CHAPTER XVIII
Reactions to, and Complications of,Blood and Plasma Transfusions
GENERAL CONSIDERATIONS
It is still true (in 1962) that, whenever large numbers oftransfusions are given, reactions will occur, though on well-controlledservices, they do not exceed 3 percent. It is also still true that some deathswill follow transfusions, though the number is smaller, in fact, than wouldoccur if transfusions were withheld.
At the onset of World War II, reactions after transfusionswere sufficiently frequent to alarm even the most enthusiastic proponents of theliberal use of whole blood.1 Theywere readily explained: Blood was usually collected by an open system, andprinciples of sterility and of absolute cleanliness of the apparatus wereenforced in only a limited number of hospitals. Many surgeons were thereforewary about using blood at all. When it began to be used in increasing amounts inthe management of battle casualties, the pendulum then swung to the otherextreme. Reactions were overlooked, and the widespread and highly erroneousclinical impression grew up that transfusion was an innocuous procedure. Therelatively easy availability of whole blood and its widespread use brought inits train great benefits but it also brought inevitable misuse.
As more experience was gained and the risks of transfusionbegan to be appreciated, there was another swing of the pendulum. The impact ofsevere reactions on persons who had supposed that transfusion was without riskwas magnified, and blood was sometimes withheld when it should have been given.
The precise incidence of reactions after transfusions inWorld 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 notfavor accurate recording. Such statistics as do exist are also of somewhatdubious accuracy, because the differential diagnosis of the reaction was notalways correct. Many casualties who were transfused were already running hightemperatures and some were having chills. Some diagnoses were therefore made ofreactions which did not exist, while some probably went unrecognized.
The incidence of reactions varied from hospital to hospitalbut invariably was smallest in hospitals which practiced routine investigationof all transfusion reactions as soon as they occurred. A critical appraisal ofthe 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 tighteningcontrols and preventing recurrences.
A listing of the most common causes of transfusion reactions carries initself the method of preventing them. They include errors in typing, hemolysisdue to overaging, physical changes from failure of refrigeration or from storageat lower or higher temperatures than the optimum, contamination, and thepresence of pyrogens.
In hospitals which used type-specific blood, transfusion of incompatibleblood could be avoided only by the most careful attention to techniques of bloodgrouping, 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 testsby experienced technicians. The plan of having the results of typing andcrossmatching checked and the tests repeated by different technicians was wellworth the time it took. Indeed, many technicians learned to develop a high indexof suspicion when they observed any departure from normal behavior in bloodtyping.
Another precaution, when it was practical, was to have the person who wouldgive the transfusion collect the blood from the laboratory, start thetransfusion, and remain with the patient long enough to be reasonably sure thatno reaction would occur or to cut off the flow of blood at once if signs andsymptoms did appear. One reason that this was a wise precaution was that theamount of blood given seemed important in hemolytic reactions. Bordley (2), forinstance, reported that 5 patients who recovered after such reactions receivedan 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 patientsas always, of course, helped to determine the outcome.
The point to be emphasized in any discussion of reactions in World War II isthat, while mass transfusions were given, mass reactions did not occur. Thenumber of reactions reported, in fact, was so small that generalizations basedon them seem scarcely valid. This important consideration should be borne inmind in reading the following pages and reflecting upon the individual casehistories presented.
ALLERGIC REACTIONS
Of the three varieties of transfusion reactions, allergic, pyrogenic, andhemolytic,2 allergic reactions werethe most frequent and the least serious (3). They followed transfusionsof whole blood and plasma and, occasionally, of human serum albumin. They werepresumably caused by a response on the part of the recipient to allergens in theblood of the donor. The recipient was sometimes sensitive to what a nonfastingdonor 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 anallergic response if he came into contact with the specific allergen. For thisreason, it was best not to use individuals suffering from major allergies asdonors.
Most allergic reactions took the form of urticaria, whichreadily responded to subcutaneous administration of 0.3-mg. doses ofepinephrine. If urticaria appeared, it was best to discontinue the transfusionunless the indications for it were extremely urgent.
Serious allergic reactions took the form of angioneuroticedema or asthma, both of which required immediate discontinuance of the infusionand prompt treatment with epinephrine. Edema of the larynx was occasionallyfatal.
It was a common experience in military hospitals to have fewreactions in the shock ward as compared with the number in the operating roomand the recovery ward, after several transfusions had been given. The intervalbetween the infusions in these cases was too short for the reactions to beexplained by the Rh factor, and a more reasonable explanation seemedsensitization of the patients to type O blood or to plasma protein which mighthave undergone denaturization. The possibility of sensitization of humans tohuman protein was the last of all explanations to be considered.
PYROGENIC REACTIONS
Historical Note
When sodium citrate was suggested as an anticoagulant in1914, by several observers at the same time (p. 218), it was at once blamed forthe undesirable and often dangerous chills and fever that followed directtransfusion. 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 distilledwater in pyrogenic reactions was demonstrated in 1923 by Seibert (5), whopointed out, in her review of the literature, that its febrile potentialitieshad been established by Billroth in 1865 and by Bergman in 1869. Hort andPenfold also made observations on contaminated distilled water in 1911.
There were no chills in the first 17 transfusions given atMount Sinai Hospital in 1915, all by the same physician, who paid carefulattention to the preparation of apparatus and solutions (6). Whenmultiple personnel began to give blood, there were numerous reactions, 24percent in one series of 365 transfusions (7). When transfusions wereconcentrated in the hands of eight senior members of the house staff, thereaction rate fell to 13 percent.
The high rate of reactions after transfusion continued untilRosenthal advanced the theory that the preparation of the equipment used in itsperformance was entirely too lax and casual. He was able to demonstrate thatposttransfusion chills were caused by foreign proteins introduced as extraneousmatter in distilled water or present in the tubing or other apparatus in theform of altered proteins left from previous intravenous injections. Such matter
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would always be present unless the instruments were cleansedwith the greatest care, immediately after use, by competent technicians, in acentral room, with no connection with the operating room or any other part ofthe 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 SinaiHospital on 1 October 1931. The results immediately proved his theory. Theprevious year, there had been 9 percent of chills in 412 transfusions. In thefirst year of the new setup, although multiple personnel gave the 477transfusions, there was 1 percent of reactions. In the 6 months before the newdepartment was set up, the incidence of chills after transfusion with citratedblood was 10 percent. In the first 6 months of the operation of the newdepartment, 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 tooconclusive to be ignored. Their experience was always duplicated when theirtechnique was followed, though as time passed, it became clear that the use oftriple-distilled water was an unnecessary precaution. At Walter Reed GeneralHospital, Washington, D.C., when the Research Division of the Army MedicalSchool took over the task of cleansing the equipment, the incidence of reactionsfell from 20 percent to 0.5 percent. All rubber tubing was washed within an hourafter use, with distilled water, which was forced through it by a 50-cc. syringeor a large Asepto syringe. The tubing was then soaked in 5-percent sodiumhydroxide. The temperature of the water and the solution was not important. Theequipment was put up in individual sets and autoclaved immediately. The resultshere and elsewhere left no doubt that the majority of posttransfusion reactionswere pyrogenic and were the result of improper cleansing of the transfusionapparatus, particularly the rubber components.
World War II Experience
In World War II, the common errors leading to pyrogenic reactions were asfollows:
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 inamounts that could not be removed by ordinary cleaning techniques.
3. Rinsing the equipment with supposedly pyrogen-free water that had becomecontaminated.
4. Allowing properly cleaned and rinsed sets to stand for 4 hours or morebefore sterilization.
The elaborate cleaning technique which was possible in civilian hospitalsproved completely impractical in combat circumstances. Transfusions could neverhave been employed as universally as they were if disposable equipment had notbeen developed and provided along with blood and plasma. The incidence ofpyrogenic reactions was invariably increased when hospitals
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insisted upon cleaning their own glassware and tubing instead of using thesterilized sets furnished (8).
The severity of the reaction depended upon the amount ofpyrogen infused and the susceptibility of the patient. Symptoms and signs mightstart at any time during or after the infusion, but most often occurred shortlyafter the infusion had been completed. The reaction varied in severity from aslight to an extreme temperature elevation (which was extremely dangerous if thepatient was already running a high fever), with chills, cyanosis, andprostration. The temperature usually returned to normal within 3 or 4 hours andfatalities scarcely ever occurred.
The prophylaxis of pyrogenic reactions was the use ofproperly cleaned transfusion sets, or, better, the use of disposable equipment.The treatment was immediate termination of the transfusion, for the principalreason that the initial clinical manifestations of serious hemolytic reactionsfrom the transfusion of incompatible blood could not be differentiated fromsimple pyrogenic reactions. Another reason was, as already pointed out, that theoutcome of the reaction depended upon the amount of pyrogenic substancesintroduced into the bloodstream.
HEMOLYTIC REACTIONS
In 1942, Kilduffe and DeBakey (9) collected from theliterature 43,284 transfusions, with 80 hemolytic reactions (0.18 percent) and45 deaths (0.14 percent). Hemolytic shock was the cause of death in 32 of the 45fatal cases. The figures leave no doubt that incompatibility reactions are thechief cause of death after transfusion and vindicate the decision to use only Oblood in the massive transfusion programs set up in the Mediterranean andthe European Theaters of Operations, U.S. Army, and the Pacific areas in WorldWar II.
At the end of the war, as the result of prewar knowledge andwartime experience, the causes of hemolytic reactions could be listed asintravascular 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 hemolyzedblood.
Hemolytic reactions, although relatively infrequent, werealways serious, and were always potentially lethal. On the other hand, there isno doubt that many of the deaths classified as caused by transfusions in WorldWar II were the result of the wound itself or of other causes not related to theuse of whole blood.
Reactions Due to Incompatibility
Clinical manifestations.-The reaction to transfusionwith incompatible blood varied from patient to patient, perhaps depending uponthe agglutinin titer of the recipient's plasma. One patient might receive 500cc. of incompatible blood and have no manifest reaction while another might havea severe
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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, theimmediate 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 ofsubsternal oppression; and, sometimes, nausea, vomiting, and involuntarymicturition and defecation. After an initial rise of blood pressure, a state ofshock might supervene, with extreme hypotension and a weak, fast pulse. Afterthe chill, the temperature might rise to 105? F. Sometimes bleeding occurredfrom 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 darkbrownish-red, was positive for protein, and contained a few red blood cells anda fair number of pigmented casts. The benzidine test was also positive.
The initial reaction was seldom fatal, but after recoveryfrom it, a number of possibilities might come to pass:
1. There might be no further signs or symptoms other than atransient bilirubinemia.
2. There might be transient oliguria, with nitrogenretention, the excretion of large quantities of urine, and then recovery.
3. There might be persistent oliguria, with increasingnitrogen retention, and death in uremia.
4. There might be oliguria leading to complete anuria, orthere 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 diedin uremia.
Death from renal failure usually occurred in 4 to 10 days. Ifthe patient had received less than 250 cc. of incompatible blood, the chance forrecovery was usually good. If he had received 500 cc. or more, the prognosis wasgenerally poor.
Pathologic process-The characteristic autopsy findingsin a death following the transfusion of incompatible blood were limited to thekidneys. Except for some swelling, there were no pathognomonic gross lesions.The most striking microscopic observation was the presence, within the renaltubules, of pigmented casts consisting of hemoglobin or degradation products ofhemoglobin, though mechanical occlusion of the tubules by hemoglobin casts wasnot believed to be the principal factor in the fatality. Characteristically, thecasts occurred only in certain portions of the tubules; namely, the ascendinglimbs of Henle, the distal convoluted tubules, and the collecting tubules. Thedistribution of the casts was irregular but not diffuse, and frequently only asmall proportion of the tubules were involved.
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Less conspicuous than the changes just described, butprobably more important, were the degenerative, sometimes necrotic, changes inthe tubular epithelium of relatively short segments of the ascending limbs ofHenle and the distal tubules. In the neighborhood of the more severely damagedsegments, the interstitial tissue often exhibited an inflammatory reaction, witha predominance of small round cells.
The changes in the tubules and their supporting stroma wereusually most evident in the zone between the cortex and the medulla. Theglomeruli and the proximal tubules; that is, the upper portion of the nephron,were usually normal.
Pathogenesis-A comprehensive clinical andexperimental study of hemoglobinuric nephrosis in traumatic shock by Mallory (10)(formerly Lieutenant Colonel, MC), in 1947, eliminated a number of theoriesof causation. Fatal renal insufficiency was not produced by the intravenousinjection of hemoglobin. Precipitation did not occur in the presence of eitheracid or alkaline urine. The Van Slyke kidney could not be reproducedexperimentally, but when renal ischemia was produced, changes were observedranging up to necrosis of proximal tubules, though no significant changesoccurred in the lower nephron. Experimental pigment-formation could not beproduced, 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 pigmentnephropathy being directly proportional to the severity of the injury. Theevidence suggested that, while renal insufficiency preceded all structuralchanges, it did not progress in the absence of pigment nephropathy. It was thelower nephron, Mallory pointed out, not the upper, in which anatomic changeswere present in the presumed posttransfusion kidney. At the end of the war,therefore, and afterward, the posttransfusion kidney remained an unsolvedproblem.
Diagnosis.-The clinical and pathologic picture justdescribed, while it might be caused by a transfusion of incompatible blood,might also be caused by a variety of other conditions, including shock, crushinginjuries, burns, sulfonamide therapy, and possibly various combinations of theseconditions. The renal involvement that followed all of them could not usually bedifferentiated from that resulting from the transfusion of incompatible blood,and no doubt a number of deaths were charged to hemolytic reactions when theywere really due to some one of these other causes.
The following test, devised by the serology section of the15th Medical General Laboratory to differentiate hemolytic from nonhemolyticreactions (11), came into rather wide use: Blood serum, drawn about 15minutes after the clinical reaction, was compared with the serum taken forcrossmatching before the transfusion. The presence or absence of hemolysis inthe posttransfusion specimen was compared with the same phenomena in thepretransfusion specimen.
This simple method proved very useful in indicating whetherthe reaction was hemolytic and required a complete investigation, or wasallergic and re-
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quired a recheck of the patient's history, or was pyrogenicand required an investigation of the technique of preparing apparatus anddistilled water.
If the posttransfusion sample contained free hemoglobin orbilirubin, additional investigation was required. Another sample was withdrawnabout 4 hours after the reaction and tested for bilirubin. If it was present, asearch for the cause was made:
1. The blood groups of the recipient and thedonor were rechecked.
2. Crossmatching tests were rechecked.
3. The presence or absence of hemolysis wasdetermined by centrifuging a specimen from the donor bottle.
4. The Rh types of the recipient and the donorwere checked. A recently transfused Rh-negative patient might show a fewRh-positive cells, and this possibility always had to be taken into account.
5. If the recipient was Rh negative, thepretransfusion sample of serum was tested for the presence of anti-Rhagglutinins.
6. If the donor was group A, B, or AB and hadreceived group O blood, his serum was titered against the recipient cells.
Treatment-The immediate treatment of hemolyticcrisis 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 neverclarified during the war, and its treatment therefore remained entirelyempirical. It consisted of any single one or a combination of the followingmethods: alkalinization, splanchnic block, decapsulation of the kidney, bloodand plasma transfusions, and regulation of the fluid and salt balance. All ofthese methods were empirical, and none of them was successful in any significantnumber of cases. Fluid regulation, it should be emphasized, was always anindividual matter, for which no general rules could be stated.
Reactions Due to Intravascular Hemolysis of Recipient'sCells
Intravascular hemolysis of the recipient's cells could becaused by the accidental administration of distilled water and by the use ofhigh-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 reactionin which the presence of incompatible isoagglutinins in high-titer blood wasmanifested by chills, fever, hemoglobinemia, and a rather persistentbilirubinemia. Destruction of red blood cells by group O blood was firstdemonstrated in a group A patient with severe leptospirosis, who was given alarge amount of plasma for 4 or 5 days and then a series of O-blood transfusionsfor rapid, progressive anemia. When the transfusions were over, every one of hisown cells had been replaced by transfused cells, but apparently not to hisdetriment, for he survived. The observations in this case confirmed Ashby's (13)earlier studies, which showed surprisingly large destruction of recipientcells. 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 largeamounts of plasma. An ante mortem Ashby count in the fatal case showed that 96percent of this patient's red blood cells had been replaced by transfusedcells.
Major Emerson's investigation also showed that theincreased fragility of recipient cells frequently noted after transfusion wasparticularly marked after injection of high-titer O blood and after repeatedtransfusions of O blood or pooled plasma (14). In discussing theseobservations, Brigadier Lionel E. H. Whitby, RAMC, stated that the fragilitycurve is always increased after severe burns, because of the external heatapplied to the cells as they pass through the burned area. The affected cellscontinue to be destroyed for many days thereafter. Major Emerson found it hardto believe that, if the patient were to survive, traumatized red cells resultingfrom a burn could possibly involve an enormously high proportion of his blood.
Since the technique of titration varied from laboratory tolaboratory, no specific general rulings were made as to the upper limit ofagglutinin titer compatible with safety. It was simply recommended that sometechnique be selected which would label all group O blood as having a highagglutinin content. It was thought unlikely that such a proportion would bepotentially dangerous, but, in view of the fact that many casualties receivedmultiple transfusions, it was also thought that the titer for universal donorblood should be kept as low as possible.
Reactions Due to Intravascular Hemolysis of CompatibleDonor Cells
Hemolysis of compatible donor cells could occur promptly aftertransfusion with blood which had been improperly handled; that is, it wasoverage or it had been stored at incorrect temperatures. Unless the blood showeddefinite in vitro hemolysis, results were seldom serious and there were often nosubjective symptoms, though the transfusion was obviously of little benefit.When the transfused blood was promptly broken down, there would be freehemoglobin in the serum, which would shortly be converted to bilirubin, andclinical jaundice might be evident.
Hemoglobinemia might be expected to have a deleterious effectupon the kidneys of a patient in shock, and fatal anuria was reported after thetransfusion of hemolyzed blood.
The proper care of preserved blood and its carefulexamination before use were all that was necessary to prevent these results.
European Theater
When Maj. (later Lt. Col.) Robert C. Hardin, MC, visited varioushospitals in the European theater in the late summer and early fall of 1944, hefound a considerable amount of confusion concerning transfusion reactions and agreat many untenable theories, which were little more than clinical impressions (15).Furthermore, fatalities were being attributed to transfusions for
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no better reason than that the patient had been given blood. It was notrealized that a hemolytic transfusion reaction cannot be diagnosed by tissuestudy, nor was it realized that intravascular hemolysis of incompatible blood isnot the only cause of hemoglobinuric nephrosis. In short, the reasoning wasentirely of the post hoc, ergo propter hoc variety-the patient had atransfusion; the patient died; therefore, his death was due to the transfusion.
Studies in the European theater corroborated those in the Mediterraneantheater and confirmed the highly dubious role of transfusion in the etiology oflower nephron nephrosis (16). In an investigation of a number of reportsof autopsies performed at the 91st Evacuation Hospital, Major Emerson foundcause to doubt the anatomic diagnoses of hemoglobinuric nephrosis. He thoughtthat the renal changes demonstrated might well be due to prolonged impairment ofthe renal blood flow, as the result of severe, long continued, hypotension. Therenal anoxia was probably further enhanced by the severe anemia induced bymassive plasma transfusions; by anoxia resulting from impaired pulmonaryventilation; and, quite possibly, by diffuse intravascular agglutinationresulting from the injection of isoagglutinins, although this factor could notbe properly evaluated, since the patients' blood groups were seldom noted ontheir records.
Most of these patients had been treated for oligemic shock. Their hypotensionhad been prolonged. They had exhibited temporary oliguria and albuminuria;reduction of the urinary pH; and, in an occasional case, excretion of red bloodcells and casts. In all but two cases, which ended fatally, these findings weretransitory, clearing within 24 to 48 hours after restoration of the arterialpressure.
Case 1.-In the first fatal case, the casualty, inaddition to multiple intestinal perforations, had required nephrectomy for asevere lacerating renal wound. He had been in a state ofoligemic shock for 8 hours and had received 4,000 cc. of O blood during hisfirst 10 hours of hospitalization. He died on the fifthday.
Case 2.-The second patient had multiple suckingwounds of the chest with severe intrapulmonary hemorrhage. He had been in severeshock, 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 first24 hours of hospitalization. He died on the ninth day.
Clinically, there was no sign of a transfusion reaction in either case, andthe Ashby count indicated no unusual degree of hemolysis of recipient cells. Thesecond patient developed severe hypertension on the sixth day. Both patientsexhibited oliguria progressing to anuria and uremia.
In the first case, necropsy showed eosinophilic granular casts of the distalportion of the nephrons of the remaining kidney, which was edematous. Thediagnosis of hemoglobinuric nephrosis was consistent with the pathologic picturedescribed by Mallory. In the second case, there were also hemoglobin casts inthe renal tubules. It was Major Emerson's opinion that these post mortemfindings, even though hemoglobinuria was not demonstrated during life, might beexplained by diffusion of small amounts of hemoglobin through the glomeruli ofischemic kidneys. Once the hemoglobin had gained entrance
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to the tubules, either insufficient reabsorption of water might occur, or thefiltration pressure of the urine might be so inadequate that any casts thatformed could not be dislodged. The benzidine test, in contrast to its efficacyin other biologic fluids, was not entirely satisfactory for the detection ofminute amounts of hemoglobin in the urine, and small amounts might be regularlyoverlooked. The free hemoglobin from which these casts were derived could beeither free hemoglobin in the transfused blood or hemoglobin derived from thepatient's own red cells hemolyzed by injected incompatible isoagglutinins. Itwas assumed that the concentration required to free plasma hemoglobin might bemuch lower than was ordinarily conceived.
Thus in the European theater, as in the Mediterraneantheater, lower nephron nephrosis remained an unsolved problem at the end of thewar. From the standpoint of this volume, the important consideration is themultiple causes other than transfusion which could give rise to what waserroneously called by many observers the posttransfusion or the transfusionkidney.
SPECIAL THEATER EXPERIENCES
Mediterranean Theater
There are no accurate reports of the reaction rate intransfusions accomplished with blood from the bank at Naples. An overall ratewould be of little significance as an index of the suitability of the bloodprovided: Each hospital in the theater prepared its own recipient sets, and thebank, while it distributed instructions for their proper cleaning andpreparation, had no control over the procedures. The incidence of reactionstherefore varied from hospital to hospital and was related to the efficiencywith which the sets were cleaned and sterilized (17).
Only once was there any serious question concerning thequality of the bank blood. This was in May 1945, when a shipment of blood, allfrom one bleeding center, resulted in 18 febrile reactions in three separatehospitals. Four of the patients died, but in only two cases was the transfusionconsidered the direct cause. Bacterial examination of two bottles from thisshipment revealed psychrophilic organisms which had probably gained entrance tothe blood because of incorrectly sterilized donor sets. There were no otherdeaths and no febrile reactions attributable to the blood itself, though 78,329units had been distributed up to the time of this survey (October 1944) (17).
In 1943, a number of febrile reactions at the 91st EvacuationHospital were attributable to the extreme difficulty experienced in cleansingthe filters of the recipient sets (18). Aside from the risk of reactions,the blood would not run through the filters. Facilities for proper cleansing oftransfusion equipment were not available in forward hospitals, and, at thishospital, as at many others, it had to be cleaned and sterilized in theoperating room. None of the reactions was serious, and no hemolytic reactionsoccurred.
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British transfusion units in the Mediterranean theaterincluded one set of sterile equipment with each two bottles of blood intendedfor forward hospitals. Disposable equipment from the Zone of Interior wasreceived in the theater too late to be useful. It would have been highlydesirable, and some reactions could have been avoided, if the Naples bank hadbeen able to prepare transfusion equipment to be supplied with the blood, butneither equipment nor personnel were in the theater in sufficient supply topermit such a plan.
European Theater
To clarify the confusion in the minds of many medical officersabout transfusion reactions and the so-called transfusion kidney, AdministrativeMemorandum No. 150 was issued on 27 November 1944, from the Office of the ChiefSurgeon, Headquarters, European Theater of Operations, U.S. Army (19). Inthis memorandum, it was frankly admitted that, because of the enormous number oftransfusions being given in the theater, a certain number of reactions wereinevitable. Allergic, pyrogenic, and hemolytic reactions were described, andtheir prevention and treatment were outlined.
In this same memorandum, all hospitals in the theater wereinstructed to submit weekly reports to the Office of the Chief Surgeon, the datato include the number of transfusions given; the number of reactions and theirclassification; 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 ofpyrogenic reactions, 3.7 percent, and of hemolytic reactions, 0.48 percent, wastoo high. The incidence of hemolytic reactions, however, was probably less thanstated because deaths were being signed out as hemoglobinuric nephroses when theblood given had nothing to do with the complication or the death. Many of thecasualties, in fact, had been anuric before they received any blood.
Special studies of the reports submitted by hospitals in thetheater and analyzed by Major Hardin and several of his associates are presentedin tables 28-31 (15). Perhaps the most interesting feature of thisanalysis is contained in table 31, which indicates the responsibility of poorpreparation of locally prepared sets in the incidence of pyrogenic reactions.
One is immediately impressed by the discrepancies in thereaction rates reported by hospitals in different echelons of medical care. Thefirst explanation of the higher rate in rear hospitals is multiple transfusionsand the development of Rh sensitivity. Patients transfused in forward hospitalson one day were often transfused again 10 to 14 days later, in general hospitalsin the rear. The possibility of producing Rh sensitivity by the indiscriminateuse of blood whose Rh type was not known was suddenly real, and subsequenttransfusion provided the opportunity for the sensitivity to become manifest.
A simpler explanation, however, is available for the lowreported incidence of reactions in forward hospitals, that in a field orevacuation hospital, during
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TABLE 28.-Reactions to blood transfusionsin field hospitals over 17-week period in the European Theater ofOperations, U.S. Army1
Weekly periods | Transfusions | Reactions | Reactions | Classification | ||
| 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 | --- | --- |
| 17,769 | 224 | 1.26 | 52 | 160 | 12 |
1There were six deaths in the 12hemolytic reactions.
a rush of casualties, mild reactions were often overlookedand only the most severe reactions were noted, let alone recorded. In generaland station hospitals, with larger staffs and less pressure, more accurateobservation 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 itwas intended, to check upon the operations of blood banks and to build a basisfor further investigation. One important thing that was learned was that it wasdangerous to accept reports of reactions based on less than 500 transfusions andthat a minimum of 1,000 transfusions was necessary for conclusions of anyvalidity.
In his report of his trip to the European theater in January1945, Capt. John Elliott, SnC, reported Major Hardin's emphatic belief thatthe reaction rate from blood flown from the United States was considerably lowerthan that of blood collected locally in the theater (20). Up to thattime, 18,460 transfusions had been given with 643 reactions, 3.5 percent. Bloodcollected locally accounted for 26 percent of the reactions but for only 10percent of the transfusions. Blood from the Zone of Interior accounted for about28 percent of the reactions but for about 60 percent of the transfusions. Bloodfrom the
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TABLE 29.-Reactions to blood transfusionsin evacuation hospitals over 20-week period in
European Theater of Operations, U.S. Army1
Weekly periods | Transfusions | Reactions | Reactions | Classification2 | ||
Allergic | Pyrogenic |
| ||||
| 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 | --- |
| 24,920 | 500 | 2.00 | 100 | 340 | 52 |
1There were 27 deaths in the 52 hemolyticreactions; 6 other deaths in the group were not attributed to the transfusions.
2In the 10th through 14th weeks, there were eight unclassifiedreactions.
TABLE 30.-Reactionsin 18 general and station hospitals after transfusion with blood obtainedfrom the United Kingdom Section, European Theater Blood Bank1
Year and month | Transfusions | Reactions | Reactions | Classification | |
| Pyrogenic | ||||
1945 | Number | Number | Percent | Number |
|
March | 1,063 | 24 | 2.2 | --- | --- |
April | 1,402 | 30 | 2.1 | 10 | 20 |
May | 307 | 4 | 1.3 | 1 | 3 |
| 2,772 | 58 | 2.1 | 11 | 23 |
1There were no hemolytic reactions in this group.
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TABLE 31.-Influence of local preparationof transfusion sets on pyrogenic reactions in various typesof hospitals
| Types of hospital | Number of | Number with | Percent |
| Field hospitals | 160 | 62 | 38.7 |
Evacuation hospitals | 340 | 136 | 40.0 |
General hospitals | 346 | 174 | 50.2 |
|
|
|
|
United States accounted for the largest proportion ofallergic reactions but by far the lowest proportion of pyrogenic and hemolyticreactions.
Similarly, striking figures were reported for February 1945.In that month, 32 percent of the transfusions which were followed by reactionsoccurred with locally prepared sets. The use of locally prepared sets alsoexplained the reactions which occurred in bloods collected by the theater bank (21).
Special studies on the effects of transfusion of incompatibleisoagglutinins were carried out at the 5th General Hospital by Major Emerson andMaj. (later Lt. Col.) Richard V. Ebert, MC (22), and were supplemented byadditional studies made by Major Emerson on detached service with the 91stEvacuation Hospital (18). They arrived at the following conclusions:
1. The repeated injection of group O blood orpooled plasma, or their injection in massive amounts, into individuals of otherthan group O produces hemolysis of recipient cells, the degree of which may besignificant. The process is occasionally accompanied by a febrile transfusionreaction.
2. The hemolytic process is associated withprogressive increase of hypotonic erythrocytic fragility, which is apparentlyrelated to the hemolytic phenomena described by Ham and Castle. These observersproduced the same processes in experimental animals by the injection ofnonspecific agglutinins.
3. Evidences of profound hemolytic disease mayappear after massive plasma transfusions given to patients of other than groupO. This phenomenon was observed in four patients and was in contrast to the goodresults in three patients with comparable injuries, who were treated similarlyand whose blood group was O.
4. A certain proportion of nonspecificpyrogenic transfusion reactions may be caused by the stroma of hemolyzed redblood cells in the transfused blood. Prevention of these reactions depends notonly on proper refrigeration of stored blood but also on the maintenance of redblood cell diffusion in the blood diluent by repeated agitation of the bottleduring storage. Results of preliminary studies suggested that the survival ofred blood cells during storage is limited by the amount supplied of anexhaustible nutrient factor.
In his separate study, Major Emerson followed 61 patientsthroughout their course in the 91st Evacuation Hospital, making elaborateclinical and laboratory studies on them during the 5-week period ending 10 May1945. All had incurred severe wounds and all required intensive replacementtherapy, including 265 units of whole blood, 222 of which were flown from theUnited States.
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During the period in question, 520 units of blood were givenin the hospital, with eight reactions. The data in one case are incomplete.Three of the reactions followed the use of partly hemolyzed blood, and theremainder occurred in casualties of groups A and B, who received O blood with ahigh titer of isoagglutinins ranging from 1 to 500 against the patient'scells.
The hemolysis was attributed to three factors: the age of theblood (10 days or more in all instances); failure to agitate the bloodfrequently during storage, so that the red cells in the bottom of the flask werenot kept in contact with the preservative diluent; and failure of refrigeration.
Major Emerson considered that, from the practical point ofview, the importance of these and other findings (space does not permit theirinclusion here) was as follows:
1. Repeated transfusion of group O blood into otherthan group O patients may be an ineffectual and uneconomicprocedure 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 causeserious hemolytic disease.
3. It is conceivable that irreversible organic changesinvolving the kidneys, liver, central nervous system, and other organs may occuras the result of prolonged, diffuse intracapillary agglutination.
4. The implication is strong that whenever feasible, strictlycompatible blood, of the recipient's blood group, should be used. Underconditions that render the exclusive use of group O blood necessary, only bloodof low titer should be supplied. There are strong reasons to suspect that evenpooled human plasma with a low agglutinin titer, if administered in very largeamounts to persons of blood groups other than O, may have undesirable and evendangerous effects, and that the use of fractionated human albumin might bepreferable in such cases.3
Occasional hospitals, during the course of the war, indicatedtheir desire to collect their own blood and not use banked blood because of fearof reactions and for other reasons. Major Hardin was willing that hospitalsshould maintain their own blood banks if they wished to, but he pointed out thatif a hospital should ever be either isolated or overwhelmed with casualties,either the system would collapse or the patients would not be adequatelytransfused (23).
Maj. Gen. Paul R. Hawley's position was unequivocal. Heconsidered that most of the deaths reported as caused by transfusion were due toother causes, including overloading kidneys already damaged from toxinselaborated in the crush syndrome or other injuries. Up to March 1945, thetransfusion death rate in the European theater was 0.12 percent, which comparedvery favorably with the 0.14 percent of transfusion deaths recorded in theliterature.
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.
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"I shall not," he wrote, "tolerate exuberantenthusiasts casting any doubt upon a technique that has saved the lives ofthousands 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 ofgrossly contaminated blood. The recipient became violently ill shortly afterreceiving the blood and death usually occurred in a few hours.
Four such reactions occurred on 23 and 24 January 1945, atthe 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 afterthe transfusion, chills occurred, without pain or respiratory difficulty. Then,the patients quickly passed into a state somewhat, but not altogether, likeshock. They were disoriented, but frank coma did not develop. The blood pressurewas well within the shock range, but the general appearance was not typical ofshock. The pulse rate was extremely rapid, but at first was of good volume andthere was no noticeable sweating. Within a short period of time, the temperaturerose sharply, in one instance to 106? F. Later, cyanosis appeared. Theoutstanding feature in each case was the profound circulatory collapse, whichpredominantly involved the peripheral vascular bed. Three patients died. At postmortem examination, the only findings common to all three cases were heartfailure, with the right ventricle primarily involved.
An elaborate investigation followed, hampered by the factthat the Baxter bottles in which the blood had been collected and the donor setsused were no longer available for examination. It was not possible to determinehow the contamination had occurred, but the situation was described as the kindthat "keeps blood bankers awake at night."
After these fatalities, Major Hardin instituted cultural spotchecks of the bloods in the United Kingdom Blood Bank and at the ContinentalBlood Bank in Paris.
LOWER NEPHRON NEPHROSIS
The lethal sequelae of shock were not appreciated at thebeginning of the war, as might have been expected; the peacetime experience withthis condition is never on the massive scale on which it occurs in wartime, andsuch sequelae are therefore numerically less frequent and tend to be lessimpressive. In World War II, they were very frequent, because of the vast numberof shocked casualties, and they became more impressive and more apparent as morepatients, with improved methods of resuscitation and surgery, lived long enoughto develop them.
These sequelae were due primarily to asphyxia of organs ortissues during the prolonged period of reduced volume flow of blood. Post mortemexaminations 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, whichproved to be incorrect, of the role of transfusion in the pathogenesis of thecondition that came to be known as lower nephron nephrosis.
Mediterranean Theater
Lower nephron nephrosis, manifested clinically by oliguriaand anuria, became a prominent feature of the crushing injuries sustained in airraids 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 SurgicalConsultants Division, Office of The Surgeon General, about 50,000 transfusionshad been given in the Mediterranean theater, 114 of which had been followed byanuria, which was usually fatal (17).
Clinical syndrome-Certain findings were characteristicof 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, butthe quantities had varied, as had the titer of the blood.
3. Although large quantities of blood were given in fixedhospitals, 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 medicalcare.
4. Lower nephron nephrosis occurred in group Orecipients aswell as in recipients of other groups who received group O blood.
5. When anuria was to develop, it appeared early, usuallywithin the first 24 hours after admission to a field or evacuation hospital.
6. The anuria was associated with a progressively increasingnonprotein nitrogen retention, which was unaffected by the injection of wholeblood, plasma, crystalloid solutions, or alkalinizing solutions; once anuriadeveloped, alkalinization was not effective.
7. Death occurred within 5 to 7 days unless the patient diedearlier from other causes.
When it was thought that lower nephron nephrosis was causedby the use of group O blood in nongroup O recipients, an endeavor wasmade to supply type-specific blood to forward hospitals. The attempt wasoverruled (p. 425) and, in the light of more correct information, it wasrealized that it would have been a futile gesture from the standpoint ofpreventing this renal complication of wounding.
Special investigations-The principal reason for thecreation of the Board for the Study of the Severely Wounded (p. 420) was theinvestigation of lower nephron nepbrosis (16). The observations of theboard may be summarized as follows:
1. Studies made after resuscitation, and after operation insurgical cases, indicated that, functionally, all portions of the nephron werealmost equally impaired for varying periods of time. The impairment dependedupon the severity of the initial insult, and the state of shock on admissionalso depended upon it. These physiologic observations did not correspond withthe histologic findings in fatal cases, in which the lesion observed was alwayspredominantly in the lower nephron.
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2. The clinical syndrome of renal insufficiency after shockwas remarkable chiefly for the paucity and mildness of its symptoms. The mostfrequent symptom, drowsiness slowly deepening into stupor, might be absent untildeath was impending. The only frequent sign was pulmonary or peripheral edema.
3. Blood pressure determinations and laboratory tests weremore useful than clinical observations. In the ascending order of diagnosticimportance, laboratory findings included proteinuria, persistent urinaryacidity, excretion of benzidine-positive material, azotemia, and fixation ofspecific gravity at a low level. When these findings were associated withhypertension, the diagnosis was established.
Other important findings included nitrogen and phosphorusretention, acidosis, hypochloremia, and an increase in the plasma volume.Practically all of the abnormalities, it should be noted, were those thatreflect rapidly diminishing renal function.
4. The case fatality rate was approximately 75 percent. Deathusually occurred within 10 days after wounding. Apparently, if the wounded mancould survive this critical period, renal function might begin to recover and hehad a chance of survival.
5. When recovery ensued, it was characterized by what wastermed "the syndrome of recovery diuresis."
6. The best treatment of lower nephron nephrosis was itsprevention, by prompt and adequate resuscitation of every casualty in shock.None of the therapeutic methods employed was really effective except theprevention of pulmonary edema by control of the fluid intake. It was a graveerror to overload the circulation during the critical 10-day period.
7. Evidence was meager that alkalinization would preventrenal complications in the severely wounded. The original plan, to give alkalisas soon as renal complications became evident, was eventually discarded, andtheir use, beyond the amount given routinely with citrated whole blood or bloodsubstitutes, was not recommended.
8. The lack of correlation between concentrations ofbenzidine-reacting pigment in the plasma and the hemoglobin or myoglobin in theurine suggested that the alteration of the threshold was variable. Theirregularity with which extensive muscle injury was followed by myoglobinuriaindicated that some factor other than necrosis of muscle cells was at work. Thisfactor-which was not shock-apparently had to do with the maintenance ofreestablishment of the circulation in the involved muscles. Occasionally, severemyoglobinuria developed in the absence of demonstrable muscle injury. The almostconstant presence of moderate or severe shock in such cases suggested thepossibility of diffuse ischemic muscle injury not recognizable morphologically.The fact that severe myoglobinuria and severe hemoglobinuria were often observedin the same patient suggested the possibility of a common mechanism.
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SOUTHWEST PACIFIC AREA
Statistics for transfusion reactions are more incomplete forthe Pacific areas than for other theaters because the circumstances of warfarewere less favorable than elsewhere for precise reporting. Reports (which wererequired, as in the European theater) were received on only 22,000 of the pintsof blood distributed from Guam, but the 3.1 percent rate indicated in them canbe accepted as accurate (26). A number of severe hemoglobinuriaswere reported, but most of the reactions were mild, and 41 percent wereallergic. As in other theaters, a number of deaths attributed to transfusionswere not related to them except in the sense that they occurred after blood hadbeen given.
The reaction rate was higher when the blood was outdated. Upto 21 days, it was between 2 and 4 percent. Between 22 and 30 days, when thespecified time limit had passed, it was 5 to 6 percent.
The low reaction rate secured in transfusions with bloodflown from the Zone of Interior was chiefly explained by the use ofdisposable recipient sets. Whenever locally prepared sets were used, thereaction rate was higher. All of the hospitals which received Zone of Interiorblood were warned that the recipient sets provided with the blood must be used.
When the plan of flying blood to the Pacific was firstannounced, many surgeons thought the reaction would be prohibitively high (27).Within a matter of weeks, their skepticism was overcome by the low rate; theconvenience of not having to crossmatch the blood; the absence of fatalities;and the beneficial results secured, which permitted major surgery with anenormous reduction in the surgical risk.
It was not surprising that hospitals using large amounts ofpreserved whole blood invariably reported reaction rates well below those ofunits using smaller amounts. Efficient refrigeration, elimination of mechanicaldifficulties, and greater experience were all contributing factors. The rateswere notably lower in hospitals in which special shock teams handled alltransfusions.
Transfusion reactions were more frequent and more severe inFilipinos than in U.S. personnel (28, 29). They were chiefly allergic andmanifested by edema and urticaria, but one station hospital reported two fatalcases of anuria soon after the landings on Leyte, and later reported a thirdfatal case. Presumably, these reactions were on the same basis as the plasmareactions which occurred in Filipino personnel.
PLASMA TRANSFUSION REACTIONS
Urticarial reactions sometimes followed the infusion ofplasma, though they were not very frequent. Almost without exception, reactionsclassified as hemolytic could be traced to the use of contaminated plasma andthus were incorrectly diagnosed as hemolytic.
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Early Experiences
The possibility of reactions to plasma therapy was firstbrought up in the Subcommittee on Blood Substitutes at the 18 July 1941 meeting (30),when 262 transfusions were reported from cooperating civilian hospitals with19 reactions, 7.3 percent; the series included transfusions with type-specificplasmas, pooled liquid plasma, and dried plasma. These reactions, it must beremembered, occurred at a period when plasma was first being tested as aso-called blood substitute and when the techniques of collection of bloodoffered 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 theliterature describing reactions to plasma infusions. The experiences reportedwere contrary to Dr. Max M. Strumia's extensive experience; in 2,200 plasmainfusions which he had observed personally, there were only five reactions, allurticarial. He was inclined to attribute the reported reactions to the use ofplasma obtained from partly clotted blood, or, less probably, to pyrogenicsubstances in the plasma. He could find no evidence that they were due to anincompatibility between the recipient's cells and the plasma injected. Pooledplasma occasionally showed a relatively high isoagglutinin titer, but, when theplasma was given at the usual rate (5-10 cc. per minute), the agglutinins werenot only diluted in the recipient's bloodstream but were apparently alsoabsorbed or inactivated as rapidly as they were injected into the circulation.
An editorial published in the Journal of the AmericanMedical Association on 19 September 1942 (p. 79) contained inaccurate andmisleading information concerning the potential toxicity of plasma (33). Itwas considered important that it be corrected at once because of its possibleeffect on the blood procurement program. The editorial which corrected theerroneous statements left much to be desired, but the article prepared by Dr.William Thalhimer and published in the Journal for 19 December 1942 was acompetent and reasoned rebuttal (34).
Production difficulties-In August 1944, complaintswere received from the Office of the Chief Surgeon, European Theater ofOperations, U.S. Army, that reactions were occurring after the administration ofdried plasma from a certain laboratory. The plasma which had caused thereactions had contained excessive amounts of fibrin particles. The use of plasmafrom this firm had been forbidden in the theater; its issue had beendiscontinued; and the New York Port of Embarkation had been requested to delayfurther shipments. All installations in the First and Third U.S. Armies, AdvanceSection, and all laboratories in the United Kingdom were requested to report, ona special questionnaire, on any reactions which had occurred after theadministration of plasma in the last 2 months.
Clinical testing with the offending lots of plasma at theArmy and the Naval Medical Centers was followed by chills and fever in about 7percent of
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the patients, and a number of the bottles used showedmoderate amounts of fibrin. When the firm which had produced the offendingplasma 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 inproduction technique were advised, including chilling of the blood beforecentrifugation, to eliminate excessive amounts of fibrin in the final product.It was also recommended that all plasma produced by this particular laboratorybefore these changes were made should be used only in the United States. Therewere 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 wasbeing made in the 91st Evacuation Hospital, a number of plasma transfusionreactions were also observed, some quite serious (35). A special studywas therefore undertaken of the plasma transfusions given during a recent 25-dayoffensive, during which 1,022 patients were handled on the surgical service.
In this group, 109 patients, 10.6 percent of the surgicaladmissions, received 323 units of plasma, an average of 3 units per patient.There were 21 reactions, of which 3 were urticarial; these reactions simplycaused discomfort and did not impede the progress of treatment. There were also14 pyrogenic reactions and 4 modified hemolytic reactions, all sufficientlysevere to delay recovery, though none were lethal. Counting only these 18reactions, the reaction rate was 5.3 percent for the 323 injections and 15.6percent for the 109 patients.
Pyrogenic reactions-The pyrogenic reactions weresimilar to those observed in reactions sometimes observed after the intravenousadministration of other fluids. Chills and temperature elevations were the chiefmanifestations. The temperature, which ranged from 101? to 104? F., returnedto normal in 3 or 4 hours. There was no fall in the blood pressure, no urinarysuppression, and no abnormalities in the urinalysis.
Many of the patients received additional plasma and bloodwithout further difficulty. The pyrogenic reactions, however, were seriousbecause they often occurred in the shock ward, in patients being prepared foroperation, and their progress through X-ray examination to the operating roomhad to be delayed for a matter of hours until recovery from the reaction tookplace.
Hemolytic reactions-The four modified hemolyticreactions were far more serious. Three patients had received no intravenousfluid except plasma. The fourth had received two units of blood, but the onsetof the reaction occurred while he was receiving plasma. One patient presented atypical picture of peripheral vascular collapse. The systolic blood pressurefell to 60 and 32 mm. Hg, respectively, in two cases and could not be obtainedin the other two. One patient had no elevation of temperature, but theelevations in the three other cases ranged from 102? to 103.4? F.
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Two of the patients were anuric for 12 and 24 hours,respectively. All had red blood cells and granular casts in the urine. All hadpositive orthotoluidine reactions.
Icterus index determinations were made 24 hours after thereaction 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 ofthe 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 routineused for hemolytic blood reactions. An attempt was made to alkalinize the urinewith sodium chloride, with careful regulation of the fluid intake and closeobservation to detect any signs of pulmonary edema; it would have been easy todrown these patients in the attempt to increase the renal output. Serum albuminwas also used and was very effective.
No reasonable explanation was found for these reactions atthe time of their occurrence. None of the patients had wounds of the urinarytract. The possibility that the findings were due to massive tissue destructionwith hemoglobin could not be excluded, but similar phenomena were not observedin other casualties with injuries of comparable kind and severity. The mostreasonable immediate explanation seemed to be that, when several infusions ofplasma were given over a relatively short time, an agglutinin titer might bebuilt up which might react with the cells of all blood types except AB. Inretrospect, these phenomena seem to an observer who did not witness thempersonally to be explained by the use of contaminated plasma rather than as truehemolytic reactions.
The Southwest Pacific Experience
There were occasional isolated reports of plasma reactions inthe Southwest Pacific, none particularly convincing and most of them readilyexplained, usually by contamination of the plasma. One experience, however, wasextremely serious (36):
On 21 April 1945, the Office of The Surgeon General receiveda report of eight fatal reactions after the use of U.S. Army plasma for Filipinocivilians in the San Lazaro Hospital in Manila, a civilian hospital staffed bycivilian Filipino physicians.
The 11 patients among whom these 8 fatalities occurred wereall greatly emaciated, debilitated and avitaminotic. All had nonspecificileocolitis, which it was thought would be improved by the administration ofplasma.
The course of events was substantially the same in 10 of the11 cases, in all of which the plasma was given on the same day, 24 March. About30 minutes after the intravenous administration of 250 cc. of normal human
4The titer seems quite low to be causing reactions.
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plasma, 9 of the 10 patients complained of chilly sensations,which lasted about 30 minutes; none of them had a real chill. All complained ofmalaise and muscular pains. Their temperatures were not taken but they wereobviously febrile. They were wrapped in blankets and each was given 2 cc. of10-percent camphorated oil intramuscularly.
Of the 10 patients, 7 died between 4 and 16 hours later, 2 in4 hours, 1 in 5 hours, 2 in 7 hours, 1 in 12 hours, and 1 in 16 hours. Autopsiesperformed in two cases revealed nothing to explain the fatal outcome.
Two units of the lot of plasma used for these patients wereset aside for analysis, and, through a tragic error, one of them was given to acritically ill patient. An hour later, he developed a chill and complained ofextreme substernal oppression and dyspnea. When this patient, the only oneobserved 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 wasrapid and thready, and the lips and nails were cyanotic.
Artificial respiration was attempted but was unsatisfactorybecause 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 inphysiologic salt solution; and a transfusion of 500 cc. of type O blood. Duringthe transfusion, the patient became conscious, asked for food, and clinicallyseemed much improved. The pulse continued rapid but was of good volume. An hourlater, after an episode of extreme dyspnea, he was dead.
A tendency to react to infusions of plasma and to bloodtransfusions had been noted elsewhere in the Philippine Islands in patients withmarked malnutrition, and it was thought that these fatal reactions might be theresult of the serious hypoproteinemia then frequent among Filipinos. It wasconsidered imperative, however, to investigate and rule out the presence ofspecial toxic factors in this particular lot of plasma. A variety of steps weretaken to achieve this purpose, and to warn all hospitals in the SouthwestPacific Area of the possible risk of plasma infusions as evidenced by thesefatalities. They were instructed to use dried human plasma with extreme cautionin Filipinos and to substitute whole blood for it whenever possible.
Of the 39 units of plasma in this particular lot, only asingle sample was left. When it was tested at the National Institute of Healthon 28 April 1945 (37), the appearance of the package and that of itscontents were in accordance with specifications. All the tests performed inrespect to solubility, moisture, sterility, and safety were in conformity withthe minimum requirements. Pyrogen tests on rabbits, however, revealed that theproduct was definitely pyrogenic.
Investigation of the production of this particular lot ofplasma 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 usualmanner. At the end of 7 days, one of the bloods was found to be contaminated,but when the plasma was tested for
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sterility, it met the minimum standards requirement, andthere was no evidence of contamination when it was tested routinely at theNational Institute of Health.
It was considered surprising that such a slight contaminationas had occurred in this lot of plasma, 1 of 50 bloods, would have caused thefinished product to be pyrogenic, particularly since the processing laboratoryreported that the contaminating organism was identified as Staphylococcusalbus, 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 onthe 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 alllots that had produced reactions was not to be used until further notice.
Eleven installations, including clearing companies, medicalbattalions, and field, evacuation, and general hospitals reported no reactions (38).The remaining seven installations (one clearing station, one portablesurgical hospital, two field hospitals, two evacuation hospitals, and onegeneral hospital) reported a total of 54 reactions, the great majority of whichoccurred in Filipino patients with debilitating diseases. The products of sevendifferent laboratories were involved, but in only the single case just describedwas it possible to investigate the plasma responsible for the reaction.
Maj. John J. McGraw, Jr., MC, Special Representative onTransfusion in the Office of The Surgeon General, made the following comments onthe San Lazaro Hospital experience (39):
1. The type of reaction was very similar to that which occurswhen grossly contaminated plasma or blood is transfused.
2. Since the sample tested at the National Institute ofHealth was sterile, the possibility exists that the plasma became contaminatedwhen it was dissolved. Minor contamination not infrequently occurs as a resultof breaks in technique. If the plasma is used promptly, the contamination isusually of little significance. If the solution is allowed to stand for severalhours before use, bacteria may eventually be present in very large numbers.Heavily contaminated plasma can produce severe and even fatal reactions. Driedplasma should always be used within 3 hours of the time it is dissolved.
3. The debilitated condition of these special patientsundoubtedly made them less able to tolerate adverse reactions.
4. No particular significance was attached to urticarialreactions, 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 thatproduced urticarial reactions also produced chills and fever in some patients wasconsidered of more significance. Theoretically, plasma should never producechills and fever. On the other hand, even minor breaks in the technique of thepreparation of distilled water or of intravenous tubing can result in theformation of pyrogenic substances. It could not be determined whether the givingsets used at San Lazaro were prepared locally.
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5. It was recommended that any lot of plasma suspected ofproducing chills and fever should be used only in a general hospital, in whichits effects could be observed under controlled conditions. If it appeared to bepyrogenic, it should be destroyed. The Surgeon General should be notified if theplasma of any single commercial house seemed excessively pyrogenic. It wasneither desirable nor necessary to withdraw a lot of plasma and destroy itbecause urticaria followed the use of some units in it.
This is a logical, well-reasoned comment on an unfortunateepisode which undoubtedly occurred because of a break in technique somewherealong the line of production and administration.
HOMOLOGOUS SERUM JAUNDICE
General Considerations
In the light of the postwar incidence of homologous serumjaundice, it is important to make certain points clear about its wartimeoccurrence after plasma transfusion:
1. Although pooled plasma was used in enormous quantities inbattle casualties all during the war, the causative relation between the plasmaitself and the numerous instances of jaundice in military personnel after itsuse was not realized until late in 1944.
2. In retrospect, what happened is clear: When blood is notpooled, a single transfusion from a donor with serum hepatitis is unlikely tocause the disease in many recipients. When, however, blood is pooled, as it iswhen plasma is processed, the chances of contracting jaundice arecorrespondingly increased.5
3. Serum hepatitis was never a problem in Zone of Interiorhospitals, in which practically all of the plasma used was liquid and poolsprepared 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 ofjaundice and serum hepatitis was finally perfectly evident, but the war waspractically over before the causal sequence was widely appreciated.
5. The lack of realization of this relation is apparent inthe lack of action in the matter on the part of the Subcommittee on BloodSubstitutes, NRC (National Research Council), whose members were remarkablyalert to all developments in the field of blood and plasma transfusion. Jaundicewas discussed at a number of meetings in 1942 (31, 32), and 1943 (40),in connection with serum albumin, particularly in regard to the developmentof jaundice after immunization against yellow fever; each immunizing dosecontained 0.04 cc. of human serum, and attention was naturally directed to it asa possible
5Since serum hepatitis often appeared without clinicaljaundice, a number of observers expressed the opinion that the disease would bemore 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 onfoot, but, at this time, no one had observed, or heard of, jaundice after plasmatransfusion. As a precaution, however, the Red Cross Blood Donor Service beganto reject all donors with a history of jaundice within the previous 6 months.
6. The homologous serum jaundice that followed plasmatransfusion was, of course, entirely distinct from the widespread outbreak ofhepatitis in the Army in 1942, which, as just mentioned, was caused by anicterogenic agent in certain lots of yellow fever vaccine then in use (41). Itwas also not related to the hepatitis which occurred among troops in NorthAfrica in 1943 and at other times during the war.
Special Studies
During 1943 and 1944, a number of reports appeared in theAmerican literature concerning the development of hepatitis after theadministration of homologous blood products. The realization of thecause-and-effect relation and of the importance of this variety of hepatitis wasbrought home when concentrations of the disease began to appear in varioushospitals overseas (table 32) and in the Zone of Interior, and specialinvestigations 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 atthat. For a number of reasons, they could hardly be otherwise:
1. The clinical and histologic pictures in both homologousserum jaundice and infectious (epidemic) hepatitis are practically identical.
2. Proof that icterogenic agents existed in the plasmatransfusions that had been given was entirely lacking.
3. Very few patients with wounds of any consequence had notreceived plasma.
4. Further confusion in differential diagnosis was caused bythe fact that there was intimate contact between patients with serum hepatitisand those with epidemic hepatitis in hospitals along the line of evacuation, inships and planes, and in Zone of Interior hospitals.
5. A controlled investigation was impossible, for the variousreasons stated, and the premises on which most reports were based were extremelyunstable and tenuous.
Survey, 1 June 1945-As of 1 June 1945, a survey wasundertaken in all Army general hospitals in the Zone of Interior to identify allpatients with hepatitis, of any degree or associated with any other condition,under the direction of Maj. Philip E. Sartwell, MC (44). The form provided wasalso to be filled out for each death from hepatitis within the preceding 30days. The survey form (fig. 153) was made as simple as possible in view of theheavy load then being carried by all general hospitals in the United States.
At this time, about 85 percent of the general hospitalpopulation in the country consisted of casualties evacuated from overseas, 85percent of them because of battle wounds and the remainder because of otherinjuries 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 |
| Percentage developing- | ||||||||
Total | Developing | Developing other hepatitis1 | Infectious | Other hepatitis1 | ||||||
ETO | MTO | ETO | MTO | ETO | MTO | ETO | MTO | ETO | MTO | |
| Disease other than hepatitis2 |
| 14,146 | 12 | 28 | 9 | 20 | 0.05 | 0.20 | 0.04 | 0.10 |
| Nonbattle injuries:3 |
|
|
|
|
|
|
|
|
|
|
| 1,275 | 737 | 3 | 2 | --- | 2 | .24 | .27 | --- | .27 |
| 1,491 | 593 | 3 | 2 | --- | 1 | .20 | .34 | --- | .17 |
| 22,378 | 12,275 | 9 | 29 | 3 | 9 | .04 | .24 | .01 | .07 |
| 25,144 | 13,605 | 15 | 33 | 3 | 13 | 0.06 | 0.24 | 0.01 | 0.10 |
| Battle wounds:3 |
|
|
|
|
|
|
|
|
|
|
| 9,446 | 5,301 | 63 | 33 | 13 | 2 | 0.67 | 0.62 | 0.14 | 0.04 |
| 5,110 | 1,769 | 19 | 20 | 6 | 3 | .37 | 1.13 | .12 | .17 |
| 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 forpsychoneurosis and a 2-percent sample of all other disease admissions exclusiveof 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 ormore before being returned to the Zone of Interior. The majority of patientsadmitted to the general hospitals from other hospitals in the United States weresuffering from conditions that required specialized types of care not availableat station or regional hospitals.
The number of cases of hepatitis reported, 1,762, with 15fatalities, was much larger than had been anticipated (table 33). All 64 generalhospitals 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 reportinghospitals were special treatment centers. Of the patients, 87 had been prisonersof war. There was, however, a higher incidence in patients from theMediterranean theater than from the European theater.
For a variety of reasons, the data concerning previous plasmaand blood transfusions were not considered reliable. Plasma transfusions werechiefly given in forward areas, in which circumstances did not favor the keepingof 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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question about transfusion was limited to the 4 monthspreceding 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 warrantthe conclusion that a large proportion of patients hospitalized with hepatitison 1 June 1945 had contracted their disease because of the presence of anicterogenic agent in transfused blood or plasma. The conclusion naturally didnot warrant the inference that any of these transfusions were not indicated orthat too much blood or plasma was used. Saving the patient's life wasobviously more important than protecting him against the remote possibility ofhis contracting hepatitis.
Other special studies in general bore out the results of thissurvey. A planned study at McCloskey General Hospital, Temple, Tex. (45), forinstance, from 1 February to 30 April 1945, showed 57 cases of hepatitis in 935battle casualty admissions, 1 in 322 patients who had received no blood orplasma, and 51 in the 528 who had received either or both. There were 5 casesof hepatitis in the remaining 75 patients whose histories were too incomplete touse.
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TABLE 33.-Data obtained in survey ofhepatitis in Army general hospitals, Zone of Interior, 1 June 19451
Information obtained in survey |
| Transfused patients | ||
| Percent | Number | Percent | |
| Total cases reported (including deaths in preceding 30 days) | 1,762 | 100 | 500 | 100 |
| Initial cause of hospitalization: |
|
|
|
|
| 607 | 34 | 434 | 87 |
| 49 | 3 | 23 | 5 |
| 934 | 53 | --- | --- |
| 165 | 9 | 42 | 8 |
Classification of hepatitis: |
|
|
|
|
| 1,499 | 86 | 469 | 95 |
| 127 | 7 | 15 | 3 |
| 120 | 7 | 9 | 2 |
Areas of service: |
|
|
|
|
| 1,311 | 75 | 373 | 75 |
| 369 | 21 | 117 | 24 |
| 62 | 4 | 3 | 0.6 |
| 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 1,762or 500 respectively because the questionnaires were not always completely filledout. In such cases, the percentages computed are based on the total number ofcompleted 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 possibletransfer 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 entirelynegative previous history. On 8 May, he played a vigorous game of baseball andknocked a home run. On the next day, he acted as a donor, and, on 10 May, hisblood was given to a 19-year-old rifleman who had sustained a gunshot wound ofthe right lower abdomen on 25 April 1944.
On the next day, 11 May, the donor reported to sick call, andhe died on 14 May, of fulminating infectious hepatitis, confirmed by theclinical course, the laboratory findings, and the necropsy findings. There wasno doubt of the diagnosis, nor was there any doubt that this man had beenperfectly well up to, and including, the fifth day before his death, when hegave 500 cc. of blood.
As soon as it became known that the donor had hepatitis, therecipient was transferred to a special ward, where he was kept under closeobservation. He remained perfectly well, and all laboratory tests were negative,until 21 May, when he began to complain of lower abdominal pain and generalizeddiscomfort. The temperature was 99.4? F. On 23 May, a blood smear showed a fewof the abnormal toxic lymphocytes ordinarily seen in early infectious hepatitis.Thereafter, the clinical course, as well as the laboratory findings, wereentirely typical of infectious hepatitis, except that jaundice did not appearuntil 1 June.
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The patient was critically ill for the next several days,but, after 8 June, his condition gradually improved and he went on to anapparently normal recovery.
In this case, although the incubation period of 11 days isextremely short, and although the events may have been no more than acoincidence, it seems reasonable to assume that they represent a direct humantransfer of hepatitis from a donor with fulminating, fatal, infectious hepatitisto a recipient who was apparently recovering normally from a minor battle wound.
Preventive Measures
Since the virus of hepatitis could not be detected by thetechniques available in 1945, when its importance began to be realized, the onlymeans of preventing its transmission was a more rigid examination of blooddonors than had hitherto been required, including a detailed history; a physicalexamination, with special reference to the liver; and a battery of laboratorytests. 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 elaboraterequirements would uncover all cases of incipient jaundice and low-grade orlatent hepatitis (43).
There seemed, in short, no practical way of eliminating theasymptomatic blood donor who never developed jaundice. By inoculating humanvolunteers with icterogenic serum, Neefe and his associates (47) were able todemonstrate that, at least in some cases, a subclinical hepatitis precedes theonset of jaundice by a considerable period. Clinical confirmation of theseexperimental observations was obtained in two cases in which studies were done amonth before the onset of jaundice.
Capt. (later Maj.) Emanuel M. Rappaport, MC, in a specialstudy of asymptomatic donors (42), suggested routine serial studies ofliver function 8 weeks after transfusion, to uncover latent hepatitis whichwould otherwise escape detection. He had observed four such cases. Such aprogram was, of course, impractical at a time when all available laboratoryfacilities were taxed to capacity with more immediate problems, and was not verypractical 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 efficacyin this respect was verified by Havens and Paul (48). Since an intimaterelation had been demonstrated between the viruses of infectious and homologousserum hepatitis, it was logical to recommend that gamma globulin be given to allpatients who had received either blood or plasma and that it be givenimmediately after the transfusion, since the incubation period of hepatitisproduced by inoculation, while it might extend to 130 days or more, might alsobe only 30 days or even less.
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This recommendation was transmitted to the Surgeon, Mediterranean Theater ofOperations, 3 June 1945, by the Office of The Surgeon General. Therecommendation was duly complied with (49). The same instructions were given tomedical officers in the European theater in Circular Letter No. 53, Office ofthe 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. FredW. Rankin was not yet convinced that the relation between transfusion andhepatitis had been incontrovertibly established, nor was he convinced of thepreventive value of gamma globulin, but he was not opposed to its prophylacticuse. Brig. Gen. Hugh J. Morgan, Consultant in Medicine, Office of The SurgeonGeneral, was sufficiently impressed with the findings of Major Sartwell'ssurvey of hepatitis in Zone of Interior hospitals to believe that gamma globulinshould be administered routinely. All present agreed to recommend that allwounded patients who had been transfused and who were received in hospitals inthe United States between 21 and 120 days after wounding should routinelyreceive gamma globulin. The recommended dose was 10 cc.
This was the last official action in regard to posttransfusion hepatitis inWorld War II. The postwar problem is described elsewhere (p. 776).
References
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5. Seibert, F. B.: Fever-Producing Substance Found in Some Distilled Waters.Am. J. Physiol. 67: 90-104, December 1923.
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14. Report, Maj. Stewart C. Wagoner, MC, to Army Surgeon, Ninth U.S. Army, 12Feb. 1945, subject: Report of Transfusion Reactions.
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28. Report, 64th Portable Surgical Hospital, 2d quarter, 1945.
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37. Letter, Dr. M. V. Veldee to Maj. J. J. McGraw, Jr., MC, 28 Apr. 1945.
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40. Minutes, meeting of Subcommittee on Blood Substitutes, Division ofMedical Sciences, NRC, 24 Feb. 1943.
41. Walker, D. W.: Some Epidemiological Aspects of Infectious Hepatitis inthe 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 HepatitisFollowing Transfusions and the Role of Asymptomatic Donors in this Syndrome, n.d.
44. Sartwell, Maj. P. E., MC: Infectious Hepatitis in Relation to BloodTransfusion. Findings of a Survey Conducted in Army General Hospitals, n.d.
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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 ofInfectious 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 WithGamma Globulin. J.A.M.A. 129: 270-272, 22 Sept. 1945.
49. Memorandum, Col. Earl Standlee, MC, to The Surgeon General, U.S. Army, 22July 1945, subject: Hepatitis in Transfused Individuals.
50. Circular Letter No. 53, Office ofthe Chief Surgeon, Headquarters, European Theater of Operations, U.S. Army, 19June 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.
