What do you think of when you encounter oxygen desaturation in a patient being transfused? Hydrostatic pulmonary edema from fluid overload may be the most likely cause, especially in a patient with underlying heart disease. However, you should also consider permeability pulmonary edema caused by transfusion-related acute lung injury (TRALI).
TRALI is now the number one cause of transfusion-related death, according to the Food and Drug Administration report at the TRALI Conference in Toronto on April 1, 2004. The incidence reported in 1985 was 1 in 5000 U transfused at the Mayo Clinic (1). Although the current incidence is unknown, the syndrome is thought to be severely under-recognized and under-reported because of a lack of sensitive and specific diagnostic criteria and poor awareness of the syndrome outside blood banks. All blood products have been associated with TRALI, including whole blood, packed red cells, platelet products, fresh frozen plasma, and rarely, cryoprecipitate, IV immunoglobulin, and stem cell preparations (2).
The cause of TRALI is unclear, and two hypotheses have been proposed. One is that transfusion of donor plasma contains antibodies to white blood cells (WBCs) which react with and agglutinate patient WBCs if the patient has the corresponding antigen(s). These agglutinates lodge in the pulmonary capillary bed, fix complement, and injure the capillaries, causing capillary leak. WBC antibodies may be directed to human leukocyte antigen (HLA) class I or II antigens, or to granulocyte-specific antigens.
Recently, another hypothesis has been developed (3), proposing a causative role for inflammatory mediators in primed or susceptible patients (“two insult” hypothesis). According to this hypothesis, the first insult is the patient’s underlying condition (e.g., sepsis, surgery) that primes circulating neutrophils, sequestering them in the lungs. These primed neutrophils become activated and injure pulmonary capillaries if exposed to a second insult such as cytokines or lipids, which accumulate in the plasma of stored red blood cells and platelets. It is important to realize that the two hypotheses are not mutually exclusive, and clinical TRALI may be a common end result of various etiologic factors. Furthermore, multiple insults (underlying sepsis, mechanical ventilation, transfusion factors) frequently coexist and may be required for the development of acute lung injury (ALI).
The diagnosis is a clinical one, and there is no single test for TRALI. TRALI is clinically defined as a new onset ALI that develops during or within 6 h of transfusion. ALI was defined by the 1994 North American European Consensus Conference (4) as acute onset of bilateral infiltrates and hypoxemia in the absence of increased left atrial pressure. Hypoxemia was defined as a Pao2/Fio2 ratio of ≤300 mm Hg. Evidence of increased left atrial pressure includes pulmonary capillary wedge pressure >18 mm Hg or clinical evidence of left atrial hypertension, including signs of fluid overload, especially in a patient with underlying congestive heart failure. The presence of left atrial hypertension suggests hydrostatic pulmonary edema as a cause of acute hypoxemia and bilateral radiographic infiltrates. It is important to realize that ALI and hydrostatic pulmonary edema may coexist, and the presence of left atrial hypertension does not necessarily exclude a TRALI reaction. If undiluted edema fluid is obtained at the time of endotracheal intubation, the edema fluid to plasma protein ratio can be determined. A ratio of ≥0.6 suggests permeability (ALI) rather than hydrostatic pulmonary edema (5). Other signs and symptoms of TRALI include dyspnea, frothy edema fluid, fever, hypertension or hypotension (1).
In the absence of other risk factors for acute respiratory distress syndrome (ARDS), e.g., sepsis or gastric aspiration, any new ALI temporally associated with transfusion is TRALI. Even in the presence of ARDS risk factor(s), TRALI may still be a significant contributing factor. Alternatively, such new ALI could be attibuted to the ARDS risk factor alone, and the transfusion could have been coincidental and mechanistically unrelated.
Laboratory findings for TRALI are inconsistent and include acute transient neutropenia (6), matching leukocyte antigen-antibody in the donor-recipient, donor antibody that activates recipient monocytes (7), and increased neutrophil priming activity in the transfused unit(s) (3). The blood bank will determine the appropriateness and feasibility of such laboratory tests on donor and recipient blood.
Acute management is summarized in Table 1. Units of blood from donors other than that of the implicated unit(s) can be transfused without special requirements. The only caveat is to inform the blood bank that TRALI is being considered and not to send units from the same donor, in the unlikely event that such units are in the blood bank. Management is supportive, which is the same as management of any patient with permeability pulmonary edema, and often includes ventilatory support. Lung protective (small tidal volume) ventilatory strategies should be used. Unless there is concomitant fluid overload, diuretics are not beneficial.
Suspected TRALI reactions should be reported to the blood bank and a transfusion reaction workup initiated. In addition to a posttransfusion patient blood specimen, bags from units of blood transfused in the last 6 h should be returned so that donor plasma can be tested without recall of the blood donor. A copy of transfusion record forms and anesthesia record will allow determination of the sequence and timing of transfused units. Results of the patient’s HLA type, if available, are important to determine whether the donor(s) has corresponding HLA antibodies.
Most patients recover within 24–48 h with supportive care. Mortality has been reported to be 11% (1) to 45% (8). Fatal cases related to transfusion must be reported by the blood bank to the Food and Drug Administration within 72 h. Nonfatal cases of TRALI should be reported by the blood bank to MedWatch.
1. Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985;25:573–7.
2. Webert KE, Blajchman MA. Transfusion-related acute lung injury. Transfus Med Rev 2003;17:252–62.
3. Silliman CC, Boshkov LK, Mehdizadehkashi Z, et al. Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood 2003;101:454–62.
4. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818–24.
5. Fein A, Grossman RF, Jones JG, et al. The value of edema fluid protein measurement in patients with pulmonary edema. Am J Med 1979;67:32–8.
6. Yomtovian R, Kline W, Press C, et al. Severe pulmonary hypersensitivity associated with passive transfusion of a neutrophil-specific antibody. Lancet 1984;1:244–6.
7. Kopko PM, Paglieroni TG, Popovsky MA, et al. TRALI: correlation of antigen-antibody and monocyte activation in donor-recipient pairs. Transfusion 2003;43:177–84.
8. Wallis JP, Lubenko A, Wells AW, Chapman CE. Single hospital experience of TRALI. Transfusion 2003;43:1053–9.