lexipafant and Shock--Septic

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.

Topics: Animals; Cardiac Output; Cardiac Tamponade; Dogs; Endotoxins; Escherichia coli; Female; Hemodynamics; Leucine; Male; Myocardial Contraction; Oxygen; Oxygen Consumption; Platelet Activating Factor; Pulmonary Wedge Pressure; Shock, Septic

Platelet-activating factor (PAF) is a potent vasoactive and inflammatory lipid mediator which has been implicated in the hemodynamic alterations of endotoxemia and sepsis. Different PAF receptor antagonists have been shown to attenuate the systemic and pulmonary disturbances of sepsis, but they were generally administered before the injection of endotoxin and their effects have not been consistent. To examine the effects of BB-882, a novel potent PAF receptor antagonist, on general hemodynamics and regional flow distribution in a canine endotoxic shock model, 14 anesthetized and ventilated dogs received 2 mg/kg of Escherichia coli endotoxin intravenously (i.v.) followed by generous fluid resuscitation. Thirty minutes later, the dogs received either BB-882 (n = 7) as a continuous i.v. infusion with hourly increasing doses (2, 5, and 10 mg/kg.h, respectively) or a corresponding amount of saline (n = 7). The administration of BB-882 resulted in a dose-dependent reduction in cardiac output and an increase in systemic and pulmonary vascular resistance. Mesenteric and renal flow were not different from control values whereas femoral blood flow progressively decreased. Another group of 7 dogs received 5 mg/kg i.v. bolus of BB-882 30 min before endotoxin. Pretreatment significantly increased mesenteric blood flow by about 50% but did not show any significant hemodynamic effects. This study demonstrates that the administration of a PAF receptor antagonist following endotoxic shock in fluid resuscitated dogs does not offer significant hemodynamic benefit. Pretreatment with BB-882 at the dose used only enhanced mesenteric perfusion. These findings do not support beneficial effects of PAF receptor antagonists in septic shock.

Topics: Animals; Dogs; Endotoxins; Female; Hemodynamics; Hemoglobins; Lactic Acid; Leucine; Male; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Regional Blood Flow; Resuscitation; Shock, Septic; Time Factors

To study the role of platelet-activating factor (PAF) antagonism in posthemorrhage septic shock in pigs.. Experimental study.. Twelve anesthetized pigs were bled, kept with a mean arterial pressure of 30 mm Hg for 30 minutes, and then resuscitated with 50 mL/kg of isotonic saline. A continuous infusion of Escherichia coli endotoxin 36 micrograms/kg/hour was given intravenously for 3.5 hours starting 30 minutes after resuscitation. The animals were divided into two groups of six each. One group received I mg/kg of BB-882 (a potent specific PAF receptor antagonist) as a bolus during resuscitation, followed by a continuous infusion of BB-882 1 mg/kg/hour. The other group received vehicle alone.. The measured variables were blood temperature, heart rate, intravascular pressures, cardiac output, systemic and pulmonary vascular resistance, lung-thorax compliance, blood gases, hemoglobin oxygen saturation, packed cell volume and blood sugar and serum lactic acid concentrations. The group treated with BB-882 had significantly higher intracardiac pressures and cardiac output, and had less increase in systemic vascular resistance. The BB-882 group had significantly less lactic acidemia than the control group (p < 0.05, analysis of variance appropriate for repeated measurement design). BB-882 had no effect on endotoxin-induced hypoxia or reduced lung-thorax compliance.. PAF antagonism reduced the increase in systemic vascular resistance, improved cardiac output, and reduced lactic acidemia in posthemorrhage septic shock in pigs, but it did not improve hypoxia or reduced lung-thorax compliance.

Topics: Animals; Body Temperature; Cardiac Output; Heart Rate; Hemodynamics; Leucine; Platelet Activating Factor; Shock, Hemorrhagic; Shock, Septic; Swine; Vascular Resistance

Endotoxemia was induced by intravenous infusion of Escherichia coli endotoxin in 18 anesthetized pigs in a dose of 36 micrograms/kg/hr. Nine pigs were pretreated with BB-882, a novel platelet-activating factor (PAF) antagonist, 33 mg/kg/hr, starting 30 min before endotoxin, and nine pigs received a similar volume of vehicle. Normotension was maintained with intravenous crystalloid resuscitation. Six pigs received only BB-882 and served as controls. Endotoxemia induced an acute transient 300% increase in pulmonary vascular resistance, identical in both groups. The initial increase was followed by a second, more gradual, rise in resistance, which was significantly attenuated by BB-882 (P < 0.01, repeated measurements ANOVA). Endotoxin-induced arterial deoxygenation and fall in lung/thorax compliance was not significantly altered by BB-882. Hematocrit was less in endotoxic pigs receiving BB-882 (P < 0.02). There were no significant changes compared to baseline in the control group. The results indicate that PAF is a minor determinant of early pulmonary dysfunction in nonhypotensive porcine endotoxemia.

Topics: Animals; Escherichia coli; Female; Leucine; Lipopolysaccharides; Lung; Lung Diseases; Male; Platelet Activating Factor; Shock, Septic; Swine; Vascular Resistance