Closed-loop Continuous Infusions of Etomidate and Etomidate Analogs in Rats: A Comparative Study of Dosing and the Impact on Adrenocortical Function

Etomidate is a sedative–hypnotic commonly used in elderly and critically ill patients because it maintains hemodynamic stability.1–4 Unfortunately, etomidate also inhibits 11β-hydroxylase, causing suppression of adrenocortical steroid synthesis.5–9 This suppression is extremely potent, occurring at subhypnotic etomidate doses.10–13 It can persist for more than a day after etomidate administration has been discontinued.8,14,15 Consequently, the use of etomidate as a continuous infusion to maintain anesthesia or sedation has been almost entirely abandoned and the use of even a single dose of etomidate for anesthetic induction is controversial.16–18 We have developed two etomidate analogs that retain etomidate's potent hypnotic activity and favorable hemodynamic profile but have little or no adrenocortical effects when given as a single intravenous bolus. Methoxycarbonyl etomidate may be considered to be a “soft” analog of etomidate because it is ultrarapidly metabolized by esterases.19 After single bolus administration, recovery of adrenocortical function occurs significantly more quickly with methoxycarbonyl etomidate than etomidate.19 (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) is a pyrrole analog of etomidate that was designed to bind to 11β-hydroxylase with much lower affinity than etomidate.20 Compared with etomidate, carboetomidate is three orders of magnitude less potent an inhibitor of in vitro adrenocortical cortisol synthesis and does not produce adrenocortical suppression when given to rats as a single bolus.20 Previous studies of methoxycarbonyl etomidate and carboetomidate focused exclusively on a single intravenous bolus administration. However, their greatest potential utility may be as continuously infused agents to maintain sedation or anesthesia without producing clinically significant adrenocortical suppression. Such infusions will logically result in higher total drug doses and produce longer drug exposure times than a single bolus. In the current study, we administered etomidate, methoxycarbonyl etomidate, and carboetomidate to rats by continuous infusion using a closed-loop system to achieve approximately equivalent hypnotic depths and tested the hypothesis that the sedative–hypnotic dosing requirements, recovery times, and adrenocortical inhibitory activities of the three sedative hypnotic agents vary.