Dexamethasone inhibits endotoxin-induced coagulopathy in human lungs

Essentials Glucocorticoids are associated with an increased risk of thrombosis. Healthy volunteers received dexamethasone or placebo in an endotoxin lung instillation model. Dexamethasone suppressed thrombin generation in bronchoalveolar lavage. Glucocorticoids inhibit endotoxin induced pulmonary coagulopathy.

Background Activation of local and systemic coagulation is a common finding in patients with pneumonia. There is evidence that glucocorticoids have procoagulant activity in the circulation, particularly in the context of inflammation. The effects of glucocorticoids on local pulmonary coagulation have not yet been investigated. Objective To use a human model of lung inflammation based on the local instillation of endotoxin in order to investigate whether glucocorticoids alter pulmonary coagulation. Methods Twenty-four healthy volunteers were randomized to receive either dexamethasone or placebo in a double-blind trial. Endotoxin was instilled via bronchoscope into right or left lung segments, followed by saline into the contralateral site. Six hours later, a bilateral bronchoalveolar lavage (BAL) was performed and coagulation parameters were measured. Results Endotoxin induced activation of coagulation in the bronchoalveolar compartment: the level of prothrombin fragment 1 + 2 (F_{1 + 2} ) was increased three-fold (248 pmol L^-1 , 95% confidence interval [CI] 43-454 versus 743 pmol L^-1 , 95% CI 437-1050) and the level of thrombin-antithrombin complex (TATc) was increased by ~ 50% (31 μg L^-1 , 95% CI 18-45 versus 49 μg L^-1 , 95% CI 36-61) as compared with saline-challenged segments. Dexamethasone reduced F_{1 + 2} (284 pmol L^-1 , 95% CI 34-534) and TATc (9 μg L^-1 , 95% CI 0.7-17) levels almost to those measured in BAL fluid from the saline-instilled segments in the placebo group. Dexamethasone even profoundly reduced F_{1 + 2} levels (80%) in saline-instilled lung segments (50 pmol L^-1 , 95% CI 12-87). In contrast, dexamethasone had no effect on systemic F_{1 + 2} levels. Conclusions Dexamethasone inhibits endotoxin-induced coagulopathy in lungs. This trial is the first to provide insights into the effects of glucocorticoids on pulmonary coagulation in response to endotoxin.