Etomidate and fatal outcome—even a single bolus dose may be detrimental for some patients
Editor—Etomidate has been used for over a quarter of a century in many countries in a variety of anaesthetic and non-anaesthetic settings. Despite problems such as pain on injection, thrombophlebitis and myoclonus, the positive pharmacologic attributes of etomidate have contributed to its continued use. The effect on cardiac output and myocardial oxygenation and its wide therapeutic index, which is approximately 6-fold better than thiopental and propofol, have logically served to maintain niche use in patients of all age groups,1–3 including haemodynamically unstable patients in pre-hospital, emergency department, intensive care and coronary care settings as well as the operating theatre. Etomidate also has roles in less urgent situations such as for procedural sedation and repeated anaesthesia for courses of electroconvulsive therapy.However, in 1983 an increase in mortality of critically ill patients associated with the use of etomidate infusions for sedation in intensive care was reported.4 Laboratory investigation revealed etomidate to be a potent inhibitor of adrenal steroidogenesis primarily through its effects on an enzyme 11 ß-hydroxylase.5 Its use for prolonged sedation was largely abandoned as a result of this report and subsequent supportive evidence.5 Most opinion at that time and currently,1 with notable exceptions,5 concluded that although etomidate by infusion for critically ill patients was detrimental, single bolus injections of etomidate in these and other groups were safe.
Recently the premise that bolus doses of etomidate are safe in septic, critically ill, patients has been challenged.6 7 The principal fear has been that the consequences of pharmacological adrenalectomy in shocked patients outweigh other perceived benefits of etomidate. These concerns have been amplified by two subsequent reports. In an observational study of 60 children with meningococcal sepsis, none of whom received steroid supplementation, biochemical evidence of impaired adrenal steroidogenesis and inhibition of 11 ß-hydroxylase was associated with the use of etomidate.8 Seven of the eight deaths in this study occurred in children who had received etomidate to facilitate tracheal intubation. Although the study design and small patient numbers precluded strong inferences, the results were of sufficient concern for the authors to recommend caution about the use of etomidate and the need for steroid supplementation after its use. In a second report, Annane's9 10 re-analysis of a subgroup of 77 patients given etomidate as part of a previously reported large randomized controlled trial provide more evidence of harm from this agent. After a single dose of etomidate, 94% of patients did not respond to a standard corticotrophin test and blockade of steroid synthesis lasted approximately 72 h, much longer than previously reported. Etomidate-treated patients required more fluids and vasopressors as supportive care, compared with those in the study who received other agents. In this trial, patients with septic shock were randomized to receive corticosteroid supplementation or placebo. In the sub-group of patients receiving etomidate the 28 day mortality was reduced from 76 to 55% with the use of corticosteroid supplementation.10 This increase in absolute risk for mortality of 21% equates to a number needed to harm for un-supplemented etomidate of only five patients. Annane's conclusions that all patients with septic shock who have been given etomidate require appropriate corticosteroid supplementation to prevent unnecessary death need to be assimilated by all those who use this agent in their practice. These data suggest that patients may have died in the past as a direct consequence of pharmacological adrenalectomy. This unacceptable outcome must be prevented in the future by avoidance of etomidate or ensuring steroid supplementation after its use in this patient population. Just as important, the use of etomidate in other patient populations must now be re-examined to assure these patients' welfare. They might include those without shock but with surgical sepsis such as peritonitis requiring anaesthesia and surgery or medical sepsis such as those with pneumonia requiring tracheal intubation for invasive respiratory support. Less physiologically stressed patients receiving repeated bolus injections in a course of treatment11 could also be at risk.
After more than a quarter of a century of use, and more than 20 yr after serious harm was first described, practitioners and drug regulatory agencies need to re-evaluate the role of etomidate in clinical practice.
Aberdeen, UK
*E-mail: d.noble{at}nhs.net
References
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