Background

  • Etomidate and ketamine are two commonly used induction agents for rapid-sequence intubation.
  • Recently, concerns have been raised regarding etomidate and its potential to cause adrenal insufficiency due to inhibition of 11-beta-hydroxylase in the adrenal glands, thereby inhibiting production of cortisol. Data supporting this association have led regulators to remove etomidate from the market in several countries.
  • While ketamine is known to increase plasma catecholamine concentrations and is postulated to maintain hemodynamic stability during intubation, ketamine skeptics cite its vasodilatory and negative inotropic effects and subsequent association with peri-intubation hypotension and arrhythmias.

Clinical Question

In critically ill adults undergoing tracheal intubation in the ED and ICU, which induction agent – etomidate or ketamine – is associated with a lower 28-day mortality?

Population

2365 patients aged 18 and older undergoing tracheal intubation in 14 emergency departments and ICUs in the United States (44.3% in ICU, 55.7% in ED).

Intervention

Etomidate or ketamine for induction of rapid sequence intubation.

Outcomes

The primary outcome was in-hospital death from any cause by day 28.

  • A prespecified secondary outcome was cardiovascular collapse during intubation, defined as SBP <65mmHg, receipt of vasopressors, or cardiac arrest between induction of anesthesia and two minutes after intubation.
  • Exploratory outcomes included peri-intubation hypoxia and hypotension (defined as SBP <80mmHg), first-pass success, time to successful intubation, ventilator-free days, vasopressor-free days, and ICU-free days.

Design

This was a pragmatic, multi-center, unblinded, randomized trial

Excluded

  • Patients with trauma and pregnant patients were excluded.
  • Patients were also excluded at the discretion of treating clinicians if it was determined that the use of ketamine or etomidate was either necessary or contraindicated.

Primary Results

  • The study found no difference in the primary outcome of all-cause mortality at day 28 – 28.1% in ketamine group and 29.1% in etomidate group, absolute risk difference -0.8, 95% CI -4.5 to 2.9.
  • The authors then performed a sub-group analysis of the primary outcome in patients with septic shock – those at theoretically highest risk for developing adrenal insufficiency with etomidate – which amounted to 1100 patients. They also found no difference in the primary outcome in this subgroup, with a roughly 38% mortality in both groups.
  • The prespecified secondary outcome of cardiovascular collapse during intubation occurred more frequently in the ketamine group – 22.1% in the ketamine group vs 17.0% in the etomidate group, absolute risk difference 5.1,n 95% CI 1.9-8.3.
  • The authors also performed a sub-group analysis of the prespecified secondary outcome in patients with septic shock and found that the results favored etomidate even more strongly in this cohort, with cardiovascular collapse during intubation occurring in 30.6% of patients in the ketamine group compared to 20.9% of patients in the etomidate group.
  • Ventilator-free days, vasopressor-free days, and ICU-free days were equal between the two groups.

Strengths

  • This is a large multicentered randomized trial with a patient-oriented primary outcome.
  • The study team used trained observers to measure these peri-intubation events, which adds to the accuracy of the reported outcomes.

Limitations

  • The biggest limitation of this trial is the exclusion of patients with trauma, limiting generalizability of the results to a pretty good chunk of the patients we are intubating down in the ED.
  • I initially had some concerns with the protocol that allowed for the treating team to decline enrollment based on a preference of one drug over the other; this could have allowed for cherry picking away the patients at highest risk for adrenal insufficiency from the etomidate group and the patients at highest risk for peri-intubation cardiovascular collapse from the ketamine group. However, looking at the Supplementary Appendix, less than 7% of all eligible patients were excluded for this reason. Most of these exclusions were just based on individual clinician comfort and preference – it seems like a few clinicians just preferred one drug over the other and didn’t want the study people involved. No clinicians cited “septic shock” or “concern for adrenal insufficiency” as a reason for requiring ketamine over etomidate.

Author's Conclusions

  • There was no difference in all-cause mortality at 28 days in patients intubated with etomidate versus ketamine. Rates of peri-intubation cardiovascular collapse were significantly higher in the ketamine group.

Our Conclusions

  • This study provides a pretty strong rebuttal to the allegations against etomidate. Based on these results, it seems that the risk of adrenal insufficiency may be more theoretical, or at least it doesn’t seem to translate into differences in mortality or ICU-free days. I’m curious to see whether this pushes some of the countries that took it off the market to reverse their decisions.
  • I have previously been taught that ketamine was one of the preferred induction agents in hypotensive patients, and this trial challenges that mantra. I am going to think differently about ketamine and the risks of peri-intubation hypotension, and I will probably avoid it in patients with softer blood pressures prior to intubation.