Introduction: The High-Stakes Choice in Rapid Sequence Intubation
Rapid sequence intubation (RSI) is a cornerstone of emergency and critical care medicine, yet the optimal pharmacological strategy for the induction of anesthesia in critically ill patients remains a subject of intense debate. For decades, etomidate has been the ‘gold standard’ for RSI due to its rapid onset and perceived hemodynamic neutrality. However, concerns regarding its ability to cause transient adrenocortical suppression have led clinicians to increasingly turn toward ketamine, a dissociative anesthetic that provides sympathomimetic support.
Two recent major publications have brought this debate back to the forefront: a large-scale cohort study from the Brazilian Airway Registry Cooperation (BARCO) published in JAMA Network Open (Maia et al., 2025) and a systematic review and meta-analysis of randomized controlled trials (RCTs) (Bandyopadhyay et al., 2025). These studies offer contrasting perspectives on mortality and safety, necessitating a critical interpretation for clinicians at the bedside.
Highlights of Recent Evidence
– The BARCO cohort study (n=1810) found that etomidate use was associated with higher 28-day in-hospital mortality (60.5%) compared to ketamine (54.4%).
– Despite the mortality findings, ketamine was associated with a higher incidence of new hemodynamic instability within 30 minutes post-intubation (24.2% vs 18.9%).
– A separate meta-analysis of four RCTs (n=1663) found no statistically significant difference in 28-day mortality between the two agents, suggesting that the debate is far from settled.
– Adrenal suppression remains the primary theoretical disadvantage of etomidate, while post-induction hypotension remains a critical concern for ketamine in the most severely shocked patients.
Background: The Adrenal Suppression vs. Sympathetic Surge Paradox
Etomidate’s primary mechanism involves the potentiation of GABA-A receptors. Its clinical appeal lies in its minimal impact on heart rate and blood pressure during the induction phase. However, etomidate is a known inhibitor of 11-beta-hydroxylase, the enzyme responsible for converting 11-deoxycortisol to cortisol. Even a single dose can suppress the adrenal response for 24 to 48 hours, which many hypothesize increases mortality in septic or critically ill patients who require a robust stress response.
Ketamine, conversely, acts primarily as an NMDA receptor antagonist. It stimulates the sympathetic nervous system, increasing catecholamine release, which theoretically supports blood pressure. However, in patients who are catecholamine-depleted (those in late-stage shock), ketamine’s direct myocardial depressant effects may emerge, leading to unexpected hypotension.
Study Design: The Brazilian Airway Registry (BARCO) and Target Trial Emulation
In the study by Maia et al., researchers utilized a target trial emulation framework to analyze observational data from 18 emergency departments in Brazil. This methodology aims to apply the rigor of a clinical trial to observational data by strictly defining inclusion/exclusion criteria and using advanced statistical weighting.
Population and Methodology
– Participants: 1810 critically ill adults undergoing RSI.
– Intervention: Induction with either etomidate (n=1296) or ketamine (n=514).
– Statistical Adjustment: Inverse probability of treatment weighting (IPTW) was used to account for the fact that ketamine patients were generally sicker at baseline (higher shock index and higher vasopressor use).
– Primary Endpoint: 28-day in-hospital mortality.
Key Findings: Mortality and Hemodynamics
Mortality Results
The findings from the BARCO study were striking. The weighted 28-day mortality was significantly higher in the etomidate group than in the ketamine group (60.5% vs 54.4%; Risk Ratio [RR], 1.14; 95% CI, 1.03-1.27). This translated to a risk difference of 7.6%, suggesting that for every 13 patients intubated with ketamine instead of etomidate, one death might be averted. This trend was consistent at the 7-day mortality mark as well (35.2% vs 30.1%; RR, 1.19).
Safety and Secondary Outcomes
Interestingly, the study challenged the notion that ketamine is always the ‘hemodynamically safer’ choice. New hemodynamic instability within 30 minutes of intubation occurred more frequently in the ketamine group (24.2% vs 18.9%; RR, 0.78 favoring etomidate). There were no significant differences in first-attempt success rates or other major adverse events like cardiac arrest or severe hypoxemia.
Comparative Analysis: The Meta-Analysis Perspective
To provide a balanced view, we must look at the systematic review by Bandyopadhyay et al. (2025). This meta-analysis pooled data from four RCTs involving 1663 patients. Unlike the observational BARCO study, the meta-analysis found no significant difference in 28-day mortality (RR 0.95; 95% CI: 0.72-1.25).
While the meta-analysis also noted a higher risk of post-induction hypotension in the ketamine group (RR 1.30), the result did not reach statistical significance in their specific pooled model. This discrepancy between large-scale observational data (suggesting ketamine superiority for survival) and smaller-scale RCTs (suggesting equipoise) is a classic challenge in evidence-based medicine.
Expert Commentary: Reconciling the Data
Why do the BARCO registry and the meta-analysis differ? Several factors may be at play:
1. Sample Size and Power: While the meta-analysis included RCTs, the total number of patients across all trials was still relatively small compared to the large observational registry. Observational studies can capture ‘real-world’ practice patterns that RCTs might miss.
2. Confounding: Despite IPTW, observational studies like BARCO may suffer from unmeasured confounding. Clinicians might have chosen ketamine for the most unstable patients, and even sophisticated weighting might not fully erase that bias.
3. The ‘Shock Index’ Factor: In the BARCO study, the ketamine group had a higher median shock index. The fact that ketamine showed better survival despite being used in ‘sicker’ patients lends weight to the argument that etomidate’s adrenal suppression is clinically meaningful.
From a biological plausibility standpoint, the ‘etomidate-induced adrenal insufficiency’ theory remains the most likely explanation for the mortality difference observed in the Brazilian cohort. In a resource-constrained or high-acuity environment, the ability of a patient to mount a cortisol response may be the difference between recovery and multi-organ failure.
Clinical Implications and Conclusion
For the practicing clinician, these studies suggest that the choice of induction agent is not a ‘one size fits all’ decision.
If the primary goal is avoiding immediate post-induction hypotension, etomidate remains a reliable choice, but it may come at the cost of long-term survival due to adrenal effects. If the goal is maximizing 28-day survival, the BARCO data suggests ketamine may be superior, provided the clinician is prepared to manage potential hemodynamic instability immediately following the procedure.
Until large-scale, multicenter randomized controlled trials (such as the ongoing KETASED II or similar large trials) provide a definitive answer, clinicians should:
1. Assess the patient’s baseline shock index and catecholamine status.
2. Consider the potential for adrenal suppression in septic patients when choosing etomidate.
3. Be prepared with vasopressors or fluid boluses if using ketamine in a severely shocked patient.
In summary, while etomidate provides a smoother transition during the ‘plastic hours’ of induction, ketamine may offer a survival advantage that manifests in the weeks following the emergency department stay.
References
1. 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.
2. Bandyopadhyay A, Haldar P, Sawhney C, Singh A. Efficacy of ketamine versus etomidate for rapid sequence intubation, among critically ill patients in terms of mortality and success rate: A systematic review and meta-analysis of randomized controlled trials. Clin Exp Emerg Med. 2025 Aug 13. doi:10.15441/ceem.24.363.
