CCA: Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults

CCA authors:
Alex Hallagan, MD
Gianmarco Raddi, MB-BChir, PhD
Alex Lucas, MD

Keywords: intubation, RSI, sedation, ketamine, etomidate

Article

Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults

RSI Trial (Randomized Trial of Sedative Choice for Intubation)

Objective

To determine the effects of the use of ketamine, as compared with etomidate, for the induction of anesthesia during emergency tracheal intubation

Background  

The ideal induction agent for emergency tracheal intubation provides a rapid onset and maintains hemodynamic stability. Etomidate is the most commonly used agent in the United States, as it has a rapid onset and is short-acting with limited effects on blood pressure and heart rate. However, its use has come under scrutiny, including concerns about etomidate-induced corticosteroid insufficiency. This has historically been of particular concern for patients with sepsis.¹ Ketamine is another popular induction agent. Ketamine increases catecholamine concentration and thus may maintain hemodynamic stability without impairing cortisol production. However, it is also a known negative inotrope and vasodilator. Ketamine is also longer acting and can be given in smaller aliquots, which may allow for increased monitoring and hemodynamic control.^2,3

Several small to moderate-sized randomized trials and meta-analyses comparing the two agents have had conflicting results. Some have shown that ketamine decreases the risk of death, while others have shown no difference in outcomes.^4,5,6 Furthermore, the exact dose of etomidate and ketamine is not standardized and can lead to a potential risk of both under and over-sedation. The selection of etomidate vs. ketamine for critically ill patients has been a long-debated topic in critical care. The RSI trial was designed to answer whether ketamine. reduces the risk of death compared to etomidate in critically ill adults undergoing emergency tracheal intubation.

Design

The RSI trial was a pragmatic, multicenter, unblinded, randomized, parallel-group trial conducted at 14 sites (6 EDs and 8 ICUs) in 6 medical centers across the US. Patients were randomly assigned in a 1:1 ratio to receive ketamine or etomidate for the induction of anesthesia. The medication in both groups was administered intravenously to induce anesthesia. Clinicians and researchers were aware of the trial-group assignments after randomization.

A nomogram was provided with a list of doses that corresponded to a full dose, intermediate dose, or reduced dose for each agent. For the ketamine group, this corresponded to a 2.0 mg/kg, 1.5 mg/kg, or 1.0 mg/kg dose using body weight.  For the etomidate group, this corresponded to a 0.3 mg/kg, 0.25 mg/kg, or 0.2 mg/kg dose using body weight. Clinicians chose the dose to administer. All other aspects of the patients’ medical care were at the discretion of the treating clinicians, including administration of vasopressors, neuromuscular blockade agents, sedation approach during mechanical ventilation, fluids, and systemic glucocorticoids.

A trained observer who was not involved in the intubation collected data on intubation duration, systolic blood pressure, and the administration of vasopressors during the interval between anesthesia induction and two minutes after intubation.

The study was powered to detect an absolute difference of 5.2 percentage points between the groups for the primary outcome. The primary analysis was an intention-to-treat comparison of the primary outcome. Secondary and exploratory outcomes were compared with the use of a chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous variables.

Inclusion Criteria

• Critically ill patients 18 years of age or older who were undergoing tracheal intubation with the use of a medication to induce anesthesia

Eclusion Criteria

• Known to be pregnant
• Known to be prisoners
• Presenting with a primary diagnosis of trauma
• Had an immediate need for tracheal intubation that precluded randomization
• If the clinician felt that the use of ketamine or etomidate was either necessary or contraindicated

Primary Outcome

• In-hospital death by day 28

Secondary Outcome

• Cardiovascular collapse during intubation. This was defined as the occurrence of any of the following between induction and two minutes after intubation:
  • Systolic blood pressure below 65 mmHg
  • Receipt of a new or increased dose of vasopressors
  • Cardiac arrest
• Cardiovascular collapse was also stratified to the two cohorts of patients with sepsis or septic shock and a high degree of illness (APACHE II score > 20).

Key Results

2,367 patients were enrolled and underwent randomization.  The ketamine group consisted of 1,176 patients, of whom 99.2% received ketamine. The etomidate group consisted of 1,189 patients of whom 99.6% received etomidate. 99.7% of each group received neuromuscular blockade. The median age of the patients was 60 years, 46.7% had sepsis or septic shock, and 22.0% were receiving vasopressors.

Primary Outcome 

• In-hospital death by day 28 occurred in 330 of 1,173 patients (28.1%) in the ketamine group and in 345 of 1,186 patients (29.1%) in the etomidate group (risk difference adjusted for trial site, -0.8 percentage points; 95% CI -4.5 to 2.9; p=0.65)

Secondary Outcome

• Cardiovascular collapse during intubation occurred in 260 of 1,176 patients (22.1%) in the ketamine group and in 202 of 1,189 patients (17.0%) in the etomidate group (risk difference, 5.1 percentage points; 95% CI, 1.9 to 8.3)
  • This was primarily driven by the need for new or escalated vasopressors
  • Ventricular tachycardia was higher with ketamine (1.0% vs. 0.2%)
• Among the patients with sepsis or septic shock, cardiovascular collapse occurred in 30.6% of the patients in the ketamine group and 20.9% of those in the etomidate group
• Among the patients with a high severity of illness, cardiovascular collapse occurred in 31.4% of the patients in the ketamine group and 20.7% of those in the etomidate group

Limitations

• Trauma Excluded: Patients with a primary diagnosis of trauma were excluded, so these results cannot be generalized to the trauma bay
• This study was an unblinded design: Clinicians knew which drug they were giving, which could have influenced their threshold to start or increase vasopressors
• Findings do not rule out the possibility of small differences in outcomes in favor of either ketamine or etomidate
• This study did not investigate the effectiveness or safety of other induction medications, such as propofol or benzodiazepines
• The median ketamine dose was 1.6 mg/kg. Some critics maintain that a lower "shock dose" (0.5–1.0 mg/kg) might have mitigated the hemodynamic collapse seen in the ketamine arm.

Discussion

This trial is one of the largest RCTs to address the debate between RSI induction agents. Overall, there was no statistical difference for the primary outcome of in-hospital death by day 28 between the two agents. For the secondary composite outcome, there was a finding of increased cardiovascular collapse for the ketamine group when compared with the etomidate group. However, the details do warrant further discussion.

Both ketamine and etomidate were dosed by total body weight, despite a median BMI of 27, and over 25% of patients meeting obesity criteria. Because ketamine’s clearance tracks more closely with lean mass, total-body-weight dosing may result in comparatively larger doses in heavier patients.⁷ The median ketamine dose was 1.6 mg/kg, with approximately 25% receiving the full 2.0 mg/kg dose. This is much higher than the reduced "shock dose" (≤1.0 mg/kg) typically reserved for patients with decompensation. Under these conditions – and for sick septic patients – ketamine’s dose-dependent, direct negative inotropy may outweigh the sympathomimetic effects. Etomidate, by contrast, was given at a median of 0.28 mg/kg, essentially its full dose. Thus, the ketamine arm received a comparatively higher dose of sedation. The trial did not perform a dose-response analysis, so it remains unknown whether the results would have changed with a weight-adjusted, reduced ketamine dose.

Secondary outcomes were also potentially skewed by slight differences in baseline vasopressor use. The etomidate cohort entered induction with higher baseline vasopressor use (23.0% vs. 20.9%) and more pre-induction vasopressor escalations (19.7% vs. 17.6%). Because "new or increased vasopressors" defined cardiovascular collapse, pre-loaded etomidate patients were less likely to trigger this composite metric within the two-minute observation window. The unblinded design potentially compounds this bias; clinicians anticipating ketamine-induced hypotension may have reacted prematurely to transient blood pressure readings. Supporting a behavioral rather than purely physiologic explanation, median systolic pressure at induction was identical between groups (127 mm Hg), yet the ketamine arm recorded more vasopressor starts during the early observation period.

This reading of the data is further reinforced by looking at the composite outcome in detail. Profound hypotension (systolic pressure < 65 mm Hg) occurred in 6.4% of the ketamine group versus 5.5% for etomidate, and peri-intubation cardiac arrest occurred in 1.0% versus 0.8%, both nonsignificant differences. The 5.1-percentage-point difference in cardiovascular collapse was driven entirely by new or increased vasopressor use (21.3% vs. 15.9%). Ketamine did produce more transient hemodynamic dipping, including a lower median nadir systolic pressure (112 vs. 118 mm Hg) and more frequent drops exceeding 30 mm Hg (23.9% vs. 14.7%). However, this effect was transient. Vasopressor use at 24 hours was higher in the etomidate arm (42.3% vs. 38.9%), while organ-support-free days and 1-hour mortality were identical between groups. The data demonstrate a brief, self-limited pressure drop met with transient vasopressors, rather than sustained cardiovascular dependence. But noting again that etomidate is associated with higher baseline vasopressor use and a relatively lower dose. The increased incidence of ventricular tachycardia with ketamine (1.0% vs. 0.2%) is relevant but relies on small numbers from a post hoc analysis.

Ultimately, this trial reassures us that neither agent altered mortality. The long-standing fear that etomidate-induced adrenal suppression translates into excess death – even in sepsis – was not realized. The trial findings should temper ketamine’s reputation as the reflexive choice in shock. Ketamine clearly lowered blood pressure more in the first two minutes and did so most in septic and crashing patients, but this did not lead to worsened vasopressor dependence, organ-support days, or survival — and this could be partly explained by high total-body-weight dosing. Both agents remain reasonable first-line induction choices for the critically ill medical patient. If etomidate is chosen, its transient adrenal effect is not a reason to avoid it. If ketamine is chosen in a patient at risk of collapse, it would be prudent to consider dosing conservatively as weight-adjusted and towards a lower end (≤1 mg/kg in established shock) rather than a reflexive 2 mg/kg. These lower doses can then be redosed as appropriate. It would also be wise to have a vasopressor infusing or immediately at hand, exactly as one should optimize hemodynamics before any high-risk intubation. What this trial cannot answer is whether reduced-dose ketamine, a push-dose-pressor-first approach, or delayed-sequence techniques would erase the hemodynamic gap between these agents.

Clinical Take-Aways  

This trial did not show a mortality benefit for ketamine or etomidate for the induction of critically ill patients undergoing emergency tracheal intubation. However, it did show a statistically significant increase in cardiovascular collapse for the ketamine group. This conflicts with any previous assumptions that etomidate is an inferior induction agent. This study demonstrates that any degree of etomidate-induced corticosteroid insufficiency does not increase mortality or adverse events.

Overall, this trial supports the safe use of etomidate or ketamine in critically ill patients. Although ketamine showed increased cardiovascular complications, it is unclear whether these transient changes result in a change in patient-centered outcomes. Both agents remain a reasonable choice for RSI.

References

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4. Matchett G, Gasanova I, Riccio CA, et al. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med. 2022;48(1):78-91. doi:10.1007/s00134-021-06577-x
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