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Chapter XVIII

Contents

CHAPTER XVIII

Reactions to, and Complications of, Blood and Plasma Transfusions

GENERAL CONSIDERATIONS

It is still true (in 1962) that, whenever large numbers of transfusions are given, reactions will occur, though on well-controlled services, they do not exceed 3 percent. It is also still true that some deaths will follow transfusions, though the number is smaller, in fact, than would occur if transfusions were withheld.

At the onset of World War II, reactions after transfusions were sufficiently frequent to alarm even the most enthusiastic proponents of the liberal use of whole blood.1 They were readily explained: Blood was usually collected by an open system, and principles of sterility and of absolute cleanliness of the apparatus were enforced in only a limited number of hospitals. Many surgeons were therefore wary about using blood at all. When it began to be used in increasing amounts in the management of battle casualties, the pendulum then swung to the other extreme. Reactions were overlooked, and the widespread and highly erroneous clinical impression grew up that transfusion was an innocuous procedure. The relatively easy availability of whole blood and its widespread use brought in its train great benefits but it also brought inevitable misuse.

As more experience was gained and the risks of transfusion began to be appreciated, there was another swing of the pendulum. The impact of severe reactions on persons who had supposed that transfusion was without risk was magnified, and blood was sometimes withheld when it should have been given.

The precise incidence of reactions after transfusions in World War II is not known, for the major reason, already stated several times, that the circumstances in which many, if not most, of them were given did not favor accurate recording. Such statistics as do exist are also of somewhat dubious accuracy, because the differential diagnosis of the reaction was not always correct. Many casualties who were transfused were already running high temperatures and some were having chills. Some diagnoses were therefore made of reactions which did not exist, while some probably went unrecognized.

The incidence of reactions varied from hospital to hospital but invariably was smallest in hospitals which practiced routine investigation of all transfusion reactions as soon as they occurred. A critical appraisal of the findings,

1In 1940, Davis (1) collected from the literature 3,273 transfusions of "conserved" blood, with 13.8 percent of reactions. He did not include Gnoinski's report on the use of 60- to 90-day old blood in six cases, with five reactions. All such compilations, as Davis noted, are open to question because criteria of reactions vary.


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with correction of errors, went far toward tightening controls and preventing recurrences.

A listing of the most common causes of transfusion reactions carries in itself the method of preventing them. They include errors in typing, hemolysis due to overaging, physical changes from failure of refrigeration or from storage at lower or higher temperatures than the optimum, contamination, and the presence of pyrogens.

In hospitals which used type-specific blood, transfusion of incompatible blood could be avoided only by the most careful attention to techniques of blood grouping, crossmatching, and typing of donors and recipients; the use of fresh, avid, high-titer typing sera, free from contamination, in adequate quantities; the use of sufficiently heavy cell suspensions; and the performance of the tests by experienced technicians. The plan of having the results of typing and crossmatching checked and the tests repeated by different technicians was well worth the time it took. Indeed, many technicians learned to develop a high index of suspicion when they observed any departure from normal behavior in blood typing.

Another precaution, when it was practical, was to have the person who would give the transfusion collect the blood from the laboratory, start the transfusion, and remain with the patient long enough to be reasonably sure that no reaction would occur or to cut off the flow of blood at once if signs and symptoms did appear. One reason that this was a wise precaution was that the amount of blood given seemed important in hemolytic reactions. Bordley (2), for instance, reported that 5 patients who recovered after such reactions received an average of 314 cc. of blood, while 10 who died received an average of 565 cc. The functional capacity of the kidneys and the general condition of the patients as always, of course, helped to determine the outcome.

The point to be emphasized in any discussion of reactions in World War II is that, while mass transfusions were given, mass reactions did not occur. The number of reactions reported, in fact, was so small that generalizations based on them seem scarcely valid. This important consideration should be borne in mind in reading the following pages and reflecting upon the individual case histories presented.

ALLERGIC REACTIONS

Of the three varieties of transfusion reactions, allergic, pyrogenic, and hemolytic,2 allergic reactions were the most frequent and the least serious (3). They followed transfusions of whole blood and plasma and, occasionally, of human serum albumin. They were presumably caused by a response on the part of the recipient to allergens in the blood of the donor. The recipient was sometimes sensitive to what a nonfasting donor had eaten. Passive transfer

2Unless otherwise indicated, the clinical and laboratory material in this chapter is taken from War Department Technical Bulletin (TB MED) 204, 24 Oct. 1945 (3).


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of sensitivity was also possible, the recipient showing an allergic response if he came into contact with the specific allergen. For this reason, it was best not to use individuals suffering from major allergies as donors.

Most allergic reactions took the form of urticaria, which readily responded to subcutaneous administration of 0.3-mg. doses of epinephrine. If urticaria appeared, it was best to discontinue the transfusion unless the indications for it were extremely urgent.

Serious allergic reactions took the form of angioneurotic edema or asthma, both of which required immediate discontinuance of the infusion and prompt treatment with epinephrine. Edema of the larynx was occasionally fatal.

It was a common experience in military hospitals to have few reactions in the shock ward as compared with the number in the operating room and the recovery ward, after several transfusions had been given. The interval between the infusions in these cases was too short for the reactions to be explained by the Rh factor, and a more reasonable explanation seemed sensitization of the patients to type O blood or to plasma protein which might have undergone denaturization. The possibility of sensitization of humans to human protein was the last of all explanations to be considered.

PYROGENIC REACTIONS

Historical Note

When sodium citrate was suggested as an anticoagulant in 1914, by several observers at the same time (p. 218), it was at once blamed for the undesirable and often dangerous chills and fever that followed direct transfusion. Practical proof to the contrary was supplied in 1933 by Lewisohn, one of those who had suggested the use of citrate, and Rosenthal (4). Scientific proof went considerably further back. The possible role of distilled water in pyrogenic reactions was demonstrated in 1923 by Seibert (5), who pointed out, in her review of the literature, that its febrile potentialities had been established by Billroth in 1865 and by Bergman in 1869. Hort and Penfold also made observations on contaminated distilled water in 1911.

There were no chills in the first 17 transfusions given at Mount Sinai Hospital in 1915, all by the same physician, who paid careful attention to the preparation of apparatus and solutions (6). When multiple personnel began to give blood, there were numerous reactions, 24 percent in one series of 365 transfusions (7). When transfusions were concentrated in the hands of eight senior members of the house staff, the reaction rate fell to 13 percent.

The high rate of reactions after transfusion continued until Rosenthal advanced the theory that the preparation of the equipment used in its performance was entirely too lax and casual. He was able to demonstrate that posttransfusion chills were caused by foreign proteins introduced as extraneous matter in distilled water or present in the tubing or other apparatus in the form of altered proteins left from previous intravenous injections. Such matter


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would always be present unless the instruments were cleansed with the greatest care, immediately after use, by competent technicians, in a central room, with no connection with the operating room or any other part of the hospital.

Such a room was set up, and the detailed technique outlined by Rosenthal, including the use of triple-distilled water, was instituted at Mount Sinai Hospital on 1 October 1931. The results immediately proved his theory. The previous year, there had been 9 percent of chills in 412 transfusions. In the first year of the new setup, although multiple personnel gave the 477 transfusions, there was 1 percent of reactions. In the 6 months before the new department was set up, the incidence of chills after transfusion with citrated blood was 10 percent. In the first 6 months of the operation of the new department, there were no chills in 154 similar transfusions.

Although the use of triple-distilled water was not accepted in some quarters, Lewisohn and Rosenthal's proof, published in 1933 (4), was too conclusive to be ignored. Their experience was always duplicated when their technique was followed, though as time passed, it became clear that the use of triple-distilled water was an unnecessary precaution. At Walter Reed General Hospital, Washington, D.C., when the Research Division of the Army Medical School took over the task of cleansing the equipment, the incidence of reactions fell from 20 percent to 0.5 percent. All rubber tubing was washed within an hour after use, with distilled water, which was forced through it by a 50-cc. syringe or a large Asepto syringe. The tubing was then soaked in 5-percent sodium hydroxide. The temperature of the water and the solution was not important. The equipment was put up in individual sets and autoclaved immediately. The results here and elsewhere left no doubt that the majority of posttransfusion reactions were pyrogenic and were the result of improper cleansing of the transfusion apparatus, particularly the rubber components.

World War II Experience

In World War II, the common errors leading to pyrogenic reactions were as follows:

1. Insufficient cleansing of the rubber tubing, or the glass or metal parts, or the entire equipment.

2. Delay in cleansing used sets, which permitted pyrogens to develop in amounts that could not be removed by ordinary cleaning techniques.

3. Rinsing the equipment with supposedly pyrogen-free water that had become contaminated.

4. Allowing properly cleaned and rinsed sets to stand for 4 hours or more before sterilization.

The elaborate cleaning technique which was possible in civilian hospitals proved completely impractical in combat circumstances. Transfusions could never have been employed as universally as they were if disposable equipment had not been developed and provided along with blood and plasma. The incidence of pyrogenic reactions was invariably increased when hospitals


653

insisted upon cleaning their own glassware and tubing instead of using the sterilized sets furnished (8).

The severity of the reaction depended upon the amount of pyrogen infused and the susceptibility of the patient. Symptoms and signs might start at any time during or after the infusion, but most often occurred shortly after the infusion had been completed. The reaction varied in severity from a slight to an extreme temperature elevation (which was extremely dangerous if the patient was already running a high fever), with chills, cyanosis, and prostration. The temperature usually returned to normal within 3 or 4 hours and fatalities scarcely ever occurred.

The prophylaxis of pyrogenic reactions was the use of properly cleaned transfusion sets, or, better, the use of disposable equipment. The treatment was immediate termination of the transfusion, for the principal reason that the initial clinical manifestations of serious hemolytic reactions from the transfusion of incompatible blood could not be differentiated from simple pyrogenic reactions. Another reason was, as already pointed out, that the outcome of the reaction depended upon the amount of pyrogenic substances introduced into the bloodstream.

HEMOLYTIC REACTIONS

In 1942, Kilduffe and DeBakey (9) collected from the literature 43,284 transfusions, with 80 hemolytic reactions (0.18 percent) and 45 deaths (0.14 percent). Hemolytic shock was the cause of death in 32 of the 45 fatal cases. The figures leave no doubt that incompatibility reactions are the chief cause of death after transfusion and vindicate the decision to use only O blood in the massive transfusion programs set up in the Mediterranean and the European Theaters of Operations, U.S. Army, and the Pacific areas in World War II.

At the end of the war, as the result of prewar knowledge and wartime experience, the causes of hemolytic reactions could be listed as intravascular hemolysis of incompatible donor cells, whether intergroup (A, B, O) or intragroup (Rh); intravascular hemolysis of recipient cells; intravascular hemolysis of compatible donor cells; and transfusion of hemolyzed blood.

Hemolytic reactions, although relatively infrequent, were always serious, and were always potentially lethal. On the other hand, there is no doubt that many of the deaths classified as caused by transfusions in World War II were the result of the wound itself or of other causes not related to the use of whole blood.

Reactions Due to Incompatibility

Clinical manifestations.-The reaction to transfusion with incompatible blood varied from patient to patient, perhaps depending upon the agglutinin titer of the recipient's plasma. One patient might receive 500 cc. of incompatible blood and have no manifest reaction while another might have a severe


654

reaction after only 20 to 50 cc. had been given. As a rule, symptoms appeared after 100 to 200 cc. had been given.

There were two clinical components of the reaction, the immediate hemolytic crisis and the later renal complications:

The initial clinical manifestations (hemolytic crisis) usually consisted of a severe chill; pain in the lower back; a sense of substernal oppression; and, sometimes, nausea, vomiting, and involuntary micturition and defecation. After an initial rise of blood pressure, a state of shock might supervene, with extreme hypotension and a weak, fast pulse. After the chill, the temperature might rise to 105 F. Sometimes bleeding occurred from needle puncture wounds or other exposed capillaries.

As a rule, the patient recovered from the initial reaction, though transfusions of plasma or compatible blood might be required, and often, in a few hours, he seemed completely well.

The first urine passed after the reaction was dark brownish-red, was positive for protein, and contained a few red blood cells and a fair number of pigmented casts. The benzidine test was also positive.

The initial reaction was seldom fatal, but after recovery from it, a number of possibilities might come to pass:

1. There might be no further signs or symptoms other than a transient bilirubinemia.

2. There might be transient oliguria, with nitrogen retention, the excretion of large quantities of urine, and then recovery.

3. There might be persistent oliguria, with increasing nitrogen retention, and death in uremia.

4. There might be oliguria leading to complete anuria, or there might be complete anuria from the onset of the reaction. In either event, fatal uremia usually occurred, although a few patients recovered after diuresis. An occasional patient continued to retain nitrogen even after diuresis and died in uremia.

Death from renal failure usually occurred in 4 to 10 days. If the patient had received less than 250 cc. of incompatible blood, the chance for recovery was usually good. If he had received 500 cc. or more, the prognosis was generally poor.

Pathologic process-The characteristic autopsy findings in a death following the transfusion of incompatible blood were limited to the kidneys. Except for some swelling, there were no pathognomonic gross lesions. The most striking microscopic observation was the presence, within the renal tubules, of pigmented casts consisting of hemoglobin or degradation products of hemoglobin, though mechanical occlusion of the tubules by hemoglobin casts was not believed to be the principal factor in the fatality. Characteristically, the casts occurred only in certain portions of the tubules; namely, the ascending limbs of Henle, the distal convoluted tubules, and the collecting tubules. The distribution of the casts was irregular but not diffuse, and frequently only a small proportion of the tubules were involved.


655

Less conspicuous than the changes just described, but probably more important, were the degenerative, sometimes necrotic, changes in the tubular epithelium of relatively short segments of the ascending limbs of Henle and the distal tubules. In the neighborhood of the more severely damaged segments, the interstitial tissue often exhibited an inflammatory reaction, with a predominance of small round cells.

The changes in the tubules and their supporting stroma were usually most evident in the zone between the cortex and the medulla. The glomeruli and the proximal tubules; that is, the upper portion of the nephron, were usually normal.

Pathogenesis-A comprehensive clinical and experimental study of hemoglobinuric nephrosis in traumatic shock by Mallory (10) (formerly Lieutenant Colonel, MC), in 1947, eliminated a number of theories of causation. Fatal renal insufficiency was not produced by the intravenous injection of hemoglobin. Precipitation did not occur in the presence of either acid or alkaline urine. The Van Slyke kidney could not be reproduced experimentally, but when renal ischemia was produced, changes were observed ranging up to necrosis of proximal tubules, though no significant changes occurred in the lower nephron. Experimental pigment-formation could not be produced, and there was no proof of a responsible toxic factor.

In Mallory's study of 60 fatal cases of battle injury, pigment excretion was found in all the casualties, the amount of pigment nephropathy being directly proportional to the severity of the injury. The evidence suggested that, while renal insufficiency preceded all structural changes, it did not progress in the absence of pigment nephropathy. It was the lower nephron, Mallory pointed out, not the upper, in which anatomic changes were present in the presumed posttransfusion kidney. At the end of the war, therefore, and afterward, the posttransfusion kidney remained an unsolved problem.

Diagnosis.-The clinical and pathologic picture just described, while it might be caused by a transfusion of incompatible blood, might also be caused by a variety of other conditions, including shock, crushing injuries, burns, sulfonamide therapy, and possibly various combinations of these conditions. The renal involvement that followed all of them could not usually be differentiated from that resulting from the transfusion of incompatible blood, and no doubt a number of deaths were charged to hemolytic reactions when they were really due to some one of these other causes.

The following test, devised by the serology section of the 15th Medical General Laboratory to differentiate hemolytic from nonhemolytic reactions (11), came into rather wide use: Blood serum, drawn about 15 minutes after the clinical reaction, was compared with the serum taken for crossmatching before the transfusion. The presence or absence of hemolysis in the posttransfusion specimen was compared with the same phenomena in the pretransfusion specimen.

This simple method proved very useful in indicating whether the reaction was hemolytic and required a complete investigation, or was allergic and re-


656

quired a recheck of the patient's history, or was pyrogenic and required an investigation of the technique of preparing apparatus and distilled water.

If the posttransfusion sample contained free hemoglobin or bilirubin, additional investigation was required. Another sample was withdrawn about 4 hours after the reaction and tested for bilirubin. If it was present, a search for the cause was made:

1. The blood groups of the recipient and the donor were rechecked.

2. Crossmatching tests were rechecked.

3. The presence or absence of hemolysis was determined by centrifuging a specimen from the donor bottle.

4. The Rh types of the recipient and the donor were checked. A recently transfused Rh-negative patient might show a few Rh-positive cells, and this possibility always had to be taken into account.

5. If the recipient was Rh negative, the pretransfusion sample of serum was tested for the presence of anti-Rh agglutinins.

6. If the donor was group A, B, or AB and had received group O blood, his serum was titered against the recipient cells.

Treatment-The immediate treatment of hemolytic crisis was stopping the transfusion at the first sign of any adverse reaction. Plasma was used if shock was present.

The mechanism of renal failure, as just stated, was never clarified during the war, and its treatment therefore remained entirely empirical. It consisted of any single one or a combination of the following methods: alkalinization, splanchnic block, decapsulation of the kidney, blood and plasma transfusions, and regulation of the fluid and salt balance. All of these methods were empirical, and none of them was successful in any significant number of cases. Fluid regulation, it should be emphasized, was always an individual matter, for which no general rules could be stated.

Reactions Due to Intravascular Hemolysis of Recipient's Cells

Intravascular hemolysis of the recipient's cells could be caused by the accidental administration of distilled water and by the use of high-titer group O blood for A, B, and AB recipients.

At the Conference on Shock and Transfusion on 25 May 1945 (12), Maj. (later Lt. Col.) Charles P. Emerson, MC, described a type of reaction in which the presence of incompatible isoagglutinins in high-titer blood was manifested by chills, fever, hemoglobinemia, and a rather persistent bilirubinemia. Destruction of red blood cells by group O blood was first demonstrated in a group A patient with severe leptospirosis, who was given a large amount of plasma for 4 or 5 days and then a series of O-blood transfusions for rapid, progressive anemia. When the transfusions were over, every one of his own cells had been replaced by transfused cells, but apparently not to his detriment, for he survived. The observations in this case confirmed Ashby's (13) earlier studies, which showed surprisingly large destruction of recipient cells. Similar observations were made in five patients with severe burns,


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one of whom died on the fourth day. All had received large amounts of plasma. An ante mortem Ashby count in the fatal case showed that 96 percent of this patient's red blood cells had been replaced by transfused cells.

Major Emerson's investigation also showed that the increased fragility of recipient cells frequently noted after transfusion was particularly marked after injection of high-titer O blood and after repeated transfusions of O blood or pooled plasma (14). In discussing these observations, Brigadier Lionel E. H. Whitby, RAMC, stated that the fragility curve is always increased after severe burns, because of the external heat applied to the cells as they pass through the burned area. The affected cells continue to be destroyed for many days thereafter. Major Emerson found it hard to believe that, if the patient were to survive, traumatized red cells resulting from a burn could possibly involve an enormously high proportion of his blood.

Since the technique of titration varied from laboratory to laboratory, no specific general rulings were made as to the upper limit of agglutinin titer compatible with safety. It was simply recommended that some technique be selected which would label all group O blood as having a high agglutinin content. It was thought unlikely that such a proportion would be potentially dangerous, but, in view of the fact that many casualties received multiple transfusions, it was also thought that the titer for universal donor blood should be kept as low as possible.

Reactions Due to Intravascular Hemolysis of Compatible Donor Cells

Hemolysis of compatible donor cells could occur promptly after transfusion with blood which had been improperly handled; that is, it was overage or it had been stored at incorrect temperatures. Unless the blood showed definite in vitro hemolysis, results were seldom serious and there were often no subjective symptoms, though the transfusion was obviously of little benefit. When the transfused blood was promptly broken down, there would be free hemoglobin in the serum, which would shortly be converted to bilirubin, and clinical jaundice might be evident.

Hemoglobinemia might be expected to have a deleterious effect upon the kidneys of a patient in shock, and fatal anuria was reported after the transfusion of hemolyzed blood.

The proper care of preserved blood and its careful examination before use were all that was necessary to prevent these results.

European Theater

When Maj. (later Lt. Col.) Robert C. Hardin, MC, visited various hospitals in the European theater in the late summer and early fall of 1944, he found a considerable amount of confusion concerning transfusion reactions and a great many untenable theories, which were little more than clinical impressions (15). Furthermore, fatalities were being attributed to transfusions for


658

no better reason than that the patient had been given blood. It was not realized that a hemolytic transfusion reaction cannot be diagnosed by tissue study, nor was it realized that intravascular hemolysis of incompatible blood is not the only cause of hemoglobinuric nephrosis. In short, the reasoning was entirely of the post hoc, ergo propter hoc variety-the patient had a transfusion; the patient died; therefore, his death was due to the transfusion.

Studies in the European theater corroborated those in the Mediterranean theater and confirmed the highly dubious role of transfusion in the etiology of lower nephron nephrosis (16). In an investigation of a number of reports of autopsies performed at the 91st Evacuation Hospital, Major Emerson found cause to doubt the anatomic diagnoses of hemoglobinuric nephrosis. He thought that the renal changes demonstrated might well be due to prolonged impairment of the renal blood flow, as the result of severe, long continued, hypotension. The renal anoxia was probably further enhanced by the severe anemia induced by massive plasma transfusions; by anoxia resulting from impaired pulmonary ventilation; and, quite possibly, by diffuse intravascular agglutination resulting from the injection of isoagglutinins, although this factor could not be properly evaluated, since the patients' blood groups were seldom noted on their records.

Most of these patients had been treated for oligemic shock. Their hypotension had been prolonged. They had exhibited temporary oliguria and albuminuria; reduction of the urinary pH; and, in an occasional case, excretion of red blood cells and casts. In all but two cases, which ended fatally, these findings were transitory, clearing within 24 to 48 hours after restoration of the arterial pressure.

Case 1.-In the first fatal case, the casualty, in addition to multiple intestinal perforations, had required nephrectomy for a severe lacerating renal wound. He had been in a state of oligemic shock for 8 hours and had received 4,000 cc. of O blood during his first 10 hours of hospitalization. He died on the fifth day.

Case 2.-The second patient had multiple sucking wounds of the chest with severe intrapulmonary hemorrhage. He had been in severe shock, as the result of hemorrhage, anoxia, and marked oligemia, for 30 hours. His blood group was A, and he had received 4,000 cc. of O blood during the first 24 hours of hospitalization. He died on the ninth day.

Clinically, there was no sign of a transfusion reaction in either case, and the Ashby count indicated no unusual degree of hemolysis of recipient cells. The second patient developed severe hypertension on the sixth day. Both patients exhibited oliguria progressing to anuria and uremia.

In the first case, necropsy showed eosinophilic granular casts of the distal portion of the nephrons of the remaining kidney, which was edematous. The diagnosis of hemoglobinuric nephrosis was consistent with the pathologic picture described by Mallory. In the second case, there were also hemoglobin casts in the renal tubules. It was Major Emerson's opinion that these post mortem findings, even though hemoglobinuria was not demonstrated during life, might be explained by diffusion of small amounts of hemoglobin through the glomeruli of ischemic kidneys. Once the hemoglobin had gained entrance


659

to the tubules, either insufficient reabsorption of water might occur, or the filtration pressure of the urine might be so inadequate that any casts that formed could not be dislodged. The benzidine test, in contrast to its efficacy in other biologic fluids, was not entirely satisfactory for the detection of minute amounts of hemoglobin in the urine, and small amounts might be regularly overlooked. The free hemoglobin from which these casts were derived could be either free hemoglobin in the transfused blood or hemoglobin derived from the patient's own red cells hemolyzed by injected incompatible isoagglutinins. It was assumed that the concentration required to free plasma hemoglobin might be much lower than was ordinarily conceived.

Thus in the European theater, as in the Mediterranean theater, lower nephron nephrosis remained an unsolved problem at the end of the war. From the standpoint of this volume, the important consideration is the multiple causes other than transfusion which could give rise to what was erroneously called by many observers the posttransfusion or the transfusion kidney.

SPECIAL THEATER EXPERIENCES

Mediterranean Theater

There are no accurate reports of the reaction rate in transfusions accomplished with blood from the bank at Naples. An overall rate would be of little significance as an index of the suitability of the blood provided: Each hospital in the theater prepared its own recipient sets, and the bank, while it distributed instructions for their proper cleaning and preparation, had no control over the procedures. The incidence of reactions therefore varied from hospital to hospital and was related to the efficiency with which the sets were cleaned and sterilized (17).

Only once was there any serious question concerning the quality of the bank blood. This was in May 1945, when a shipment of blood, all from one bleeding center, resulted in 18 febrile reactions in three separate hospitals. Four of the patients died, but in only two cases was the transfusion considered the direct cause. Bacterial examination of two bottles from this shipment revealed psychrophilic organisms which had probably gained entrance to the blood because of incorrectly sterilized donor sets. There were no other deaths and no febrile reactions attributable to the blood itself, though 78,329 units had been distributed up to the time of this survey (October 1944) (17).

In 1943, a number of febrile reactions at the 91st Evacuation Hospital were attributable to the extreme difficulty experienced in cleansing the filters of the recipient sets (18). Aside from the risk of reactions, the blood would not run through the filters. Facilities for proper cleansing of transfusion equipment were not available in forward hospitals, and, at this hospital, as at many others, it had to be cleaned and sterilized in the operating room. None of the reactions was serious, and no hemolytic reactions occurred.


660

British transfusion units in the Mediterranean theater included one set of sterile equipment with each two bottles of blood intended for forward hospitals. Disposable equipment from the Zone of Interior was received in the theater too late to be useful. It would have been highly desirable, and some reactions could have been avoided, if the Naples bank had been able to prepare transfusion equipment to be supplied with the blood, but neither equipment nor personnel were in the theater in sufficient supply to permit such a plan.

European Theater

To clarify the confusion in the minds of many medical officers about transfusion reactions and the so-called transfusion kidney, Administrative Memorandum No. 150 was issued on 27 November 1944, from the Office of the Chief Surgeon, Headquarters, European Theater of Operations, U.S. Army (19). In this memorandum, it was frankly admitted that, because of the enormous number of transfusions being given in the theater, a certain number of reactions were inevitable. Allergic, pyrogenic, and hemolytic reactions were described, and their prevention and treatment were outlined.

In this same memorandum, all hospitals in the theater were instructed to submit weekly reports to the Office of the Chief Surgeon, the data to include the number of transfusions given; the number of reactions and their classification; and, for each reaction, the type of blood, its source, its age, and the source of the giving set (disposable, or prepared locally).

By 30 December 1944, 3,741 transfusions had been reported, with 188 reactions of all types. Major Hardin considered that the incidence of pyrogenic reactions, 3.7 percent, and of hemolytic reactions, 0.48 percent, was too high. The incidence of hemolytic reactions, however, was probably less than stated because deaths were being signed out as hemoglobinuric nephroses when the blood given had nothing to do with the complication or the death. Many of the casualties, in fact, had been anuric before they received any blood.

Special studies of the reports submitted by hospitals in the theater and analyzed by Major Hardin and several of his associates are presented in tables 28-31 (15). Perhaps the most interesting feature of this analysis is contained in table 31, which indicates the responsibility of poor preparation of locally prepared sets in the incidence of pyrogenic reactions.

One is immediately impressed by the discrepancies in the reaction rates reported by hospitals in different echelons of medical care. The first explanation of the higher rate in rear hospitals is multiple transfusions and the development of Rh sensitivity. Patients transfused in forward hospitals on one day were often transfused again 10 to 14 days later, in general hospitals in the rear. The possibility of producing Rh sensitivity by the indiscriminate use of blood whose Rh type was not known was suddenly real, and subsequent transfusion provided the opportunity for the sensitivity to become manifest.

A simpler explanation, however, is available for the low reported incidence of reactions in forward hospitals, that in a field or evacuation hospital, during


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TABLE 28.-Reactions to blood transfusions in field hospitals over 17-week period in the European Theater of Operations, U.S. Army1

Weekly periods

Transfusions

Reactions

Reactions

Classification


Allergic

Pyrogenic

Hemolytic

 

Number

Number

Percent

Number

Number

Number

1

253

2

0.79

---

2

---

2

742

18

2.42

1

16

1

3

579

9

1.55

---

8

1

4

939

5

.53

2

3

---

5

1,233

26

2.11

7

16

3

6

1,307

18

1.38

3

15

---

7

1,104

15

1.36

3

11

1

8

1,304

27

2.01

6

20

1

9

907

18

1.98

---

18

---

10

1,043

8

.77

1

7

---

11

929

16

1.72

5

9

2

12

1,039

7

.67

2

5

---

13

1,101

18

1.63

7

9

2

14

1,111

14

1.26

3

11

---

15

1,494

5

.34

---

4

1

16

1,228

15

1.22

10

5

---

17

803

1

.12

1

---

---



Total

17,769

224

1.26

52

160

12

1There were six deaths in the 12 hemolytic reactions.

a rush of casualties, mild reactions were often overlooked and only the most severe reactions were noted, let alone recorded. In general and station hospitals, with larger staffs and less pressure, more accurate observation and recording were possible.

The figures in these tables cannot be accepted unequivocally, for the reasons mentioned, but the collection served the purpose for which it was intended, to check upon the operations of blood banks and to build a basis for further investigation. One important thing that was learned was that it was dangerous to accept reports of reactions based on less than 500 transfusions and that a minimum of 1,000 transfusions was necessary for conclusions of any validity.

In his report of his trip to the European theater in January 1945, Capt. John Elliott, SnC, reported Major Hardin's emphatic belief that the reaction rate from blood flown from the United States was considerably lower than that of blood collected locally in the theater (20). Up to that time, 18,460 transfusions had been given with 643 reactions, 3.5 percent. Blood collected locally accounted for 26 percent of the reactions but for only 10 percent of the transfusions. Blood from the Zone of Interior accounted for about 28 percent of the reactions but for about 60 percent of the transfusions. Blood from the


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TABLE 29.-Reactions to blood transfusions in evacuation hospitals over 20-week period in 
European Theater of Operations, U.S. Army
1

Weekly periods

Transfusions

Reactions

Reactions

Classification2

Allergic

Pyrogenic


Hemolytic

 

Number

Number

Percent

Number

Number

Number

1

761

36

4.72

12

17

7

2

1,060

40

3.77

5

27

8

3

1,372

33

2.40

3

29

1

4

1,878

32

1.70

5

24

3

5

2,400

47

1.95

9

32

6

6

1,545

37

2.43

12

23

2

7

1,909

31

1.62

12

15

4

8

1,101

27

2.45

10

14

3

9

807

17

2.11

3

13

1

10

1,210

51

4.21

2

39

9

11

817

33

4.04

4

22

5

12

1,063

21

1.97

4

16

1

13

1,316

33

2.51

4

25

2

14

1,338

12

.89

4

5

---

15

1,800

2

.11

---

2

---

16

1,306

19

1.43

3

16

---

17

1,095

11

1.00

2

9

---

18

778

10

1.28

4

6

---

19

969

7

.72

2

5

---

20

397

1

.25

---

1

---


Total

24,920

500

2.00

100

340

52

1There were 27 deaths in the 52 hemolytic reactions; 6 other deaths in the group were not attributed to the transfusions.
2In the 10th through 14th weeks, there were eight unclassified reactions.

TABLE 30.-Reactions in 18 general and station hospitals after transfusion with blood obtained from the United Kingdom Section, European Theater Blood Bank1

Year and month

Transfusions

Reactions

Reactions

Classification


Allergic

Pyrogenic

1945

Number

Number

Percent

Number


Number

March

1,063

24

2.2

---

---

April

1,402

30

2.1

10

20

May

307

4

1.3

1

3


Total

2,772

58

2.1

11

23

1There were no hemolytic reactions in this group.


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TABLE 31.-Influence of local preparation of transfusion sets on pyrogenic reactions in various types of hospitals

 

Types of hospital

Number of
pyrogenic
reactions

Number with
locally prepared
sets

Percent

Field hospitals

160

62

38.7

Evacuation hospitals

340

136

40.0

General hospitals

346

174

50.2


Total


846


372


44.0

United States accounted for the largest proportion of allergic reactions but by far the lowest proportion of pyrogenic and hemolytic reactions.

Similarly, striking figures were reported for February 1945. In that month, 32 percent of the transfusions which were followed by reactions occurred with locally prepared sets. The use of locally prepared sets also explained the reactions which occurred in bloods collected by the theater bank (21).

Special studies on the effects of transfusion of incompatible isoagglutinins were carried out at the 5th General Hospital by Major Emerson and Maj. (later Lt. Col.) Richard V. Ebert, MC (22), and were supplemented by additional studies made by Major Emerson on detached service with the 91st Evacuation Hospital (18). They arrived at the following conclusions:

1. The repeated injection of group O blood or pooled plasma, or their injection in massive amounts, into individuals of other than group O produces hemolysis of recipient cells, the degree of which may be significant. The process is occasionally accompanied by a febrile transfusion reaction.

2. The hemolytic process is associated with progressive increase of hypotonic erythrocytic fragility, which is apparently related to the hemolytic phenomena described by Ham and Castle. These observers produced the same processes in experimental animals by the injection of nonspecific agglutinins.

3. Evidences of profound hemolytic disease may appear after massive plasma transfusions given to patients of other than group O. This phenomenon was observed in four patients and was in contrast to the good results in three patients with comparable injuries, who were treated similarly and whose blood group was O.

4. A certain proportion of nonspecific pyrogenic transfusion reactions may be caused by the stroma of hemolyzed red blood cells in the transfused blood. Prevention of these reactions depends not only on proper refrigeration of stored blood but also on the maintenance of red blood cell diffusion in the blood diluent by repeated agitation of the bottle during storage. Results of preliminary studies suggested that the survival of red blood cells during storage is limited by the amount supplied of an exhaustible nutrient factor.

In his separate study, Major Emerson followed 61 patients throughout their course in the 91st Evacuation Hospital, making elaborate clinical and laboratory studies on them during the 5-week period ending 10 May 1945. All had incurred severe wounds and all required intensive replacement therapy, including 265 units of whole blood, 222 of which were flown from the United States.


664

During the period in question, 520 units of blood were given in the hospital, with eight reactions. The data in one case are incomplete. Three of the reactions followed the use of partly hemolyzed blood, and the remainder occurred in casualties of groups A and B, who received O blood with a high titer of isoagglutinins ranging from 1 to 500 against the patient's cells.

The hemolysis was attributed to three factors: the age of the blood (10 days or more in all instances); failure to agitate the blood frequently during storage, so that the red cells in the bottom of the flask were not kept in contact with the preservative diluent; and failure of refrigeration.

Major Emerson considered that, from the practical point of view, the importance of these and other findings (space does not permit their inclusion here) was as follows:

1. Repeated transfusion of group O blood into other than group O patients may be an ineffectual and uneconomic procedure except in emergency replacement therapy.

2. The transfusion of very large amounts of group O blood, and even of pooled plasma, into recipients of other blood groups may cause serious hemolytic disease.

3. It is conceivable that irreversible organic changes involving the kidneys, liver, central nervous system, and other organs may occur as the result of prolonged, diffuse intracapillary agglutination.

4. The implication is strong that whenever feasible, strictly compatible blood, of the recipient's blood group, should be used. Under conditions that render the exclusive use of group O blood necessary, only blood of low titer should be supplied. There are strong reasons to suspect that even pooled human plasma with a low agglutinin titer, if administered in very large amounts to persons of blood groups other than O, may have undesirable and even dangerous effects, and that the use of fractionated human albumin might be preferable in such cases.3

Occasional hospitals, during the course of the war, indicated their desire to collect their own blood and not use banked blood because of fear of reactions and for other reasons. Major Hardin was willing that hospitals should maintain their own blood banks if they wished to, but he pointed out that if a hospital should ever be either isolated or overwhelmed with casualties, either the system would collapse or the patients would not be adequately transfused (23).

Maj. Gen. Paul R. Hawley's position was unequivocal. He considered that most of the deaths reported as caused by transfusion were due to other causes, including overloading kidneys already damaged from toxins elaborated in the crush syndrome or other injuries. Up to March 1945, the transfusion death rate in the European theater was 0.12 percent, which compared very favorably with the 0.14 percent of transfusion deaths recorded in the literature.

3Certain of these assumptions are based on the false premise that group O blood instead of type-specific blood was advised for routine use in peacetime as well as in war. This, of course, was not true. It was recommended for use in the circumstances of war, particularly in combat areas, because it was considered far safer as a universal replacement agent than type-specific blood could possibly be. It is believed that the results fully vindicated this decision.


665

"I shall not," he wrote, "tolerate exuberant enthusiasts casting any doubt upon a technique that has saved the lives of thousands of American soldiers" (24).

REACTIONS FROM CONTAMINATED BLOOD

One of the most serious complications of blood transfusion, but one which fortunately occurred only infrequently, followed the use of grossly contaminated blood. The recipient became violently ill shortly after receiving the blood and death usually occurred in a few hours.

Four such reactions occurred on 23 and 24 January 1945, at the 43d General Hospital, two in German prisoners of war and two in U.S. soldiers (25).

The course in each case was almost identical. Shortly after the transfusion, chills occurred, without pain or respiratory difficulty. Then, the patients quickly passed into a state somewhat, but not altogether, like shock. They were disoriented, but frank coma did not develop. The blood pressure was well within the shock range, but the general appearance was not typical of shock. The pulse rate was extremely rapid, but at first was of good volume and there was no noticeable sweating. Within a short period of time, the temperature rose sharply, in one instance to 106 F. Later, cyanosis appeared. The outstanding feature in each case was the profound circulatory collapse, which predominantly involved the peripheral vascular bed. Three patients died. At post mortem examination, the only findings common to all three cases were heart failure, with the right ventricle primarily involved.

An elaborate investigation followed, hampered by the fact that the Baxter bottles in which the blood had been collected and the donor sets used were no longer available for examination. It was not possible to determine how the contamination had occurred, but the situation was described as the kind that "keeps blood bankers awake at night."

After these fatalities, Major Hardin instituted cultural spot checks of the bloods in the United Kingdom Blood Bank and at the Continental Blood Bank in Paris.

LOWER NEPHRON NEPHROSIS

The lethal sequelae of shock were not appreciated at the beginning of the war, as might have been expected; the peacetime experience with this condition is never on the massive scale on which it occurs in wartime, and such sequelae are therefore numerically less frequent and tend to be less impressive. In World War II, they were very frequent, because of the vast number of shocked casualties, and they became more impressive and more apparent as more patients, with improved methods of resuscitation and surgery, lived long enough to develop them.

These sequelae were due primarily to asphyxia of organs or tissues during the prolonged period of reduced volume flow of blood. Post mortem examinations by knowledgeable pathologists demonstrated, in such delayed deaths, irreparable damage to the brain, the kidney, and the liver. These sequelae


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must be mentioned here because of the implication, which proved to be incorrect, of the role of transfusion in the pathogenesis of the condition that came to be known as lower nephron nephrosis.

Mediterranean Theater

Lower nephron nephrosis, manifested clinically by oliguria and anuria, became a prominent feature of the crushing injuries sustained in air raids on London during the first months of the war. Up to October 1944, when Lt. Col. (later Col.) Douglas B. Kendrick, MC, reported on it to the Surgical Consultants Division, Office of The Surgeon General, about 50,000 transfusions had been given in the Mediterranean theater, 114 of which had been followed by anuria, which was usually fatal (17).

Clinical syndrome-Certain findings were characteristic of the renal complications that occurred after injury and transfusion:

1. All the patients had gone into shock after wounding.

2. All had received blood and plasma before operation, but the quantities had varied, as had the titer of the blood.

3. Although large quantities of blood were given in fixed hospitals, in preparation for reparative surgery, sometimes 1,000 to 1,500 cc. for 2 or 3 days, anuria was almost never observed at this echelon of medical care.

4. Lower nephron nephrosis occurred in group O recipients as well as in recipients of other groups who received group O blood.

5. When anuria was to develop, it appeared early, usually within the first 24 hours after admission to a field or evacuation hospital.

6. The anuria was associated with a progressively increasing nonprotein nitrogen retention, which was unaffected by the injection of whole blood, plasma, crystalloid solutions, or alkalinizing solutions; once anuria developed, alkalinization was not effective.

7. Death occurred within 5 to 7 days unless the patient died earlier from other causes.

When it was thought that lower nephron nephrosis was caused by the use of group O blood in nongroup O recipients, an endeavor was made to supply type-specific blood to forward hospitals. The attempt was overruled (p. 425) and, in the light of more correct information, it was realized that it would have been a futile gesture from the standpoint of preventing this renal complication of wounding.

Special investigations-The principal reason for the creation of the Board for the Study of the Severely Wounded (p. 420) was the investigation of lower nephron nepbrosis (16). The observations of the board may be summarized as follows:

1. Studies made after resuscitation, and after operation in surgical cases, indicated that, functionally, all portions of the nephron were almost equally impaired for varying periods of time. The impairment depended upon the severity of the initial insult, and the state of shock on admission also depended upon it. These physiologic observations did not correspond with the histologic findings in fatal cases, in which the lesion observed was always predominantly in the lower nephron.


667

2. The clinical syndrome of renal insufficiency after shock was remarkable chiefly for the paucity and mildness of its symptoms. The most frequent symptom, drowsiness slowly deepening into stupor, might be absent until death was impending. The only frequent sign was pulmonary or peripheral edema.

3. Blood pressure determinations and laboratory tests were more useful than clinical observations. In the ascending order of diagnostic importance, laboratory findings included proteinuria, persistent urinary acidity, excretion of benzidine-positive material, azotemia, and fixation of specific gravity at a low level. When these findings were associated with hypertension, the diagnosis was established.

Other important findings included nitrogen and phosphorus retention, acidosis, hypochloremia, and an increase in the plasma volume. Practically all of the abnormalities, it should be noted, were those that reflect rapidly diminishing renal function.

4. The case fatality rate was approximately 75 percent. Death usually occurred within 10 days after wounding. Apparently, if the wounded man could survive this critical period, renal function might begin to recover and he had a chance of survival.

5. When recovery ensued, it was characterized by what was termed "the syndrome of recovery diuresis."

6. The best treatment of lower nephron nephrosis was its prevention, by prompt and adequate resuscitation of every casualty in shock. None of the therapeutic methods employed was really effective except the prevention of pulmonary edema by control of the fluid intake. It was a grave error to overload the circulation during the critical 10-day period.

7. Evidence was meager that alkalinization would prevent renal complications in the severely wounded. The original plan, to give alkalis as soon as renal complications became evident, was eventually discarded, and their use, beyond the amount given routinely with citrated whole blood or blood substitutes, was not recommended.

8. The lack of correlation between concentrations of benzidine-reacting pigment in the plasma and the hemoglobin or myoglobin in the urine suggested that the alteration of the threshold was variable. The irregularity with which extensive muscle injury was followed by myoglobinuria indicated that some factor other than necrosis of muscle cells was at work. This factor-which was not shock-apparently had to do with the maintenance of reestablishment of the circulation in the involved muscles. Occasionally, severe myoglobinuria developed in the absence of demonstrable muscle injury. The almost constant presence of moderate or severe shock in such cases suggested the possibility of diffuse ischemic muscle injury not recognizable morphologically. The fact that severe myoglobinuria and severe hemoglobinuria were often observed in the same patient suggested the possibility of a common mechanism.


668

SOUTHWEST PACIFIC AREA

Statistics for transfusion reactions are more incomplete for the Pacific areas than for other theaters because the circumstances of warfare were less favorable than elsewhere for precise reporting. Reports (which were required, as in the European theater) were received on only 22,000 of the pints of blood distributed from Guam, but the 3.1 percent rate indicated in them can be accepted as accurate (26). A number of severe hemoglobinurias were reported, but most of the reactions were mild, and 41 percent were allergic. As in other theaters, a number of deaths attributed to transfusions were not related to them except in the sense that they occurred after blood had been given.

The reaction rate was higher when the blood was outdated. Up to 21 days, it was between 2 and 4 percent. Between 22 and 30 days, when the specified time limit had passed, it was 5 to 6 percent.

The low reaction rate secured in transfusions with blood flown from the Zone of Interior was chiefly explained by the use of disposable recipient sets. Whenever locally prepared sets were used, the reaction rate was higher. All of the hospitals which received Zone of Interior blood were warned that the recipient sets provided with the blood must be used.

When the plan of flying blood to the Pacific was first announced, many surgeons thought the reaction would be prohibitively high (27). Within a matter of weeks, their skepticism was overcome by the low rate; the convenience of not having to crossmatch the blood; the absence of fatalities; and the beneficial results secured, which permitted major surgery with an enormous reduction in the surgical risk.

It was not surprising that hospitals using large amounts of preserved whole blood invariably reported reaction rates well below those of units using smaller amounts. Efficient refrigeration, elimination of mechanical difficulties, and greater experience were all contributing factors. The rates were notably lower in hospitals in which special shock teams handled all transfusions.

Transfusion reactions were more frequent and more severe in Filipinos than in U.S. personnel (28, 29). They were chiefly allergic and manifested by edema and urticaria, but one station hospital reported two fatal cases of anuria soon after the landings on Leyte, and later reported a third fatal case. Presumably, these reactions were on the same basis as the plasma reactions which occurred in Filipino personnel.

PLASMA TRANSFUSION REACTIONS

Urticarial reactions sometimes followed the infusion of plasma, though they were not very frequent. Almost without exception, reactions classified as hemolytic could be traced to the use of contaminated plasma and thus were incorrectly diagnosed as hemolytic.


669

Early Experiences

The possibility of reactions to plasma therapy was first brought up in the Subcommittee on Blood Substitutes at the 18 July 1941 meeting (30), when 262 transfusions were reported from cooperating civilian hospitals with 19 reactions, 7.3 percent; the series included transfusions with type-specific plasmas, pooled liquid plasma, and dried plasma. These reactions, it must be remembered, occurred at a period when plasma was first being tested as a so-called blood substitute and when the techniques of collection of blood offered an invitation to infection and to other complications.

At two later meetings of the subcommittee in 1942 (31, 32), the subject came up again, since several articles had appeared in the literature describing reactions to plasma infusions. The experiences reported were contrary to Dr. Max M. Strumia's extensive experience; in 2,200 plasma infusions which he had observed personally, there were only five reactions, all urticarial. He was inclined to attribute the reported reactions to the use of plasma obtained from partly clotted blood, or, less probably, to pyrogenic substances in the plasma. He could find no evidence that they were due to an incompatibility between the recipient's cells and the plasma injected. Pooled plasma occasionally showed a relatively high isoagglutinin titer, but, when the plasma was given at the usual rate (5-10 cc. per minute), the agglutinins were not only diluted in the recipient's bloodstream but were apparently also absorbed or inactivated as rapidly as they were injected into the circulation.

An editorial published in the Journal of the American Medical Association on 19 September 1942 (p. 79) contained inaccurate and misleading information concerning the potential toxicity of plasma (33). It was considered important that it be corrected at once because of its possible effect on the blood procurement program. The editorial which corrected the erroneous statements left much to be desired, but the article prepared by Dr. William Thalhimer and published in the Journal for 19 December 1942 was a competent and reasoned rebuttal (34).

Production difficulties-In August 1944, complaints were received from the Office of the Chief Surgeon, European Theater of Operations, U.S. Army, that reactions were occurring after the administration of dried plasma from a certain laboratory. The plasma which had caused the reactions had contained excessive amounts of fibrin particles. The use of plasma from this firm had been forbidden in the theater; its issue had been discontinued; and the New York Port of Embarkation had been requested to delay further shipments. All installations in the First and Third U.S. Armies, Advance Section, and all laboratories in the United Kingdom were requested to report, on a special questionnaire, on any reactions which had occurred after the administration of plasma in the last 2 months.

Clinical testing with the offending lots of plasma at the Army and the Naval Medical Centers was followed by chills and fever in about 7 percent of


670

the patients, and a number of the bottles used showed moderate amounts of fibrin. When the firm which had produced the offending plasma was visited in October 1944 by Colonel Kendrick, Capt. Lloyd R. Newhouser, MC, USN, and Lt. (later Lt. Cdr.) Henry S. Blake, MC, USN, certain changes in production technique were advised, including chilling of the blood before centrifugation, to eliminate excessive amounts of fibrin in the final product. It was also recommended that all plasma produced by this particular laboratory before these changes were made should be used only in the United States. There were no adverse reports from any of the hospitals to which it was distributed.

Special Investigations in the European Theater

Early in 1945, while a survey of transfusion reactions was being made in the 91st Evacuation Hospital, a number of plasma transfusion reactions were also observed, some quite serious (35). A special study was therefore undertaken of the plasma transfusions given during a recent 25-day offensive, during which 1,022 patients were handled on the surgical service.

In this group, 109 patients, 10.6 percent of the surgical admissions, received 323 units of plasma, an average of 3 units per patient. There were 21 reactions, of which 3 were urticarial; these reactions simply caused discomfort and did not impede the progress of treatment. There were also 14 pyrogenic reactions and 4 modified hemolytic reactions, all sufficiently severe to delay recovery, though none were lethal. Counting only these 18 reactions, the reaction rate was 5.3 percent for the 323 injections and 15.6 percent for the 109 patients.

Pyrogenic reactions-The pyrogenic reactions were similar to those observed in reactions sometimes observed after the intravenous administration of other fluids. Chills and temperature elevations were the chief manifestations. The temperature, which ranged from 101 to 104 F., returned to normal in 3 or 4 hours. There was no fall in the blood pressure, no urinary suppression, and no abnormalities in the urinalysis.

Many of the patients received additional plasma and blood without further difficulty. The pyrogenic reactions, however, were serious because they often occurred in the shock ward, in patients being prepared for operation, and their progress through X-ray examination to the operating room had to be delayed for a matter of hours until recovery from the reaction took place.

Hemolytic reactions-The four modified hemolytic reactions were far more serious. Three patients had received no intravenous fluid except plasma. The fourth had received two units of blood, but the onset of the reaction occurred while he was receiving plasma. One patient presented a typical picture of peripheral vascular collapse. The systolic blood pressure fell to 60 and 32 mm. Hg, respectively, in two cases and could not be obtained in the other two. One patient had no elevation of temperature, but the elevations in the three other cases ranged from 102 to 103.4 F.


671

Two of the patients were anuric for 12 and 24 hours, respectively. All had red blood cells and granular casts in the urine. All had positive orthotoluidine reactions.

Icterus index determinations were made 24 hours after the reaction in two cases and were reported as 9 and 11, respectively; 2 days later, the values were 5 and 6, respectively.

Three of the patients were group A and the fourth, group O. All received large amounts of plasma in relatively short periods. The titer of the plasma to the recipient's cells was 1:8 in two cases and 1:16 and 1:54, respectively, in the other two.4

All four patients were treated successfully by the routine used for hemolytic blood reactions. An attempt was made to alkalinize the urine with sodium chloride, with careful regulation of the fluid intake and close observation to detect any signs of pulmonary edema; it would have been easy to drown these patients in the attempt to increase the renal output. Serum albumin was also used and was very effective.

No reasonable explanation was found for these reactions at the time of their occurrence. None of the patients had wounds of the urinary tract. The possibility that the findings were due to massive tissue destruction with hemoglobin could not be excluded, but similar phenomena were not observed in other casualties with injuries of comparable kind and severity. The most reasonable immediate explanation seemed to be that, when several infusions of plasma were given over a relatively short time, an agglutinin titer might be built up which might react with the cells of all blood types except AB. In retrospect, these phenomena seem to an observer who did not witness them personally to be explained by the use of contaminated plasma rather than as true hemolytic reactions.

The Southwest Pacific Experience

There were occasional isolated reports of plasma reactions in the Southwest Pacific, none particularly convincing and most of them readily explained, usually by contamination of the plasma. One experience, however, was extremely serious (36):

On 21 April 1945, the Office of The Surgeon General received a report of eight fatal reactions after the use of U.S. Army plasma for Filipino civilians in the San Lazaro Hospital in Manila, a civilian hospital staffed by civilian Filipino physicians.

The 11 patients among whom these 8 fatalities occurred were all greatly emaciated, debilitated and avitaminotic. All had nonspecific ileocolitis, which it was thought would be improved by the administration of plasma.

The course of events was substantially the same in 10 of the 11 cases, in all of which the plasma was given on the same day, 24 March. About 30 minutes after the intravenous administration of 250 cc. of normal human

4The titer seems quite low to be causing reactions.


672

plasma, 9 of the 10 patients complained of chilly sensations, which lasted about 30 minutes; none of them had a real chill. All complained of malaise and muscular pains. Their temperatures were not taken but they were obviously febrile. They were wrapped in blankets and each was given 2 cc. of 10-percent camphorated oil intramuscularly.

Of the 10 patients, 7 died between 4 and 16 hours later, 2 in 4 hours, 1 in 5 hours, 2 in 7 hours, 1 in 12 hours, and 1 in 16 hours. Autopsies performed in two cases revealed nothing to explain the fatal outcome.

Two units of the lot of plasma used for these patients were set aside for analysis, and, through a tragic error, one of them was given to a critically ill patient. An hour later, he developed a chill and complained of extreme substernal oppression and dyspnea. When this patient, the only one observed by a U.S. Army medical officer, was first seen, he was unconscious, with shallow, gasping respirations, at the rate of 5 per minute. The pulse was rapid and thready, and the lips and nails were cyanotic.

Artificial respiration was attempted but was unsatisfactory because a chest spica was in situ. Blankets and hot water bottles were applied, and the foot of the bed was elevated. Other treatment consisted of Adrenalin (epinephrine), 1 cc. intramuscularly; an infusion of 5-percent glucose in physiologic salt solution; and a transfusion of 500 cc. of type O blood. During the transfusion, the patient became conscious, asked for food, and clinically seemed much improved. The pulse continued rapid but was of good volume. An hour later, after an episode of extreme dyspnea, he was dead.

A tendency to react to infusions of plasma and to blood transfusions had been noted elsewhere in the Philippine Islands in patients with marked malnutrition, and it was thought that these fatal reactions might be the result of the serious hypoproteinemia then frequent among Filipinos. It was considered imperative, however, to investigate and rule out the presence of special toxic factors in this particular lot of plasma. A variety of steps were taken to achieve this purpose, and to warn all hospitals in the Southwest Pacific Area of the possible risk of plasma infusions as evidenced by these fatalities. They were instructed to use dried human plasma with extreme caution in Filipinos and to substitute whole blood for it whenever possible.

Of the 39 units of plasma in this particular lot, only a single sample was left. When it was tested at the National Institute of Health on 28 April 1945 (37), the appearance of the package and that of its contents were in accordance with specifications. All the tests performed in respect to solubility, moisture, sterility, and safety were in conformity with the minimum requirements. Pyrogen tests on rabbits, however, revealed that the product was definitely pyrogenic.

Investigation of the production of this particular lot of plasma showed that it represented the pooling of 50 separate bleedings. Sterility tests of the blood were all negative at the end of 48 hours' incubation, and the bloods were therefore pooled and processed in the usual manner. At the end of 7 days, one of the bloods was found to be contaminated, but when the plasma was tested for


673

sterility, it met the minimum standards requirement, and there was no evidence of contamination when it was tested routinely at the National Institute of Health.

It was considered surprising that such a slight contamination as had occurred in this lot of plasma, 1 of 50 bloods, would have caused the finished product to be pyrogenic, particularly since the processing laboratory reported that the contaminating organism was identified as Staphylococcus albus, which is ordinarily regarded as only mildly pyrogenic.

On 28 March 1945, the Office of the Surgeon, Headquarters, Luzon Base Section, requested information from all the hospitals in the area on the plasma reactions that had occurred in the past 30 days among U.S. soldiers, Filipino soldiers, and interned civilians. It was directed that plasma from all lots that had produced reactions was not to be used until further notice.

Eleven installations, including clearing companies, medical battalions, and field, evacuation, and general hospitals reported no reactions (38). The remaining seven installations (one clearing station, one portable surgical hospital, two field hospitals, two evacuation hospitals, and one general hospital) reported a total of 54 reactions, the great majority of which occurred in Filipino patients with debilitating diseases. The products of seven different laboratories were involved, but in only the single case just described was it possible to investigate the plasma responsible for the reaction.

Maj. John J. McGraw, Jr., MC, Special Representative on Transfusion in the Office of The Surgeon General, made the following comments on the San Lazaro Hospital experience (39):

1. The type of reaction was very similar to that which occurs when grossly contaminated plasma or blood is transfused.

2. Since the sample tested at the National Institute of Health was sterile, the possibility exists that the plasma became contaminated when it was dissolved. Minor contamination not infrequently occurs as a result of breaks in technique. If the plasma is used promptly, the contamination is usually of little significance. If the solution is allowed to stand for several hours before use, bacteria may eventually be present in very large numbers. Heavily contaminated plasma can produce severe and even fatal reactions. Dried plasma should always be used within 3 hours of the time it is dissolved.

3. The debilitated condition of these special patients undoubtedly made them less able to tolerate adverse reactions.

4. No particular significance was attached to urticarial reactions, which occur in about 2 percent of all blood and plasma transfusions, usually on a background of allergy. The fact that the same lot of plasma that produced urticarial reactions also produced chills and fever in some patients was considered of more significance. Theoretically, plasma should never produce chills and fever. On the other hand, even minor breaks in the technique of the preparation of distilled water or of intravenous tubing can result in the formation of pyrogenic substances. It could not be determined whether the giving sets used at San Lazaro were prepared locally.


674

5. It was recommended that any lot of plasma suspected of producing chills and fever should be used only in a general hospital, in which its effects could be observed under controlled conditions. If it appeared to be pyrogenic, it should be destroyed. The Surgeon General should be notified if the plasma of any single commercial house seemed excessively pyrogenic. It was neither desirable nor necessary to withdraw a lot of plasma and destroy it because urticaria followed the use of some units in it.

This is a logical, well-reasoned comment on an unfortunate episode which undoubtedly occurred because of a break in technique somewhere along the line of production and administration.

HOMOLOGOUS SERUM JAUNDICE

General Considerations

In the light of the postwar incidence of homologous serum jaundice, it is important to make certain points clear about its wartime occurrence after plasma transfusion:

1. Although pooled plasma was used in enormous quantities in battle casualties all during the war, the causative relation between the plasma itself and the numerous instances of jaundice in military personnel after its use was not realized until late in 1944.

2. In retrospect, what happened is clear: When blood is not pooled, a single transfusion from a donor with serum hepatitis is unlikely to cause the disease in many recipients. When, however, blood is pooled, as it is when plasma is processed, the chances of contracting jaundice are correspondingly increased.5

3. Serum hepatitis was never a problem in Zone of Interior hospitals, in which practically all of the plasma used was liquid and pools prepared from more than eight bloods were seldom used. Up to 50 bloods per pool, however, were used in the early stages of the dried plasma program, and later, in 1944-45, even larger pools were frequently used.

4. The relation of these various facts to the development of jaundice and serum hepatitis was finally perfectly evident, but the war was practically over before the causal sequence was widely appreciated.

5. The lack of realization of this relation is apparent in the lack of action in the matter on the part of the Subcommittee on Blood Substitutes, NRC (National Research Council), whose members were remarkably alert to all developments in the field of blood and plasma transfusion. Jaundice was discussed at a number of meetings in 1942 (31, 32), and 1943 (40), in connection with serum albumin, particularly in regard to the development of jaundice after immunization against yellow fever; each immunizing dose contained 0.04 cc. of human serum, and attention was naturally directed to it as a possible

5Since serum hepatitis often appeared without clinical jaundice, a number of observers expressed the opinion that the disease would be more correctly termed "homologous serum hepatitis" rather than "homologous serum jaundice."


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vehicle for a wild virus. A number of inquiries were set on foot, but, at this time, no one had observed, or heard of, jaundice after plasma transfusion. As a precaution, however, the Red Cross Blood Donor Service began to reject all donors with a history of jaundice within the previous 6 months.

6. The homologous serum jaundice that followed plasma transfusion was, of course, entirely distinct from the widespread outbreak of hepatitis in the Army in 1942, which, as just mentioned, was caused by an icterogenic agent in certain lots of yellow fever vaccine then in use (41). It was also not related to the hepatitis which occurred among troops in North Africa in 1943 and at other times during the war.

Special Studies

During 1943 and 1944, a number of reports appeared in the American literature concerning the development of hepatitis after the administration of homologous blood products. The realization of the cause-and-effect relation and of the importance of this variety of hepatitis was brought home when concentrations of the disease began to appear in various hospitals overseas (table 32) and in the Zone of Interior, and special investigations were begun on them (42-45).

The conclusions drawn in most of these investigations are, unfortunately, little more than assumptions, and not very convincing ones at that. For a number of reasons, they could hardly be otherwise:

1. The clinical and histologic pictures in both homologous serum jaundice and infectious (epidemic) hepatitis are practically identical.

2. Proof that icterogenic agents existed in the plasma transfusions that had been given was entirely lacking.

3. Very few patients with wounds of any consequence had not received plasma.

4. Further confusion in differential diagnosis was caused by the fact that there was intimate contact between patients with serum hepatitis and those with epidemic hepatitis in hospitals along the line of evacuation, in ships and planes, and in Zone of Interior hospitals.

5. A controlled investigation was impossible, for the various reasons stated, and the premises on which most reports were based were extremely unstable and tenuous.

Survey, 1 June 1945-As of 1 June 1945, a survey was undertaken in all Army general hospitals in the Zone of Interior to identify all patients with hepatitis, of any degree or associated with any other condition, under the direction of Maj. Philip E. Sartwell, MC (44). The form provided was also to be filled out for each death from hepatitis within the preceding 30 days. The survey form (fig. 153) was made as simple as possible in view of the heavy load then being carried by all general hospitals in the United States.

At this time, about 85 percent of the general hospital population in the country consisted of casualties evacuated from overseas, 85 percent of them because of battle wounds and the remainder because of other injuries and


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TABLE 32.-Percentage of patients developing hepatitis while hospitalized for some other condition, European and Mediterranean theaters, 1944

Cause of hospitalization


Number of cases

Percentage developing-

Total

Developing
infectious hepatitis 

Developing other hepatitis1

Infectious
hepatitis

Other hepatitis1

ETO

MTO

ETO

MTO

ETO

MTO

ETO

MTO

ETO

MTO

Disease other than hepatitis2


24,697

14,146

12

28

9

20

0.05

0.20

0.04

0.10

Nonbattle injuries:3

 

 

 

 

 

 

 

 

 

 

Penetrating and perforating wounds

1,275

737

3

2

---

2

.24

.27

---

.27

Compound fractures

1,491

593

3

2

---

1

.20

.34

---

.17

All others

22,378

12,275

9

29

3

9

.04

.24

.01

.07

Total

25,144

13,605

15

33

3

13

0.06

0.24

0.01

0.10

Battle wounds:3

 

 

 

 

 

 

 

 

 

 

Penetrating and perforating wounds

9,446

5,301

63

33

13

2

0.67

0.62

0.14

0.04

Compound fractures

5,110

1,769

19

20

6

3

.37

1.13

.12

.17

All others

9,711

4,873

35

37

2

7

.36

.76

.02

.14

Total

24,267

11,943

117

90

21

12

0.48

0.75

0.09

0.10

1Includes cases with a diagnosis of hepatitis or jaundice unqualified.
2Based on a 20-percent sample of admissions for psychoneurosis and a 2-percent sample of all other disease admissions exclusive of those admitted with hepatitis.
3Based on a 20-percent sample of admissions.

Source: Medical Statistics Division, Office of The Surgeon General, Department of the Army.

diseases. Most of them had been hospitalized for a month or more before being returned to the Zone of Interior. The majority of patients admitted to the general hospitals from other hospitals in the United States were suffering from conditions that required specialized types of care not available at station or regional hospitals.

The number of cases of hepatitis reported, 1,762, with 15 fatalities, was much larger than had been anticipated (table 33). All 64 general hospitals reported at least 1 case and the majority reported from 5 to 30 cases. The regional distribution was not significant because so many of the reporting hospitals were special treatment centers. Of the patients, 87 had been prisoners of war. There was, however, a higher incidence in patients from the Mediterranean theater than from the European theater.

For a variety of reasons, the data concerning previous plasma and blood transfusions were not considered reliable. Plasma transfusions were chiefly given in forward areas, in which circumstances did not favor the keeping of precise records. The patient's own recollections could not be accepted. Finally, additional confusion was introduced by the fact that, although the


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FIGURE 153.-Form used in 1 June 1945 survey of hepatitis in Army general hospitals in Zone of Interior.

question about transfusion was limited to the 4 months preceding the onset of hepatitis, a number of reports, though by no means all, gave information about the use of plasma and blood for longer periods.

The data collected in this survey were considered to warrant the conclusion that a large proportion of patients hospitalized with hepatitis on 1 June 1945 had contracted their disease because of the presence of an icterogenic agent in transfused blood or plasma. The conclusion naturally did not warrant the inference that any of these transfusions were not indicated or that too much blood or plasma was used. Saving the patient's life was obviously more important than protecting him against the remote possibility of his contracting hepatitis.

Other special studies in general bore out the results of this survey. A planned study at McCloskey General Hospital, Temple, Tex. (45), for instance, from 1 February to 30 April 1945, showed 57 cases of hepatitis in 935 battle casualty admissions, 1 in 322 patients who had received no blood or plasma, and 51 in the 528 who had received either or both. There were 5 cases of hepatitis in the remaining 75 patients whose histories were too incomplete to use.


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TABLE 33.-Data obtained in survey of hepatitis in Army general hospitals, Zone of Interior, 1 June 19451

Information obtained in survey


Total patients

Transfused patients


Number

Percent

Number

Percent

Total cases reported (including deaths in preceding 30 days)

1,762

100

500

100

Initial cause of hospitalization:

 

 

 

 


Wounds

607

34

434

87


Nonbattle injuries

49

3

23

5


Initial hepatitis

934

53

---

---


Disease other than hepatitis

165

9

42

8

Classification of hepatitis:

 

 

 

 


Acute

1,499

86

469

95


Recurrent

127

7

15

3


Chronic (over 6 months' duration)

120

7

9

2

Areas of service:

 

 

 

 


European and Mediterranean theaters

1,311

75

373

75


Pacific and Asiatic theaters

369

21

117

24


United States

62

4

3

0.6


Other areas

9

0.5

2

0.4

Cases in liberated American prisoners

87

5

3

0.8

1The totals in several categories do not add up to 1,762 or 500 respectively because the questionnaires were not always completely filled out. In such cases, the percentages computed are based on the total number of completed reports.

Case History

While general surveys were inconclusive, an occasional case, such as the one reported by Lt. Col. (later Col.) Marion H. Barker, MC (46), from the Mediterranean theater, offers rather strong proof of the possible transfer of the disease to a recipient from a donor in whom it proved fatal. The (greatly abbreviated) history is as follows:

The sergeant who made the donation was a 235-lb., strong, well-muscled member of a general hospital medical detachment, with an entirely negative previous history. On 8 May, he played a vigorous game of baseball and knocked a home run. On the next day, he acted as a donor, and, on 10 May, his blood was given to a 19-year-old rifleman who had sustained a gunshot wound of the right lower abdomen on 25 April 1944.

On the next day, 11 May, the donor reported to sick call, and he died on 14 May, of fulminating infectious hepatitis, confirmed by the clinical course, the laboratory findings, and the necropsy findings. There was no doubt of the diagnosis, nor was there any doubt that this man had been perfectly well up to, and including, the fifth day before his death, when he gave 500 cc. of blood.

As soon as it became known that the donor had hepatitis, the recipient was transferred to a special ward, where he was kept under close observation. He remained perfectly well, and all laboratory tests were negative, until 21 May, when he began to complain of lower abdominal pain and generalized discomfort. The temperature was 99.4 F. On 23 May, a blood smear showed a few of the abnormal toxic lymphocytes ordinarily seen in early infectious hepatitis. Thereafter, the clinical course, as well as the laboratory findings, were entirely typical of infectious hepatitis, except that jaundice did not appear until 1 June.


679

The patient was critically ill for the next several days, but, after 8 June, his condition gradually improved and he went on to an apparently normal recovery.

In this case, although the incubation period of 11 days is extremely short, and although the events may have been no more than a coincidence, it seems reasonable to assume that they represent a direct human transfer of hepatitis from a donor with fulminating, fatal, infectious hepatitis to a recipient who was apparently recovering normally from a minor battle wound.

Preventive Measures

Since the virus of hepatitis could not be detected by the techniques available in 1945, when its importance began to be realized, the only means of preventing its transmission was a more rigid examination of blood donors than had hitherto been required, including a detailed history; a physical examination, with special reference to the liver; and a battery of laboratory tests. Aside from the fact that such a routine would be completely impractical, if only from the standpoint of expense, it was doubtful that the most elaborate requirements would uncover all cases of incipient jaundice and low-grade or latent hepatitis (43).

There seemed, in short, no practical way of eliminating the asymptomatic blood donor who never developed jaundice. By inoculating human volunteers with icterogenic serum, Neefe and his associates (47) were able to demonstrate that, at least in some cases, a subclinical hepatitis precedes the onset of jaundice by a considerable period. Clinical confirmation of these experimental observations was obtained in two cases in which studies were done a month before the onset of jaundice.

Capt. (later Maj.) Emanuel M. Rappaport, MC, in a special study of asymptomatic donors (42), suggested routine serial studies of liver function 8 weeks after transfusion, to uncover latent hepatitis which would otherwise escape detection. He had observed four such cases. Such a program was, of course, impractical at a time when all available laboratory facilities were taxed to capacity with more immediate problems, and was not very practical at any other time.

Prophylactic and Therapeutic Use of Gamma Globulin

Soon after gamma globulin was introduced by Stokes and Neefe (47), in 1945, as a prophylactic measure in infectious hepatitis, its efficacy in this respect was verified by Havens and Paul (48). Since an intimate relation had been demonstrated between the viruses of infectious and homologous serum hepatitis, it was logical to recommend that gamma globulin be given to all patients who had received either blood or plasma and that it be given immediately after the transfusion, since the incubation period of hepatitis produced by inoculation, while it might extend to 130 days or more, might also be only 30 days or even less.


680

This recommendation was transmitted to the Surgeon, Mediterranean Theater of Operations, 3 June 1945, by the Office of The Surgeon General. The recommendation was duly complied with (49). The same instructions were given to medical officers in the European theater in Circular Letter No. 53, Office of the Chief Surgeon, 19 June 1945 (50).

At a conference in the office of Brig. Gen. James S. Simmons, Director, Preventive Medicine Division, Office of The Surgeon General, on 25 July 1945 (51), the prophylactic use of gamma globulin was fully discussed. Brig. Gen. Fred W. Rankin was not yet convinced that the relation between transfusion and hepatitis had been incontrovertibly established, nor was he convinced of the preventive value of gamma globulin, but he was not opposed to its prophylactic use. Brig. Gen. Hugh J. Morgan, Consultant in Medicine, Office of The Surgeon General, was sufficiently impressed with the findings of Major Sartwell's survey of hepatitis in Zone of Interior hospitals to believe that gamma globulin should be administered routinely. All present agreed to recommend that all wounded patients who had been transfused and who were received in hospitals in the United States between 21 and 120 days after wounding should routinely receive gamma globulin. The recommended dose was 10 cc.

This was the last official action in regard to posttransfusion hepatitis in World War II. The postwar problem is described elsewhere (p. 776).

References

1. Davis, H.A.: The Transfusion of Conserved Blood. Am. J. Surg. 50: 698-702, December 1940.

2. Bordley, J. III: Reactions Following Transfusion of Blood, With Urinary Suppression and Uremia. Arch. Int. Med. 47: 288-315, February 1931.

3. War Department Technical Bulletin (TB MED) 204, 24 Oct. 1945, subject: Complications of Blood Transfusion.

4. Lewisohn, R., and Rosenthal, N.: Prevention of Chills Following Transfusion of Citrated Blood. J.A.M.A. 100: 466-469, 18 Feb. 1933.

5. Seibert, F. B.: Fever-Producing Substance Found in Some Distilled Waters. Am. J. Physiol. 67: 90-104, December 1923.

6. Lewisohn, R.: A New and Greatly Simplified Method of Blood Transfusion. A Preliminary Report. M. Rec. 87: 141-142, 23 Jan. 1915.

7. Lewisohn, R.: Blood Transfusion: 50 Years Ago and Today. Surg. Gynec. & Obst. 101: 362-368, September 1955.

8. Administrative and Logistical History of the Medical Service, Communications Zone, European Theater of Operations, vol. 13, chapter 14, Professional Aspects of the Medical Service. [Official record.]

9. Kilduffe, Robert A., and DeBakey, Michael: The Blood Bank and the Technique and Therapeutics of Transfusions. St. Louis: C. V. Mosby Co., 1942.

10. Mallory, T. B.: Hemoglobinuric Nephrosis in Traumatic Shock. Am. J. Clin. Path. 17: 427-443, June 1947.

11. History, 15th Medical General Laboratory, 20 Dec. 1942-31 May 1944, 31 Oct. 1944.

12. Conference on Shock and Transfusion, afternoon session, 25 May 1945. Office of the Chief Surgeon, Headquarters, European Theater of Operations, U.S. Army.

13. Ashby, W.: The Determination of the Length of Life of Transfused Blood Corpuscles in Man. J. Exper. Med. 29: 267-281, 1 Mar. 1919.


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14. Report, Maj. Stewart C. Wagoner, MC, to Army Surgeon, Ninth U.S. Army, 12 Feb. 1945, subject: Report of Transfusion Reactions.

15. Hardin, Lt. Col. Robert C., MC, Holt, Maj. Benton B., MC, and Coulson, Maj. Forest H., MC: Reactions to Transfusions, n.d.

16. Medical Department, United States Army. Surgery in World War II. The Physiologic Effects of Wounds. Washington: U.S. Government Printing Office, 1952.

17. Report, Lt. Col. Douglas B. Kendrick, MC, to The Surgeon General, 15 Jan. 1945, subject: Trip to the North African Theater of Operations.

18. Emerson, Maj. Charles P., MC: Investigation of Transfusion Therapy-Ninth U.S. Army, 6 April-10 May 1945.

19. Administrative Memorandum No. 150, Office of the Chief Surgeon, Headquarters, European Theater of Operations, U.S. Army, 22 Nov. 1944, subject: Blood Transfusion.

20. Memorandum, Capt. John Elliott, SnC, to Chief, Surgical Consultants Division, Office of The Surgeon General, through Director, Army Medical School, 1 Feb. 1945, subject: Transportation of Blood from the U.S. to the ETO Blood Bank in Paris.

21. ETMD, European Theater of Operations, U.S. Army, for February 1945.

22. Emerson, C. P., and Ebert, R. V.: A Study of Shock in Battle Casualties. Measurements of the Blood Volume Changes Occurring in Response to Therapy. Ann. Surg. 122: 745-772, November 1945.

23. Memorandum, Maj. Robert C. Hardin, MC, to Chief Consultant in Surgery, Professional Services Division, Office of the Chief Surgeon, Headquarters, European Theater of Operations, 21 Mar. 1945, subject: Transfusion Reactions.

24. Letter, Maj. Gen. Paul R. Hawley to Col. William E. Shambora, MC, 24 Mar. 1945.

25. Report, Lt. Col. Francis P. Parker, MC, to the Commanding Officer, 43d General Hospital, 22 Feb. 1945, subject: Investigation of Transfusion Reactions.

26. Minutes, Conference on Blood Preservation and Red Cell Resuspension, Division of Medical Sciences, NRC, 6 Dec. 1945.

27. ETMD, Pacific Ocean Area, for January 1945.

28. Report, 64th Portable Surgical Hospital, 2d quarter, 1945.

29. Clinical abstract, Fatal Transfusion Reaction, 311th General Hospital, 24 Nov. 1945.

30. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 18 July 1941.

31. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 12 May 1942.

32. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 20 Oct. 1942.

33. Toxicity of Human Plasma. J.A.M.A. 120: 206-207, 19 Sept. 1942.

34. Thalhimer, W.: Intravenous Injection of Pooled Normal Plasma or Serum. Is it Dangerous? J.A.M.A. 120: 1263-1267, 19 Dec. 1942.

35. Letter, Maj. Stewart C. Wagoner, MC, to Army Surgeon, Ninth U.S. Army, 21 Mar. 1945, subject: Plasma Reactions.

36. Letter, Brig. Gen. Guy B. Denit to The Surgeon General, Army Service Forces, 21 Apr. 1945, subject: Reports of Reactions Following Administration of Human Blood Plasma, Item 1608900.

37. Letter, Dr. M. V. Veldee to Maj. J. J. McGraw, Jr., MC, 28 Apr. 1945.

38. Letter, Office of Surgeon, Headquarters, Luzon Base Section, to commanding officers of hospitals in the area, 28 Mar. 1945, subject: Plasma Reactions; Summary of replies, entitled "Plasma Reaction Summary," n.d.

39. Memorandum, Maj. J. J. McGraw, Jr., MC, to Liaison Branch, Purchase Division (attention: Maj. A. O. Glasson), 17 May 1945, subject: Reactions Following Administration of Plasma in Far East.


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40. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 24 Feb. 1943.

41. Walker, D. W.: Some Epidemiological Aspects of Infectious Hepatitis in the U.S. Army. Am. J. Trop. Med 25: 75-82, March 1945.

42. Rappaport, E. M.: Hepatitis Following Blood or Plasma Transfusions. Observations in Thirty-Three Cases. J.A.M.A. 128: 932-939, 28 July 1945.

43. Rappaport, Capt. E. M., MC: Further Observations on Delayed Hepatitis Following Transfusions and the Role of Asymptomatic Donors in this Syndrome, n.d.

44. Sartwell, Maj. P. E., MC: Infectious Hepatitis in Relation to Blood Transfusion. Findings of a Survey Conducted in Army General Hospitals, n.d.

45. Grossman. E. B., and Stokes, J., Jr.: Post-Transfusion Hepatitis in Battle Casualties and a Study of Its Prophylaxis by Means of Human Immune Serum Globulin. J.A.M.A. 129: 991-994, 8 Dec. 1945.

46. ETMD, North African Theater of Operations, U.S. Army, for August 1944.

47. Stokes, J., Jr., and Neefe, J. R.: The Prevention and Attenuation of Infectious Hepatitis by Gamma Globulin. J.A.M.A. 127: 144-145, 20 Jan. 1945.

48. Havens, W. P., and Paul, J. R.: Prevention of Infectious Hepatitis With Gamma Globulin. J.A.M.A. 129: 270-272, 22 Sept. 1945.

49. Memorandum, Col. Earl Standlee, MC, to The Surgeon General, U.S. Army, 22 July 1945, subject: Hepatitis in Transfused Individuals.

50. Circular Letter No. 53, Office of the Chief Surgeon, Headquarters, European Theater of Operations, U.S. Army, 19 June 1945, subject: Homologous Serum Jaundice (sec. II).

51. Memorandum, Maj. P. E. Sartwell, MC, for file, 25 July 1945, subject: Prevention of Post Transfusion Hepatitis.

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