IBUPROFEN IMPROVES SURVIVAL FROM ENDOTOXIC-SHOCK IN THE RAT

Abstract

During endotoxemia, there is a significant increase in arachidonic acid-derived metabolites. To test the hypothesis that 1 or more of these metabolites play a significant role in the pathogenesis of endotoxic shock, the therapeutic efficacy of varying doses of ibuprofen, a cyclooxygenase inhibitor, on the pathophysiologic sequelae of endotoxic shock in the Long-Evans rat, induced by Salmonella enteritidis endotoxin (20 mg/kg) was studied. Pretreatment with ibuprofen (1-3.75 mg/kg) produced an optimal survival rate of 80% compared to only 11% in the vehicle-treated group. Doses of 0.1, 0.5 and 30 mg/kg of ibuprofen significantly (P < 0.05) improved survival over nontreated shocked controls. Plasma thromboxane B2 and 6-keto-prostaglandin F1.alpha.(PFG1.alpha.) levels rose from < 200 pg/ml to 2207 .+-. 282 (n = 16) and 840 .+-. 59 (n = 8), respectively, within 30 min after injection. The rise in plasma thromboxane. B2 and 6-keto-PGF1.alpha. levels was reduced with ibuprofen (3.75 and 30 mg/kg) to > 200 pg/ml. Ibuprofen (3.75 and 30 mg/kg) reduced thrombin-induced in vitro platelet thromboxane B2 synthesis by 95 and 99%, respectively. The severity of coagulopathies as reflected by elevations in serum fibronogen fibrin degradation products and lysosomal integrity were like-wise significantly reduced (40%) with ibuprofen (3.75 mg/kg) pretreatment. Arachidonic acid metabolites play a significant early role in the pathogenesis of endotoxic shock. Agents which inhibit fatty acid cycloxygenase may be beneficial in endotoxic shock.