Recombinant human tumor necrosis factor produces hemodynamic changes characteristic of sepsis and endotoxemia.

Abstract

Tumor necrosis factor (TNF) is a macrophage-derived peptide mediator released during endotoxemia and sepsis. We examined the systemic and visceral hemodynamic response to low doses of human recombinant TNF in rats. Each animal received a 30-minute intravenous infusion of either saline solution (n = 8) or TNF (n = 8) in a dose of 0.25 mg/kg or 1.0 mg/kg. Thermodilution cardiac output, blood pressure, pulse, vascular resistance, effective hepatic blood flow (galactose clearance), and effective renal plasma flow (p-aminohippurate clearance) were determined at time = 2 hours. The 0.25-mg/kg dose had no apparent effect on systemic hemodynamics. The 1.0-mg/kg dose produced a hyperdynamic systemic circulatory response with an elevated cardiac output, tachycardia, and a diminished systemic vascular resistance. Effective hepatic blood flow was exquisitely sensitive to even the lowest dose of TNF, with a 29% reduction despite the normal cardiac output. Renal flow was unaffected by either dose. Tumor necrosis factor-induced systemic and visceral hemodynamic changes are remarkably similar to those seen in gram-negative sepsis, suggesting that TNF may occupy a proximal position in the pathogenesis of overwhelming infection.