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Long B, Gottlieb M. Ketamine versus etomidate for induction of intubation in critically ill patients. Academic Emergency Medicine. 2024;31(9):937-938.

Study Population: 2978 participants from eight studies of critically ill adults sedated for endotracheal intubation

Efficacy Endpoints

All-cause mortality at longest follow-up available

Harm Endpoints

Not reported

Narrative

Endotracheal intubation (ETI) is a common procedure performed in the prehospital, emergency department, and intensive care unit settings that carries a significant risk of morbidity and mortality.1^, 2 Rapid sequence intubation involves the use of induction agents (sedatives), of which ketamine and etomidate are two of the most commonly used. It has been suggested that the delayed effects of etomidate may be problematic due to increased rates of adrenal insufficiency.3^, 4^, 5 However, several studies have compared the two with conflicting results.4^, 5

The systematic review summarized here included seven randomized controlled trials and one propensity-matched study (n = 2978 participants) between 2009 and 2023 of critically ill adult patients undergoing emergency ETI who received ketamine or etomidate.6 Here we summarize only the data from randomized trials, comparing ketamine with other sedatives for sedation in patients with critical illness. The primary outcome was mortality at the longest available follow-up. Secondary outcomes included Sequential Organ Failure Assessment (SOFA) score, vasopressor-free days, ventilator-free days, postsedation mean arterial pressure, and successful intubation on first attempt. The review utilized a Bayesian random-effects meta-analysis, reporting posterior probability distributions for relative treatment effects using risk ratios. The authors also performed a sensitivity analysis for the primary outcome using a frequentist approach with a Mantel–Haenszel random-effects model.

Of the included studies, four trials were conducted in the United States, one trial was in France, one was in the Netherlands, and one was in Thailand. All studies except one were single center.7 Ketamine dosing ranged from 1 to 2 mg/kg in all studies but one, which combined 0.5 mg/kg ketamine with 0.5 mg/kg propofol.8 The time point of mortality assessment was hospital discharge in three studies, 28 days in three studies, and 30 days in one study.

Compared to etomidate, ketamine did not reduce mortality (RR 0.96, 95% CI 0.8–1.1). No difference was found in any secondary outcome including SOFA score, vasopressor-free days, ventilator-free days, blood pressure, and first-attempt success. On Bayesian analysis of trial results, the authors report a probability of 68.6% that ketamine reduced mortality by up to 1% and a probability of 41.6% that ketamine reduced mortality by ≥1% when compared to etomidate.

Caveats

There are several factors that complicate interpreting these results.6 First, while the review utilized Bayesian methods, this has limitations including the need for estimating prior probability (the likelihood of one agent being worse or better based on information available before the analysis), which can be difficult and subjective but directly informs numerical results. The review found ketamine has a 68.6% probability of lowering mortality by up to 1% and a probability of 41.6% that ketamine reduced mortality by ≥1% when compared to etomidate, but a traditional frequentist interpretation would characterize this as “no difference” (see comments below for more on Bayesian vs. frequentist). Second, most larger trials were open label, introducing bias. Third, there was variation in the timepoints for mortality assessment in the included studies, with assessment including 28 days, 30 days, and at hospital discharge. Fourth, there was no standardization of peri-intubation interventions (e.g., paralytics, opioids, vasopressors), introducing further potential confounders. Fifth, one study combined ketamine with propofol, confounding the drug's effects.8

Of note, a 2022 meta-analysis of nine studies found less postintubation hypotension with etomidate, but included six retrospective studies,4 while a 2023 meta-analysis of 11 trials found increased mortality with etomidate but evaluated multiple agents (propofol, midazolam, thiopental, and ketamine).5 Based on weak methodology in the first review, and the desire to focus on comparing the two agents head to head, we did not summarize these meta-analyses.

On the reliability and utility of “Bayesian” versus traditional “frequentist” methods of analyzing, the issue is hotly debated. For the purposes of this paper, one distinction is crucial. Traditional frequentist methods demand that any difference in numerical results cross a certain threshold (usually 95% mathematical likelihood) to be considered a “true” difference, providing a dichotomous (yes/no) answer. Conversely, Bayesian methods assign a sliding scale of probability to the existence of a difference, providing a percentage likelihood. In both cases; however, the calculations are embedded with assumptions such as a total absence of bias and methodologic perfection in the underlying data. Of course, this might not be true, but mathematical representations of study results are two dimensional—they are just numbers. This is why studies require careful, expert interpretation, and numerical results must be placed in context.

Based on current data it is unclear whether ketamine lowers mortality compared to etomidate. Therefore, we have selected a color recommendation of yellow (equal efficacy) for the use of ketamine in critically ill adult patients requiring induction for ETI. Further data are needed using clearly defined patient populations, outcomes, and standardized peri-induction management and dosing of etomidate and ketamine.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

Author

Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD

Published/Updated

November 12, 2024