Case

A critically ill patient presents to the emergency department (ED) requiring an emergent, definitive airway. While preparing to perform the endotracheal intubation with video laryngoscopy, you remember a randomized controlled trial (RCT) recently suggesting etomidate could increase mortality if used as the induction agent.

Background

Etomidate has been a popular induction agent for critically ill patients for more than a decade. This is due to its being hemodynamically neutral and its fast onset of action. However, a 2012 systematic review and meta-analysis (SRMA) reported that etomidate was associated with adrenal insufficiency and increased mortality in septic patients.¹

There have been multiple randomized trials studying the effect of etomidate as an induction agent on adrenal function and mortality. These studies have reported mixed results—with some finding a statistically significant increase in mortality. A recent, single-center, randomized trial compared etomidate versus ketamine in adult patients requiring emergency endotracheal intubation.² The primary outcome was all-cause mortality at seven days and showed an eight percent absolute increase for patients allocated to the etomidate group. This outcome was no longer statistically different at 28 days. There were multiple issues with this trial including a lack of masking and potential selection bias.

A new SRMA was published in 2021 that reported an associated increase in adrenal suppression and mortality with etomidate. However, this review combined high-level studies (five randomized controlled trials) with low-level studies (nine post hoc and 15 retrospective studies).³

Clinical Question

Will using etomidate as an induction agent in critically ill adult patients cause an increase in mortality?

Reference: Kotani, et al. Etomidate as an induction agent for endotracheal intubation in critically ill patients: A meta-analysis of randomized trials. J Crit Care. 2023;77:154317.

Population: Critically ill adult patients requiring emergency endotracheal intubation

• Exclusions: Pediatric patients less than or equal to 15 years old, etomidate as an infusion, non-randomized trials, systematic reviews, commentaries or editorials, literature reviews, studies not addressing the review question
• Intervention: Etomidate
• Comparison: Any other induction agent
• Outcomes:
  • Primary Outcome: Mortality at the main time point defined by trial authors
  • Secondary Outcome: Adrenal insufficiency

Authors’ Conclusions

“This meta-analysis found a high probability that etomidate increases mortality when used as an induction agent in critically ill patients with a number needed to harm [NNH] of 31.”

Results

Eleven randomized trials were included in this study (n=2,704 patients). Etomidate was compared in four studies to ketamine, in four studies to midazolam, in one study to thiopental, in one study to ketamine with midazolam, and in one study to ketamine with propofol.

Key Result

There is a high probability that etomidate increases mortality when used as an induction agent in critically ill patients.

• Primary Outcome: All-cause mortality
  • Etomidate increased mortality at the main timepoint defined by trial authors in 23 percent versus comparator 20 percent; NNH 31; risk ratio = 1.16 (95 percent confidence interval [CI], 1.01 to 1.33; P=0.03)
• Secondary Outcome: Adrenal insufficiency
  • Etomidate increased development of adrenal insufficiency in 21 percent versus comparator 10 percent; risk ratio=2.01 (95 percent CI, 1.59 to 2.56, P<0.001)

EBM Commentary

1. Risk of Bias: Five studies were graded as having a low risk of bias, five had some concerns, and one was graded high-risk. The majority (57 percent) of patients included in the trials were in open-label studies. Another 24 percent of the patients included in the SRMA came from a single-blinded trial. This large lack of masking could have introduced bias into the results, which increases the uncertainty of the results.
2. Mortality Outcome: There was a wide range of time points for all-cause mortality (24 hours to 30 days). The primary outcome for the SRMA was all-cause mortality at the main time point defined by the trial, which did demonstrate a statistically significant increase with etomidate use. However, if you include the secondary outcome of 28-day all-cause mortality data from the Matchett trial, which represented 30 percent of the SRMA data, the statistical difference is lost (RR, 1.07 [95 percent CI, 0.95 to 1.21]).
3. Diversity of Patients: These were patients from a variety of settings including out-of-hospital, ED, and intensive care unit. There was also a diversity of critically ill medical and surgical patients. Some patients had more cardiovascular morbidities than other patients. This might make the results more generalizable but could also mean that the results do not apply to the individual patient presenting to the emergency department.

Bottom Line

There remains uncertainty whether using etomidate as an induction agent increases mortality in critically ill adult ED patients requiring emergent endotracheal intubation.

Case Resolution

You decide to use ketamine as your induction agent in this case and successfully intubate the critically ill patient.

Thank you to Dr. Amber Gombash, who is an emergency physician in Concord, N.C., for her help with this article.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

Dr. Milne is chief of emergency medicine and chief of staff at South Huron Hospital, Ontario, Canada. He is on the Best Evidence in Emergency Medicine faculty and is creator of the knowledge translation project the Skeptics’ Guide to Emergency Medicine.

References

1. Chan CM, et al. Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis*. Crit Care Med. 2012;40(11):2945-53.
2. Matchett G, et al. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med. 2022;48(1):78-91.
3. Albert SG, Sitaula S. Etomidate, Adrenal insufficiency and mortality associated with severity of illness: A meta-analysis. J Intensive Care Med. 2021;36(10):1124-1129.