Transfusion Reactions

Hemolytic Transfusion Reaction

In 2003, the three most common causes of transfusion-related deaths were hemolytic transfusion reactions, septic transfusions, and transfusion-related acute lung injury (TRALI) ( Table 47-7 ). ^[97] Since 1975, the FDA has required that all fatal reactions occurring in blood recipients or donors be reported within 24 hours by telephone or within 7 days in writing by all FDA-registered transfusion services. In the 10-year period from 1976 to 1985, 328 deaths have been reported and analyzed. ^[98] Of these deaths, 159 were acute from hemolytic reactions and 23 from delayed reactions. Of the 159 deaths due to acute hemolytic reaction, 137 were caused by errors involving ABO incompatibility. More than one half of these mistakes occurred after the blood had been issued by the

TABLE 47-7 -- Transfusion-related fatalities in the United States, 2001–2002

Cause of Fatalities	No. of Fatalities
Bacterial contamination	17
Transfusion-related acute lung injury (TRALI)	16
Mistransfusion: ABO mismatch	14
Data from the Food and Drug Administration, October 1, 2001 to September 30, 2002.

blood bank and were committed by nurses and physicians in the operating room, emergency room, or ward. The incidence of hemolytic transfusion reaction is sufficient enough that the Joint Accreditation of Healthcare Organizations (JCAHO) requires peer-review programs to reduce transfusion errors and complications. Undoubtedly, new technologies (e.g., bar coding) will be used to facilitate a decreased incidence of transfusion-related errors. However, when delayed hemolytic reactions (discussed later) are included, the incidence of ABO-incompatible RBC transfusions is higher.^[99] Overall, these adverse responses occur infrequently, but the anesthesiologist must know the principles of recognizing and treating hemolytic transfusion reactions because of the high morbidity and mortality rates. One of the most catastrophic transfusion reactions is that arising from intravascular hemolysis. Intravascular hemolysis occurs when there is a direct attack on transfused donor cells by recipient antibody and complement. Such a reaction can occur from infusion of as little as 10 mL of blood.^[100] Between 20% and 60% of patients with severe symptomatic hemolytic reactions may die, and these deaths usually result from ABO blood group incompatibility between the donor and the patient. Hemolytic transfusion reactions involving extravascular RBC destruction are generally less serious than those of the intravascular variety. In these cases, recipient antibody coats but does not immediately hemolyze the transfused RBCs. Destruction occurs primarily in the reticuloendothelial system.

Signs and Symptoms

The clinical consequences of incompatible blood transfusions are very serious but quite variable. Factors include volume of transfused blood, number of antigenic sites on the red cell membrane, and activity of the reticuloendothelial system. The properties of the antibody, including concentration and ability to activate complement, are also important.

The classic signs and symptoms ( Table 47-8 ) of a hemolytic transfusion reaction—chills, fever, chest and flank pain, and nausea—are masked by anesthesia. Under general anesthesia, the only signs may be hemoglobinuria, bleeding diathesis, or hypotension. In my experience and that of Huh and Lichtiger^[101] with six and four hemolytic transfusion reactions, respectively, the presenting sign was hemoglobinuria in 9 of the 10 cases. As little as 50 mL of incompatible blood may exceed the binding capacity of haptoglobin, which is a protein that

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Treatment

If a hemolytic reaction is suspected, blood and urine samples should be sent to the laboratory for examination. The blood bank should check all paperwork to ensure that the correct blood component was transfused to the patient. Laboratory tests should be performed to determine

Figure 47-9 Schematic representation of what happens to hemolyzed erythrocytes (RBC) as a result of the administration of incompatible blood.

Although there are several consequences of intravascular hemolysis, mainly the renal and coagulation systems are affected. The exact cause of acute renal failure from intravascular hemolysis is controversial, but the most common hypothesis is that hemoglobin in the form of acid hematin precipitates in the distal tubule and causes mechanical tubular blockage. The magnitude of the precipitation probably is inversely related to the volume of urine flow and its pH. The primary emphasis of therapy should be directed toward maintaining urinary output in excess of 75 mL/hour by generous administration of intravenous fluids and diuretics. One approach is summarized in Table 47-9 and includes the administration of lactated Ringer's solution to maintain the central venous pressure between 10 and 15 cm H₂ O while initially administering 12.5 to 50 g of mannitol. If ineffective, the dose of mannitol may be increased or the use of more potent diuretics, such as furosemide, which increases blood flow to the renal cortex, may be required to maintain adequate urinary output. Alkalinization of the urine to prevent precipitation of acid hematin in the distal tubules is of questionable value but is easy and therefore recommended. DIC commonly occurs with hemolytic transfusion reactions, probably because RBC stroma is severed, releasing erythrocytin, which activates the intrinsic system of coagulation. This activated coagulation leads to fibrin formation. Subsequently, platelets and factors I, II, V, and VII are consumed. As soon as a hemolytic transfusion reaction is recognized, platelet count,

TABLE 47-9 -- Steps for the treatment of a hemolytic transfusion reaction

1. STOP THE TRANSFUSION.

2. Maintain the urine output at a minimum of 75 to 100 mL/hour by the following methods:

a. Generously administer fluids intravenously and possibly mannitol (12.5 to 50 g, given over 5 to 15 minutes).

b. If intravenously administered fluids and mannitol are ineffective, administer furosemide (20 to 40 mg) intravenously.

3. Alkalinize the urine; because bicarbonate is preferentially excreted in the urine, only 40 to 70 mEq of sodium bicarbonate per 70 kg of body weight is usually required to raise the urine pH to 8, whereupon repeat urine pH determinations indicate the need for additional bicarbonate.

4. Assay urine and plasma hemoglobin concentrations.

5. Determine platelet count, partial thromboplastin time, and serum fibrinogen level.

6. Return unused blood to blood bank for repeat crossmatch.

7. Send patient's blood and urine sample to blood bank for examination.

8. Prevent hypotension to ensure adequate renal blood flow.

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Another approach to treatment of a severe hemolytic transfusion reaction has been proposed by Seager and coworkers,^[104] who postulated that the kidneys might be spared from exposure to massive amounts of hemolyzed red cells by removing all blood from a patient and replacing it with compatible blood. This was accomplished in a patient who had received 3000 mL of incompatible blood by hemodilution by use of an extracorporeal circuit. Because the patient had rapid recovery of urinary function, this method shows much promise.

In summary, hemoglobinuria or hemolysis should be assumed to be a hemolytic transfusion reaction until proved otherwise. The steps outlined in Table 47-9 should be taken when the diagnosis is suspected or confirmed.

Delayed Hemolytic Transfusion Reaction (Immune Extravascular Reaction)

An immediate hemolytic transfusion reaction often is a dramatic event because the concentration of the antibody is high enough to cause immediate and appreciable RBC destruction. In many cases of hemolytic transfusion reaction, the transfused donor cells may survive well initially, but after a variable delay (2 to 21 days), they are hemolyzed.^{[105] [106]} This type of reaction occurs mainly in recipients sensitized to RBC antigens by previous blood transfusions or pregnancy. As a result, this type of delayed reaction is more common in females who have a known disposition of alloimmunization. These reactions are delayed hemolytic transfusion reactions and are those in which the level of antibody at the time of transfusion is too low to be detected or too low to cause RBC destruction. RBC destruction occurs only when the level of antibody is increased after a secondary stimulus (i.e., anamnestic response). These delayed reactions are often manifested only by a decrease in the post-transfusion hematocrit value. However, jaundice and hemoglobinuria can occur in these patients and can cause some impairment in renal function, but only rarely do they lead to death. Unlike immediate reactions, antibodies most commonly involved in delayed hemolytic reactions are those in the Rh and Kidd systems rather than the ABO system. Although improved blood-banking procedures have decreased the incidence of immediate hemolytic transfusion reactions, the delayed hemolytic reaction may not be preventable, because pretransfusion testing is unable to detect very low levels of antibody present in potential blood recipients.

Although impairment of renal function is uncommon, the surgical team should include in their differential diagnosis a delayed hemolytic transfusion reaction in any patient who has an unexplained decrease in hematocrit 2 to 21 days after a transfusion, even without obvious manifestation of hemolysis. This is especially important in a postoperative patient when the decrease in hematocrit value is thought to be from blood loss and may be an important criterion as to whether additional surgery is necessary.

Nonhemolytic Transfusion Reactions

Nonhemolytic reactions to blood transfusions usually are not serious and are febrile or allergic in nature. Specific infectious cases of febrile reactions are discussed in "Infectivity of Blood." Occasionally, fever may be the first sign of a hemolytic reaction or of bacterial contamination.

For less serious febrile reactions, the most common adverse reactions to blood transfusions are the febrile reactions. The symptoms consist of chills, fever, headache, myalgia, nausea, and nonproductive cough occurring shortly after blood transfusion. Less frequently, the patient may have hypotension, chest pain, vomiting, and dyspnea. Even pulmonary infiltrations with x-ray evidence of prehilar nodule formation and lower lung infiltrates along with overt pulmonary edema have been reported.^[107] Because febrile reactions obviously involve fever, they can be easily confused with a hemolytic transfusion reaction. A direct antiglobulin test readily differentiates a hemolytic reaction from a febrile reaction because this test rules out the attachment of an RBC antibody to transfused donor RBCs. There is no clear consensus on whether the transfusion should be terminated when a febrile reaction occurs.^{[108] [109]}

Most allergic transfusion reactions are mild and are thought to be caused by the presence of foreign protein in the transfused blood. The most common symptom is urticaria associated with itching. Occasionally, the patient has facial swelling. Allergic reactions occur in about 3% of all transfusions. When these reactions are accompanied by fever or any other symptoms suggestive of a serious hemolytic reaction, it is not necessary to discontinue the transfusion. Antihistamines are used to relieve the symptoms of the allergic reaction. Infrequently, a more severe form of allergic reaction involving anaphylaxis occurs in which the patient has dyspnea, hypotension, laryngeal edema, chest pain, and shock. These are anaphylactic reactions caused by the transfusion of IgA to patients who are IgA deficient and have formed anti-IgA. This type of reaction does not involve red cell destruction and occurs very rapidly, usually after the transfusion of only a few milliliters of blood or plasma. The patients who experience these anaphylactic reactions must be given transfusions with washed RBCs from which all traces of donor IgA have been removed or with blood lacking the IgA protein. Several investigators have reviewed many other rare transfusion reactions.^{[98] [100] [101]}