REBEL Cast Ep120: Etomidate vs Ketamine for RSI in the ED?

Background: Standard rapid sequence intubation (RSI) in the emergency department involves administration of an induction agent and a neuroblocking agent in quick succession.  RSI inherently carries with it risks of complications such as post-intubation hypotension and cardiac arrest in the most extreme cases.  It is possible that the induction agent used could play an important role on hemodynamic effects in critically ill adults.

REBEL Cast Ep120:  Etomidate vs Ketamine for RSI in the ED?

Paper: Knack SKS et al. The Effect of Ketamine Versus Etomidate for Rapid Sequence Intubation on Maximum SOFA Score: A Randomized Clinical Trial. JEM 2023. PMID:

Clinical Question: Does a single dose of ketamine or etomidate used for rapid sequence intubation (RSI) of critically adults in the ED impact the SOFA score within 3 days of hospitalization?

What They Did:

• Single-center, randomized parallel-group trial
• Comparing ketamine vs etomidate for RSI in critically ill ED adult patients
• Performed under exception from informed consent (EFIC)
• Patients randomized 1:1
  • Ketamine 2mg/kg IV
  • Etomidate 0.3mg/kg IV

Outcomes:

• Primary: Maximum SOFA score within 3 days of hospitalization
• Key Secondary:
  • Post intubation hypotension
  • 30d mortality
  • First attempt successful intubation

Inclusion:

• Adult patients (≥18 years of age)
• Undergoing RSI

Exclusion:

• Conditions in which elevated HR or BP could be hazardous (i.e. Aneurysmal SAH, HTN emergency)
• Known or suspected to have increased ICP
• Known contraindication or allergy to ketamine or etomidate
• Wearing a bracelet with the words “KvE declined”
• Prisoners or under arrest
• Female patients of childbearing age (18 to 50 years of age) without a negative pregnancy test during encounter

Results:

• 143 patients enrolled in the trial
  • Two most common indications for intubation: Trauma (20%) and overdose (20%)
  • Most common neuromuscular blocking agent: succinylcholine in 91% of intubations
  • Most common laryngoscope used was Macintosh VL in 91% of intubations
  • 20% of patients had a suspicion for sepsis
  • Received assigned induction agent
    • 96% of patients in the ketamine group received ketamine for RSI (Median dose 2mg/kg)
    • 97% of patients in the etomidate group received etomidate for RSI (Median dose 0.27mg/kg)
  • >99% of patients received preoxygenation before intubation
  • Median SpO2 before intubation was 100% (Range 97 to 100%)
  • Macintosh VL was used for 94% of patients in the ketamine group and 88% in the etomidate group
• Maximum SOFA Score
  • Ketamine: 6.5 (Range 5 to 9)
  • Etomidate: 7.0 (Range 5 to 9)
  • Diff -0.2; 95% CI -1.4 to 1.1; p = 0.79
• First Pass Success
  • Ketamine: 94%
  • Etomidate: 89%
  • Diff 5%; 95% CI -4 to 13%
• Post-Intubation Hypotension in ED:
  • Ketamine: 28%
  • Etomidate: 26%
  • Diff 2%; 95% CI -13 to 17%
• 30d Mortality
  • Ketamine: 11%
  • Etomidate: 21%
  • Not Statistically Significant
• No difference in vasopressor-free days, ventilator-free days, orICU-free days

 Strengths:

• Asks a clinically important question.
• Sound methodology with excellent randomization
• ICU team blinded to group assignment
• 10% of enrolled patients had a second reviewer abstract SOFA scores for interobserver agreement (Agreement for maximum SOFA score was 87% with a kappa value of 0.85, indicating excellent agreement)
• Used an intention-to-treat analysis which included all patients in the group they were assigned to, regardless of medication received which better mimics what happens in the real world

Limitations:

• ED team was aware of group assignment which may affect post-intubation care in the ED and alter outcomes
• Many potential confounders, such as patient positioning, preoxygenation strategy, choice of neuromuscular blocking agent, choice of intubation devices, and post-intubation sedation were at the discretion of the ED team all of which could cause confounding imbalances between groups
• Subsequent ICU care was also left to the discretion of the treating team which could cause confounding imbalances between groups
• Primary outcome not a patient-centered one (Maximum SOFA Score at 3d)
• Single-center study that was partially blinded which can affect generalizability of results
• Study underpowered to detect small differences between groups in the secondary/exploratory outcomes
• There were 38 eligible patients not enrolled in this study with the most common reason being physician decision making this a convenience sample
• There were some baseline differences between groups which could bias the results of this trial

Discussion:

• For the first 103 patients enrolled the primary outcome of the study was mortality at hospital discharge or at 30 days, however this was changed to the maximum median SOFA score by 3 days after hospitalization as a surrogate of mortality
• This study took all comers needing intubation (this will dilute the chance of finding a difference). A better way would have been to enroll patients at higher risk for harm from cardiovascular collapse to better delineate between these two agents
• The authors should be commended as they went to extraordinary lengths to make sure this trial was ethical (i.e. Got FDA exemption as well as went to the community and made sure their community was ok with the trial). This should be the way to go about doing an RCT where you can’t get consent at the point of contact
• Why I am not surprised by the results of this trial
  • Over ½ of the patients included in the trial were intubated for airway protection not due to hemodynamic/physiologic derangements
    • Median systolic blood pressure prior to intubation in this trial was 140mmHg
      • Only 10% of patients were anticipated to have clinical deterioration
    • Median oxygen saturation at induction was 100% in both groups
      • Only 7% of patients intubated for hypoxia
      • Only 22% of patients intubated for respiratory failure
    • SOFA score ranges from 0 to 24 (The higher the score the higher the mortality)
      • A score of 0 to 6 is associated with a <10% mortality
      • A score of 7 to 9 is associated with a 15 to 20% mortality
      • The median maximum SOFA Score in this trial was 6.5 and 7
    • Although people like to debate this fact, in hemodynamically tenuous patients the agent used is less important than…
      • The resuscitation that occurs prior to intubation (Resuscitation Sequence Intubation)
      • The dose of the induction agent used until appropriate sedation is required (Delayed Sequence Intubation)
    • I think the authors overstep here a bit by stating ketamine or etomidate don’t affect the incidence of post-intubation hypotension
      • This is a secondary outcome which is great for discussion or hypothesis generation, but the trial is not powered for this outcome

Author Conclusion: “There were no significant differences in maximum SOFA score or post-intubation hypotension between critically ill adults receiving ketamine versus etomidate for RSI.”

Clinical Take Home Point: When the majority of your intubations are done on a group of patients for airway protection (low GCS), who really don’t have physiologic/hemodynamic derangements prior to intubation it probably doesn’t matter which agent (ketamine or etomidate) you use for intubation as a one-time dose would have almost no effect on mortality or in this case 3 day maximum SOFA score.

References:

1. Knack SKS et al. The Effect of Ketamine Versus Etomidate for Rapid Sequence Intubation on Maximum SOFA Score: A Randomized Clinical Trial. JEM 2023. PMID:

For More Thoughts on This Topic Checkout:

• REBEL EM: Etomidate Vs. Ketamine – A Systematic Review and Meta-Analysis

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)