This article is part of a Pro and Con debate and is accompanied by the following Invited Commentary and article:
• Payen J-F. Etomidate for critically ill patients: let us clarify the debate. Eur J Anaesthesiol 2012; 29:504–505.
• Ray DC, McKeown DW. Etomidate for critically ill patients. Pro: yes can use it. Eur J Anaesthesiol 2012; 29:506–510.
Etomidate is a carboxylated imidazole-derived hypnotic, first discovered in the late 1960s and then commercialised in the 1970s. It is short-acting, has negligible cardiovascular effects due to α2b-adrenoreceptor activation, limited respiratory depression and does not cause histamine release.1,2 These qualities have justified its use as an induction agent in anaesthesia for haemodynamically unstable patients, especially in the setting of rapid sequence induction.3 In the 1980s, the indication for sedation with continuous etomidate infusion was withdrawn when reports presented compelling evidence of increased mortality.4 The pathophysiological basis for this increased death rate after prolonged etomidate administration was attributed to etomidate-induced inhibition of adrenal 11β-hydroxylase, leading to adrenal insufficiency with decreased serum cortisol concentrations.5,6 Today, there is no doubt that even a single subanaesthetic bolus dose causes adrenal dysfunction ranging from 12 to 48 h.7–10 These early postoperative hours are often crucial for haemodynamic stabilisation, particularly in trauma, acute myocardial infarction, stroke and sepsis.11 Malerba et al.12 investigated 62 consecutively collected, acutely ill patients needing mechanical ventilation for more than 24 h. Twenty-seven patients were classified as nonresponders to corticotrophin stimulation testing (i.e. adrenal insufficiency) and 35 as responders. Multivariate analysis concluded that only etomidate administration as a single bolus was related to a reduced response to corticotrophin [odds ratio 12.21, 95% confidence interval (CI) 2.99 to 49.74]. Iribarren et al.13 prospectively evaluated 120 elective patients scheduled for cardiac surgery with cardiopulmonary bypass, which can be considered as a model for traumatic and inflammatory injury. In this study, 78 patients received etomidate; 69 of them (88%) developed adrenal insufficiency. Etomidate was the only independent risk factor associated with adrenal insufficiency (odds ratio 6.6, 95% CI 2.3 to 14.5; P < 0.001).
In critically ill patients with sepsis, liver failure or trauma, in whom cortisol storage capacities are diminished and higher levels are needed to achieve homeostasis,14 further adrenal dysfunction caused by administration of etomidate may increase morbidity and mortality. This has nourished a vigorous debate in recent years from firm disapproval to moderate adherence.15,16
Supporters may argue that the immediate haemodynamic benefits outweigh the risks of time-limited adrenal insufficiency. This point of view is often based on single centre, retrospectively collected data, with doubtful adverse clinical outcome reporting.17–20 Furthermore, the internal validity of retrospective studies is notoriously low due to collection bias, personal drug preference, incomplete and imprecise outcome data reporting and unmeasured biases. In pharmacological drug studies, large randomised controlled trials should be performed and only the best evidence should be considered. On the basis of this critical appraisal, retrospective investigations provide poor evidence for recommendations in clinical practice, may be misleading, and will, therefore, not be considered further in this review.
A considerable number of prospective studies with high-quality methodology have highlighted the risks and clinical consequences ranging from increased adrenal insufficiency to morbidity and even mortality. The present review will summarise the clinical evidence suggesting that single-dose etomidate administration in critically ill patients can have harmful consequences. Finally, it will deal with alternative anaesthetic agents or strategies that make etomidate a questionable agent for these patients.
Harmful effects of etomidate in critically ill patients
Numerous prospective studies have addressed either directly or indirectly the issue of administration of etomidate to critically ill patients. Two types of population have been investigated: patients with septic shock and patients with major trauma.
Harmful effects of etomidate in septic patients
The first randomised controlled trial indirectly providing information on the harmful consequences of a single dose of etomidate was published in 2002; 299 patients were enrolled to evaluate the benefits of corticosteroid administration in septic shock.21 The investigators observed that 94% of patients treated with a single dose of etomidate had adrenal insufficiency, compared with 71% of those who received none. Although the results achieved statistical significance, no differences in mortality were observed.22
Cuthbertson et al.22 re-examined the data collected from the randomised controlled multicentre trial entitled CORTICUS (Corticosteroid Therapy of Septic Shock).23 They observed that 96 of 499 (19.2%) patients with septic shock had received etomidate, 61.0% of whom developed adrenal insufficiency, with a 28-day mortality of 42.7%. In contrast, only 44.6% of the 403 patients who did not receive etomidate had adrenal insufficiency, with a 28-day mortality of 30.5%. These results demonstrate a clear and statistically significant survival benefit for etomidate-free patients.22,23 Moreover, the use of etomidate predicted death in both univariate (odds ratio 1.7, 95% CI 1.07 to 2.68; P = 0.02) and multivariate analyses (odds ratio 1.75, 95% CI 1.06 to 2.90; P = 0.03) adjusting for severity of illness.
A small, randomised controlled trial performed by Tekwani et al.24 compared a single dose of etomidate with midazolam for rapid sequence induction in 120 patients with presumed sepsis. Etomidate was associated with a 7% increase in in-hospital mortality. However, the 95% CIs were large because of the small sample size and the difference was not statistically significant. Intubation conditions and haemodynamic stability were similar in both groups.
Albert et al.25 recently published a meta-analysis on the effect of etomidate and outcome consequences in critical illness. A total of 3715 patients from eight randomised controlled trials, and 13 either retrospective or prospective observational studies, were included (19 datasets). In the subgroup analysis including only septic patients, etomidate was associated with a significantly increased relative risk of mortality (relative risk 1.22, 95% CI 1.11 to 1.35).
In this subpopulation of critically ill septic patients, etomidate is no innocent bystander, and, based on the best currently available evidence, its use in septic shock should be avoided because of the potentially fatal consequences.
Harmful effects of etomidate in trauma patients
In a small, singe centre, prospective randomised trial, Hildreth et al.26 compared 30 trauma patients assigned to receive either etomidate or midazolam for rapid sequence induction. Although baseline characteristics were similar, patients who received etomidate had significantly lower postintubation cortisol concentrations, needed more blood products (4.1 vs. 0.7 units), had longer lengths of stay in the ICU (6.3 vs. 1.5 days), more ventilator days (28 vs. 17 days) and longer lengths of stay in hospital (11.6 vs. 6.4).
Roquilly et al.27 observed the effect of a single dose of etomidate in a subgroup analysis of the large, randomised controlled trial entitled HYPOLYTE (hydrocortisone in multiple trauma). Of 95 patients who received etomidate, 49 (56.7%) developed a hospital-acquired pneumonia compared with 14 of the 54 patients (25.9%) who did not receive etomidate.
A meta-analysis by Albert et al.25 concluded that the use of etomidate in nonseptic patients (most often trauma patients) was associated with an increase in mortality (relative risk 1.15, 95% CI 0.97 to 1.35). However, because of the small number of patients, this difference did not achieve statistical significance.
In this subpopulation of critically ill patients, etomidate has questionable effects on mortality. Nevertheless, increased morbidity and prolonged hospital length of stay are sufficient safety indicators to avoid its use in unstable trauma patients based on the current available evidence.
Physicians who treat critically ill patients need to balance the immediate potential haemodynamic instability during tracheal intubation with the more distant adverse effects associated with adrenal insufficiency. This art of decision-making is similar to central venous catheter insertion in which an unhygienic, fast procedure increases catheter-related bloodstream infection some days later. A bundle approach for insertion is one of the keys to avoid serious complications related to central venous catheters.28 Similarly, a bundle approach including alternative hypnotic agents and concomitant haemodynamic treatment strategies including catecholamine and fluid administration may curtail both short-term adverse haemodynamic effects and long-term complications.
Ketamine and midazolam are two alternative induction agents that achieve better haemodynamic profiles in haemodynamically unstable patients than the classical induction drugs such as propofol or thiopental. A comprehensive summary of the advantages and disadvantages of these is beyond the scope of this essay and can be found elsewhere.29,30 Midazolam has been tested as an alternative to etomidate in two small, randomised controlled trials addressed previously,24,26 both confirming its safety in sepsis and trauma patients. Ketamine was compared to etomidate in a large randomised controlled prospective multicentre trial.31 In this study, 469 acutely ill patients received either ketamine or etomidate for rapid sequence induction. Endpoints were early morbidity [Sequential Organ Failure Assessment Score (SOFAS)] and 28-day mortality. Twelve percent of these patients were in shock at the time of induction and 16% had confirmed sepsis. Among the 232 patients with adrenal axis assessment, those who received etomidate had an increased incidence of adrenal insufficiency compared to those who were given ketamine (86 vs. 48%). Intubation conditions were similar in both groups. There was a trend towards lower SOFAS with ketamine (9.3 vs. 10.3; P = 0.056) and no difference in mortality (31 vs. 35%). These results should favour ketamine administration rather than the use of etomidate.
The pharmacological industry is investigating a new etomidate pyrrole analogue, methoxycarbonyl-etomidate (carboetomidate). Promising animal studies demonstrate equal haemodynamic stability and potent hypnosis but drastically diminished inhibition of adrenocortical steroid synthesis.32,33 Other preclinical studies are under way and future clinical studies may provide sufficient evidence for the replacement of the original etomidate with this new proxy.
Single-dose etomidate is unsafe in patients with septic shock because it increases mortality, based on the currently available evidence. This is too often ignored in clinical practice despite the statistical significance, the strong clinical relevance and the considerable efforts made to improve patients’ safety in both anaesthesiology and intensive care. Some physicians minimise the adrenal insufficiency related to etomidate in these highly vulnerable patients because it is reversible and even treatable. The observation that there is no benefit of hydrocortisone substitution in patients receiving etomidate34 raises the question of additional harms unexplained by sole adrenal insufficiency. In any event, steroid therapy replacement has its own well known adverse effects. It seems paradoxical to continue to use etomidate and to treat its harmful consequences with steroids when simple alternatives are available.
Etomidate in trauma patients has been investigated less extensively and has greater consequences on morbidity and hospital length of stay than on mortality. Given that other drugs achieve safer profiles and similar haemodynamic stability, we suggest simply avoiding its use in this population. We recommend a bundle approach combining alternative hypnotic agents and concomitant haemodynamic treatment strategies to avoid immediate adverse hypotension and to decrease long-term complications.
Assistance with the article: none declared.
Financial support and sponsorship: BW received support from the Swiss National Foundation (SNF; K-23K1-122264/1), Swiss Accident Company and Bangerter-Rhyner Foundation. The funding agencies had no role in the preparation, review or approval of the article.
Conflicts of interest: none declared.
Comment from the Editor: this article was checked and accepted by the editors but was not sent for external peer-review. BW is an editor of the European Journal of Anaesthesiology.
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