The platelet-activating factor antagonist bb-882 does not improve tissue oxygen extraction in endotoxic shock

Abstract

We investigated whether BB-882, a novel potent PAF antagonist, could influence systemic and pulmonary hemodynamics and oxygen extraction capabilities during an acute reduction in blood flow induced by cardiac tamponade after endotoxin challenge. Twenty-one anesthetized, ventilated, and endotoxin-shocked (2 mg/kg i.v. Escherichia coli endotoxin) dogs were randomly divided in three groups. One group (N = 7) served as control. A second group (N = 7) received BB-882 as a single bolus dose of 5 mg/kg, 30 minutes before endotoxin administration. A third group (N = 7) received BB-882 as a continuous infusion of 5 mg/kg x h, started 30 minutes after endotoxin. Hemodynamic and gazometric measurements were obtained in all dogs 30 minutes after endotoxin injection and repeated 30 minutes after cardiac filling pressures were restored to baseline by generous saline infusion. Saline infusion rate was then set at 20 mL/kg x h and tamponade was induced by repeated bolus injections of warm saline into the pericardial sac. Compared with controls, pretreatment with BB-882 attenuated the early endotoxin-induced decrease in arterial pressure (70 +/- 17 v 51 +/- 14 mm Hg, P < .05), cardiac index (118 +/- 29 v 91 +/- 15 mL/ kg x min, P < .05), stroke index (1.0 +/- 0.2 v 0.7 +/- 0.3 mL/kg, P < .05), and left ventricular stroke work index (0.9 +/- 0.3 v 0.4 +/- 0.2 g x m/kg, P < .05), but these effects were not sustained after fluid resuscitation. In contrast, BB-882 post-treatment maintained arterial pressure and improved cardiac performance at lower filling pressures in the later phase of endotoxic shock. BB-882 did not influence pulmonary hemodynamics. Treatment with BB-882 did not influence oxygen extraction at critical oxygen delivery (51.5 +/- 9.9% and 52.8 +/- 13.9% v 46.6 +/- 9.0%, respectively BB-882 pretreatment and post-treatment v control). We conclude that in this model of endotoxic shock the administration of BB-882, either before or after endotoxin challenge, has time-related beneficial hemodynamic and cardiac effects but does not improve global oxygen extraction capabilities. The potential benefit of adjunctive treatment with a platelet-activating factor antagonist in sepsis remains doubtful.