Secondary Logo

Journal Logo

Invited commentary

Etomidate for critically ill patients: let us clarify the debate

Payen, Jean-Francois

Author Information
European Journal of Anaesthesiology: November 2012 - Volume 29 - Issue 11 - p 504-505
doi: 10.1097/EJA.0b013e32835819e0
  • Free

This Invited Commentary is part of a Pro and Con debate and is accompanied by the following articles:

• Ray DC, McKeown DW. Etomidate for critically ill patients. Pro: yes we can use it. Eur J Anaesthesiol 2012; 29:506–510.

• de la Grandville B, Arroyo D and Walder B. Etomidate for critically ill patients. Con: do you really want to weaken the frail? Eur J Anaesthesiol 2012; 29:511–514.

The issue over the use of etomidate for critically ill patients is generating considerable debate. Accordingly, two opposing views concerning the use of single bolus doses of etomidate to facilitate tracheal intubation in critically ill patients are published in this issue of the European Journal of Anaesthesiology.1,2 The authors should be praised for their efforts to convince the reader with extensive analyses of the literature. As a referee in this fierce debate, I would like to take the opportunity to clarify some issues.

First, there can be no doubt that bolus doses of etomidate impair the adrenal synthesis of cortisol (primary adrenal insufficiency). This blockade is reversed within 48 h of administration. However, continuous infusion of nonhypnotic doses of etomidate has for years been an approach to treating severe presentations of Cushing's syndrome and carries no safety risks.3 In addition, we found no cardiovascular benefit from moderate-dose hydrocortisone administered to overcome etomidate-related adrenal insufficiency, suggesting that the drug-induced transient hormonal disturbance might be considered as a minor contributor, if any, to cardiovascular dysfunction in critically ill patients.4

Second, other hypnotics and opioids can also affect cortisol production through reduced secretion of adrenocorticotropic hormone (ACTH; secondary adrenal insufficiency). In patients with severe traumatic brain injury, metabolic suppression obtained with high-dose propofol or thiopental was associated with low serum cortisol and ACTH concentrations.5 This suggests that sedatives other than etomidate, such as those used in critically ill patients, may blunt the baseline secretion of cortisol through a central mechanism.

Third, readers should consider that an association found between variables does not necessarily indicate a causal relationship. Because etomidate is usually prescribed for inherently sicker patients, it appears highly speculative to draw conclusions about the real risk of etomidate even after statistical adjustment in cohort studies. In this particular context, two randomised controlled trials designed to explore the impact of etomidate on patient outcome found no differences compared with either ketamine or midazolam.6,7 Notably, half of the patients given ketamine in the study by Jabre et al.6 were nonresponders to the corticotropin stimulation test, underscoring the wide range of causes for adrenal disturbance among critically ill patients.

Fourth, a large body of evidence supports an association between exposure to episodes of arterial hypotension and poorer outcome, in particular in patients with severe traumatic brain injury. The haemodynamic profile of etomidate is superior to all currently available induction agents at limiting this side-effect.

Fifth, the main issue over the use of etomidate concerns patients with severe sepsis and septic shock. However, the fact that sepsis alone induces metabolic effects on hypophyseal and adrenal tissues should be considered and there are numerous factors that interact in the relationship between adrenal function and sepsis.8 Up to 60% of patients with severe sepsis and septic shock met criteria for adrenal insufficiency,9 and the occurrence of adrenal insufficiency in these patients is associated with higher rates of mortality.10 Etomidate-induced blockade of cortisol synthesis induces a serum accumulation of 11β-deoxycortisol and a low response of serum cortisol to the corticotropin stimulation test, giving two diagnostic criteria that can be used to indicate drug-induced adrenal impairment. No other clinical situations result in adrenal inhibition with a concomitant accumulation of serum 11β-deoxycortisol apart from the rare inherited deficiency of 11β-hydroxylase. The concomitant assessment of levels of serum cortisol and 11β-deoxycortisol, therefore, seems essential to evaluate etomidate-related adrenal insufficiency during severe sepsis. Surprisingly, these criteria have never been exploited in studies exploring the contribution of etomidate towards adrenal insufficiency in patients with severe sepsis, making all statements about the impact of etomidate in this population speculative.

So, which induction agent should be used to facilitate tracheal intubation in critically ill patients? In patients with severe traumatic brain injury, etomidate should be the first-line agent because avoidance of any episode of arterial hypotension is crucial to preserve brain circulation. In my opinion, there remain uncertainties about the contribution of etomidate towards sepsis-related adrenal insufficiency. However, it appears, for now, prudent to avoid etomidate and to propose ketamine as an alternative in patients with severe sepsis and septic shock. Further studies with concomitant measurements of serum cortisol and 11β-deoxycortisol concentrations in this population are warranted to clarify this point. In other critically ill situations, the choice of induction agent might be determined by the presence or not of concomitant shock: in patients with shock, etomidate or ketamine could be preferentially used, and thiopental or propofol for patients without shock. Midazolam remains a sedative agent with less predictable effects.

There are several controversies surrounding how best to care for critically ill patients among which the use of etomidate represents one leading debate. Decisions on the possible use of etomidate as an induction agent must be based upon clinical studies specifically designed to address its impact on outcome.


Assistance with the Commentary: none declared.

Financial support and sponsorship: none declared.

Conflicts of interest: none declared.

Comment from the Editor: this Invited Commentary was checked and accepted by the editors but was not sent for external peer-review.


1. Ray DC, McKeown DW. Etomidate for critically ill patients. Pro: yes, we can use it. Eur J Anaesthesiol 2012; 29:506–510.
2. de la Grandville B, Arroyo D, Walder B. Etomidate for critically ill patients. Con: do you really want to weaken the frail? Eur J Anaesthesiol 2012; 29:511–514.
3. Nieman LK. Medical therapy of Cushing's disease. Pituitary 2002; 5:77–82.
4. Payen JF, Dupuis C, Trouve-Buisson T, et al. Corticosteroid after etomidate in critically ill patients: a randomized controlled trial. Crit Care Med 2012; 40:29–35.
5. Cohan P, Wang C, McArthur DL, et al. Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study. Crit Care Med 2005; 33:2358–2366.
6. Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet 2009; 374:293–300.
7. Tekwani KL, Watts HF, Sweis RT, et al. A comparison of the effects of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a prospective, randomized study. Ann Emerg Med 2010; 56:481–489.
8. Prigent H, Maxime V, Annane D. Science review: mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids. Crit Care 2004; 8:243–252.
9. Annane D, Maxime V, Ibrahim F, et al. Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med 2006; 174:1319–1326.
10. Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000; 283:1038–1045.
© 2012 European Society of Anaesthesiology