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Management of Blood Transfusion Reactions
Management of Blood Transfusion Reactions THOMAS H. SELDON
ALTHOUGH the operation of blood banks and transfusion services has improved measurably during the past few years, a number of untoward reactions following the administration of whole citrated blood still are encountered. The one who administers the blood must make a real effort to differentiate the type of reaction or to institute the proper therapy after the untoward reaction occurs. The usual causes for such seeming lack of adequate care of the patient are: 1. The attending physician may not recognize the signs, symptoms and effects of a blood transfusion reaction. 2. If the physician recognizes an untoward reaction, he may not place the reaction in the proper category. 3. The physician may recognize the reaction but he may not be familiar with the proper therapy for the patient. The attending physician should have a thorough knowledge of untoward reactions to blood transfusion. He is the one most familiar with the physical status and particular illness of that patient. The blood-bank personnel and the personnel in the laboratory of clinical pathology also should have close contact with the actual administration of whole blood. Whereas one physician may have contact with only a small number of blood transfusions, blood-bank personnel and personnel in the laboratory of clinical pathology have contact with many hundreds of blood transfusions. The occasional transfusion reaction seen by the individual physician does not give him the background that blood-bank personnel acquire by their contact with many hundreds of transfusions. Consequently, in many instances, the blood-bank personnel and the personnel in the laboratory of clinical pathology can offer a valuable service to the patient that may not be fully appreciated by the attending physician. Thus, the attending physician, instead of being hypercritical because his patient has an untoward reaction to transfusion, would be well advised to seek the advice and help of his well-informed colleagues.
1217
Thomas H. Seldon
1218
The reported incidence of blood transfusion reactions in various centers ranges from less than 1 per cent to more than 12 per cent; hence, an incidence of 1 per cent is much lower than the over-all average for the country. A reportedly low incidence may be indicative of lack of close association between the blood bank and the laboratory of clinical pathology on the one hand, and the attending physician and the patient on the other. It may be that the attending physician did not recognize the reaction and so did not report it, or that the blood-bank personnel and the personnel in the laboratory of clinical pathology did not follow the transfusion closely enough to know about the untoward effect. A high incidence of blood transfusion reactions is open to some question and criticism. Perhaps the blood-bank techniques are faulty or careless, perhaps the laboratory investigations are carried out hurriedly or inaccurately, perhaps the technique of administration is not well pcrformed, or perhaps the equipment used for the transfusion is not perfedly clean and sterile. Table REACTIONS IN
8,222
TRANSFUSIONS FOR THE YEAR
TYPE OF REACTION
Hyperthermic ..... Allergic ... . Circulatory .... . Hemolytic ... . Undetermined .. TOTAL . . . . .
NUMBER
170 lOG 1
o
41 318
1954
PI<;R CENT OF
8,222
2.1 1.3 0.5 3.!)
Blood transfusion is a valuable therapeutic procedure but it is not without danger, and death can occur. Therefore, the author believes that blood-bank and laboratory personnel should have very close scrutiny of all blood-banking procedures, from the procuring of the blood from the donor to the actual administration of the blood to the patient. Blood transfusion reactions at the Clinic are divided into five categories, namely, hyperthermic or pyrogenic, allergic, circulatory, hemolytic, and an undetermined category that includes many bizarre happenings which do not fit any of the other four categories. During 1954, the incidence of these reactions, based on the total number of transfusions, was 3.9 per cent (Table). For reactions in each category there are certain measures that may be used to help the patient. HYPERTHERMIC OR PYROGENIC REACTIONS
This type of reaction is characterized by chills and fever, which appear during or a few minutes after the transfusion. This is the most common
Management of Blood Transfusion Reactions
1219
complication of blood transfusion. Reactions of this type were associated with 2.1 per cent of the transfusions at the Clinic in 1954 (Table). Whether freshly drawn blood or properly refrigerated blood is used seems to make little or no difference in this rate. In the mildest cases there may be slight chilliness with no fever, and in the more severe forms there may be violent chills and a temperature of 104° F. The fever usually persists for less than 4 hours, during which time the patient may be very uncomfortable. Complete recovery usually occurs within 24 hours. Diagnosis. Hyperthermic or pyrogenic reactions must be differentiated from the febrile manifestations of the primary disease of the patient and from hemolytic reactions. A hemolytic reaction can be differentiated by the presence of free hemoglobin in the serum of blood collected immediately after the symptoms have occurred. Although the patient is uncomfortable, the reaction usually is not dangerous. Treatment. Treatment is symptomatic. The transfusion may be or may not need to be discontinued, depending on the severity of the reaction. Codeine, 30 to 60 mg. (;11 to 1 grain), is injected intravenously. This medication does not stop the reaction, but it does make the patient much more comfortable. If the patient feels very chilled, the application of heat is comforting. ALLERGIC REACTIONS
Hives and occasionally angioneurotic edema may occur. Close questioning of the donor and the recipient usually does not reveal any history of allergic manifestations. In the author's experience, the use of fasting donors has not reduced, to any degree, the incidence of this type of reaction. Urticaria is the second most common complication in blood transfusion. Allergic reactions were associated with 1.3 per cent of the transfusions at the Clinic in 1954 (Table). During or soon after the transfusion, hives appear. The lesions may be local or widespread. Sometimes the pruritus is very uncomfortable. Angioneurotic edema, particularly of the face and neck, may occur in the severe cases. In the most severe type, edema of the glottis may appear. Very occasionally, asthmatic symptoms accompany these reactions. Diagnosis. The diagnosis is easily made on the basis of the cutaneous manifestations. If asthma is present, it must be differentiated from breath sounds consequent to edema of the lungs caused by circulatory overload. Recovery without further complications is usual. Edema of the glottis is rare and may be serious. Treatment. Epinephrine hydrochloride, 0.25 to 0.5 cc. of a 1: 1000 solution, may be administered unless contraindicated by the patient's physical ailment. Sedation with codeine, 30 to 60 mg. injected intravenously, is helpful. Diphenhydramine hydrochloride (Benadryl), 50 to 100 mg., tripelennamine hydrochloride (Pyribenzamine), 2.5 mg., or chlorprophenpyridamine (Chlor-Trimeton) maleate, 10 mg., may be admin-
1220
Thomas H. Seldon
istered intravenously. For future transfusions, epinephrine, codeine or one of the antihistamines may be added to the bottle of blood or administered directly to the patient before the start of the transfusion. Donors with a history of spontaneous angioneurotic edema, frequent urticaria, active hay fever or allergic asthma should not be used. CIRCULATORY REACTIONS
When the blood volume is increased excessively by the addition of fluid or blood, the left side of the heart becomes dilated and sometimes fails. Pulmonary congestion and edema develop. Perhaps circulatory overload is the most common cause of death from blood transfusion. During the transfusion or very shortly thereafter, the patient becomes dyspneic, orthopneic and cyanotic. Blood-tinged frothy fluid may be coughed up. The lungs are filled with sibilant rales. The cardiac rhythm may be normal, but auricular fibrillation or flutter may occur. The venous pressure is elevated and the jugular veins are visibly engorged. If the patient survives, peripheral edema may occur. During 1954, there was one circulatory transfusion reaction at the Clinic. Diagnosis. The reaction must be recognized promptly. Asthma is the only condition to confuse the examining physician. Death frequently follows if the condition goes undiagnosed. Treatment. Prompt application of tourniquets to the proximal portions of the four extremities is an emergency measure. Care must be taken not to occlude the arterial pulses. This measure pools about 15 per cent of the circulating blood in the extremities and thus relieves some of the load on the heart. Phlebotomy should be done and an amount of blood at least equal to the amount administered should be withdrawn. The patient should have inhalation of oxygen under positive pressure, and appropriate care in bed should be given. Drugs must not be relied upon for treatment of the circulatory overload. In future transfusions, blood should be used only in small quantities and it should be administered very slowly. HEMOL YTIC REACTIONS
Perhaps more attention has been paid to this type of reaction than to any other, but there is still much to learn about this type. Whenever excessive amounts of hemolyzed blood are present in the circulation, serious changes occur in the body. It is accepted by most workers that the free hemoglobin released by the rupture of erythrocytes is the toxic substance that causes the severe complications. Possible causes for the hemolysis of blood prior to administration include accidental freezing of the refrigerated blood, improper storage, injudicious warming of blood prior to administration, and the addition of hypertonic or hypotonic solutions to the blood. There are also causes for the intravascular hemolysis of the blood, such as increased osmotic fragility of the donor's cells, transfusion
M anagement of Blood Tran8fusion Reactions
1221
of incompatible donor cells, and transfusion of high-titer incompatible antibodies present in the donor's plasma. During 1954, no hemolytic reactions occurred in the transfusion service at the Clinic. The early symptoms of a hemolytic reaction may occur after 50 to 100 cc. of blood has been administered to the patient. This is one of the very good reasons that the first 50 to 100 cc. of blood in every transfusion should be administered slowly. Severe pain in the lumbar region and in the legs, severe substernal constriction, chills that vary in nature from mild to very severe, and a temperature ranging as high as 105° F. are characteristic. The skin becomes flushed and the breathing becomes rapid and labored. Shock may follow quickly, with marked decrease in systolic blood pressure. Most of these symptoms may be masked if the patient is under general anesthesia, but incompatibility of the blood often manifests itself during a surgical procedure by widespread uncontrollable oozing of blood at the operative site. Jaundice usually appears in about 12 hours. Hemoglobinuria occurs within a few minutes after the concentration of hemoglobin in the blood plasma has reached the renal threshold. The volume of urine actually may be increased during this time. Most writers agree that serious renal damage usually is not observed in adults with hemolysis of less than 200 cc. of blood. The early symptoms are followed by a feeling of lassitude, nausea and some vomiting. Frequently the patient is irrational. If the hemolytic reaction is a serious one, convulsions may occur, and coma and death may follow in 4 days or more. Diagnosis. A severe pyrogenic reaction may occasionally be mistaken for a mild hemolytic reaction. The reverse also may occur. The demonstration of hemoglobinemia and hemoglobinuria is direct proof of this untoward reaction. Further steps in the definite diagnosis of the reaction may be summarized as follows: 1. Check the blood group and the Rh factor of a sample of blood from the donor bottle used and also a fresh sample of blood withdrawn from the donor. 2. Check the recipient's blood group and Rh factor. 3. Repeat the crossmatching of the second sample of blood from the donor bottle and the fresh sample from the donor with the recipient's blood. Treatment. Shock is an early symptom and must be treated vigorously. Transfusion with known compatible blood is in order. Massive exchange transfusion has been used, but this procedure, however, has not been accepted in general by many centers. To support the blood pressure during shock therapy, the administration of vasopressor drugs may be advisable. These drugs may be administered intramuscularly or intravenously, depending on the indication for the necessity of speed of effect. Epinephrine hydrochloride, 0.25 to 0.5 cc. of a 1: 1,000 dilution, may be administered intramuscularly. Ephedrine hydrochloride, 25 mg., may be
1222
Thomas H. Seldon
given intravenously. One to 2 cc. of 0.2 per cent Levophed Bitartrate solution in 1,000 cc. of 5 per cent solution of dextrose in distilled water may be administered intravenously, or 1 to 2 cc. of 1 per cent solution of phenylephrine (Neosynephrine) hydrochloride in 1,000 cc. of 5 per cent solution of dextrose in distilled water may be administered intravenously. The administration of these fluids into the vein must be carefully watched to prevent an excessive rise of the systolic blood pressure. A very accurate record of the intake and output of fluids must be started immediately. The specific gravity of the specimens of urine must be determined. Early in the treatment, fluid and electrolyte replacement should be made as required, but the total amount of fluid administered should not be more than 2,000 to 3,000 ce. If, in the first 24 hours, less than 500 cc. of urine is excreted, oliguria should be suspected. Patients with an output of 500 to 800 cc. of urine must be treated conservatively. The rationale for the use of sodium bicarbonate or sodium citrate to alkalinize the urine is now questioned. To force a diuresis by the intravenous administration of sodium sulfate or large volumes of fluids is to be condemned. If renal failure should occur, these excess fluids and electrolytes would be a disadvantage to the patient. If the patient becomes anuric or oliguric, the intake of fluids, either parenterally or orally, should be restricted to 500 to 800 cc. daily, in addition to the 1,000 cc. that is given daily to replace that lost through the skin and lungs. If more than this quantity is lost through vomiting, fistula drainage and so forth, the loss must also be replaced. At least 100 gm. of carbohydrate to supply some calories should be given daily, but no protein to produce nitrogen should be administered. The administration of excess sodium salts to these patients may produce an alkalosis and tetany, as well as a possible pulmonary edema and congestive heart failure. The electrocardiographic status, hemoglobin, hematocrit reading, nonprotein nitrogen or urea, sodium, potassium, chloride and carbon dioxide-combining power should be determined regularly. High levels of nitrogen, lowered levels of sodium or chloride and acidosis usually are tolerated, but if the level of sodium falls to a critical one (120 mEq. per liter or below) with elevation of the level of potassium, 5 per cent solution of dextrose in isotonic solution of sodium chloride, or 10 per cent solution of dextrose in isotonic solution of sodium chloride, covered with insulin, may aid in combating the rctention of potassium. If the carbon dioxide-combining power drops below 15 mEq. of bicarbonate per liter of plasma, 500 to 1,000 cc. of sixth molar sodium lactate solution or 250 to 500 cc. of 5 per cent solution of sodium bicarbonate may be necessary. If the patient's fluid and electrolyte balance can be adequately maintained and if development of uremic symptoms can be forestalled for a sufficient length of time, reversal of the renal condition may occur.
M anagernent of Blood Transfusion Reactions
1223
If, however, at the end of 5 to 7 days there has been no indication of resumed urinary excretion, if the values for urea, sulfate, phosphate, and other metabolic waste products in the blood continue to rise, and if the symptoms and signs of clinical uremia develop in spite of conservative measures, extrarenal means may be necessary to relieve the uremia. Various methods have been described for clearing metabolic waste products from the body as a means of sustaining patients through the critical or anuric period, until the kidneys are capable again of forming urine. Such methods include continuous lavage of the stomach and upper part of the small bowel, peritoneal lavage and extracorporeal dialysis ("artificial kidney"). The recent literature contains many clinical reports on patients with acute renal failure treated by one of the means mentioned. Because of the rather elaborate setups required, the relatively high percentage of failures, and the numerous technical difficulties involved in carrying out methods of extrarenal excretion, a conservative program of treatment tried for as long as possible cannot be emphasized too strongly. However, if conservative measures fail and death appears likely, then one of the methods of extrarenal excretion should be seriously considered as a lifesaving measure. At the present time, hemodialysis utilizing one of the several methods described in the literature seems to show some promise. When formation of urine is resumed and the onset of diuresis occurs, a second distinct hazard arises. With large volumes of urine passing through the kidneys, excessive quantities of sodium chloride are lost, resulting in depletion of the serum sodium or plasma chloride to critical levels. If, and when, the kidney assumes its role of excretion of urine again, the fluid intake of the patient still must be carefully regulated according to the output of urine. Frequent determination of the plasma chlorides, the carbon dioxidecombining power and the serum sodium must be made. If the concentrations of these electrolytes appear to be decreasing, it may be necessary to replace these ions. Consequently, the intake of sodium chloride must be increased. The intake of protein also is increased as the uremia lessens. Many patients have died during this period of diuresis because of inadequate treatment, even though the underlying renal disease has improved. Acute suppression of urine is extremely serious and the prognosis always must be guarded. UNDETERMINED REACTIONS
Not infrequently there are bizarre manifestations that cannot be excluded as results of the blood transfusion and yet that cannot be definitely attributed to the transfusion. Because these manifestations accompany or follow a transfusion, the transfusion is left open to doubt and criticism. The symptoms may be mild or severe and may follow a pattern that
1224
Thomas H. Seldon
is typical of a mixture of several of the previously described categories of reactions. Into the category of undetermined reactions must go a whole hodgepodge of happenings. Specific description of symptoms is impossible. Reactions of an undetermined nature were associated with 0.5 per cent of the transfusions at the Clinic in 1954 (Table). Treatment. Treatment is symptomatic and hence varies according to the manifestations of the untoward occurrence.
ALTHOUGH the operation of blood banks and transfusion services has improved measurably during the past few years, a number of untoward reactions following the administration of whole citrated blood still are encountered. The one who administers the blood must make a real effort to differentiate the type of reaction or to institute the proper therapy after the untoward reaction occurs. The usual causes for such seeming lack of adequate care of the patient are: 1. The attending physician may not recognize the signs, symptoms and effects of a blood transfusion reaction. 2. If the physician recognizes an untoward reaction, he may not place the reaction in the proper category. 3. The physician may recognize the reaction but he may not be familiar with the proper therapy for the patient. The attending physician should have a thorough knowledge of untoward reactions to blood transfusion. He is the one most familiar with the physical status and particular illness of that patient. The blood-bank personnel and the personnel in the laboratory of clinical pathology also should have close contact with the actual administration of whole blood. Whereas one physician may have contact with only a small number of blood transfusions, blood-bank personnel and personnel in the laboratory of clinical pathology have contact with many hundreds of blood transfusions. The occasional transfusion reaction seen by the individual physician does not give him the background that blood-bank personnel acquire by their contact with many hundreds of transfusions. Consequently, in many instances, the blood-bank personnel and the personnel in the laboratory of clinical pathology can offer a valuable service to the patient that may not be fully appreciated by the attending physician. Thus, the attending physician, instead of being hypercritical because his patient has an untoward reaction to transfusion, would be well advised to seek the advice and help of his well-informed colleagues.
1217
Thomas H. Seldon
1218
The reported incidence of blood transfusion reactions in various centers ranges from less than 1 per cent to more than 12 per cent; hence, an incidence of 1 per cent is much lower than the over-all average for the country. A reportedly low incidence may be indicative of lack of close association between the blood bank and the laboratory of clinical pathology on the one hand, and the attending physician and the patient on the other. It may be that the attending physician did not recognize the reaction and so did not report it, or that the blood-bank personnel and the personnel in the laboratory of clinical pathology did not follow the transfusion closely enough to know about the untoward effect. A high incidence of blood transfusion reactions is open to some question and criticism. Perhaps the blood-bank techniques are faulty or careless, perhaps the laboratory investigations are carried out hurriedly or inaccurately, perhaps the technique of administration is not well pcrformed, or perhaps the equipment used for the transfusion is not perfedly clean and sterile. Table REACTIONS IN
8,222
TRANSFUSIONS FOR THE YEAR
TYPE OF REACTION
Hyperthermic ..... Allergic ... . Circulatory .... . Hemolytic ... . Undetermined .. TOTAL . . . . .
NUMBER
170 lOG 1
o
41 318
1954
PI<;R CENT OF
8,222
2.1 1.3 0.5 3.!)
Blood transfusion is a valuable therapeutic procedure but it is not without danger, and death can occur. Therefore, the author believes that blood-bank and laboratory personnel should have very close scrutiny of all blood-banking procedures, from the procuring of the blood from the donor to the actual administration of the blood to the patient. Blood transfusion reactions at the Clinic are divided into five categories, namely, hyperthermic or pyrogenic, allergic, circulatory, hemolytic, and an undetermined category that includes many bizarre happenings which do not fit any of the other four categories. During 1954, the incidence of these reactions, based on the total number of transfusions, was 3.9 per cent (Table). For reactions in each category there are certain measures that may be used to help the patient. HYPERTHERMIC OR PYROGENIC REACTIONS
This type of reaction is characterized by chills and fever, which appear during or a few minutes after the transfusion. This is the most common
Management of Blood Transfusion Reactions
1219
complication of blood transfusion. Reactions of this type were associated with 2.1 per cent of the transfusions at the Clinic in 1954 (Table). Whether freshly drawn blood or properly refrigerated blood is used seems to make little or no difference in this rate. In the mildest cases there may be slight chilliness with no fever, and in the more severe forms there may be violent chills and a temperature of 104° F. The fever usually persists for less than 4 hours, during which time the patient may be very uncomfortable. Complete recovery usually occurs within 24 hours. Diagnosis. Hyperthermic or pyrogenic reactions must be differentiated from the febrile manifestations of the primary disease of the patient and from hemolytic reactions. A hemolytic reaction can be differentiated by the presence of free hemoglobin in the serum of blood collected immediately after the symptoms have occurred. Although the patient is uncomfortable, the reaction usually is not dangerous. Treatment. Treatment is symptomatic. The transfusion may be or may not need to be discontinued, depending on the severity of the reaction. Codeine, 30 to 60 mg. (;11 to 1 grain), is injected intravenously. This medication does not stop the reaction, but it does make the patient much more comfortable. If the patient feels very chilled, the application of heat is comforting. ALLERGIC REACTIONS
Hives and occasionally angioneurotic edema may occur. Close questioning of the donor and the recipient usually does not reveal any history of allergic manifestations. In the author's experience, the use of fasting donors has not reduced, to any degree, the incidence of this type of reaction. Urticaria is the second most common complication in blood transfusion. Allergic reactions were associated with 1.3 per cent of the transfusions at the Clinic in 1954 (Table). During or soon after the transfusion, hives appear. The lesions may be local or widespread. Sometimes the pruritus is very uncomfortable. Angioneurotic edema, particularly of the face and neck, may occur in the severe cases. In the most severe type, edema of the glottis may appear. Very occasionally, asthmatic symptoms accompany these reactions. Diagnosis. The diagnosis is easily made on the basis of the cutaneous manifestations. If asthma is present, it must be differentiated from breath sounds consequent to edema of the lungs caused by circulatory overload. Recovery without further complications is usual. Edema of the glottis is rare and may be serious. Treatment. Epinephrine hydrochloride, 0.25 to 0.5 cc. of a 1: 1000 solution, may be administered unless contraindicated by the patient's physical ailment. Sedation with codeine, 30 to 60 mg. injected intravenously, is helpful. Diphenhydramine hydrochloride (Benadryl), 50 to 100 mg., tripelennamine hydrochloride (Pyribenzamine), 2.5 mg., or chlorprophenpyridamine (Chlor-Trimeton) maleate, 10 mg., may be admin-
1220
Thomas H. Seldon
istered intravenously. For future transfusions, epinephrine, codeine or one of the antihistamines may be added to the bottle of blood or administered directly to the patient before the start of the transfusion. Donors with a history of spontaneous angioneurotic edema, frequent urticaria, active hay fever or allergic asthma should not be used. CIRCULATORY REACTIONS
When the blood volume is increased excessively by the addition of fluid or blood, the left side of the heart becomes dilated and sometimes fails. Pulmonary congestion and edema develop. Perhaps circulatory overload is the most common cause of death from blood transfusion. During the transfusion or very shortly thereafter, the patient becomes dyspneic, orthopneic and cyanotic. Blood-tinged frothy fluid may be coughed up. The lungs are filled with sibilant rales. The cardiac rhythm may be normal, but auricular fibrillation or flutter may occur. The venous pressure is elevated and the jugular veins are visibly engorged. If the patient survives, peripheral edema may occur. During 1954, there was one circulatory transfusion reaction at the Clinic. Diagnosis. The reaction must be recognized promptly. Asthma is the only condition to confuse the examining physician. Death frequently follows if the condition goes undiagnosed. Treatment. Prompt application of tourniquets to the proximal portions of the four extremities is an emergency measure. Care must be taken not to occlude the arterial pulses. This measure pools about 15 per cent of the circulating blood in the extremities and thus relieves some of the load on the heart. Phlebotomy should be done and an amount of blood at least equal to the amount administered should be withdrawn. The patient should have inhalation of oxygen under positive pressure, and appropriate care in bed should be given. Drugs must not be relied upon for treatment of the circulatory overload. In future transfusions, blood should be used only in small quantities and it should be administered very slowly. HEMOL YTIC REACTIONS
Perhaps more attention has been paid to this type of reaction than to any other, but there is still much to learn about this type. Whenever excessive amounts of hemolyzed blood are present in the circulation, serious changes occur in the body. It is accepted by most workers that the free hemoglobin released by the rupture of erythrocytes is the toxic substance that causes the severe complications. Possible causes for the hemolysis of blood prior to administration include accidental freezing of the refrigerated blood, improper storage, injudicious warming of blood prior to administration, and the addition of hypertonic or hypotonic solutions to the blood. There are also causes for the intravascular hemolysis of the blood, such as increased osmotic fragility of the donor's cells, transfusion
M anagement of Blood Tran8fusion Reactions
1221
of incompatible donor cells, and transfusion of high-titer incompatible antibodies present in the donor's plasma. During 1954, no hemolytic reactions occurred in the transfusion service at the Clinic. The early symptoms of a hemolytic reaction may occur after 50 to 100 cc. of blood has been administered to the patient. This is one of the very good reasons that the first 50 to 100 cc. of blood in every transfusion should be administered slowly. Severe pain in the lumbar region and in the legs, severe substernal constriction, chills that vary in nature from mild to very severe, and a temperature ranging as high as 105° F. are characteristic. The skin becomes flushed and the breathing becomes rapid and labored. Shock may follow quickly, with marked decrease in systolic blood pressure. Most of these symptoms may be masked if the patient is under general anesthesia, but incompatibility of the blood often manifests itself during a surgical procedure by widespread uncontrollable oozing of blood at the operative site. Jaundice usually appears in about 12 hours. Hemoglobinuria occurs within a few minutes after the concentration of hemoglobin in the blood plasma has reached the renal threshold. The volume of urine actually may be increased during this time. Most writers agree that serious renal damage usually is not observed in adults with hemolysis of less than 200 cc. of blood. The early symptoms are followed by a feeling of lassitude, nausea and some vomiting. Frequently the patient is irrational. If the hemolytic reaction is a serious one, convulsions may occur, and coma and death may follow in 4 days or more. Diagnosis. A severe pyrogenic reaction may occasionally be mistaken for a mild hemolytic reaction. The reverse also may occur. The demonstration of hemoglobinemia and hemoglobinuria is direct proof of this untoward reaction. Further steps in the definite diagnosis of the reaction may be summarized as follows: 1. Check the blood group and the Rh factor of a sample of blood from the donor bottle used and also a fresh sample of blood withdrawn from the donor. 2. Check the recipient's blood group and Rh factor. 3. Repeat the crossmatching of the second sample of blood from the donor bottle and the fresh sample from the donor with the recipient's blood. Treatment. Shock is an early symptom and must be treated vigorously. Transfusion with known compatible blood is in order. Massive exchange transfusion has been used, but this procedure, however, has not been accepted in general by many centers. To support the blood pressure during shock therapy, the administration of vasopressor drugs may be advisable. These drugs may be administered intramuscularly or intravenously, depending on the indication for the necessity of speed of effect. Epinephrine hydrochloride, 0.25 to 0.5 cc. of a 1: 1,000 dilution, may be administered intramuscularly. Ephedrine hydrochloride, 25 mg., may be
1222
Thomas H. Seldon
given intravenously. One to 2 cc. of 0.2 per cent Levophed Bitartrate solution in 1,000 cc. of 5 per cent solution of dextrose in distilled water may be administered intravenously, or 1 to 2 cc. of 1 per cent solution of phenylephrine (Neosynephrine) hydrochloride in 1,000 cc. of 5 per cent solution of dextrose in distilled water may be administered intravenously. The administration of these fluids into the vein must be carefully watched to prevent an excessive rise of the systolic blood pressure. A very accurate record of the intake and output of fluids must be started immediately. The specific gravity of the specimens of urine must be determined. Early in the treatment, fluid and electrolyte replacement should be made as required, but the total amount of fluid administered should not be more than 2,000 to 3,000 ce. If, in the first 24 hours, less than 500 cc. of urine is excreted, oliguria should be suspected. Patients with an output of 500 to 800 cc. of urine must be treated conservatively. The rationale for the use of sodium bicarbonate or sodium citrate to alkalinize the urine is now questioned. To force a diuresis by the intravenous administration of sodium sulfate or large volumes of fluids is to be condemned. If renal failure should occur, these excess fluids and electrolytes would be a disadvantage to the patient. If the patient becomes anuric or oliguric, the intake of fluids, either parenterally or orally, should be restricted to 500 to 800 cc. daily, in addition to the 1,000 cc. that is given daily to replace that lost through the skin and lungs. If more than this quantity is lost through vomiting, fistula drainage and so forth, the loss must also be replaced. At least 100 gm. of carbohydrate to supply some calories should be given daily, but no protein to produce nitrogen should be administered. The administration of excess sodium salts to these patients may produce an alkalosis and tetany, as well as a possible pulmonary edema and congestive heart failure. The electrocardiographic status, hemoglobin, hematocrit reading, nonprotein nitrogen or urea, sodium, potassium, chloride and carbon dioxide-combining power should be determined regularly. High levels of nitrogen, lowered levels of sodium or chloride and acidosis usually are tolerated, but if the level of sodium falls to a critical one (120 mEq. per liter or below) with elevation of the level of potassium, 5 per cent solution of dextrose in isotonic solution of sodium chloride, or 10 per cent solution of dextrose in isotonic solution of sodium chloride, covered with insulin, may aid in combating the rctention of potassium. If the carbon dioxide-combining power drops below 15 mEq. of bicarbonate per liter of plasma, 500 to 1,000 cc. of sixth molar sodium lactate solution or 250 to 500 cc. of 5 per cent solution of sodium bicarbonate may be necessary. If the patient's fluid and electrolyte balance can be adequately maintained and if development of uremic symptoms can be forestalled for a sufficient length of time, reversal of the renal condition may occur.
M anagernent of Blood Transfusion Reactions
1223
If, however, at the end of 5 to 7 days there has been no indication of resumed urinary excretion, if the values for urea, sulfate, phosphate, and other metabolic waste products in the blood continue to rise, and if the symptoms and signs of clinical uremia develop in spite of conservative measures, extrarenal means may be necessary to relieve the uremia. Various methods have been described for clearing metabolic waste products from the body as a means of sustaining patients through the critical or anuric period, until the kidneys are capable again of forming urine. Such methods include continuous lavage of the stomach and upper part of the small bowel, peritoneal lavage and extracorporeal dialysis ("artificial kidney"). The recent literature contains many clinical reports on patients with acute renal failure treated by one of the means mentioned. Because of the rather elaborate setups required, the relatively high percentage of failures, and the numerous technical difficulties involved in carrying out methods of extrarenal excretion, a conservative program of treatment tried for as long as possible cannot be emphasized too strongly. However, if conservative measures fail and death appears likely, then one of the methods of extrarenal excretion should be seriously considered as a lifesaving measure. At the present time, hemodialysis utilizing one of the several methods described in the literature seems to show some promise. When formation of urine is resumed and the onset of diuresis occurs, a second distinct hazard arises. With large volumes of urine passing through the kidneys, excessive quantities of sodium chloride are lost, resulting in depletion of the serum sodium or plasma chloride to critical levels. If, and when, the kidney assumes its role of excretion of urine again, the fluid intake of the patient still must be carefully regulated according to the output of urine. Frequent determination of the plasma chlorides, the carbon dioxidecombining power and the serum sodium must be made. If the concentrations of these electrolytes appear to be decreasing, it may be necessary to replace these ions. Consequently, the intake of sodium chloride must be increased. The intake of protein also is increased as the uremia lessens. Many patients have died during this period of diuresis because of inadequate treatment, even though the underlying renal disease has improved. Acute suppression of urine is extremely serious and the prognosis always must be guarded. UNDETERMINED REACTIONS
Not infrequently there are bizarre manifestations that cannot be excluded as results of the blood transfusion and yet that cannot be definitely attributed to the transfusion. Because these manifestations accompany or follow a transfusion, the transfusion is left open to doubt and criticism. The symptoms may be mild or severe and may follow a pattern that
1224
Thomas H. Seldon
is typical of a mixture of several of the previously described categories of reactions. Into the category of undetermined reactions must go a whole hodgepodge of happenings. Specific description of symptoms is impossible. Reactions of an undetermined nature were associated with 0.5 per cent of the transfusions at the Clinic in 1954 (Table). Treatment. Treatment is symptomatic and hence varies according to the manifestations of the untoward occurrence.