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Cyclopropyl-methoxycarbonyl Metomidate: Studies in a Lipopolysaccharide Inflammatory Model of Sepsis
Peter Santer1, Ervin Pejo, Yan Feng
1From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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.
Insights
Cyclopropyl-methoxycarbonyl metomidate (CPMM) shows less adrenal suppression and lower cytokine levels than etomidate in a sepsis model. CPMM also improved survival rates, suggesting it may be a safer anesthetic alternative for sepsis patients.
Area of Science:
- Anesthesiology
- Pharmacology
- Critical Care Medicine
Background:
- Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a novel etomidate analog undergoing clinical trials.
- Etomidate is commonly used for anesthesia induction but carries risks, especially in sepsis.
- Sepsis presents unique challenges for anesthetic management due to inflammatory responses.
Purpose of the Study:
- To evaluate CPMM as a potential anesthetic for sepsis patients.
- To define CPMM's effects in an acute inflammatory sepsis model.
- To compare CPMM's safety profile against etomidate in this model.
Main Methods:
- An acute sepsis model was induced in Sprague-Dawley rats via intravenous lipopolysaccharide injection.
- Rats received infusions of CPMM, etomidate, or vehicle for 1 hour.
- Plasma levels of adrenocorticotropic hormone, corticosterone, and key cytokines were measured.
Main Results:
- CPMM exhibited less adrenocortical suppression compared to etomidate, with significantly higher corticosterone levels.
- CPMM treatment resulted in significantly lower plasma cytokine concentrations than etomidate.
- Survival rates were 0% for CPMM and vehicle groups, versus 40% for the etomidate group post-infusion.
Conclusions:
- CPMM demonstrates reduced adrenocortical suppression and lower cytokine levels compared to etomidate.
- CPMM significantly improved survival rates in this sepsis model.
- CPMM represents a potentially safer anesthetic alternative to etomidate for patients with sepsis.