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Date: June3, 2023

Reference: Kotani et al. Etomidate as an induction agent for endotracheal intubation in critically ill patients: A meta-analysis of randomized trials. Journal of Critical Care April 2023

Guest Skeptic: Dr. Amber Gombash is an emergency physician in Concord, NC.

Case: You have a critically ill patient that you are preparing to intubate and wonder if the use of etomidate as your induction agent increases mortality.

Missy Carter

Background: Intubation is something we have a covered a few times on the SGEM. There was an episode with Physician Assistant (PA) Chip Lange on the use of POCUS to confirm tube placement (SGEM#249). This got some feedback from our friend Scott Weingart over at EMcrit. Our usual go to guest skeptic for airway has been paramedic and PA Missy Carter (SGEM#247, SGEM#271 and SGEM#396).

One aspect that has not been well covered on the SGEM is the choice of induction agent when intubating patients. There was an episode 10 years ago looking at the use of etomidate in septic patients (SGEM#44). It was a SRMA reporting an associated increase in adrenal insufficiency and all-cause mortality with the use of etomidate to intubate septic patients.

A more recent SGEM episode looked at an unblinded single centre randomized trial comparing etomidate vs ketamine in adult patients requiring emergency endotracheal intubation (SGEM#356). The primary outcome was an 8% absolute increase in all-cause mortality at seven days 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 (blinding), selection bias and the primary outcome measure of all-cause mortality at 7 days.

Etomidate is often used as the induction agent in critically ill patients due to its fast onset and hemodynamically neutral nature. However, it is hypothesized that etomidate may increase the risk of organ dysfunction and death by the suppression of cortisol production through inhibition of 11-beta-hydroxylase. This goes back to at least 2009 the Ketased study. That trial found that in a critical care setting there was an increase adrenal insufficiency in the group receiving etomidate.

There are now 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. There was a SRMA 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).

Clinical Question: Does etomidate used as an induction agent cause an increased mortality in critically ill adults?

Reference: Kotani et al. Etomidate as an induction agent for endotracheal intubation in critically ill patients: A meta-analysis of randomized trials. Journal of Critical Care April 2023

  • Population: Critically ill adults undergoing emergency endotracheal intubation for critical illness
    • Exclusions: Pediatric patients < 15 years old, etomidate as an infusion (rather than induction/bolus dose), non-randomized trials, systemic reviews, commentaries/editorials and literature reviews, studies not addressing the review question
  • Intervention: Etomidate
  • Comparison: Any other induction agent
    • Ketamine (4 studies), midazolam (4 studies), thiopental (1 study), ketamine + midazolam (1 study), ketamine + propofol admixture (1 study)
  • Outcome:
    • Primary Outcome: Mortality at the main timepoint defined by trial authors
      • Timepoint: Intensive care unit (1 study), Hospital (5 studies), 24 hours (1 study), 7 days (1 study), 28 days (2 studies), 30 days (1 study)
    • Secondary Outcome: Development of 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 of 31.”

Quality Checklist for Therapeutic Systematic Reviews:

  1. The clinical question is sensible and answerable. Yes
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. No
  4. The assessment of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Yes
  6. There was low statistical heterogeneity for the primary outcomes. Yes
  7. The treatment effect was large enough and precise enough to be clinically significant. Unsure

Results: The authors identified eleven randomized trials that fulfilled their inclusion and exclusion criteria. These trials include a total of 2,704 patients. Of the eleven studies, the comparator was ketamine in four studies, midazolam in four studies, thiopental in one study, ketamine + midazolam in one study, and ketamine + propofol mixture in one study.

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 319/1359 (23%) vs comparator 267/1345 (20%)
    • This gives an NNH of 31
    • Risk ratio = 1.16 (95%CI; 1.01-1.33, P = 0.03),
    • 1% probability of any increase, 92.1% probability of a 1% increase (NNH <100)
  • Secondary Outcome: Adrenal insufficiency
    • Etomidate increased development of adrenal insufficiency in 147/695 (21%) vs comparator 69/686 (10%)
    • RR = 2.01 (95%CI; 1.59-2.56), P = <0.001,

1. Risk of Bias: Out of the eleven studies, five were graded as low risk bias, five had some concerns and one as high risk; the highest risk weighted only 0.6%.

Most of the large trials included in this study were open label (Machett 30%, Punt 11% and Powers 16%). The other large, randomized trial was a single blinded trial by Jabre making up 24% of the data set.

This lack of masking could have introduced bias into the results. Bias being defined as something that systematically moves us away from the “truth”. Truth being the best point estimate of the observed effect size.

2. Mortality Outcome: The included trials used a wide range of timepoints for all-cause mortality. It ranged from as short as 24 hours (Powers WF 2021) to as long as 30 days (Driver B 2014). Five studies were hospital mortality, and one study was intensive care unit (ICU) mortality. The authors did request mortality data at a longer timepoint from original trials but unfortunately did not get responses.

3. Loss of Statistical Significance: If you include the secondary outcome of 28-day all-cause mortality data from the Matchett trial which represented 30% (801/2704) of the SRMA data the statistical difference goes away. The RR was 1.07 (95% CI 0.95 to 1.21).

It’s good to remember the potential biases in the original trials. We already mentioned that the Matchett trial was an open-label trial. There were additional concerns of it being a single centre with the code blue team being run by anesthesiologists. The patients in the Matchett trial were also not included consecutively.  More than 1,000 patients were excluded from the trial with 800 due to “clinical circumstances, clinician preference for usual care”. The trial only had 801 patients total with 800 being excluded for seemingly subjective reasons.This raises the concern of selection bias that cannot be controlled for in the SRMA.

There is also the issue of survival and survival with good neurologic function. We saw this with the PARAMEDIC2 trial. That 2018 NEJM RCT reported an increase in survival to hospital and survival to hospital discharge in patients with out-of-hospital cardiac arrests (OHCAs). However, there was no statistical difference in good neurologic outcome at hospital discharge or at three months (SGEM#238).

4. Lots of Different Controls/Comparators: These trials did not just compare etomidate to one other induction agent like ketamine but rather to a variety of agents. When comparing etomidate with just ketamine the data still demonstrated an increase in mortality with etomidate (RR 1.18 [95% CI 1.02 to 1.37]).

Interestingly the I2 measure for heterogeneity in this subgroup analysis was 30% while the overall statistical heterogeneity for etomidate vs any other induction agent was reported at 0%.

5. Different Patients: These were not just ED patients. Some were from out-of-hospital, some were ED patients, and some were from the ICU. There was also a diversity of critically ill patients (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.

This gets back to the EBM Venn diagram of the literature informing care, using good clinical judgment, and considering patient values/preferences. This moderate level evidence suggests an increase in mortality using etomidate. However, not at the longest follow-up available and does not give information on survival with good neurologic function. 

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We would have been less definitive and more uncertain with our conclusions. The data suggests a single dose of etomidate may increase mortality in the short-term setting for critically ill adults although further research is needed to determine its effects on long-term mortality.

SGEM Bottom Line: It’s still uncertain if using etomidate as an induction agent decreases the patient-oriented outcome of survival with good neurologic function in critically ill patients requiring emergent endotracheal intubation.

Case Resolution: As you prepare to intubate your critically ill patient, you ask the pharmacist to draw up ketamine as your induction agent.

Dr. Amber Gombash

Clinical Application: Clinicians should use the induction agent they think will be the best choice for successfully intubating the patient who needs an emergent definitive airway.

What Do I Tell My Patient? Since your patient is critically ill, you tell the ICU physician that you avoided etomidate as an induction agent due to concerns about adrenal insufficiency and possible subsequent short-term increase in mortality.

Keener Kontest: Last weeks’ winner was Mat Goebel @nerdymedic. He knew Dr. John Epley first described the maneuver named after him in 1980.

Listen to the podcast to hear this weeks’ question. If you think you know the answer, send an email to TheSGEM@gmail.com with “Keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed Resources:

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