Etomidate vs Ketamine for Rapid Sequence Intubation in Critical Patients: What the RSI Trial Reveals

What the largest pragmatic trial to date suggests about mortality and hemodynamic stability during induction for intubation in critically ill adults.

Key takeaways#

Clinical question and mortality

• The key clinical question was straightforward: in critically ill adults undergoing unscheduled intubation, does ketamine reduce mortality compared to etomidate?
• In the RSI trial (NEJM, December 9, 2025; n = 2365), there was no statistically significant difference in mortality up to day 28 between ketamine and etomidate.

Hemodynamics during intubation

• The finding that changes the conversation was hemodynamic: cardiovascular collapse during intubation was more frequent with ketamine (absolute difference of +5.1 percentage points).
• In higher-risk subgroups (sepsis/septic shock; APACHE II ≥ 20), the difference in cardiovascular collapse was even more pronounced, again favoring etomidate.

Adrenal suppression and risk interpretation

• Transient adrenal suppression from etomidate remains a relevant physiological phenomenon, but did not translate to increased mortality versus ketamine in this single-dose induction scenario.

Where ketamine remains useful

• Ketamine remains extremely useful in specific contexts (e.g., severe bronchospasm, status asthmaticus, situations where some preservation of respiratory drive is desired before intubation), but the study indicates that it was not "more stable" in terms of blood pressure in the overall sample.

Why has this choice always been controversial?#

For many years, the choice of induction agent for rapid sequence intubation (RSI) in critical patients has been controversial.

On one side, etomidate: hemodynamically "friendly," but accused of suppressing the adrenal axis and potentially increasing mortality, especially in sepsis.

On the other, ketamine: considered more stable in terms of blood pressure, with sympathomimetic action, and viewed by many as "safer" in severely ill patients.

Observational studies and small trials pointed to conflicting results. Societies and guidelines in some countries even discouraged etomidate due to concerns about adrenal suppression.

What was missing was a large, pragmatic study designed to answer the question that matters at the bedside: in critically ill adults undergoing emergency intubation, does using ketamine instead of etomidate reduce mortality?

This is exactly what the Randomized Trial of Sedative Choice for Intubation (RSI), recently published in the New England Journal of Medicine on December 9, 2025, set out to answer.

The RSI study in 1 minute#

The RSI study: how was it designed?#

The RSI is a randomized, multicenter, pragmatic, parallel trial conducted in:

• 14 units (6 emergency departments and 8 ICUs),
• at 6 medical centers in the United States,
• including 2365 critically ill adults undergoing emergency intubation.

Who was enrolled in the study?

Inclusion

• ≥18 years
• Critically ill patients
• Need for tracheal intubation with induction medication, in ICU or emergency department.

Exclusion

• Pregnancy
• Prisoners
• Primary diagnosis of trauma
• "Crash intubation" without time for randomization
• Situations where the physician judged one of the drugs was clearly necessary or contraindicated.

Randomization and intervention

Patients were randomized 1:1 to:

Ketamine group

• Ketamine IV for induction of anesthesia.
• Nomogram with "full" dose 2.0 mg/kg, intermediate 1.5 mg/kg, or reduced 1.0 mg/kg, at physician discretion.

Etomidate group

• Etomidate IV for induction.
• Nomogram with "full" dose 0.3 mg/kg, intermediate 0.25 mg/kg, or reduced 0.2 mg/kg.

Adherence was excellent: 99.2% of patients in the ketamine group actually received ketamine and 99.6% in the etomidate group received etomidate.

All other management (vasopressors, fluid, choice of neuromuscular blocker, post-intubation sedation, corticosteroids, etc.) was at the discretion of the care team, mirroring real practice.

Outcomes: what did the study measure?#

Primary outcome

• In-hospital death up to day 28 (all-cause).

Key secondary outcome

• Cardiovascular collapse during intubation, defined as at least one of the following between induction and 2 min after intubation:

  • SBP < 65 mmHg
  • need to start or increase vasopressor
  • cardiac arrest

Exploratory

• Lowest blood pressure during the procedure
• vasopressor requirement
• desaturation
• first-attempt success
• time to intubation
• ventilator-free, vasopressor-free, and ICU-free days

The study was adequately powered to detect an absolute difference of approximately 5 percentage points in mortality, with 80% power and 5% alpha error.

What did the RSI find?#

Mortality: tie (and that's important)

In-hospital death up to day 28:

• Ketamine: 28.1% (330/1173)
• Etomidate: 29.1% (345/1186)
• Adjusted risk difference: –0.8 percentage point (95% CI –4.5 to 2.9; p = 0.65)

There was no statistically significant difference in mortality between the two drugs.

All subgroup analyses (including sepsis/septic shock) and individual risk models reached the same conclusion: neither ketamine nor etomidate proved superior in mortality.

Periprocedural hemodynamics: the finding that surprised many

Cardiovascular collapse during intubation

• Ketamine: 22.1% (260/1176)
• Etomidate: 17.0% (202/1189)
• Absolute difference: +5.1 percentage points favoring etomidate.

In higher-risk subgroups, the difference was even more pronounced:

• Sepsis/septic shock: collapse in 30.6% (ketamine) vs 20.9% (etomidate).
• APACHE II ≥ 20: 31.4% (ketamine) vs 20.7% (etomidate).

Other hemodynamic findings

• Lowest SBP during the procedure was, in median, 6 mmHg lower in the ketamine group (112 vs 118 mmHg).

• SBP < 80 mmHg during intubation:

  • Ketamine: 14.4%
  • Etomidate: 10.6%

• SBP drop > 30 mmHg:

  • Ketamine: 23.9%
  • Etomidate: 14.7%

Additionally, a post-hoc safety outcome showed more episodes of ventricular tachycardia with ketamine (1.0% vs 0.2%).

Other clinical outcomes: no relevant difference

• Ventilator-free, vasopressor-free, and ICU-free days were similar between groups.
• At 28 days, there were no signs of functional benefit or support time advantage for either drug.

Results table for quick reference#

How robust is this study?#

Strengths

• N = 2365, practically the same number combined from all previous trials on this topic.
• Multicenter, with different patient profiles (ED and ICU).
• High adherence to the assigned drug (>99%).
• Very low loss to follow-up for the primary outcome.
• Severely ill population: nearly 30% mortality at 28 days, >40% with sepsis/septic shock, and ~22% on vasopressors pre-intubation.

Limitations

• Unblinded study (could influence management and assessment of some hemodynamic outcomes).
• Excluded trauma, so caution when extrapolating to polytrauma.
• Does not answer anything about comparison with propofol, benzodiazepines, barbiturates.

Even so, for anesthesiology and intensive care medicine, it's a strong enough study to influence practice.

What changes for anesthesiologists in daily practice?#

In the context of emergency intubation in critically ill adults, switching from etomidate to ketamine did not reduce mortality.

This weakens the argument that "I can't use etomidate because it increases mortality," at least in this specific scenario (single dose for induction in RSI).

And here's the key point: ketamine was not more "hemodynamically stable."

How might this change your choice of induction agent?

Practical implications, the way they matter in routine:

• In severe septic patients, on vasopressors, hemodynamically unstable:

  • this study gives a strong signal to consider etomidate as a first-line option for induction,
  • with lower risk of hemodynamic collapse during intubation, but still needing to be prepared for hemodynamic instability (20.9%).

• Transient adrenal suppression from etomidate bolus continues to exist as a physiological phenomenon, but did not translate to increased mortality compared to ketamine.

• Ketamine remains extremely useful, for example:

  • in patients with severe bronchospasm,
  • status asthmaticus,
  • situations where some preservation of respiratory drive is desired before intubation (delayed sequence intubation),
  • and also in critical patients, knowing that the chance of hemodynamic compromise may occur more frequently, despite the physiological rationale.

Want to bring this type of evidence into your routine without opening 20 tabs?#

If you use AnestCopilot, this is the type of question worth reviewing with Deep Evidence: you ask in natural language and receive an applied synthesis, with options for concise or deep review, to support decision-making and management discussion with more consistency.

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