Selective thromboxane A 2 synthase inhibition by OKY-046 prevents cardiopulmonary dysfunction after ovine smoke inhalation injury

Abstract

Background: Because thromboxane A 2 is implicated in the pathophysiology of acute lung injury, the aim of this study was to evaluate the effects of selective thromboxane A 2 synthase inhibition on cardiopulmonary function in the experimental setting of severe smoke inhalation injury. Methods: Sixteen adult sheep were operatively instrumented for chronic study. The injured intervention group was treated with the selective thromboxane A 2 synthase inhibitor OKY-046, whereas the injured control group received only the vehicle (n = 8 each). Results: The progressive increase in thromboxane B 2 lung lymph concentrations in control animals was associated with increased transvascular fluid flux, augmented resistances in the pulmonary and systemic circulation, and a reciprocal decrease in cardiac output. In addition, end-systolic pressure-diameter relation and maximum +dp/dt were markedly depressed as compared with baseline (24 h: 14.3 ± 0.9 vs. 8.9 ± 0.5 mmHg/mm and 2,120 ± 50 vs. 1,915 ± 40 mmHg/s, respectively; each P < 0.05). Infusion of OKY-046 significantly inhibited pulmonary thromboxane B 2 delivery, attenuated the early increase in pulmonary vascular resistance, and blocked the increase in systemic vascular resistance. In addition, OKY-046 blunted and delayed the decrease in cardiac output and maintained end-systolic pressure-diameter relation, +dp/dt, and lung lymph flow at baseline values. Conclusions: These findings suggest that selective thromboxane A 2 synthase inhibition may represent a goal-directed therapeutic approach to alleviate cardiovascular and pulmonary dysfunction in the setting of smoke inhalation injury. © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.