Abstract
ObjectiveET-26 HCl is a promising sedative–hypnotic anesthetic with virtually no effect on adrenocortical steroid synthesis. However, whether or not ET-26 HCl also has a sufficiently wide safety margin and hemodynamic stability similar to that of etomidate and related compounds remains unknown. In this study, the effects of ET-26 HCl, etomidate and propofol on therapeutic index, heart rate (HR), mean arterial pressure (MAP), maximal rate for left ventricular pressure rise (Dmax/t), and maximal rate for left ventricular pressure decline (Dmin/t) were investigated in healthy rats and a rat model of uncontrolled hemorrhagic shock (UHS).Methods50% effective dose (ED50) and 50% lethal dose (LD50) were determined after single bolus doses of propofol, etomidate, or ET-26 HCl using the Bliss method and the up and down method, respectively. All rats were divided into either the normal group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group) or the UHS group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group). In the normal group, after preparation for hemodynamic and heart-function monitoring, rats were administered a dose of one of the test agents twofold-higher than the established ED50, followed by hemodynamic and heart-function monitoring. Rats in the UHS group underwent experimentally induced UHS with a target arterial pressure of 40 mmHg for 1 hour, followed by administration of an ED50 dose of one of the experimental agents. Blood-gas analysis was conducted on samples obtained during equilibration with the experimental setup and at the end of the experiment.ResultsIn the normal group, no significant differences in HR, MAP, Dmax/t and Dmin/t (all P > 0.05) were observed at any time point between the etomidate and ET-26 HCl groups, whereas HR, MAP and Dmax/t decreased briefly and Dmin/t increased following propofol administration. In the UHS group, no significant differences in HR, MAP, Dmax/t and Dmin/t were observed before and after administration of etomidate or ET-26 HCl at ED50 doses (all P > 0.05). Administration of propofol resulted in brief, statistically significant reductions in HR and Dmax/t, with a brief increase in Dmin/t (P ˂ 0.05), while no significant differences in MAP were observed among the three groups. The blood-lactate concentrations of rats in the ET-26 HCl group were significantly lower than those in etomidate and propofol groups (P ˂ 0.05).ConclusionsET-26 HCl provides a similar level of hemodynamic stability to that obtained with etomidate in both healthy rats, and rat models of UHS. ET-26 HCl has the potential to be a novel induction anesthetic for use in critically ill patients.
Highlights
An abundance of evidence indicates that hypotension has an adverse effect on critically ill patients during the perioperative period
Administration of propofol resulted in brief, statistically significant reductions in heart rate (HR) and Dmax/t, with a brief increase in Dmin/t (P < 0.05), while no significant differences in mean arterial pressure (MAP) were observed among the three groups
ET-26 HCl provides a similar level of hemodynamic stability to that obtained with etomidate in both healthy rats, and rat models of uncontrolled hemorrhagic shock (UHS)
Summary
An abundance of evidence indicates that hypotension has an adverse effect on critically ill patients during the perioperative period. Induction of anesthesia using the commonly used anesthetic propofol carries an increased risk of hypotension, resulting in cardiovascular adverse effects [4]. The incidence of hypotension is substantially lower among patients in critical care who are anesthetized using etomidate compared with those whose anesthesia is induced using propofol or midazolam. Etomidate has virtually no effect on hemodynamic stability [8,9], the suppression of corticosteroid synthesis associated with this agent limits its use; whether or not etomidate-induced suppression of adrenal gland function affects mortality remains controversial [10,11,12,13,14]. The development of a novel anesthetic that has the hemodynamic stability of etomidate without affecting corticosteroid synthesis is an important step in the development of safer anesthetics
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