Abstract
We investigated effects of pentoxifylline during septic shock. Two-year-old (10–12 kg), purpose-bred beagles were infected i.p. withEscherichia 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 · kg−1 · h−1 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 · kg−1, 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.
Footnotes
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Send reprint requests to: Dr. Charles Natanson, Critical Care Medicine Department, National Institutes of Health, Building 10, Room 7D43, 9000 Rockville Pike, Bethesda, MD 20892.
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↵1 Preliminary data were published in abstract form in Quezado ZMN, Natanson C, Banks SM, Koev CA, Danner RL, Elin RJ, Hosseini JM, Bacher JD and Hoffman WD (1993) Pentoxifylline can increase tumor necrosis factor level and decrease survival in a canine model of Gram negative septic shock (abstract). Crit Care Med21:S281.
- Abbreviations:
- CFU
- colony-forming units
- TNF
- tumor necrosis factor
- ANOVA
- analysis of variance
- Received April 17, 1998.
- Accepted July 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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