Although cross-matching of donor and recipient blood and the advent of bloodcomponent therapy has signified a safer base for transfusion therapy, im-.
IntensiveCare Medicine
Intensive Care Med (1988) 14:654-657
© Springer-Verlag1988
Transfusion-related acute lung injury R. O. B. Gans, V. A. M. Duurkens, A. A. van Zundert and S. J. Hoorntje Department of Medicine, Catharina Hospital Eindhoven, The Netherlands Received: 15 June 1987; accepted: 15 May 1988
Abstract. Noncardiogenic pulmonary edema after transfusion therapy is an infrequent but hazardous complication. The occurrence of this entity is linked to the presence of circulating leukoagglutinins. The clinical features are described on the basis of four cases. The hemodynamic changes, underlying mechanisms and therapeutic strategies are discussed. Key words: Transfusion Noncardiogenic Pulmonary edema - Leukoagglutinins
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Although cross-matching of donor and recipient blood and the advent of bloodcomponent therapy has signified a safer base for transfusion therapy, immunologically and non-immunologically mediated transfusion reactions are still common and associated with a considerable morbidity and, to a lesser extent, mortality. Many of the non-hemolytic febrile transfusion reactions can be linked to circulating leukoagglutinins [1], but the relation of the latter with the occurrence of noncardiogenic pulmonary edema is still not fully appreciated. Recently we were able to diagnose this type of a transfusion reaction in four patients; on one of them we reported previously [2]. The clinical features are described and data are presented regarding the possible underlying mechanisms as well as therapeutic modalities. Methods Blood group compatibility was confirmed by retesting blood samples from each patient and all donor(s). Likewise the presence of IgA antibodies was excluded. Patient serum and serums of each donor were tested for the presence o f leucocyte antibodies by a leucocyte
agglutination test [3] and a lymphocyte cytotoxicity test [4]. A granulocyte immunofluorescence test [5] and a platelet immunofluorescence test [6] were performed in only two. Patient 1
A 42-year-old male underwent an anterior thoracic spondylodesis for vertebral fractures after a traffic accident. Initially both lungs were ventilated. Pulmonary artery pressures (PAP) were 28/12 mmHg, pulmonary capillary wedge pressure (PCWP) 10 mmHg and right atrial pressure (RAP) 7 mmHg. When one-lung ventilation was instituted, the PAP, P C W P and RAP all increased slightly. During surgery blood loss was replaced with a total of 6 units of whole blood. After 5 hours of stable ventilation the arterial PaO2 fell peroperatively suddenly from 110 to 4 7 m m H g whereas the pCO2 increased from 36 to 63 mmHg. At the same time the PAP increased to 53/28 mmHg with a P C W P of 1 5 m m H g and a RAP of 12mmHg. Arterial blood pressure was unchanged. Rectal temperature was 39.4 °C. After the institution of two-lung ventilation with 7.5 cmH20 positive end-expiratory pressure (PEEP) and a FiO 2 of 0.6, arterial blood gas determination showed a PaO 2 of 187 mmHg and a pCO 2 of 29 mmHg. A chest X-ray showed a normal cardiac silhouette and a diffuse fine alveolar opacification of the left lung, while the right lung showed a patchy infiltrate with a right-sided pleural effusion. The white blood count fell from 6.4× 109/1, preoperatively, to 3.6x109/1 w i t h 6% eosinophils. Because of the striking rise in body temperature, the maintenance of a strict fluid balance during the operation and the normal cardiac size without pulmonary vascular engorgement on the chest X-ray, a diagnosis of transfusion-related noncardiogenic pulmonary edema was considered most likely. An intravenous dose of 100rag dexamethasone was given. For the
R. O. B. Gans et al.: Transfusion-related acute lung injury same reasons, volume overload was discarded, despite the slight rise of P C W P ; consequently, no diuretics or positive inotropic drugs were administered. Blood cultures were performed, but antibiotics were withheld. The patient made an uneventful recovery with resolution of the radiological findings within 48 h. HLA-specific antibodies against leukocytes of the recipient were found in one of the 6 donors. The serum of the recipient did not contain antibodies against leukocytes of the donors (Table 1). All blood cultures remained sterile. Patient 2
A 28-year-old female underwent a hysterectomy for excessive and irregular uterine bleeding. The day before surgery she received two units of packed red cells without problems. Two days postoperatively she again received 1 unit of packed ceils. A few hours afterwards she had chills and became lethargic. Tachypnea and cyanosis were noted and arterial blood pressure measured 85/50 m m H g with a pulse rate of 140/rain. On auscultation fine rales were heard bilaterally over the lungs. Rectal temperature was 39.4 °C. A chest X-ray showed perihilar infiltrates without cardiac enlargement, consistent with acute pulmonary edema. Arterial bloodgas analysis showed a profound hypoxaemia, PaO 2 of 41 m m H g with a p C O 2 of 32 m m H g . On ventilatory support with a FiO 2 of 0.6 and P E E P of 10cmH20, the PaO2 increased to 1 3 7 m m H g . H e m o d y n a m i c analysis revealed a P C W P of 10 m m H g , a PAP of 26/10 m m H g , a R A P of 7 m m H g and a cardiac index of 3.1 1/min/m 2. An intravenous bolus of 100mg dexamethasone was given. Blood cultures were performed, but antibiotics were withheld. No positive inotropic support was needed. The
Table 1. Serological results
L.A.T. Patient Donor L.C.T. Patient Donor G.I.F.T. Patient Donor P.I.F.T. Patient Donor
Patient 1
Patient 2
Patient 3
Patient 4
Neg Weaklypos
Weakly pos Neg
Pos Neg
Neg Pos
Neg Pos
Pos Neg
Pos Neg
Neg Pos
n.t. n.t.
Weakly pos Neg
Neg Neg
n.t. n.t.
n.t. n.t.
Pos Neg
Pos Neg
n.t. n.t.
Abbreviations: L.A.T. = leucocyte agglutination test; L.C.T. = lymphocyte cytotoxicity test; G.I.F.T. = granulocyte immunofluorescence test; P.I.F.T. = platelet immunofluorescence test; n.t. = not tested
655 patient made a rapid recovery with disappearance of the radiological findings within 36 hours. Polyspecific HLA-antibodies against lymphocytes, platelets and, weakly, granulocytes of all three donors were found in the patient serum. The sera of the donors did not contain antibodies against leukocytes (Table 1). All blood cultures remained sterile. Patient 3
A 32-year-old male underwent an uneventful mitralvalve replacement. Postoperatively he remained stable and was subsequently transferred from the intensive care unit. On the fourth postoperative day he received one unit of packed red cells. After one hour he suddenly became severely dyspnoeic. Cyanosis was present and on auscultation fine tales were heard at the base of the lungs. Arterial blood pressure remained stable 120/70 m m H g with a pulse rate of 120/min. Rectal temperature was 38.7 °C. A chest X-ray revealed diffuse pulmonary edema with a normal cardiac silhouette. Arterial bloodgas analysis showed a p C O 2 of 34 m m H g and a PaO2 of 40 m m H g , improving to 87 m m H g after administration of 5 1 0 z by mask. An intravenous bolus of 100mg dexamethasone was given. Blood cultures were performed, but antibiotics were withheld. After 30 h his clinical status improved and no mechanical ventilation was needed. The radiological findings cleared after 52 hours. HLA-specific antibodies against leukocytes and platelets of the donor were found in the patient serum. No antibodies in the donor serum could be detected (Table 1). All blood cultures remained sterile. Patient 4
A 27-year-old female underwent a percutaneous nephrostomy because of one-sided hydronephrosis. Afterwards she received transfusion of 2 units of packed red cells. One hour after the transfusion she had chills and the sudden onset o f dyspnoe and cyanosis were noted. Blood pressure fell to 90/50 m m H g with a pulse rate of 120/min. Rectal temperature was 39 °C. A chest X-ray showed bilateral perihilar infiltrates and a normal cardiac silhouette. Bloodgas analysis showed a p C O 2 of 20 m m H g and a PaO2 of 54 m m H g , improving to 107 m m H g with the administration of 41 02 by mask. A Swan-Ganz catheter was inserted and revealed a PAP of 38/12 m m H g , R A P of 10 m m H g , a P C W P of 10 m m H g and a CI of 2.9 1/min/m 2. An intravenous bolus of 100mg dexamethasone was given. Blood cultures were performed, but no antibiotics were given. Neither inotropic support, nor mechanical ventilation was required. After 32 hours the PAP fell gradually down to
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R.O.B. Gans et al.: Transfusion-relatedacute lung injury
Fig. 1. Typicalradiologicalfindings (patient 2) showingbilateral pulmonaryinfiltrateswithout cardiacenlargementconsistentwith acute noncardiogenic pulmonary edema Fig. 2. Chest X-ray of patient 2 showing completeresolution of the pulmonary infiltrates within 36 h
26/8 mmHg with a RAP of 6 mmHg; a chest X-ray taken at the same time showed some residual rightsided pleural effusions. HLA-specific antibodies against leukocytes of the patient were found in one of the donors serum. No leukocyte antibodies in the serum of the recipient could be demonstrated (Table 1). All blood cultures remained sterile. Discussion The various types of cardiac and noncardiac pulmonary edema are sometimes virtually indistinguishable. Pulmonary edema developing during or following transfusion therapy may represent such a problem. Mostly it will be ascribed to circulatory overload. However, it is not until recently that the occurrence of pulmonary edema after a transfusion of whole blood or its components has been linked to circulating antileukocyte antibodies. With an estimated incidence of 1:5000 transfusions, the occurrence o f this type of transfusion-related acute lung injury is rather infrequent [7]. Still, considering the huge daily practice of transfusion therapy it is remarkable that this syndrome has not been described more often in intensive care journals. All our patients had a rather uniform but nonspecific clinical picture with chills, fever, tachycardia with or without hypotension, and various degrees of respiratory distress. The chest X-ray demonstrated perihilar pulmonary infiltrates without cardiac
enlargement or pulmonary vascular engorgement, compatible with acute noncardiogenic pulmonary edema (Fig. 1). Hemodynamic monitoring confirmed the absence of left ventricular failure, as denoted by a P C W P and cardiac indices within normal limits. A diagnosis of a sepsis was discarded, because of the rapid hemodynamic stabilization with adequate oxygenation, the absence of a hyperdynamic state and, last but not least, familiarity with this type of transfusion reaction. Notably, pulmonary artery pressures were elevated in two of our patients, whereas in previous cases this has been infrequently reported [8]. The passive transfer of donor antibodies against leukocytes [9-12], as well as, more rarely, leukocyte antibodies in the recipient serum [9, 13], or interdonor leukocyte reactions [14], have been implicated in this form of acute lung injury. The most convincing evidence was produced by Brittingham, who administered 50 ml of leukoagglutinin-containing whole blood into a normal subject who subsequently developed the described clinical picture [16]. Others have made similar observations and additional support is provided by the frequent occurrence of severe pulmonary reactions after granulocyte-transfusion therapy [15]. Still, a positive cause and effect relation is not conclusively established. The role of pulmonary leukostasis per-se in the pathogenesis of this syndrome is also unclear [17]. In the few autopsies thusfar performed, neither the presence of prominent aggregates of leukocytes nor
R. O.B. Gans et al.: Transfusion-related acute lung injury
the presence of immunoglobulin - or C 3 - deposits were found [10, 13]. Leucopenia is usually not seen either, however this can be a transient phenomenon. Finally, the more or less expected increase of pulmonary artery pressures is usually absent, but this naturally depends on both the extent of the reaction with its concomitant hypoxaemia as well as the ability to recruit normally underperfused areas of the pulmonary vasculature. Some support for this latter mechanism in preventing a rise in pulmonary pressures is provided by patient 1. With one-lung ventilation the ventilated lung received the greater part of the right ventricular output with only a slight increase of pulmonary pressure due to recruitment of pulmonary vessels. Potential microemboli, e.g. leukocyte-aggregates, would also be preferentially distributed to this lung. This can explain the marked increase of pulmonary pressures in this patient noted, since the ability to recruit additional vessels was already diminished. Although the presence of antileucocyte antibodies appears to be the trigger in the development of this syndrome, its infrequent occurrence in contrast to the relatively high incidence of leucocyte antibodies in the donor pool [11], suggests that other factors such as the character of the antibody, the nature and distribution of the related antigen, the initiation and extent of concomitant complement activation and probably other synergistic operating mechanisms as well e.g. hypoxia and platelet-interaction, are important variables determining the final clinical response [18, 19]. Adequate respiratory support, not infrequently necessitating mechanical ventilation with the addition of P E E P forms the mainstay of treatment and usually suffices to overcome the effect of the pulmonary damage done. Most patients show a rapid recovery with the resolution of the pulmonary infiltrates within four days (Fig. 2). However, irreversible respiratory failure has been reported [6]. Corticosteroids may be of potential benefit since they are capable of inhibiting the release of mediators from - and the aggregation of - granulocytes [18]. Conclusive evidence of their efficacy in this condition though is still lacking. Occasionally the use of diuretics has been reported, but their use in the absence of left ventricular failure is not without danger [12]. Prevention of the syndrome is difficult. The available assays do not yet reliably predict these transfusion reactions [20]. Although others have advocated to use blood of implicated donors only as frozen or washed red cells [6], the most feasible approach is probably to abandon its use completely. In conclusion transfusion-related noncardiogenic pulmonary edema is relatively rare. A high index of suspicion and the appropriate clinical picture in close association with a transfusion should make one aware of this probable diagnosis. Adequate respiratory sup-
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port is of prime importance. On theoretical grounds, corticosteroids may be of potential benefit. References 1. Perkins HA, Payne R, Ferguson J, Wood M (1966) Nonhemolytic febrile transfusion reactions. Vox Sang 11:578 2. De Wolf AM, van den Berg BW, Hoffman H J, van Zundert AA (1987) Pulmonary dysfunction during one-lung ventilation caused by HLA-specific antibodies against leukocytes. Anesth Analg 66:463 3. McCullough J, Clay ME, Priest JR, Jensen N J, Hau S, Noreen H J, Krivit W, Halezari P (1981) A comparison of methods for detecting leucocyte antibodies in auto-immune neutropenia. Transfusion 21:483 4. National Institute of Allergy and Infectious Diseases (1980) Manual of tissue typing techniques. National Institutes of Health, Bethesda, 92 (DHEW puplication no (MH) 80-545) 5. Verheugt FWA, Borne AEG, Decary F, Engelfriet CP (1977) The detection of granulocyte alloantibodies with an indirect immunofluorescence test. Br J Haematol 36:533 6. Borne AEG, Helmerhorst FM, van Leeuwen EF, Pegels JG, von Riesz E, Engelfriet CP (1980) Autoimmune thrombocytopenia: detection of platelet autoantibodies with the suspension immunofluorescence test. Br J Haematol 45:319 7. Popovsky MA, Moore SB (1985) Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 25:573 8. Latson TW, Kickler TS, Baumgartner WA (1986) Pulmonary hypertension and noncardiogenic pulmonary edema following cardiopulmonary bypass associated with an antigranulocyte antibody. Anesthesiology 64:106 9. Ward H (1970) Pulmonary infiltrates associated with leukoagglutin transfusion reactions. Ann Intern Med 73:689 10. Kernoff PBA, Durrant I J, Rizza CR, Wright FW (1972) Severe allergic pulmonary oedema after plasma transfusion. Br J Haematol 23:777 11. Popovsky MA, Abel MD, Moore SB (1983) Transfusion-related acute lung injury associated with passive transfer of antileukocyte antibodies. Am Rev Respir Dis 128:185 12. Levy GJ, Shabot NM, Hart ME, Mya WW, Goldfinger D (1986) Transfusion-associated noncardiogenic pulmonary edema. Transfusion 26:278 13. Wolf CFW, Canale VC (1976) Fatal pulmonary hypersensitivity reaction to HL-A incompatible blood transfusion. Transfusion 16:135 14. Andrews AT, Zmijewski CM, Bowman HS, Reihart JK (1976) Transfusion reaction with pulmonary infiltration associated with HL-A-specific leukocyte antibodies. Am J Clin Pathol 66:483 15. Higby DJ, Burnett D (1980) Granulocyte transfusions: current status. Blood 55:2 16. Brittingham TE (1957) Immunologic studies on leucocytes. Vox Sang 2:242 17. Fountain SW, Martin BA, Musclow CE, Cooper JD (1980) Pulmonary leukostasis and its relationship to pulmonary dysfunction in sheep and rabbits. Circ Res 46:175 18. Jacob HS (1983) Complement-mediated leucoembolization. Q J Med 207:289 19. Westaby S (1986) Mechanisms of membrane damage and surfactant depletion in acute lung injury. Intensive Care Med 12:2 20. Ungerleider RS, Appelbaum FR, Trapani R J, Deisseroth AB (1979) Lack of predictive value of antileukocyte antibody screening in granulocyte transfusion therapy. Transfusion 19:90 Dr. R.O.B. Gans , Department of Medicine Free University Hospital De Boelelaan 1117 NL-1081 HV Amsterdam, The Netherlands
