Etomidate and adrenal insufficiency: the controversy continues

Background 
Critically ill patients often require emergency intubation. The use of etomidate as the sedative agent in this context has been challenged because it may cause a reversible adrenal insufficiency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients. 
 
Methods 
In this randomized, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerized random-number generator list to receive 0-3 mg/kg of etomidate (n = 328) or 2 mg/kg of ketamine (n = 327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. The primary endpoint was the maximum score of the sequential organ failure assessment during the first 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00440102. 
 
Findings 
234 patients were analyzed in the etomidate group and 235 in the ketamine group. The mean maximum SOFA score between the two groups did not differ significantly (10.3 [SD 3.7] for etomidate vs. 9.6 [3.9] for ketamine; mean difference 0.7 [95% CI 0.0-1.4], p = 0.056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0-3] in both groups; p = 0.70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6.7, 3.5-12.7). We recorded no serious adverse events with either study drug. 
 
Interpretation 
Our results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis.


Background
Critically ill patients often require emergency intubation. Th e use of etomidate as the sedative agent in this context has been challenged because it may cause a reversible adrenal insuffi ciency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients.

Methods
In this randomized, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerized random-number generator list to receive 0·3 mg/kg of etomidate (n = 328) or 2 mg/kg of ketamine (n = 327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. Th e primary endpoint was the maximum score of the sequential organ failure assessment during the fi rst 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modifi ed intention to treat). Th is trial is registered with ClinicalTrials.gov, number NCT00440102.

Findings
234 patients were analyzed in the etomidate group and 235 in the ketamine group. Th e mean maximum SOFA score between the two groups did not diff er signifi cantly (10.3 [SD 3.7] for etomidate vs. 9.6 [3.9] for ketamine; mean diff erence 0.7 [95% CI 0.0-1.4], p = 0.056). Intubation conditions did not diff er signifi cantly between the two groups (median intubation diffi culty score 1 [IQR 0-3] in both groups; p = 0.70). Th e percentage of patients with adrenal insuffi ciency was signifi cantly higher in the etomidate group than in the ketamine group (OR 6.7, 3.5-12.7). We recorded no serious adverse events with either study drug.

Interpretation
Our results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis.

Commentary
A single dose of etomidate is associated with decreased serum concentrations of cortisol for at least 24 hours after its administration [1,2]. Continuous intravenous adminis tration of etomidate has been associated with adreno cortical dysfunction and increased patient mortality [3][4][5]. Several studies have suggested an association between etomidate-induced adrenal insuffi ciency and increased morbidity in the critically ill, particularly in those with sepsis [6,7]. Yet, etomidate continues to be used commonly for rapid sequence intubation as it is less likely to cause hypotension. Th is favorable cardiovascular profi le is important in critically ill patients with severe sepsis. Th is study was designed to investigate the possibility of a causal relationship between etomodiate use and increased morbidity or mortality. Etomidate was compared to ketamine, which has similar cardiovascular profi le, but may be associated with adverse psychiatric events [8].
Jabre et al. conducted a prospective, randomized controlled single-blind trial where subjects requiring intubation were randomized to etomidate (0.3 mg/kg) or ketamine (2 mg/kg) with succinylcholine prior to ICU admission. Th e primary endpoint was the maximum score of the sequential organ failure assessment during the fi rst 3 days in the intensive care unit. Secondary endpoints were identifi ed as organ dysfunction and failure occurring after admission to the intensive care unit (Δ-SOFA), 28-day all-cause mortality, days free from intensive care unit, organ support-free days, and measure ment and correlation with adrenal insuffi ciency. A modifi ed intention-to-treat (ITT) analysis was used, where randomized patients who died before reaching hospital and those discharged from the intensive care unit within 3 days were excluded. Th is analysis adjusted for age, simplifi ed acute physiology score II, and sex to ensure that these factors were equally distributed between these groups because the modifi ed ITT analysis was performed in 469 of the 655 subjects who were randomized.
Th e results did not demonstrate any signifi cant diff erences in mean SOFA max score, 28-day mortality, catecholamine use, median ventilator-free days, and median hospital-free days between the two groups. Since the investigators had specifi c concerns for patients with severe sepsis or trauma, these populations were identifi ed as subgroups of interest a priori; however, no signifi cant diff erences in maximum SOFA were seen. Th e investigators did fi nd that the percentage of patients with adrenal insuffi ciency was signifi cantly higher in the etomidate group (86% vs. 48%, p < 0.0001). However, no signifi cant diff erences in morbidity or mortality were found in those with adrenal insuffi ciency. Th e authors concluded that ketamine is a safe and valuable alternative to etomidate and should be considered in those with sepsis. Th is recommendation seems to be derived from the post hoc analysis of CORTICUS trial [9] suggesting that patients with severe sepsis had a signifi cantly higher 28-day mortality rate if they received etomidate (p = 0·03).
Th e strength of this study is the randomized controlled prospective design. Randomization in the modifi ed intention to treat analysis appeared to be complete. It adds to the body of literature suggesting that a single dose of etomidate may be associated with adrenal insuffi ciency but is not associated with an increase in morbidity or mortality. Th e weakness of the study is that the design was underpowered to detect diff erences in the subgroups of interest (patients with trauma and sepsis, n = 180) and it was also underpowered to detect diff erences in mortality. Th is study may not be generalizable to inpatients requiring emergent intubation as this study was conducted in the pre-hospital and emergency department setting, where the majority of intubations were performed for "comatose" patients.
In conclusion, this study found no diff erence in early and 28-day morbidity and mortality after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients. Th is study was unable to answer questions about the impact of etomidate and its related adrenal insuffi ciency on trauma and sepsis populations and larger randomized controlled trials will be needed.

Recommendations
One bolus of etomidate is not associated with a signifi cant increase in morbidity or mortality compared to ketamine. Etomidate can still be safely be used for rapid sequence intubation.