Etomidate associated with increased mortality in sepsis: meta-analysis

Etomidate: Unsafe for Intubation in Patients with Sepsis?

by Blair Westerly, MD

Etomidate is commonly used for rapid sequence intubation; however, even after one dose, it has been associated with adrenal axis suppression in critically ill patients. Though both adrenal insufficiency and increased mortality in sepsis have been associated with etomidate, the relationship of the two has not been clearly defined because of too few studies and small sample sizes.

What They Did

Authors performed a meta-analysis of etomidate for induction during intubation in septic patients to evaluate its association with mortality and adrenal insufficiency.  All in all, ten studies were included for the analysis: five were randomized controlled trials, two were prospective observational studies, and three were retrospective observational studies. To assess mortality, the authors used prospective studies that compared etomidate to a control group and provided mortality as an outcome. Both prospective and retrospective studies  were included to evaluate adrenal insufficiency, adrenal insufficiency was objectively evaluated with a cosyntropin stimulation test in all of them. The primary outcome was all cause mortality and adrenal insufficiency was the secondary outcome. Authors used the modified Jadad scale to evaluate the quality of the included studies, which is always an important variable for meta-analyses. A variety of statistical and analytical methods were used to minimize biases imposed by both the study design and the various outcomes and definitions used in individual studies.

What They Found

Studies included in the analysis had an average modified Jadad score of 5.5, and the authors recognize the limited quality of the included studies in their discussion. Frankly, there weren’t many studies to include and those included varied in comparative sedatives, severity of illness score used, and definitions of mortality and timing to evaluating for adrenal insufficiency, etc, all of which may have introduced biases into the analyses. All that said, the pooled analysis for mortality showed an association between mortality and the use of etomidate (RR of death 1.20, 95% CI 1.02-1.42), though only one of the five included studies demonstrated an association on its own. This association remained significant when only randomized controlled trials were included, which also excluded the lowest quality trial since it was a prospective observational study (RR 1.26, 95% CI 1.06-1.50) and when RCT’s using 28-day mortality were analyzed (RR 1.28, 95% CI 1.06-1.54).  However, the trim and fill method applied to RCT’s and those RCT’s with 28-day mortality resulted in non-significant change in RR, suggesting potential publication bias. The seven studies included for assessment of adrenal insufficiency collectively confirmed an association between etomidate and adrenal insufficiency in patients with sepsis (RR 1.33, 95% CI 1.22-1.46). This was also preserved when only randomized controlled trials were used (RR 1.35, 95% CI 1.24-1.47).

What It Means

Once again, etomidate has been shown to be associated with an increased mortality in critically ill patients, specifically sepsis in a review of the highest quality studies conducted to date, though they are clearly with limitations by design and numbers and the analysis may also suggest a publication bias in the current literature.  While the attractive features of etomidate, including minimal hemodynamic and respiratory side effects, make it a mainstream induction agent for intubation, clinicians are again warned of the potential for harm in patients with sepsis and septic shock. We should not confuse the results of this meta-analysis as definitive data for causation, as no clear relationship between etomidate-induced adrenal insufficiency and mortality has been established, but instead, use its results to further guide our choice of the most appropriate agents for a given patient. Ultimately, the clinical usefulness of a meta-analysis is dependent upon the quality of the product going into the analysis before statistical manipulations are made, and the authors here admit each individual study had flaws that may have impacted results, which should give us hesitation when interpreting the results of this study and applying to our practice. Clinical Takeaway: Etomidate as an anesthesia induction agent for intubation was associated with increased mortality among septic patients in this meta-analysis, which was flawed by study heterogeneity and possible publication bias. Chee Man Chan et al. Etomidate is associated with mortality and adrenal insufficiency in sepsis: A meta-analysis. Crit Care Med 2012; vol 40(11):2945-53.