Transfusion related acute lung injury (TRALI) in cardiac surgery patients: incidence, risk factors and underlying pathophysiology

With the reduction of clerical errors transfusion-related acute lung injury
(TRALI) has currently surpassed hemolytic reactions as the leading cause of
transfusion-related morbidity and mortality. Generally considered to be rare,
TRALI is almost certainly underdiagnosed and underreported. At this moment we
have a consensus about the definition of TRALI, the patient needs to confirm
the definition of acute lung injury (ALI) and in the past 6 hours given a
transfusion and no other riskfactor for ALI may be present. However, clinical
diagnosis of TRALI stays difficult by the absence of specific markers of this
disease. As a consequence, most cases of TRALI remain unnoticed, misdiagnosed
as fluid overload or ALI of other etiology. Two distinct mechanisms of TRALI
have been suggested: the traditional theory proposes an antibody-mediated
reaction between recipient leukocytes and anti-leukocyte antibodies from donors
who were sensitized during pregnancy (multiparous women) or by previous
transfusion. Recently, an alternative mechanism has been put forward
implicating pro-inflammatory molecules that accumulate during blood storage. In
either case, TRALI is considered to be a *double hit* entity, in which the
condition of the patient at the time of transfusion (e.g., surgery, shock,
mechanical ventilation) predisposes to priming and adherence of neutrophils in
the lung vasculature.
Cardiac surgery patients may form a group of patients at high risk for
TRALI: first, during the intra-thoracic surgical procedure the lungs are
usually left deflated and non-ventilated for several hours. This procedure may
cause injury to the lung vasculature (the *primary hit* in the *double hit*
theory). Second, these patients often receive transfusion of numerous blood
products, in particular red blood cells and furthermore fresh frozen plasma and
platelets. The basis for the proposed study follows from our preliminary data
that oxygenation of post-cardiac surgery patients in 1 in 15 patients rapidly
declines without any obvious reason. Indeed, these patients are confronted with
oxygenation problems, which do not seem to be caused by simple fluid overload
or pulmonary atelectasis. The majority of these patients received a transfusion
during or after cardiac surgery, from which we suggest that these patients may
have had TRALI.

(i.) to determine the incidence of and risk factors for TRALI in a prospective
cohort of cardiac surgery patients

(ii.) to test the hypotheses of TRALI in this patient group

(iii.) to study local inflammatory responses during TRALI

(iv.) to determine the role of old and new biomarkers of lung injury in the
diagnosis of TRALI.

In a observational cohort study of cardiac surgery patients we expect to
recruit a total of 100 TRALI-patients from approximately 1500 patients after
cardiac surgery with transfusion. Patients receiving bloodproducts without
developing TRALI and patients developing ALI without receiving bloodproducts, a
total of maximum 400, will be included in the control groups by using a matched
case control design. Assuming this incidence of ALI after blood transfusion of
approximately 6,6% and a standard deviation of 15% and an alpha of 0.05, we
will have > 80% power to detect modest independent increase in risk for
development of TRALI. Since not all cardiopulmonary surgery patients will
receive blood product transfusions, we expect 2* years to be needed to recruit
enough patients in the study. The whole project is performed in 3 years.

Bloodsampling will be done during standard clinical rounds. Lung lavage is a
standard procedure in intubated and mechanically ventilated patients (normally
the obtained fluid is discarded)