EBM Review Series: Ketamine vs Etomidate for rapid sequence intubation (RSI)
VACEP Evidence-Based Medicine for General Emergency Physicians Series
Authors: Authors: Enjana Bylykbashi, MD PGY-3 & Emily Kershner, MD | VCU Health
Reviewers: Megyn Christensen, DO & Martin D. Klinkhammer, MD, MPH, FACEP | Eastern Virginia Medical School at Old Dominion University
Editor: Winston Wu, MD | Virginia Tech Carilion School of Medicine
The VACEP Evidence-Based Medicine Review Series allows Virginia emergency medicine residents and attendings to share and analyze a recent peer-reviewed clinical study. You can also read the full article, “Ketamine vs Etomidate for Tracheal Intubation of Critically Ill Adults” from the New England Journal of Medicine’s December 18, 2025 issue.
THE CASE
A 72-year-old woman presents to the emergency department via EMS after becoming acutely altered. Her family reported that she was in her usual state of health this morning but progressively complained of feeling unwell. She then became unresponsive. On arrival to the ED, she has a GCS of 3 with sonorous respirations. Further history is limited as there are no other historians at bedside. EMS is unaware on any past medical history. Vital signs are: BP 96/62 mmHg, HR 112 bpm, RR 10 bpm. She is afebrile with blood glucose 110 mg/dL. The decision is made to intubate for airway protection.
When choosing induction agents, does ketamine decrease the risk of death compared to etomidate?
BACKGROUND
The use of an appropriate induction agent for anesthesia is a familiar topic in the field of emergency medicine and will continue to inspire debate in the quest for the safest option for rapid sequence intubation (RSI). Etomidate remains the most used induction agent for intubation in EDs and intensive care units (ICUs) in the United States (1). It offers the advantages of rapid onset and minimal cardiovascular effects. However, the use of etomidate has been associated with transient inhibition of adrenal steroid synthesis which has spurred deliberation about its use in certain patient populations, particularly septic patients (2).
Ketamine is an NMDA receptor antagonist with both dissociative and analgesic properties that gained popularity as an alternative due to its theoretical advantages for maintaining hemodynamic stability and preservation of adrenal function. However, despite numerous previous randomized control trials and meta-analyses, there has yet to be a consensus on differences in mortality between the use of etomidate and ketamine (3).
STUDY SUMMARY
This article aimed to investigate whether ketamine, when used to induce anesthesia for emergency tracheal intubation in critically ill adults, results in lower mortality than etomidate (4). This was a pragmatic, multicenter, unblinded randomized trial conducted in 14 EDs and ICUs across six U.S. medical centers. Adults (≥ 18 years) requiring emergency intubation and administration of an induction drug were eligible, excluding those with trauma, pregnancy, incarceration, or clinical contraindication to either drug. Participants were randomized 1:1 to receive ketamine (1.0–2.0 mg/kg IV) or etomidate (0.2–0.3 mg/kg IV) for anesthesia induction. The dose of each medication and all other clinical management was at physician discretion.
The primary outcome investigated was in‑hospital death from any cause by Day 28. The secondary pre-specified outcome was cardiovascular collapse during intubation, defined as either systolic blood pressure < 65 mm Hg, the initiation or escalation of vasopressors, or cardiac arrest within 2 minutes of intubation. Exploratory outcomes included blood pressure and oxygenation indices, intubation success and timing, and days free from ventilation, vasopressors, and ICU stay.
The authors found that by Day 28, in‑hospital death occurred in:
28.1% of ketamine recipients (330/1173)
29.1% of etomidate recipients (345/1186)
…yielding an adjusted absolute risk difference of −0.8 percentage points (95% CI, −4.5 to 2.9; P = 0.65). Mortality rates were similar across all predefined subgroups, including those with sepsis (38.8% vs 38.2%), vasopressor use, and high APACHE II scores.
Sensitivity and modeling analyses confirmed the absence of treatment‑effect heterogeneity. Interestingly, cardiovascular collapse during intubation was more frequent with ketamine, 22.1% (260/1176) versus 17.0% (202/1189) with etomidate (risk difference 5.1 percentage points; 95% CI, 1.9 to 8.3). The difference was most pronounced among patients with sepsis (30.6% vs 20.9%) and those with severe illness (APACHE II ≥ 20).
The authors concluded that there is no reduction in mortality with ketamine compared with etomidate for anesthesia induction during emergency tracheal intubation of critically ill adults. Despite the theoretical advantage of avoiding adrenal suppression, ketamine use was associated with increased hemodynamic instability during intubation, challenging the long-held idea that ketamine may be the preferred agent in patients with unstable vital signs. The authors note that although etomidate may transiently suppress cortisol synthesis, this mechanism did not translate into higher mortality rates. Conversely, ketamine’s sympathomimetic effects may not prevent hypotension in critically ill, catecholamine‑depleted patients and may even exacerbate instability among those with sepsis or severe shock.
About the EBM Review Series
This is a literature review series started by the University of Virginia’s Josh Easter, MD, MSc, a VACEP board member working to connect the academic community in Virginia. We invite each residency in Virginia (and D.C.) to create a faculty/resident team to submit and review articles. Sign up to submit one.
Goals
Provide a brief monthly synopsis of a high yield article germane to the practice of emergency medicine for distribution to all VACEP members
Provide an opportunity for a peer reviewed publication and invited presentation for faculty and trainees
Foster an academic community focused on evidenced based medicine for emergency medicine residency programs in the region
STRENGTHS & LIMITATIONS
The key strengths of this study include its randomized multicenter design, large sample size, and a pre-published protocol with rational power calculations. Additionally, the pragmatic design makes it easier to translate into clinical practice. It also has the strength of having excellent baseline similarities between the two groups. Most notably, the groups had a similar amount of “sepsis” patients in each group. The study achieved sufficient power to detect clinically relevant mortality differences and had minimal loss to follow‑up. Some limitations include the open‑label design and exclusion of trauma patients which may limit generalizability.
Additionally, there is potential for selection bias based on the excluded patients described in the Supplementary Appendix. The authors report that 347 patients were intubated before enrollment could occur and were therefore excluded from analysis. They also note that in 236 cases, clinicians declined randomization because they believed a specific induction agent was required, with 134 patients judged to require etomidate and 102 judged to require ketamine. Excluding these patients may limit generalizability, particularly if the sickest or most clinically complex patients were preferentially managed outside of the trial protocol.
CONCLUSION
This study aimed to address the long-standing emergency medicine dilemma of the best RSI induction agent. The authors found that among critically ill adults, the use of ketamine did not lead to a significantly lower incidence of in-hospital death by day 28 than etomidate. Ketamine also seemed to be associated with higher incidences of complications, including hypotension, receipt of vasopressors, and ventricular tachycardia. Thus, when deciding on an induction agent for your critically ill patient, you opt to use etomidate as your agent of choice as is your usual practice.
REFERENCES
1. Kei J, Eurick T, Hauck TA. Intubation Practices in Community Emergency Departments. Ann Emerg Med. 2025 Aug;86(2):169-174. doi: 10.1016/j.annemergmed.2024.11.021. Epub 2025 Jan 10. PMID: 39797884.
2. Payen JF, Dupuis C, Trouve-Buisson T, Vinclair M, Broux C, Bouzat P, Genty C, Monneret D, Faure P, Chabre O, Bosson JL. Corticosteroid after etomidate in critically ill patients: a randomized controlled trial. Crit Care Med. 2012 Jan;40(1):29-35.
3. Acquisto NM, Mosier JM, Bittner EA, Patanwala AE, Hirsch KG, Hargwood P, Oropello JM, Bodkin RP, Groth CM, Kaucher KA, Slampak-Cindric AA, Manno EM, Mayer SA, Peterson LN, Fulmer J, Galton C, Bleck TP, Chase K, Heffner AC, Gunnerson KJ, Boling B, Murray MJ. Society of Critical Care Medicine Clinical Practice Guidelines for Rapid Sequence Intubation in the Critically Ill Adult Patient. Crit Care Med. 2023 Oct 1;51(10):1411-1430. doi: 10.1097/CCM.0000000000006000. Epub 2023 Sep 14. PMID: 37707379.
4. Casey JD, Seitz KP, Driver BE, Gibbs KW, Ginde AA, Trent SA, Russell DW, Muhs AL, Prekker ME, Gaillard JP, Resnick-Ault D, Stewart LJ, Whitson MR, DeMasi SC, Robinson AE, Palakshappa JA, Aggarwal NR, Brainard JC, Douin DJ, Marvi TK, Scott BK, Alber SM, Lyle C, Gandotra S, Van Schaik GW, Lacy AJ, Sherlin KC, Erickson HL, Cain JM, Redman B, Beach LL, Gould B, McIntosh J, Lewis AA, Lloyd BD, Israel TL, Imhoff B, Wang L, Spicer AB, Churpek MM, Rice TW, Self WH, Han JH, Semler MW; RSI Investigators and the Pragmatic Critical Care Research Group. Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults. N Engl J Med. 2025 Dec 9:10.1056/NEJMoa2511420. doi: 10.1056/NEJMoa2511420. Epub ahead of print. PMID: 41369227; PMCID: PMC12711137.
QUESTIONS FOR AUTHORS
Q: Was there a minimal SBP goal prior to intubation or any preceding resuscitation efforts before RSI in patients deemed high risk for cardiovascular collapse during intubation?
A: There were no pre-specified goals in the resuscitative efforts prior to RSI for patients. The authors note that all other aspects of intubating, including any fluid resuscitation or vasopressor initiation, was determined by the clinician according to protocols in the respective study locations. Table S16 in the supplemental materials details the hemodynamic status by trial group: 20.9% of patient in the ketamine group and 23.0% of patients in the etomidate group were receiving vasopressors at the time of intubation. These interventions that could potentially modify the effect of ketamine vs etomidate on patient outcomes were then prospectively studied. Table S5 notes the number of patients receiving respiratory support in the hour prior to intubation. These clinical decisions were at the discretion of the treating clinician which further highlights the pragmatic approach to this trial.
Q: Was cardiovascular collapse with ketamine administration associated with higher dosing of ketamine at 2.0 mg/kg compared to 1.5 or 1.0 mg/kg?
A: The authors do not specifically address or provide data analyzing the dose effects on each outcome.
Q: Are there other studies that suggest that cardiovascular collapse with intubation is more common with ketamine vs. etomidate administration? (see systematic review below which showed that etomidate use compared to ketamine for RSI was associated with a lower need for vasopressor support (OR 0.71 95% CI 0.53-0.96))
A: Several additional studies have examined the hemodynamic effects of ketamine compared with etomidate during rapid sequence intubation. A few are listed below with their general conclusions.
Matchett, G., Gasanova, I., Riccio, C.A. et al. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med 48, 78–91 (2022). https://doi.org/10.1007/s00134-021-06577-x
Matchett et al. performed a randomized clinical trial and found that a greater percentage of patients who received ketamine required acute hemodynamic support with bolus dose vasopressors compared with patients who received etomidate. They also noted that the ketamine group was associated with a higher rate of post induction hemodynamic collapse as defined by the Vanderbilt Definition.
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. Sci Rep. 2023; 13:6362
Srivilaithon et al. conducted a randomized controlled trial in septic patients and found no difference between etomidate and ketamine for peri intubation arrest or post intubation hypotension.
Greer, A. , Hewitt, M. , Khazaneh, P. , Ergan, B. , Burry, L. , Semler, M. , Rochwerg, B. & Sharif, S. (2025). Ketamine Versus Etomidate for Rapid Sequence Intubation: A Systematic Review and Meta-Analysis of Randomized Trials. Critical Care Medicine, 53 (2), e374-e383. doi: 10.1097/CCM.0000000000006515.
Greer et al. performed a meta analysis of seven randomized controlled trials and found that ketamine likely increases hemodynamic instability in the peri intubation period relative risk 1.29, 95 percent CI 1.07 to 1.57, moderate certainty.
Maia IWA, Decker SRR, Oliveira J. e Silva L, et al. Ketamine, Etomidate, and Mortality in Emergency Department Intubations. JAMA Netw Open. 2025;8(12):e2548060. doi:10.1001/jamanetworkopen.2025.48060
Maia et al., in a cohort study of 18 Brazilian emergency departments, found that new hemodynamic instability within 30 minutes after intubation was more frequent in the ketamine group compared with the etomidate group.
