Medical Science Publication No. 4, Volume 1
THE SAFETY OF BLOOD TRANSFUSION IN THE TREATMENT OF MASS CASUALTIES*
LIEUTENANT COLONELWILLIAM H. CROSBY, MC
In Korea, for the first time, the transfusion service in support ofa fighting army was able to provide ample amounts of fresh whole bloodwherever it was needed: in mobile surgical hospitals supporting the combatdivisions and even at battalion aid stations during periods of heavy action.Medical officers learned that large, rapid transfusions given early couldsave the lives of many of the most desperately wounded. But some observers,looking beyond these excellent results, expressed disquieting fears thatthe transfusion of such amounts of blood-especially stored blood-mightof itself be injurious. The U. S. Army Surgical Research Team installedat one of the forward hospitals undertook, among other problems, a studyof the effects of blood transfusions in battle casualties. They examinedthe problems of "overtransfusion," pigment metabolism, hemostasis,potassium and citrate intoxications and the relation of transfusion toacute renal insufficiency. Results of these studies are most reassuring.The quality of blood delivered to Korea was good, and transfusion as atherapeutic instrument was not abused. In fact it was found that the requirementsfor transfusion of the severely wounded were rather consistently, thoughnot seriously, underestimated. The fears regarding injury from transfusionproved, on the whole, to be groundless.
Even as vigilance is the price of freedom, so it is also the price ofa good transfusion service. Every transfusion involves certain dangers,and the vigilance of those who operate a transfusion service keeps thedanger to a minimum. This is difficult enough when a single hospital encompassesthe transfusion service, but difficulties multiply when the service isspread throughout a theater of war. The agency supplying the combat zonehas a responsibility to provide blood that is:
1. Adequate in quantity and delivered frequently.
2. As fresh as possible.
3. As well preserved as possible.
4. As safe as possible.
*Presented 20 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington, D. C.
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We shall consider only the last part of this problem, the safety ofthe blood as it is provided and also as it is used.
Universal Donor Blood. In the Korean experience incompatibletransfusion reactions were almost completely obviated by the decision touse only group O, Universal Donor Blood. Thus, one type of blood was givento all recipients irrespective of their individual blood groups. The planhas much to commend it.
1. Transfusions may be started without waiting for cross-matching.
2. Skilled personnel for cross-matching are not needed.
3. An adequate blood bank can be maintained with fewer units of bloodthan are required when all types of blood must be provided.
4. Small stocks of blood may be established and used in remote aid stations.
5. The Army in the field is relieved of the responsibility of assuringthe compatibility between donor and recipient.
The value of Universal Donor Blood resides in the fact that its redcells possess no antigens that may be attacked by the spontaneously occurringantibodies of the ABO blood group system. There is no incompatibility directedat the donor red cells (figs. 1A and B). The donor plasma, however, containsanti-A and anti-B antibodies. These are incompatible with the red cellsof A or B recipients but usually do no damage because they are rapidlydispersed, diluted and neutralized during the course of the transfusion.Even so, the indiscriminate use of Universal Donor Blood is unsafe becausea few of these donors possess antibodies of high titer or great virulenceso that transfusion of their plasma may provoke a severe hemolyticreaction in a recipient of group A, B, or AB (fig. 1C). (The group O recipientis safe because there is no incompatibility.) It is necessary to eliminatethe "dangerous universal donors" from the panel of a transfusionservice that depends on Universal Donor Blood. The meticulous laboratorycontrol of the transfusion service that supported the Korean war was carriedout at Travis Air Force Base, California, and at the 406 Medical GeneralLaboratory in Tokyo where the blood collected in the United States andJapan was processed. It cannot be overemphasized that under this systemthe prevention of incompatible transfusion reactions in the combat zonerests entirely upon the laboratory control at the blood donor centers.To prevent such reactions two tests were essential :
1. Verification of blood group to be certain that no weakly-reactingbloods of group A or B had mistakenly been labeled group O.
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FIGURE1. Solid arrow indicatesan incompatibility between plasma and red cells tht can cause a severetransfusion reaction. Dotted arrow indicates an incompatibility of no clinicalsignificance. UDB stands for Universal Donor Blood.
2. Establishment of the titer of anti-A and anti-B antibodies in theplasma of each unit of blood to eliminate dangerous universal donors.
The second was accomplished by a screening test of the agglutinatingantibodies. Serum was diluted with saline 1: 200 or
1: 250, and a mixture of A and B red cells was suspended in it. If agglutinationoccurred, the blood was labeled HIGH TITER. Where no agglutination occurred,the blood was considered to be low titer and safe Universal Donor Blood.
About 15 percent of the blood sent to Korea was high titer. It was plainlymarked as such with an additional admonition "To be used only in groupO recipients." Much of this blood was not used and became outdated.The medical officers suspected that it was dangerous, or somehow off color,and refused to accept it, even for group O recipients. Although their reasonsfor this were more intuitive than rational, they were right to refuse.The blood group that is
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stamped on a soldier's dogtag is incorrect in 15 percent of the cases.If a group A man, improperly identified as group O, were transfused withhigh-titer blood he might possibly have a severe transfusion reaction dueto the incompatibility of the plasma (fig. 1C). Before the war came toa close it had been recommended that only low-titer group O blood be providedfor the combat zone.
Parenthetical to this discussion, it should be pointed out that we needa better test to identify dangerous universal donors. By the present standardsonly 55 to 65 percent of group O donors can be classified as low titer.The others are not all "dangerous" yet the test is intended toeliminate only those who are. It errs on the side of caution. Several typesof antibodies are involved in incompatible transfusion reactions: agglutinins,hemolysins, incomplete antibodies and perhaps others. Blood is classifiedas high titer or low on the basis of an agglutination test because, ofthe several sorts of antibodies, the agglutinin is easiest to demonstrate.However, the agglutinin itself is not the dangerous antibody. Hemolysinsand incomplete antibodies are believed to be the ones that cause reactions.The agglutinin test eliminates dangerous donors because a high titer ofhemolysin is usually associated with a high titer of agglutinin. The lackof selectivity of this procedure wastefully restricts the panel of universaldonors. For this reason, it is important to characterize the dangerousuniversal donor more completely and then to devise a precise test to identifyhim.
The Surgical Research Team found that even low-titer Universal DonorBlood, when used in large amounts, is not without some effect upon thered cells of the recipient. A group A patient who received 15 or 20 pintsof group O blood would be found immediately after the transfusion to haveabout 70 percent of his native red cells replaced by donor cells. (Thiswas demonstrated by using anti-A typing serum to agglutinate the groupA cells. The group O donor cells remain unagglutinated and can be countedin the usual manner.) Subsequently the proportion of donor cells wouldincrease without any further transfusion. This meant that the native groupA red cells were being eliminated. Sometimes all of them disappeared, sothat a patient of group A would be found to have practically 100 percentof group O cells in his blood. The selective loss of his own cells afterbleeding and transfusion had ceased was undoubtedly due to the activityof the anti-A antibodies in the plasma of the donor blood. It is emphasizedthat the hemolysis was a gradual process. It was not associated with anabrupt, shocking reaction of the sort encountered after incompatible transfusions.Clinically one could not tell that a hemolytic process was at work, andthe patients suffered no obvious harm.
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In some men who received large transfusions of Universal Donor Bloodit was possible to demonstrate the persistence in their plasma of incompatibleantibodies that had been tranfused into them. For example, a patient ofgroup A might be found to have anti-A agglutinins in his blood. Althoughthis situation-as pointed out above-was of little clinical detriment, itwas recognized to be a source of potential danger to the patient. Medicalofficers at forward hospitals in Korea sometimes deemed it desirable toprovide fresh blood for men who had received large amounts of bank blood,and in ordering such transfusions they often asked that group-specificblood be obtained. The laboratory technician was then confronted with theproblem of determining the blood group of a patient whose blood containedtwo sorts of red cells: the group O universal donor cells and those ofhis hereditary group. Sometimes there were so few of his own that the typingserum would produce only a few pinpoints of agglutination, a difficultresult to interpret. The cross-match was equally difficult when the presenceof "foreign" antibodies would cause agglutination of blood cellsof the patient's own group. This indicated that the patient could no longerbe safely transfused with blood of his hereditary group. The passivelyacquired antibodies were incompatible with his own blood group. Supposenow the technician after testing 20 donors, decides that several of thecross-matchings looked less incompatible than the others and releases thoseunits of blood for transfusion. An incompatible transfusion reaction mightresult (fig. 1D).
The same accident may happen in a more subtle way. For example, a severelywounded man was admitted to a surgical hospital. It was apparent that hewould require many units of blood during the period of resuscitation andsurgery. It was decided to use, in part, fresh, group-specific blood, andblood for cross-matching was taken from the patient. Donors were calledfrom nearby troop units. Six of them were cross-matched against the patientand were bled. This required several hours to complete. Meanwhile the patienthad received 18 pints of Universal Donor Blood. When the fresh blood wasbegun the patient went into shock and his plasma was found to be staineddark red with hemoglobin, the obvious signs of an incompatible transfusionreaction. Unfortunately, the patient's red plasma was not examined forthe antibodies that might have caused the reaction.
Because of this danger, the Department of the Army has issued a transfusionprecaution: "The use of group-specific blood may be dangerous followinglarge transfusions of group O, Universal Donor Blood, causing severe hemolyticreactions. In any instance where multiple transfusions have been made withgroup O blood, subsequent
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transfusions given within a period of 2 weeks following the initialtransfusion will be with group O blood."
Rh-positive blood was the only type used in Korea. As a consequenceof this, about half of the Rh-negative patients who received transfusionsdeveloped anti-Rh (anti-D) antibodies. The use of Rh-positive blood inRh-negative recipients involves no threat of an incompatible transfusionreaction unless the recipient has been immunized against the Rh antigenprior to the transfusion. Such immunization requires preliminary transfusionor pregnancy both of which are unlikely in a population composed almostentirely of healthy young males. Where civilian populations are involvedthe problem is more difficult. While it is not desirable to immunize againstthe Rh antigen any women with child-bearing potential, still one is leftno choice when he must decide between immunization and the saving of life.The case of mass casualties inevitably requires some compromises and decisionsare often dictated by expediency. A woman should not be perinitted to diewhile her blood is typed and crossmatched.
The establishment of a blood donor service in the Korean combat zonewas suggested from time to time during the war. This was not undertakenfor several reasons:
1. An Army in the field should not be required, except under extremeconditions, to provide its own supplies.
2. It is difficult in the field to maintain the standards of sterility,technical excellence and detachment that are the minimal requirements ofsuch a service.
3. The service would be vulnerable to enemy action. A blood depot canbe re-established in a few hours by bringing up more blood but a blooddonor service with its essential laboratory and skilled technicians cannot be quickly or easily replaced.
It was mentioned previously that a small quantity of blood had beenobtained locally in Korea from our own troops and was used in the Armysurgical hospitals. It is believed that most of the incompatible transfusionreactions that occurred were a result of the use of this sort of blood.In 1952 only four patients were admitted to the Renal Treatment Centerin Wonju with a history or evidence of post-transfusion hemoglobinuriaand renal insufficiency. In all four patients the reaction had been associatedwith the administration of blood procured locally. The laboratory of amobile hospital is not intended and is not equipped to operate a bloodprocurement service and the technicians are not trained well enough tobe relied upon. The danger outweighs any value that fresh blood may haveover stored
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blood. Excepting emergencies, the local procurement of blood in thecombat zone is not recommended.
The use of cadaver blood was considered but not investigated.This source of blood is unattractive for more reasons than an estheticone.
1. The killed in action are usually widely dispersed and priority ofrecovery must be given to the living wounded.
2. Most of those killed in action die as a result of cutting a majorblood vessel, hence much of the blood could not be recovered.
3. Bacterial contamination of blood remaining in the body after deathfrom gunshot wounds would be a hazard.
4. The objections, outlined above, to the local procurement of bloodin the combat zone apply with equal force here.
Recognition of transfusion reactions is a problem that troublesevery good transfusion service. The clinician who administers the bloodis not always discriminating. Sometimes he fails to report reactions andsometimes he assumes that any coincidental fever or chill is due to thetransfusion. Without a careful examination of each case suspected of areaction, even an expert can be wrong. One visitor to the hospitals inKorea reported that the rate of transfusion reactions was probably highbecause patients receiving transfusions were observed to shiver and somepatients after transfusion passed dark urine. The Surgical Research Teamformed a different opinion. They examined the blood of such patients andfound no evidence of transfusion reactions. It should be noted that shiveringmay be due to cold and that severely wounded patients were rapidly transfusedwith ice-cold blood. Shivering can also be due to bacteremia, a conditionthat is not unexpected in casualties with extensive, heavily contaminatedwounds. Dark urine is also to be expected in patients with severe musclewounds. The pigment that appears in the urine of these patients is myoglobin,not hemoglobin.
On the basis of the observations of the Surgical Research Team it isconcluded that the incidence of incompatible transfusion reactions in Koreawas exceptionally low. The statistics of the Renal Treatment Center supportthis. Over 50,000 transfusions were given in Korea in 1952. In that year,as mentioned before, only four patients were admitted to the Center withacute renal insufficiency due to an incompatible transfusion. There probablywere more than four reactions: some died and some recovered without goingto Wonju. Inquiries found few of them.
Although the rate of incompatible transfusion reactions was low, thereare no accurate figures on the subject. This should not happen again. Itis important to have a continual examination of the problem. The carefulstudy of each reaction provides information that is needed to prevent subsequentreactions. Even the meager informa-
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tion provided by the statistics of the Renal Treatment Center suggestedthat most, if not all reactions in Korea, were a result of using locallyprocured blood. To the end of obtaining this essential information tworecommendations are made:
1. The personnel who administer transfusions should be well trainedto recognize reactions and should know what records to take and what specimensto collect so that the cause of the reaction can be identified.
2. There should be quickly available in the combat zone an expert whocan interpret the evidence and identify the cause of the reaction.
Transfusion reactions due to bacterial contamination of stored bloodare rare but when they occur they are usually fatal. In most transfusionservices in the United States there is no provision for culturing bloodthat is assumed to be sterile. In a few centers where carefully controlledstudies of the problem have been made it has been found that about 3 percentof the units of blood collected under vacuum into glass equipment werecontaminated. When blood was collected into plastic equipment, with thedonor tube fused to the bag (fig. 2), the rate of contamination was 0.6percent. These studies were based upon cultures incubated at warm temperatures,and most warm-growing organisms do not grow in the cold. On the other hand,certain cold-growing bacilli do not proliferate in warm cultures althoughthey multiply freely at refrigerator temperatures.
Bacterial contamination does not appear to be an important problem inthe United States. In most transfusion services, blood is turned over rapidly,much of it remaining in storage less than 5 days. This reduces the opportunityfor bacteria to increase to dangerous numbers. Blood used in the combatzone has been stored longer, and the danger is therefore somewhat greater.With the development of methods to extend further the storage period ofbank blood the problem of bacterial contamination may become more serious.Although, in the Korean experience there were no known instances of "transfusioncatastrophe" due to bacterially contaminated blood, they may haveoccurred without being recognized. Under the circumstances, the basis ofsuch reactions would have been difficult if not impossible to prove. Nevertheless,the problem confronts us, and it is one of the most compelling reasonsfor adoption of plastic blood-collecting equipment. The plastic bag shouldhave the donor set fused to it as an integral part to eliminate the mostlikely cause of contamination, the trapping of bacterially contaminatedair. This type of blood bag permits still another safeguard against thetransfusion of contaminated blood. After phlebotomy, the plastic donortube, sealed at its distal end, remains attached to the blood bag. Beforethe unit is
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FIGURE 2. PlasticBlood Collection Container with Integral Donor Set.
After the bag is filled with blood one knot is set inthe tube (A) and the blood between the knot and the bag is stripped intothe bag. Blood distal to the knot can be used for typing. When it is desiredto test for bacterial contamination the blood that refluxed to the tubeis again stripped into the bag. After the tube has refilled itself, a secondknot is set at B. With aseptic care the tube is cut between A and B. Theblood obtained can be cultured or otherwise examined for contamination.
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used the blood in the tube is milked into the bag and the tube is permittedto refill. Another seal is made in the tube, closer to the bag. The tubeis then cut between the two seals and a smear of the blood is stained andexamined for bacteria (fig. 2).
Plastic transfusion equipment obviates another source of danger. Rapidtransfusion was often necessary to save the lives of severely exsanguinatedmen. It was the custom in Korea to pump air into the transfusion bottle.The danger, of course, was that of air embolism and to prevent this a technicianwas detailed to the job of watching the pressure transfusion. When plasticequipment is used pressure is applied not by inflation but by squeezingthe collapsible bag.
The adoption of plastic equipment has already been recommended by thethree Armed Services and it should become standard within a year. If amongits other attributes of less weight, less volume and less breakage, theuse of plastic can permit blood to be dropped from aircraft, our transfusionservice will become even more flexible.
The use of old blood was once suspected to be a serious fault of thetransfusion service in Korea. The blood received at the forward hospitalswas 8 to 10 days old and most of it was 10 to 15 days old before it wasused. Fears were expressed that the blood might have been injured by itslong journey across the Pacific during which the refrigeration could havebeen interrupted. The blood arriving at the forward hospitals was suspectedof containing a high proportion of nonviable red cells, cells that couldlive in the circulation less than 24 hours. It was suggested that the destructionof these red cells in patients who received large transfusions would producehemoglobinemia intense enough to damage their kidneys. The work of theSurgical Research Team demonstrated that the blood arriving at the forwardhospitals was well preserved (fig. 3), that refrigeration had been wellmaintained and that the proportion of nonviable red cells was probablynot much greater than it is in blood stored for similar periods in theUnited States. The destruction of these nonviable red cells by the recipientwas not associated with significant levels of hemoglobinemia (fig. 4).The cells were lost from the circulation within 24 hours, but the evidenceindicates that most of them did not release their hemoglobin into the plasmaand their destruction did not throw an excretory burden upon the kidneysof the patient.
Far from being injurious, it seems that "outdated" blood couldbe of value as a plasma substitute. Hemoglobin comprises 80 percent ofthe protein of whole blood but it cannot be given as a concentrated solutionbecause of its dangerous vasorenal effects. Given as old blood the hemoglobinis not released to the plasma as such. The patient may receive the bloodas an antidote for shock, and even though a high proportion of the cellsdid not survive for many hours, their protein,
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PLASMA HEMOGLOBIN IN BANK BLOOD
FIGURE3. The concentration of hemoglobinin the plasma of bank blood is a good index of the care it has received.The values indicated above are agreeably low. Even at 20 days a plasmahemoglobin concentration of 70 mg. per 100 ml. represents the loss of only0.5 percent of the total red cells in the bottle.
SIZE OF TRANSFUSION (UNITS)
FIGURE4. Patient's plasma hemoglobin after transfusionwith stored blood. Even large transfusions of relatively blood did notcause hemoglobinuria of a degree apt to be detrimental.
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when they are destroyed, becomes available to the patient. There seemsgood reason to suggest that outdated blood may be useful for treatmentof the moderately wounded who require less thall 5 units of blood.
Summary
1. The decisions to use Universal Donor Blood in the combat zone inKorea obviated incompatible transfusion reactions. This practice in thehandling of mass casualties permits transfusion to begin without delayfor cross-matching, and it places the responsibility for compatibilityof the trausfusion upon the supplying agency in the rear rather than uponthose who use the blood under adverse conditions. The few incompatiblereactions that occurred in Korea were usually due to blood that had beenprocured locally in the combat zone.
2. It was found that massive transfusions of Universal Donor Blood inrecipients of other groups sometimes resulted in an accumulation of transfusedantibodies that were active against red cells of the recipient. This madeit unsafe to transfuse the patient with blood of his own hereditary groupwhen subsequent transfusions were required. The foreign antibodies requiredas long as 2 weeks to disappear.
3. The problem of bacterial contamination of stored blood did not appearto be the cause of reactions, but the matter deserves study as to how bestto prevent or control it. The use of plastic bags is expected to improvethis situation.
4. The use of old blood, even in large amounts rapidly given, causedlittle if any damage that could be attributed to the age of the blood.Declaring stored blood to be outdated after 21 days seems a reasonableprecaution, but it is suggested that well refrigerated blood up to 60 daysof age may be employed as a "plasma substitute" in the less severelywounded.
