Anaesthesia, 2006, 61, pages 777–785 doi:10.1111/j.1365-2044.2006.04742.

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REVIEW ARTICLE
Transfusion-related acute lung injury: a literature review
N. A. Barrett1 and P. C. A. Kam2
1 Registrar in Intensive Care, Intensive Therapy Unit, University of Sydney at The Royal North Shore Hospital,
St Leonards, NSW 2065, Australia
2 Nuffield Professor of Anaesthetics, University of Sydney, Department of Anaesthetics, Royal Prince Alfred Hospital,
Missenden Road, Camperdown, NSW 2050, Australia

Summary
Transfusion-related acute lung injury (TRALI) is a serious and potentially fatal complication of
transfusion of blood and blood components. TRALI is under-diagnosed and under-reported
because of a lack of awareness. A number of models have been proposed to explain the patho-
genesis of TRALI: an antibody mediated model; a two-event biologically active mediator model;
and a combined model. TRALI can occur with any type of blood product and can occur with as
little as one unit. Its presentation is similar to other forms of acute lung injury and management is
predominantly supportive. The main strategy in combating TRALI is prevention both through
manipulation of the donor pool and through clinical strategies directed at reducing transfusion of
blood products including, but not limited to, evidence-based lower transfusion thresholds. This
article presents a review of TRALI and addresses the definition, pathology, pathogenesis, clinical
manifestations, treatment and prevention of the syndrome.
. ......................................................................................................
Correspondence to: Professor P. C. A. Kam
E-mail: pkam@usyd.edu.au
Accepted: 27 February 2006

Blood supplies have become safer with regard to the towards optimising management strategies has been under-
transmission of infective agents and the attention of taken because it is a relatively rare condition.
transfusion medicine is now focused on understanding
and eliminating other serious complications associated
Definition
with blood component transfusion. Transfusion-related
acute lung injury (TRALI) is a serious and potentially fatal Respiratory complications following blood transfusion
complication of transfusion of blood and blood compo- that resemble the syndrome of TRALI have been
nents. TRALI was not recognised as a clinical entity until reported since the 1950s [5]. The syndrome has previ-
the 1980s. The United States Food and Drug Adminis- ously been called pulmonary hypersensitivity reaction,
tration (FDA) currently estimates it to be the leading allergic pulmonary oedema, non-cardiogenic pulmonary
cause of transfusion-related mortality [1]. However, oedema, and pulmonary leucoagglutinin reaction. The
TRALI is under-diagnosed and under-reported because term ‘transfusion-related acute lung injury’ was proposed
of a lack of awareness [2, 3]. by Popovsky to refer to pulmonary oedema complicating
The aim of this article is to review the definition, blood transfusion. The lack of a consensus definition of
pathology, pathogenesis, clinical manifestations and the TRALI contributed to its under-recognition as a cause of
treatment and prevention of TRALI. The available arti- acute lung injury and has inhibited research into TRALI
cles retrieved from Pub-Med, Medline and EMBASE [2, 3]. A definition emerged from the TRALI consensus
consisted of case reports, consensus statements from conference in 2004 and from the US National Heart,
conferences, animal research, retrospective case series, Lung and Blood Institute [6, 7]. The definition was based
observational studies from haemovigilance networks and on the widely used definition of acute lung injury
one randomised controlled trial of multiparous donors. proposed by the American-European Consensus Com-
Despite the fact that it is estimated to be the leading cause mittee (AECC) [8]. Acute lung injury (ALI) is defi-
of transfusion-associated death [1, 4], little research ned by the AECC as a syndrome based on clinical and

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2006 The Association of Anaesthetists of Great Britain and Ireland 777
N. A. Barrett and P. C. A. Kam Æ Transfusion-related acute lung injury Anaesthesia, 2006, 61, pages 777–785
. ....................................................................................................................................................................................................................

radiological findings rather than a pathological or a mates of the incidence of TRALI include: 1 in 5000
pathophysiological diagnosis. The AECC definition of blood and blood components transfused [17]; 1 in 2000
ALI is characterised by: an acute onset; hypoxaemia plasma-containing components [26]; 1 in 7900 units of
(PaO2 ⁄ FiO2 ¼ 300 mmHg (40 kPa) at sea level (adjusted fresh frozen plasma [27]; 1 in 432 units of whole blood-
downward depending on altitude) regardless of level of derived platelet concentrates [18]; and 1 in 1323 blood
positive end-expiratory pressure or SpO2 < 90% on room components transfused [18]. The fact that packed red cells
air); bilateral pulmonary infiltrates on the frontal chest and cryoprecipitate can cause TRALI suggests that small
radiograph; and no clinical evidence of left atrial quantities of plasma (as little as 10% of a blood component
hypertension or circulatory overload, or the pulmonary unit) are sufficient to cause TRALI [7].
artery occlusion pressure £ 18 mmHg [8]. ALI is a clini- However, TRALI is believed to be under-diagnosed
cal syndrome which may be caused by several direct or because of difficulties in diagnosis and lack of awareness
indirect injuries to the lung [9–12]. The potential causes [2, 3, 28]. Various haemovigilance networks have repor-
of ALI include aspiration, pneumonia, toxic inhalation, ted a greater incidence of TRALI than was previously
lung contusion, near drowning, severe sepsis, shock states, thought. The FDA estimated that TRALI is the leading
multiple trauma, burn injury, massive transfusion, acute cause of transfusion-related death in the US [1, 29, 30].
pancreatitis, cardiopulmonary bypass and drug overdose Similarly the United Kingdom Serious Hazards of
[9–13]. Risk factors associated with the development of Transfusion Committee (SHOT) reported that TRALI
ALI include increased age, ethanol or tobacco abuse, was a leading cause of transfusion-related morbidity and
severe illness and the presence of the variant surfactant B mortality in the UK [4]. The French haemovigilance
gene [11–14]. network reported that 15% of transfusion related fatalities
The TRALI consensus conference and the US Nati- were caused by TRALI [31]. In Germany, 101 out of 765
onal Heart, Lung and Blood Institute defined TRALI as a cases associated with complications of blood transfusion
form of acute lung injury meeting the criteria proposed that were not related to infections were caused by TRALI
by the AECC that is temporally and mechanistically related [32]. In 23 of these cases, antileucocyte antibodies
to transfusion of blood or blood components [6, 7, 15]. directed against antigens on host leucocytes were dem-
For a diagnosis of TRALI to be made there must be onstrated in donor plasma [32].
no pre-existing ALI before transfusion, the onset of signs
and symptoms must occur during or within 6 h of
Aetiology
transfusion and there must be no temporal relationship
to an alternative risk factor for ALI. If both transfusion Two theories have been proposed to explain the patho-
and another cause for ALI are temporally related, the genesis of TRALI. The first is an antibody-mediated
consensus conference recommended that the term ‘poss- reaction following transfusion of antigranulocyte anti-
ible TRALI’ be used in these cases [6, 7, 15]. ‘Possible bodies into patients who have leucocytes that express the
TRALI’ is defined when the following criteria exist: cognate antigens. The second postulates that it is medi-
evidence of ALI; absence of a pre-existing ALI before ated by an interaction between biologically active medi-
transfusion; onset of symptoms or signs of ALI within 6 h ators and the lung.
after the transfusion; and the presence of an alternative
risk factor for ALI. The antibody-mediated model
Multiple blood transfusion is a risk factor for the The antibody-mediated model postulates that the reac-
development of ALI [11–13,16]. However, massive tion is secondary to antibodies in donor plasma against
transfusion (defined as the replacement of one or more antigens present on the recipient’s leucocytes. These may
blood volumes within a 24-h period with either packed be antibodies to the human leucocyte antigen (HLA) or
red cells or whole blood) is not a requirement of the to other leucocyte antigens. HLA antibodies may be
committee’s definition of TRALI [6, 7, 15]. An acute directed against either HLA class I antigens that are
lung injury should be ascribed to TRALI or possible present in all leucocytes or HLA class II antigens found on
TRALI if other factors for ALI are present, provided that B lymphocytes and monocytes [7, 19, 33–38] or infusion
the signs and symptoms commence within 6 h of the last of donor leucocytes into a recipient whose antibodies
blood component transfused. are directed against these donor leucocytes [17, 39, 40].
Most reactions are caused by antibodies in donor plasma
and less than 10% of reactions are caused by plasma anti-
Incidence
bodies in the recipient that agglutinate the donor leuco-
TRALI has been reported following transfusion of cytes [17, 39, 40]. The antibody–antigen interaction
plasma-containing blood components [13, 17–25]. Esti- causes complement activation, resulting in the pulmonary

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2006 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2006, 61, pages 777–785 N. A. Barrett and P. C. A. Kam Æ Transfusion-related acute lung injury
. ....................................................................................................................................................................................................................

sequestration and activation of neutrophils, endothelial from a multiparous donor who had anti-HLA class I
cell damage and a capillary leak syndrome in the lungs antibodies and that found 15% of recipients experienced
leading to TRALI. TRALI [50]. Win et al. [51] examined the clinical records
Rabbit and rat models for antibody-mediated TRALI of previous recipients of blood products from six donors
have been developed [41–43]. The rabbit model is an who had antileucocyte antibodies. They found that each
ex vivo model utilising isolated rabbit lungs perfused with donor was associated with one documented case of
a mixture containing human granulocytes (5b-positive), TRALI but there was no evidence of TRALI reactions
antibodies to granulocyte 5b, and rabbit plasma as a source in other recipients. A recent study by Toy et al. [52]
of complement [41]. In this model, pulmonary oedema examined the records of 103 patients who had received
occurred 3–6 h after infusion of the mixture. There was blood from a donor associated with a known TRALI
no pulmonary oedema if any one of the three com- reaction. Only one patient developed TRALI even
ponents was absent [41]. The rat model is an ex vivo though 54 patients had known HLA antigens to the
model of TRALI in which rat lungs are perfused with donor’s antibodies. Nicolle et al. found that only one out
neutrophils that bear HNA-2a antigen and HNA-2a of the 18 patients who received blood components from
antibodies. This caused increased pulmonary capillary two donors who were implicated in TRALI reactions
leakage, increased total lung water and increased lung experienced TRALI [53]. In summary these ‘look-back’
neutrophil accumulation [42, 43]. The activation of studies demonstrated that single donors could cause
neutrophils with subsequent release of reactive oxygen TRALI reactions in more than one patient, lending
species led to TRALI [43]. In this model TRALI support for the antibody-mediated hypothesis. However,
developed without the addition of complement, thus blood containing antileucocyte antibodies may be trans-
bringing into question its role in the reaction [42, 43]. fused without causing TRALI, indicating that the anti-
The pulmonary changes observed in the rat and rabbit body alone is insufficient to cause the syndrome.
models are similar to those observed in a study of patients There is also evidence that TRALI is commoner in
with TRALI at autopsy [44]. This study also demonstra- recipients of blood products from multiparous donors
ted granulocyte sequestration within the pulmonary who are more likely to possess anti-HLA and anti-HNA
capillaries, extravasation of granulocytes into the alveoli antibodies [54–58]. A randomised controlled crossover
and pulmonary oedema with proteinaceous material in trial of plasma obtained from multiparous donors com-
the alveoli [44]. pared with plasma obtained from women with no history
Clinical studies of patients who experienced TRALI of transfusion or pregnancy reported that one patient
have demonstrated the presence of either anti-HLA or developed TRALI after transfusion of plasma obtained
antigranulocyte antibodies in donor plasma [7, 17, 25, from a multiparous donor [58]. IgG antineutrophil
33–39, 45]. In two large series of patients with suspected antibodies were found in the multiparous donor’s plasma
TRALI, specific anti-HLA and antigranulocyte antibod- [58]. A significant reduction in oxygenation followed
ies have been found [36, 46]. In a case series of 46 patients transfusion of plasma obtained from the multiparous
Popovsky and Haley [36] identified antibodies to human donors but not the control donors. Insunza et al. [59]
leucocyte antigens in 28% and granulocyte antibodies in examined the effect of excluding plasma derived from
41% of the patients. An earlier study reported leucocyte multiparous donors which tested positive for anti-HLA
antibodies in 89% and lymphocyte antibodies in 72% of antibodies. There was a reduction in reported episodes of
36 patients with a clinical syndrome resembling TRALI TRALI, from five cases in the 25 months before their
[46]. Other studies have demonstrated antigranulocyte intervention to no cases in 15 months after the interven-
antibodies specific for HNA-3a (5b) [40, 47], anti-NB2 tion. However, a major criticism of this study was the
[48], HNA-2a (NB1) [39] and anti-A2 [49] in the potential for under-reporting the incidence of TRALI
implicated donor units. because it relied on voluntary reporting by clinicians to
Several ‘look-back’ studies followed up recipients of the regional blood bank.
blood components from a donor implicated in a TRALI
reaction to determine the risk associated with subse- The two-event (biologically active mediator)
quent transfusions from such donors [28, 50–53]. Kopko model
et al. examined the records of previous recipients of a The biologically active mediator model postulates that
multiparous female frequent blood donor who had a TRALI is the result of two events. The first event is
granulocyte 5b antibody [28]. Seven mild to moderate the clinical condition of the patient, resulting in pulmon-
reactions were identified in six recipients and eight severe ary endothelial activation and neutrophil sequestration,
reactions were identified in eight recipients. Cooling and the second event is the transfusion of biologically
examined the case records of recipients of blood products active mediators (lipids, antigranulocyte antibodies) that

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2006 The Association of Anaesthetists of Great Britain and Ireland 779
N. A. Barrett and P. C. A. Kam Æ Transfusion-related acute lung injury
. ....................................................................................................................................................................................................................
activate adherent neutrophils leading to endothelial
damage, capillary leak and TRALI [18, 60–62].
The first event can be caused by a variety of insults to the
pulmonary vascular endothelium such as sepsis, cardio-
pulmonary bypass, haematological malignancy, ther-
mal injury and trauma [17, 18, 41, 63]. In an isolated rat
lung model non-cardiogenic pulmonary oedema devel-
oped after the pulmonary vasculature was primed by
lipopolysaccharide with subsequent infusion of superna-
tant from 42-day-old red cell concentrates and from
5-day-old platelet concentrates [60, 64]. ALI did not
develop when fresh (day 0) red cell or platelet supernatants
were used or when the tissue was not initially primed with
lipopolysaccharide [60, 64].
Pre-existing clinical conditions contribute to the first
event of the two-event model. In a retrospective case-
control study by Silliman et al. [26], 10 patients who
experienced TRALI were compared with 10 patients
with febrile or allergic transfusion reactions. All the patients
with TRALI had one or more predisposing clinical
conditions: active infection in five patients; recent surgery
in five patients; cytokine administration in two patients and
massive blood transfusion in one patient. Only two patients
out of the 10 control patients had predisposing factors.
In a prospective case-control study of TRALI [18], the
roles of cytotoxic HLA class I, class II and antigranulocyte
antibodies were examined. The investigators examined 81
patients who experienced 90 TRALI reactions. The first
46 reactions were analysed in a nested case control study.
Patient and blood transfusion data in these patients were
compared with a control group of 225 recipients of
platelet concentrates. TRALI was associated with cardiac
disease or a haematological malignancy in the patients,
and an increasing age of the platelet concentrate trans-
fused. TRALI was not correlated with the patients’ age or
gender, the number of previous blood transfusions, or the
type or number of previous transfusion reactions. There
was increased neutrophil priming activity (neutral lipids
and lysophosphatidylcholines) in all TRALI patients. This
study showed that TRALI was caused by two events: the
first was the clinical condition of the patient, and the
second was the infusion of active lipids in the stored blood
component [18]. Inflammatory cytokines and lipids accu-
mulate during storage of platelets and red blood cells
[18, 26, 60, 65–69]. Platelet-derived CD40 ligand may be
a cofactor in the pathogenesis of TRALI. CD40 ligand
accumulates during routine storage of packed red blood
cells, whole blood and platelet concentrates (especially
apheresis platelets). CD40 ligand primes neutrophils and
this leads to pulmonary endothelial damage [70]. The
inflammatory cytokines increase with the duration of
storage and are decreased by pre-storage leucodepletion
[65]. However, leucodepletion has not been shown to
780
Anaesthesia, 2006, 61, pages 777–785
reduce the incidence of TRALI [68]. Studies examining
the relationship between patient morbidity and duration
of storage of blood products have, however, reported
conflicting results such as no impact on morbidity
[71–74], an increased risk of nosocomial pneumonia
[75], an increased risk of multiple organ failure [76] and
an increased overall mortality [61].
Combined model
Kopko et al. demonstrated that the antineutrophil [HNA-
3 (5b)] antibody can prime neutrophils and cause a
respiratory burst effect, similar to the effects of biologic-
ally active lipids (that accumulate during routine blood
storage) on neutrophils [77]. They suggested that TRALI
occurred in patients when the pulmonary vascular bed
was primed by sepsis, trauma or transfusion followed by
the activation of primed neutrophils by either biologically
active mediators or by antigranulocyte antibodies leading
to pulmonary vascular endothelial damage [77].
Pathology
Autopsy of patients who have died from TRALI
demonstrates dilation of pulmonary capillaries associated
with sequestration of granulocytes within the capillaries,
extravasation of granulocytes into the alveoli, interstitial
and intra-alveolar oedema and the presence of proteina-
ceous material in the alveoli [44]. The oedema fluid has a
high protein concentration (oedema fluid ⁄ plasma protein
ratio ¼ 0.75) [78–80].
Clinical manifestations and diagnosis
The diagnosis of TRALI is based on the criteria
recommended by the TRALI consensus conference:
there must be no pre-existing ALI before transfusion,
the onset of signs and symptoms must occur during or
within 6 h of transfusion and there must be no temporal
relationship with an alternative risk factor for ALI [6, 7].
It is important to remember that TRALI may be caused
by single unit transfusions of any blood product [6, 15].
Common symptoms and signs of TRALI include
progressive dyspnoea, tachypnoea, frothy sputum, hypox-
aemia and hypotension or (rarely) hypertension [6, 7, 17,
18, 28, 36, 46, 81–83]. The chest radiograph commonly
shows bilateral pulmonary infiltrates consistent with non-
cardiogenic pulmonary oedema. It is difficult to differ-
entiate TRALI from other causes of ALI other than on
the basis of history because the clinical features of TRALI
are non-specific [83]. It is important to exclude elevated
left atrial pressures and signs of left ventricular failure.
Surveillance by SHOT and the FDA suggest that TRALI
is more common than expected and should be considered

2006 The Authors
Journal compilation
2006 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2006, 61, pages 777–785 N. A. Barrett and P. C. A. Kam Æ Transfusion-related acute lung injury
. ....................................................................................................................................................................................................................

when these symptoms and signs occur within 6 h of the 97–100]. In a multicentre randomised controlled clinical
completion of a transfusion. trial of transfusion requirements in critical care, critically
There are no specific laboratory markers to confirm ill patients were randomised to maintain a haemoglobin
TRALI. However, neutropenia [84] and the finding of of 7–9 g.dl)1 or 10–12 g.dl)1. The patients who were
antileucocyte antibody–antigen pairs support the diagno- randomly assigned to the lower haemoglobin group
sis [18, 33]. A high protein content in pulmonary oedema received fewer units of red cells. Although the two groups
fluid can help to differentiate TRALI from fluid overload had a similar 30-day mortality, there was a trend towards a
and cardiogenic pulmonary oedema [78–80, 85]. lower in-hospital mortality in the restrictive transfusion
TRALI reaction should be reported to the transfusion group (22.2% vs 28.1%, p ¼ 0.05). Younger (age < 55
service within the hospital so that antileucocyte antibody years) and less critically ill patients (Acute Physiology
screening tests can be performed on the donor plasma and and Chronic Health Evaluation II score £ 20) had a
donors who have anti-leucocyte antibodies excluded significantly lower mortality (8.7% in the restrictive-
from the donor pool. strategy group and 16.1 in the liberal-strategy group; p ¼
0.03). The number of patients with multi-organ dysfunc-
tion was not statistically different between the two groups
Management
nor was the incidence of ARDS (7.7% in the restrictive
The management of TRALI is supportive. Transfusion of group vs 11.4% in the liberal strategy group) [16]. The
the suspected blood product should cease immediately risk of TRALI provides further stimulus to utilise
when TRALI is suspected [7, 82, 83, 86]. Respiratory transfusion guidelines at the lower threshold. The British
support is dictated by the clinical picture (varying from Committee for Standards in Haematology Guidelines
oxygen supplementation in mild TRALI to non-invasive supports the use of strict transfusion thresholds in chronic
ventilation or tracheal intubation and mechanical ventila- and acute anaemia [101]. Peri-operative strategies that
tion in severe TRALI) [63]. The optimal method of reduce transfusion include pre-operative optimisation
ventilation is unknown [7, 82, 83, 86, 87]. In ALI and the using dietary supplements or erythropoietin, preven-
acute respiratory distress syndrome (ARDS) randomised tion of hypothermia, the use of antifibrinolytic drugs and
controlled trials support the use of small volume, high cell salvage [102–104]. Coagulation factor and platelet
frequency ventilation with limits set on inspired pressures, replacement should be guided by formal laboratory tests
optimising positive end-expiratory pressure (PEEP) and or thromboelastography wherever possible. The British
fraction of inspired oxygen, and allowing permissive Committee for Standards in Haematology have issued
hypercapnia [87]. In a series of 37 patients with TRALI, guidelines outlining the appropriate, evidenced-based use
all patients required oxygen supplements and 72% required of platelets and fresh frozen plasma in a variety of clinical
mechanical ventilation [17]. Haemodynamic support may settings to limit blood product use [105, 106].
be required. The use of diuretics is controversial [7, 18, 28, The management of donors to prevent episodes of
82, 83, 86, 88, 89] and hasty and uncontrolled use of TRALI is a difficult and contentious issue [7, 15, 86]. The
diuretics may be harmful [22, 90, 91]. The efficacy of preservation of blood supplies whilst maintaining appro-
corticosteroids in TRALI is unproven [7, 18, 28, 82, 83, priate patient safety remains a problem. At present there is
86, 88, 89, 92, 93], although there are anecdotal case no universally agreed approach to donor management.
studies that have reported the use of high dose steroids as Given that there is evidence of TRALI occurring in
part of a successful treatment regimen [4, 94, 95]. multiple recipients linked to single donors [28, 50], it is
suggested that donors implicated in TRALI and who have
demonstrable antibodies should be permanently disquali-
Prognosis
fied from the donor pool [33, 81, 86, 88, 107]. This
Most patients with TRALI recover within 48–96 h prudent approach is supported by the 2004 consensus
[17, 18, 27, 96] but hypoxaemia and radiological evidence conference on TRALI [7, 15].
of pulmonary infiltration can persist for 7 days in 20% Several studies have demonstrated that multiparous
of patients [17]. Approximately 70% of patients require donors are more likely to possess antileucocyte antibodies
mechanical ventilation. The in-hospital mortality is esti- [54–58]. Studies also suggest that there is a higher
mated at 5–10% [17, 46, 63]. incidence of TRALI associated with transfusions of
plasma derived from multiparous women [46, 58, 96],
although a causal link between plasma from multiparous
Prevention
donors and TRALI is not always clearly established
The most important step in reducing episodes of TRALI [55, 108]. Insunza et al. reported a reduction in the inci-
is to limit the transfusion of blood products using [16, 86, dence of TRALI by excluding multiparous donors from

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N. A. Barrett and P. C. A. Kam Æ Transfusion-related acute lung injury Anaesthesia, 2006, 61, pages 777–785
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contributing to the plasma pool [59]. The simple exclusion 6 Toy P, Popovsky M, Abraham E, et al., The National
of multiparous donors would substantially reduce the Heart Lung and Blood Institute Working Group on
donor pool. In 2002, SHOT recommended that consid- TRALI. Transfusion-related acute lung injury: Definition
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7 Goldman M, Webert K, Arnold D, Freedman J, Hannon J,
estimated that at present 90% of plasma products are
Blajchman M. Proceedings of a consensus conference:
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cytokines and lipids accumulate during storage of platelets nation. American Journal of Respiratory and Critical Care
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121.
range from mild respiratory impairment to severe fulmi-
14 Gong M, Wei Z, Xu L, Miller P, Thompson B, Christiani
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reported to blood banks may represent just the tip of an and the risk of direct pulmonary injury and ARDS. Chest
iceberg, and transfusion may play an important role in 2004; 125: 203–11.
more cases of ALI than currently realised. TRALI has 15 Kleinman S, Caulfield T, Chan P, et al. Toward an
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requirements in critical care. Transfusion requirements in
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Anaesthesia, 2006, 61, pages 777–785 N. A. Barrett and P. C. A. Kam Æ Transfusion-related acute lung injury
. ....................................................................................................................................................................................................................

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