The individual survival benefits of tumor necrosis factor soluble receptor and fluid administration are not additive in a rat sepsis model

Abstract

Tumor necrosis factor (TNF) antagonists [e.g., TNF soluble receptor (TNFsr)] improved survival in preclinical but not clinical sepsis trials. However fluid support-itself beneficial-is standard clinically but rarely employed in preclinical sepsis models. We hypothesized that these therapies may not have additive benefit. Antibiotic-treated rats (n=156) were randomized to intratracheal or intravenous Escherichia coli challenges (>LD50) and either placebo or TNFsr and 24h fluid treatments alone or together. The survival effects of these therapies did not differ significantly comparing challenge routes. When averaged across route, while TNFsr or fluid alone decreased the hazard ratio of death significantly [ln±standard error (SE): -0.65±0.30 and -0.62±0.30, respectively, p≤0.05], together they did not (p=0.16). Furthermore, the observed effect of TNFsr and fluid together on reducing the hazard ratio was significantly less than estimated (-0.37±0.29 versus -1.27±0.43, respectively, p=0.027) based on TNFsr and fluid alone. While each treatment increased central venous pressure at 6 and 24h, the observed effects of the combination were also less than estimated ones (p≤0.0005). The individual survival benefits of TNFsr and fluids were not additive in this rat sepsis model. Investigating new sepsis therapies together with conventional ones during preclinical testing may be informative.