Matchett G, Gasanova I, Riccio CA, et al. - EvK Clinical Trial Collaborators. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med. 2022;48(1):78-91.
To determine whether there is a survival benefit of ketamine over etomidate for sedation of critically ill patients during emergency endotracheal intubation
Both ketamine and etomidate are often used to sedate critically ill patients during emergency endotracheal intubation as they both have rapid-onset and are hemodynamically stable. Recent studies have looked into whether one is superior to the other. Ketased, the largest randomized trial comparing ketamine vs. etomidate (n = 655) reported no significant difference in hemodynamic effects between the two drugs. Recent observational studies from the National Emergency Airway Registry (NEAR) Database, however, reported that ketamine was associated with more-frequent hypotension compared to etomidate.
It is also known that etomidate inhibits 11-beta hydroxylase in the adrenal glands, which some studies have concluded leads to increased mortality even after a single dose.1,2 In 2015, quality improvement data from the authors’ hospital concluded that there was survival benefit at Day 7 from avoiding etomidate compared to other induction agents. To test this hypothesis, the authors designed this clinical trial to determine if ketamine in particular was a superior induction option to etomidate.
Prospective, randomized, parallel-assignment, open-label, single-center trial between 6/6/2016 and 9/7/2020 in an urban, academic, Level-1 Trauma Hospital in Dallas with all rapid-sequence intubations performed by a procedure-focused airway team (staffed by the Department of Anesthesiology and distinct from the ICU teams).
Patients were randomized to either receive etomidate or ketamine as the primary anesthetic (suggested dose ranges of 0.2-0.3 mg/kg IV and 1-2 mg/kg IV, respectively), though members of the airway team were permitted to adjust the doses as they believed were clinically appropriate. All subsequent medical or surgical care was at the discretion of the treating critical care teams.
Other routine aspects of the airway team include: two or more skilled operators present, head up (20-30°) positioning, deliberate pre-oxygenation, routine use of rapid sequence induction with neuromuscular blocking agents and intubating stylets, frequent use of cricoid pressure, frequent first-pass use of videolaryngoscopy, confirmation of tube placement with end-tidal CO2, and early treatment of post-intubation hypotension with bolus-dose vasopressors and IV fluids.
- Age > 18 years old in need of emergency endotracheal intubation
- Children < 18 years of age
- Pregnant women
- Patients previously enrolled in the trial
- Patients requiring endotracheal intubation without sedative medication (eg, for those in cardiac arrest, who are neurologically obtunded, or who require awake intubation)
- Allergy to etomidate or ketamine
- Anyone who formally opted out of the clinical trial
Powered to detect a 10% difference in Day 7 survival if 750 patients were enrolled. In total, 801 critically ill patients requiring emergency endotracheal intubation were enrolled with 396 in the etomidate arm and 395 in the ketamine arm (some patients were lost to post-enrollment withdrawals).
Proportions survived on Study Day 7
Proportion survived on study Day 28, duration of mechanical ventilation, ICU length-of-stay, usage and duration of vasopressor therapy, serial SOFA scores on Day 1-4, and an assessment of a new diagnosis of adrenal insufficiency by the treating critical care teams
Immediate technical endpoints, including induction drug dose, neuromuscular blocking agent and dose, choice of laryngoscope, number of intubation attempts, and complications such as major soft-tissue trauma, dental trauma, aspiration events, clinically significant bleeding, or requirement for surgical airway.
Immediate hemodynamic outcomes: measurement of blood pressure and heart rate before and after induction as well as acute interventions for post-intubation hypotension such as bolus-dose vasopressors, IV fluid bolus, or CPR.
General Group Characteristics
Most patients were intubated on the medical floors with 50% ultimately being diagnosed with sepsis before or immediately post-intubation. Mean MAP pre-intubation was 80-85 mmHg. Mean etomidate dose was 0.2 mg/kg while mean ketamine dose was 1.2 mg/kg. Direct laryngoscope was used in 50% of cases with a first pass success rate of 91%. Rocuronium was the primary neuromuscular blocking agent (~80% of patients).
Day 7 survival for the etomidate and ketamine groups were 77.3% (90 deaths out of 396) and 85.1% (59 deaths out of 395), respectively (p value = 0.005). Thus, patients in the etomidate arm were 1.6x more likely to die at 7 days compared to patients in the ketamine arm (hazard ratio = 1.6, 95% confidence interval: 1.2, 2.2). See Figure 2 below taken from the article.
Day 28 survival for etomidate and ketamine groups were 64.1% (142 deaths out of 396) and 66.8% (131 deaths out of 395), respectively. The difference was not statistically significant (p value = 0.294). In addition, the other secondary outcomes were also not statistically significant between the two groups.
A greater percentage of patients randomized to ketamine received acute hemodynamic support in the form of bolus-dose vasopressors vs. patients randomized to etomidate, however, they did not require more continuous vasopressor infusions overall. Commenting on this finding, the authors note that there was missing data taken from the nursing code sheets (for 51 and 41 of the patients randomized to etomidate and ketamine, respectively) and there were otherwise similarities between post-induction heart rates and blood pressures, so these differences were thought to be of uncertain clinical significance and instead should be viewed as hypothesis-generating. There were no other statistically significant differences between the groups.
- Single-center trial with a specialized, high-volume airway team with most intubations occurring on medical floors which limits generalizability to emergency medicine.
- The two groups were unblinded to the induction medication which introduces clinician bias.
- Clinicians were able to screen out patients when they felt a specific induction medication was indicated (eg, opioid, propofol, benzodiazepine), biasing the trial enrollment towards patients where the clinician felt that etomidate or ketamine would be the right choice.
- Given the large standard deviations and small absolute differences between the groups in the exploratory endpoints, the trial was not large enough to detect a reliable difference between the two groups.
- Day 7 survival as a primary outcome may be clinically unimportant as an outcome for patients. It was chosen based on empirical observations of their QI data and because they wanted to place the primary endpoint relatively close in time to the randomization event, but the relevance of Day 7 survival to long-term outcomes is uncertain.
In this single-center RCT, critically ill patients who received ketamine for rapid-sequence induction had > 7-day survival over those who received etomidate. The tradeoff was more rescue therapy with vasopressors due to cardiovascular collapse in patients in the ketamine arm so be prepared to have vasopressors ready if electing to use ketamine.
- Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-. Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis. 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK121473/
- Albert SG, Sitaula S. Etomidate, Adrenal Insufficiency and Mortality Associated With Severity of Illness: A Meta-Analysis. J Intensive Care Med. 2021;36(10):1124-1129.