Vol. 288, Issue 1, 107-113, January 1999

Increasing Doses of Pentoxifylline as a Continuous Infusion in Canine Septic Shock¹

Zenaide M. N. Quezado, William D. Hoffman, Steven M. Banks, Robert L. Danner, Peter Q. Eichacker, Gregory M. Susla and Charles Natanson

Departments of Critical Care Medicine (Z.M.N.Q, W.D.H, S.M.B., R.L.D, P.Q.E., C.N.) and Pharmacy (G.M.S.), Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland

We investigated effects of pentoxifylline during septic shock. Two-year-old (10-12 kg), purpose-bred beagles were infected i.p. with Escherichia coli 0111:B4 (1.2-1.5 × 10⁹ colony-forming units per kilogram b.wt.) in a fibrin clot and then immediately treated with one of five doses of pentoxifylline (0.5-20 mg · kg¹ · h¹ i.v.) as a 36-h continuous infusion or placebo. All animals received antibiotics and fluid resuscitation. Pentoxifylline levels increased in a dose-dependent manner during (p = .001) and were undetectable 12 h after stopping the infusion. During infusion of pentoxifylline at all doses, there were increases (p = .003), and once the infusion was stopped, there were decreases (p = .049) in endotoxin levels compared with controls. After clot implantation, at all pentoxifylline doses there was a significant increase in tumor necrosis factor levels, compared with controls (p = .025). The relative risk of death was significantly increased with pentoxifylline therapy in a dose-dependent fashion (20  10  5.0  1.0  0.5 mg · kg¹, p = .008). One hypothesis consistent with these data is that high pentoxifylline levels slowed endotoxin clearance, resulting in high levels of endotoxemia and increased proinflammatory mediator release and death. Pentoxifylline, used as a long-term continuous infusion as is commonly done clinically, can be harmful during Gram-negative septic shock.