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Transfusion related lung injury. TRALI
Current Anaesthesia & Critical Care 20 (2009) 93–97
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Current Anaesthesia & Critical Care journal homepage: www.elsevier.com/locate/cacc
HAEMATOLOGY
Transfusion related lung injury. TRALI Neil Soni Department of Anaesthesia, Chelsea and Westminster Hospitals, 369 Fulham Road, London SW10 9NH, UK
s u m m a r y Keywords: HLA TACO TRALI
Transfusion related lung injury is almost certainly related to the administration of blood products containing antibodies in the plasma. Those antibodies may have developed during pregnancy or following blood transfusion. They react with specific ‘cognate’ antigens in the recipient and in some patients, but not all, this results in an acute lung injury pattern. The problem resides in the plasma, so the incidence with FFP is far higher than with red cells. Blood transfusion services have adopted several ways of reducing risk such as using untransfused male donors. Leucodepletion may also have a benefit. Diagnosis is an issue as it is easily confused with transfusion associated circulatory overload TACO and often the right preconditions exist for both. Although most sources agree that the condition usually occurs within 6 h of transfusion some new information from critically ill patients has suggested that a condition called ‘delayed TRALI’ may exist, but this is currently contentious. The natural history of the condition is extremely variable and there is an associated mortality, 5–10%. Most patients do require ventilation but most do well. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction TRALI is described as acute dyspnoea with hypoxia and new or worsening pulmonary infiltrates arising during or within 6 h of transfusion of plasma, cellular blood components or immunoglobulins.1 Blood transfusion has always had associated risks. The risks were those intrinsic to the stored blood, such as infection or immunological reaction. The latter may be from ABO or other sources of incompatibility and in particular granulocyte or HLA antibodies. The reaction is between the donor plasma and recipient. Under this general description comes the syndrome of TRALI, transfusion related lung injury, which is an immunological response to blood products. Other risks could be considered extrinsic. These include transfusion associated circulatory overload, TACO. This is associated with fluid administration often in circumstances where there are significant fluid shifts, such as in resuscitation, or where there is cardiovascular instability either from the acute illness itself or from existent comorbidity. Particularly susceptible to TACO are patients perceived to already have a predisposition to pulmonary interstitial oedema usually associated with what is conceptually described as increased pulmonary ‘capillary permeability’, such as those with sepsis. In recent times despite the massive publicity associated with infection risk, that risk is actually diminishing. Paradoxically the
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relative importance of TRALI is rising and with a rate reputedly approaching 1 per 5000 transfusions.2 Some sources suggest that it is now the most common single cause of transfusion related death. FFP is the product most commonly implicated accounting for half of all cases with red cells about a third.3,4 In the UK an average of 20 cases of TRALI are reported a year with about half being ‘probable’ (see below). Almost all cases were within 6 h of a products transfusion so that now the definition of TRALI suggests the time limit for temporal association is 6 h. Seventy percent of these patients required admission to ITU and about half were ventilated. Mortality was about 20% in those meeting TRALI criteria.1 TACO is usually considered to be an obvious and easy diagnosis and curiously seems to have a limited place in the review of transfusion related problems, yet clinically in acute situations TACO is seen as a real and present danger. This will be discussed later as the boundary between TRALI and TACO is rarely distinct. 2. TRALI; postulated mechanisms It is generally considered that TRALI is an immunologically mediated reaction and that it constitutes a form of incompatibility between donor blood product and the recipient. In the majority of cases described as TRALI, HLA or neutrophil-specific antibodies could be found in the plasma of one or more of the donors. A corresponding antigen was often found in the recipient. It was, therefore, proposed that this antibody – antigen reaction triggers an inflammatory response. The response affects pulmonary
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endothelium increasing permeability and allowing interstitial oedema to form. This is supported by reports of two healthy volunteers in studies who developed TRALI in response to HLA antibodies.5,6 It seems clear that HLA antibodies can cause TRALI. It has also been shown that the interaction between HLA-DR and DR13 antigen in vitro stimulates inflammatory cytokine release from monocytes. So there is a mechanism, in vitro, for a TRALI type reaction.7 While this is currently accepted as the predominant mechanism almost every reported series has cases where no white cell antibodies in the donor can be found. This has been called antibody negative TRALI. The incidence of this may be between 11% and 39% depending on sources.8,9 A second mechanism is, therefore, postulated. For this mechanism the storage of blood allows the release of cell components in particular lipids. These agents will promote neutrophil activation and are in effect ‘priming agents’. In sick patients, whether from blood loss or infection, there is already a degree of activation of their immune system and this is susceptible to further activation if a priming agent is infused. The transfusion infuses the free lipid components from cells and primes the reaction. This is called the ‘two hit’ mechanism for TRALI.10–12 Given the relatively non-specific nature of TRALI as a predominantly clinical description it is not unreasonable to consider that a range of ‘insults’ could produce this rather general picture (see below) but nevertheless it seems quite clear that in many cases HLA antibodies play a significant role.13 The situation is made more complex by the prevalence of HLA antibodies in blood products. When cryoprecipitate, fresh frozen plasma red cells and apheresis platelets were analysed, 22% contained HLA alloantibodies with a high preponderance in the plasma of female donors.14 Case reports of TRALI and the likely trigger demonstrating some of the spectrum of both products and antibodies. Product
Reaction
Red blood cells15,16 Platelets14,17,18 Immunoglobulins19,20
HLA antibody, antigranulocyte antibodies Antigranulocyte antibody HNA-3a. Lipids Cryglobulinaemia in Sjogrens. Granulocyte reactive antibody. HLA antibodies Granulocyte reactive antibodies HLA antibodies in plasma HLA antibodies and Fcgamma R111b reactivity
FFP21 FFP22 Plasma exchange – plasma23,24 Anti-D25
3. Methods of reducing risk FFP or cryosupernatant has six times and platelets eight times the risk of TRALI than for red blood cells.1 If potential donors who may have antibodies can be identified then the risks could be reduced. It is quite clear that multiparous females have a higher incidence of HLA antibodies. A single pregnancy is associated with 10% of women having one or more HLA antibodies and multiple pregnancies it rises to 25–30%. This may also be the case in donors who themselves have had blood products previously where the rate may be as high as 50%.26 Circumstantial evidence comes from an observation that transfusion of plasma from multiparous donors seems to result in a higher incidence of lung dysfunction in critically ill patients.27 Therefore, screening donors for pregnancy or transfusion would seem a simple step. Screening previously pregnant apheresis donors for HLA antibodies can be done. The yield shows 18% of these donors have HLA antibodies.28 In another report 40% of multiparous women had either granulocyte or HLA antibodies. The authors point out that of the cases of TRALI occurring 2 of 3 did not involve multiparous donors.29 Screening is expensive and does not prevent all TRALI. It is also important to appreciate that even with HLA antibodies in the
donor and cognate antigens in the recipient, TRALI does not necessarily occur.30,31 Nevertheless it seems logical that the risk must be reduced if the donors are known to be antibody free.32 Using only untransfused male donors may be easier still.33 Leucoreduction should in theory be helpful and that has been standard in the UK since 1999. Prestorage white cell reduction appears to reduce the incidence of general non-haemolytic reactions.34 With platelets, risk may be reduced by using platelet additive solutions and thence removing 70% of the plasma or by suspending the platelets in male donor plasma.35,36 The type of plasma used may help. Quarantine–stored FFP (QFFP) comes from a single donation while methylene blue-light treated plasma (MLP) uses a chemical and ultraviolet light to treat plasma. Neither reduces TRALI risk but solvent/detergent treated plasma (SDP) are derived from large plasma pools and have a lower TRALI risk.3,37 A further strategy is to reduce the use of blood products and to encourage clinicians to be more discerning in the use of FFP. For example, using FFP to reverse warfarin poses risks not present with prothrombin complex. In the UK, a strategy to reduce risk by firstly using plasma from male donors for FFP and, secondly, suspension of buffy coat derived pooled platelets where possible. Also all products are leucoreduced from late 1999 so that red blood cells will usually have less than 30 ml plasma, although cases where less than 20 ml of residual plasma triggered TRALI have been reported.36 The incidence of TRALI appears to be falling. 4. Clinical description of TRALI Acute dyspnoea with hypoxia and new or worsening pulmonary infiltrates arise during or within a few hours of transfusion of plasma, cellular blood components or immunoglobulins. Originally the definition of a few hours was up to 24 h, but as of 2006 it has been reduced to 6 h. When histology is available it shows the lungs have oedema with proteinaceous fluid, there is capillary leucostasis and neutrophil sequestration.10 Pleural effusions are common. In one study of two cases, alveolar damage was not seen which may reflect the rapidity of the demise in these cases.38 Various other laboratory tests have been suggested to be diagnostically helpful. Transient leucopenia associated with pulmonary oedema has been described and an elevated fluid/plasma protein ratio may indicate TRALI.39 Attempts to use atrial natriuretic peptide to differentiate between TACO and TRALI have shown the test to be unhelpful.40 In effect there is no rapid clinically relevant diagnostic test. Immunological testing is not a rapid diagnostic method. Hence, emphasis has remained on clinical diagnosis. This syndrome is, in practice, often difficult to differentiate from other causes. Hence a means of assessing the likelihood of TRALI has evolved and is described in Table 1. 5. Serology Positive serology is the presence of donor white blood cell (WBC) antibodies which correspond with one or more recipient antigens and/or a positive white blood cell crossmatch between donor and recipient. Donor WBC antibodies that fail to recognise cognate antigens in the recipient samples are considered irrelevant. Of course this is only valid if the recipient samples are available. Ideally, finding neutrophil or HLA antibodies in the donor plasma which is shown to have specificity for one of the recipient’s HLA antigens or alternatively a white cell crossmatch indicates TRALI. In a New Zealand report 88% of cases HLA antibodies were found and just over half of these had either an antigen or a positive
N. Soni / Current Anaesthesia & Critical Care 20 (2009) 93–97 Table 1 Diagnosis of TRALI. Probability Description Highly likely Probable
Possible Unlikely
No other cause identified for the symptoms and positive serology. Either positive serology as defined below but with other causes for symptoms also present OR no other causes present, but with either absent or incomplete serology. Clinical picture compatible with TRALI, with no other cause present, but results of patient and donor investigation negative as defined below. Another cause of symptoms present AND results of patient and donor investigation negative.
crossmatch.41 In the UK, white cell antibodies in the donor with cognate antigen in the recipient were found in 65% of cases. All the donors were female. To clarify the position: Donor antibodies should not be there. They will often be there in multiparous women. They may also be present in any donor who has previously had a blood transfusion. Cognate antigens are unfortunately very common in recipients with some suggesting up to 70% of a normal population of recipients. An implicated component is one that is transfused from a donor with positive serology. In patients with probable TRALI and without positive serology it is impossible to determine which component is the cause unless only one was given. It is the donor side that is more relevant. HLA antibodies do not always result in TRALI.
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is very sick has had a massive transfusion, with some renal failure, some cardiac failure and maybe a suggestion of sepsis both TACO and TRALI could be present. While this example is clearly exceptional some degree of complexity in the clinical scenario is far more common than the simple transfusion with obvious cause and effect. Added to this is the fact that a relatively small volume of blood products may produce TACO in a susceptible individual. In many acute situations the patient, even if previously young and fit, may be transiently susceptible to rapid infusion, while in the older or more infirm population susceptibility is more obvious. Fluid given quickly, the failing ventricle, the ‘leaky lungs from trauma or sepsis all predispose to fluid-induced pulmonary oedema. Then there is the issue of filling pressures. Measurement supposedly clarifies whether it is a high filling pressure ‘cardiogenic’ situation or a low pressure ‘noncardiogenic’ state. This assumes a static state where raised pressures stay raised and low pressures stay low. In reality, it is almost always a dynamic situation with fluctuations in filling pressures, ventricular function and the formation of oedema changing with time and not a fixed phenomenon. Filling pressures when measured may not reflect what was happening when the event occurred. Flooding the lungs with oedema may actually reduce filling pressures as the fluid has by definition, relocated. This all compromises differentiation of TACO and TRALI. TACO is very common in the acutely sick, in those being resuscitated and especially in those critically ill with comorbidities. It is a diagnosis in the forefront of a clinicians mind and a condition that is perceived as avoidable and hence should be avoided. TRALI as a diagnosis rarely occupies pole position but could be a preferable and more honourable diagnosis than fluid overload. The differential is fraught but TACO is more common. These two cases may serve to illustrate the diagnostic dilemma that TRALI poses.
6. Natural history 7.1. Case 1 It is difficult to define the natural history of TRALI. The temporal relationship currently used implies severe lung dysfunction occurring within 6 h of transfusion. About 60–70% of these cases require ventilation. Most cases will resolve relatively quickly over hours or days and one paper suggests that the infiltrates clear on Xray in less than 96 h in most patients.9 In about 20% of all cases, the lung injury will be sustained often associated with the other comorbidities making differentiation of the TRALI component difficult. It will also make the mortality attributable to TRALI almost impossible to define. A mortality of 5–10% has been quoted.42,43 Treatment is supportive. A large diuresis after a small dose of diuretic might indicate a volume component but is by no means diagnostic. 7. Clinical practice In clinical practice products are used by a range of clinicians. In the oncological haematological areas where products are used extensively but usually in a semi-elective situation it is assumed that most haematologists know about the condition. In the ward scenario where products are given electively the knowledge base amongst junior doctors and nurses may be poor. In the acute scenario where surgeons, anaesthetists and intensivists are using blood products urgently not only may the knowledge base may be weak, but also there may be complex scenarios where TRALI seems a rather distant possibility.44 The implication is that it may be far more common and is under reported. The real problem with TRALI is that it is a clinical diagnosis often in a difficult or complex clinical scenario. If a patient is well and has a single unit of blood product and develops the classical syndrome it is easy to make the diagnosis with cause and effect. If the patient
A young patient with a haematological disorder needs platelets. An elective platelet transfusion is half way through the infusion when the patient complains of dyspnoea and their saturations fall. An X-ray shows bilateral infiltrates. The patient is admitted and improves on oxygen over the next 12 h. The clinician suspects TRALI and reports the case and the surveillance team undertakes testing and finds antibodies in donor platelets. 7.2. Case 2 A 75-year-old man with known ischaemic heart disease is admitted with major lower GI bleeding. He is profoundly hypotensive and in atrial fibrillation at a rate of 150 beats per minute. His initial CVP is very low. He is resuscitated and improves after 2 l of crystalloid, 1 l of colloid and four units of blood. Cold and shut down, his CVP is now high. He is taken to theatre where he has an attempted colonoscopy which has to be abandoned and proceeds to hemicolectomy during which he requires inotropes and fluid with a falling CVP. There is some surgical spillage of watery faeces and blood into the peritoneal cavity. After a stormy 4 h he is bleeding from multiple sites and his clotting is deranged. He is given FFP and platelets. He has a further six units of blood and at least two more litres of crystalloid. He is returned to ICU ventilated and with ongoing bleeding. His oxygen requirements are high and he has bilateral pulmonary infiltrates. His CVP is 7 cm H2O. Overnight he settles, warms and dilates and needs more fluid with a very low CVP. He remains ventilator dependent and the CVP is now 5 cm H2O. On the round TRALI is suggested. In case 1 there is no real possibility of TACO and there is only the platelets that are implicated and there is the right temporal
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association. TRALI is highly likely and is confirmed on testing. In the second case the situation is more confused but is a common type of presentation. It is highly likely this patient will have oxygenation problems and pulmonary infiltrates given these circumstances and one does not need to invoke TRALI as the cause. He has profound hypotension, a massive transfusion and faecal spillage all predisposing to lung problems and if he has ventricular impairment then some failure might have occurred. TACO almost certainly occurred at some stage during all these fluid shifts but may have been transient. The CVP was both high and low at different times but afterwards when his ventricular function returned towards normal the CVP was reasonably low. That CVP seen in ICU hours later says little about the dynamic fluid shifts previously. Temporally he is right for TRALI but it is only one of many potential reasons for the infiltrates. The diagnosis is difficult. Even if a donor unit proved positive for antibodies it would not necessarily be TRALI as not all transfused donor antibodies result in TRALI. Diagnostically it would be possible TRALI. This emphasises the difficulties with the diagnosis and the potential difficulties in confirming the event was TRALI. A new dilemma is arising in the study of the critically ill where sickness is associated with the necessity to use blood products and the possibility of TRALI while providing the ideal scenario for TACO. A recent study has indicated that in the critically ill 8% of transfused patients developed an ALI picture within 6 h of transfusion. Risk factors included sepsis and alcohol abuse, but most interesting was the odds ratio of a patient with ALI having had products from a female donor was 5.09. The odds ratios for pregnancies amongst donors, antigranulocyte antibodies in donors and lysophosphatidylcholine in the product were all increased.45,46 It has also been suggested that the development of ALI in the 6–72 h after transfusion is common and occurs in up to 25% of critically ill patients. Seventy-two hours is a long time in ICU and defines a population who are sick enough to stay in ICU greater than 72 h as the average stay in many units in Europe, is less than this. There was circumstantial evidence to suggest TRALI. The authors of that study considered these patients to have possible TRALI and have coined the term ‘delayed TRALI syndrome’’.47 This potentially poses problems for surveillance programs. 8. Conclusions TRALI is a clinical diagnosis which is relatively difficult to make and expensive to confirm. As it overlaps with TACO it is hard to differentiate the two in situations where both are possibly present. Considering the diagnosis is key to making the diagnosis, and in turn determining its true incidence, which may be underestimated. Prevention may be the key. As donor antibodies are implicated, most of the time, efforts to reduce exposure to donor units with antibodies focuses on identifying multiparous donors or those who have had blood transfusions. Education will potentially reduce inappropriate plasma administration and techniques such as leucoreduction of red cells may also have a role albeit hard to prove currently. Recent publications suggest that there may be growing interest in the critically ill where the condition may be camouflaged by all the other clinical events occurring. Increasing awareness of the problem will almost certainly increase the rate of provisional diagnosis of TRALI in the critically ill, and will expose even more difficult clinical scenarios to unravel for those involved in surveillance. References 1. Chapman CE, Stainsby D, Jones H, Love E, Massey E, Win N, et al. Ten years of hemovigilance reports of transfusion-related acute lung injury in the United Kingdom and the impact of preferential use of male donor plasma. Transfusion; 2008 Oct 28.
2. Cruz J, Skipworth E, Blue D, Waxman D, McCarthy L, Smith D. Transfusionrelated acute lung injury: a thrombotic thrombocytopenic purpura treatmentassociated case report and concise review. J Clin Apher 2008;23(2):96–103. 3. Flesland O. A comparison of complication rates based on published haemovigilance data. Intensive Care Med 2007 Jun;33(Suppl. 1):S17–21. 4. Holness L, Knippen MA, Simmons L, Lachenbruch PA. Fatalities caused by TRALI. Transfus Med Rev 2004 Jul;18(3):184–8. 5. Flesch BK, Neppert J. Transfusion-related acute lung injury caused by human leucocyte antigen class II antibody. Br J Haematol 2002 Mar;116(3):673–6. 6. Dooren MC, Ouwehand WH, Verhoeven AJ, von dem Borne AE, Kuijpers RW. Adult respiratory distress syndrome after experimental intravenous gammaglobulin concentrate and monocyte-reactive IgG antibodies. Lancet 1998 Nov 14;352(9140):1601–2. 7. Sakagawa H, Miyazaki T, Fujihara M, Sato S, Yamaguchi M, Fukai K, et al. Generation of inflammatory cytokines and chemokines from peripheral blood mononuclear cells by HLA Class II antibody-containing plasma unit that was associated with severe nonhemolytic transfusion reactions. Transfusion 2007 Jan;47(1):154–61. 8. Popovsky MA, Haley NR. Further characterization of transfusion-related acute lung injury: demographics, clinical and laboratory features, and morbidity. Immunohematology 2000;16(4):157–9. 9. Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985 Nov–Dec;25(6):573–7. 10. Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury (TRALI). Br J Haematol 2007 Mar;136(6):788–99. 11. Curtis BR, McFarland JG. Mechanisms of transfusion-related acute lung injury (TRALI): anti-leukocyte antibodies. Crit Care Med 2006 May;34(5 Suppl.):S118–23. 12. Silliman CC. The two-event model of transfusion-related acute lung injury. Crit Care Med 2006 May;34(5 Suppl.):S124–31. 13. Middelburg RA, van Stein D, Briet E, van der Bom JG. The role of donor antibodies in the pathogenesis of transfusion-related acute lung injury: a systematic review. Transfusion 2008 Oct;48(10):2167–76. 14. Bray RA, Harris SB, Josephson CD, Hillyer CD, Gebel HM. Unappreciated risk factors for transplant patients: HLA antibodies in blood components. Hum Immunol 2004 Mar;65(3):240–4. 15. Guglin M, Dey C, Meny GM, Sultan W, Weisberg LS. Pulmonary edema after transfusion in a patient with end-stage renal disease. Clin Nephrol 2003 Jun;59(6):475–9. 16. Laoutid J, Baite A, Atmani M, Safi L. Transfusion-related acute lung injury. A case report. Ann Fr Anesth Reanim 2007 Oct;26(10):855–8. 17. Ganguly S, Carrum G, Nizzi F, Heslop HE, Popat U. Transfusion-related acute lung injury (TRALI) following allogeneic stem cell transplant for acute myeloid leukemia. Am J Hematol 2004 Jan;75(1):48–51. 18. Silliman CC, Boshkov LK, Mehdizadehkashi Z, Elzi DJ, Dickey WO, Podlosky L, et al. Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood 2003 Jan 15;101(2):454–62. 19. Cailleux N, Levesque H, Bastit D, Cuvelier A, Muir JF, Courtois H. A rare cause of intra-alveolar hemorrhage: a transfusion-related incident with leukoagglutination due to antigranulocyte antibodies (Trali syndrome). Rev Med Interne 1998 Jun;19(6):434–7. 20. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001 Feb;41(2):264–8. 21. Brander L, Reil A, Bux J, Taleghani BM, Regli B, Takala J. Severe transfusionrelated acute lung injury. Anesth Analg 2005 Aug;101(2):499–501. table of contents. 22. Davoren A, Smith OP, Barnes CA, Lawlor E, Evans RG, Lucas GF. Case report: four donors with granulocyte-specific or HLA class I antibodies implicated in a case of transfusion-related acute lung injury (TRALI). Immunohematology 2001;17(4):117–21. 23. Askari S, Nollet K, Debol SM, Brunstein CG, Eastlund T. Transfusion-related acute lung injury during plasma exchange: suspecting the unsuspected. J Clin Apher 2002;17(2):93–6. 24. Mateen FJ, Gastineau D. Transfusion related acute lung injury (TRALI) after plasma exchange in myasthenic crisis. Neurocrit Care 2008;8(2):280–2. 25. Berger-Achituv S, Ellis MH, Curtis BR, Wolach B. Transfusion-related acute lung injury following intravenous anti-D administration in an adolescent. Am J Hematol 2008 Aug;83(8):676–8. 26. Powers A, Stowell CP, Dzik WH, Saidman SL, Lee H, Makar RS. Testing only donors with a prior history of pregnancy or transfusion is a logical and costeffective transfusion-related acute lung injury prevention strategy. Transfusion 2008 Dec;48(12):2549–58. 27. Palfi M, Berg S, Ernerudh J, Berlin G. A randomized controlled trial of transfusion-related acute lung injury: is plasma from multiparous blood donors dangerous? Transfusion 2001 Mar;41(3):317–22. 28. Insunza A, Romon I, Gonzalez-Ponte ML, Hoyos A, Pastor JM, Iriondo A, et al. Implementation of a strategy to prevent TRALI in a regional blood centre. Transfus Med 2004 Apr;14(2):157–64. 29. Sachs UJ, Link E, Hofmann C, Wasel W, Bein G. Screening of multiparous women to avoid transfusion-related acute lung injury: a single centre experience. Transfus Med 2008 Dec;18(6):348–54. 30. Nicolle AL, Chapman CE, Carter V, Wallis JP. Transfusion-related acute lung injury caused by two donors with anti-human leucocyte antigen class II antibodies: a look-back investigation. Transfus Med 2004 Jun;14(3):225–30. 31. Zupanska B, Uhrynowska M, Michur H, Maslanka K, Zajko M. Transfusionrelated acute lung injury and leucocyte-reacting antibodies. Vox Sang 2007 Jul;93(1):70–7.
N. Soni / Current Anaesthesia & Critical Care 20 (2009) 93–97 32. Maslanka K, Michur H, Zupanska B, Uhrynowska M, Nowak J. Leucocyte antibodies in blood donors and a look back on recipients of their blood components. Vox Sang 2007 Apr;92(3):247–9. 33. Eder AF, Herron R, Strupp A, Dy B, Notari EP, Chambers LA, et al. Transfusionrelated acute lung injury surveillance (2003–2005) and the potential impact of the selective use of plasma from male donors in the American Red Cross. Transfusion 2007 Apr;47(4):599–607. 34. Yazer MH, Podlosky L, Clarke G, Nahirniak SM. The effect of prestorage WBC reduction on the rates of febrile nonhemolytic transfusion reactions to platelet concentrates and RBC. Transfusion 2004 Jan;44(1):10–5. 35. MacLennan S, Williamson LM. Risks of fresh frozen plasma and platelets. J Trauma 2006 Jun;60(6 Suppl.):S46–50. 36. Win N, Chapman CE, Bowles KM, Green A, Bradley S, Edmondson D, et al. How much residual plasma may cause TRALI? Transfus Med 2008 Oct;18(5): 276–80. 37. Hellstern P. Fresh-frozen plasma, pathogen-reduced single-donor plasma or bio-pharmaceutical plasma? Transfus Apher Sci 2008 Aug;39(1):69–74. 38. Danielson C, Benjamin RJ, Mangano MM, Mills CJ, Waxman DA. Pulmonary pathology of rapidly fatal transfusion-related acute lung injury reveals minimal evidence of diffuse alveolar damage or alveolar granulocyte infiltration. Transfusion 2008 Nov;48(11):2401–8. 39. Church GD, Price C, Sanchez R, Looney MR. Transfusion-related acute lung injury in the paediatric patient: two case reports and a review of the literature. Transfus Med 2006 Oct;16(5):343–8.
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40. Li G, Daniels CE, Kojicic M, Krpata T, Wilson GA, Winters JL, et al. The accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic) in the differentiation between transfusion-related acute lung injury and transfusion-related circulatory overload in the critically ill. Transfusion 2009 Jan;49(1):13–20. 41. Dunn P, Dinesh D. Transfusion-related acute lung injury (TRALI): a review of investigations by the National Tissue Typing Laboratory of cases reported in New Zealand since June 2004. N Z Med J 2008 Jun 20;121(1276):42–7. 42. Win N, Massey E, Lucas G, Sage D, Brown C, Green A, et al. Ninety-six suspected transfusion related acute lung injury cases: investigation findings and clinical outcome. Hematology 2007 Oct;12(5):461–9. 43. Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang 2005 Jul;89(1):1–10. 44. Kram R, Loer SA. Transfusion-related acute lung injury: lack of recognition because of unawareness of this complication? Eur J Anaesthesiol 2005 May;22(5):369–72. 45. Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, et al. Transfusion-related acute lung injury in the critically ill: prospective nested case– control study. Am J Respir Crit Care Med 2007 Nov 1;176(9):886–91. 46. Rana R, Fernandez-Perez ER, Khan SA, Rana S, Winters JL, Lesnick TG, et al. Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study. Transfusion 2006 Sep;46(9):1478–83. 47. Marik PE, Corwin HL. Acute lung injury following blood transfusion: expanding the definition. Crit Care Med 2008 Nov;36(11):3080–4.
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Current Anaesthesia & Critical Care journal homepage: www.elsevier.com/locate/cacc
HAEMATOLOGY
Transfusion related lung injury. TRALI Neil Soni Department of Anaesthesia, Chelsea and Westminster Hospitals, 369 Fulham Road, London SW10 9NH, UK
s u m m a r y Keywords: HLA TACO TRALI
Transfusion related lung injury is almost certainly related to the administration of blood products containing antibodies in the plasma. Those antibodies may have developed during pregnancy or following blood transfusion. They react with specific ‘cognate’ antigens in the recipient and in some patients, but not all, this results in an acute lung injury pattern. The problem resides in the plasma, so the incidence with FFP is far higher than with red cells. Blood transfusion services have adopted several ways of reducing risk such as using untransfused male donors. Leucodepletion may also have a benefit. Diagnosis is an issue as it is easily confused with transfusion associated circulatory overload TACO and often the right preconditions exist for both. Although most sources agree that the condition usually occurs within 6 h of transfusion some new information from critically ill patients has suggested that a condition called ‘delayed TRALI’ may exist, but this is currently contentious. The natural history of the condition is extremely variable and there is an associated mortality, 5–10%. Most patients do require ventilation but most do well. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction TRALI is described as acute dyspnoea with hypoxia and new or worsening pulmonary infiltrates arising during or within 6 h of transfusion of plasma, cellular blood components or immunoglobulins.1 Blood transfusion has always had associated risks. The risks were those intrinsic to the stored blood, such as infection or immunological reaction. The latter may be from ABO or other sources of incompatibility and in particular granulocyte or HLA antibodies. The reaction is between the donor plasma and recipient. Under this general description comes the syndrome of TRALI, transfusion related lung injury, which is an immunological response to blood products. Other risks could be considered extrinsic. These include transfusion associated circulatory overload, TACO. This is associated with fluid administration often in circumstances where there are significant fluid shifts, such as in resuscitation, or where there is cardiovascular instability either from the acute illness itself or from existent comorbidity. Particularly susceptible to TACO are patients perceived to already have a predisposition to pulmonary interstitial oedema usually associated with what is conceptually described as increased pulmonary ‘capillary permeability’, such as those with sepsis. In recent times despite the massive publicity associated with infection risk, that risk is actually diminishing. Paradoxically the
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relative importance of TRALI is rising and with a rate reputedly approaching 1 per 5000 transfusions.2 Some sources suggest that it is now the most common single cause of transfusion related death. FFP is the product most commonly implicated accounting for half of all cases with red cells about a third.3,4 In the UK an average of 20 cases of TRALI are reported a year with about half being ‘probable’ (see below). Almost all cases were within 6 h of a products transfusion so that now the definition of TRALI suggests the time limit for temporal association is 6 h. Seventy percent of these patients required admission to ITU and about half were ventilated. Mortality was about 20% in those meeting TRALI criteria.1 TACO is usually considered to be an obvious and easy diagnosis and curiously seems to have a limited place in the review of transfusion related problems, yet clinically in acute situations TACO is seen as a real and present danger. This will be discussed later as the boundary between TRALI and TACO is rarely distinct. 2. TRALI; postulated mechanisms It is generally considered that TRALI is an immunologically mediated reaction and that it constitutes a form of incompatibility between donor blood product and the recipient. In the majority of cases described as TRALI, HLA or neutrophil-specific antibodies could be found in the plasma of one or more of the donors. A corresponding antigen was often found in the recipient. It was, therefore, proposed that this antibody – antigen reaction triggers an inflammatory response. The response affects pulmonary
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endothelium increasing permeability and allowing interstitial oedema to form. This is supported by reports of two healthy volunteers in studies who developed TRALI in response to HLA antibodies.5,6 It seems clear that HLA antibodies can cause TRALI. It has also been shown that the interaction between HLA-DR and DR13 antigen in vitro stimulates inflammatory cytokine release from monocytes. So there is a mechanism, in vitro, for a TRALI type reaction.7 While this is currently accepted as the predominant mechanism almost every reported series has cases where no white cell antibodies in the donor can be found. This has been called antibody negative TRALI. The incidence of this may be between 11% and 39% depending on sources.8,9 A second mechanism is, therefore, postulated. For this mechanism the storage of blood allows the release of cell components in particular lipids. These agents will promote neutrophil activation and are in effect ‘priming agents’. In sick patients, whether from blood loss or infection, there is already a degree of activation of their immune system and this is susceptible to further activation if a priming agent is infused. The transfusion infuses the free lipid components from cells and primes the reaction. This is called the ‘two hit’ mechanism for TRALI.10–12 Given the relatively non-specific nature of TRALI as a predominantly clinical description it is not unreasonable to consider that a range of ‘insults’ could produce this rather general picture (see below) but nevertheless it seems quite clear that in many cases HLA antibodies play a significant role.13 The situation is made more complex by the prevalence of HLA antibodies in blood products. When cryoprecipitate, fresh frozen plasma red cells and apheresis platelets were analysed, 22% contained HLA alloantibodies with a high preponderance in the plasma of female donors.14 Case reports of TRALI and the likely trigger demonstrating some of the spectrum of both products and antibodies. Product
Reaction
Red blood cells15,16 Platelets14,17,18 Immunoglobulins19,20
HLA antibody, antigranulocyte antibodies Antigranulocyte antibody HNA-3a. Lipids Cryglobulinaemia in Sjogrens. Granulocyte reactive antibody. HLA antibodies Granulocyte reactive antibodies HLA antibodies in plasma HLA antibodies and Fcgamma R111b reactivity
FFP21 FFP22 Plasma exchange – plasma23,24 Anti-D25
3. Methods of reducing risk FFP or cryosupernatant has six times and platelets eight times the risk of TRALI than for red blood cells.1 If potential donors who may have antibodies can be identified then the risks could be reduced. It is quite clear that multiparous females have a higher incidence of HLA antibodies. A single pregnancy is associated with 10% of women having one or more HLA antibodies and multiple pregnancies it rises to 25–30%. This may also be the case in donors who themselves have had blood products previously where the rate may be as high as 50%.26 Circumstantial evidence comes from an observation that transfusion of plasma from multiparous donors seems to result in a higher incidence of lung dysfunction in critically ill patients.27 Therefore, screening donors for pregnancy or transfusion would seem a simple step. Screening previously pregnant apheresis donors for HLA antibodies can be done. The yield shows 18% of these donors have HLA antibodies.28 In another report 40% of multiparous women had either granulocyte or HLA antibodies. The authors point out that of the cases of TRALI occurring 2 of 3 did not involve multiparous donors.29 Screening is expensive and does not prevent all TRALI. It is also important to appreciate that even with HLA antibodies in the
donor and cognate antigens in the recipient, TRALI does not necessarily occur.30,31 Nevertheless it seems logical that the risk must be reduced if the donors are known to be antibody free.32 Using only untransfused male donors may be easier still.33 Leucoreduction should in theory be helpful and that has been standard in the UK since 1999. Prestorage white cell reduction appears to reduce the incidence of general non-haemolytic reactions.34 With platelets, risk may be reduced by using platelet additive solutions and thence removing 70% of the plasma or by suspending the platelets in male donor plasma.35,36 The type of plasma used may help. Quarantine–stored FFP (QFFP) comes from a single donation while methylene blue-light treated plasma (MLP) uses a chemical and ultraviolet light to treat plasma. Neither reduces TRALI risk but solvent/detergent treated plasma (SDP) are derived from large plasma pools and have a lower TRALI risk.3,37 A further strategy is to reduce the use of blood products and to encourage clinicians to be more discerning in the use of FFP. For example, using FFP to reverse warfarin poses risks not present with prothrombin complex. In the UK, a strategy to reduce risk by firstly using plasma from male donors for FFP and, secondly, suspension of buffy coat derived pooled platelets where possible. Also all products are leucoreduced from late 1999 so that red blood cells will usually have less than 30 ml plasma, although cases where less than 20 ml of residual plasma triggered TRALI have been reported.36 The incidence of TRALI appears to be falling. 4. Clinical description of TRALI Acute dyspnoea with hypoxia and new or worsening pulmonary infiltrates arise during or within a few hours of transfusion of plasma, cellular blood components or immunoglobulins. Originally the definition of a few hours was up to 24 h, but as of 2006 it has been reduced to 6 h. When histology is available it shows the lungs have oedema with proteinaceous fluid, there is capillary leucostasis and neutrophil sequestration.10 Pleural effusions are common. In one study of two cases, alveolar damage was not seen which may reflect the rapidity of the demise in these cases.38 Various other laboratory tests have been suggested to be diagnostically helpful. Transient leucopenia associated with pulmonary oedema has been described and an elevated fluid/plasma protein ratio may indicate TRALI.39 Attempts to use atrial natriuretic peptide to differentiate between TACO and TRALI have shown the test to be unhelpful.40 In effect there is no rapid clinically relevant diagnostic test. Immunological testing is not a rapid diagnostic method. Hence, emphasis has remained on clinical diagnosis. This syndrome is, in practice, often difficult to differentiate from other causes. Hence a means of assessing the likelihood of TRALI has evolved and is described in Table 1. 5. Serology Positive serology is the presence of donor white blood cell (WBC) antibodies which correspond with one or more recipient antigens and/or a positive white blood cell crossmatch between donor and recipient. Donor WBC antibodies that fail to recognise cognate antigens in the recipient samples are considered irrelevant. Of course this is only valid if the recipient samples are available. Ideally, finding neutrophil or HLA antibodies in the donor plasma which is shown to have specificity for one of the recipient’s HLA antigens or alternatively a white cell crossmatch indicates TRALI. In a New Zealand report 88% of cases HLA antibodies were found and just over half of these had either an antigen or a positive
N. Soni / Current Anaesthesia & Critical Care 20 (2009) 93–97 Table 1 Diagnosis of TRALI. Probability Description Highly likely Probable
Possible Unlikely
No other cause identified for the symptoms and positive serology. Either positive serology as defined below but with other causes for symptoms also present OR no other causes present, but with either absent or incomplete serology. Clinical picture compatible with TRALI, with no other cause present, but results of patient and donor investigation negative as defined below. Another cause of symptoms present AND results of patient and donor investigation negative.
crossmatch.41 In the UK, white cell antibodies in the donor with cognate antigen in the recipient were found in 65% of cases. All the donors were female. To clarify the position: Donor antibodies should not be there. They will often be there in multiparous women. They may also be present in any donor who has previously had a blood transfusion. Cognate antigens are unfortunately very common in recipients with some suggesting up to 70% of a normal population of recipients. An implicated component is one that is transfused from a donor with positive serology. In patients with probable TRALI and without positive serology it is impossible to determine which component is the cause unless only one was given. It is the donor side that is more relevant. HLA antibodies do not always result in TRALI.
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is very sick has had a massive transfusion, with some renal failure, some cardiac failure and maybe a suggestion of sepsis both TACO and TRALI could be present. While this example is clearly exceptional some degree of complexity in the clinical scenario is far more common than the simple transfusion with obvious cause and effect. Added to this is the fact that a relatively small volume of blood products may produce TACO in a susceptible individual. In many acute situations the patient, even if previously young and fit, may be transiently susceptible to rapid infusion, while in the older or more infirm population susceptibility is more obvious. Fluid given quickly, the failing ventricle, the ‘leaky lungs from trauma or sepsis all predispose to fluid-induced pulmonary oedema. Then there is the issue of filling pressures. Measurement supposedly clarifies whether it is a high filling pressure ‘cardiogenic’ situation or a low pressure ‘noncardiogenic’ state. This assumes a static state where raised pressures stay raised and low pressures stay low. In reality, it is almost always a dynamic situation with fluctuations in filling pressures, ventricular function and the formation of oedema changing with time and not a fixed phenomenon. Filling pressures when measured may not reflect what was happening when the event occurred. Flooding the lungs with oedema may actually reduce filling pressures as the fluid has by definition, relocated. This all compromises differentiation of TACO and TRALI. TACO is very common in the acutely sick, in those being resuscitated and especially in those critically ill with comorbidities. It is a diagnosis in the forefront of a clinicians mind and a condition that is perceived as avoidable and hence should be avoided. TRALI as a diagnosis rarely occupies pole position but could be a preferable and more honourable diagnosis than fluid overload. The differential is fraught but TACO is more common. These two cases may serve to illustrate the diagnostic dilemma that TRALI poses.
6. Natural history 7.1. Case 1 It is difficult to define the natural history of TRALI. The temporal relationship currently used implies severe lung dysfunction occurring within 6 h of transfusion. About 60–70% of these cases require ventilation. Most cases will resolve relatively quickly over hours or days and one paper suggests that the infiltrates clear on Xray in less than 96 h in most patients.9 In about 20% of all cases, the lung injury will be sustained often associated with the other comorbidities making differentiation of the TRALI component difficult. It will also make the mortality attributable to TRALI almost impossible to define. A mortality of 5–10% has been quoted.42,43 Treatment is supportive. A large diuresis after a small dose of diuretic might indicate a volume component but is by no means diagnostic. 7. Clinical practice In clinical practice products are used by a range of clinicians. In the oncological haematological areas where products are used extensively but usually in a semi-elective situation it is assumed that most haematologists know about the condition. In the ward scenario where products are given electively the knowledge base amongst junior doctors and nurses may be poor. In the acute scenario where surgeons, anaesthetists and intensivists are using blood products urgently not only may the knowledge base may be weak, but also there may be complex scenarios where TRALI seems a rather distant possibility.44 The implication is that it may be far more common and is under reported. The real problem with TRALI is that it is a clinical diagnosis often in a difficult or complex clinical scenario. If a patient is well and has a single unit of blood product and develops the classical syndrome it is easy to make the diagnosis with cause and effect. If the patient
A young patient with a haematological disorder needs platelets. An elective platelet transfusion is half way through the infusion when the patient complains of dyspnoea and their saturations fall. An X-ray shows bilateral infiltrates. The patient is admitted and improves on oxygen over the next 12 h. The clinician suspects TRALI and reports the case and the surveillance team undertakes testing and finds antibodies in donor platelets. 7.2. Case 2 A 75-year-old man with known ischaemic heart disease is admitted with major lower GI bleeding. He is profoundly hypotensive and in atrial fibrillation at a rate of 150 beats per minute. His initial CVP is very low. He is resuscitated and improves after 2 l of crystalloid, 1 l of colloid and four units of blood. Cold and shut down, his CVP is now high. He is taken to theatre where he has an attempted colonoscopy which has to be abandoned and proceeds to hemicolectomy during which he requires inotropes and fluid with a falling CVP. There is some surgical spillage of watery faeces and blood into the peritoneal cavity. After a stormy 4 h he is bleeding from multiple sites and his clotting is deranged. He is given FFP and platelets. He has a further six units of blood and at least two more litres of crystalloid. He is returned to ICU ventilated and with ongoing bleeding. His oxygen requirements are high and he has bilateral pulmonary infiltrates. His CVP is 7 cm H2O. Overnight he settles, warms and dilates and needs more fluid with a very low CVP. He remains ventilator dependent and the CVP is now 5 cm H2O. On the round TRALI is suggested. In case 1 there is no real possibility of TACO and there is only the platelets that are implicated and there is the right temporal
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association. TRALI is highly likely and is confirmed on testing. In the second case the situation is more confused but is a common type of presentation. It is highly likely this patient will have oxygenation problems and pulmonary infiltrates given these circumstances and one does not need to invoke TRALI as the cause. He has profound hypotension, a massive transfusion and faecal spillage all predisposing to lung problems and if he has ventricular impairment then some failure might have occurred. TACO almost certainly occurred at some stage during all these fluid shifts but may have been transient. The CVP was both high and low at different times but afterwards when his ventricular function returned towards normal the CVP was reasonably low. That CVP seen in ICU hours later says little about the dynamic fluid shifts previously. Temporally he is right for TRALI but it is only one of many potential reasons for the infiltrates. The diagnosis is difficult. Even if a donor unit proved positive for antibodies it would not necessarily be TRALI as not all transfused donor antibodies result in TRALI. Diagnostically it would be possible TRALI. This emphasises the difficulties with the diagnosis and the potential difficulties in confirming the event was TRALI. A new dilemma is arising in the study of the critically ill where sickness is associated with the necessity to use blood products and the possibility of TRALI while providing the ideal scenario for TACO. A recent study has indicated that in the critically ill 8% of transfused patients developed an ALI picture within 6 h of transfusion. Risk factors included sepsis and alcohol abuse, but most interesting was the odds ratio of a patient with ALI having had products from a female donor was 5.09. The odds ratios for pregnancies amongst donors, antigranulocyte antibodies in donors and lysophosphatidylcholine in the product were all increased.45,46 It has also been suggested that the development of ALI in the 6–72 h after transfusion is common and occurs in up to 25% of critically ill patients. Seventy-two hours is a long time in ICU and defines a population who are sick enough to stay in ICU greater than 72 h as the average stay in many units in Europe, is less than this. There was circumstantial evidence to suggest TRALI. The authors of that study considered these patients to have possible TRALI and have coined the term ‘delayed TRALI syndrome’’.47 This potentially poses problems for surveillance programs. 8. Conclusions TRALI is a clinical diagnosis which is relatively difficult to make and expensive to confirm. As it overlaps with TACO it is hard to differentiate the two in situations where both are possibly present. Considering the diagnosis is key to making the diagnosis, and in turn determining its true incidence, which may be underestimated. Prevention may be the key. As donor antibodies are implicated, most of the time, efforts to reduce exposure to donor units with antibodies focuses on identifying multiparous donors or those who have had blood transfusions. Education will potentially reduce inappropriate plasma administration and techniques such as leucoreduction of red cells may also have a role albeit hard to prove currently. Recent publications suggest that there may be growing interest in the critically ill where the condition may be camouflaged by all the other clinical events occurring. Increasing awareness of the problem will almost certainly increase the rate of provisional diagnosis of TRALI in the critically ill, and will expose even more difficult clinical scenarios to unravel for those involved in surveillance. References 1. Chapman CE, Stainsby D, Jones H, Love E, Massey E, Win N, et al. Ten years of hemovigilance reports of transfusion-related acute lung injury in the United Kingdom and the impact of preferential use of male donor plasma. Transfusion; 2008 Oct 28.
2. Cruz J, Skipworth E, Blue D, Waxman D, McCarthy L, Smith D. Transfusionrelated acute lung injury: a thrombotic thrombocytopenic purpura treatmentassociated case report and concise review. J Clin Apher 2008;23(2):96–103. 3. Flesland O. A comparison of complication rates based on published haemovigilance data. Intensive Care Med 2007 Jun;33(Suppl. 1):S17–21. 4. Holness L, Knippen MA, Simmons L, Lachenbruch PA. Fatalities caused by TRALI. Transfus Med Rev 2004 Jul;18(3):184–8. 5. Flesch BK, Neppert J. Transfusion-related acute lung injury caused by human leucocyte antigen class II antibody. Br J Haematol 2002 Mar;116(3):673–6. 6. Dooren MC, Ouwehand WH, Verhoeven AJ, von dem Borne AE, Kuijpers RW. Adult respiratory distress syndrome after experimental intravenous gammaglobulin concentrate and monocyte-reactive IgG antibodies. Lancet 1998 Nov 14;352(9140):1601–2. 7. Sakagawa H, Miyazaki T, Fujihara M, Sato S, Yamaguchi M, Fukai K, et al. Generation of inflammatory cytokines and chemokines from peripheral blood mononuclear cells by HLA Class II antibody-containing plasma unit that was associated with severe nonhemolytic transfusion reactions. Transfusion 2007 Jan;47(1):154–61. 8. Popovsky MA, Haley NR. Further characterization of transfusion-related acute lung injury: demographics, clinical and laboratory features, and morbidity. Immunohematology 2000;16(4):157–9. 9. Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985 Nov–Dec;25(6):573–7. 10. Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury (TRALI). Br J Haematol 2007 Mar;136(6):788–99. 11. Curtis BR, McFarland JG. Mechanisms of transfusion-related acute lung injury (TRALI): anti-leukocyte antibodies. Crit Care Med 2006 May;34(5 Suppl.):S118–23. 12. Silliman CC. The two-event model of transfusion-related acute lung injury. Crit Care Med 2006 May;34(5 Suppl.):S124–31. 13. 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Askari S, Nollet K, Debol SM, Brunstein CG, Eastlund T. Transfusion-related acute lung injury during plasma exchange: suspecting the unsuspected. J Clin Apher 2002;17(2):93–6. 24. Mateen FJ, Gastineau D. Transfusion related acute lung injury (TRALI) after plasma exchange in myasthenic crisis. Neurocrit Care 2008;8(2):280–2. 25. Berger-Achituv S, Ellis MH, Curtis BR, Wolach B. Transfusion-related acute lung injury following intravenous anti-D administration in an adolescent. Am J Hematol 2008 Aug;83(8):676–8. 26. Powers A, Stowell CP, Dzik WH, Saidman SL, Lee H, Makar RS. Testing only donors with a prior history of pregnancy or transfusion is a logical and costeffective transfusion-related acute lung injury prevention strategy. Transfusion 2008 Dec;48(12):2549–58. 27. Palfi M, Berg S, Ernerudh J, Berlin G. A randomized controlled trial of transfusion-related acute lung injury: is plasma from multiparous blood donors dangerous? Transfusion 2001 Mar;41(3):317–22. 28. Insunza A, Romon I, Gonzalez-Ponte ML, Hoyos A, Pastor JM, Iriondo A, et al. Implementation of a strategy to prevent TRALI in a regional blood centre. Transfus Med 2004 Apr;14(2):157–64. 29. Sachs UJ, Link E, Hofmann C, Wasel W, Bein G. Screening of multiparous women to avoid transfusion-related acute lung injury: a single centre experience. Transfus Med 2008 Dec;18(6):348–54. 30. Nicolle AL, Chapman CE, Carter V, Wallis JP. Transfusion-related acute lung injury caused by two donors with anti-human leucocyte antigen class II antibodies: a look-back investigation. Transfus Med 2004 Jun;14(3):225–30. 31. Zupanska B, Uhrynowska M, Michur H, Maslanka K, Zajko M. Transfusionrelated acute lung injury and leucocyte-reacting antibodies. Vox Sang 2007 Jul;93(1):70–7.
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40. Li G, Daniels CE, Kojicic M, Krpata T, Wilson GA, Winters JL, et al. The accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic) in the differentiation between transfusion-related acute lung injury and transfusion-related circulatory overload in the critically ill. Transfusion 2009 Jan;49(1):13–20. 41. Dunn P, Dinesh D. Transfusion-related acute lung injury (TRALI): a review of investigations by the National Tissue Typing Laboratory of cases reported in New Zealand since June 2004. N Z Med J 2008 Jun 20;121(1276):42–7. 42. Win N, Massey E, Lucas G, Sage D, Brown C, Green A, et al. Ninety-six suspected transfusion related acute lung injury cases: investigation findings and clinical outcome. Hematology 2007 Oct;12(5):461–9. 43. Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang 2005 Jul;89(1):1–10. 44. Kram R, Loer SA. Transfusion-related acute lung injury: lack of recognition because of unawareness of this complication? Eur J Anaesthesiol 2005 May;22(5):369–72. 45. Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, et al. Transfusion-related acute lung injury in the critically ill: prospective nested case– control study. Am J Respir Crit Care Med 2007 Nov 1;176(9):886–91. 46. Rana R, Fernandez-Perez ER, Khan SA, Rana S, Winters JL, Lesnick TG, et al. Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study. Transfusion 2006 Sep;46(9):1478–83. 47. Marik PE, Corwin HL. Acute lung injury following blood transfusion: expanding the definition. Crit Care Med 2008 Nov;36(11):3080–4.