Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia

Compared with etomidate, carboetomidate produces less suppression of adrenocortical function and smaller increases in proinflammatory cytokine production in an endotoxemia model of sepsis. These findings suggest that carboetomidate could be a useful alternative to etomidate for maintaining anesthesia for a prolonged period of time in patients with sepsis.

We developed a novel pyrrole analog of etomidate, (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), which retains etomidate's desirable anesthetic and hemodynamic properties but lacks its potent inhibitory affect on adrenocorticotropic hormone-stimulated steroid synthesis. The objective of this study was to test the hypothesis that in contrast to etomidate, carboetomidate neither suppresses the adrenocortical response to endotoxemia nor enhances the accompanying production of proinflammatory cytokines. Design: Animal study. Setting: University research laboratory. Subjects: Male Sprague-Dawley rats. Interventions: For both single and multiple anesthetic dose studies, rats were injected with Escherichia coli lipopolysaccharide immediately followed by a hypnotic dose of etomidate, carboetomidate, or vehicle alone (dimethyl sulfoxide) as a control. For single-dose studies, no additional anesthetic (or vehicle) was administered. For multiple anesthetic dose studies, additional doses of anesthetic (or vehicle) were administered every 15 mins for a total of eight anesthetic (or vehicle) doses. Measurements and main

Plasma adrenocorticotropic hormone, corticosterone, and cytokine concentrations were measured before lipopolysaccharide administration and intermittently throughout the 5-hr experiment. In single anesthetic dose studies, plasma adrenocorticotropic hormone and cytokine concentrations were not different at any time point among the etomidate, carboetomidate, and vehicle groups, whereas plasma corticosterone concentrations were briefly (60-120 mins) reduced in the etomidate group. In multiple anesthetic dose studies, plasma corticosterone concentrations were persistently lower and peak plasma interleukin-1β and interleukin-6 concentrations were higher in the etomidate group vs. the carboetomidate and control groups. Peak plasma interleukin-10 concentrations were similarly elevated in the etomidate and carboetomidate groups vs. the control group. Conclusions: Compared with etomidate, carboetomidate produces less suppression of adrenocortical function and smaller increases in proinflammatory cytokine production in an endotoxemia model of sepsis. These findings suggest that carboetomidate could be a useful alternative to etomidate for maintaining anesthesia for a prolonged period of time in patients with sepsis.