During the first 24 h after massive transfusion and on subsequent days, there was no significant difference in total transfusion between patients with and without ARDS (14.0 ± 6.8 U vs. 10.6 ± 7.3 U, P = 0.17). The amount of transfused leucodepleted packed red blood cells was identical in patients with and without ARDS (3.0 ± 4.3 U vs. 3.1 ± 4.1 U P = 0.94). However, the amount of fresh frozen plasma (FFP) given during the first 24 h was significantly larger in patients who developed ARDS (21.8 ± 10.6 U vs. 10.7 ± 14.7 U, P = 0.02) (Table 4).
During the first 24 h after massive transfusion, patients who developed ARDS had a lower PaO2, a higher FiO2, a lower PaO2/FiO2 ratio and a lower pH than the other patients (Table 4). The minute ventilation during the first 24 h after transfusion was significantly higher in patients who developed ARDS (10.6 ± 2.8 L min−1) than in those who did not (7.9 ± 1.8 L min−1) (P = 0.03) but the differences in tidal volume, PaCO2 and respiratory rate during the first 24 h did not reach statistical significance (Table 4).
Using a logistic regression technique, thoracic trauma and a low PaO2 during the first 24 h were identified as independent risk factors for ARDS.
Seventy-six patients (73.8%), including 5 of the 10 patients with ARDS, survived. Factors associated with mortality were circulatory shock at admission, in particular if prolonged, gastrointestinal bleeding and pneumonia (Table 3). Bleeding during a transplantation procedure had a better prognosis as 22 of 23 transplanted patients survived.
During the first 24 h, non-survivors had a higher FiO2, a lower pH, a lower PaCO2 and a higher arterial lactate concentration than the survivors (Table 4). Non-survivors were also more often treated by mechanical ventilation during the first 24 h. More non-survivors received vasopressor catecholamines during the first 24 h (Table 4).
There was no significant difference between survivors and non-survivors in the amount of leucodepleted blood received (3.2 ± 4.3 U vs. 2.9 ± 3.7 U, P = 0.77).
Logistic regression analysis showed that gastrointestinal bleeding and a high arterial lactate concentration during the first 24 h were independent variables related to death.
ARDS is a clinical syndrome developing as a consequence of a systemic reaction associated with the release of inflammatory mediators. Many factors can contribute to its development, and blood transfusions are usually listed among them [1-4]. However, patients requiring multiple transfusions usually have other factors that could favour the development of ARDS, including circulatory shock, polytrauma and chest trauma [1,2]. In the present study, multiple transfusion, as defined by the transfusion of at least six units of packed red blood cells during 24 h, was associated with a relatively low incidence of ARDS (only 10%). A multivariable analysis revealed that the development of ARDS was related more to underlying factors than to the multiple transfusions.
Considerable effort has been deployed to avoid complications related to transfusion of blood products, including acute haemolysis subsequent to ABO incompatibility, other immunological alterations and transmission of infectious micro-organisms [10-12]. Specific respiratory alterations following transfusions were first recognized in 1951 by Barnard , but it was only in 1983 that Popovsky and colleagues  introduced the term TRALI. TRALI is attributed to a leucoagglutination phenomenon and to the presence of lymphotoxic antibodies targeted against the white blood cells of the transfused patient [15-17]. Lipids released in the plasma during red blood cell conservation may also be involved .
Clinically, symptoms of TRALI (including dyspnoea, cyanosis, arterial hypotension, fever and cough) typically occur 1-2 h after transfusion and persist for 4-6 h after the transfusion [15,16]. Data on the frequency of TRALI are rare and vary widely as definitions of TRALI differ considerably among studies, but a recent consensus panel summarized an incidence rate of between 1 in 4000 and 1 in 557 000 per unit of red blood cells transfused, 1 in 432 and 1 in 88 000 per unit of platelets transfused, and 1 in 8000 and 1 in 74 000 per unit of FFP transfused . Even though TRALI often requires mechanical ventilation, the associated mortality is not as high as that associated with other causes of ARDS (6% vs. 30-50%) . The incidence of TRALI has probably decreased over time, especially with the implementation of routine leucodepletion, which may reduce the incidence of immunological reactions during transfusion [20,21]. In our study, no difference in the development of ARDS or mortality was attributed to leucodepletion, but the size of the study limits the interpretation of this finding.
All blood components have been incriminated in the occurrence of TRALI [22-24]. In our study, only the amount of FFP given during the first 24 h was higher for patients who developed ARDS, but this may reflect the greater severity of the disease state in these patients, even though one study incriminated FFP as the leading cause of ARDS after pneumectomy . During the first 24 h, ARDS patients receive more FFP either because their bleeding cannot be controlled or because they develop coagulopathy. In these situations, haemorrhagic shock occurs or will occur .
In practice, it is difficult to separate TRALI from other causes of ALI/ARDS. In our study, patients who developed ARDS already had more severe hypoxaemia in the first 24 h. On the other hand, circulatory shock, polytrauma and thoracic trauma, which are considered as risk factors for ARDS [1,2], were more common in the ARDS patients. Massive transfusions are usually required in the context of circulatory shock and it seems that shock, more than transfusion, was the cause of ARDS. In our study, polytrauma was a common cause of ARDS, and is associated with the systemic release of inflammatory mediators . Polytrauma, in particular when it includes a thoracic component, contributes to a pulmonary inflammatory reaction and to the development of ARDS. A higher SOFA score in the patients who developed ARDS compared with those who did not indicated a more severe degree of organ failure at admission. During the first 24 h, patients with ARDS also required more vasopressor agents and had somewhat more severe lactic acidosis than the other patients. Likewise, Eberhard and colleagues showed that the degree of initial metabolic acidosis was a reliable predictor for ALI in trauma patients . Another study on polytrauma patients  showed that arterial lactate concentration is a good predictor of early ARDS and the related liberation of the cytokines.
Silliman and colleagues have already noted that TRALI only develops if immunological reactions in the blood are associated with specific clinical situations [18,30]. Clinical situations necessitating massive transfusion include shock, polytrauma and thoracic trauma. In our study, patients who developed ARDS required a higher minute volume ventilation (due to a combination of a higher tidal volume and faster respiratory rate) than the other patients. This was likely to compensate for a more severe metabolic acidosis. Although large tidal volumes are associated with a worse outcome in ALI/ARDS, and may be associated with a greater inflammatory response that could contribute to lethality even in the early stages of the acute illness , tidal volume was not retained in the multivariable model.
Mortality was associated with both shock and lactic acidosis. Patients with gastrointestinal bleeding had the worst prognosis, while transplantation was associated with a good prognosis, probably because transplantations are performed in patients who are kept in an optimal state before the intervention and because bleeding could be controlled.
Our study is limited by its retrospective nature and the limited number of patients. Massive transfusions are relatively rare over 10 months in an 850-bed university hospital, even though the criterion we used for massive transfusion, six transfused units in 24 h, may be somewhat lower than that used in some other studies [32,33]. This relatively low definition for massive transfusion may in itself be seen as a limitation; however, Gong and colleagues  reported a stepwise increase in the rate of lung injury in those receiving just one to three units of red blood cells, suggesting that the requirement for massive transfusion as a risk factor for ALI may be overly restrictive . The differences in the patients' predisposing factors for ARDS and in their source of bleeding may also potentially have influenced the results.
In conclusion, our study suggests that the development of ARDS following massive transfusions may be due to factors other than massive transfusion per se.
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Keywords:© 2007 European Society of Anaesthesiology
BLOOD TRANSFUSION, adverse effects; RESPIRATORY DISTRESS SYNDROME; ADULT; ACIDOSIS; TRAUMA