Choosing an induction agent starts with the patient’s physiology: perfusion, ventricular reserve, oxygenation, and the consequences of apnea. A reassuring drug reputation cannot replace preparation for deterioration.
Study in a Nutshell
The RSI trial (online December 2025; print April 2026) randomized 2,365 critically ill adults in 14 US EDs/ICUs to ketamine or etomidate. ED trauma presentations were excluded.
Main Results
Primary outcome: in-hospital mortality by day 28 was 28.1% versus 29.1%; adjusted difference −0.8 percentage points (95% CI −4.5 to 2.9). The secondary cardiovascular-collapse outcome occurred in 22.1% versus 17.0%; difference 5.1 points (95% CI 1.9–8.3), ketamine first throughout. Collapse meant systolic pressure below 65 mmHg, new/increased vasopressors, or cardiac arrest, from induction through two minutes after intubation.
No statistically significant mortality difference was detected; equivalence was not established. The unblinded composite includes treatment decisions; it is not an arrest rate. Subgroups cannot establish a universally preferred drug or mechanism. Etomidate is a reasonable option when peri-intubation hypotension is the main concern. RSI trial.
Physiology: Why Would Ketamine Look Worse in Shock?
Ketamine often raises blood pressure and heart rate, but hypotension, arrhythmias, and cardiac decompensation are also reported. Suspected catecholamine depletion is a relevant caution. Sepsis and a high illness-severity score do not directly measure catecholamine stores, so avoid assigning that mechanism to an individual patient from the diagnosis alone. Ketamine prescribing information.
Physiologically, blood pressure depends on both cardiac output and vascular tone. During airway management, loss of compensatory sympathetic activity and the transition to positive-pressure ventilation can threaten an already fragile circulation. A pressure fall should prompt reassessment of preload, ventricular function, vascular tone, and ventilation rather than an automatic assumption that more fluid is needed.
What About Adrenal Suppression and Etomidate?
Etomidate inhibits adrenal steroid synthesis. Its prescribing information describes reduced cortisol and aldosterone for approximately 6–8 hours after induction. That interval is not a guaranteed recovery time in critical illness. Etomidate prescribing information.
A small prospective study in critically ill patients without sepsis found adrenal inhibition persisting beyond that interval in some patients. Biochemical suppression and patient-important harm are different questions; a laboratory effect alone does not establish a survival penalty. Adrenal inhibition study.
The 2023 SCCM RSI guideline suggests against giving corticosteroids solely to counter etomidate-induced adrenal suppression. An independent indication for corticosteroids requires its own assessment. SCCM RSI guidance (2023).
Important Caveat: Dosing Matters
The protocol allowed clinicians to adjust doses. Drug assignment was randomized; reduced-dose versus standard-dose ketamine was not. The study cannot identify an optimal shock dose. Trial protocol.
Individualize induction under the local airway protocol while ensuring adequate hypnosis when neuromuscular blockade is used. Fear of hypotension should not leave an aware patient paralyzed. SCCM RSI guidance (2023).
How Should This Change Our ED Practice?
Before induction, agree on the blood-pressure rescue plan, ensure reliable drug delivery, and reassess perfusion. Choose fluids or vasoactive support according to the cause of instability and the patient’s response. Preparation remains necessary with either drug.
Check contraindications rather than relying on a broad “safe in shock” label. Ketamine is contraindicated when a substantial blood-pressure rise would pose a serious hazard, and with known hypersensitivity. Its use does not guarantee spontaneous ventilation: respiratory depression, apnea, airway obstruction, and laryngospasm can occur. Ketamine prescribing information.
Etomidate is contraindicated with hypersensitivity. It provides hypnosis without analgesia, and the reviewed formulation is not intended for prolonged infusion. Sepsis alone is not a listed contraindication. Etomidate prescribing information.
Prepare post-intubation analgesia and sedation before the procedure and continue appropriate monitoring during paralysis. A single induction bolus is not a maintenance plan. SCCM neuromuscular-blockade guidance.
Practical Take-Home Messages
For the unstable patient, select an agent with a clear understanding of its limitations, then protect oxygenation and perfusion through the entire procedure. Reassess after induction, after intubation, and after ventilation begins.
