Ketamine versus Etomidate | The RSI trial
Citation:
Morgenstern, J. (2025). Ketamine versus Etomidate | The RSI trial. First10EM. https://doi.org/10.51684/FIRS.144668
Introduction:
In the realm of emergency medicine, certain topics ignite passionate debates, and the choice of drugs for intubation is one of them. The discussion between ketamine and etomidate has been a long-standing one, with each side presenting compelling arguments. While etomidate was favored during the author's training, its availability in emergency departments was limited, and concerns about adrenal suppression emerged. The question of whether etomidate truly impacts patient outcomes or merely alters biochemical measures has been a subject of intense debate, with ketamine advocates claiming it increases mortality. However, the author argues that the data supporting ketamine has always been questionable.
The Study:
The RSI trial, a pragmatic, unblinded, multicenter randomized controlled trial (RCT), was conducted across 6 emergency departments and 8 intensive care units in the United States. The primary objective was to determine if ketamine results in lower mortality compared to etomidate as an induction agent for intubation in critically ill adults.
Methods:
The trial included critically ill adult patients undergoing intubation with a medication to induce anesthesia. Exclusions were made for patients with pregnancy, prisoners, trauma, immediate need for randomization, and those where the treating clinician deemed ketamine or etomidate necessary or contraindicated. The intervention was ketamine induction, with options for full dose (2mg/kg), intermediate dose (1.5mg/kg), and low dose (1mg/kg). Etomidate was used for induction, with full dose (0.3mg/kg), intermediate (0.25mg/kg), and low (0.2mg/kg) options.
Findings:
The study enrolled 2365 patients out of 3439 screened, with a median age of 60. Approximately half had sepsis or septic shock, and 22% were receiving vasopressors at enrollment. Intubations in the emergency department accounted for 55% of the cases. Interestingly, the groups were very similar at baseline.
The primary outcome, all-cause mortality by 28 days, showed no significant difference between the ketamine and etomidate groups (28.1% vs 29.1%, risk difference -0.8 percentage points, 95% CI -4.5 to 2.9, P = 0.65). However, there was a higher incidence of peri-intubation cardiovascular collapse in the ketamine group (22% vs 17%, ARR 5.1%, 95% CI 1.9 to 8.3). This difference was more pronounced among patients with septic shock and those with high APACHE II scores.
Author's Perspective:
Despite the limitations of the New England Journal of Medicine, the author acknowledges the representation of emergency medicine research in the journal. The study is praised for its impact on critical care research, but the author highlights several methodology issues.
One significant concern is the exclusion criteria, which allows clinicians to opt out of the trial if they deem one agent necessary or contraindicated. This subjectivity biases the results, as it implies that certain patients were excluded based on the clinicians' beliefs rather than scientific evidence. The author suggests that this exclusion criteria may have led to a false negative finding.
Another issue is the dosing pattern, which may not represent standard emergency practice in all settings. The author also points out the discrepancy between the registry and the published manuscript, which lists specific doses not mentioned in the registry. This change, though minor, affects the confidence in the study.
Controversial Interpretation:
The author introduces a controversial interpretation, suggesting that the trial's secondary outcome, cardiovascular collapse, might be clinically irrelevant. The data indicates that despite the higher vasopressor use in the etomidate group, the overall mortality was not significantly different. This leads the author to question the clinical significance of the secondary outcome.
Conclusion:
In summary, the RSI trial, despite being underpowered, does not demonstrate a difference in mortality between ketamine and etomidate. The author concludes that these two agents are likely equivalent for important long-term outcomes in sick patients. However, the trial does suggest a small but real increase in mortality with etomidate, while ketamine shows no such negative outcomes.
Further Reading:
- EMCrit Wee - The RSI Trial
- PulmCrit: Hot take on RSI trial of ketamine vs etomidate
- Evidence Triage: It’s the Etomidate vs. Ketamine Showdown
- Evidence based medicine is easy
- The EBM bibliography
- Evidence based medicine resources
- EBM deep dives
References:
Casey JD, Seitz KP, Driver BE, et al. (2025). Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults. N Engl J Med. https://doi.org/10.1056/NEJMoa2511420
Matchett G, Gasanova I, Riccio CA, et al. (2022). Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med. https://doi.org/10.1007/s00134-021-06577-x
