Recombinant human tumor necrosis factor produces hemodynamic changes characteristic of sepsis and endotoxemia
W. J. Schirmer, J. M. Schirmer and D. E. Fry
Department of Surgery, Veterans Administration Medical Center, Cleveland, OH 44106.
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.
