High-dose recombinant endotoxin neutralizing protein improves survival in rabbits with Escherichia coli sepsis

Objective: To assess the benefit of a recombinant endotoxin neutralizing protein from Limulus polyphemus in treating Gramnegative bacterial sepsis in rabbits, Design: Prospective, blinded, controlled, laboratory trial, Setting: Animal research laboratory, Subjects: New Zealand White rabbits, Interventions: We established a rabbit model of Escherichia coli peritonitis and bacteremia, with high mortality rate, despite treatment with gentamicin and ceftriaxone. Twenty-five pairs of male New Zealand White rabbits were challenged intraperitoneally with E. coli O18ac K1 in 5% porcine mucin (mean 7 x 10(9) colony-forming units). All animals were treated with intravenous gentamicin (2.5 mg/kg) and ceftriaxone (100 mg/kg), and with either intra venous endotoxin neutralizing protein (50 mg/kg) or saline 1 hr after E. coli challenge, Measurements and Main Results: All animals were bacteremic 1 hr after challenge (mean 3.6 x 10(5) colony-forming units/mL), Animals in both groups developed tachycardia, hypotension, and acidosis (NS), Geometric mean serum endotoxin and tumor necrosis factor (TNF) concentrations were significantly (p < .001) higher 1 hr after challenge compared with baseline prechallenge concentrations in both groups, From 1 to 2 hrs after challenge, endotoxin concentrations increased 2.5-fold in control animals (95% confidence interval = 13.1 to 32.9 endotoxin units/mL, p = .024), whereas endotoxin concentrations increased only 1.5-fold in endotoxin neutralizing protein-treated animals (95% confidence interval = 20.4 to 23.8 endotoxin units/mL, NS), TNF concentrations increased significantly (p < .001) in both groups from 1 to 2 hrs after challenge, Eighteen (72%) of 25 endotoxin neutralizing protein treated animals vs, 11 (44%) of 25 controls survived 24 hrs (p = .032), Conclusions: Treatment with endotoxin neutralizing protein had the following effects: a) the increase in serum endotoxin was blunted, but not TNF concentrations measured 1 hr after antibiotic treatment; and b) survival in rabbits with E. coli sepsis was improved.