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The Safety of Blood Transfusion in the Treatment of Mass Casualties

Medical Science Publication No. 4, Volume 1

THE SAFETY OF BLOOD TRANSFUSION IN THE TREATMENT OF MASS CASUALTIES*

LIEUTENANT COLONEL WILLIAM H. CROSBY, MC

In Korea, for the first time, the transfusion service in support of a fighting army was able to provide ample amounts of fresh whole blood wherever it was needed: in mobile surgical hospitals supporting the combat divisions and even at battalion aid stations during periods of heavy action. Medical officers learned that large, rapid transfusions given early could save the lives of many of the most desperately wounded. But some observers, looking beyond these excellent results, expressed disquieting fears that the transfusion of such amounts of blood-especially stored blood-might of itself be injurious. The U. S. Army Surgical Research Team installed at one of the forward hospitals undertook, among other problems, a study of the effects of blood transfusions in battle casualties. They examined the problems of "overtransfusion," pigment metabolism, hemostasis, potassium and citrate intoxications and the relation of transfusion to acute renal insufficiency. Results of these studies are most reassuring. The quality of blood delivered to Korea was good, and transfusion as a therapeutic instrument was not abused. In fact it was found that the requirements for transfusion of the severely wounded were rather consistently, though not seriously, underestimated. The fears regarding injury from transfusion proved, on the whole, to be groundless.

Even as vigilance is the price of freedom, so it is also the price of a good transfusion service. Every transfusion involves certain dangers, and the vigilance of those who operate a transfusion service keeps the danger to a minimum. This is difficult enough when a single hospital encompasses the transfusion service, but difficulties multiply when the service is spread throughout a theater of war. The agency supplying the combat zone has 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 of the blood as it is provided and also as it is used.

Universal Donor Blood. In the Korean experience incompatible transfusion reactions were almost completely obviated by the decision to use only group O, Universal Donor Blood. Thus, one type of blood was given to all recipients irrespective of their individual blood groups. The plan has 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 blood than 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 assuring the compatibility between donor and recipient.

The value of Universal Donor Blood resides in the fact that its red cells possess no antigens that may be attacked by the spontaneously occurring antibodies of the ABO blood group system. There is no incompatibility directed at the donor red cells (figs. 1A and B). The donor plasma, however, contains anti-A and anti-B antibodies. These are incompatible with the red cells of A or B recipients but usually do no damage because they are rapidly dispersed, diluted and neutralized during the course of the transfusion. Even so, the indiscriminate use of Universal Donor Blood is unsafe because a few of these donors possess antibodies of high titer or great virulence so that transfusion of their plasma may provoke a severe hemolytic reaction in a recipient of group A, B, or AB (fig. 1C). (The group O recipient is safe because there is no incompatibility.) It is necessary to eliminate the "dangerous universal donors" from the panel of a transfusion service that depends on Universal Donor Blood. The meticulous laboratory control of the transfusion service that supported the Korean war was carried out at Travis Air Force Base, California, and at the 406 Medical General Laboratory in Tokyo where the blood collected in the United States and Japan was processed. It cannot be overemphasized that under this system the prevention of incompatible transfusion reactions in the combat zone rests 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-reacting bloods of group A or B had mistakenly been labeled group O.


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FIGURE 1. Solid arrow indicates an incompatibility between plasma and red cells tht can cause a severe transfusion reaction. Dotted arrow indicates an incompatibility of no clinical significance. UDB stands for Universal Donor Blood.

    2. Establishment of the titer of anti-A and anti-B antibodies in the plasma of each unit of blood to eliminate dangerous universal donors.

The second was accomplished by a screening test of the agglutinating antibodies. Serum was diluted with saline 1: 200 or
1: 250, and a mixture of A and B red cells was suspended in it. If agglutination occurred, 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 plainly marked as such with an additional admonition "To be used only in group O 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 reasons for 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 with high-titer blood he might possibly have a severe transfusion reaction due to the incompatibility of the plasma (fig. 1C). Before the war came to a close it had been recommended that only low-titer group O blood be provided for the combat zone.

Parenthetical to this discussion, it should be pointed out that we need a better test to identify dangerous universal donors. By the present standards only 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 to eliminate only those who are. It errs on the side of caution. Several types of antibodies are involved in incompatible transfusion reactions: agglutinins, hemolysins, incomplete antibodies and perhaps others. Blood is classified as high titer or low on the basis of an agglutination test because, of the several sorts of antibodies, the agglutinin is easiest to demonstrate. However, the agglutinin itself is not the dangerous antibody. Hemolysins and incomplete antibodies are believed to be the ones that cause reactions. The agglutinin test eliminates dangerous donors because a high titer of hemolysin is usually associated with a high titer of agglutinin. The lack of selectivity of this procedure wastefully restricts the panel of universal donors. For this reason, it is important to characterize the dangerous universal donor more completely and then to devise a precise test to identify him.

The Surgical Research Team found that even low-titer Universal Donor Blood, when used in large amounts, is not without some effect upon the red cells of the recipient. A group A patient who received 15 or 20 pints of group O blood would be found immediately after the transfusion to have about 70 percent of his native red cells replaced by donor cells. (This was demonstrated by using anti-A typing serum to agglutinate the group A cells. The group O donor cells remain unagglutinated and can be counted in the usual manner.) Subsequently the proportion of donor cells would increase without any further transfusion. This meant that the native group A red cells were being eliminated. Sometimes all of them disappeared, so that a patient of group A would be found to have practically 100 percent of group O cells in his blood. The selective loss of his own cells after bleeding and transfusion had ceased was undoubtedly due to the activity of the anti-A antibodies in the plasma of the donor blood. It is emphasized that the hemolysis was a gradual process. It was not associated with an abrupt, shocking reaction of the sort encountered after incompatible transfusions. Clinically one could not tell that a hemolytic process was at work, and the patients suffered no obvious harm.


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In some men who received large transfusions of Universal Donor Blood it was possible to demonstrate the persistence in their plasma of incompatible antibodies that had been tranfused into them. For example, a patient of group A might be found to have anti-A agglutinins in his blood. Although this situation-as pointed out above-was of little clinical detriment, it was recognized to be a source of potential danger to the patient. Medical officers at forward hospitals in Korea sometimes deemed it desirable to provide fresh blood for men who had received large amounts of bank blood, and in ordering such transfusions they often asked that group-specific blood be obtained. The laboratory technician was then confronted with the problem of determining the blood group of a patient whose blood contained two sorts of red cells: the group O universal donor cells and those of his hereditary group. Sometimes there were so few of his own that the typing serum would produce only a few pinpoints of agglutination, a difficult result to interpret. The cross-match was equally difficult when the presence of "foreign" antibodies would cause agglutination of blood cells of the patient's own group. This indicated that the patient could no longer be safely transfused with blood of his hereditary group. The passively acquired antibodies were incompatible with his own blood group. Suppose now the technician after testing 20 donors, decides that several of the cross-matchings looked less incompatible than the others and releases those units of blood for transfusion. An incompatible transfusion reaction might result (fig. 1D).

The same accident may happen in a more subtle way. For example, a severely wounded man was admitted to a surgical hospital. It was apparent that he would require many units of blood during the period of resuscitation and surgery. It was decided to use, in part, fresh, group-specific blood, and blood for cross-matching was taken from the patient. Donors were called from nearby troop units. Six of them were cross-matched against the patient and were bled. This required several hours to complete. Meanwhile the patient had received 18 pints of Universal Donor Blood. When the fresh blood was begun the patient went into shock and his plasma was found to be stained dark red with hemoglobin, the obvious signs of an incompatible transfusion reaction. Unfortunately, the patient's red plasma was not examined for the antibodies that might have caused the reaction.

Because of this danger, the Department of the Army has issued a transfusion precaution: "The use of group-specific blood may be dangerous following large transfusions of group O, Universal Donor Blood, causing severe hemolytic reactions. In any instance where multiple transfusions have been made with group O blood, subsequent


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transfusions given within a period of 2 weeks following the initial transfusion will be with group O blood."

Rh-positive blood was the only type used in Korea. As a consequence of this, about half of the Rh-negative patients who received transfusions developed anti-Rh (anti-D) antibodies. The use of Rh-positive blood in Rh-negative recipients involves no threat of an incompatible transfusion reaction unless the recipient has been immunized against the Rh antigen prior to the transfusion. Such immunization requires preliminary transfusion or pregnancy both of which are unlikely in a population composed almost entirely of healthy young males. Where civilian populations are involved the problem is more difficult. While it is not desirable to immunize against the Rh antigen any women with child-bearing potential, still one is left no choice when he must decide between immunization and the saving of life. The case of mass casualties inevitably requires some compromises and decisions are often dictated by expediency. A woman should not be perinitted to die while her blood is typed and crossmatched.

The establishment of a blood donor service in the Korean combat zone was suggested from time to time during the war. This was not undertaken for several reasons:

    1. An Army in the field should not be required, except under extreme conditions, 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 of such a service.

    3. The service would be vulnerable to enemy action. A blood depot can be re-established in a few hours by bringing up more blood but a blood donor service with its essential laboratory and skilled technicians can not be quickly or easily replaced.

It was mentioned previously that a small quantity of blood had been obtained locally in Korea from our own troops and was used in the Army surgical hospitals. It is believed that most of the incompatible transfusion reactions that occurred were a result of the use of this sort of blood. In 1952 only four patients were admitted to the Renal Treatment Center in Wonju with a history or evidence of post-transfusion hemoglobinuria and renal insufficiency. In all four patients the reaction had been associated with the administration of blood procured locally. The laboratory of a mobile hospital is not intended and is not equipped to operate a blood procurement service and the technicians are not trained well enough to be relied upon. The danger outweighs any value that fresh blood may have over stored


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blood. Excepting emergencies, the local procurement of blood in the combat 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 esthetic one.

    1. The killed in action are usually widely dispersed and priority of recovery must be given to the living wounded.

    2. Most of those killed in action die as a result of cutting a major blood vessel, hence much of the blood could not be recovered.

    3. Bacterial contamination of blood remaining in the body after death from gunshot wounds would be a hazard.

    4. The objections, outlined above, to the local procurement of blood in the combat zone apply with equal force here.

Recognition of transfusion reactions is a problem that troubles every good transfusion service. The clinician who administers the blood is not always discriminating. Sometimes he fails to report reactions and sometimes he assumes that any coincidental fever or chill is due to the transfusion. Without a careful examination of each case suspected of a reaction, even an expert can be wrong. One visitor to the hospitals in Korea reported that the rate of transfusion reactions was probably high because patients receiving transfusions were observed to shiver and some patients after transfusion passed dark urine. The Surgical Research Team formed a different opinion. They examined the blood of such patients and found no evidence of transfusion reactions. It should be noted that shivering may be due to cold and that severely wounded patients were rapidly transfused with ice-cold blood. Shivering can also be due to bacteremia, a condition that is not unexpected in casualties with extensive, heavily contaminated wounds. Dark urine is also to be expected in patients with severe muscle wounds. 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 is concluded that the incidence of incompatible transfusion reactions in Korea was exceptionally low. The statistics of the Renal Treatment Center support this. Over 50,000 transfusions were given in Korea in 1952. In that year, as mentioned before, only four patients were admitted to the Center with acute renal insufficiency due to an incompatible transfusion. There probably were more than four reactions: some died and some recovered without going to Wonju. Inquiries found few of them.

Although the rate of incompatible transfusion reactions was low, there are no accurate figures on the subject. This should not happen again. It is important to have a continual examination of the problem. The careful study of each reaction provides information that is needed to prevent subsequent reactions. Even the meager informa-


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tion provided by the statistics of the Renal Treatment Center suggested that most, if not all reactions in Korea, were a result of using locally procured blood. To the end of obtaining this essential information two recommendations are made:

    1. The personnel who administer transfusions should be well trained to recognize reactions and should know what records to take and what specimens to collect so that the cause of the reaction can be identified.

    2. There should be quickly available in the combat zone an expert who can interpret the evidence and identify the cause of the reaction.

Transfusion reactions due to bacterial contamination of stored blood are rare but when they occur they are usually fatal. In most transfusion services in the United States there is no provision for culturing blood that is assumed to be sterile. In a few centers where carefully controlled studies of the problem have been made it has been found that about 3 percent of the units of blood collected under vacuum into glass equipment were contaminated. When blood was collected into plastic equipment, with the donor tube fused to the bag (fig. 2), the rate of contamination was 0.6 percent. 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 although they multiply freely at refrigerator temperatures.

Bacterial contamination does not appear to be an important problem in the United States. In most transfusion services, blood is turned over rapidly, much of it remaining in storage less than 5 days. This reduces the opportunity for bacteria to increase to dangerous numbers. Blood used in the combat zone has been stored longer, and the danger is therefore somewhat greater. With the development of methods to extend further the storage period of bank blood the problem of bacterial contamination may become more serious. Although, in the Korean experience there were no known instances of "transfusion catastrophe" due to bacterially contaminated blood, they may have occurred without being recognized. Under the circumstances, the basis of such reactions would have been difficult if not impossible to prove. Nevertheless, the problem confronts us, and it is one of the most compelling reasons for adoption of plastic blood-collecting equipment. The plastic bag should have the donor set fused to it as an integral part to eliminate the most likely cause of contamination, the trapping of bacterially contaminated air. This type of blood bag permits still another safeguard against the transfusion of contaminated blood. After phlebotomy, the plastic donor tube, sealed at its distal end, remains attached to the blood bag. Before the unit is


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FIGURE 2. Plastic Blood Collection Container with Integral Donor Set.

After the bag is filled with blood one knot is set in the tube (A) and the blood between the knot and the bag is stripped into the bag. Blood distal to the knot can be used for typing. When it is desired to test for bacterial contamination the blood that refluxed to the tube is again stripped into the bag. After the tube has refilled itself, a second knot is set at B. With aseptic care the tube is cut between A and B. The blood 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 permitted to refill. Another seal is made in the tube, closer to the bag. The tube is then cut between the two seals and a smear of the blood is stained and examined for bacteria (fig. 2).

Plastic transfusion equipment obviates another source of danger. Rapid transfusion was often necessary to save the lives of severely exsanguinated men. 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 technician was detailed to the job of watching the pressure transfusion. When plastic equipment is used pressure is applied not by inflation but by squeezing the collapsible bag.

The adoption of plastic equipment has already been recommended by the three Armed Services and it should become standard within a year. If among its other attributes of less weight, less volume and less breakage, the use of plastic can permit blood to be dropped from aircraft, our transfusion service will become even more flexible.

The use of old blood was once suspected to be a serious fault of the transfusion service in Korea. The blood received at the forward hospitals was 8 to 10 days old and most of it was 10 to 15 days old before it was used. Fears were expressed that the blood might have been injured by its long journey across the Pacific during which the refrigeration could have been interrupted. The blood arriving at the forward hospitals was suspected of containing a high proportion of nonviable red cells, cells that could live in the circulation less than 24 hours. It was suggested that the destruction of these red cells in patients who received large transfusions would produce hemoglobinemia intense enough to damage their kidneys. The work of the Surgical Research Team demonstrated that the blood arriving at the forward hospitals was well preserved (fig. 3), that refrigeration had been well maintained and that the proportion of nonviable red cells was probably not much greater than it is in blood stored for similar periods in the United States. The destruction of these nonviable red cells by the recipient was not associated with significant levels of hemoglobinemia (fig. 4). The cells were lost from the circulation within 24 hours, but the evidence indicates that most of them did not release their hemoglobin into the plasma and their destruction did not throw an excretory burden upon the kidneys of the patient.

Far from being injurious, it seems that "outdated" blood could be of value as a plasma substitute. Hemoglobin comprises 80 percent of the protein of whole blood but it cannot be given as a concentrated solution because of its dangerous vasorenal effects. Given as old blood the hemoglobin is not released to the plasma as such. The patient may receive the blood as an antidote for shock, and even though a high proportion of the cells did not survive for many hours, their protein,


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PLASMA HEMOGLOBIN IN BANK BLOOD

FIGURE 3. The concentration of hemoglobin in 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 plasma hemoglobin concentration of 70 mg. per 100 ml. represents the loss of only 0.5 percent of the total red cells in the bottle.

SIZE OF TRANSFUSION (UNITS)

FIGURE 4. Patient's plasma hemoglobin after transfusion with stored blood. Even large transfusions of relatively blood did not cause hemoglobinuria of a degree apt to be detrimental.


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when they are destroyed, becomes available to the patient. There seems good reason to suggest that outdated blood may be useful for treatment of the moderately wounded who require less thall 5 units of blood.

Summary

1. The decisions to use Universal Donor Blood in the combat zone in Korea obviated incompatible transfusion reactions. This practice in the handling of mass casualties permits transfusion to begin without delay for cross-matching, and it places the responsibility for compatibility of the trausfusion upon the supplying agency in the rear rather than upon those who use the blood under adverse conditions. The few incompatible reactions that occurred in Korea were usually due to blood that had been procured locally in the combat zone.

2. It was found that massive transfusions of Universal Donor Blood in recipients of other groups sometimes resulted in an accumulation of transfused antibodies that were active against red cells of the recipient. This made it unsafe to transfuse the patient with blood of his own hereditary group when subsequent transfusions were required. The foreign antibodies required as long as 2 weeks to disappear.

3. The problem of bacterial contamination of stored blood did not appear to be the cause of reactions, but the matter deserves study as to how best to prevent or control it. The use of plastic bags is expected to improve this situation.

4. The use of old blood, even in large amounts rapidly given, caused little if any damage that could be attributed to the age of the blood. Declaring stored blood to be outdated after 21 days seems a reasonable precaution, but it is suggested that well refrigerated blood up to 60 days of age may be employed as a "plasma substitute" in the less severely wounded.