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 (F1 + 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 F1 + 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 F1 + 2levels (80%) in saline-instilled lung segments (50 pmol L-1, 95% CI 12-87). In contrast, dexamethasone had no effect on systemic F1 + 2levels. 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.
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
J
J
Bartko
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
C
C
Schoergenhofer
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
M
M
Schwameis
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
N
N
Buchtele
Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
J
J
Wojta
Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
G
G
Schabbauer
Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
L
L
Stiebellehner
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
B
B
Jilma
D000328:Adult; D000990:Antithrombin III / Q000737:chemistry; D001777:Blood Coagulation; D001778:Blood Coagulation Disorders / Q000188:drug therapy*; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid; D003907:Dexamethasone / Q000494:pharmacology*; D004311:Double-Blind Method; D004731:Endotoxins / Q000009:adverse effects*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000187:drug effects*; D008297:Male; D010447:Peptide Hydrolases / Q000737:chemistry; D013927:Thrombosis; D055815:Young Adult
D004731:Endotoxins; D005938:Glucocorticoids; C046193:antithrombin III-protease complex; D003907:Dexamethasone; D000990:Antithrombin III; D010447:Peptide Hydrolases
acute respiratory distress syndrome; coagulation; dexamethasone; lung; pneumonia