Editor:
Sadis and colleagues [Reference Sadis, Dubois, Melot, Lambermont and Vincent1] investigated risk factors for the development of ARDS in patients receiving multiple transfusions and found that it was not the number of transfusions but thoracic trauma and hypoxia that were associated with the subsequent development of ARDS. Patients who developed ARDS received significantly more fresh frozen plasma. Previous studies showed that septicaemia is an additional predisposing factor for transfusion-related ARDS [Reference Silliman2]. Another condition commonly associated with pulmonary oedema during infusion of large amounts of intravenous fluids is diabetic ketoacidosis [Reference Dixon, Jude, Banerjee and Bain3]. All these conditions with their different pathophysiology have in common the release of large amounts of cytokines including tumour necrosis factor (TNF) and interleukin-1 (IL-1). Transfusion of an anti-CD28 monoclonal antibody into human volunteers stimulated T-cells to release large amounts of these two cytokines and led to pulmonary oedema in all subjects of this trial [Reference Suntharalingam, Perry and Ward4]. The mechanism by which these cytokines lead to or predispose to pulmonary oedema has recently been clarified: Alveolar epithelial fluid clearance in pulmonary oedema is dependent on pulmonary epithelial sodium and chloride transport through the apical alveolar epithelial sodium channel and the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel generating the osmotic gradient, which removes water through alveolar aquaporin channels and paracellular pathways from the alveolar air space [Reference Matthay, Folkesson and Clerici5]. TNF is a powerful down-regulator of alveolar epithelial sodium channel expression and was found to induce pulmonary oedema in various animal studies. IL-1 was found to reduce pulmonary alveolar epithelial sodium channel function and expression and sodium uptake in alveolar type II cells. IL-1 can also reduce pulmonary epithelial chloride transport by down-regulation of prostanoid receptors, which leads to a reduction in cyclic adenosine monophosphate (cAMP) and subsequently in cAMP-dependent CFTR function. Pulmonary oedema in meningococcal septicaemia has recently been associated with reduced systemic chloride channel function [Reference Eisenhut6]. The hypoxia found in patients developing ARDS subsequently indicated a reduced fluid clearance associated with a direct cytokine effect preceding the development of ARDS. The association of ARDS with FFP administration may be related to the fact that TNF caused a coagulopathy [Reference Esmon7] prompting the administration of FFP. Contributing to the predisposition to ARDS by inflammatory conditions may be the upregulation of P-selectins on vascular endothelial cells, which facilitates the adhesion of neutrophils in the pulmonary circulation and their subsequent migration into the alveolar space. Neutrophil leucocytes are an important source of IL-1 and TNF production.
Future research needs to focus on treatments that can prevent the development of ARDS associated with cytokine-induced reduction of alveolar fluid clearance. The prophylactic application of beta-agonists, which are able to up-regulate alveolar epithelial sodium and chloride transport and were found to reduce lung water in the recent beta agonist lung injury trial, may be able to reduce the risk of this complication.
