SGEM#500: Don’t You Want Me – Etomidate or Ketamine for Induction of Critically Ill Patients

Date: January 17, 2026 Reference:  Casey et al. RSI Investigators and the Pragmatic Critical Care Research Group. Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults. NEJM. 2025 Dec Guest Skeptic: Dr. Scott Weingart is an ED Intensivist from New York. He did fellowships in Trauma, Surgical Critical Care, and ECMO. Scott is best known for talking to himself about Resuscitation and Critical Care on the podcast EMCrit, which has been downloaded more than 50 million times. Scott and I will both be presenting at Incrementum 2026 in Spain.  Case:  You’re working an evening shift in a busy tertiary-care emergency department (ED). Emergency Medical Services (EMS) rolls in a 62-year-old woman with a history of hypertension and type 2 diabetes. She’s febrile at 39.2°C, tachycardic at 125 beats/min, hypotensive at 86/52 mm Hg despite 2 L of crystalloid and breathing 32/min on a non-rebreather with oxygen saturation of 88%. Chest X-ray shows a right‑lower‑lobe infiltrate; lactate is 5.6 mmol/L. She’s now on a norepinephrine infusion at 0.15 µg/kg/min and still looks exhausted and altered. You decide she needs emergent rapid sequence intubation (RSI) for worsening work of breathing and impending respiratory failure. The respiratory therapist is at the bedside, the pharmacist has arrived with the RSI box, and your resident says: “For induction, should we go with ketamine because she’s septic and hypotensive, or etomidate because we’re worried about pushing her over the edge?” Background: Intubating critically ill patients can be one of those high-stakes, high-adrenaline things we do often in emergency medicine (EM), but the physiology is stacked against us. These patients are often hypoxic, hypotensive, acidotic and catecholamine-depleted before we even reach for the laryngoscope. Emergency airway registries and multicentre cohorts consistently report serious peri-intubation complications (profound hypotension, hypoxemia, cardiac arrest, failed or difficult intubation) in roughly 10% to 20% of critically ill adult intubations in the ED and ICU [1].  Even a single episode of severe hypotension or hypoxemia during intubation is associated with increased mortality and organ failure in the ICU population [2].  So, the choice of induction agent seems to matter. Etomidate became the darling of emergency RSI because it has a rapid onset, short duration, and relatively preserved hemodynamics compared with agents like thiopental or high‑dose propofol [3].  The flip side is adrenal suppression: a single dose transiently inhibits 11‑β hydroxylase and measurably blunts cortisol production for 24–72 hours. Observational studies and post‑hoc analyses in septic shock raised alarms that etomidate might increase mortality by worsening relative adrenal insufficiency, leading some guidelines and regulators to discourage or even remove etomidate in sepsis [4]. But those were mostly non-randomized data, and prior RCTs comparing etomidate with other agents were small and gave conflicting signals about mortality. Ketamine, by contrast, is a dissociative NMDA antagonist with a very different vibe. It provides profound amnesia and analgesia, maintains airway reflexes to some degree, and has sympathomimetic properties that can increase heart rate and blood pressure by catecholamine release [5]. Those properties have made ketamine attractive in shocked patients where we’re worried that propofol or midazolam will “tank the pressure”. However, in catecholamine-depleted septic shock, ketamine’s direct myocardial depressant effects may become more apparent, and registry data suggest its hemodynamic advantage over etomidate is not as clear as many of us were taught on shift.  Old concerns that ketamine raises intracranial pressure have largely been debunked in modern neurocritical care literature, further widening its appeal.  Other agents are still in the mix. Propofol remains widely used in operating theatre practice and some EDs because of its familiarity and ease of titration, but it predictably causes vasodilation and negative inotropy, making it a frequent offender in peri‑intubation hypotension among critically ill patients [6]. Benzodiazepines (midazolam) have a slower onset, a more variable effect and a longer half‑life, and when used as primary induction agents in shock, they’ve been associated with more hypotension and delirium compared with etomidate or ketamine. Fentanyl and other opioids are often layered on for analgesia or “blunting” the sympathetic surge, but they can also precipitate abrupt hypotension and apnea in the already fragile patient. So for years we’ve been stuck between the theoretical adrenal toxicity of etomidate and the hoped‑for hemodynamic benefits of ketamine, without a large, definitive randomized trial in ED/ICU patients powered for patient‑important outcomes like mortality. Clinical Question: In critically ill adults undergoing emergency tracheal intubation in the ED or ICU, which induction agent is better, ketamine or etomidate? Reference:  Casey et al. RSI Investigators and the Pragmatic Critical Care Research Group. Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults. NEJM. 2025 Dec Population: Critically ill adults (≥18 years) undergoing or planned to undergo tracheal intubation in an ED or ICU, where the treating clinician intended to use either ketamine or etomidate for induction, conducted at six EDs and eight ICUs in the US. Excluded: Known or suspected pregnancy, prisoners. acute trauma as the primary indication for intubation, immediate “crash” intubations where there was no time for randomization, known or suspected allergy or contraindication to either ketamine or etomidate, situations where the treating clinician believed that either ketamine or etomidate was specifically required or contraindicated (strong clinician preference), or patients previously enrolled in the trial. Intervention: The Ketamine group received 1.0–2.0 mg/kg given immediately before intubation.  Treating clinicians chose neuromuscular blocking agents, pre‑ and post‑intubation vasopressors, fluids, and other medications according to local practice. Comparison: The Etomidate group received 0.2–0.3 mg/kg. Again, all other aspects of airway management and resuscitation were at the clinician's discretion. Outcomes: Primary Outcome: In-hospital death by day 28 after randomization.  Secondary Outcomes: A composite of “cardiovascular collapse” during the interval between induction of anesthesia and 2 minutes after tracheal intubation, defined as any of: Systolic BP <65 mm Hg, or A new vasopressor started or an increase in vasopressor dose, or Cardiac arrest.  Exploratory Outcomes Type of Study: A therapeutic, parallel‑group, multicenter randomized controlled trial Authors’ Conclusions: “Among critically ill adults undergoing tracheal intubation, the use of ketamine to induce anesthesia did not result in a significantly lower incidence of in-hospital death by day 28 than etomidate.” Quality Checklist for Randomized Clinical Trials: Did the study population include or focus on ED patients? Yes Were patients adequately randomized? Yes  Was the randomization process concealed? Yes Were patients analyzed in the groups to which they were randomized (intention‑to‑treat)? Yes Were patients recruited consecutively (no selection bias)? Unsure Were both groups similar with respect to prognostic factors? Yes Were all participants (patients, clinicians, outcome assessors) blinded? No Were all groups treated equally except for the intervention? Unsure Was follow‑up complete (≥80% in both groups)? Yes Were all patient‑important outcomes considered? Yes Was the treatment effect large enough and precise enough to be clinically significant? No Who funded the trial? The trial was funded by the Patient-Centred Outcomes Research Institute (PCORI), the US National Heart, Lung, and Blood Institute, and the US Department of Defence, among others; the funders had no role in study design, conduct, analysis, or manuscript preparation.  Did the authors declare any conflicts of interest? Several authors reported research funding and consulting fees from various organizations (NIH, DoD, Octapharma, monitoring companies), although none were manufacturers of ketamine or etomidate. Results: They randomized 2,365 patients with a median age of 60 years, ~42% female, and ~56% intubated in the ED.  Nearly half had sepsis or septic shock, the median APACHE II score was 18, and about 22% were receiving vasopressors in the hour before intubation.   Key Result: For critically ill adults undergoing emergency tracheal intubation in the ED/ICU, ketamine and etomidate produced similar 28-day in-hospital mortality, but ketamine was associated with more cardiovascular collapse and hypotension around the time of intubation. Primary Outcome: In-hospital death by day 28: Ketamine 28.1% vs Etomidate 29.1% Risk difference adjusted for trial site: −0.8% (95% CI: −4.5% to 2.9%). Secondary Outcomes: Open Label Open‑label: This was an open-label trial, with neither clinicians nor research staff being masked to assignment. The lack of blinding can bias both cointerventions (performance bias) and outcome measurement (detection bias), especially for outcomes that rely on clinician judgment. The primary outcome (death by day 28) may not be impacted by this, but the key secondary outcome, like cardiovascular collapse, is partly defined by starting or escalating vasopressors, which is inherently a clinician’s decision. If clinicians believed ketamine was safer or more pressure-friendly, they might delay vasopressors or, conversely, might treat etomidate patients more aggressively with prophylactic pressors, biasing the composite in either direction.