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CRITICAL CARE AND TRAUMA

Severe Transfusion-Related Acute Lung Injury

Lukas Brander, MD^*, Angelika Reil, MD, Juergen Bux, MD, PhD, Behrouz Mansouri Taleghani, MD, Bruno Regli, MD^*, and Jukka Takala, MD, PhD^*

*Department of Intensive Care Medicine and Department of Hematology and Central Hematology Laboratory, Division of Transfusion Medicine, University Hospital-Inselspital, Bern, Switzerland; and Blood Transfusion Service, SRC Bern Ltd., Bern, Switzerland

Address correspondence to Lukas Brander, MD, Department of Intensive Care Medicine, University Hospital, Inselspital, 3010 Bern, Switzerland. Address e-mail to lukas.brander{at}insel.ch.

	Abstract

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A 46-yr-old man developed severe hypoxemia, pulmonary infiltrates, and an acute decrease in his leukocyte count shortly after transfusion of fresh-frozen plasma (FFP) during recovery from cardiac surgery. Cardiogenic pulmonary edema was excluded. Granulocyte-reactive and agglutinating alloantibodies were detected in the serum of the fresh-frozen plasma donor. The cross-match with the patient’s granulocytes revealed antibodies specific for HLA class I. Transfusion-related acute lung injury (TRALI) is a potentially life-threatening, under-recognized and under-reported complication of transfusion. Conservative transfusion strategies and preclusion of the implicated blood donors with granulocyte-reactive antibodies from future blood donation may prevent TRALI and could save lives.

	Introduction

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Transfusion-related acute lung injury (TRALI) denotes noncardiogenic pulmonary edema in conjunction with transfusion of plasma-containing blood products (1,2). TRALI is potentially life-threatening and ranks second only to ABO mismatch as a cause of transfusion-related fatalities, with an estimated incidence of 0.01% to 0.08% per plasma-containing unit transfused and an associated mortality rate of 5% to 14% (1–3). TRALI is probably one of the most under-diagnosed adverse effects of transfusion, particularly in its milder presentation (4,5). Although most TRALI cases occur in the operating room or intensive care unit (6), the condition has only rarely been reported in the anesthesiology literature.

	Case Report

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A dilated aortic root was an unexpected finding during evaluation of thoracic pain in a previously healthy 46-yr-old man. Surgical reconstruction of the aortic root with cardiopulmonary bypass was uneventful. Postoperative values are shown in Table 1. After the chest tubes drained 500 mL blood within the first hour of admission to the intensive care unit and with the values of coagulation study available (Table 1) 2 units of fresh-frozen plasma (FFP) were transfused. Except for propofol and fentanyl, no other medications were administered. Within 2 h after completion of the transfusion, partial oxygen pressure in arterial blood (Pao₂) rapidly decreased to 34 mm Hg while the patient was mechanically ventilated with an oxygen fraction in inspired air (Fio₂) of 1.0 and arterial blood pressure decreased from 100/60 mm Hg to 62/20 mm Hg. No erythema or urticaria was noticeable. An oximetry pulmonary artery catheter was inserted.

Auscultation of the chest revealed rales, and a chest radiograph was obtained (Fig. 1). Cardiac auscultation and an electrocardiogram were normal. Transesophageal echocardiography performed 45 min after transfusion showed normal myocardial function, intact heart valves, and no evidence of pericardial tamponade. The reaction started after the transfusion and when the FFP bags were no longer available for culture. Blood cultures remained sterile.

View larger version (117K): [in this window] [in a new window]   Figure 1. Anteroposterior chest radiograph in a supine position revealed extensive, diffuse bilateral pulmonary infiltrates consistent with pulmonary edema 1 h after transfusion of fresh-frozen plasma.

Initial resuscitation procedures comprised mechanical ventilation with positive end-expiratory pressure (15 cm H₂O), epinephrine (Table 1), 3000 mL IV fluids, muscle paralysis with vecuronium, meropenem, methylprednisolone, ranitidine, and clemastine. His mean arterial blood pressure increased from 40 mm Hg to more than 60 mm Hg within 30 min and Pao₂ increased from 34 mm Hg to 94 mm Hg (Fio₂ of 1.0) within 2 h. Bleeding was controlled without any further intervention. The patient’s condition improved within 25 h of transfusion and he was in excellent condition 1 yr after surgery.

Granulocyte-reactive and agglutinating alloantibodies were detected in the serum of one of the two FFP donors using granulocyte and lymphocyte immunofluorescence and granulocyte agglutination tests. The cross-match with the patient’s granulocytes and lymphocytes revealed antibodies specific for human leukocyte antigens (HLA) class I. Antibody specificity was confirmed by a glycoprotein-specific enzyme immunoassay (MAIGA).

	Discussion

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Acute lung injury can be caused by aspiration of gastric contents, pneumonia, major trauma, sepsis, acute pancreatitis, anaphylaxis, and transfusion of blood products (7). In this case, at least aspiration, sepsis, anaphylaxis, and transfusion of blood products had to be considered.

Based on the close timely correlation with FFP transfusion, the acute development and the severity of the oxygenation disturbance, the diffuse bilateral pulmonary infiltrates, the normal echocardiography findings, and the lack of a gradient between diastolic pulmonary artery pressure and pulmonary artery occlusion pressure suggesting increased pulmonary capillary permeability without increased capillary pressure, our initial differential diagnosis included TRALI and septic or anaphylactic shock with acute lung injury. Aspiration of gastric contents was unlikely and extracorporeal circulation, as well as cardiac surgery, were considered as possible predisposing factors.

TRALI was later confirmed by laboratory studies and the FFP donor, a multiparous, never-transfused woman, was precluded from future blood donation.

With TRALI, respiratory impairment normally occurs within 30 minutes to 2 hours, but it may develop as late as 6 hours after transfusion (1,8,9). Symptoms and signs range from mild dyspnea to full-blown respiratory failure, severe hypoxemia, and fever, and may develop suddenly and fulminantly. Severe forms are indistinguishable from the acute respiratory distress syndrome. The most consistent manifestations are dyspnea, cough, fever, diffuse bilateral pulmonary edema on chest radiograph, hypoxemia, leukopenia, and no evidence of heart failure (1).

Acute, severe leukopenia and restoration to marked leukocytosis within 24 hours was present in our case. With TRALI, leukopenia is assumed to be the result of sequestration of leukocytes in the pulmonary circulation, and leukocytosis might result from consecutive activation of the bone marrow to restore the circulating leukocyte pool. Unexplained leukopenia after transfusion may suggest TRALI.

Multiple factors may help explain the marked transient decrease in systemic blood pressure in our patient, such as intravascular hypovolemia (as a result of rewarming after surgery in conjunction with acute, increased permeability pulmonary edema), temporarily impaired systemic vasoregulation after extracorporeal circulation, and, possibly, cardiac dysfunction. We speculate that the initial increase in mean pulmonary artery pressure with normal or only slightly decreased cardiac output (increased pulmonary vascular resistance) might be explained by factors such as hypoxic pulmonary vasoconstriction, positive pressure ventilation, and potentially pulmonary capillary obstruction by agglutinated leukocytes.

Respiratory impairment in conjunction with transfusion of blood products should heighten the clinician’s suspicion of TRALI, and cardiogenic pulmonary edema must be excluded. Treatment is nonspecific and includes oxygen supplementation, mechanical ventilation, and hemodynamic support. Local transfusion facilities should trace the donor of suspect blood products and restrict transfusion of blood products from donors with leukocyte-reactive antibodies.

The pathogenesis of TRALI is not completely clear, but alloimmune mechanisms, including donor alloantibodies, have been identified to be directed against granulocytes or human leukocyte antigens (anti-HLA) (1). Implicated blood donors are usually multiparous women with antibodies produced after exposure to paternally derived alloantigens on the fetal leukocytes. In the antigen-positive recipient, leukocytes coated with recipient-type antibodies agglutinate and compartmentalize in the microvasculature of the lungs (10). As transfusion rates of antibody-containing blood components exceed the reported prevalence of TRALI, recipient-related predisposing factors and nonimmunologic mechanisms are currently under investigation (9,11). In the absence of antibodies against neutrophils, biologically active lipids may play an important role in the activation of neutrophils (12).

The true incidence of TRALI is likely to be underestimated (5). Mild to moderate cases might be misdiagnosed as volume overload, and acute lung injury from concomitant circumstances (such as trauma, sepsis, and hemorrhagic shock) might confuse recognition of TRALI. The combination of lack of awareness, high numbers of plasma containing blood products transfused, and the potential severity of the respiratory failure renders patients at risk. Reducing the numbers of blood products transfused by adhering to transfusion guidelines, timely tracing of implicated blood donors, and preclusion of donors with granulocyte-reactive antibodies from future blood donation, may prevent TRALI and potentially saves the lives of future transfusion recipients.

The authors are indebted to J. Wurz for assistance in the preparation of the manuscript.

	Footnotes

 
Lukas Brander is recipient of Grant 1130 of the Swiss Foundation for Fellowships in Medicine and Biology provided by Novartis AG.

Accepted for publication February 1, 2005.

	References

Top Abstract Introduction Case Report Discussion References

 

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3. Bux J. Transfusion-related acute lung injury: a neglected but life-threatening transfusion reaction. Infus Ther Transf Med 2004;29:271–6.
4. Popovsky MA. Transfusion-related acute lung injury. Curr Opin Hematol 2000;7:402–7.[ISI][Medline]
5. Wallis JP. Transfusion-related acute lung injury (TRALI): under-diagnosed and under-reported. Br J Anaesth 2003;90:573–6.[Free Full Text]
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7. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334–49.[Free Full Text]
8. Kopko PM, Marshall CS, MacKenzie MR, et al. Transfusion-related acute lung injury: report of a clinical look-back investigation. JAMA 2002;287:1968–71.[Abstract/Free Full Text]
9. 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.[Abstract/Free Full Text]
10. McCullough J, Clay M, Hurd D, et al. Effect of leukocyte antibodies and HLA matching on the intravascular recovery, survival, and tissue localization of 111-indium granulocytes. Blood 1986;67:522–8.[Abstract/Free Full Text]
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12. Silliman CC, Voelkel NF, Allard JD, et al. Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest 1998;101:1458–67.[ISI][Medline]

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999