Continuously infused methylene blue modulates the early cardiopulmonary response to endotoxin in awake sheep

Background: In endotoxemia and septic shock, enhanced generation of endogenous nitric oxide (NO) contributes to myocardial depression, hypotension, and derangement of gas exchange. We hypothesized that continuous infusion of methylene blue (MB), an inhibitor of the NO pathway, would counteract these effects in endotoxemic sheep. Methods: Twenty-one sheep were anesthetized and instrumented for a chronic study with vascular catheters. On the day of the experiment, 18 conscious animals randomly received either an intravenous injection of MB 10 mg(.)kg(-1) or isotonic saline. Thirty minutes later, sheep received a 20-min intravenous infusion of Escherichia coli endotoxin 1 mug(.)kg(-1) and either an intravenous infusion of MB 2.5 mg(.)kg(-1.)h(-1) or isotonic saline, respectively, for 5 h. In addition, 3 animals were exposed to the same dose of MB alone. Results: MB reduced the early endotoxin-induced declines in stroke volume, left ventricular stroke work and cardiac indices, and prevented mean arterial pressure from falling. Moreover, MB ameliorated the increases in pulmonary arterial pressure and pulmonary vascular resistance index. In addition, MB reduced the increments in venous admixture and AaPO(2), decreased the falls in PaO(2), SaO(2), and oxygen delivery, and maintained oxygen consumption. MB also prevented the rises in body temperature and plasma nitrites and nitrates, and delayed the elevation of plasma lactate. When given alone to healthy sheep, MB transiently reduced plasma lactate and PaO(2), and increased AaPO(2). Conclusion: In ovine endotoxemia, continuously infused MB counteracts the early myocardial dysfunction and derangement of hemodynamics and gas exchange.