HISTAMINE-RECEPTOR ANTAGONISTS, CYCLOOXYGENASE BLOCKADE, AND TUMOR-NECROSIS-FACTOR DURING ACUTE SEPTIC INSULT

Tumor necrosis factor (TNF) may be a major endogenous mediator of seps is-induced acute organ injury. We proposed that treatment of septic pi gs with the combined agents ibuprofen, a cyclooxygenase inhibitor, and histamine receptor antagonists, cimetidine (H-2 antagonist) and diphe nhydramine (H-1 antagonist) would result in lower circulating levels o f TNF and decreased parameters of sepsis-induced injury in these anima ls. To test this, plasma TNF activity, cardiac index, systemic and pul monary arterial pressures, arterial PO2 and bronchoalveolar ravage pro tein content were monitored for 300 min in four groups of anesthetized pigs: saline-infused control pigs (n = 4); pigs infused for 60 min wi th Pseudomonas aeruginosa (5 x 10(8) organisms/mL, .3 mL/20 kg/min) (n = 5) and pigs infused for 60 min with P. aeruginosa plus ibuprofen (1 2.5 mg/kg) alone (n = 4) or ibuprofen plus cimetidine (150 mg) and dip henhydramine (30 mg/kg) at 0 and 120 min (CID, n = 4). Within 60 min, pigs infused with P. aeruginosa exhibited increased plasma TNF activit y (>8-fold increase in ng/mL TNF; L929 cytolysis assay) and showed alt erations in all hemodynamic and pulmonary parameters. Ibuprofen or CID administration in the septic pigs decreased peak TNF activity by 4.6 and 10.2 ng/mL, respectively, and CID treatment was correlated with be tter attenuation of certain sepsis-induced alterations. These results show that CID treatment attenuates sepsis-induced injury and that this is correlated with reduced plasma TNF activity in a porcine model of sepsis-induced acute organ injury.