1. Publication
- Title: Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults (RSI Trial)
- Acronym: RSI
- Year & Journal: New England Journal of Medicine, published December 9, 2025
- Citation: Casey JD, Seitz KP, Driver BE, et al. N Engl J Med. 2025. doi:10.1056/NEJMoa2511420
2. Context & Rationale
Background: Observational studies suggested etomidate (via adrenal suppression) may increase mortality risk vs ketamine in critically ill intubation, but this had not been tested in an adequately powered RCT. Peri-intubation cardiovascular instability (occurring in ~43% of cases per the INTUBE study) is independently associated with worse mortality (adjusted OR 2.47).
Research Question/Hypothesis: In critically ill adults undergoing tracheal intubation, does ketamine (vs etomidate) induction reduce 28-day in-hospital mortality?
3. Design & Methods
- Study Type: Multicenter, randomized, open-label trial
- Setting & Centers: 14 EDs/ICUs, United States
- Population: Critically ill adults undergoing tracheal intubation (median age 60y, 46.7% sepsis/septic shock)
- Intervention: Ketamine, 1-2 mg/kg IV (n=1176)
- Comparator: Etomidate, 0.2-0.3 mg/kg IV (n=1189)
- Randomization: 2365 patients total
- Blinding: Open-label
- Statistical Power & Follow-Up: Primary: in-hospital death by day 28. Secondary: cardiovascular collapse during intubation (SBP<65, new/increased vasopressors, or cardiac arrest).
4. Key Results
2365 patients randomized.
Outcome | Ketamine | Etomidate | Effect Size | 95% CI | p-value | Notes |
In-hospital death by day 28 (primary) | 330/1173 (28.1%) | 345/1186 (29.1%) | Adjusted RD −0.8pp | −4.5 to 2.9 | 0.65 | No significant difference |
Cardiovascular collapse during intubation | 260/1176 (22.1%) | 202/1189 (17.0%) | RD 5.1pp | 1.9–8.3 | Significant | Higher with ketamine |
SBP <80mmHg (induction to 2min post-intubation) | 14.4% | 10.6% | — | — | — | Higher with ketamine |
Death by 28 days, any location | 378/1176 (32.2%) | 384/1189 (32.4%) | — | — | — | No significant difference |
5. Internal Validity Assessment
Large (2365-patient), well-powered, multicenter trial with an objective hard primary endpoint. Overall: Strong — clean, precise null mortality result plus a genuinely important, statistically significant safety signal (more cardiovascular collapse with ketamine, the opposite of conventional teaching).
6. External Validity Assessment
US, 14-site ED/ICU population undergoing emergency intubation, nearly half with sepsis/septic shock — broadly representative of real-world critical-illness intubation populations.
7. Strengths & Limitations
Strengths: Large, definitive, hard-outcome trial resolving decades of observational-data-driven practice patterns; both agents tested at standard doses.
Limitations: Open-label design; single-country trial.
8. Interpretation & Practice Impact
Does not support ketamine over etomidate for mortality reduction — contrary to prior observational and small-trial signals suggesting ketamine benefit. Notably, ketamine showed MORE cardiovascular collapse than etomidate, challenging the common assumption that ketamine is uniformly the more hemodynamically stable choice. Both agents can cause early cardiovascular instability at these doses.
9. Controversies & Subsequent Evidence
A prior Bayesian meta-analysis (7 RCTs + 1 propensity-matched study, 2978 patients) had suggested an 83.2% probability that ketamine reduces mortality (RR 0.93, 95% CrI 0.79-1.08) — this large, definitive RSI trial provides a much more precise, null estimate that should now dominate the evidence synthesis. Independent commentary (REBEL EM, St Emlyn's) explicitly pushes back on social-media claims that this trial "is the death of ketamine," noting etomidate showed better early hemodynamic stability but neither drug is clearly superior overall.
10. Summary & Executive Takeaway
Summary: The RSI trial randomized 2365 critically ill US adults undergoing intubation to ketamine or etomidate induction. 28-day in-hospital mortality was not significantly different (28.1% vs 29.1%, P=0.65), but cardiovascular collapse during intubation was significantly MORE common with ketamine (22.1% vs 17.0%).
Overall Takeaway: This large, definitive trial found no mortality difference between ketamine and etomidate for critical-illness intubation, while showing ketamine paradoxically caused more peri-intubation cardiovascular collapse — challenging the common assumption of ketamine's hemodynamic superiority and indicating neither agent should be considered uniformly preferred on safety grounds.
11. Bibliography
- Russotto V, Tassistro E, Myatra SN, et al. Peri-intubation cardiovascular collapse: INTUBE study. Am J Respir Crit Care Med. 2022;206:449-458.
- Ketamine versus etomidate Bayesian meta-analysis. Crit Care. 2024.