GENTAMICIN AND INDOMETHACIN IN THE TREATMENT OF SEPTIC SHOCK - EFFECTS ON PROSTACYCLIN AND THROMBOXANE-A2 PRODUCTION

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 225  (1) , 94-101
Abstract
The effects of the thromboxane synthetase inhibitor 7-(1-imidazolyl)heptanoic acid (7-IHA) and the fatty acid cyclooxygenase inhibitors indomethacin or ibuprofen in the treatment of fecal peritonitis in the rat were investigated. The effects of gentamicin [an antibacterial agent] alone and in combination with reduction of arachidonic acid metabolism by treatment with indomethacin or essential fatty acid deficiency was also investigated. 7-IHA (60 mg/kg), administered i.p. 30 min before i.p. instillation of a fecal suspension, significantly reduced the plasma levels of immunoreactive (i) TxB2 [thromboxane B2] from 1066 .+-. 194 pg/ml (14) to nondetectable (< 200 pg/ml; 9) (P < 0.01) at 1 h and from 1695 .+-. 218 (16) to 508 .+-. 56 pg/ml (6) (P < 0.01) at 4 h after instillation of feces. The levels of i6-keto-prostaglandin (PG)F1.alpha., the stable metabolite of prostacyclin, were significantly elevated by 7-IHA pretreatment from vehicle-treated septic control levels of 3777 .+-. 414 (16) to 5185 .+-. 467 pg/ml (9) (P < 0.05) at 1 h. Plasma i6-keto-PGF1.alpha. at 4 h in 7-IHA-treated rats (5503 .+-. 665 pg/ml) (6) was not different from vehicle-treated controls. Survival associated with fecal peritonitis was not altered by 7-IHA pretreatment. Indomethacin (10 mg/kg) or ibuprofen (5 mg/kg) administered i.p. 30 min before the fecal suspension significantly decreased iTxB2 and i6-keto-PGF1.alpha. plasma levels when measured at 4 h and prolonged survival time (P < 0.05). Fibrinogen/fibrin degradation products were elevated (P < 0.01) during fecal peritonitis and were reduced by indomethacin (P < 0.01) or 7-IHA (P < 0.05). Gentamicin significantly increased mean survival time from 8.6 .+-. 0.2 (50) to 23.8 .+-. 2.6 h (16) (P < 0.01). Gentamicin in combination with indomethacin or essential fatty acid deficiency further improved mean survival time and resulted in long-term survivals (> 48 h) of 35 (17) and 30% (7), respectively (P < 0.01 compared with gentamicin). Gentamicin pretreatment did not significantly alter plasma iTxB2 levels, but decreased i6-keto-PGF1 from 9465 .+-. 792 (7) to 3096 .+-. 1174 pg/ml (5; P < 0.01) at 6 h after induction of fecal peritonitis. Thus, inhibition of fatty acid cyclooxygenase may be a useful adjunct to antibiotic therapy in the treatment of septic shock.