The Etomidate Conundrum

Induction for rapid sequence intubation (RSI) in the critically ill often feels like the swing of a pendulum. Toward etomidate—haemodynamic poise, clean hypnosis, and familiar dosing. Back toward ketamine—sympathomimetic support, bronchodilation, and neuro-myths in slow retreat. The science, at times, looks just as mercurial. This review examines the terrain with a steady eye: what goes wrong when we intubate the critically ill; why physiology, not just anatomy, governs risk; what etomidate and ketamine truly offer; what the best comparative trials show; and where ongoing research is taking the field.

Why intubating the critically ill is different

Tracheal intubation in the critically ill is a high risk–high stakes intervention. In the international INTUBE study, which enrolled 3,659 critically ill adults across 197 ICUs in 29 countries, at least one major peri‑intubation adverse event occurred in 45.2% of patients—chiefly haemodynamic instability (hypotension in 42.6%), severe hypoxemia (SpO₂ <80% in 9%), and cardiac arrest (3.1%).¹ In contrast, the low incidence of an anatomically difficult airway (4.7%) demonstrates that in the critically ill, intubation is predominantly a physiological challenge.¹ These complication rates dwarf those seen with elective anesthesia, reflecting the physiologic derangements—shock, hypoxaemic respiratory failure, metabolic acidosis—that convert laryngoscopy from a procedural challenge into a systemic stress test.²

Guidelines developed for the critically ill, therefore, emphasize optimizing oxygenation, ventilation, and perfusion over device choice alone. The Difficult Airway Society/Intensive Care Society guideline codifies a bundle approach (team roles, preoxygenation, haemodynamic preparation, and human factors) tailored to ICU and ED environments,³ while the Society of Critical Care Medicine (SCCM) guideline on RSI synthesizes evidence across preoxygenation, induction, neuromuscular blockade, and immediate post‑intubation care for the critically ill adult.⁴ The concept of the “physiologically difficult airway”—where hypoxaemia, shock, or acidosis potentiate harm from even technically routine intubations—has moved from editorial caution to consensus recommendation.⁵

One of the most important contributors to the physiological success of a rapid sequence intubation is the choice of anaesthetic agent. The INTUBE study reported high preferences for propofol (41.5%) and midazolam (36.4%), with less preference for etomidate (17.8%) and ketamine (14.2%).¹ With potent myocardial depressent and vasodilatory properties, propofol was associated with a greater risk of cardiovascular instability (63.7%) than etomidate (49.5%).

Etomidate: pharmacology, promise, and the endocrine price

Etomidate, an imidazole‑derived intravenous hypnotic, potentiates GABA_A receptor–mediated inhibitory currents, producing rapid loss of consciousness with minimal direct myocardial depression and limited vasodilation at standard induction doses (0.2–0.3 mg/kg).⁶ These properties explain its durable appeal for haemodynamically fragile patients: compared with barbiturates or propofol, etomidate preserves sympathetic tone, usually causes less apnoea, and tends to maintain arterial pressure during laryngoscopy.⁶

But etomidate has a uniquely inconvenient toxicity: dose‑dependent inhibition of adrenal 11β‑hydroxylase, the terminal enzyme in cortisol biosynthesis. The mechanism—potent binding of etomidate to cytochrome P450 11β‑hydroxylase—was defined in classic endocrine studies and contemporaneous clinical reports in the 1980s.^{7, 8} Subsequent ICU work refined the time course: in critically ill adults, a single induction dose measurably suppresses adrenal responsiveness to ACTH for roughly 12–24 hours, occasionally longer, even as hypnosis resolves within minutes.⁹ This pharmacodynamic mismatch—brief hypnosis, prolonged steroidogenesis inhibition—has fueled debate whenever etomidate is used in sepsis.

Formulation issues matter practically. The traditional 35% propylene glycol vehicle stings and can cause phlebitis; lipid emulsion preparations reduce injection pain and hemolysis relative to aqueous formulations.¹⁰ Myoclonus (transient, non‑epileptic) is common during induction and can be attenuated by pretreatment with small doses of benzodiazepines or opioids, or by split‑dose etomidate titration; these strategies are largely based on peri‑operative anesthesia data rather than ICU trials.⁶

Ketamine: dissociation, sympathetic tilt, and evolving neuro-dogma

Ketamine is a phencyclidine congener that induces dissociative anesthesia via activity‑dependent NMDA receptor blockade, with downstream effects on thalamocortical transmission and limbic networks. At 1–2 mg/kg IV, induction is rapid and amnestic; at lower dosing, potent analgesia and bronchodilation are prominent. Unlike GABAergic hypnotics, ketamine typically raises heart rate and blood pressure through central sympathetic stimulation and inhibition of noradrenaline reuptake.¹¹ These features, together with maintenance of airway reflexes in non‑paralyzed settings, have made ketamine attractive for physiologically challenging inductions, including severe asthma exacerbations and haemodynamic instability.¹¹

Older teaching cautioned that ketamine increases intracranial pressure (ICP). Contemporary systematic review data in severe traumatic brain injury and other neurocritical states, however, do not support a consistent ICP increase when patients are mechanically ventilated with controlled PaCO₂; several included studies show stable or improved cerebral perfusion pressure with ketamine boluses under modern clinical conditions.¹² The pendulum, here too, has swung back towards nuance.

Head‑to‑head: what the best comparative trials show

Pre‑ICU/ED randomised trials. The KETASED multicenter RCT (n=655) compared etomidate with ketamine for RSI among acutely ill adults and found no significant difference in the primary endpoint of maximum Sequential Organ Failure Assessment (SOFA) score at 72 hours; early haemodynamic complications and 28‑day mortality were likewise similar.¹³ More recently, a single‑center ICU/ED RCT from an anesthesiology‑led airway team randomised 801 patients and reported higher 7‑day survival with ketamine in adjusted analyses, but with more post‑induction vasopressor use; the trial did not demonstrate a difference in key longer‑term outcomes.¹⁴

Emergency department pragmatic RCT. In a randomised clinical trial (n=143) of ED intubations, Knack and colleagues found no difference between ketamine and etomidate in maximum SOFA over the first three hospital days (median 6.5 vs 7.0) and no difference in post‑intubation hypotension or 30‑day mortality.¹⁵

Large registries. Observational data from the National Emergency Airway Registry (NEAR) provide countervailing signals. Across a broad sample of ED intubations, ketamine (vs etomidate) was associated with higher odds of peri‑intubation hypotension after adjustment for illness severity and indication;¹⁶ in a sepsis‑specific NEAR cohort, etomidate was associated with less hypotension than ketamine in multivariable models.¹⁷ Residual confounding is always a concern, but these datasets sharpen the physiologic question: is “haemodynamic stability” agent‑intrinsic, or patient‑contingent?

Sepsis‑focused randomised data. A single‑center RCT in ED patients with suspected sepsis (n=260) likewise found no difference in 28‑day survival between etomidate and ketamine; however, the etomidate arm had more vasopressor use within 24 hours (43.9% vs 17.7%).¹⁸

Syntheses. A 2024 meta‑analysis in Critical Care pooling randomised and rigorously adjusted observational studies judged a moderate probability that ketamine induction is associated with lower mortality versus etomidate—but acknowledged considerable imprecision and heterogeneity across settings and illness phenotypes.¹⁹ Earlier comprehensive analyses focused on sepsis reached a different conclusion: single‑dose etomidate was not associated with increased mortality in sepsis (despite more adrenal axis suppression) when compared with alternative agents,^{20, 21} underscoring how inferences can pivot on inclusion criteria, comparators, and outcome windows.

Interpreting the pendulum: physiology over pharmacology

Why do high‑quality studies sometimes point in different directions? The mechanistic answer is not mysterious. Etomidate’s cardiovascular neutrality does not add sympathetic tone; in catecholamine‑depleted shock, intubation itself (induction, laryngoscopy, positive pressure ventilation) may precipitate hypotension regardless of hypnotic. Ketamine’s sympathomimetic effects can be blunted or reversed in prolonged shock or in catecholamine‑refractory states—where its direct myocardial depressant properties emerge.¹¹ Registry signals that ketamine is associated with more hypotension in “sicker” patients, and RCT signals that etomidate can be followed by more vasopressor use in sepsis, are not paradoxes so much as reflections of patient selection and timing.^{16, 17, 18}

Neurophysiology offers a similar lesson. The dogma that ketamine invariably raises ICP has not held under ventilated, contemporary care. Systematic review finds no consistent ICP increase and preservation (or improvement) of cerebral perfusion pressure, contradicting older, non‑controlled observations from spontaneously breathing patients under light sedation.¹² Etomidate, for its part, reduces cerebral metabolic rate and ICP while maintaining perfusion—benefits weighed against endocrine effects that likely do not matter for all patients, and may matter quite a lot for some.^{6, 9}

Guidelines: what do they actually say?

The SCCM RSI guideline does not anoint a single “best” induction agent for all critically ill adults. Instead, it recommends choosing the sedative based on the patient’s physiology (shock, hypoxaemia, acidosis, suspected intracranial pathology), the intended neuromuscular blocker, and the team’s preparation to manage haemodynamic instability—strongly endorsing the use of an NMBA when a sedative‑hypnotic is selected for RSI and emphasising structured preoxygenation and peri‑intubation haemodynamic optimisation.⁴ The 2018 PADIS guidelines address post‑intubation analgesia and sedation paradigms rather than induction choice; they favor light, analgesia‑first strategies, minimizing benzodiazepines, and early mobilization and sleep stewardship across the ICU course.²²

Etomidate beyond induction: sedation is (still) off-limits

After seminal data linked continuous etomidate infusions to sustained adrenal suppression and worse outcomes, long‑term etomidate sedation fell out of practice; modern guidelines do not recommend etomidate for ongoing ICU sedation.^{8, 22} For post‑intubation management, PADIS‑concordant regimens (e.g., opioid‑forward analgesia with propofol or dexmedetomidine for light sedation) remain the evidence‑based default.²²

Ketamine beyond induction: when the sympathomimetic helps (and when it does not)

Ketamine’s haemodynamic signature can be an asset during induction in distributive physiology, and its bronchodilatory properties support its use when dynamic hyperinflation or severe bronchospasm complicate oxygenation—albeit with generally low‑certainty evidence in status asthmaticus and heterogeneous practice.¹¹ Dysphoria and emergence reactions are less relevant in paralyzed, mechanically ventilated patients. As with etomidate, ketamine’s value is contextual: dose, co‑induction choices, pre‑induction resuscitation, and the trajectory of the underlying illness often dominate drug “class effects.”

Future directions: endocrine‑sparing etomidate analogs and definitive comparative trials

Medicinal chemistry has explored etomidate analogs designed to preserve haemodynamic neutrality but avoid adrenal enzyme inhibition. “Soft” etomidate derivatives (e.g., cyclopropyl‑methoxycarbonyl metomidate, ABP‑700) exhibit rapid metabolism to inactive carboxylate metabolites and, in phase I studies, minimal ACTH‑stimulated cortisol suppression; however, involuntary movements and excitatory phenomena have limited further development to date.^{23, 24}

On the comparative effectiveness front, the field is moving toward large, pragmatic, multicenter RCTs with patient‑centered endpoints and minimized selection bias. A comprehensive 2025 review in the American Journal of Respiratory and Critical Care Medicine outlines this agenda and discusses ongoing work designed to resolve whether ketamine or etomidate confers clinically meaningful advantages across phenotypes of critical illness.²⁵

So, is etomidate “bad”? Is ketamine “good”? The upcoming RSI trial will provide an answer

The fairest reading of current evidence is deliberately restrained. A single induction dose of etomidate reliably produces transient adrenal suppression but has not been shown to increase mortality in sepsis or across heterogeneous ICU and ED populations in a way that is consistent and causal.^{20, 21} Ketamine, while often haemodynamically helpful, may not prevent hypotension in profoundly catecholamine‑depleted states and—depending on case mix—has been associated with more peri‑intubation hypotension in large registries.^{16, 17} Multiple RCTs—including KETASED and recent single‑center trials—show no decisive difference in early organ dysfunction or survival between the two agents in unselected acutely ill adults,^{13, 14, 15} and a sepsis‑specific RCT likewise finds equipoise on mortality with differing peri‑intubation vasopressor needs.¹⁸ Meta‑analytic signals that ketamine might reduce mortality remain hypothesis‑generating pending large pragmatic trials with minimal crossover and standardized co‑interventions.¹⁹

In other words, the pendulum’s movement reflects physiology as much as pharmacology. The agent you choose can help—or hinder—depending on the pathophysiologic ground beneath your feet. The upcoming RSI trial,²⁶ a 2,364 patient RCT comparing etomidate with ketamine for emergency tracheal intubation in the critically ill, will provide more conclusive data on this question. The trial results will be presented at CCR Down Under, in Melbourne, December 9th and 10th, 2025. Join us to hear the results of this pivital trial.

Key take‑home points

• Complications are common: nearly half of critically ill adults experience a major peri‑intubation event.¹
• Physiology first: organize RSI around oxygenation and perfusion; induction choice should follow physiologic context, not fashion.^{3, 4, 5}
• Etomidate: rapid hypnosis and haemodynamic neutrality counterbalanced by predictable, transient adrenal suppression.^{6, 7, 9}
• Ketamine: dissociation with sympathetic augmentation and bronchodilation; modern data do not show inevitable ICP rises under controlled ventilation.^{11, 12}
• Comparative trials: multiple RCTs and meta‑analyses demonstrate no clear superiority overall; signals vary by phenotype and setting.^{13, 14, 15, 19}
• Guidelines: choose the agent that fits the physiology, and deliver RSI within a structured bundle; do not use etomidate for ongoing ICU sedation.^{4, 22}
• The Answer?: join us in Melbourne, December 9th & 10th, either in-person or virtually, to hear Matthew Semler and Jonathan Casey present the results of the highly anticipated RSI trial.²⁶ 

Disclosure: This narrative review synthesizes peer‑reviewed evidence. It does not provide procedural advice.

References

Added September 4th, 2025