For Doctors in a Hurry
- Clinicians remain uncertain whether ketamine or etomidate is safer for induction during tracheal intubation in critically ill adults.
- The researchers conducted a randomized trial involving 2365 patients across 14 emergency departments and intensive care units.
- In-hospital death by day 28 occurred in 28.1 percent of the ketamine group and 29.1 percent of the etomidate group.
- The authors concluded that ketamine did not result in a significantly lower incidence of death compared to etomidate.
- Clinicians should note that ketamine was associated with a higher incidence of cardiovascular collapse during the intubation procedure.
The Induction Dilemma in Critical Airway Management
Tracheal intubation in critically ill adults is a high-risk procedure frequently complicated by severe hypotension and cardiac arrest [1]. For decades, etomidate has been a preferred induction agent due to its reputation for hemodynamic stability, yet its known inhibition of adrenal steroidogenesis (the biological process by which the adrenal glands produce cortisol and other essential hormones) has raised persistent concerns regarding increased mortality [2, 3]. While ketamine is often utilized as an alternative to maintain mean arterial pressure through sympathetic stimulation, its impact on long-term survival remains a subject of active debate [4, 5]. Current clinical practice guidelines emphasize the need for evidence-based sedative choices to mitigate the risks of cardiovascular collapse in the intensive care unit [6, 7]. A recent multicenter randomized trial now provides definitive data to help clinicians navigate this fundamental choice in emergency airway management.
A Large-Scale Multicenter Comparison
The researchers conducted this randomized trial across 14 emergency departments and intensive care units in the United States, providing a broad clinical context for the results. The study population consisted of 2,365 critically ill adults undergoing tracheal intubation, a group at high risk for procedural complications. By utilizing a multicenter approach, the trial aimed to account for variations in institutional protocols and patient demographics, ensuring the findings are applicable to a wide range of acute care settings. This design enhances the external validity of the study, meaning the results are more likely to be reproducible in diverse clinical environments where staffing levels and patient acuity vary. A total of 2,365 patients underwent randomization and were included in the final trial population to compare the efficacy and safety of the two induction agents. Within this cohort, 1,176 patients were assigned to the ketamine group, while 1,189 patients were assigned to the etomidate group. This large sample size was designed to provide the statistical power necessary to evaluate the primary outcome of in-hospital death from any cause by day 28, as well as secondary hemodynamic outcomes. The trial, which is registered under the RSI ClinicalTrials.gov number NCT05277896, was funded by the Patient-Centered Outcomes Research Institute and other supporting organizations. This independent funding structure supports the objective analysis of these two common induction agents in a real-world clinical environment, where the choice between ketamine and etomidate remains a frequent decision point for emergency and intensive care physicians.
Primary Survival Outcomes and Statistical Equivalence
The clinical rationale for this trial stems from the fact that observational studies suggest etomidate for anesthesia induction in critically ill adults may increase the risk of death, likely due to its known suppression of adrenal function. However, it has remained uncertain whether using ketamine instead of etomidate decreases the risk of death in real-world emergency and intensive care settings. To resolve this ambiguity, the researchers defined the primary outcome as in-hospital death from any cause by day 28, a robust measure of overall survival following the high-risk procedure of tracheal intubation. The trial data revealed that in-hospital death by day 28 occurred in 330 of 1173 patients (28.1%) in the ketamine group, while 345 of 1186 patients (29.1%) in the etomidate group reached the same endpoint. The risk difference for death adjusted for trial site was -0.8 percentage points (95% confidence interval, -4.5 to 2.9; P = 0.65). These results indicate that the small numerical variance between the two cohorts was not statistically significant, demonstrating that the choice of induction agent did not meaningfully alter the probability of survival to 28 days. In summary, the study found that ketamine did not result in a significantly lower incidence of in-hospital death by day 28 than etomidate. For practicing physicians, these findings suggest that the purported mortality risks associated with etomidate in observational literature are not substantiated by randomized controlled data when compared to ketamine. Consequently, the selection between these two agents may be better guided by immediate hemodynamic considerations rather than concerns regarding 28-day mortality.
Hemodynamic Stability and Safety Profiles
While the primary mortality endpoint showed no significant difference, the researchers closely monitored the immediate physiological impact of each induction agent through a secondary outcome of cardiovascular collapse during intubation. This composite endpoint was defined by the occurrence of a systolic blood pressure below 65 mm Hg, the initiation of a new vasopressor or an increased dose of an existing vasopressor, or the occurrence of cardiac arrest. These clinical markers represent the most acute risks during the transition from spontaneous to positive pressure ventilation, where the choice of sedative can directly influence hemodynamic stability. The trial data indicated a higher incidence of hemodynamic instability in the ketamine cohort. Specifically, cardiovascular collapse during intubation occurred in 260 of 1176 patients (22.1%) in the ketamine group, compared to 202 of 1189 patients (17.0%) in the etomidate group. This resulted in a risk difference for cardiovascular collapse of 5.1 percentage points (95% confidence interval, 1.9 to 8.3). This finding is particularly relevant for clinicians managing patients with marginal hemodynamic reserve, as it suggests that etomidate may offer superior protection against immediate post-induction hypotension. Despite this divergence in immediate hemodynamic performance, the researchers noted that prespecified safety outcomes were similar in the two groups, suggesting that the increased rate of transient cardiovascular collapse associated with ketamine did not translate into a higher burden of other serious adverse events or long-term complications within the study population. For the practicing clinician, these results clarify that while neither drug offers a survival advantage, etomidate may be associated with a lower risk of acute cardiovascular instability during the intubation procedure itself.
References
1. Zhang X, Zhao X, Xu J, Liu H, Yuan S, Zhang J. Efficacy and safety of esketamine for emergency endotracheal intubation in ICU patients: a double-blind, randomized controlled clinical trial. Scientific Reports. 2025. doi:10.1038/s41598-025-91016-w
2. Bandyopadhyay A, Haldar P, Sawhney C, Singh A. Efficacy of ketamine versus etomidate for rapid sequence intubation of critically ill patients in terms of mortality and success rate: a systematic review and meta-analysis of randomized controlled trials.. Clinical and experimental emergency medicine. 2025. doi:10.15441/ceem.24.363
3. Srivilaithon W, Bumrungphanithaworn A, Daorattanachai K, et al. Clinical outcomes after a single induction dose of etomidate versus ketamine for emergency department sepsis intubation: a randomized controlled trial. Scientific Reports. 2023. doi:10.1038/s41598-023-33679-x
4. Koroki T, Kotani Y, Yaguchi T, et al. Ketamine versus etomidate as an induction agent for tracheal intubation in critically ill adults: a Bayesian meta-analysis. Critical Care. 2024. doi:10.1186/s13054-024-04831-4
5. Smischney NJ, Seisa MO, Morrow AS, et al. Effect of Ketamine/Propofol Admixture on Peri-Induction Hemodynamics: A Systematic Review and Meta-Analysis. Anesthesiology Research and Practice. 2020. doi:10.1155/2020/9637412
6. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Critical Care Medicine. 2018. doi:10.1097/ccm.0000000000003299
7. Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Critical Care Medicine. 2017. doi:10.1097/ccm.0000000000002255
