Acta Anaesthesiol Scand 2014; 58: 380–389 Printed in Singapore. All rights reserved

© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/aas.12289

Review Article

Etomidate – a review of robust evidence for its use in various clinical scenarios G. Erdoes, R. M. Basciani and B. Eberle Department of Anaesthesiology and PainTherapy, University Hospital Bern, Bern, Switzerland

Etomidate is an intravenous hypnotic with a favourable clinical profile in haemodynamic high-risk scenarios. Currently, there is an active debate about the clinical significance of the drug’s side effects and its overall risk–benefit ratio. Etomidate-induced transient adrenocortical suppression is well documented and has been associated with increased mortality in sepsis. In surgical patients at risk of hypotensive complications, however, a review of current literature provides no robust evidence to contraindicate a single-bolus etomidate

Purpose of the review

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urrently, the short-acting hypnotic agent etomidate experiences a renaissance of scientific interest. An early-2014 PubMed medical database search identified 2266 hits for the term etomidate. It recovers 90 published articles in 2012, the highest count since the early 1970s when the drug was initially investigated in animals and humans.1–4 After the introduction into clinical practice in 1972, etomidate gained increasing popularity due to its reportedly ideal pharmacokinetics5 and its favourable effects on the cardiovascular,6 respiratory,7 and central nervous system,8 which promoted its use in a wide variety of indications in adult and paediatric population.9,10 Since the early 1980s, however, concerns have been raised about adrenocortical suppression which was statistically associated with negative clinical outcomes.11–16 Meanwhile, it has been proven that etomidate causes reversible and dose-dependent adrenocortical suppression by inhibiting 11-betahydroxylase, a mitochondrial enzyme which plays a central role in the conversion of cholesterol to cortisol.17–19 Triggered by observations after longterm intensive care unit (ICU) sedation by Ledingham,20,21 the result has been a protracted sci-

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induction. Large randomised controlled trials as well as additional observational data are required to compare safety of etomidate and its alternatives. Accepted for publication 27 January 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

entific and clinical debate about risk-benefit ratios for various indications, administration regimens, and clinical scenarios, which still continues to divide the medical community in ‘Pro’ and ‘Con’ factions. A considerable number of institutions continue to use etomidate as a single-dose induction agent in daily practice, whereas current literature mostly emphasises etomidate’s harmful potential and recommends the use of alternatives.22–27 The aim of this article is to review the current literature on etomidate and the evidence base for its use in selected clinical situations.

Methodology of literature review PubMed medical database* and the Cochrane Central Register of Controlled Trials† were used to search scientific reports related to etomidate. The search strategy included following key words [MeSH Terms]: [etomidate] OR [etomidate] AND [anesthesia/anaesthesia] OR [anesthesia induction/ anaesthesia induction] OR [cardiac surgery] OR [trauma] OR [emergency medicine] OR [critically ill] OR [sepsis] OR [children] OR [pediatric/paediatric]. *https://ncbi.nlm.nih.gov/pubmed [Accessed 31 January 2014] †https://thecochranelibrary.com [Accessed 31 January 2014]

Etomidate debate update

The search was limited to full-version English, German, or French manuscripts released up to and including January 2014. The published articles were initially selected by systematic search. Potentially relevant reports were then downloaded as complete manuscripts and assessed for compliance to inclusion and exclusion criteria. The inclusion criteria were: 1) prospective randomised, controlled trial (RCT); 2) review article; 3) meta-analysis; or 4) case series related to the use of etomidate in general anaesthesia, cardiac surgery, trauma patients, critical care, and emergency medicine. Exclusion criteria were: 1) only (congress) abstract available; 2) case report; or 3) manuscripts not accessible by online search.

Etomidate – a unique agent among injected anaesthetics Structural formula and associated actions Etomidate is a carboxylated imidazole-containing compound, which is chemically unrelated to any other drugs used for intravenous (IV) induction of anaesthesia. The anaesthetic effect consists of hypnosis, amnesia, and inhibition of nociceptive responses. It is based on the exclusive interaction with γ-aminobutyric acid type A (GABAA) receptors by binding directly to specific sites and enhancing the affinity of the inhibitory neurotransmitter GABA (= positive modulation of GABA-mediated activity).28 In supraclinical doses, however, etomidate is able to activate directly synaptic GABAA receptor channels even in the absence of GABA (= allosteric agonism), which is unique among IV anaesthetics.29,30 The structural formula contains an imidazole ring and is probably the reason for interactions with enzymes of adrenal steroidogenesis. Etomidate inhibits adrenal steroid synthesis by blocking the activity of CYP11B1, also known as 11β-hydroxylase, a cytochrome enzyme which converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. Consequently, after etomidate administration, plasma levels of cortisol, cortisone, and aldosterone decrease, whereas those of 11deoxycorticosterone, 11-deoxycortisol, progesterone, and 17-hydroxyprogesterone increase.31–33 Also, etomidate exerts sympathomimetic activity on alpha-2B adrenergic receptors held accountable for haemodynamic stability during injection, and on transient receptor potential type A1 (TRPA1) cation

channels, which are responsible for nociceptive sensations like occasional venous irritation.34,35

Pharmacokinetics and pharmacodynamics After a common IV induction dose of 0.2–0.3 mg/ kg, the onset of unconsciousness occurs within one circulation time. Occasionally, involuntary myoclonic movements are observed during induction as a result of alteration in the balance of inhibitory and excitatory influences on thalamocortical tracts. Awakening after a single IV dose of etomidate is rapid. There is no evidence of hangover or cumulative drug effect since etomidate is rapidly metabolised by hydrolysis to a pharmacologically inactive compounds. Plasma elimination of etomidate can be described by a three compartment model. The various decline phases with differing half-times may explain the contrast between the short duration of hypnotic effect (approximately 8 min) and the prolonged duration of adrenocortical suppression (up to 72 h) after a single-bolus injection.36

Clinical effects Etomidate as an agent for IV anaesthesia induction offers several advantages: 1) simple dose regimen; 2) fast onset of action; 3) short duration of effect; 4) rapid metabolism; 5) extremely low risk of histamine release; and 6) haemodynamic stability on bolus injection. Induction typically elicits only minimal changes in heart rate, stroke volume, and cardiac output.37,38 Likewise, depression of spontaneous breathing appears to be less pronounced than with other IV anaesthetics. In the majority of cases, the drug-induced decrease in tidal volume is compensated by an increase in respiratory rate. There is also evidence for a direct hypercarbia-like stimulation of medullar centres.39 In the brain, etomidate lowers intracranial pressure, cerebral blood flow, and cerebral metabolic rate for oxygen (CMRO2) by a direct cerebral vasoconstrictor mechanism.40,41

Adrenocortical insufficiency and mortality Transient inhibition of adrenal steroid synthesis is definitely considered the most significant adverse effect of etomidate. It has considerably impacted its use in anaesthesia and critical care environments. A retrospective study in critically ill trauma patients observed that long-term etomidate infusion was associated with increased mortality and pointed to drug-induced adrenocortical insufficiency as a potential mechanism. Subsequent prospective controlled studies in unstressed volunteers and surgical

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patients confirmed laboratory evidence of adrenocortical suppression, even after single-dose administration of etomidate.20,42–46 It was also noted that etomidate’s inhibitory potential on steroid synthesis greatly exceeds its anaesthetic effect: to achieve adrenal cortical suppression, a plasma concentration of 10 ng/ml is required, whereas for its hypnotic effect, concentrations above 200 ng/ml are necessary.17,47 Since etomidate undergoes hydrolytic inactivation by hepatic microsomal enzyme systems, its hypnotic, and even more so its adrenocortical suppressive actions, will be prolonged by substances which inhibit microsomal activity, and also by hepatic insufficiency. Despite clear endocrinological proof of etomidate’s potentially adverse effect and worldwide termination of its repetitive use for sedation, the clinical impact of a single-dose etomidate administration on adrenal insufficiency-associated and all-cause mortality remains controversial. A systematic review with meta-analysis of five RCTs,23,25,48–50 two prospective51,52 and three retrospective observational studies,53–55 focusing exclusively on 865 sepsis patients receiving etomidate for rapid sequence intubation concluded that the administration of a single dose of etomidate increased the risk of adrenal insufficiency (relative risk, 1.33) and all-cause mortality (relative risk, 1.20) in sepsis. The included studies, however, demonstrate obvious limitations in terms of: 1) heterogeneity; 2) small sample size or only subgroup analysis; 3) variation in the type of comparative sedative, severity of illness score, timing to determine adrenal insufficiency; 4) limited quality of study randomisation, blinding, description of inclusion, and exclusion criteria; and 5) discrepancies in follow-up and reporting of 28-day mortality. Only one of the five RCTs, a subgroup analysis of the CORTICUS trial48 demonstrated an association between etomidate and increased mortality in septic shock; only two studies assessed adrenal function and associated mortality in the same patient population. The three higher quality RCTs in this set were unable to demonstrate increased mortality related to a single dose of etomidate, this in comparison to midazolam,23 ketamine,25 or other sedatives.50 Another systematic review of 18 RCTs and two nonrandomised studies, performed in elective surgical as well as critically ill patients, did not show that the transient adrenal inhibition by a bolus dose of etomidate had a significant effect on mortality.56 Effects on outcome of the specific adrenocortical suppression by etomidate are difficult to quantify

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because adrenal insufficiency is not consistently defined in the medical literature, because prevalence of relative adrenocortical insufficiency is already high in multi-morbid and critically ill patients without etomidate, and because its clinical impact is still not well defined. A multicentre, randomised, double-blind, placebo-controlled trial (CORTICUS) including 499 patients was unable to demonstrate a survival benefit for sepsis patients treated with 50 mg hydrocortison for 5 days vs. placebo, regardless of their corticotropin responder status.57 In posthoc analyses of this sepsis cohort, exposure to etomidate was indeed statistically associated with an increased 28-day mortality, without an effect of hydrocortisone substitution.48,58,59

Etomidate use in specific clinical situations Rapid sequence induction Rapid sequence induction (RSI) is used in anaesthesia, critical care, and emergency medicine to rapidly induce loss of consciousness and paralysis for prompt tracheal intubation, airway protection, and institution of ventilator support. Because patients requiring RSI typically suffer from vital organ dysfunction, the anaesthetic drug choice for RSI calls for both rapid onset of action and haemodynamic stability. Post-induction hypotension has been linked to prolonged post-operative length of stay and mortality; since the use of propofol for induction of anaesthesia is a clear predictor of subsequent hypotension, particularly in elderly and risk patients, etomidate is still preferred in many institutions for induction of such patients.60 In a double-blinded RCT, studying anaesthesia induction in patients with severe aortic stenosis, etomidate has been shown to cause significantly less hypotension than propofol.61 Furthermore, hypnotic agents have been shown to influence intubating conditions, for instance, by affecting haemodynamics, and hence distribution pharmacokinetics of neuromuscular blocking drugs.62 In this regard, etomidate has been reported to be superior to thiopental and propofol.63,64 The largest study investigating etomidate for RSI is the multicentre randomised controlled singleblind trial performed by Jabre et al. in 2009.25 Etomidate was compared with ketamine in 655 critically ill, mostly trauma, or sepsis patients undergoing sedation for emergency intubation. There were no significant differences between the groups in terms of intubation conditions and sequential organ

Etomidate debate update

failure assessment (SOFA) score, nor in serious adverse events or 28-day mortality, although the percentage of patients with adrenal insufficiency was higher in the etomidate group. In general, it is difficult to compare clinical studies on this topic since they come from various fields of practice, i.e. pre-hospital, emergency room, ICU, or anaesthesia induction rooms. Practitioners’ induction and intubation experience and skills will differ considerably but are rarely reported. Also, there appears to exist some bias related to the field of practice. Most publications from intensive care medicine nowadays discourage the use of etomidate for RSI in general, despite rather low-grade evidence mostly from sepsis patients for worse outcomes following RSI with single-dose etomidate.48,57,58,65,66 In emergency anaesthesia in and outside the operating room, however, the risk– benefit balance remains unclear. Clinical data attest to haemodynamic advantages of etomidate as an induction hypnotic in elderly and high-risk surgical patients, whereas a negative effect on major outcomes has not been seen due to lack of power of the prospective series published so far.56

Use of etomidate in patients in or at risk of sepsis Transient inhibition of the adrenocortical axis by even a single dose of etomidate has been proven unequivocally. Current evidence suggests that the choice of etomidate as a hypnotic induction agent in patients suffering from sepsis or septic shock carries the risk of increasing 28-day mortality. Until today, a considerable number of publications support this thesis although the original database remains small.23,48,55,57,58,67,68 Methodological concerns have been raised by numerous authors, questioning the robustness of current evidence.69–71 Recently, a large retrospective cohort analysis in 2014 adult ICU patients fulfilling criteria for sepsis, severe sepsis, or septic shock looked at in-hospital mortality as primary endpoint.72 The 1102 patients receiving single-dose etomidate for anaesthesia induction experienced no increased ICU or hospital mortality, and no increase in vasopressor requirements, duration of mechanical ventilation, ICU, and hospital length of stay when compared to patients intubated while using other sedatives. Although the retrospective nature of this study is a limitation, this appears as the largest and best documented retrospective series to date. It is derived from a contemporary electronic clinical database, and it contradicts the historic as well as

most consecutive retrospective analyses which incriminate etomidate of impairing outcome in sepsis. It also fails to reproduce the findings of the CORTICUS sub-analysis on this topic.25,48 Although the CORTICUS sub-study found a weak statistical association of etomidate use and 28-day all-cause mortality in sepsis, the quality of its evidence is limited, too. Etomidate patients constituted only a fifth of the entire subsample, and it was not powered for mortality as outcome. There are alternative explanations for poorer outcome following etomidate exposure in the CORTICUS sub-study.48 Etomidate patients started at higher severity of illness (SAPS II); practitioners intubated with etomidate despite discouragement by the study protocol, which may also indicate selection bias, i.e. a more critical condition of etomidate patients at the time of intubation; interestingly, a smaller percentage of etomidate patients died from refractory shock, whereas more deaths were attributed to multi-organ failure. Also, a 28-day all-cause mortality appeared higher after etomidate exposure in only one multivariate model, but not so in adrenocorticotropic hormone (ACTH) nonresponders. Mortality of the two samples started to diverge only at 10–13 days after the single etomidate exposure. Thus, based on the CORTICUS data, a causative effect of etomidate on sepsis mortality remains unproven. Despite these limitations, this single trial dominated the conclusion of a recent meta-analysis.55 The KETASED trial,25 part of the same meta-analysis, found no significant difference in mortality between etomidate and ketamine recipients even in its sepsis subgroup analysis (n = 76). Here again, mortality did not differ significantly between corticotropin non-responders and responders. In summary, there is solid evidence that even single-dose etomidate reduces basal as well as ACTH-stimulated cortisol levels for up to 72 h, i.e. to a larger degree than other induction hypnotics. There is low-level evidence of a statistical association between etomidate use and mortality in patients with or at risk of sepsis. There is, however, no proof of causation yet, since etomidate recipients developed no worse SOFA scores over the subsequent week than controls.48 Moreover, although adrenal insufficiency has been reported to worsen prognosis in septic shock,73 corticotropin-responder status was not predictive of mortality in pertinent studies.25,48 Thus, it still remains a hypothesis that etomidate increases mortality in sepsis, with the presumed mechanism subject to a host of ill-defined

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confounders. Nevertheless, following the principle of primum nil nocere, the results of current metaanalyses on etomidate in septic patients suggest to avoid its use in patients with, or at risk of, sepsis in view of viable alternative induction hypnotics like ketamine.25

Procedural sedation Procedural sedation is increasingly used for short and/or minimally invasive interventions requiring hypnosis and some degree of analgesia. Consequently, procedural sedation is preferred for interventions which carry less cardiocirculatory or respiratory risks, and elicit less stress response, than a formal induction–intubation sequence itself. Its use in endoscopic, endovascular, and imaging procedures in frail or paediatric patients allows to forego intubation and positive pressure ventilation, haemodynamic alterations and in particular, hypotensive complications in patients at risk.74 An ideal drug for procedural sedation should be sedative and analgetic, short acting to permit rapid titration and recovery and with minimal respiratory and cardiocirculatory depression. Since etomidate has no analgesic properties, it is often combined with small doses of opioids. Five RCTs have studied etomidate for use in short-term sedation for emergency room and imaging procedures. In the adult population, single-dose etomidate has been compared with midazolam75,76 and propofol76 in a total of 397 patients, e.g. emergency room interventions like joint reposition. Results were in favour of etomidate in terms of recovery time (vs. midazolam) and haemodynamic stability (vs. propofol). No benefits were found, however, in patient discharge parameters from the emergency department,75 rate of respiratory depression, and complications.77 For induction during fibre-optic intubation, a doubleblinded RCT with propofol as control showed faster recovery of spontaneous respiration after etomidate than after propofol. By the authors, this was considered a safety feature of their airway management algorithm.78 In the paediatric cohort, etomidate has been compared with pentobarbital79 and midazolam80 for procedural sedation. Similar to adult data, these studies found shorter induction and recovery times with etomidate than with other sedatives.

Induction of general anaesthesia for non-cardiac surgery A recent analysis from the Cleveland Clinic’s large electronic anaesthesia record database compared,

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after propensity score matching, 2144 ASA physical status III and IV adult patients receiving etomidate as anaesthetic induction agent for non-cardiac surgery with 5233 patients given propofol.81 In the etomidate cohort, minimum systolic pressures were significantly lower prior to induction and significantly higher thereafter until wound closure. Nevertheless, etomidate use was found to be significantly associated with increased 30-day mortality, major cardiovascular morbidity, and length of hospital stay. There were no differences in infectious morbidity or intra-operative vasopressor use between the induction agents. This study, though retrospective, matches an impressive number of patients by propensity scoring. Authors postulate that their conclusion on etomidate’s mortality statistic be robust, even to a strong unmeasured confounder. In fact, however, in their list of pre-specified and matched confounders, several very strong candidates are absent or lumped together with rather unlikely ones. Thus, prominent contributors to perioperative mortality in noncardiac surgery like pre-existing ischemic heart disease, peripheral vascular disease, cerebrovascular disease, renal insufficiency, or other predictors of post-operative patient outcome remained largely unaccounted for.82,83 Even after propensity score matching, imbalances persisted in outcome-relevant characteristics, e.g. ASA class IV, emergency procedure, and/or surgical aortic repair, which needed additional statistical adjustment. Also, effect–time interactions during the 4 years of practice analysed were not reported. Thus, the association between etomidate use and outcomes found by this retrospective analysis remains, again, hypothesis generating only. By no means can it prove causation of an impressive increase in 30-day mortality from 2.5% to 6.5% by administering a single induction dose of etomidate.

Anaesthesia induction of patients at cardiovascular risk Etomidate’s relative cardiocirculatory inertness made it a preferred induction hypnotic in elderly, compromised, and especially so in cardiovascular risk patients.60 Due to the side effect of blunting adrenocortical stress response, however, administration of more than a single induction dose of 0.3 mg/kg BW (body weight) has virtually subsided. Hence, disposition, metabolism, and elimination of continuous etomidate administration, e.g. under conditions of cardiopulmonary bypass (CPB), hypothermia, haemodilution, etc. have been well

Etomidate debate update

described during previous decades but appear hardly relevant to the drug’s current spectrum of use.84 Haemodynamic effects of etomidate bolus injection are characterised by dose-dependent negative inotropy. Etomidate induces a decrease of tension developed by isolated cardiac muscle obtained from failing and non-failing hearts. This, however, occurs only at concentrations far in excess to those reached under clinical conditions.38,85 Therefore, negative inotropic effects of etomidate can be considered negligible in the clinical context. Post-induction hypotension has long been identified, by multivariate analysis of a large automated anaesthesia record database, as a predictor of prolonged post-operative stay and/or death.60 In patients at increased risk for cardiovascular complications, e.g. with a history of congestive heart failure, myocardial infarction or stroke, known systolic or diastolic ventricular dysfunction, coronary artery, severe valvular or cerebrovascular disease, pulmonary hypertension or renal insufficiency, old age or frailty, haemodynamic stability during and after anaesthesia induction is an important contribution of anaesthetic management to overall perioperative outcome. With regard to avoidance of post-induction hypotension, several studies have demonstrated superiority of etomidate over propofol. The Mount Sinai database analysis identified ASA-PS ≥ III, baseline MAP < 70 mmHg, age ≥ 50 year, and the use of propofol as induction hypnotic as significant multivariate predictors of post-induction hypotension.60 A prospective, double-blind, randomised study in 66 patients with severe aortic stenosis showed that propofol elicited more, and more severe, postinduction hypotension than etomidate; the requirement of phenylephrine rescue therapy was more than double with propofol.61 Another small prospective randomised trial in patients undergoing anaesthesia induction for coronary surgery found that arterial blood pressure decreased to a lesser degree with etomidate than with sevoflurane.86 Etomidate’s impact on outcomes due to shortterm adrenocortical suppression is even more difficult to assess in surgical patients at cardiovascular risk but without pre-dispositions for adrenocortical insufficiency due to low rates of pertinent clinical events. Mortality of study cohorts in septic shock ranges between 30%50 and 58%,75 whereas perioperative mortality after routine coronary artery bypass surgery is around 1%. Also, transient reductions of cortisol levels or adrenocortical responsive-

ness are not an exclusive side effect of etomidate only, but occur, albeit to a lesser degree, in septic or non-septic patients with midazolam, propofol (45%),57 and ketamine (48%),25 too. Hence, the laboratory constellation of transient adrenocortical insufficiency has also been documented consistently after single-bolus etomidate induction in cardiac surgery patients, in contrast to a significantly lower incidence after midazolam or propofol.87,88 A nonrandomised unblinded prospective study in a mixed patient cohort undergoing cardiac surgery on CPB observed relative adrenal insufficiency for less than 24 h in 88% (69/78) of patients induced with etomidate, vs. 57% of control patients (24/42; adjusted OR 6.55, P < 0.001).87 The study appears flawed in several aspects. Unfortunately, no information whatsoever was given about etomidate exposure as a risk factor for vasopressor requirement, major morbidity and mortality.87 A higher average vasopressor dose was recorded in the group with relative adrenal insufficiency, but the methods section contained no information whether this vasopressor use, as the primary endpoint, was controlled per protocol. No differences in mortality and ICU length of stay were noted between patients with and without relative adrenal insufficiency, but the study was underpowered for these clinical endpoints. Thus, this study merely confirms that etomidate increases the proportion of corticotropin non-responders, and that a blunted corticotropin response has no major impact on post-operative mortality in elective cardiac surgical patients. In contrast to this poorly controlled open nonrandomised series, a randomised double-blinded comparison of etomidate with propofol as singledose induction hypnotic found, in 100 elective cardiac surgical patients, no intergroup difference in norepinephrine requirement or time course of vasopressor weaning.88 Again, a higher proportion of patients experienced relative adrenal insufficiency for 24 post-operative hours after etomidate (100%) than after propofol induction (40%). The incidence of serious adverse events (cardiogenic shock, stroke, mediastinal complications) was higher in the propofol group (18%) than after etomidate (6%; P = 0.04). Hospital length of stay and hospital mortality did not differ, although this study was underpowered for these clinical outcomes. Its results are, however, supported by a recent retrospective analysis of post-operative outcomes in 3127 patients undergoing heterogeneous cardiac surgery.89 These authors found no differences in the incidence of severe hypotension, duration of

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mechanical ventilation, length of hospital stay or in-hospital mortality when comparing single-dose etomidate with propofol, midazolam, or a combination of both for anaesthesia induction. Propensity score matching did not change these findings. The respective mortality odds ratio for etomidate was 0.74 (95% CI, 0.38–1.44) in this cardiac surgical cohort, whose observed overall in-hospital mortality was 3.4%. This obvious lack of effect appears in striking contrast to the significant 30-day mortality odds ratio of 2.49 (98% CI, 1.85–3.35) for etomidate in the non-cardiac surgical Cleveland cohort, whose observed overall mortality was quite similar at 3.7%.81 Thus, in two heterogeneous cohorts of several thousand patients at quite similar risk of perioperative death, the choice of the induction hypnotic appears to make a huge difference after non-cardiac, but virtually non-following cardiac surgery. To our knowledge, pathophysiological explanations of this phenomenon are lacking. This is particularly vexing since for both patient populations, there is ample proof of transient adrenocortical suppression by etomidate. Notwithstanding the reassuring signals from several cardiac surgical series, safety of etomidate in this patient population remains yet to be confirmed by more robust RCT data. Thus, current evidence from cardiac surgical patients is well in agreement with earlier findings compiled in a systematic review of etomidate effects in non-cardiac surgical or in critically ill patients.56 Likewise, this review found no evidence that the transient adrenal inhibition by a bolus dose of etomidate affected mortality or health services utilisation. To date, the related literature offers no compelling clinical evidence to dispose of etomidate as a single-bolus induction agent in patients at cardiovascular risk.

Conclusion Recent evidence sheds new light on safety, risks and benefits of etomidate as an induction hypnotic. Based on retrospective or low-quality prospective studies, and inference from cortisol profiles and corticotropin testing, etomidate has become obsolete for long-term sedation and in sepsis. However, the chain of causation between etomidate use, drug-induced suppression of cortisol synthesis, and increased mortality has not yet been established, nor has a multitude of confounders in critically ill patients been accounted for. Nevertheless, etomidate use in the intensive care setting appears entirely dispensable nowadays, since

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good alternatives exist for virtually all indications (midazolam, propofol, ketamine, remifentanil, dexmedetomidine). In the perioperative and emergency room setting, single-bolus etomidate for anaesthesia induction and intubation provides excellent haemodynamic stability, short duration of hypnotic action, and minimal post-operative adverse clinical effects. This profile has been shown to favourably modify perioperative morbidity and mortality in patients at risk of hypotension. In contrast, the clinical significance of transient etomidate-induced suppression of cortisol synthesis remains elusive in non-septic perioperative patients. Based on current evidence from randomised controlled studies in surgical patients with significant cardiovascular disease, the risk– benefit ratio of single-dose etomidate for induction is not inferior to that of its competitor induction hypnotics. In particular, there is at present no compelling evidence to contraindicate single-dose etomidate induction in patients at high cardiovascular risk. Conflicts of interest: None. Funding: None.

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Address: Gabor Erdoes Department of Anaesthesiology and Pain Therapy University Hospital Bern Freiburgstrasse CH-3010 Bern Switzerland e-mail: [email protected]

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Etomidate--a review of robust evidence for its use in various clinical scenarios.

Etomidate is an intravenous hypnotic with a favourable clinical profile in haemodynamic high-risk scenarios. Currently, there is an active debate abou...
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