Ketamine or Etomidate for RSI? What the Largest U.S. Randomized Trial Really Found

Prepared by the LSE Editorial Team. Reviewed by Joseph Andrade, Jr., RN, NRP.

For years, ketamine has been treated as the induction drug that protects blood pressure while etomidate carries the baggage of adrenal suppression. A large randomized U.S. trial complicates that story.

🚑 The blood pressure was already marginal

The patient needs an airway.

They are hypoxic, tiring, and barely maintaining a systolic pressure in the 90s. The laryngoscope is ready. Suction is checked. The paralytic is drawn up.

Now comes the question airway teams have debated for years:

Ketamine or etomidate?

For many clinicians, the answer has felt almost automatic. Etomidate has a reputation for cardiovascular stability, but its well-known suppression of adrenal steroid synthesis has kept concern alive, especially in sepsis and shock. Ketamine, meanwhile, developed a reputation as the induction agent that could preserve or even support blood pressure through sympathetic stimulation.

That mental model made ketamine especially attractive in the sick patient whose circulation already looked fragile.

Then came the RSI Trial.

Published in the New England Journal of Medicine, the multicenter randomized trial compared ketamine with etomidate in 2,365 critically ill adults undergoing emergency tracheal intubation in U.S. emergency departments and intensive care units.

The primary question was straightforward: would ketamine reduce death by day 28 compared with etomidate?

It did not.

The secondary result was more surprising. Patients assigned to ketamine experienced more cardiovascular collapse around intubation.

That does not make ketamine a bad drug. It does mean the shortcut of “ketamine equals hemodynamic safety” deserves an update.

📊 What the trial actually studied

The RSI Trial was a pragmatic, multicenter, randomized study conducted at 14 sites across six U.S. medical centers, including six emergency departments and eight intensive care units.

• 1,176 patients were assigned to ketamine.
• 1,189 patients were assigned to etomidate.

The median age was about 60 years. Roughly 46.7% of patients had sepsis or septic shock, and about 22% were already receiving vasopressors before intubation.

The trial excluded several groups that matter when applying the findings to EMS. Patients with a primary diagnosis of trauma were excluded, as were patients whose need for intubation was so immediate that randomization could not occur. Clinicians also could exclude a patient when they believed one of the study drugs was necessary or contraindicated.

Almost every enrolled patient received neuromuscular blockade.

The median ketamine dose was about 1.6 mg/kg of actual body weight. The median etomidate dose was about 0.28 mg/kg.

⚖️ The main result: no survival advantage

The primary outcome was in-hospital death from any cause by day 28.

The adjusted absolute risk difference was -0.8 percentage points, with a 95% confidence interval from -4.5 to 2.9 percentage points. The P value was 0.65.

In plain language, the trial did not show that ketamine improved survival compared with etomidate.

That matters because much of the long-running debate has centered on whether etomidate’s adrenal suppression could translate into worse outcomes. In this trial, choosing ketamine did not produce a statistically significant mortality benefit.

It also does not prove the two drugs are identical in every patient or that a very small mortality difference is impossible. The confidence interval still allows for the possibility of a modest advantage in either direction.

❤️ The surprise was in the two minutes around the tube

The secondary outcome was cardiovascular collapse during intubation.

Researchers counted the outcome if, between induction and two minutes after tracheal intubation, the patient experienced any of the following:

• systolic blood pressure below 65 mm Hg,
• a new or increased dose of vasopressors,
• or cardiac arrest.

Cardiovascular collapse occurred in:

• 22.1% of patients receiving ketamine
• 17.0% of patients receiving etomidate

That is an absolute difference of 5.1 percentage points.

The composite difference was driven largely by new or increased vasopressor use, but the exploratory blood-pressure data pointed in the same direction: patients receiving ketamine had a lower median nadir systolic blood pressure and more episodes of substantial blood-pressure decline.

🧠 Why would ketamine lower blood pressure?

Ketamine often increases heart rate and blood pressure because of its sympathomimetic effects. That effect is real, but it is not unlimited.

Critically ill patients may already be operating under intense endogenous catecholamine stimulation. In severe shock, the ability to generate an additional sympathetic response may be limited.

Ketamine also has direct myocardial depressant and vasodilatory effects. Those effects can become more visible when the patient’s catecholamine reserve is exhausted.

The more useful model for training is therefore not “ketamine raises blood pressure.” It is: the patient’s physiology determines how much sympathetic reserve is available to offset ketamine’s direct cardiovascular effects.

🦠 The sepsis signal deserves attention, but not overstatement

The cardiovascular-collapse difference was larger in some of the sickest subgroups.

Among patients with sepsis or septic shock:

• ketamine: 30.6%
• etomidate: 20.9%

Among patients with an APACHE II score of 20 or greater:

• ketamine: 31.4%
• etomidate: 20.7%

Those differences are clinically interesting. They should still be interpreted cautiously. Subgroup analyses are less secure than the primary randomized comparison, especially when multiple subgroup comparisons are examined.

The responsible teaching point is not “never use ketamine in sepsis.” It is: do not assume ketamine protects the circulation in severe sepsis or high-acuity shock.

🧪 What about etomidate and adrenal suppression?

Etomidate suppresses adrenal steroid synthesis by inhibiting 11-beta-hydroxylase. That pharmacologic effect is real.

The clinical argument has always been about what that biochemical effect means for outcomes. Does one induction dose increase mortality? Does it worsen shock? Should clinicians avoid it in sepsis?

For years, observational studies and smaller trials produced mixed answers.

The 2023 Society of Critical Care Medicine RSI guideline concluded that available evidence did not show a mortality or peri-intubation hemodynamic advantage of one induction agent over another strong enough to prefer ketamine or etomidate across all critically ill adults. The guideline also suggested against administering corticosteroids solely to counteract etomidate-induced adrenal suppression.

The RSI Trial adds substantially stronger randomized evidence to that conversation. It still found no survival penalty for etomidate compared with ketamine.

That does not erase adrenal suppression. It does change how confidently clinicians should assume that the biochemical effect translates into worse survival.

🚨 Does this mean etomidate is now the better RSI drug?

No single trial creates a universal induction agent.

Ketamine and etomidate have different properties. Ketamine may still be useful in situations involving severe bronchospasm, analgesic needs, some agitation scenarios, delayed-sequence intubation strategies, or other cases where its dissociative and analgesic effects are valuable.

Etomidate may offer more predictable immediate hemodynamics in some severely unstable patients.

The best drug still depends on the reason for intubation, shock state, cardiac function, catecholamine reserve, bronchospasm, neurologic concerns, protocol options, clinician familiarity, dosing strategy, and the team’s peri-intubation resuscitation plan.

The new data makes drug selection more nuanced, not less.

🚑 What does this mean for EMS?

This is where restraint matters.

The RSI Trial was not a prehospital trial. It took place in emergency departments and ICUs.

Prehospital RSI has different realities:

• transport time,
• different monitoring environments,
• variable vasopressor availability,
• different clinician exposure,
• different patient mixes,
• trauma systems,
• limited backup,
• and different post-intubation resources.

Trauma patients were excluded from the trial, which is especially important for EMS systems that use RSI frequently in trauma.

The useful EMS interpretation is therefore not “switch every ketamine RSI to etomidate.”

Stop treating ketamine as physiologically protective by default.

That is also consistent with how NAEMSP has translated the trial for prehospital clinicians: the study does not create a universal winner, but it should temper the reflexive idea that ketamine is automatically the safer choice in shock.

🩸 The bigger lesson is still “resuscitate before you intubate”

This trial fits directly with a principle LSE has emphasized in its existing airway content.

A technically successful tube can still be a physiologically dangerous intubation.

Before RSI, the team should know:

• What is the blood pressure trend?
• Is the patient in shock?
• Is the patient already on vasopressors?
• Does the patient need blood, fluid, or another resuscitative intervention first?
• What happens to venous return when positive-pressure ventilation begins?
• What is the plan if pressure falls after induction?
• Are vasopressors immediately available when indicated?
• Is oxygenation optimized?
• Who is watching the monitor while the airway operator is looking at the cords?

If a patient has a systolic pressure of 78 mm Hg before induction, the important question is not only whether ketamine or etomidate is drawn up. The more important question is whether the team is ready for what happens after the drug is pushed.

💉 Dose matters too

The RSI Trial allowed clinicians to choose full, intermediate, or reduced doses based on the patient’s condition.

The typical administered doses landed near commonly used full-strength ranges. That matters because clinicians sometimes discuss induction drugs as though the only decision is the medication name.

It is not.

A severely shocked patient receiving a large induction dose may respond differently from a stable patient receiving the same agent.

Protocol-driven dosing still has to allow clinicians to recognize fragile physiology within the limits of local policy and medical direction.

This trial should prompt educators to teach:

drug + dose + physiology + preparation

rather than simply “drug A versus drug B.”

⚡ Put the pressor plan on the airway checklist

One practical change after this study is simple: if an agency performs RSI, the airway checklist should force the team to address hemodynamics before induction.

Not after the pressure crashes.

That does not mean every patient needs prophylactic vasopressors. It means the team should not be surprised by a complication common enough to anticipate.

🫁 The tube is still only one part of the procedure

The trial should not cause airway education to become a pharmacology contest.

The core risks remain broader:

• hypoxemia,
• hypotension,
• apnea,
• failed laryngoscopy,
• aspiration,
• dysrhythmia,
• cardiac arrest,
• poor post-intubation ventilation,
• inadequate analgesia or sedation,
• and failure to recognize the physiologically difficult airway.

LSE already addresses this in The Tube Was Successful, but Was the Intubation Safe?

The ketamine-versus-etomidate trial strengthens that message. A medication choice can influence risk. It cannot make a badly prepared intubation safe.

🎓 What instructors should change

This trial is ideal for scenario-based education.

Instead of asking, “What drug do you use for RSI?”, give learners a patient:

That teaches clinical reasoning. A multiple-choice question asking whether ketamine or etomidate is “better” does not.

📚 What the trial does not prove

The study does not prove:

• that ketamine is unsafe,
• that etomidate should always be preferred,
• that ketamine increases mortality,
• that etomidate’s adrenal suppression is irrelevant,
• that the result applies unchanged to trauma,
• that it applies directly to every EMS system,
• or that existing protocols should be changed without medical-direction review.

The best interpretation is narrower and more useful:

Ketamine did not improve 28-day survival and was associated with more peri-intubation cardiovascular collapse in this large hospital-based randomized trial.

❓ Frequently Asked Questions

Did ketamine reduce mortality compared with etomidate?

No statistically significant mortality difference was found. In-hospital death by day 28 occurred in 28.1% of patients assigned to ketamine and 29.1% assigned to etomidate.

Which drug caused more cardiovascular collapse?

Ketamine was associated with more cardiovascular collapse during the peri-intubation period: 22.1% versus 17.0%.

Does that mean ketamine should no longer be used for RSI?

No. The trial does not support that conclusion. Ketamine remains a useful induction agent, but clinicians should not assume it is automatically protective against hypotension in critically ill patients.

What about sepsis?

The trial found a larger cardiovascular-collapse difference in the sepsis/septic-shock subgroup, favoring etomidate. This is an important signal, but subgroup analyses should not be treated as a definitive universal rule.

Does etomidate still suppress adrenal function?

Yes. Etomidate’s adrenal steroid suppression remains a known pharmacologic effect. The important finding here is that ketamine did not produce a significant survival advantage over etomidate despite that concern.

Should EMS protocols change because of this trial?

Not automatically. The study was hospital-based and excluded some populations commonly encountered in EMS. Agencies should review the evidence with medical direction and consider it alongside prehospital-specific data, local protocols, patient population, and operational capability.

🔗 Continue Learning with LSE

• The Tube Was Successful, but Was the Intubation Safe?
• What If Your Airway Expert Could See What You See?
• LSE Professional Development & Continuing Education

📚 Sources and Further Reading

1. Casey JD, Seitz KP, Driver BE, et al. Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults. New England Journal of Medicine. 2026;394:1608-1620. https://doi.org/10.1056/NEJMoa2511420
2. PubMed PMID 41369227. https://pubmed.ncbi.nlm.nih.gov/41369227/
3. Society of Critical Care Medicine. Guidelines for Rapid Sequence Intubation in the Critically Ill Adult Patient. SCCM RSI guideline
4. American College of Emergency Physicians Critical Care Medicine Section. CCA: Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults. ACEP Critical Care review

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