For years, emergency and critical care clinicians have debated which induction agent is best for hemodynamically unstable intubations, especially in sepsis.

Two big beliefs have dominated:

1. Etomidate
   • Pros: Hemodynamically stable
   • Cons: Adrenal suppression → might worsen sepsis outcomes
2. Ketamine
   • Pros: Preserves blood pressure (supposedly), offers analgesia, bronchodilation
   • Cons: Theoretical concern for myocardial depression in catecholamine-depleted patients

A recent NEJM trial comparing ketamine and etomidate for emergency intubation in critically ill adults gives us the best data we’ve ever had to answer a simple question:

If you pick ketamine instead of etomidate for RSI in sick ED/ICU patients, do your patients actually do better?

Short answer: No.
But the details are important, and they should change how we think about both drugs.

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Study in a Nutshell

Design

• Multicenter, pragmatic randomized trial in 14 EDs/ICUs.
• Adults ≥18 undergoing non-trauma emergency intubation.
• Randomized to:
  • Ketamine (clinician-chosen dose 1.0–2.0 mg/kg; median ~1.6 mg/kg)
  • Etomidate (0.2–0.3 mg/kg; median ~0.28 mg/kg)
• Almost everyone also received a paralytic.

Population

• 2,365 patients analyzed
• ~56% intubated in the ED, ~44% in the ICU
• ~47% had sepsis or septic shock
• ~22% were already on vasopressors
• The median APACHE II score was about 18, showing these were very sick patients, not elective OR cases.

Outcomes

• Primary: In-hospital death by day 28
• Key secondary: “Cardiovascular collapse” between induction and 2 minutes after intubation
  (SBP <65, new/increased vasopressor, or cardiac arrest)
• Exploratory: nadir SBP, SBP <80, drop >30 mmHg, ventilator/vasopressor/ICU-free days, VT.

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Main Results

1. Mortality: No Difference

• Ketamine: 28.1% in-hospital death by day 28
• Etomidate: 29.1%
• The adjusted risk difference was about −0.8%, with a 95% confidence interval from −4.5 to +2.9, showing no significant difference.

This held true across subgroups, including:

• Sepsis/septic shock
• Patients on vasopressors
• Higher APACHE II scores

Takeaway:
Using ketamine instead of etomidate did not reduce mortality, even in septic or very sick patients.

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2. Hemodynamics: Ketamine Was Less Stable

This is where the trial gets interesting.

Cardiovascular collapse (composite outcome):

• Ketamine: 22.1%
• Etomidate: 17.0%
• Absolute difference: +5.1%

In the sicker groups, the difference was more striking:

• Sepsis / septic shock:
  • 30.6% (ketamine) vs 20.9% (etomidate)
  • ≈10% absolute increase in “collapse” with ketamine
• APACHE II ≥20:
  • 31.4% vs 20.7%
  • Again ≈11% absolute increase with ketamine

Other hemodynamic measures told the same story:

• Lower median nadir SBP with ketamine
• More patients with SBP <80 mmHg
• More patients with a drop in SBP >30 mmHg
• More vasopressor escalation
• More VT (1.0% vs 0.2%, post-hoc)

Yet: ventilator-free days, vasopressor-free days, and ICU-free days were similar.

Takeaway:
In this real-world group, ketamine caused more peri-intubation hypotension and collapse than etomidate, especially in septic and very sick patients, but this did not lead to a detectable difference in mortality in this trial.

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Physiology: Why Would Ketamine Look Worse in Shock?

This trial actually matches what we already know about ketamine’s cardiovascular physiology.

Ketamine Has Two Opposing Effects

1. Indirect sympathetic stimulation
   • Inhibits catecholamine reuptake
   • Increases circulating norepinephrine/epinephrine
   • This leads to increased heart rate, blood pressure, and cardiac output.
   • This is what we see in young, catecholamine-replete trauma patients or short illness.
2. Direct myocardial depression + vasodilation
   • Negative inotropic effect on the heart
   • Vasodilation at higher doses
   • In catecholamine-depleted states such as septic shock, prolonged critical illness, chronic shock, or high APACHE scores, the sympathetic boost is reduced:
     • Catecholamine stores are low
     • Receptors are downregulated/desensitized

When catecholamine stores are low and receptors are less responsive, the direct depressant and vasodilatory effects become stronger, causing blood pressure to drop.

Etomidate’s Profile

• Mainly GABA-ergic hypnotic
• Minimal intrinsic myocardial depression
• Minimal effect on SVR (at induction doses)
• So in patients with sepsis or low catecholamine levels, etomidate is more likely to maintain blood pressure during RSI.

That is exactly what the trial shows. In the sickest patients, using full-dose ketamine for induction led to more hemodynamic collapse than etomidate.

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What About Adrenal Suppression and Etomidate?

Etomidate does inhibit 11β-hydroxylase and blunts the cortisol response for 12–24+ hours.

This is not controversial.

The controversial part has always been:

Does that hormonal effect actually worsen outcomes?

In this large trial:

• Etomidate showed no increase in 28-day mortality
• No increase in ICU-free, ventilator-free, or vasopressor-free days
• No clear signal of worse clinical outcomes compared with ketamine

So what can we say honestly?

• Yes, a single dose of etomidate causes biochemical adrenal suppression.
• No, this study did not find that this suppression produced a measurable mortality penalty.

It doesn’t prove “etomidate is completely harmless,” but it does weaken the argument that “we must avoid etomidate in sepsis because it kills people.”

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Important Caveat: Dosing Matters

Median ketamine dose: ~1.6 mg/kg
Median etomidate dose: ~0.28 mg/kg

These are full induction doses, which are appropriate for healthy or mildly ill patients but are often too high for patients in true shock.

Many experienced clinicians already do this intuitively:

• Etomidate
  • Standard: 0.3 mg/kg
  • In shock: often 0.2–0.3 mg/kg
• Ketamine
  • Standard: 1–2 mg/kg
  • In shock: often 0.5–1.0 mg/kg, combined with vasopressors

This trial tells us what happens when you give full-dose ketamine to very sick, often catecholamine-depleted patients:

More hypotension and cardiovascular collapse than with etomidate.

What the study does not tell us is whether a low-dose ketamine strategy in shock would have different results, because that was not tested.

So we should not apply the conclusions to doses that were not actually used in the study.

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How Should This Change Our ED Practice?

1. Retire the Dogma “Never Etomidate in Sepsis”

The trial provides strong evidence that:

• A single induction dose of etomidate in sepsis does not increase 28-day mortality.
• Adrenal suppression is real but did not manifest as worse survival or longer organ support in this study.

So “etomidate is contraindicated in sepsis” is no longer defensible.

Using etomidate in septic shock is supported by evidence, especially when you are most concerned about peri-intubation hypotension.

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2. Ketamine may not be “Hemodynamically Safe” in Shock

Ketamine is not universally hemodynamically protective.

• In catecholamine-replete trauma/asthma patients:
  • Ketamine often supports BP and is an excellent choice.
• In septic shock / high APACHE / prolonged critical illness, at standard induction doses:
  • Ketamine increased rates of cardiovascular collapse compared with etomidate.

WeWe should not stop using ketamine, but we should avoid teaching that it is always the best agent for blood pressure stability in all shock cases.

3. Adjust Your Dosing Strategy: “Shock Dose” vs “Textbook Dose”

For hemodynamically unstable patients, a reasonable approach is:

• Etomidate
  • 0.2–0.3 mg/kg (not routinely higher)
• Ketamine
  • Use 0.5 to 1.0 mg/kg in shock, not 1.5 to 2 mg/kg.

And pair any induction agent with:

• Started or ready vasopressor (e.g., norepinephrine)
• Push-dose pressor available
• Some resuscitation done before RSI, if time allows

The trial suggests that drug choice and dose both matter, but standard full-dose ketamine in septic shock is likely too much.

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4. Individualize the Agent to the Patient

Where etomidate may be preferable:

• Septic or vasodilatory shock
• Very high risk of peri-intubation hypotension
• Poor LV function or significant cardiac disease
• Concern that even a transient BP drop may be catastrophic

Where ketamine remains extremely valuable:

• Severe asthma/COPD with bronchospasm
• Delayed sequence intubation (DSI) or awake techniques
• Hyperactive delirium/agitated patients needing control while preserving respiratory drive
• Young trauma patients or catecholamine-replete states (with appropriate dosing)

In many real-world cases, either drug is acceptable. However, this trial suggests choosing etomidate when hemodynamics are the main concern, and ketamine when airway, bronchospasm, or behavior are the main issues.

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Practical Take-Home Messages

For the ED and ICU resuscitation bay:

1. Etomidate in sepsis is not “forbidden”
   A single RSI dose did not increase mortality in this large trial.
2. Ketamine is not automatically safer in shock
   At full doses in sick, often catecholamine-depleted patients, ketamine caused more cardiovascular collapse than etomidate.
3. Use “shock doses,” not “textbook doses”
   Reduce your induction dose and increase your preparation for managing blood pressure.
4. Let physiology guide your choice
   • Need bronchodilation / awake control / agitation management → ketamine
   • Need maximal hemodynamic stability in septic shock → etomidate is a very reasonable first choice.
5. No new dogma, just better nuance
   This trial doesn’t crown a winner.
   It simply tells us that:
   • Mortality is similar between ketamine and etomidate.
   • Etomidate is more hemodynamically stable in very sick patients.
   • Ketamine’s benefits depend heavily on the patient’s physiologic state and dose.