet. The test tubes

and blood-drawing equipment were kept during the working period in the

same boxes in which they were moved, and the pipets were bound in groups of

10 and wedged into the working cabinet drawer. The laboratory could therefore be dismantled, packed, and loaded within four or five hours.

The first move into the field indicated that certain standards of protection

in inclement weather were imperative. During the winter period the laboratory

tent was winterized by completely boarding up the front and back as illustrated. close-fitting door was installed, the floor was gravelled, and an oil

stove was kept burning day and night. The final set-up during the spring was

the most convenient. No stove was required and the work tables were grouped

about the center of the tent. To eliminate the discomforts of heat and the roar

of the ovens, the dishwashing, drying, and autoclaving were done in pyramidal

tent adjacent to the chemistry tent.

The need of conservation of electricity made it quite obvious that drying

could not be effected by electric oven nor could hot plates be used. Alcohol

burners and gasoline stoves served satisfactorily for this purpose. During one

particularly dusty period it was necessary to operate the centrifuge and spectrophotometer in the mobile laboratory vehicle, and it was often necessary to

plug with cotton all the flasks and cylinders and to box the tubes and pipets

to keep them dust-free.

In the months of the study, the laboratory moved seven times, and over

12,000 biochemic analyses representing 56 different types of tests were made:

8,269 on blood (31 types), 3,961 on urine (22 types), and 58 (3 types) on tissue.

The scope of these chemical analyses is shown in Appendix where the methods used are described.

detailed listing of the number of chemical analyses is given on page 322.

All work was done in connection with the Board material except for 3-day

hepatitis survey.

The field laboratory proved its value in this study. It was shown that

mobile laboratory unit could be established and could function well close to the

line of combat, and that it could do accurate and comprehensive biochemic

analyses in this situation.
22 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Chemical Analyses

Blood Chemistry

Hemoglobin --

636 Sulfonamides 108

Hematocrit __

636 Glucose 377 Plasma protein --

639 Blood volume 207 Plasma hemoglobin 892 Bromsulfalein 45 Nonprotein nitrogen 605 Sulfate

Creatinine 580 Methemoglobin 15 Chlorides --

59 Urea nitrogen 80

Uric acid 195 Vitamin

Carbon-dioxide combining power- -- Sl Cephalin flocculation test 119 Van den Bergh 700 Mannitol clearance 75 Phosphorus --

44° Renal blood flow 40

PH 28 Total mass—hippurate 29 Sodium --

474 Total mass—glucose

Potassium 26 Lactic acid 27 Calcium 42 Bilirubin (acetone) Magnesium __

158 Total 8,269

Urine Chemistry

Routine urinalysis 670 Ammonia 130 pH 774 Titratable acidity 13° Benzidine 662 Organic acids 91 Myoglobin 144 Urobilinogen

Chlorides 289 Bromsulfalein

Phenolsulfonphthalein 385 Urea nitrogen 96 Concentration test 43 Magnesium

Sulfadiazine 33 Methylene blue test 119 Hippuric acid Spectroscopic examination

Bile 32 Titratable alkalinity Creatinine 197 Creatine 83 Total 3,961

Tissue Chemistry

Myoglobin

Sulfadiazine

Magnesium 11

Total 58

Total Analyses 12,288
APPENDIX

Contents Page

Blood Analyses 324 Normal values 324 Preparation of precipitants 324 Blood and plasma volume

Modification of Gregersen method 326 Procedure for determination of blood volume 330

Blood Chemistry

Nonprotein nitrogen products 332

(Nonprotein nitrogen in plasma creatinine in plasma ..uric acid in

plasma urea nitrogen in plasma)

Acid-base analyses 337

(Blood pH serum sodium serum potassium serum calcium

magnesium in plasma phosphorus in plasma C0 combining power

of plasma ..chlorides in plasma ...lactic acid in plasma)

Glucose in plasma 343

Sulfonamides in whole blood 343

Determination of methemoglobin 343

Plasma bilirubin 344

Hemoglobin, hematocrit, and plasma protein 344

Plasma hemoglobin determination 344

Liver Function Test 345

Renal Function Tests 346 (Mannitol ..para-amino hippuric acid phenosulfonphthalein test)

Urinalyses 349

(Routine ... the benzidine test... titratable acidity .. organic acids ,.creatinine

and creatine)

Determination of Myoglobin 354

(Urine and tissue)
Biochemic Methods

The biochemic procedures to be used in this study were selected on the

basis of their accuracy and their applicability to the anticipated conditions in

combat area. Many procedures were modified so that the critical quantitative

readings might be made on the spectrophotometer. Those described for the

determination of blood volume; plasma magnesium, serum sodium; creatinine

and creatine in urine; the bromsulfalein and phenolsulfonphthalein tests, and

the determination of myoglobin, for example, offer generally useful modifications of standard procedures. Methods in which any changes in the standard

procedure were made are described in detail.

Blood Analyses

Normal Values in the Blood Analyses

The ranges of normal values for analyses made on the blood as shown in

Table 118 are essentially those given in the literature. For convenience it was

often necessary to assume single figure as representing the standard normal

level for particular analysis in order to contrast it with the average findings

in certain groupings of the cases in this study. The figure used for the standard

normal was selected as result of our experience with each method.

Preparation of Blood and Plasma Protein Precipitants

Tungstic Acid Filtrate

Reagent.—Van Slyke and Hawkins tungstic acid. (Twenty-five ml. of 2/3 sulfuric

acid and 25 ml. of 10-percent sodium tungstate are combined and diluted to 225 ml. with

water.) This reagent is satisfactory for week. Turbidity due to precipitation of tungstic

acid does not interfere with preparation of the filtrate.

Procedure.—To volume of blood or plasma in flask are added volumes
APPENDIX 325

Table 118.—Normal Values Used in this Study

of the tungstic acid reagent, the mixture is allowed to stand for 10 minutes and

is then filtered.

Trichloracetic Acid Filtrates

Reagents.—Trichloracetic acid, 10-percent solution, 15-percent solution, and 20-percent

solution. (Prepared by titration.)

Procedure.—Prepare filtrates (as required by the analysis to be performed)

Determination or Test Range of Normal

Range of

Equivalents

mEq./L.

Standard Normal

Blood

Volume 8-9% of body weight

14-17.5 Gm./lOO ml.

8.5% of body weight.

Hemoglobin 16 Gm./lOO mi.

Hematocrit value 42-52 ml. cells in 100

ml 47 ml. cells in 100 ml.

PH 7.38-7.48

Plasma

Protein 6-7 Gm./lOO ml. ... 6.5 Gm./lOO ml.

"Hemoglobin”

Nonprotein nitrogen

Less than 10 mg./100

ml

5-40 mg./100 ml. 33 mg./lOO ml.

Urea nitrogen 10-20 mg./100 ml. 15 mg./lOO ml.

Creatinine 0.5-1.2 mg./lOO ml. 1.0 mg./lOO ml.

Uric acid 1.5-3.5 mg./lOO ml. 3.0 mg./lOO ml.

Phosphorus 1.8-3.5 mg./lOO ml. 1.04-2.0 3.0 mg./lOO ml.

Magnesium 1.0-3.0 mg./lOO ml. 0.8-2.5 1.8 mg./lOO ml.

Chlorides 570-620 mg./lOO ml. 97.5-104 585 mg./lOO ml.; 100

CO2 combining power 53-70 vol. 24-31

mEq./L.

60 vol. %; 27 mEq./L.

Bilirubin (van den Bergh) 0.1-0.5 mg./lOO ml.

Bromsulfalein Less than 3% (5 mg./Kg. in 45 min.)

Lactic acid 10-20 mg./lOO ml. 15 mg./lOO ml.

Serum

Sodium 320-340 mg./lOO ml. 139-149 330 mg./lOO ml.; 143

Potassium 15-21 mg./lOO ml. 3-9-5.3

mEq./L.

Calcium 9-11 mg./lOO ml.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Determination of Blood and Plasma Volume

Modification of Gregersen Method

Blood and plasma volume was determined in this study by modification of

the method developed by Gregersen 12 primarily for use of the Armed Forces.

The dye T-i824 was used and the basic principles of the method were followed.

The Gregersen method, in brief, consists in injecting known quantity of

dye into the antecubital vein, waiting about twenty minutes for the dye to be

distributed through the circulating blood, and taking three or four samples of

blood at 20-minute intervals. The plasma is separated and its concentration

of dye is measured and plotted against time. The curve so obtained is extrapolated back to zero time to correct for dye lost during the mixing period. This

value at zero time gives the theoretical concentration of dye that would have

occurred in the plasma if uniform mixing had been effected at the instant of

injection and none of the dye had been excreted. The total blood volume is

calculated from the plasma volume (measured by the dye) and the hematocrit

value.

Experience with the method revealed two serious objections, one practical

and one technical. The practical objection was that the method was too timeconsuming for use with battle casualties before operation; therefore, more

rapid procedure was sought. This will be discussed later. The technical flaw

in the procedure was that the difference in turbidity between the blank, dyefree plasma and the dye-containing samples yielded spectrophotometric readings which had to be resolved as amount of dye plus or minus turbidity. Plotted

points using such readings rarely indicated excretion of dye as an exponential

function, and very often, when considerable variations in turbidity existed,

would lead to gross errors of reading at zero time. Corresponding errors resulted

in the calculation of the blood volume.

The cause of this turbidity, which varies during the course of determination,

has not- been ascertained. The plasma, however, does not clear upon centrifugation. The following observations made the application of turbidity-correction

Gregersen, M. I.; Gibson, J. G., and Stead, E. A.; Plasma volume determination with dyes: errors

in colorimetry; use of the blue dye T—1824. Am. J. Physiol. 113: 54—55, Sept. 1, 1935.

Gregersen, M. I.: practical method for the determination of blood volume with the dye T—1824;

survey of the present basis of the dye-method and its clinical applications. J. Lab. Clin. Med. 29; 1266—

1286, December 1944.
APPENDIX

factor reasonable: (1) The reading of turbidity at 620 fx was almost the same

as at 680 /x, while (2) the dye reading at 680 m/x was the reading at 620

millimicrons.

If the dyed plasma, therefore, is less turbid than the blank, dye-free plasma,

the difference in readings of the dyed plasma at 620 mjx and 680 m/x expressed

as OD (optical density), multiplied by 4/3, would give the corrected value for

the dye only.

Example: OD at 620 m/u. 0.309

OD at 680 m/x 0.055

OD corrected (0.309 0.055) 4/3 0.340

If the dyed plasma is more turbid than the dye-free plasma, which it is if

the reading of optical density at 680 is more than the reading at 620, similar

correction is made.

Example A: OD at 620 m/* 0.300

OD at 680 mp 0.091

OD corrected (0.300 —0.091) 4/32=0.279

Example B: OD at 620 mp 0.409

OD at 680 mp 0.188

OD corrected (0.409 —0.188) 4/3 0.295

When the dyed plasma and the blank plasma are of the same order of turbidity, no correction factor is necessary.

The application of the correction factor for turbidity materially improved

the character of the blood-volume curves, and indicated that the excretion of

the dye approximated an exponential function.

Practically, the use of four points to determine blood volume is too timeconsuming to be used in battle casualties before operation. Therefore, more

rapid method was sought, and the accuracy of blood volume determination

based on only one blood sample was studied.

Since the excretion of the dye followed an exponential curve, and the log

of the concentration of the dye plotted against time formed straight line, it

remained only to determine the constancy of the slope of the disappearance

curve, and to ascertain point on the line, at specified time, to calculate the

optical density (OD) at zero time. This was done in 68 cases in which blood

volumes had been determined by using 3-point, 4-point, and 5-point curves to

establish the optical density at zero time.

First it was necessary to consider the factor of albuminuria. Because the dye

T--1824 is thought to be bound to the plasma albumin, variability of slope
328 THE PHYSIOLOGIC EFFECTS OF WOUNDS

according to the presence or absence of albuminuria was expected. Such relationship was demonstrated by grouping the dye disappearance-rate slopes in

67 cases according to the amount of albumin in urine specimens obtained in

these cases at about the time the blood volume was determined. The disappearOD minutes ance of dye from plasma was expressed by the slope factor OD 60 minutes

If the slope factor is divided into 1,000 and multiplied by 100, it gives the percentage of dye remaining in the plasma hour after injection; subtraction of

the result yields the percentage of dye lost in hour. The average percentage of

dye lost in hour in the urines of patients with no urinary suppression and

with albuminuria (Group V), as compared with the average loss in hour in

the other four groups combined, would indicate that the dye, bound to albumin,

is lost through the urine in this manner (Table 119).

Table 119. Comparison of Albumin Loss in Urine withPlasma Dye Loss

Average of 67 Cases

Dye Retained Dye Lost in

Number of Cases and OD minutes after Hour Hour

Groups Urinary Findings

OD 60 minutes percent) percent)

Average of 36 cases

(Output normal; albumin neg. or

faint trace)

1.105 90.5 9.5±0.58

II Average of cases

(Output normal; albumin +)

1.148 87.2 12.8±2.4

III Average of 14 cases

(Patients anuric; albumin or

over)

1.111 90.0 10±0.85

IV Average of cases

(Patients oliguric; albumin

or over)

1.150 87.3 12.7 ±2.1

Average of cases

(Output normal; albumin or

over. Two patients polyuric;

albumin, trace)

1.195 83.7 16.3±2.8

Average of cases in Groups

through IV 1.112 90 10.0±0.46

(58 cases)

Average of total cases 1.128 88.7 11.3±0.62
APPENDIX 329

When the cases in Groups through IV were combined and averaged,

weighted slope of 1.112 was obtained, corresponding to 10-percent loss of

dye per hour, or change per minute of 0.00187 or-——. It was possible, then, 60

to calculate the OD at zero time, when the OD at specific time was known,

by multiplying by 0.00187 the interval (in minutes) between injecting the dye

and taking the sample, and adding to this figure. The OD at zero minutes

was obtained by multiplying this value by the observed OD corrected for turbidity.

Example: OD 30 minutes (corrected): 0.317 1. 30 0.00187 0.0561 2. 0.056 1.056

3. 0.317 1.056 0.335 (OD zero time)

To test the validity of this procedure, the first point of each of the 68 multiplepoint blood volume tests was taken and the blood volume was calculated from

it and compared with the blood volume obtained by determining the disappearance curve from multiple points. The results are indicated in Table 120.

Table 120.—Relation of Calculation of Single-Point to Multiple-Point

Method—68 Cases

According to these data, in 69 percent of the 68 cases the calculation of

blood volumes was higher by the single-point method, in 31 percent it was

lower, and was within 100 ml. in 56 percent. In 90 percent of all cases it was

within 300 ml. of the calculation obtained by the multiple-point method. In

this series the value determined by the one-point method was clinically unsatisfactory in one case (960 ml. too high). The second point in this case

Relation ofSingle Point to Multiple Point

Number of Cases

Above MultiplePoint Value

Number of Cases

Below MultiplePoint Value

Within 100 ml 27 11

Within 101-200 ml

Within 201-300 ml

Over 300 ml

Total Cases 47 21
THE PHYSIOLOGIC EFFECTS OF WOUNDS 33°

yielded value 330 ml. too high. This series demonstrated that the blood

volume determined by the one-point test compares favorably with that obtained

by the multiple-point test.

Procedure for Determination of Blood and Plasma Volume

Reagents

1. T-1824 solution, mg. per milliliter. (The contents of ten 5-ml. ampules of

0.5-percent T-i824 are removed and made up to 250-ml. solution, using sterile technique.)

2. Standard copper sulfate solutions, (specific gravity series for determination of

hematocrit value).

3. Sodium chloride, 0.9-percent solution.

Procedure

sterile 10-ml. syringe is filled with exactly 10 ml. of T-1824 and placed

where it will be readily available. About twenty milliliters of blood are drawn

from the antecubital vein with sterile syringe, leaving the needle in the vein.

Exactly ml. of blood are measured into specially oxalated bottle for determination of the hematocrit value, and the remaining blood is transferred to

lithium oxalate bottle. This is the blank tube. The syringe containing the

dye is carefully attached to the needle remaining in the vein, and all the dye

is injected. (Any indication of pain by the patient during the injection of the

dye should be regarded as evidence that some dye is passing outside the vein,

thus invalidating the analysis.) The exact time of injection is noted. After an

interval of from 20 to 40 minutes, 15 ml, of blood are drawn from the antecubital vein of the opposite arm and placed into lithium oxalate bottle. This

is the dye-containing tube. Again the exact time the blood is drawn is noted.

The hematocrit value is determined from the 5-ml. sample (the blank

blood), using the copper sulfate method of Phillips et al. All the samples are

centrifuged and the supernatant plasma is separated. The two tubes of blank

plasma are pooled, at least 5.5 ml. are placed in 19- by 150-mm. Coleman

cuvette, and the same quantity of the dye-containing plasma is placed in

similar cuvette, (In the event that the amount of plasma is inadequate, dilutions

‘Phillips, R. A.; Van Slyke, D. D.; Dole, V. P.; Emerson, K., Jr.; Hamilton, P. B., and Archibald, R. M.: Copper sulfate method for measuring specific gravities of whole blood and plasma. BUMED

News Letter, U. S. Navy, June 25, 1943, p. 1—16.
APPENDIX 331

are made with o.p-percent saline solution, treating both tubes in the same

manner.)

The blank tube is set to read at 100-percent transmission at 620 mjtt in the

spectrophotometer and the optical density of the plasma in the dye tube is

noted. This procedure is repeated at 680 millimicrons. Exactly ml. of T-1824 solution is diluted to 500 ml. with water, placed in matched cuvette, and,

blanking out with distilled water, the optical density at 620 m/t is determined.

Calculation

1. From the readings at 620 ji and 680 jjl the corrected optical density

(OD) is calculated as discussed previously.

2. The optical density is calculated at zero minutes, using the factor for

the number of minutes after injection as previously discussed.

3. Plasma volume:

OD corrected optical density at zero minutes for dyed plasma.

OD dye optical density of (1:500) dilution of dye that was injected for test.

Plasma volume dye

500 10. KJLJo

(The figure of 500 represents the dilution factor of the dye as read in the instrument, and

the figure 10 is the number of milliliters injected.)

4. Blood volume:

100 minus the hematocrit value percentage of plasma PI)

Plasma volume Blood volume 100 PI

Summary

1. The technique for determining the circulating blood volume by means

of the dye T-1824 and spectrophotometer is described.

2. The correction for variable turbidity of samples is described.

3. The disappearance of the dye in battle casualties was 10 percent of the

injected substance at the end of hour.

4. Albuminuria increased the disappearance rate.

5. The feasibility of blood volume determinations based on only one dyecontaining sample is demonstrated.

956507 0—52 26
THE PHYSIOLOGIC EFFECTS OF WOUNDS 33

Blood Chemistry

Nonprotein Nitrogen Products

Nonprotein Nitrogen in Plasma—Modified from Koch and McMeehjn

Reagents

1. Sulfuric acid, 50-percent aqueous solution by volume.

2. Potassium persulfate, saturated solution. (Seven Gm. in 100 ml. of water.)

3. Potassium mercuric iodide for Nessler’s solution: (a) Using i-liter Erlenmeyer

flask, 22.5 Gm. of iodine are dissolved in 20 ml. of water containing 30 Gm. of potassium

iodide, (b) After the solution is complete, 30 Gm. (about 2.5 ml.) of mercury are added

and the mixture is shaken vigorously in order to break the mercury into globules, cooling

it from time to time by immersing the flask in cold water. The shaking is continued until

the supernatant fluid has lost all color due to iodine, (c) The supernatant is decanted from

the excess mercury and tested for free iodine by adding drop or two of the solution to

ml. of i-percent starch solution. If the result of the starch test for iodine is negative,

few drops of an iodine solution of the same concentration as described in (a) are added

until faint excess of iodine can be detected by the starch test, (d) The double iodide

solution is diluted to 200 ml. with distilled water and mixed thoroughly.

4. Nessler’s reagent. (By titration 10-percent sodium hydroxide solution is accurately

prepared from saturated solution of sodium hydroxide that has been allowed to stand

until all carbonates have settled. To 975 ml. of this solution is added the entire solution

(200 ml.) of potassium mercuric iodide prepared as described, after which it is mixed

thoroughly and allowed to settle.)

5. Ammonium sulfate standard solution. (Prepared by dissolving 4.716 Gm. of pure,

dry ammonium sulfate in 0.2 sulfuric acid and making up to volume of 1,000 ml.

with the 0.2 sulfuric acid (1 ml. mg. of nitrogen).)

6. Dilute nitrogen standard solution. (Five ml. of stock standard solution is diluted

to 100 ml. with 0.2 sulfuric acid (3 ml. 0.15 mg. nitrogen).)

Procedure

To 2.5 ml. of protein-free tungstic acid plasma filtrate in an ignition tube

graduated at 35 ml. is added ml. of 50-percent sulfuric acid solution, together

with glass bead to prevent bumping, and it is boiled vigorously until it

becomes brown and dense white fumes appear. funnel is then placed in the

tube and the solution is digested for about one minute, when the flame and

funnel are removed, drops of potassium persulfate are added, and the mixIn Hawk, P. B., and Bergeim, O. Practical Physiological Chemistry, xoth ed. Philadelphia, Blakiston,

I93U P- 415-
APPENDIX 333

ture is boiled gently for several minutes. If brown color persists, another

drops of potassium persulfate are added and the mixture is again boiled

gently. (A greenish-yellow color at this point indicates an excess of tungstic

acid. This color will clear up after the addition of the Nessler’s reagent.) It is

cooled, diluted to the 35-ml. mark with water, and mixed by inversion.

Into an identical ignition tube are placed ml. of working standard and

ml. of 50-percent sulfuric acid solution; this is made up to the 35-ml. mark

with water and mixed by inversion. Into third ignition tube is placed ml.

of the sulfuric acid solution, water is added to the 35-ml. mark, and it is mixed

by inversion. This is the blank. Next, 3.5 ml. each of the sample, the standard,

and the blank are transferred to small cuvette (12 by 75 mm.), 1.5 ml. of

Nessler’s reagent is added, the contents are mixed by inversion, and read in

the Coleman Junior Spectrophotometer at 440 /a on the optical density scale,

blanking out with the blank solution.

If the nonprotein nitrogen value is high, ml. of the solution and 1.5 ml.

of the blank are nesslerized. In this case the final value is multiplied by sevenfourths. Other appropriate dilutions that bring the color intensity into the

standard range can be used.

Calculation

The working nitrogen standard is equivalent to 60 mg. of nitrogen per

100 ml. of plasma. (Rs OD of the standard, Ru OD of the sample.)

60

Rs Ru

60 Ru ——

mg./100 ml. nitrogen plasma sample.

Comment

The method as modified has the following advantages: (1) Nessler’s solution is used sparingly; less than 10 percent of the quantity used in the standard

procedure is necessary. (2) The procedure is expedited by the digestion of

half the quantity of filtrate ordinarily used. (3) An objective reading of the

nesslerized solutions increases the accuracy of reading the yellow color. (4)

In the event the nonprotein nitrogen level is extremely high, further dilution

of the initial digestion can be made, rather than repeating the entire analysis.

(5) The use of saturated potassium persulfate in the oxidation provides substance which is nitrogen-free, stable, and unlike superoxol, is non-injurious.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 334

Creatinine in Plasma—Modified from Folin and Wu

Reagent.—Alkaline picrate solution. (Five volumes of saturated picric acid are mixed

with volume of 10-percent sodium hydroxide solution. This is freshly prepared before

each series of analyses.) reference curve is prepared from standard creatinine solutions

read on the spectrophotometer at 500 m[X after following the conditions of the test.

Procedure.—Five ml. of tungstic acid plasma filtrate are placed in one

cuvette, and ml. of water in another. To each of the samples and the water

blank are added 2.5 ml. of alkaline picrate solution and they are allowed to

stand for 10 minutes. The blank is set at 100-percent transmission and the

percentage transmission of each sample is read at 500 millimicrons.

Calculation.—Reference of the observed percentage transmission to the

standard curve gives the milligrams of creatinine per 100 ml. of plasma. If

very high creatinine values are anticipated, appropriate dilutions of the tungstic

acid filtrate are made with water before addition of the alkaline picrate.

Uric Acid in Plasma—Modified from Polin'

Reagents

1. Standard solution of uric acid. (Exactly Gm. of uric acid is transferred to

i-liter volumetric flask. To 0.5 Gm. of lithium carbonate in beaker, 150 ml. of water

are added and this solution is heated to 6o° C. until all the carbonate has dissolved. All of

the hot carbonate solution is then added to the uric acid in the volumetric flask. As soon

as clear solution is obtained, it is cooled, diluted to about five hundred ml. with water,

and 25 ml. of formaldehyde are added. This is well mixed and ml. of glacial acetic acid

are added. The mixture is shaken to remove most of the carbon dioxide, diluted to liter,

mixed, and stored in brown bottles.)

2. Working standard. (Immediately before each series of analyses, 0.4 ml. of the

standard solution is diluted to 100 ml. with water.)

3. Five-percent sodium cyanide solution.

4. Uric acid reagent, (To 100 Gm. of sodium tungstate (molybdate-free) in 500-ml. Florence flask is added dilute phosphoric acid, made by dissolving 33 ml. of 85-percent

phosphoric acid in 150 ml. of water, and the solution is mixed. Several glass beads are

added to the flask and the mixture is boiled gently for hour, using funnel containing

flask of cold water as condenser. It is decolorized with little bromine water, the excess

bromine is boiled off, and the mixture is cooled and diluted to volume of 500 ml.)

In Hawk, P. B., and Bergeim, O. Practical Physiological Chemistry. loth ed. Philadelphia, Blakiston,

1931, p. 421-423.

In Simmons, J. S., and Gentzkow, C. J. Laboratory Methods of the United States Army. Philadelphia, Lea Febiger, 1944, p. 207.
APPENDIX 335

Procedure

To ml. of tungstic acid filtrate in cuvette are added ml. of water. Into

another cuvette is pipeted ml. of dilute standard, and ml. of water are

added. This is the standard solution corresponding to mg. of uric acid per

100 ml. of plasma. Four ml. of water in third cuvette constitutes the blank

tube. To each of the samples, the uric acid standard, and the blank tube, ml.

of sodium cyanide are added, using an automatic pipet, and the solutions are

mixed, after which ml. of the uric acid reagent are added to each tube, and

the solutions are again mixed and are allowed to stand for 30 minutes. The

blank is set at 100-percent transmission on the spectrophotometer and the

optical density of the standard and each of the samples at 650 m/x is noted.

Calculation

The calculation of milligrams per 100 milliliters of plasma is obtained by

setting up proportion comparing the optical density of the standard of

known strength with the observed reading of the sample.

Example: OD of sample 0.150

OD of standard 0.200

Standard mg./100 ml.

Sample (calculated) mg. of uric acid per 100 ml. of plasma.

Comment

The advantages of the method as modified are that it (1) yields nonclouding color development when sodium cyanide and phosphotungstic acid

are used, (2) avoids the danger of color development varying with the temperature by the preparation of standard and blank at the same time and by

reading the color on the optical density scale of the spectrophotometer, and

(3) insures against decomposition of the working standard by preparation of

fresh standard before each series of analyses.

Urea Nitrogen in Plasma—Modified from Karr

Reagents

1. Urease solution. (A mixture of 0.3 Gm. of double-strength urease in 2.5 ml. of

water and 7.5 ml. of glycerin is centrifuged and decanted. The supernatant solution is the

urease extract and lasts for at least months.)

In Hawk, P. B., and Bergeim, O. Practical Physiological Chemistry. 10th ed. Philadelphia, Blakiston,

1931, p. 418.
336 THE PHYSIOLOGIC EFFECTS OF WOUNDS

2. Acetate buffer solution. (To 15 Gm. of sodium acetate dissolved in 50 ml. of water

is added ml. of glacial acetic acid, and the mixture is diluted to 100 ml. with water.)

3. Dilute standard nitrogen solution. (Same as for nonprotein nitrogen.)

4. Potassium mercuric iodide. (Same as for nonprotein nitrogen.)

5. Urea Nessler’s reagent. (Thirty ml. of potassium mercuric iodide are mixed with

30 ml. of water and 140 ml. of 5-percent sodium hydroxide solution are added.)

6. 2/3 sulfuric acid,

7. Sodium tungstate, 10-percent solution.

Procedure

To ml. of plasma in tube are added 6.7 ml. of water, drops of urease

solution, and drops of acetate buffer, and the tube is incubated at 40° to 50 C.

for 15 minutes. One ml. each of the sulfuric acid and the sodium tungstate

solution are added, the solution is mixed, allowed to stand for several minutes,

and filtered. Into another tube are placed ml. of filtrate and ml. of water.

Into tube graduated at 22.5 ml. are placed 1.5 ml. of the working nitrogen

standard, the solution is diluted to the mark, mixed, and ml. of this dilute

standard is placed in tube. To each of the samples and the dilute standard

solution is added ml. of urea Nessler’s reagent, they are mixed and read in

the colorimeter.

Calculation

The unknown is set at 15 mm. and the reading of the standard will be

the milligrams of urea nitrogen per 100 ml. of plasma. In the event that

high urea nitrogen is expected, aliquots of the 2-ml. sample of filtrate are taken

and the contents of the tube made up to ml. with water. The observed level

is then multiplied by the proper factor.

Example: 0.5 ml. taken instead of 2.0 ml.; multiply answer by for mg. of urea

nitrogen per 100 ml. of plasma.

urease blank should be determined about every days. The urease blank

usually averaged between and mg. expressed as urea nitrogen per 100 ml.

of plasma and was subtracted from the observed values.

Comment

The method as modified has the following advantages: (1) It yields nonturbid, stable solution upon direct nesslerization; (2) the reagents are stable

at room temperature and are used sparingly, and (3) if the urea nitrogen level
APPENDIX 337

is extremely high, further dilution of the initial filtrate of the incubation

mixture can be made, rather than repeating the entire analysis.

Acid-Base Analyses

Blood pH (from Haw\ins, Hastings, and Sendroy

Preparation of the bicolor standards was taken from Peters and Van Slyke’s

Quantitative Clinical Chemistry (cited below) p. 797, Table 65. The preparation of the reagents (p. 796) and Hawkins’ modification (p. 801) for using

sample of whole blood were also followed.

Procedure

The phenol red tube and the saline tube are prepared immediately before

the analysis, using tubes similar to those for the preparation of standards.

{Phenol red tube: After placing ml. of freshly adjusted saline solution (which

contains ml. of 0.0075-percent phenol red solution per 100 ml.) in tube,

about one-quarter inch of liquid petrolatum is stratified above this solution.

Saline tube: Five ml. of freshly prepared saline are put into similar tube.)

Drawing blood samples: glass bead is placed in the barrel of 2-ml.

syringe with needle attached, about 0.5 ml. of sterile liquid petrolatum and

small drop of saturated potassium oxalate are added, and the plunger is

inserted in the syringe. The syringe is inverted so that the needle is pointing

upward, the droplet of potassium oxalate is allowed to fall to the bottom of

the solution, and all the air and excess petrolatum are slowly expressed until

the movement of the plunger is arrested by the glass bead. The excess petrolatum is wiped off the needle, blood sample of about 1.5 to milliliters is

taken, and the syringe is inverted several times to insure mixing with the

oxalate. After waiting moment for the petrolatum to stratify to the top of

the syringe, the needle is placed under the petrolatum layer of the phenol red

tube and exactly 0.5 ml. of blood is expressed into the tube. In similar manner

0.5 ml. of blood is placed in the saline tube. The petrolatum is siphoned off

from the phenol red tube, which is then sealed with inch of paraffin, and

the contents of both tubes are mixed by inversion and centrifuged.

In Peters, J. P., and Van Slyke, D. D. Quantitative Clinical Chemistry, vol. II: Methods. Baltimore, Williams Wilkins, 1932, p. 796—Sox.
338 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Color comparison is made by arrangement of the tubes in the comparator

as illustrated in Fig. 87 of Peters and Van Slyke’s Quantitative Clinical Chemistry. Readings are made between 18 and 20 C, noting the temperature in

the saline tube.

Correction of Observed pH to pH at 38° C.

Since the standards were prepared to read pH at 38° C., it is necessary only

to subtract the observed temperature from 38° C., multiply this difference by

0.005 an subtract this product from the observed pH to obtain blood pH at

38° Centigrade.

Example:

1. Observed pH 7.48 at 20 C.

2. 38 20 18

3. 18 0.005 0.09

4. 7.48 0.09 pH 7.39 at 38° C.

Normal controls are run with each series of analyses.

Serum Sodium—Modified from Weinhach’s Modification of Butler

and Tuthill’s Method

Reagents

1. Trichloracetic acid, 20-percent solution.

2. Sodium reagent (uranyl zinc acetate), ((a) Uranium acetate, 38.5 Gm., and glacial

acetic acid, 14 ml., are dissolved in 150 ml. of distilled water with the aid of heat, (b) Zinc

oxide, 37.5 Gm., and glacial acetic acid, 63 ml., are dissolved in 150 ml. of distilled water

with the aid of heat, (c) The two solutions are combined, mixed, cooled, and made up to

500 ml. with distilled water, (d) This solution is transferred to reagent bottle, about

0.5 Gm. of the salt sodium uranyl zinc acetate is introduced, and this mixture is shaken

to effect saturation with the sodium uranyl zinc acetate.)

3. Standard sodium solution, 330 mg. of sodium per 100 milliliters. (Sodium chloride,

0.840 Gm., is diluted to 100 ml. with water and stored in paraffin-lined bottle.)

4. 95-percent ethyl alcohol.

5. Acetone wash. (Sodium uranyl zinc acetate, 0.5 Gm., is introduced into bottle

containing about one liter of acetone, the bottle is well shaken and allowed to stand at least

overnight before using.)

6. 0.0348 solution of sodium hydroxide.

In Hawk, P. B., and Bergeim, O. Practical Physiological Chemistry, nth ed. Philadelphia, Blakiston,

937> P- 472-473-
APPENDIX 339

7. Sodium uranyl zinc acetate. (One ml. of 5-percent solution of sodium chloride

is added to 15 ml. of the sodium reagent in 50-ml. Erlenmeyer flask, and ml. of 95-percent ethyl alcohol is added at 5-minute intervals until ml. have been added. The mixture

is filtered, using suction, and the precipitate of sodium uranyl zinc acetate is washed three

times with alcohol and three times with ether, sucking dry after each washing.)

Preparation of Glassware.—Two clean graduated centrifuge tubes for each determination and two for the standard are prepared by rinsing them four times with distilled water

and drying in an oven.

Procedure

One volume of serum, volumes of water, and volume of 20-percent trichloracetic acid are mixed in tube by inversion, and the process is repeated,

using volume of the standard sodium solution instead of serum. Into each of

two of the specially prepared centrifuge tubes are placed 0,5 ml. of the serum

filtrate, and into each of the two other specially prepared centrifuge tubes 0.5 ml.

of the dilute standard. Five ml. of filtered sodium reagent are then added to

each tube, followed by 0.3 ml. of 95-percent ethyl alcohol at 5-minute intervals

until 2.1 ml. have been added to each, when the supernatant fluid is centrifuged

and decanted, allowing the tubes to drain and taking care not to dislodge the

residue. Five ml. of filtered acetone wash are blown into the residue, the tubes

are centrifuged, and the supernatant is decanted and drained. This process is

repeated two more times, making three washings in all. Using 25 ml. of distilled water, the residue is dissolved and transferred quantitatively to 125-ml. Erlenmeyer flask and titrated with 0.0348 sodium hydroxide using phenolphthalein as the indicator.

Calculation

ml. of 0.0348 sodium hydroxide 100 mg. of sodium per 100 ml. of

serum.

Actual strength of standard: 330 mg./100 ml.

Determined strength of standard: 337 mg./ioo ml.

Difference (blank); mg./ioo ml.

Therefore, 344 337 mg. of sodium per 100 ml. of serum.

Mg./ioo ml. sodium 10/23 milliequivalents of sodium.

Example:

Titration of Sample Sample II Average

Serum 3.43 3.45 3.44 or 344 mg./100 ml.

Standard 3.38 3.36 3-37 or 337 S-/ 100 ml
THE PHYSIOLOGIC EFFECTS OF WOUNDS 340

Comment

The modified method used was further modified (1) by changing the

strength of the sodium hydroxide used, thus simplifying the calculation, (2) by

using standard of known sodium concentration to ascertain the reagent blank,

and (3) by an additional acetone washing.

Serum Potassium (Kramer and Tisdall 10

The standard procedure was followed, with duplicate analyses of each

sample and potassium standards for every analysis.

Serum Calcium (Clar\-Collip Modification of Kramer and Tisdall Method 11

The standard procedure was followed.

Magnesium in Plasma—Modified from Herschfelder and Series 12

Reagents

1. Titan yellow, 0.05-percent solution. (This keeps for about two weeks.)

2. Sodium hydroxide, 10-percent solution.

3. Trichloracetic acid, 10-percent solution.

4. Stock magnesium standard solution. (One Gm. of magnesium sulfate heptahydrate

is dissolved with little water and then made up to 100-ml. solution.)

5. Working magnesium standard solution. (1.45 ml. of stock standard diluted to

100 ml. with water. (7 milliliters 0.1 mg. magnesium.) standard reference curve is

prepared, using this solution according to conditions of the test. The color is read at 535 m[x in the spectrophotometer.)

Procedure

To ml. of plasma are added ml. of water and ml. of 10-percent

trichloracetic acid. The solution is mixed, allowed to stand for several minutes,

10 In Todd, J. C., and Sanford, A. H. Clinical Diagnosis by Laboratory Methods. 10th ed. Philadelphia, W. B. Saunders, 1943, p. 420—421. 11 In Hawk, P. B., and Bergeim, O. Practical Physiological Chemistry. 10th ed. Philadelphia, Blakiston,

1931, p. 460—461. 12 Herschfelder, A. D., and Serles, E. R.: simple adaptation of Kolthoff colorimetric method

for the determination of magnesium in biological fluids. J. Biol. Chem. 104: 635, March 1934.
APPENDIX 34

centrifuged, and filtered. To ml. of plasma filtrate in cuvette, 1.6 ml. of

water is added, and ml. of water in another cuvette serves as the blank. One

ml. of titan yellow is then added to each of the samples and to the blank. Two

ml. of the sodium hydroxide solution are added to the blank tube, the contents

are mixed, and the tube is set to read at 100-percent transmission on the spectrophotometer at 535 millimicrons. Similarly, 2.4 ml. of the sodium hydroxide

solution are added to each of the samples, and the solution is mixed and read

immediately on the spectrophotometer at 535 millimicrons.

Calculation

Milligrams of magnesium per 100 ml. of plasma are determined by reference of the observed percentage transmission to the standard curve.

Comment

This method is simple, rapid procedure. Recoveries of added magnesium

and comparisons of normal range of plasma magnesium with that of other

methods (1.5-2.0 mg. per 100 ml.) indicate its accuracy.

Phosphorus in Plasma—Modified from Bodans\y 13

The method was modified by making up the standard in trichloracetic acid.

This permitted of more exact color comparison and eliminated the need for the

two molybdate solutions which the original method demands.

Carbon-Dioxide Combining Power of Plasma

(Van Sly\e and Cullen *)

Chlorides in Plasma (Schales and Schales 13

Plasma chlorides were determined by the method of Schales and Schales.

13 In Todd, J. C., and Sanford, A. H. Clinical Diagnosis by Laboratory Methods, xoth ed. Philadelphia, W. B. Saunders, 1943, p. 404—411. 14 The procedure was followed as described in Methods for Laboratory Technicians, War Department

Technical Manual 8—227, October 1946, p. 123—129. 15 In Simmons, J. S., and Gentzkow, C. J. Laboratory Methods of the United States Army. Philadelphia, Lea Febiger, 1944, p. 209.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 34

Lactic Acid in Plasma—Modified from Mendel and Goldschieder16

Reagents

1. Metaphosphoric acid, 5-percent solution, prepared daily.

2. Copper sulfate, 15 percent by weight of pentahydrate.

3. Blank-free concentrated sulfuric acid. (The quality of the sulfuric acid should be

such that no yellow color develops on the addition of 0.1 ml. of o.i25-percent veratrole to

ml. of acid. good reagent grade of sulfuric acid is satisfactory.)

4. Lactic acid, 100 mg. per 100 ml., prepared from lithium lactate.

5. Sodium fluoride, 0.1-percent solution.

6. Veratrole, 0.125 percent in absolute alcohol.

Procedure

To ml. of plasma separated from freshly drawn blood are added ml. of

water, ml. of sodium fluoride, and ml. of metaphosphoric acid. The whole

is shaken vigorously, allowed to stand for several minutes, and filtered. To

ml. of the protein-free filtrate in centrifuge tube are added ml. of copper

sulfate solution and Gm. of calcium hydroxide, the mixture is allowed to

stand about 30 minutes, shaking several times, and is then centrifuged. The

pellicle of copper hydroxide is broken with glass rod and the supernatant is

decanted into another tube and centrifuged again, resulting in clear, sugarfree filtrate. The standard lactic acid solution is diluted 1:10, corresponding to

100 mg. of lactic acid per 100 ml. of plasma, according to the conditions of the

test. Weaker dilutions corresponding to 75, 50, 25, and 12.5 mg. of lactic acid

per 100 ml. of plasma are also prepared.

To 0.5 ml. of the clear sugar-free filtrate (obtained by centrifugation only),

to 0.5 ml. of each standard, and to 0.5 ml. of water in carefully cleaned test

tube, ml. of concentrated sulfuric acid are slowly added while the tubes are

cooled in cold water. The tubes are then placed in boiling water bath for

exactly minutes, removed and immersed in cold water for minutes. To

each tube 0.1 ml. of the veratrole solution is added, and the solution is mixed

and allowed to stand for 20 minutes, after which it is decanted into small

cuvettes (12 by 75 mm.) and read in the spectrophotometer at 545 m/x, blanking out with the water reagent blank and reading the optical density scale.

ia In Peters, J. P., and Van Slyke, D. D. Quantitative Clinical Chemistry, vol. II; Methods. Baltimore, Williams Wilkins, 1932, p. 618—620.
APPENDIX 343

Note: In the process of color development, brown color may form in addition to the pink of the test color. This is due to unclean glassware and contaminated filtrate. In these instances the analysis is repeated.

Calculation

proportion is set up comparing the reading of the sample with that of the

nearest standard.

Comment

The test was set up on the spectrophotometer, and readings were made on

the optical density scale, using series of standards with each run, since color

development is not reproducible from day to day as required for using permanent chart. The color development does not satisfactorily follow Beer’s law,

and the optical density reading of the closest standard was used in calculating

the value of the sample.

The use of ml. of sodium fluoride in the dilution of the plasma permits

preservation of the lactic acid level until series of samples has accumulated.

Glucose in Plasma

The standard procedure of Folin and Wu17 was followed for the determination of glucose in plasma.

Sulfonamides in Whole Blood

The method of Bratton and Marshall 18 was followed.

Determination of Methemoglobin

The method of Paul and Kemp 19 was followed.

1T In Simmons, J. S., and Gentzkow, C. J. Laboratory Methods of the United States Army. Philadelphia, Lea Febiger, 1944, p. 207-208. 18 In Simmons, J. S., and Gentzkow, C. J. Laboratory Methods of the United States Army. Philadelphia, Lea Febiger, 1944, p. 219-220. 18Paul, W. D., and Kemp, C. R.: Methemoglobin; normal constituent of blood. Proc. Soc. Exp,

Biol. Med. 56: 55-56, 1944.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 344

Plasma Bilirubin (van den Bergh)

The method of Evelyn and Malloy 20 was followed.

Hemoglobin, Hematocrit, and Plasma Protein

The method of Phillips et al. 21 for the calculation of hemoglobin, hematocrit

value, and plasma proteins by means of copper sulfate was followed with the

exception that, since chemical balance was available, all the solutions were

checked and standardized so that they were correct to within ±2 units in the

fourth decimal place, using 25-ml, pyknometer and water at the same temperature as the standard solution. Each bottle was prepared in i-liter quantity

and replacements were made from this stock. Bottles were prepared for each

unit difference in the third decimal place.

Plasma Hemoglobin Determination

Plasma Hemoglobin—Modified from Bing and Baker 22

Reagents

1. Benzidine reagent. (Five Gm. of good quality of benzidine are dissolved in

50 milliliters of glacial acetic acid, warming gently to effect solution. The mixture is

cooled, diluted to 250 ml. with distilled water, about Gm. of decolorizing charcoal are

added, and the solution is thoroughly mixed, allowed to stand for approximately 10 minutes, and filtered into brown bottle.)

2. Hydrogen peroxide, 3-percent solution.

3. Hemoglobin standard solution. (A 20-mg. per 100 ml. solution of hemoglobin is

prepared in i-percent boric acid by diluting blood of known hemoglobin content.)

4. Acetic acid, 20-percent solution.

Procedure

To 0.2 ml. of each sample and of the standard in separate tubes are added

20 In Simmons, J. S., and Gentzkow, C. J. Laboratory Methods of the United States Army. Philadelphia, Lea Febiger, 1944, p. 214—215. 11 Phillips, R. A.; Van Slyke, D. D.; Dole, V. P.; Emerson, K., Jr.; Hamilton, P. B., and Archibald, R. M.: Copper sulfate method for measuring specific gravities of whole blood and plasma. BUMED

News Letter, U. S. Navy, June 25, 1943, p. 1-16.

Bing, F. C., and Baker, R. W.; The determination of hemoglobin in minute amounts of blood by

Wu’s method. J. Biol. Chem. 92: 589—600, August 1931.
APPENDIX 345

ml. of the benzidine reagent, and each is thoroughly mixed. One ml. of the

3-percent hydrogen peroxide is then added to each tube and they are allowed

to stand for 30 minutes, at the end of which time the mixtures are diluted with

6.8 ml. of the acetic acid and allowed to stand until all the tubes have developed

the red color (about 30 minutes), when they are compared in the colorimeter.

Calculation

The sample is set on 20 millimeters. The reading of the standard equals

milligrams of benzidine-reacting substance per 100 ml. of plasma. As has been

explained in Chapter VIII of the text, this entire benzidine-reacting substance

was termed “plasma hemoglobin” because means for its further breakdown

was not available to us.

Liver Function Test

Bromsulfalein Test—Modified from Rosenthal 23

Reagents

Bromsulfalein, 5-percent solution, in sterilized, sealed ampules.

Sodium hydroxide, 10-percent solution.

3. Sodium chloride, 0.9-percent solution.

Procedure

The patient’s weight is recorded in kilograms and the amount of dye to

be injected is calculated on the basis of mg. per Kg. of body weight. simple

procedure is to divide the body weight in kilograms by 10 to yield the exact

amount in milliliters of bromsulfalein to be used for injection. The required

amount of dye is drawn into 10-ml. syringe and slowly injected into vein

in the patient’s arm, the exact time of injection being recorded. Forty-five minutes after injection, sample of blood from the opposite arm is collected in the

standard lithium oxalate bottle, the blood specimen is centrifuged, and the

plasma is collected.

23 In Todd, J. C., and Sanford, A. H. Clinical Diagnosis by Laboratory Methods. 10th ed. Philadelphia, W. B. Saunders, 1943, p. 428—429.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

To ml. of plasma placed in cuvette ml. of 0.9-percent solution

of sodium chloride are added. The contents are well mixed and the spectrophotometer is set to read 100-percent transmission at 575 millimicrons with

this solution. Three drops of 10-percent solution of sodium hydroxide are

then added to the same tube and it is inverted and read on the spectrophotometer.

The transmission percentage is noted and the percentage of dye retention is

obtained from the curve plotted from standard bromsulfalein solution, following the conditions of the test wherein 10 mg. per 100 ml. is considered

100-percent retention.

Comment

The standard procedure for the determination of dye retention using the

Hynson, Westcott Dunning Comparator Block was abandoned because various degrees of hemolysis in the samples would result in readings that indicated

as much as 5-percent retention when no bromsulfalein was present. Low retention figures, therefore, could not be expressed with any degree of certainty, as

results were often not reproducible to within —5-percent retention. Furthermore the method was time-consuming.

The test was set up on the Coleman Junior Spectrophotometer Model No. 6,

using 1:6 dilution of plasma and reading the color of the alkalinized bromsulfalein at 575 millimicrons.

Renal Function Tests

Determination of Mannitol—Modified from Smith, 24

MEASUREMENT OF GLOMERULAR FILTRATION RATE

Reagents

1. 20-percent yeast suspension. (Bakers’ yeast, 25 Gm., is placed in about 100 ml.

of water, allowed to incubate overnight, and then washed by repeated centrifugation until

clear supernatant is obtained (about washings are necessary). The resulting suspension

is diluted to contain 20 percent by volume of yeast. This is washed several times each day

24 In Goldring, W., and Chassis, H. Hypertension and Hypertensive Disease. New York, The Commonwealth Fund, 1944. Appendix D.
APPENDIX 347

before using and readjusted to the 20-percent volume.)

2. 1.1 sodium hydroxide.

3. Zinc sulfate solution. (A solution of zinc sulfate is prepared and adjusted so that

ml. of zinc sulfate are equivalent to 2.2 ml. of 1.1 sodium hydroxide.)

4. 0.005 sodium thiosulfate. (The normality is determined by using 10 ml. of

0.010 potassium iodate. The factor for 0.005 thiosulfate is; ml. 4.6 mg. of mannitol. The factor for the determined normality is calculated daily rather than adjusting the

strength of the thiosulfate.)

5. Potassium periodate, 0.1-percent solution. (Prepared with the aid of heat.)

6. Sulfuric acid, percent by volume,

7. Acid potassium periodate. (A solution of three parts of 0.1-percent potassium

periodate and two parts of 5-percent sulfuric acid is prepared daily.)

8. Potassium iodide, 50-percent solution. (Prepared just before the analysis is made.)

9. Starch, i-percent solution. (Prepared just before the analysis is made.)

Procedure

Six ml. of the 20-percent yeast suspension are placed in each of as many

tubes as there are specimens and in blank tube.

For plasma analyses, ml. of water is first added to each of the yeast tubes

and then ml. of each mannitol-containing plasma specimen is added. Similarly,

to another yeast tube are added ml. of water and ml. of blank (mannitolfree) plasma.

For urine analyses, the urine samples are diluted to contain from 100 to

150 mg. of mannitol per 100 ml. of urine. Two ml. from each such diluted

sample are added to ml. of yeast. Another tube containing ml. of water and

ml. of yeast serves as the urine blank.

The yeasted tubes are shaken at intervals, and allowed to stand for 20 minutes,

then centrifuged, and the supernatant fluid is decanted. Four ml, of each supernatant are measured into ml. of zinc sulfate solution, mixed, and ml. of

1.1 sodium hydroxide are added. The tubes are shaken vigorously, and allowed to stand for 10 minutes, centrifuged, and filtered. Two ml. of each filtrate

are placed in 50-ml. Erlenmeyer flask, and exactly ml. of acid potassium

periodate are added with scrupulous care with an Ostwald pipet. glass bead

is placed in the flask and glass stopper is placed in the mouth of the flask to

effect condensation. The contents are boiled gently for minutes and when

cooled ml. of 50-percent potassium iodide is added. The liberated iodine is

titrated with sodium thiosulfate, adding 0.5 ml. of starch just before the endpoint and titrating until the blue color disappears.

956507 0—52 27
348 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Calculation

Plasma

ml. of thiosulfate used for plasma blank ml. of thiosulfate for sample ml.

of thiosulfate for mannitol in plasma.

mg. of mannitol per 100 ml. of plasma ml. of thiosulfate used 4.6 (thiosulfate factor) 24 (dilution factor).

Urine

ml. of thiosulfate for water blank ml. of thiosulfate used for urine sample

ml. of thiosulfate for mannitol in urine.

mg. of mannitol per 100ml. of urine ml. of thiosulfate used 4.6 12

(dilution factor).

Where:

4.6 thiosulfate factor

urine dilution

washout dilution factor

12 dilution factor for analysis

Mannitol Clearance (rate of glomerular filtration):

Um Cm (in ml./minute rm

Where:

Cm mannitol clearance

urine volume in ml. per minute

Um mg. mannitol in ml. of urine

Pm mg. mannitol in ml. of plasma

Para-Amino Hippuric Acid

MEASUREMENT OF EFFECTIVE RENAL PLASMA FLOW

AND MAXIMUM TUBULAR EXCRETORY CAPACITY

The method of Homer Smith25 was followed.

Phenolsulfonphthalein Test Modified—Analytical Procedure 26

Reagents

i. Sodium hydroxide, 2-percent solution.

Ibid.

20 In Todd, J. C., and Sanford, A. H.: Clinical Diagnosis by Laboratory Methods. 10th ed. Philadelphia, W. B. Saunders, 1943, p. 163—167.
APPENDIX 349

2. Acetic acid, 10-percent solution,

standard curve is prepared from the phenolsulfonphthalein standard solution according to conditions of the test, blanking out with the acid color of the indicator at 540 millimicrons.

Procedure

The volumes of four urine specimens (timed) are measured and aliquots

representing one-hundredth of the volume of each specimen are each pipeted

into two cuvettes, one being designated as the acid tube and one the alkaline

tube for the individual specimens. All the samples are diluted to 9.75 ml. with

water, and to the alkaline tubes 0.25 ml. of the sodium hydroxide solution is

added, and 0.25 ml. of the acetic acid to the acid tubes. Unless the solutions

are absolutely clear, they are filtered. The alkaline tube is read in the spectrophotometer at 540 mfx, blanking out with the corresponding acid tube. The

percentage transmission is noted for each alkaline tube and the milligrams of

phenolsulfonphthalein content are recorded from the chart. In the event that

excretion is markedly diminished, the procedure is repeated, using one-tenth

aliquots of each specimen and dividing the chart readings by ten.

Comment

This method is much more accurate than methods depending on the usual

comparator block because color due to urinary pigments is entirely blanked out.

Urinalyses

Routine Urinalysis

Specific Gravity.—Specific gravity is measured with urinometer. If the

specimen is not sufficient, the specific gravity is determined by weighing.

Appearance.—The color and appearance of the urine are noted.

Albumin.—Approximately ml. of the specimen are placed in test tube,

the upper part of which is heated gently to the boiling point, any change in

turbidity being carefully observed. Three drops of acetic acid in 20-percent solution are added and the upper portion is again heated to boiling. The heated

portion is compared with the portion in the bottom of the tube, and depending

upon the density of the precipitate, is read as negative, trace, i-plus, 2-plus,

3-plus, or 4-plus.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

pH.—Indicators used: Phenol red, bromcresol purple, and methyl red.

Procedure for determining hydrogen ion concentration: Three tubes of the

same size as the indicator tubes are used, each of two of them containing ml.

of urine and ml. of water, and the third containing ml. of water only. To

one of the tubes containing urine 0.25 ml. of bromcresol purple is added. The

color resulting is compared with the standard solutions, 27 arranging the tubes

so the diluted urine to which the indicator has been added is backed by distilled

water and the standard tube is backed by the other diluted urine tube. If the

pH is above 7.0, phenol red is used in similar manner. If the pH is below 5.8,

methyl red is used. Methyl red ranges from red to yellow between pH of 4.4

and 6.0.

The Benzidine Test.—Reagents: (1) Benzidine solution. (Five Gm. of

reagent grade of benzidine are dissolved in 50 ml. of glacial acetic acid with

the aid of gentle heat, cooled, and diluted to 250 ml. with distilled water, Gm.

of animal charcoal is added, and the mixture is shaken and filtered into brown

bottle. It should be kept cool.) (2) Hydrogen peroxide, 3-percent solution.

(3) Hemoglobin standard, 20 mg. of hemoglobin per 100 ml. in boric acid,

i-percent solution. (Lasts week or 10 days.)

Procedure for performing the benzidine test: To ml. of benzidine reagent

in clean tube are added 0,2 ml. of urine and ml. of hydrogen peroxide. This

is allowed to stand for from 30 to 60 minutes, the shorter time being for higher

temperatures, and is then diluted to 10 ml. with 20-percent acetic acid solution.

The red color may turn blue at this point, in which case the solution is allowed

to stand in warm place until the red color again develops. The standard is

prepared exactly as if it were sample. The solutions are filtered and compared in the colorimeter, with the unknown set on 20 millimeters. The reading

of the standard yields the milligrams of hemoglobin per 100 ml. of urine.

Bile {Rosenbach’s Modification of Gmelins Test 28 ).—A portion of the urine

is filtered and drop of fuming nitric acid is introduced into the cone of the

filter paper. succession of colors—green, blue, violet, and red in ring pattern

—is interpreted as positive result.

The following urinalyses were performed by the standard methods indi21Preparation of the Clark and Lubs standard buffer mixture is described on p. 24 of Hawk, P. B.,

and Bergeim, O. Practical Physiological Chemistry. 10th ed. Philadelphia, Blakiston, 1931. 28 Ibid. Page 762,
APPENDIX 35

cated: Ammonia (Folin and Bell 29 ); urea nitrogen (Folin and Youngburg 30 );

titratable acidity (Henderson and Palmer31 ); chlorides (Schales and Schales32 ).

Organic Acids in Urine—Modified from Van Slyke and Palmer 33

Reagents

1. Calcium hydroxide.

2. Thymol blue indicator solution. (0.1 Gm. of thymol blue and 2.1 ml. of 0.1

sodium hydroxide are made up to too milliliters.)

3. 0.50 hydrochloric acid.

4. Phenolphthalein. (1 percent in 50-percent alcohol.)

Procedure

The urine is tested for albumin. If the albumin is i-plus or higher, noted

volume of urine (greater than 100 ml.) is acidified with 0.5 ml. of concentrated

hydrochloric acid, boiled for several minutes to coagulate the protein, cooled,

made up to the initial volume, and filtered. If the urine is protein-free, it is

used directly. Next, 0.5 ml. of phenolphthalein is added to 100 ml. of urine (or

the protein-free urine filtrate) and powdered calcium hydroxide is added until

the body of the solution turns pink (about to Gm. are required). The mixture is allowed to stand for hour. It is then filtered and 50 ml. of the filtrate

are measured into 125-ml.Erlenmeyer flask, decanting the remaining filtrate

into an identical flask. To discharge the phenolphthalein color in both flasks

0.5 HC1 is added.

Two ml. of thymol blue are added to the 50-ml. sample of the urine, and

ml. of thymol blue and 0.3 ml. of 0.5 hydrochloric acid to 50 ml. of distilled water, and the flasks are arranged for titration. (The 50-ml. urine flask

is placed in front of flask of distilled water, and the flask containing the dilute

29 In Hawk, P. B., and Bergeim, O. Practical Physiological Chemistry. 10th ed. Philadelphia, Blakiston,

1931, p. 829. 30 Ibid. Page 825. 31 In Peters, J. P., and Van Slyke, D. D. Quantitative Clinical Chemistry, vol. II; Methods. Baltimore, Williams Wilkins, 1932, p. 8271 32 In Simmons, J. S., and Gentzkow, C. J. Laboratory Methods of the United States Army. Philadelphia, Lea Fcbiger, 1944, p. 209. 33 In Peters, J. P., and Van Slyke, D. D. Quantitative Clinical Chemistry, vol. II: Methods. Baltimore,

Williams Wilkins, 1932, p. 647—651.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 352

hydrochloric acid and thymol blue is placed in front of the urine flask that does

not contain thymol blue.) The 50-ml. urine specimen is titrated until its color

matches the other set of flasks.

Calculation

24-hr. urine volume! Gm, creatinine in 24-hr. urine! (ml required 0.3 100 |_ 100

ml. of acid

Comment

The original method was modified by the use of thymol blue as the indicator

instead of tropeolin 00, which was not available for the study, and by introducing into the comparator-block system sample of the phosphate-free urine to

compensate for urinary pigments in the titration flask.

Creatinine and Creatine in Urine—Modified from Folin and from Folin-Benedict and Myers3i

Reagents

1. Saturated picric acid.

2. Sodium hydroxide, 10-percent solution.

3. hydrochloric acid.

4. 0.25 sodium hydroxide.

5. Alkaline picrate. (Made by combining volumes of saturated picric acid with

volume of 10-percent sodium hydroxide solution. It is freshly prepared before each series

of analyses.)

Procedure for Determination of Creatinine

One-thousandth of the volume of 24-hour urine specimen is made up to

10 milliliters. This is designated as the first tube. One milliliter of the contents

of this tube is then diluted to 10 ml. with water, and designated as the second

tube. Three ml. of the contents of the second tube are diluted to 10 milliliters,

forming the third tube. Five ml. of the contents of this third tube are placed

in cuvette, and 2.5 ml. of alkaline picrate are added. The color is allowed to

34 In Hawk, P. B., and Bergeim, O. Practical Physiological Chemistry. 10th ed. Philadelphia, Blakiston, 1931, p. 835-837.
APPENDIX 353

develop for 10 minutes and is then read in the spectrophotometer at 500 m/x,

blanking out with solution containing ml. of water and 2.5 ml. of alkaline

picrate solution prepared at the same time as the sample. Grams of creatinine

per 24-hour urine specimen are calculated by reference to the chart used for

plasma creatinine and dividing by three.

Procedure for Determination of Creatine

To 2.5 ml. of the first creatinine tube, placed in 25-ml. volumetric flask,

is added ml. of hydrochloric acid and the flask is placed in an autoclave

at i20°C. for 15 minutes, cooled, and made up to volume with water.

portion of the contents of the flask is titrated with 0.25 sodium hydroxide,

using phenolphthalein as an indicator to determine the amount required to

neutralize milliliters. 3-ml. aliquot is neutralized and made up with water

to 10 ml., 5.0 ml. are transferred to cuvette, 2.5 ml. of alkaline picrate are

added, and the color is read as for creatinine.

The turbidity correction factor is determined and subtracted in this manner:

The autoclaved solution in the volumetric flask is placed in cuvette, blanked

out with the contents of the second creatinine tube, and its value in terms of

optical density is determined. The value is muliplied by 0.3, changed to the

transmission percentage at the creatine reading, and added to that reading.

Example: Creatinine plus creatine reading; 50-percent T. (transmission)

OD of flask contents: 0.003

0.003 0.3 0.0009 O.OOI

OD of 0.001 corresponds to 1.5% T. at 50% T., making the corrected

creatine reading 51.5-percent transmission.

The corrected creatine plus creatinine reading is converted to grams per

24-hour urine specimen by reference to the chart and then dividing by three.

The creatine content is determined by subtracting creatinine from the combined creatinine and creatine.

Comment

The method as modified had these advantages: (1) The analysis was set

up on the spectrophotometer, which yielded more accurate colorimeter readings, and equipment and reagents were used sparingly, and (2) turbidity

correction factor was introduced into the creatine analysis which compensates

for turbidity formed during the autoclaving process.
THE PHYSIOLOGIC EFFECTS OF WOUNDS 354

Determination of Myoglobin

Myoglobin, the red coloring matter of muscle, is conjugated protein consisting of protein part called globin and the iron pyrol compound known

as hematin; it has molecular weight of 17,000.

As stated in Chapter VIII, spectroscope sufficiently sensitive to distinguish

between hemoglobin and myoglobin was not available to us, and it did not

prove possible to separate the two pigments in the plasma. The measurement

of myoglobin in tissue and urine involved the following considerations: (1) It

was necessary to find some property of myoglobin which would permit its

quantitative separation from hemoglobin; (2) convenient procedure for

measuring the ultimately separated myoglobin, one that would be sufficiently

sensitive to measure the small quantities anticipated in urine, was required,

and (3) rapid urine test was deemed essential since identification of myoglobin in the urine might influence the treatment of the patient.

Quantitative determination by means of the benzidine reagent was determined as the most satisfactory method. This test, however, was not satisfactory in media containing large amounts of phosphates and sulfates which

caused gross precipitation of the benzidine reagent. These ions were present

when it was attempted to separate myoglobin from hemoglobin by fractional

crystallization procedures as described by Morgan30 and Rossi-Fanelli, 36 using

lead acetate in phosphate buffer solutions or in concentrated ammonium

sulfate. An efficient means of dialysis was not available at the time of the study

and this method of separation was not pursued.

The myoglobin for further experimentation was extracted from perfused

normal human skeletal muscle. saline extract was made of finely minced

muscle, eluting with constant shaking for hour, using ml. of saline for

each gram of muscle tissue and allowing it to stand overnight in refrigerator.

The suspension was centrifuged to eliminate any red cells and then filtered

(the muscle was completely bleached).

The concentration of myoglobin in this extract was determined by the

benzidine test. The benzidine test measures the hematin part of the hemo85 Morgan, V. E.: The solubility of myoglobin in concentrated ammonium sulfate solutions. J. Biol.

Chem. 112:557-563, January 1936. 36Rossi-Fanelli, A.: Crystalline human myoglobin; some physicochemical properties and chemical

composition. Science 108: 15—16, July 2, 1948.
APPENDIX 355

globin, or myoglobin molecule, and since the relationship of myoglobin (one

hematin molecule, molecular weight 17,000) to hemoglobin (four hematin

molecules, molecular weight 68,000) indicates the same proportion of benzidine-positive substance per unit weight of protein, reference can be made to

standard hemoglobin solutions for quantitative measurement of myoglobin.

portion of the stock myoglobin solution obtained as described above was

diluted with normal urine to yield level of 50 mg. per 100 ml., and control

solution containing 50 mg. of hemoglobin in 100 ml. of urine was prepared.

On the addition of 0.5 ml. of 2.5 sodium hydroxide to 10-ml. of each sample,

striking difference in the behavior of the two solutions was noted. The solution containing the myoglobin retained its reddish tint, while that containing

the hemoglobin turned brown with the formation of alkali hematin. When

acid, in equivalent amount to that of the alkali previously added, was added

to each of the samples, the one containing myoglobin precipitated as brownish-red protein, while in the hemoglobin tube the precipitation yielded white

protein material and the supernatant fluid remained brown due to the hematin.

The contents of the tubes were then centrifuged.

The following chemical pattern indicates the different properties of the

two proteins:

alkali acidify and centrifuge Myoglobin myoglobin

myoglobin (precipitate) hematin-free supernatant

benzidine-positive benzidine-negative

alkali acidify and centrifuge Hemoglobin alkali hematin globin

globin (precipitate) hematin supernatant

benzidine-negative benzidine-positive

The supernatant fluid of the hemoglobin tube reflects the original concentration of the hemoglobin as hematin. The precipitate in the myoglobin tube

was the myoglobin present. This dissolved readily in little weak alkali and

was made up to the 10-ml. volume. Quantitative estimation of myoglobin could

then be made by the benzidine test.

Determinations made with hemoglobin solutions in urine indicated that

on the average 90 percent of the hemoglobin could be recovered as hematin

in the supernatant fluid while the precipitate would contain 10 percent of

benzidine-positive material in the form of undecomposed hemoglobin. Determinations with myoglobin solutions in urine indicated that from 65 to 85 percent could be recovered in the precipitate (the myoglobin fraction of the reac-
356 THE PHYSIOLOGIC EFFECTS OF WOUNDS

tion) and that the remainder had been decomposed by the alkali to alkali

hematin, yielding different proportions (15 to 35 percent) of myoglobin which

would be measured as hemoglobin in the supernatant.

Recoveries from mixtures of myoglobin and hemoglobin indicated that

separation could be effected between the two proteins, and that quantitative

estimation of myoglobin in urine as well as in tissue was feasible. The following standards were established for interpretation of the findings:

1. urine sample reflecting an analysis as 90 percent of the total benzidinepositive substance as hemoglobin and the remainder as myoglobin was considered to be all hemoglobin, while an analysis reflecting between 80 and 90

percent as hemoglobin was considered doubtful for myoglobin, and was also

recorded as myoglobin-negative. sample of urine yielding level of less

than mg. of myoglobin per 100 ml., with higher level in the hemoglobin

fraction, was considered doubtful for myoglobin and recorded as negative.

2. sample was considered to contain myoglobin beyond doubt if it

turned red or retained its reddish tint on addition of alkali and if, after separation of the protein, the precipitate was 20 percent or more of the total benzidine-positive substance. Recoveries in the myoglobin tube were considered as

70 percent; the value found was divided by 0.7 and the result reported in terms

of the recovery factor.

For the first month of the survey each day’s run of benzidine-positive urines

was accompanied by control recovery tubes of hemoglobin and myoglobin.

Solutions of methemoglobin or hematin failed to show the analytical pattern

described.

DETERMINATIONOF MYOGLOBIN IN URINE

Following are the details of performing the test on urine.

Reagents

1. Benzidine solution. (As for plasma hemoglobin.)

2. Hydrogen peroxide, 3-percent solution. (As for plasma hemoglobin.)

3. Hemoglobin standard solution, 20 mg. per 100 cc. (As for plasma hemoglobin.)

4. Sodium hydroxide, 10-percent solution.

5. 2.5 hydrochloric acid.

6. 0.1 sodium hydroxide.

Procedure

To 10 ml. of urine in test tube is added 0.5 ml. of the 10-percent sodium
APPENDIX 357

hydroxide solution. (Reddening of the urine at this time serves as qualitative test for the presence of myoglobin.) The solution is allowed to stand for

minutes, 0.5 ml. of the 2.5 hydrochloric acid is added dropwise, mixing

between each drop, and the solution is allowed to stand for 10 minutes, after

which the tube is centrifuged for 10 minutes and the supernatant carefully

decanted into another tube to be called the hemoglobin tube. To the residue

in the first tube are added ml. of water and ml. of the 0.1 sodium

hydroxide, and this is mixed to effect complete solution of the protein precipitate. This is called the myoglobin tube. The “plasma hemoglobin” test is then

made on the contents of both the hemoglobin and myoglobin tubes, using

0.2 ml. of each.

Calculation

mg. of hemoglobin per 100 ml. found in the hemoglobin tube n/io mg. of hemoglobin in 100 ml. of urine,

mg. of myoglobin per 100 ml. in the myoglobin tube divided by

0.7 mg. of myoglobin per 100 ml. of urine.

If the urine contains over 100 mg. of benzidine-positive pigments per 100

ml., it is diluted to contain no more than from 50 to 75 mg.; the dilution is

accounted for before making the final calculation. If the concentration in the

myoglobin tube is low, instead of making the contents of this tube up to

10 ml., the precipitate is dissolved and made up to 2.5 ml. and the resulting

calculation is divided by four.

DETERMINATION OF MYOGLOBIN IN TISSUE

The procedure followed for the determination of myoglobin in tissue is

essentially the same as that for the determination of myoglobin in urine. The

wet tissues are minced, finely ground, and weighed. Two ml, of saline are

added for each gram of wet tissue and the mixture is shaken for 30 minutes

and allowed to stand overnight. The contents of the tube are then centrifuged

and filtered. Two ml. of the filtrate (corresponding to Gm. of tissue) are

placed in tube, ml. of water are added, and from this point the sample is

handled as urine sample.

Calculation

mg. of myoglobin per 100 ml. of diluted extract

Gm. of myoglobin per Kg. of wet tissue. 0.7 10

APPENDIX

Survey of Case Records

COMPOSITION OF GROUP

The 186 patients studied, the majority of them American infantrymen,

were largely battle casualties classified under U. S. Army policy as “wounded

in action” (WIA). Wounds were inflicted by gunshot, bullet, shell fragmentation, grenade, mine explosion, and collapse of buildings. In addition, there

were two patients seriously injured in truck accidents, one in plane crash,

one in tent fire, and three who had been accidentally shot or stabbed. Two

medical cases were included for comparison of renal lesions. Six patients were

civilians wounded during combat, and 13 were wounded German prisoners

of war. The term “severely wounded” (nontransportable wounded or injured

patients) has been used to designate the entire group because the distinctions

between those wounded by direct enemy action, by other agent, or injured

accidentally are military ones, and because the causative agent was not

significant factor in any phase of this report.

DEATH RATES

Of the 186 patients studied, 65 died, case fatality rate of 35 percent. With

few exceptions, these deaths all occurred in the forward hospitals. It was impossible in most instances for the Board to follow case once the patient had

left the forward area, so the death rate applies only to the evacuation or field

hospital level (field hospital as it operated in the Mediterranean Theater of

Operations). The death rate of these seriously wounded was approximately

double that of the field hospital average death rate, which included all

wounded, at the time this study was being made.

Fifty, or nearly 70 percent, of the 73 patients with high azotemia included

in the study died, and of these, 73 patients, uremia appeared to be the major

cause of death in thirty-five. The importance of uremia as cause of death
360 THE PHYSIOLOGIC EFFECTS OF WOUNDS

in the severely wounded is evident when the number dying of this complication is compared with the total number of severely wounded. Of the 35 patients

dying of uremia, 32 were battle casualties. Since it was estimated that there

were, during the period of this study, between 201 and 252 severely wounded

men among the 10,073 battle casualties admitted to forward hospitals in the

area where the study was conducted, it is apparent that at least 14 to 17 percent of the severely wounded were dying of uremia.

CLASSIFICATION OF CASE RECORDS

table in which the cases have been classified so that they may be readily

located according to various aspects of the study follows. Cases 10, 46, 59, and

94 were discarded because data were inadequate; hence the omission of these

numbers between Cases and 150.

The “A” series (A-i through A-40) represent group in which attention was focused primarily on blood-volume data. For these data to have significance, large number of determinations was needed. Therefore temporary

branch of the Board’s activities was established in field hospital during

period of heavy combat activity in the vicinity. All pertinent data possible were

obtained on these patients at the time of their entry to this forward hospital

but, with the exception of few cases and of outcome, no follow-up studies

were made by us, and no intake-output records were kept on these cases.

Therefore the series records are, for the most part, very brief. Two patients

of this group died.

Resumes of the case records on which the study is based are on file in the Treadwell

Library, Massachusetts General Hospital, Boston, Massachusetts.
APPENDIX 361

Table 121.—Total Cases Classified according to Shock on Admission, Major

Wounds or Injuries, and Outcome

(B): Cases that were classified by the Board and that had admission laboratory data.

Case

No. Age Shock onAdmission Major Wound or Injury Patient’s

Outcome

21 Moderate

(B)

Soft part with fracture Lived.

22 Moderate

(B)

Soft part with fracture Lived.

29 None

(B)

Soft part without fracture Lived.

23 Severe

(B)

Intra-abdominal; bladder; soft part with fracture. Died.

27 Slight Soft part without fracture Lived. 31 Slight

(B)

Thoracic Lived.

20 None Soft part without fracture Lived.

24 Severe Intra-abdominal; bladder Died. 25 None Thoracic (transfusion reaction) Died. 11 19 Moderate

(B)

Soft part with fracture Lived.

12 26 Severe Intra-abdominal; kidney (nephrectomy done) Died. 13 19 Moderate

(B)

Soft part with fractures; intra-abdominal; liver Lived.

14 22 Severe Thoraco-abdominal; kidney (nephrectomy done). Lived. 15 22 Slight

(B)

Soft part without fracture Lived.

16 Moderate

(B)

Soft part with fractures Lived.

17 20 None Soft part with fracture Lived. 18 22 Slight Soft part without fracture Lived. 19 Moderate Traumatic amputation of extremity Died. 20 20 None Soft part with fracture Lived. 21 25 None Ureteral obstruction (disease) Lived. 22 19 None Soft part with fractures Died. 23 28 None

(B)

Soft part with fracture Lived.

24 28 Moderate Intra-abdominal; liver Died.

25 19 Severe Intra-abdominal; liver; kidney (nephrectomy

done).

Died.

26 20 Unclassified Thoraco-abdominal; liver; kidney Died.

27 25 Moderate Thoracic Lived.

(recovery

diuresis)

28 21 Moderate Spinal cord; soft part with fractures Lived.
362 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 121.—Total Cases Classified according to Shock on Admission, Major

Wounds or Injuries, and Outcome Continued

Case

No, Age Shock on

Admission Major Wound or Injury Patient’s

Outcome

29 18 Moderate Intra-abdominal Lived.

30 19 Moderate Intra-abdominal Lived.

(recovery

diuresis)

31 Moderate Thoraco-abdominal; spinal cord; liver; kidney

(nephrectomy done).

Died.

32 Severe Thoraco-abdominal; intra-abdominal; liver Died.

33 25 Slight

(B)

Soft part with fractures Lived.

34 30 Severe

(B)

Soft part with fractures Died.

35 18 Moderate

(B)

Soft part with fracture Lived.

36 Severe

(B)

Soft part withfracture Lived.

37 Moderate Thoracic; liver Lived.

38 22 Severe Intra-abdominal (volvulus) Lived.

39 19 Moderate

(B)

Soft part with fracture Lived.

40 40 Severe

(B)

Traumatic amputation of extremity Lived.

41 33 Slight Thoracic Died. 42 28 Severe Soft part with fractures Lived.

43 25 Slight Intra-abdominal Lived.

(recovery

diuresis)

44 19 Moderate Thoracic Lived.

(recovery

diuresis)

45 20 Severe Intra-abdominal Died.

47 23 Slight Soft part with fracture Died.

48 22 Moderate

(B)

Soft part without fracture Died.

49 32 Severe Intra-abdominal; transection, ureter Died. 50 23 Moderate

(B)

Soft part with fracture Lived.

51 20 Severe Intra-abdominal Died. 52 31 Severe Intra-abdominal Died.

53 26 Moderate

(B)

Thoracic Lived.

54 27 Moderate Soft part with fractures Lived.

55 29 Severe Intra-abdominal; kidney (nephrectomy done) Died.
APPENDIX

Table 121.—Total Cases Classified according to Shock on Admission, Major

Wounds or Injuries, and Outcome Continued

956507 0—52 28

Case

No. Age Shock on

Admission Major Wound or Injury Patient’sOutcome

56 25 None

(B)

Crush Lived.

57 29 Slight Soft part with fracture Lived.

58 28 Moderate

(B)

Spinal cord Lived.

60 26 Severe

(B)

Soft part with fracture Lived.

(recovery

diuresis)

61 22 Slight Thoracic Lived.

62 20 Slight

(B)

Intra-abdominal Lived.

63 26 Moderate Intra-abdominal Lived.

64 20 Moderate

(B)

Intra-abdominal; bladder; soft part with fracture. Lived.

65 23 Severe Thoraco-abdominal; liver Died.

66 20 Severe Intra-abdominal Died.

67 26 Severe Intra-abdominal; urinary tract Died.

68 36 None Kidney (disease) Lived.

69 21 None

(B)

Crush Died.

70 25 None Crush Died. 71 23 Moderate Intra-abdominal Lived.

72 16 Severe

(B)

Intra-abdominal; kidney Lived.

73 34 None Crush Lived.

74 25 Slight Burn Died.

75 Slight Thoracic Lived.

76 25 Moderate

(B)

Soft part with fracture Lived.

77 27 Severe Thoraco-abdominal; liver Died.

78 19 Slight

(B)

Crush Died.

79 27 Slight

(B)

Soft part with fractures Lived.

80 19 Severe Thoracic; liver Died.

81 25 Severe

(B)

Thoracic Lived.

82 21 Severe Thoraco-abdominal; liver; kidney (nephrectomy

done).

Died.

83 28 Slight

(B)

Thoraco-abdominal; liver Lived,

84 30 Slight

(B)

Soft part with fractures Lived.
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 121.—Total Cases Classified according to Shock on Admission, Major

Wounds or Injuries, and Outcome Continued

Case

No. Age Shock onAdmission Major Wound or Injury Patient’sOutcome

85 38 Severe Thoracic Died.

86 29 Severe Soft part with fractures Died.

87 Severe

(B)

Soft part with fractures Lived.

88 25 Severe Intra-abdominal; kidney (nephrectomy done) Died.

89 24 Severe

(B)

Traumatic amputation of extremity Lived.

90 34 Moderate

(B)

Thoraco-abdominai; liver; kidney (nephrectomy

done).

Lived.

91 27 None

(B)

Soft part with fracture Lived.

92 29 Slight Soft part with fracture Died.

93 32 Severe

(B)

Crush Died.

95 28 Severe Intra-abdominal Died.

96 27 None Soft part with fracture Lived.

97 27 Severe Intra-abdominal Died.

98 20 Moderate Intra-abdominal; bladder Died.

99 23 None

(B)

Crush Lived.

100 24 Severe

(B)

Soft part with fractures Died.

101 20 Moderate Intra-abdominal Lived.

102 32 None

(B)

Intra-abdominal Died.

103 35 Unclassified Soft part with fractures Lived.

104 32 Moderate Intra-abdominal; bladder Lived.

(recovery

diuresis)

105 34 Severe Intra-abdominal Died. 106 21 None

(B)

Soft part without fracture Lived.

107 Moderate

(B)

Intra-abdominal Died.

108 27 Severe

(B)

Soft part with fracture' Died.

109 29 None

(B)

Intra-abdominal; liver Lived.

110 35 Severe

(B)

Soft part with fracture Lived.

111 35 Slight

(B)

Intra-abdominal Lived.

112 21 Severe

(B)

Traumatic amputation of extremity Lived.
APPENDIX 365

Table 121.—Total Cases Classified according to Shock on Admission, Major

Wounds or Injuries, and Outcome Continued

Case

No. Age Shock onAdmission Major Wound or Injury Patient’s

Outcome

113 23 Slight

(B)

Thoracic Lived.

114 35 Moderate Traumatic amputation of extremity Died.

115 24 Moderate Intra-abdominal; liver Died.

116 20 Moderate Thoraco-abdominal; kidney Died. 117 25 Moderate Intra-abdominal; liver Died.

118 18 Severe Thoracic Died.

119 31 Severe Thoraco-abdominal Died.

120 23 None Soft part without fracture Died,

121 20 Severe Thoraco-abdominal; liver Died.

122 22 Severe

(B)

Thoraco-abdominal;kidney (nephrectomy done) Died.

123 19 Severe Traumatic amputation of extremity; thoracic. Died.

124 23 None

(B)

Crush Lived.

125 34 Severe

(B)

Soft part with fractures; thoracic Lived.

(recovery

diuresis)

12 23 Moderate

(B)

Thoraco-abdominal; liver; kidney Died.

127 32 Slight

(B)

Soft part with fractures Lived.

128 21 Slight

(B)

Soft part without fracture Lived.

129 20 Moderate

(B)

Soft part with fractures; kidney Died.

130 27 Severe

(B)

Soft part with fractures Lived.

131 27 Severe

(B)

Intra-abdominal; thoracic Died.

132 22 None Crush Died.

133 26 Severe Intra-abdominal Lived.

(recovery

diuresis)

134 33 None

(B)

Intra-abdominal Lived.

135 21 Severe Intra-abdominal; liver Died.

136 22 Moderate Thoraco-abdominal; kidney Died.

137 22 None Soft part without fracture Lived.

138 32 None Thoracic Lived.

(recovery

diuresis)

139 26 Severe

(B)

Thoracic; soft part with fractures Lived.
66 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 121.—Total Cases Classified according to Shock on Admission, Major

Wounds or Injuries, and Outcome Continued

Case

No. Age Shock onAdmission Major Wound or Injury Patient’sOutcome

140 23 Slight

(B)

Intra-abdominal Lived.

141 19 Slight

(B)

Thoraco-abdominal; liver Lived.

142 24 Moderate

(B)

Thoracic Lived.

143 28 Moderate

(B)

Thoraco-abdominal; liver Died.

144 32 Slight

(B)

Soft part with fractures Lived.

145 41 Slight

(B)

Soft part with fractures; thoracic Lived.

146 39 Severe Thoraco-abdominal; liver; kidney (nephrectomy done).Died.

147 23 Severe

(B)

Intra-abdominal Died.

148 25 Moderate

(B)

Traumatic amputation, both extremities. Lived.

149 26 Severe

(B)

Intra-abdominal; bladder Died.

150 27 Moderate Thoraco-abdominal Lived.

(recovery

diuresis)

A-l 23 Slight

(B)

Thoracic Lived,

A-2 21 Slight

(B)

Intra-abdominal Lived,

A-3 25 Moderate

(B)

Intra-abdominal; kidney (nephrectomy done) Lived.

A-4 37 None

(B)

Soft part without fracture Lived.

A-5 17 Slight

(B)

Traumatic amputation of extremity Lived.

A-6 22 Moderate

(B)

Intra-abdominal; liver Lived.

A-7 30 Unclassified

(B)

Head injury Lived.

A-8 31 Slight

(B)

Soft part without fracture Lived.

A-9 18 Moderate

(B)

Thoracic Lived.

A-10 24 Slight

(B)

Soft part without fracture Lived,
APPENDIX 367

Table 121.—Total Cases Classified according to Shock on Admission, Major

Wounds or Injuries, and Outcome Continued

Case

No. Age Shock onAdmission Major Wound or Injury Patient’s

Outcome

A-l Slight

(B)

Thoracic Lived.

A-12 22 Moderate

(B)

Thoracic Lived.

A-l 21 None

(B)

Traumatic amputation of extremity Lived.

A-14 22 Moderate

(B)

Thoracic Lived.

A-l 21 Moderate

(B)

Soft part with fracture Lived.

A-16 23 None

(B)

Thoraco-abdominal; liver; kidney Lived.

A-17 21 Slight

(B)

Traumatic amputation, extremity; intra-abdominal.Lived.

A-18 35 Moderate

(B)

Traumatic amputation of extremity; soft part

with fracture.

Lived.

A-19 26 None

(B)

Soft part with fracture Lived.

A-20 29 Slight

(B)

Traumatic amputation of extremity Lived.

A-21 21 Severe

(B)

Soft part with fracture Lived.

A-22 21 None

(B)

Intra-abdominal; liver; kidney Lived.

A-2 18 None

(B)

Soft part without fracture Lived.

A-2 19 None

(B)

Intra-abdominal Lived.

A-2 23 Slight

(B)

Soft part with fracture Lived.

A-26 32 Slight

(B)

Thoracic Lived.

A-2 25 None

(B)

Intra-abdominal Lived.

A-2 20 Severe

(B)

Soft part with fractures Lived.

A-2 20 Severe

(B)

Soft part without fracture Lived.

A-30 24 Moderate

(B)

Soft part with fracture Died.

A-31 20 Moderate

(B)

Thoracic Lived.

A-32 19 Moderate

(B)

Thoracic Lived.
368 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Table 121.—Total Cases Classified according to Shock on Admission, Major

Wounds or Injuries, and Outcome Continued

Case

No. Age Shock on

Admission Major Wound or Injury Patient’s

Outcome

A-33 19 Moderate

(B)

Traumatic amputation of extremity Lived.

A-34 31 Severe

(B)

Soft part with fractures Lived.

A-35 25 Moderate

(■

Soft part with fractures Lived.

A-36 21 Moderate

(B)

Soft part without fracture Died.

A-37 19 Moderate

(B)

Soft part with fracture Lived.

A-38 19 Severe

(B)

Soft part with fracture Lived,

A-39 19 None

(B)

Thoracic Lived.

A-40 25 Slight

(B)

Thoraco-abdominal; kidney Lived.
Index

Abnormalities. See also Biochemic and physiologic

findings.

of blood: 39-68, 127-162, 172-174, 207-215,

259-266 of cardiovascular system: 33-37

of urine: 68-71, 111-114, 116—119, 163-167,

174-177, 215-220, 242-244, 267-270 Acid-base

analysis, procedure for: 337-343

anions: 148-155 cations: 155-157

relationships: 61-65, 68, 148-157, 195-200

Acid urine. See Urine.

Acidosis, metabolic: 61-65, 148-150, 195-200

Adrenal gland, lipid depletion in: 298-301 Age of patients in series: 121, 361-368 Albumin, loss in urine

in crush syndrome: 269 method for determination of: 328 Alcohol, therapeutic use of: 188, 279

Alkalis

effect of initial shock on tolerance: 195-196

effect on circulatory system: 184-185, 189-190 effect on metabolic acidosis: 194-195

effect on urine: 189-190, 195, 270, 279

production of metabolic alkalosis: 195-200, 282

questionable therapeutic value: 189-190,

200,282

use of in traumatic shock: 189-190, 194-200,

78~ 79

Alkalosis in renal failure: 195-200, 282

Aminophylline, use of in renal failure: 188

Anemia, correction of in renal failure: 192

Anesthesia

effect on kidney function: 91-93

effect on liver function: 85-88 spinal, use of in renal failure: 190-192

Anions: 148—155 Anuria

case fatality: 122-123

definition:

incidence in series: m, 122, 169, 180, 267-268 relationship to

high azotemia: 123, 128-134, 180

initial shock: vii, 17, 123-124

plasma nonprotein nitrogen and electrolytes:

M5

wounds: 125

Autopsy. See Necropsy material.

Azotemia, high

case fatality: 122-123, 359

definition: 112

incidence in series: 112, 114, 116-119, 122

nonprotein nitrogen levels in: 128, 264 physiologic and biochemic findings in: 127-169,

172-180 relationship to

delay in hospital arrival: 59-61 hypertension: 126

initial shock: 123-124

other clinical findings: 127 urinary suppression: 123, 180

wounds: 59-60, 125

Bank blood. See Blood, stored.

Battle casualties. See also Case records survey;

Patients; Severely wounded,

crush syndrome in: 255-282 definition of: 21

preparation of, for surgery: 39

rates in North African-Mediterranean Theater:

v, 22

sulfonamide therapy in: 249—253 Benzidine test: 201, 350

Benzidine-positive substance. See Pigment.

Bilirubin. See Plasma.

Biochemic analyses, number made: 322

Biochemic and physiologic findings

clinical correlation: 121-183 in blood and plasma: 39-44, 58-68, 127-162,

172-174, 259-266 in crush syndrome: 259-272

in recovery diuresis: 168-180

in severely wounded: 59-72, 75-109, 127-183 in urine: 163-167, 174-180, 267-270 Biochemic methods used in study: 324-357

Blood. See also Hemoglobin; Plasma.

abnormalities of: 39-68, 127-162, 172-174,

259-267 analyses: 324-344

bank, see Blood, stored

grouping: 203, 214-215

loss (See also Blood, volume)

measurement of: 45-51

Correction A: 48-49 Correction B: 49
THE PHYSIOLOGIC EFFECTS OF WOUNDS

Blood —Continued

loss—Continued

relationship to

degree of shock: 48-51, 56—58 liver function: 78-80 plasmaprotein and hematocrit levels: 41-42 plasma therapy: 54-55

time after wounding: 55

type of wound: 51-55

normal values in: 325

pH: 148-149 precipitants, preparation of: 324-325

pressure: 35, 112, 118 (See also Hypertension)

stored

age of: 203-204

analyses of: 202-206

free hemoglobin in: 203-205

iso-agglutinins in: 214-215

specifications of: 203

sugar in: 205-206 substitutes

policy on in World War II: 5—n

sulfonamide levels in: 250-253

method for determination of: 343

theater blood banks: 11, 18-19, 203

therapy: 38-39, 192

effect on liver function: 80

transfusion

National Research Council committee on: 7-9

reaction: 18, 203

types, see Blood, grouping

volume, method for determination of: 45-51,

326-331 {See also Blood, loss)

whole, use of in World War II: 5-11, 38-39,

56-57

Blood bank. See Blood, stored.

Blood chemistry. See also Plasma; Serum,

acid-base analyses, procedure for: 337-343

hemoglobin, hematocrit values, and plasma protein, method of calculation: 344

methemoglobin, method for determination of;

343

nonprotein nitrogen products, methods for determination of; 332-337

relationship to

clinical condition: 6i-66

delay in hospital arrival: 59-61

type and location of wound: 59-60

Board for the Study of the Severely Wounded:

Frontispiece

Board for the Study of the Severely Wounded:

—Continued

establishment of: vii, 5, 16—20

events leading to: 1-19

organization and operation: 307-314 Bromsulfalein

retention

average hospital admission levels: 72-77 effect of ether anesthesia on: 85-88 in crush syndrome: 271

relationship to

blood loss: 78-80 degree of shock: 72, 78-79 plasma therapy: 72, 80

time after wounding: 72 wound: 72, 77

test of liver function: 72, 75-77, 345-346

Calcium. See Serum.

Carbon-dioxide combining power of plasma. See

also Acidosis, metabolic; Plasma,

in azotemia: 127, 129

in severely wounded: 63-64 method for determination of: 341

Cardiac changes. See Heart.

Cardiovascular findings: 33-36 blood pressure; 35, 112, 118

electrocardiograms: 33-34

“irreversible changes”: 35-36 pulse rate and volume: 34-35

Case fatality rates. See Fatalities.

Case records survey; 359-368 Casualty, definition of: 21. See also Battle casualties.

Cations: 155-157

Chemical methods used. See Biochemic methods.

Chemistry, blood. See Blood chemistry.

Chlorides. See Plasma.

Circulatory system, overloading: 184-186 Clearance tests. See Renal clearance tests; Urine.

Clinical condition of patients on hospital arrival:

27-39, 59-73, 257-259

Clinical, physiologic, and biochemic correlation in

lower nephron nephrosis: 121-183 Clinicopathologic correlation

in diagnosis of lower nephron nephrosis: 110-

120

in pathogenesis of shock kidney: 244-247 Creatine and creatinine. See Plasma; Urine.

Crush syndrome: 255-282 albuminuria in: 269
INDEX 371

Crush syndrome—Continued

clinical features: 257-259

hemoconcentration in: 261-264, 281

initial shock: 257 kidney damage: 259, 277-278

described early in war: 17

muscle damage: 272-275 myoglobin in kidney and muscle: 274, 281-282

pathologic findings: 272-278 in kidneys: 275-278 in liver; 272

in lungs: 272

in skeletal muscles: 272-275

physiologic and biochemic findings: 259-272

in blood and plasma: 259-266 in urine; 267-270 liver function: 271

pigment

in muscle: 274

in plasma: 265-266 in urine: 269 nephropathy: 277 pulmonary edema in: 281

recovery diuresis in: 282

treatment: 278-281 alkalinization of urine: 278-279 correction of hemoconcentration: 278 dehydrating agents: 280

diuretics: 279-280 other measures: 280—281

Deaths. See Fatalities.

Decolorization of muscle in crush syndrome: 272-

274

Diuresis. See Recovery diuresis.

Diuretics, use of: 188, 279—280 Drugs and procedures used to stimulate renal function: 186-192, 278-281

Edema. See Pulmonary edema.

Electrocardiographic observations: 33-34

Electrolytes. See Plasma.

Embolism, fat. See Fat embolism.

Ether anesthesia

effect on kidney function: 91-93

effect on liver function: 85-88 Evacuation time: 23-25

Fat

depletion in adrenal cortex: 299-301, 304

embolism, pulmonary: 288-289, 305

Fat—Continued

vacuolation

in ascending limb of Henle’s loop: 227-232,

297-298 in liver: 293-296

in myocardium: 289-292 Fatalities

in azotemia: 122-123, 359

in crush syndrome: 259

in entire series: 122—124, 359-360, 361-368 in hypertension: 126

in oliguria and anuria: 122-123

in “shock kidney”: 119

incidence in first 10 days after wounding: 124,

126, 135, 185 uremia as cause: 123-124, 359-360 Field laboratory: viii, 315-322

Fluid intake

cause of plasma volume increase: 185, 281

excess as cause of pulmonary edema: 184-186,

281

restriction of in treatment of lower nephron

nephrosis: 186, 281

Fractures. See Wounds.

Free hemoglobin. See Plasma, “hemoglobin.”

Glomerular filtration, measurement of: 97-101,

346-348 Glucose in plasma, method for determination of:

343

Granulomas, interstitial: 235

Heart

cardiovascular findings: 33—36 pathologic findings: 289-292 Hematocrit value

and plasma proteins: 39-44, 160—162

in crush syndrome: 261-264 determination of: 39, 344

influence of plasma therapy on; 42-43

Heme pigment. See Myoglobin; Pigment, heme;

Plasma, “hemoglobin.”

Hemoconcentration in crush syndrome: 261-264

correction of: 278 Hemoglobin, See also Pigment; Plasma; Urine,

pigment,

calculation: 344

excretion in urine, see Urine, pigment

free, in plasma, see Plasma, “hemoglobin”

levels in wounded men: 46-51, 66—68

loss of total (See also Blood)
37 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Hemoglobin—Continued

loss of total—Continued

determination of: 45-51

effect of blood therapy on: 54-55

relationship to degree of shock: 56-58 relationship to time after wounding: 55

relationship to type of wound: 51-55 methemoglobin: 343

Hemoglobinuria. See Pigment, excretion; Urine,

pigment.

Henle’s loop: 227-232

fat vacuolation in: 230, 297-298 High azotemia. See Azotemia, high.

Histologic findings. See Kidney, pathology;

Pathology.

Historical background of study: 1-20

Hydrogen ion concentration, determination of:

337-338, 350. See also pH.

Hydronephrosis, internal: 226-227 Hypertension

definition: 112

in high azotemia: 126

in lower nephron nephrosis: 112, 116, 118, 126

Hypertonic solutions; 187

Injury, definition of: 21

Interstitial inflammation: 232-234

Ions. See Anions; Cations.

“Irreversible” shock: 3-4, 11, 35-36, 56-57 Iso-agglutinins: 214-215

Kidney. See also Lower nephron nephrosis,

decapsulation: 192

function: 17, 90-109, 111, 121-122

drugs and procedures to stimulate: 186-192 effect of anesthesia: 91-93

effect of shock: 17, 91-92

effect of sulfonamides: 251-253

recovery diuresis; 168-180

significance of pigment casts: 246-247 tests

phenolsulfonphthalein; 90-97, 348-349 renal clearance: 97-105, 346-349

urine concentration: 105-106 lesion

pathogenesis of: 240-244

pathology: 224-248, 275-278, 297-298 clinical correlation: 244-247 gross: 237-239, 275-277

in crush syndrome: 275-278 microscopic: 225-237, 277-278

Kidney—Continued

pathology—Continued

pigment precipitation: 225-226, 242-244,

274, 277

“shock kidney,” see Lower nephron nephrosis

Laboratory, field; 315-322

Lactic acid in plasma; 63-65 method for determination of: 342-343

Latent consequences of wounds: 21

Lipid depletion in adrenal glands; 299-301

Liver

fat vacuolation in; 293-296 function: 75-89 bromsulfalein test for: 72, 75-77, 345-346 effect of ether anesthesia on: 85-88 effect of plasma therapy on; 80

in crush cases: 271 in newly wounded: 72, 75-89 plasma bilirubin levels: 83-85 relationship to

location of major wound: 77

postoperative course: 81-88

shock and blood loss: 78-80 time from wounding: 77

histologic findings in, in crush syndrome: 272 Loops of Henle. See Henle’s loop.

Lower nephron nephrosis

abnormalities of blood: 127-162, 169, 172-174

abnormalities of urine: 163-167, 169, 174-177

clinical features; 115-119, 122-127, 240-242

clinical, physiologic, and biochemic correlation:

I2i'-x83 clinicopathologic correlation: 110-120, 244-247 diagnosis; 1x0-120

pathogenesis: 240-242

pathology: 224-248, 275-278 treatment: 184-193 Lungs, pathologic findings in: 272, 285-289. See

also Pulmonary edema; Pulmonary fat embolism.

Magnesium

plasma: 134

method for determination of: 340-341

sulfate, use in renal failure: 189 Mannitol

method for determination of: 346-348 use in renal clearance studies: 97-101

Metabolic acidosis in shock. See Acidosis,

metabolic.
INDEX 373

Methemoglobin, method for determination of: 343

Muscles

decolorized, in crush syndrome: 272-275

myoglobin in: 274, 281

necrosis of, in crush syndrome: 275

Myocardium, fat vacuolation in: 289—292 Myoglobin. See also Pigment,

in kidneys: 242, 274

in muscle: 274, 281-282

in plasma: 201, 266

in urine: 216—220, 266, 269

method for determination of: 201-202, 354-357

Myoglobinuria

in wounded men: 215-220

relation to hemoglobinuria: 219-220

Necropsy material: 240, 284-285

Necrosis of skeletal muscles in crush cases; 218-219 Nephrons, lower, precipitation of pigment in: 243-

244

Nephropathy, pigment. See Pigment.

Nephrosis. See Lower nephron nephrosis.

Nitrogenous waste products: 135-148 Nonprotein nitrogen. See Plasma.

Nontransportable patient, definition of: 21, 359

Nutrition in treatment of lower nephron nephrosis:

2_I 93

“O” group blood: 18, 203

Oliguria. See also Urine, suppression,

case fatality: 123, 180

definition:

incidence in series: m, xi8, 122, 169, 180,

267-268 relationship to

high azotemia: 128-134 initial shock: 123-124

lower nephron nephrosis: 247

plasma N.P.N. and electrolytes: 144

renal tubule degeneration: 247

wounds: 125

Organic acids in urine, procedure for determination of; 351-352

Pain in wounded men: 27 Para-amino hippuric acid: x02-105, 348 Pathology of traumatic shock

crush syndrome; 272-278 kidney: 275-278 liver: 272

lungs; 272

skeletal muscles: 272-275

Pathology of traumatic shock—Continued

general: 283-305 adrenal gland: 298-301, 304

heart: 289-292 kidney: 224-248, 297-298 liver: 293-296 lungs: 285-289 pattern of pathognomonic changes: 301-305

reversibility of lesions: 302-304

“shock kidney”

clinical correlation: 110-120, 244-247

gross changes: 237-239

microscopic changes: 225-237

pathogenesis of: 240-242

Patients. See also Battle casualties; Case records

survey.

age of, in series: 121, 361—368

clinical condition on hospital arrival: 27-39

nontransportable: 21

pH

of blood: 148-149, 337-338 of urine: 114, 150, 165-167, 350

Phenolsulfonphthalein

excretory capacity: 90-97

effect of anesthesia on: 91-93

in first days after wounding: 91

rate of improvement in: 93-97

test: 90-91, 177, 348-349 Phosphorus. See Plasma, phosphorus.

Physiologic findings. See Biochemic and physiologic findings; Urine, suppression.

Pigment, heme. See also Myoglobin; Plasma,

“hemoglobin”; Urine,

casts, staining reactions of: 225-230

excretion in urine: 113, 116-119, 167, 202,

215-220, 269 functional significance of: 246 relationship to initial shock: 242

hemoglobin, see Plasma, “hemoglobin”

identification of: 201—202, 242, 344-345, 350,

354-357

in muscle and kidney, see Myoglobin; Pigment,

precipitation

in pathogenesis of “shock kidney”; 240-244

in plasma, see Plasma, “hemoglobin”

mobilization in severely wounded men: 201-

223

nature of: 242-243, 266

nephropathy (See also Kidney, pathology)

incidence in severely wounded: no—in,

225-226, 243, 277, 282
THE PHYSIOLOGIC EFFECTS OF WOUNDS 374

Pigment, heme—Continued

nephropathy—Continued

relationship to shock: 244

renal insufficiency in: m-114

precipitation in renal tubules: 225-226, 243-244

Plasma

bilirubin: 66-68, 73, 82-84 method for determination of: 344

carbon-dioxide combining power: 63-65, 129,

148-150 method for determination of: 341

chlorides: 63, 130, 150-153, 264-265 method for determination of: 341-343

creatinine: 61-62, 137-142

method for determination of: 334

electrolytes in shock and renal failure: 63-65,

144-145 glucose, method for determination of: 343

“hemoglobin” (See also Myoglobin; Pigment)

determination of: 201-203, 344-345

levels in crush syndrome: 265-266 levels in stored blood: 203-206 levels in wounded men: 207-214, 265-266 relationship to hemoglobinuria: 215-216 lactic acid: 63-65 method for determination of: 342-343

magnesium: 134, 156 method for determination of: 340-341

myoglobin; 201, 266

nonprotein nitrogen (See also Azotemia, high)

levels

in crush syndrome: 264 in high azotemia: 112, 1x6-119, 128, 135-

137

in recovery diuresis: 172-174 in severely wounded: 59-62, 112, 118, 122,

x8x

method for determination of: 332-334

products, method for determination of: 332—

337

normal values in: 325

phosphorus: 131, 142-143, 154

method for determination of: 341

relationship to calcium: 143—147

pigment: 201-223 (See also Myoglobin; Pigment; Plasma, “hemoglobin”)

method for determination of: 344-345

precipitants, preparation of: 324-325

proteins: 39-44, 132, 154-155

determination of: 39, 344

in crush syndrome: 261-262

Plasma—Continued

therapy, prior to hospital entry: 38-39 urea nitrogen; 137-142

method for determination of: 335-337 uric acid: 82-84, 147-148 method for determination of: 334-335 volume

effect of fluid intake on: 157-160 increased in renal insufficiency: 157-162 method for determination of: 326-331 relationship to plasma protein, hematocrit,

and blood volume: 160-162

Posttraumatic renal insufficiency, syndrome of. See

Lower nephron nephrosis.

Potassium, serum: 156, 340

Potassium chloride: 189

Proteins. See Plasma.

Proteinuria: 113, 167

P.S.P. test. See Phenolsulfonphthalein.

Pulmonary edema: 281, 286-288

prevention of: 184-186, 305

Pulmonary fat embolism: 288-289, 305

Pulse rate and volume: 34-35

Recovery diuresis: 168-180

blood chemistry: 172-174

clinical features: 169-172

in crush syndrome: 282

plasma volume in: 174

urinary findings: 174-179

Renal clearance tests: 97-105 and phenolsulfonphthalein excretion in crush

cases: 177

Renal failure. See also Kidney, function; Lower

nephron nephrosis,

relationship to

hypertension: 126

initial shock: 123-124

other clinical findings: 127

survival period: 124

type of wound; 125

Renal function in severely wounded. See Kidney,

function.

Renal lesions. See Kidney, pathology.

Renal tubules. See Tubules, renal.

Resuscitation. See Shock, traumatic, resuscitation

from.

Retention. See Bromsulfalein; Urine, suppression.

Reversibility of lesions in shock: 302-304
INDEX 375

Serum

calcium

method for determination of; 340

relationship to phosphorus: 143, 147 normal values in: 325

potassium: 156 method for determination of; 340

sodium: 133, 144-145, 155-156 method for determination of: 338-340 Severely wounded

Board for the Study of. See Board for the Study

of the Severely Wounded,

classification of cases: 361-368

definition of: 21, 359

initial blood changes: 46-51 initial studies on: 23-39

internal state on entry to forward hospital: 21-74

management of in World War II: 5-20

number of in Mediterranean Theater of Operations: 22

pigment mobilization in: 201—223

Shock, traumatic

biochemic and physiologic findings: 61-65, 67,

70-71 blood and plasma therapy: 38-39, 56-57, 194-

195

blood loss: 48-51, 56-58 blood pressure: 35 degree of: 27-29, 361-368 in anuria and oliguria: m, 116-118

in azotemia: 112, 116-119 in crush syndrome: 257

in lower nephron nephrosis: 110-120, 240—

242

in relation to time after wounding: 29-31

in relation to type of wound: 30-33

in renal insufficiency: 123-124

early concepts: 1-4

electrocardiograms in cases of: 33-34

hemoglobin loss: 48-51, 56-58

incidence: 29, 361-368 “irreversible”; 3-4, 11, 35-36, 56-57 kidney function in: 91-96 liver function in: 72, 78-80 management of in World War II: 5-20

National Research Council subcommittee on: 3-4

pathogenesis of: 305

pathognomonic changes in; 303-304

pathology of: 283-305 pigment mobilization in: 207-220

plasma protein and hematocrit levels in: 43-44

Shock, traumatic—Continued

pulse rate and volume in: 34-35

renal failure in: 123-124

resuscitation from: 12-15, 38-39, 56-57 treatment: 184-200 (See also Alkalis)

preliminary planning for: 5-9

“Shock kidney.” See Kidney; Lower nephron

nephrosis.

Sodium. See also Serum.

bicarbonate, administration of: 189-190, 194-

195

chloride, administration of; 151-153, 186-187 citrate, in stored blood and plasma: 194—195 Spinal anesthesia. See Anesthesia.

Staining reaction of pigment casts: 225-230

Stored blood. See Blood, stored.

Sulfonamides in relation to “shock kidney”: 18, 249-253

method for determination of in blood: 343

Sympathectomy in treatment of lower nephron

nephrosis: 192

Tests

benzidine: 201, 350 bromsulfalein: 72, 75-77, 345-346 phenolsulfonphthalein: 90-97, 177, 348-349 renal clearance: 97-105, 177, 346-349 urine concentration: 105-106 Therapy. See Treatment.

Thrombophlebitis in “shock kidney”: 235-237

Trauma. See Wounds.

Traumatic shock. See Shock, traumatic.

Treatment

errors to avoid: 184-186 of crush syndrome: 278-281 of renal failure and lower nephron nephrosis:

184-193, 194-200

of shock and blood loss: 38—39 sulfonamide: 249-254

Tubules, renal. See also Henle’s loop; Kidney,

pathology,

degeneration of: 227-232, 247

excretory capacity of: 102-105

fat vacuolation in: 227-232

rupture of: 234-235

Urea nitrogen, in plasma

and creatinine: 137-142 method for determination of: 335-337

Uremia as cause of death: 122-124, 359-360
376 THE PHYSIOLOGIC EFFECTS OF WOUNDS

Uremic symptomatology: 115-116

Uric acid in plasma: 82-84

method for determination of: 334-335

Urinalyses: 349-353. 35 ~357

Urine

abnormalities

in crush syndrome; 267-270

in lower nephron nephrosis: 113-114, 163-

167, 174-177, 215-220, 242

in recovery diuresis: 174-177

in wounded men: 68-71, m, 114

acid: 68, 243-244

acidity, persistent: 114, 150, 243-244

alkalinization of: 189-190, 194-200, 278-279 benzidine-positive substance in, see Urine, pigment

chlorides: 63-65

clearance tests: 97-105, 177, 346-349

concentrated: 68, 108, 163-165

concentration test: 105-106

creatine and creatinine: 69-71, 142

method for determination of: 352-353

pH; 114, 150, 165-167, 350

phenolsulfonphthalein excretion in: 90-97, 177

pigment

excretion: 113, 116-119, 167, 201-202, 215-

220, 269

method for determination of: 201—202, 356—

357

relation of hemoglobinuria to myoglobinuria:

219—220

relationship to hemoglobin in plasma: 215-216

protein excretion: 113, 167

specific gravity, fixed, in lower nephron nephrosis: 114, 163-165, 174, 270

rine—Continued

suppression (See also Anuria; Oliguria)

in crush syndrome: 267-268 relationship of anuria, oliguria, and azotemia:

123, 128-134 relationship to proved pigment nephropathy:

243-244

time as factor in development of; 124

Vacuolation. See Fat.

Van den Bergh test. See Plasma bilirubin.

Vasoconstriction, result of blood loss: 58 Visceral changes, pattern of: 304-305

Whole blood. See Blood.

Wound shock. See Shock, traumatic.

Wounded in action, definition of: 21

Wounded men. See Battle casualties; Severely

wounded.

Wounds

how incurred: 359

latent consequences of: 21

major, in entire series: 25-27, 361-368 relationship to

blood chemistry findings: 59-60 blood loss: 51-55

development of renal failure: 125

hemoglobin loss: 52-55

liver function: 72, 77 pain; 27

plasma bilirubin and hemoglobin levels; 66-67 plasma protein and hematocrit values: 40,

43-44

shock: 30-33

type and location of major: 25-27, 361-368 (See also Crush syndrome)

in renal insufficiency: 125

in recovery diuresis; 169

U. S. GOVERNMENT PRINTING OFFICE: 1952 956507