Doxapram preserves the pulmonary vascular response to hypoxia in endotoxin-treated canine lung lobes

Abstract

We studied the direct effects of doxapram on pulmonary vascular resistance and hypoxic pulmonary vasoconstriction in normal canine lung lobes (N = 6) before and after endotoxin administration. We used the technique of arterial and venous occlusions to subdivide pulmonary vascular resistance into total (Rtot), arterial, venous, and middle (Rm) segment resistances. We sequentially ventilated the lobes with control (35% O 2) and hypoxic (3% 0 2) gas mixtures prior to and following both low-dose (20 μg/kg/min) and high-dose (200 μg/kg/min) infusions of doxapram. We then administered endotoxin (1 mg/kg) and repeated control and hypoxic ventilatory periods during low-dose doxapram infusion. An additional six lobes were identically treated except that saline was infused instead of doxapram, and all measurements were repeated. Rtot and Rm increased ( P < .05) during hypoxic ventilation compared with control gas ventilation before endotoxin administration. We found that during hypoxic ventilation, Rm was significantly higher ( P < .01) during low-dose doxapram infusion compared with the equivalent period during saline infusion. Following endotoxin administration, values of Rm increased significantly ( P < .05) from control to hypoxic ventilation periods during doxapram infusion (0.006 ± 0.003 cm H 2O/mL/min and 0.027 ± 0.015 cm H 2O/mL/min, respectively) but not during saline infusion (0.007 ± 0.004 cm H 2O/mL/min and 0.006 ± 0.003 cm H 2O/mL/min, respectively). We conclude that doxapram can directly augment hypoxic pulmonary vasoconstriction even in the absence of systemic neuronal or humeral input. Of more clinical importance, doxapram infusion may allow expression of hypoxic pulmonary vasoconstriction following endotoxin. This in turn could act to improve ventilation/ perfusion matching and also to decrease pulmonary edema.