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  1. Transfusion reactions
    1. Acute hemolytic transfusion reactions most commonly occur when ABO-incompatible blood is transfused, resulting in recipient anti-A and/or anti-B antibodies attaching to donor RBC antigens and forming antigen-antibody complexes. These antigen-antibody complexes activate complement, precipitating intravascular hemolysis with the release of RBC stroma and free Hb. Immune system activation also results in endothelial and mast cell activation, stimulating the release of serotonin, histamine, and bradykinin; these mediators set off a cascade of widespread vasodilation, diffuse inflammation, and acute hypotension. The net results may include shock, kidney injury due to Hb precipitation in renal tubules, and DIC (see Section IX.B). Many signs and symptoms of an acute hemolytic transfusion reaction appear immediately and include fever, chest pain, anxiety, back pain, and dyspnea. Many are masked by general anesthesia, but intraoperative clues to the diagnosis include fever, hypotension, hemoglobinuria, unexplained bleeding, or failure of the Hct to increase after transfusion. Table 36.3 outlines steps to take if a transfusion reaction is suspected. The incidence of fatal hemolytic transfusion reactions in the United States is approximately 1 in every 250,000 to 1,000,000 units transfused. Most reactions occur because of administrative errors, with the majority caused by improper identification of the blood unit or patient. The importance of adhering to strict policies of checking blood and matching to the correct patient in the operating room cannot be overemphasized.

      Table 36-3 Approach to Suspected Acute Hemolytic Transfusion Reaction

      1. Stop the transfusion.
      2. Quickly check for error in patient identity or donor unit.
      3. Send the donor unit and a newly obtained blood sample to blood bank for repeat cross-match.
      4. Treat hypotension with fluids and vasopressors as necessary.
      5. If ongoing transfusion is required, administer type O-negative PRBC and type AB FFP as necessary.
      6. Insert a Foley catheter and support renal function with fluids to correct hypovolemia and, if needed, alkaline diuresis (sodium bicarbonate + furosemide ± mannitol) to maintain brisk urine output.
      7. Monitor for signs of DIC clinically and with appropriate laboratory studies; treat supportively (see Section IX.B).
      8. Send patient blood sample for direct antiglobulin (Coombs) test, free Hb, and haptoglobin; send urine for Hb.

      DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; PRBC, packed red blood cells.

    2. Delayed hemolytic transfusion reactions occur because of antibodies targeting minor RBC antigens (eg, Kidd) and are characterized by extravascular hemolysis. Delayed hemolytic transfusions reactions are most common in patients with a history of multiple prior transfusions, especially those with chronic anemias or hemoglobinopathies. These reactions often present days to weeks after transfusion. Patients may experience minimal symptoms but may display signs of anemia and jaundice. Laboratory studies reveal a positive direct antiglobulin test, hyperbilirubinemia, decreased haptoglobin levels, and hemosiderin in the urine. Treatment is aimed at correcting the anemia.
    3. Febrile nonhemolytic transfusion reactions (FNHTRs) are the most common transfusion reactions, occurring in approximately 1% of RBC transfusions and up to 30% of platelet transfusions. These may occur in response to cytokines in the stored product or may occur when anti-leukocyte or anti-HLA antibodies in the recipient react with donor white blood cells or platelets in the transfused blood product, thus producing pyrogen and proinflammatory cytokine release. Signs and symptoms include fever, chills, rigors, tachycardia, malaise, nausea, and vomiting. Approach to treatment involves first stopping the transfusion and excluding an acute hemolytic transfusion reaction or bacterial contamination of the donor unit. Acetaminophen and meperidine may diminish fever and rigors, respectively. Once the diagnosis of FNHTR has been made, future reactions may be avoided or diminished by administering leukoreduced blood products (see Section IV.B.2), premedicating at-risk patients with acetaminophen and hydrocortisone (50-100 mg IV), and administering the transfusion slowly.
    4. Allergic transfusion reactions are common, occurring in 1% to 3% of transfusions. They arise from recipient IgE-mediated antibody responses to donor plasma proteins. Urticaria with pruritus and erythema is the most common manifestation, but bronchospasm or anaphylaxis may occur in rare instances. Many patients also develop fevers. Patients with IgA deficiency may be at an increased risk of allergic transfusion reactions and anaphylaxis because of the presence of anti-IgA antibodies that react with transfused IgA; this is best prevented by administering plasma-free blood products (eg, washed PRBCs) to patients with known IgA deficiency. Treatment involves stopping the transfusion, excluding more severe reactions (see above), and administering antihistamines (eg, diphenhydramine 50 mg IV and ranitidine 50 mg IV). A significant reaction may warrant administration of a corticosteroid (methylprednisolone 80 mg IV). Bronchospasm and anaphylaxis should be treated as described in Chapter 17.
    5. TRALI is a condition involving rapid-onset respiratory insufficiency following blood, FFP, cryoprecipitate, or platelet transfusion. Signs and symptoms include fevers, dyspnea, hypoxemia, hypotension, and low-pressure pulmonary edema developing within 4 hours of transfusion. TRALI is thought to occur when anti-HLA and anti-leukocyte antibodies present in donor plasma target recipient neutrophils, which damage the lung parenchyma. This mechanism also accounts for the transient leukopenia that may be observed in recipients who develop TRALI. TRALI may rapidly progress to hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS) and is currently the leading cause of transfusion-related mortality in the United States. Most cases are traced to plasma-containing blood products from multiparous female donors who have developed anti-HLA antibodies; therefore, measures to prevent plasma donation by women who have been pregnant may reduce the incidence of TRALI-related episodes.
    6. Transfusion-associated circulatory overload (TACO) is a condition of circulatory congestion secondary to the fluid volumes administered during massive transfusion. Symptoms often mimic those of decompensated congestive heart failure and include dyspnea, high-pressure pulmonary edema, tachycardia, and jugular venous distention. While TRALI usually produces pulmonary edema in the absence of overt hypervolemia, signs of hypervolemia and increased left ventricular filling pressures may be observed in TACO. TACO often affects patients at risk for congestive heart failure and occurs in less than 1% of transfusions. If a patient is at risk for fluid overload with high-volume transfusion, diuretics or volume-reduced blood products may be administered prophylactically. However, as TACO is often traced to overly aggressive transfusion in patients with preexisting myocardial dysfunction, the clinician should also be judicious with respect to the volume transfused.
    7. GVHD is a rare and serious complication of blood transfusion resulting from an attack of immunocompetent donor lymphocytes on the host’s tissues. In a great majority of transfusions, donor lymphocytes are destroyed by the recipient’s immune system, thus preventing GVHD. However, if the host is immunodeficient or if a specific type of partial donor-recipient HLA matching occurs, the risk of GVHD is increased. The condition often develops 4 to 30 days after transfusion, with patients typically presenting with fever and an erythematous rash that may become generalized. Other symptoms include anorexia, vomiting, abdominal pain, and cough. The diagnosis is made by skin biopsy and confirmed by demonstrating the presence of circulating lymphocytes with a different HLA phenotype, verifying their origin from the donor. GVHD is poorly responsive to most available treatments. Therefore, prevention is of utmost importance and is achieved by exposing lymphocyte-containing components to gamma radiation, thereby inactivating donor lymphocytes. In addition to immunocompromised recipients, patients receiving blood products from family donors or HLA-matched platelets are viable candidates for transfusion of irradiated blood components owing to an associated risk of partial HLA matching.
  2. Metabolic complications of blood transfusions
    1. Hyperkalemia is common with rapid blood transfusion but most often becomes clinically significant in cases involving massive transfusion or renal failure. During storage, red cells leak potassium into the extracellular environment, elevating potassium levels to greater than 20 mEq/U PRBCs after approximately 2 weeks. However, this state is rapidly corrected with transfusion and repletion of cellular energy stores.
    2. Hypocalcemia. Citrate, which chelates calcium, is used as an anticoagulant in stored blood products. Consequently, rapid transfusion decreases ionized calcium levels in the recipient, potentially producing neuromuscular or cardiovascular complications. Although hypocalcemia is usually insignificant owing to efficient hepatic metabolism of the infused citrate, it may become problematic in small children, in patients with impaired liver function, in hypothermic or alkalemic patients, in patients with decreased hepatic blood flow, and during the anhepatic phase of liver transplantation. It is also more common with the transfusion of FFP, which contains higher concentrations of citrate. Ionized calcium levels should be followed, as total serum calcium includes inactive citrate-bound calcium and may not accurately reflect free serum calcium.
    3. Acid-base abnormalities. Banked PRBCs become acidic because of accumulated red cell metabolites, with pH decreasing linearly to approximately 6.6 after 2 weeks in storage. However, the actual acid load delivered to the patient is minimal. Metabolic acidosis in the face of severe blood loss is more likely due to hypoperfusion and will typically improve with volume resuscitation. The development of a metabolic alkalosis is also common following massive blood transfusion because citrate is rapidly metabolized in the liver to bicarbonate.
    4. Hypothermia. With the exception of platelets, blood products are typically refrigerated to a standard temperature of 4 °C. Rapid administration of a large volume of PRBCs and other cooled blood products may precipitate hypothermia, which may have adverse effects on immune function, wound healing, coagulation, myocardial function, and maintenance of electrolyte balance. Therefore, blood products other than platelets are best transfused through a primed warming device.
    5. Iron overload. Repeated or high-volume transfusion of red cells has the potential to produce or worsen a state of hemochromatosis (systemic iron overload with consequent organ impairment). Although this is typically of little immediate concern in the setting of acute surgical or traumatic hemorrhage, patients with preexisting hereditary or transfusion-related hemochromatosis may exhibit progressive hepatic dysfunction, cardiomyopathy, and insulin resistance in addition to other endocrine abnormalities. As the body lacks a finely tuned mechanism for the elimination of excess iron, serial phlebotomy and iron chelation may be required as therapeutic measures. To minimize the buildup of excess iron in high-risk patients, perioperative blood-conserving approaches such as cell salvage and ANH may be appropriate (see Section VII).
    6. Derangements from blood storage. It is known that stored red blood cells undergo progressive structural and functional alterations that decrease their functionality and viability following transfusion. For example, prolonged storage may diminish microvascular flow as red cells lose their deformability. A decrease in oxygen delivery also occurs secondary to depletion of 2,3-diphosphoglycerate, which results in a leftward shift of the oxyhemoglobin dissociation curve as well as increased adhesion and aggregation of red cells. In addition, there is an accumulation of proinflammatory substances and priming of the nicotinamide adenine dinucleotide phosphate (NADP+) system with reduction in concentrations of nitric oxide (NO) and adenosine triphosphate (ATP). Some studies have suggested increased rates of complications and mortality following cardiac surgery in patients who received blood that was stored for more than 2 weeks, highlighting the potential clinical consequences of prolonged blood storage.
  3. Infectious complications of blood transfusions have decreased with improved laboratory testing for transmissible diseases. Exposure to pooled products (eg, cryoprecipitate) increases the risk in proportion to the number of donors. See Chapter 8 for all infectious diseases transmitted by blood transfusion.
    1. Hepatitis B virus. The risk of hepatitis B infection from a blood transfusion has decreased since testing donated blood for hepatitis B antigen became routine in 1971. The current risk is estimated to be 1:60,000 to 1:120,000 units transfused.
    2. Hepatitis C virus (HCV). The institution of routine testing for antibodies to HCV in 1990 (and recently nucleic acid testing) has reduced the risk of transfusion-related HCV to approximately 1:800,000 to 1:1.6 million units transfused.
    3. Human immunodeficiency virus (HIV). Because of improved screening and testing of patients and blood products, the risk of transfusion-associated HIV has been estimated to be about 1:1.4 to 1:2.4 million units transfused in the United States.
    4. Cytomegalovirus. The prevalence of antibodies to CMV in the general adult population is approximately 70%. The incidence of transfusion-associated CMV infection in previously noninfected patients is quite high, and CMV remains the most common infectious agent transmitted via blood product administration. Infection is typically asymptomatic; however, because immunosuppressed patients and neonates may develop severe disease, CMV-negative or leukoreduced blood products may be recommended.
    5. West Nile virus (WNV). Following the 2002 epidemic of WNV in the United States, it was found that transfusion of red cells, platelets, and FFP can transmit WNV. With universal screening, the risk of WNV from transfusion has decreased to less than 1:1 million.
    6. Bacterial sepsis caused by transfused blood products remains rare. Donors with evidence of infectious disease are excluded from transfusion, and the storage of PRBCs at 4 °C minimizes the risk of infection. Nonetheless, PRBCs may become contaminated, most frequently with Yersinia enterocolitica. Platelets, which are stored at room temperature, are more problematic, with an estimated infection rate of 1:1000 to 1:2000 units. The most common organisms associated with platelet contamination are Staphylococcus species (especially S. aureus and S. epidermidis) and diphtheroids. The risk of infection is directly related to the storage time of the product, with 15% to 25% of infected units causing severe sepsis in the recipient. Signs of infection usually become apparent during transfusion and should trigger immediate discontinuation of the transfusion and testing of the unit for contamination. Individual outcomes from transfusion-related sepsis depend on the size of the bacterial inoculum and the immunocompetence of the recipient, but overall mortality remains high at approximately 60%.
  4. Transfusion-related immunomodulation. Transfusion of allogeneic blood is known to suppress the immune system. Although the exact mechanism is unknown, theories suggest that transfusion of donor leukocytes may induce an “immune-tolerant” state in the recipient. Thus, allogeneic blood transfusion has been used preoperatively and intraoperatively in renal transplant recipients to improve graft viability, although studies supporting this practice were largely performed prior to the advent of modern immunosuppressants such as cyclosporine. More controversial are the potential detrimental effects of intraoperative allogeneic blood transfusion on cancer recurrence rates, postoperative infections, activation of latent viral infections, and postoperative mortality. Some experts contend that many of the adverse immunomodulatory effects of allogeneic blood transfusion may be diminished by universal blood product leukoreduction, and promising research suggests that the use of leukoreduced blood products may improve survival in cardiac surgery. Universal leukoreduction protocols have therefore been increasingly adopted in various institutions.