A synthetic lipid A analog,B464,provides significant protection against the cardiopulmonary derangements in porcine Gram-negative sepsis

Abstract

Many of the cardiopulmonary derangements associated with Gram-negative sepsis result from the activation of monocytes and macrophages by endotoxin with the resultant release of humoral mediators such as TNFα. Lipid A has been shown to retain the majority of endotoxin toxicity, however lipid A from nontoxic organisms has been shown, in vitro, to antagonize the action of other toxic endotoxin species. We examined the effects of a synthetic analog of lipid A (B464), on the evolution of hemodynamic derangements and acute lung injury following experimental Gram-negative sepsis. Anesthetized, ventilated swine were made septic with a 1 h intravenous infusion of live Pseudomonas aeruginosa and studied for 5 h. A treatment group received a bolus of B464 (100 μg/kg) prior to sepsis and a 1 h infusion (100 μg/kg/h) during the P. aeruginosa induction. A control group received simply 0.9% saline. All animals were studied for 5 h. B464 treatment failed to alter septic pulmonary hypertension or the decline in cardiac output. Late recovery from systemic hypotension was associated with reversal of arterial acidosis. Septic neutropenia was unaltered and was associated with increased lung neutrophil (PMN) sequestration measured by lung myeloperoxidase activity. However, decreased bronchoalveolar lavage protein content and improved arterial oxygen tension indicated attenuated acute lung injury in B464 treated animals. These preliminary data indicate that B464 may prove to be an effective tool in the treatment of human sepsis.