Ketamine vs. etomidate in EMS airway management

editor’s Note: This article originally appeared in National Association of EMS Physicians Blog and is reprinted here with permission.

By Michael DeFilippo, DO Assistant Professor of EM and EMS – Washington University in St. Louis School of Medicine

EditorS: Aaron Lacey, MD Assistant Professor of EM – Washington University in St. Louis School of Medicine; Sara E. Fabiano, MD, FACEP, FAAEM, FAEMS Clinical Associate Professor, Department of Emergency Medicine, Prisma Health-Upstate University of South Carolina School of Medicine Greenville

background. Over the years, ketamine has been widely adopted as a “hemodynamically safe” induction agent in EMS. Many of us learned it as the drug of choice for the borderline hypotensive patient; Something that supports catecholamines, preserves blood pressure and keeps people stable during one of the most physically stressful procedures we do.

| More: Understanding Prehospital Ketamine: Dosing for Deficiencies

A new multicenter trialThe RSI test challenges that assumption. The results are not against ketamine; Instead, they give us a clearer and more realistic picture of how ketamine behaves in the sickest patients we intubate. In summary: Ketamine is still an excellent RSI drug, but it is not as neutral towards blood pressure as we previously believed.

Let’s look at what the data actually shows and how it translates into EMS practice.

RSI test in brief

The investigators enrolled 2365 critically ill adults undergoing ED or ICU intubation. Patients were randomized to receive ketamine or etomidate as induction agent. About half the patients had sepsis or septic shock, and about one-fifth were already on vasopressors before intubation. Patients were excluded if they were cases of trauma, were in cardiac arrest at the time of intubation, were undergoing intubation without paralysis or were already in deep anesthesia.

Mortality at 28 days was essentially similar between the groups: ketamine: 28.1% versus etomidate: 29.1%. Even in the larger subgroup with sepsis and septic shock, mortality rates remained almost similar (ketamine 38.8% vs etomidate 38.2%).

However, the shorter peri-intubation period tells a different story.

Researchers tracked a composite called cardiovascular collapse from induction to 2 minutes after tube placement. These included systolic pressure less than 65 mmHg, need for new or higher vasopressors, or cardiac arrest.

Cardiovascular collapse occurred more frequently with etomidate (17.0%) than with ketamine (22.1%). This difference was largely driven by the more pronounced blood pressure drops in the ketamine group. Patients receiving ketamine had lower nadir systolic pressure, more episodes of systolic pressure below 80 mmHg, greater 30 mmHg decline in systolic pressure, higher rates of vasopressor increase, and more ventricular tachycardia.

Its effect was most pronounced in the sickest patients, particularly those with septic shock and very high Apache II scores:

• Sepsis and Septic Shock
  • Ketamine: 30.6%
  • Etomidate: 20.9%
  • Absolute difference: 9.7 percentage points
• Apache II ≥ 20
  • Ketamine: 31.4%
  • Etomidate: 20.7%
  • Absolute difference: 10.7 percentage points

This does not mean that ketamine is unsafe; Rather, it means that ketamine produces more acute hemodynamic instability than many of us would expect, especially when patients are already catecholamine deficient. These short-term hemodynamic fluctuations matter because induction in critical disease is one of the most vulnerable 2-minute windows, and small perturbations can accelerate downstream decline.

Despite higher rates of early hemodynamic events with ketamine, there were no meaningful differences between groups in first-pass success, hypoxemia, ICU-free days, ventilator-free days, or vasopressor-free days. In other words, the additional peri-intubation hypotension associated with ketamine did not translate into worse long-term organ support requirements or mortality.

Understanding the Nuances Behind the Numbers

The trial was large and open-label, and the cardiovascular collapse outcome includes elements that could theoretically be influenced by physician behavior. For example, if a physician expects ketamine to lower blood pressure, they may have already increased the pressure during the intubation preparation phase. However, this concern must be kept in perspective. Less than 1% of patients (~14 of 2,400) did not receive their assigned induction agent, suggesting that the true randomization was largely preserved. Furthermore, supplemental analyzes showed no significant differences between groups in vasopressor use before intubation, within 1 hour of intubation, or in prophylactic vasopressor administration. Overall, while the open-label design introduces some nuances, it is unlikely that physician behavior meaningfully biases the hemodynamic findings.

The study showed that the mortality rate was 1% higher with etomidate (29.1% vs. 28.1%). The challenge is that such small differences cannot be meaningfully interpreted by a trial of this size. The authors conducted extensive sensitivity analyses, and in a high-quality, multicenter trial with careful patient matching and standardized, weight-based dosing, caution should be exercised when interpreting non-statistically significant differences. In critical care, even a 1% change in mortality may matter, but detecting or refuting a subtle signal would require a huge study that is unlikely to ever be done. As a result, while mortality appears to be similar overall, the trial cannot definitively exclude a small but clinically meaningful difference between the agents. For additional context and a more in-depth look at the methodology and interpretation of the test, Dr. Farkas’ PulmCrit blog post Worth reading.

The most important message for EMS physicians is not that one medication is right and another is wrong. It’s that ketamine is not the “BP safe” drug many of us believed it to be. This is excellent; But it’s not magical.

Clinical implications for EMS RSI

Etomidate may provide more predictable hemodynamics in the following situations:

• deep septic shock
• high vasopressor requirement or pronounced catecholamine exhaustion
• cardiogenic shock or severe pump failure
• Known ventricular arrhythmia risk
• significant RV failure or pulmonary hypertension

In these scenarios, the combination of ketamine’s negative inotropy under catecholamine-depleted conditions and the small but significant increase in ventricular tachycardia observed in the trial should ameliorate this.

That being said, ketamine is still the drug of choice in many EMS scenarios:

• Severe asthma or COPD where preservation of respiratory drive is necessary before apnea
• status epilepticus
• Patients with severe pain or multiple trauma requiring Analgesia Plus sedation is ideal
• Delayed sequence intubation is important while maintaining respiratory drive.
• Most “routine” medical intubations that involve mild or moderate shock, but not profound circulatory collapse,

preparation matters most

The most important adjustment for EMS RSI is not the choice of drug; This is preparation around intubation. The lawsuit does not argue against ketamine; It simply cures our overconfidence. Be prepared for a possible drop in blood pressure and treat ketamine like any other induction agent that may highlight underlying instability. Regardless of whether ketamine or etomidate is used:

• Resuscitate before intubation
• to pass push-dose presser ready and willing
• Start or increase vasopressors early if indicated
• Minimize peri-intubation pauses and optimize oxygenation
• Recognize delicate physiology early and actively support it

Ketamine remains a powerful and versatile tool in the EMS airway kit; It simply requires the same respect that we give to all induction agents. The RSI test reminds us that airway management is fundamentally a physiological phenomenon, not just a technical phenomenon. Drug selection is important, but the real determinants of safety are preparation, resuscitation, and fear of instability.

When EMS physicians approach RSIs with that mindset, both ketamine and etomidate can be used safely and effectively in the field. It is also worth noting that ketamine may provide additional benefits beyond hemodynamics; emerging data There are suggestions that it may reduce the patient’s awareness during paralysis and potentially reduce post-intubation psychological distress, although these findings are inconclusive and are the subject of ongoing investigation.

key takeaways

• Ketamine and etomidate have similar mortality outcomes for critically ill patients.
• Ketamine causes greater peri-intubation hypotension, pressure escalation, and ventricular tachycardia.
  • These effects are strongest in patients with septic shock and very high severity.
• Etomidate may be preferable in severe septic shock, cardiogenic shock, or significant ventricular dysfunction.
• Ketamine remains excellent for preserving respiratory drive during unconsciousness, seizures, induced hypoxia, trauma, and moderate illness.
• The most important determinant of safe RSI is not the medication; This is preparation, resuscitation and hemodynamic preparation.

| Watch: Understanding Prehospital Ketamine