• 💀 Mortality: No statistically significant difference in 28-day mortality between ketamine vs etomidate for intubation in critically ill patients, though there was a ~1% absolute difference favoring ketamine. 📉
• 🫀⚠️ Hemodynamics: Ketamine induction was associated with more cardiovascular collapse, mainly driven by new/increased vasopressor use (dose escalation or addition of a vasoactive agent). 💉⬆️

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Etomidate or ketamine? The debate over the ideal agent for emergency rapid sequence intubation (RSI) has raged for years with no clear winner. Etomidate has been touted in the past for its rapid onset and minimal intrinsic effects on hemodynamics. However, the drug is well known as a transient adrenal suppressant though the impact of this suppression isn’t clear. Ketamine has risen in recent years as an alternative, due to its perceived hemodynamic stability, analgesic properties and absence of adrenal suppression. Additionally, recent data points towards improved mortality when ketamine was selected over etomidate (Kotani 2023). High quality randomized controlled trials are needed to further elucidate which agent should be selected in critically ill patients.

Casey JD et al. Ketamine or etomidate for tracheal intubation of critically ill adults. NEJM 2025. PMID: 41369227

• REBEL EM: The EvK Trial: Ketamine vs Etomidate for Rapid Sequence Intubation
• REBEL EM: From Debate to Data: Emerging Insights into RSI Induction with Ketamine vs Etomidate

In critically ill adults undergoing tracheal intubation, does the use of ketamine instead of etomidate result in improved 28 day mortality?

Multicenter, randomized, open-label trial in both emergency departments and ICUs.

Inclusion Criteria:

• Critically ill patients > 18 years of age undergoing tracheal intubation with the use of an induction agent

Exclusion Criteria:

• Known pregnancy
• Prisoners
• Primary diagnosis of trauma
• Need for immediate intubation precluding randomization
• Clinicians determined that the use of ketamine or etomidate was either necessary or contraindicated

Intervention (HFNC Group):

• Ketamine administered based on a provided nomogram: full dose (2.0 mg/kg), intermediate dose (1.5 mg/kg) or reduced dose (1.0 mg/kg)

Comparator (BPAP Group):

• Etomidate administered based on a provided nomogram: full dose (0.3 mg/kg), intermediate dose (0.25 mg/kg) or reduced dose (0.2 mg/kg)

• Primary: In-hospital death from any cause by day 28.

• Secondary:

• • • Cardiovascular collapse during intubation defined as SBP < 65 mm Hg, receipt of new or increased dose of vasopressors or cardiac arrest.

• Exploratory Procedural:

• • • Lowest systolic blood pressure
    • Lowest systolic blood pressure below 80 mmHg
    • Highest systolic blood pressure above 180 mmHg
    • Lowest oxygen saturation
    • Lowest oxygen saturation below 80%
    • Successful first attempt intubation
    • Time from induction to intubation

• Exploratory Clinical:

• • • Number of ventilator free days
    • Vasopressor-free days
    • ICU free days 

• Safety:

• •  Systolic blood pressure at 24 hours after enrollment
  • Ongoing receipt of vasopressors at 24 hours

• 2365 patients were randomized
  • Ketamine: 1176
  • Etomidate: 1189
• > 99% of patients received the drug they were randomized to receive
• NMBA: 69% of patients in both groups received rocuronium
• ~ 95% of patients had video laryngoscopy for the primary intubation attempt

• Multicenter ED + ICU cohort of critically ill patients → improves external validity
• Strong randomization → balanced baseline characteristics
• Right population for the question → appropriately focused on a sick cohort where induction choice matters most
• High protocol adherence → most patients received the agent they were randomized to
• Excellent follow-up → minimal loss to follow-up / outcome capture

• No blinding → potential performance/resuscitation bias
• Trauma excluded → limits applicability to peri-intubation trauma care
• Case-mix skewed toward septic shock → may reduce generalizability to other shock etiologies
• Power assumptions → designed to detect a 5% mortality difference (possibly overly ambitious)
• Equipoise-only enrollment → excluded patients with clear indication/contraindication → selection bias + reduced real-world applicability
• Composite secondary outcome with non-equivalent endpoints (e.g., cardiac arrest vs vasopressor titration)
• Ketamine dosing by actual body weight (vs ideal) → may have increased dose/exposure in some patients

• The increase in cardiovascular collapse seen with ketamine was driven by the “new or increased vasopressor use” piece of the composite outcome not by the more clinically relevant severe hypotension (SBP < 65 mm Hg) or cardiac arrest.
• The increase in CV collapse is a secondary outcome and hypothesis generating only
• Care beyond induction agent isn’t clearly delineated and may have varied between groups
• Reasons why there was more CV collapse in the ketamine group:
  • Patients in the etomidate group were more likely to be on pressors or have pressor increases prior to induction agent administration
  • Ketamine has analgesic properties which may affect hemodynamics (etomidate does not have analgesic effects)
  • The standard ketamine dose of 2 mg/kg is higher than the induction dose used by most (1-1.5 mg/kg)
  • Ketamine dosing was based on actual body weight though ideal body weight dosing is more accepted. This may have resulted in unnecessarily large ketamine doses that may have had a greater effect on hemodynamics.
• This is a study of patients with clinical equipoise
  • Patients who the clinician determined would clearly benefit from one agent or the other or in whom one agent or the other was contraindicated were excluded from the study.
  • This may add a selection bias to the results.
• Clinicians were not blinded to the induction agent administered
  • The absence of blinding can introduce bias.
  • For instance, knowledge of the agent the patient was randomized to may result in different resuscitative treatment prior to intubation.
• An induction agent nomorgram was provided to allow clinicians to choose their induction dose depending on patient stability.
• A 5% difference in mortality may be overly ambitious. As Josh Farkas points out in his post on this article, PCI for STEMI only has a 3% absolute difference in mortality versus standard care.
• The 1% absolute difference in mortality while not statistically significant would be clinically significant if it was real. 
  • The study would have to be much larger to show a statistically significant 1% difference.
• About 2% of patients in each group received additional medications during induction (propofol, benzodiazepines, opiates). It is unclear why these agents were selected in specific cases and how they may have affected the outcomes in question.

“Among critically ill adults undergoing tracheal intubation, the use of ketamine to induce anesthesia did not result in a significantly lower incidence of in-hospital death by day 28 than etomidate.“

In this well done RCT, induction with ketamine did not result in a lower 28-day mortality when compared to induction with etomidate in critically ill adults. The secondary outcome of an increase in cardiovascular collapse is interesting and should be studied more in the future.

This data should not drive clinicians to abandon the use of ketamine in RSI. To the contrary, the study leaves open the possibility of a clinically meaningful difference in mortality favoring ketamine that may be borne out in a larger study. However, etomidate can be considered as a first-line option for RSI and may be the superior drug in patients at high-risk for cardiovascular decompensation.

Post Peer Reviewed By: Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), Frank Lodeserto, MD and Anand Swaminathan, MD (X: @EMSwami)

Kotani Y et al. Etomidate as an induction agent for endotracheal intubation in critically ill patients: a meta-analysis of randomized trials J Crit Care 2023;77:154317. PMID: 37127020

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