Cyclopropyl-methoxycarbonyl Metomidate: Studies in a Lipopolysaccharide Inflammatory Model of Sepsis. (August 2015)

• Record Type: Journal Article
• Authors: Santer, Peter; Pejo, Ervin; Feng, Yan; Chao, Wei; Raines, Douglas E.
• Is Part Of: Anesthesiology. Volume 123:Number 2(2015)
• Publication Date: 2015-08
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000000721
• Languages: English
• ISSNs: 0003-3022

Abstract

Abstract : Background: Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a rapidly metabolized etomidate analog that is currently in clinical trials. The goal of this study is to assess CPMM's potential value as an anesthetic agent for use in patients with sepsis by defining its actions in an acute inflammatory model of sepsis. Methods: Escherichia coli lipopolysaccharide (1 mg/kg) was injected intravenously into Sprague–Dawley rats. Thirty minutes later, CPMM, etomidate, or vehicle (n = 8 per group) was infused for 1 h. Plasma adrenocorticotropic hormone, corticosterone, and cytokine (interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor-α) concentrations were measured before, during, and after infusion. Results: After lipopolysaccharide injection, adrenocorticotropic hormone concentrations changed similarly over time in all three groups. Compared with vehicle group rats, CPMM group rats had significantly lower corticosterone concentrations at only a single study time point during infusion and no significant differences in cytokine concentrations at any time during the study period. Compared with etomidate group rats, CPMM group rats had significantly higher corticosterone concentrations (up to nine-fold) during and after hypnotic infusion. Cytokine concentrations in CPMM group rats and vehicle group rats were not significantly different, but they were significantly lower than those in etomidate group rats. Postinfusion mortality was 40% in etomidate group rats and 0% in CPMM and vehicle group rats. Conclusion: Compared with etomidate, CPMM produces less adrenocortical suppression, lower plasma cytokine concentrations, and improved survival in a lipopolysaccharide inflammatory model of sepsis. These results suggest that CPMM may be a safer alternative to etomidate in patients with sepsis. Abstract : A 1-h cyclopropyl-methoxycarbonyl metomidate infusion produced less suppression of adrenocortical steroid synthesis, less elevated plasma inflammatory cytokine concentrations, and lower mortality than did an etomidate infusion in an Escherichia coli lipopolysaccharide rat model of sepsis.