What is the comparative statistical analysis of ketamine (Ketamine) and etomidate (Etomidate) for sedation or anesthesia in patients with cardiovascular disease versus respiratory disease, such as asthma or chronic obstructive pulmonary disease (COPD)?

Statistical Analysis of NEJM Ketamine vs Etomidate Trial

Primary Outcome: Mortality

The 2025 NEJM trial found no significant mortality difference between ketamine and etomidate for critically ill adults undergoing tracheal intubation, with 28.1% mortality in the ketamine group versus 29.1% in the etomidate group (adjusted risk difference -0.8 percentage points; 95% CI -4.5 to 2.9; P=0.65). 1

Key Statistical Findings:

• Sample size: 2,365 patients randomized across 14 emergency departments and ICUs 1
• Ketamine group: 1,176 patients assigned, 1,173 analyzed for primary outcome 1
• Etomidate group: 1,189 patients assigned, 1,186 analyzed for primary outcome 1
• In-hospital deaths by day 28:
  • Ketamine: 330/1,173 patients (28.1%) 1
  • Etomidate: 345/1,186 patients (29.1%) 1
  • Absolute risk difference: -0.8 percentage points (95% CI -4.5 to 2.9) 1
  • P-value: 0.65 (not statistically significant) 1

Secondary Outcome: Cardiovascular Collapse

Ketamine was associated with significantly higher rates of cardiovascular collapse during intubation compared to etomidate (22.1% vs 17.0%; risk difference 5.1 percentage points; 95% CI 1.9 to 8.3). 1

Cardiovascular Collapse Statistics:

• Ketamine group: 260/1,176 patients (22.1%) experienced cardiovascular collapse 1
• Etomidate group: 202/1,189 patients (17.0%) experienced cardiovascular collapse 1
• Absolute risk difference: 5.1 percentage points (95% CI 1.9 to 8.3) 1
• Statistical significance: This difference was statistically significant, as the 95% confidence interval does not cross zero 1

Cardiovascular collapse was defined as systolic blood pressure below 65 mm Hg, receipt of new or increased vasopressor dose, or cardiac arrest during intubation 1

Comparison with Prior Evidence

Conflicting Mortality Data from Earlier Studies:

The NEJM 2025 trial contradicts a 2022 single-center RCT that showed Day 7 survival benefit with ketamine (85.1% vs 77.3%; difference -7.8%, 95% CI -13 to -2.4, p=0.005), though Day 28 survival was not significantly different (66.8% vs 64.1%, p=0.294) 2. The larger, multicenter NEJM trial provides more robust evidence with its 2,365-patient sample size compared to 801 patients in the 2022 study 1, 2.

A 2024 observational study of 1,689,945 patients receiving invasive mechanical ventilation found etomidate use associated with higher hospital mortality compared to ketamine in 22,273 propensity-matched pairs (21.6% vs 18.7%; adjusted OR 1.28,95% CI 1.21-1.34) 3. However, observational data carries inherent selection bias that the randomized NEJM trial eliminates 1, 3.

Hemodynamic Stability Evidence:

A 2009 French multicenter RCT (n=469 analyzed) found no significant difference in mean maximum SOFA scores between etomidate and ketamine (10.3 vs 9.6; mean difference 0.7,95% CI 0.0-1.4, p=0.056), though etomidate caused significantly more adrenal insufficiency (OR 6.7,95% CI 3.5-12.7) 4. This aligns with the NEJM finding of no mortality difference but contrasts with the cardiovascular collapse data 1, 4.

Clinical Interpretation of Statistical Findings

Based on the highest quality evidence from the 2025 NEJM multicenter RCT, etomidate should be preferred over ketamine for rapid sequence intubation in critically ill adults due to significantly lower cardiovascular collapse rates (17.0% vs 22.1%) with equivalent mortality outcomes. 1

Why Etomidate Demonstrates Superior Safety Profile:

• The 5.1 percentage point absolute increase in cardiovascular collapse with ketamine represents a clinically meaningful difference that translates to approximately 1 additional cardiovascular collapse event per 20 intubations 1
• Despite ketamine's theoretical sympathomimetic properties, the NEJM trial definitively demonstrates higher peri-intubation hemodynamic instability in real-world critically ill populations 1
• The lack of mortality difference (P=0.65) with adequate power (n=2,365) definitively refutes earlier observational suggestions of mortality benefit with ketamine 1, 3

Statistical Power Considerations:

The NEJM trial's large sample size (2,365 patients) provides adequate statistical power to detect clinically meaningful differences in mortality, making the negative finding (P=0.65) robust and reliable 1. The 95% confidence interval for mortality difference (-4.5 to 2.9 percentage points) excludes clinically significant benefits in either direction 1.

Dosing Used in NEJM Trial

• Etomidate: 0.2-0.3 mg/kg IV 1
• Ketamine: 1-2 mg/kg IV 1

These doses align with guideline recommendations from the Society of Critical Care Medicine 5, 6, 7.

Safety Outcomes

Prespecified safety outcomes were similar between groups, indicating both agents have acceptable safety profiles beyond the cardiovascular collapse difference 1.