Etomidate

CLASS

• General anesthetic
• Carboxylated imidazole derivative 

PHYSICOCHEMICAL PROPERTIES

• ­1-­(1­-ethylphenyl)imidazole-­5­-ethyl ester
• It has a chiral center (* in figure) – the R(+) isomer of etomidate is ten times more potent than its S(−) isomer at potentiating GABA-A receptor activity
• weak base with a pKa of 4.2

MECHANISM OF ACTION

• Acts primarily as a positive allosteric potentiator of the gamma-aminobutyric acid (GABA) type A receptor (increases the effect of GABA) by stabilising the open state of the channel.
  • In supra-clinical doses also has a direct agonist effect on GABA-A receptors.
• Anatomic Locations:
  • Enhances GABAergic inhibition in the reticular activating system of the brainstem, leading to sedation and hypnosis.
• Second Messenger Pathways:
  • Increases chloride ion influx through GABA-A receptor channels, hyperpolarizing neurons and inhibiting action potentials.
• Pharmacodynamic Effects:
  • Sedation and Hypnosis: Rapid onset of unconsciousness.
  • Minimal Cardiovascular Effects: Maintains hemodynamic stability.
  • Adrenal Suppression: Inhibits 11β-hydroxylase, reducing cortisol synthesis. This effect has much higher potency than the sedative/ hypnotic effect.
  • No analgesic effect.
• Duration of action:
  •  3-8 minutes with standard induction doses, due to  rapid redistribution to muscle and later to fat.
  • Duration of action increases linearly with increasing dose – each 0.1 mg/kg IV provides about 100 seconds of unconsciousness.

PHARMACEUTICS

• Formulations:
  • Intravenous (IV) injection
• Concentrations: Typically available as 2 mg/mL solution in 35% propylene glycol due to poor water solubility
• Aqueous solution has pH 6.9
• Lipid emulsion form is less irritant and faster onset.

DOSE

• IV Bolus: 0.2-0.6 mg/kg over 30-60 seconds for induction of anesthesia.
• Continuous Infusion: 0.04-0.05 mg/kg/hr for adrenal suppression to treat severe Cushing syndrome (off-label).

INDICATION

• Induction of general anesthesia.
  • Rapid sequence intubation when haemodynamic stability is a priority
  • Procedural sedation for very brief procedures
• Emergency management of severe Cushing syndrome (“Cushing crisis”) (off-label use).

CONTRA-INDICATIONS

Absolute

• Hypersensitivity
• Porphyria

Precautions

• Adrenal insufficiency
• Cirrhosis and oesophageal varices – VD and elimination half-life are doubled.

DRUG-DRUG INTERACTIONS

• Alcohol, opioids, sedatives, sodium oxybate, MAO inhibitors – additive sedative effect
• Verapamil, reserpine – additive cardiovascular depression
• GLP-1 agonists – additive nausea/vomiting risk due to slow gastric emptying

ADVERSE EFFECTS

• Cardiovascular:
  • Usually minimal changes in HR and BP
  • Minimal decrease in SVR
  • Negligible cardiodepressant effect at induction doses (e.g. <0.6 mg/kg).
  • does not alter sympathetic or baroreceptor reflexes
  • Hypotension/ cardiovascular collapse in the critically ill, in the elderly, if hypovolaemia present, or combined with other agents
• Neurological:
  • Myoclonus (>50%)
  • Excitatory spikes on EEG (~20%), seizures (rare).
  • Awareness post-intubation due to rapid offset if ongoing analgo-sedation is not commenced promptly.
  • decreases CMRO2, cerebral blood flow (20-30% on induction) and ICP.
  • Decreases intraocular pressure
  • Not neuroprotective in animal studies
• Endocrine:
  • Transient adrenal suppression from single induction boluses, chronic adrenal insufficiency can occur from etomidate infusions and recreational abuse
• Respiratory:
  • Hypoventilation, apnea.
  • Case reports of laryngospasm
• Gastrointestinal:
  • Nausea, vomiting (more common than propofol and thiopentone)
• Other
  • Pain on injection (20-50%) and phlebitis (polyethylene glycol formulations).

PHARMACOKINETICS

• Absorption: Rapid onset within 1 minute of IV administration.
• Distribution: High lipid solubility, rapid brain uptake. Distribution t1/2 = 2-4 min; central VDss = 2.5-4.5 L/kg. Very large peripheral volume of distribution, 74.9 litres/kg (due to solubility in fat). Protein binding 77% (especially albumin). Little increase in context-sensitive half-time with prolonged infusion.
• Metabolism: Hydrolyzed by hepatic and plasma esterases to inactive metabolites.
• Excretion: Primarily renal (78%), with some biliary excretion (22%). Clearance 18-25 mL/kg/min. Elimination t1/2 2.9-5.3h.

PREGNANCY AND LACTATION

• Pregnancy: Use only if clearly needed; potential risk to the fetus.
• Lactation: Small amounts excreted in breast milk; generally considered safe for breastfeeding once the mother is fully awake.

DOSE ADJUSTMENTS IN ORGAN FAILURES

• Renal Impairment: No specific adjustments; monitor for prolonged effects.
• Liver Impairment: Use with caution due to hepatic metabolism.
• Renal Replacement Therapy: No specific guidelines; monitor closely.

EVIDENCE

RSI trial (Casey et al, 2025) 

• Multi-center randomised trial in 8 EDs and ICUs in North America
  • Pragmatic design, not blinded
• N = 2,444 non-trauma critically ill patients.
• Compared etomidate (2-3 mg/kg IV actual body weight) and ketamine (1-2 mg/kg IV actual body weight) when used for emergency intubation
  • Clinicians selected the actual dose given using a weight-based nomogram
• Findings
  •  no mortality difference
  • Cardiovascular collapse (composite of new/ increased vasopressors or SBP <65 mmHg within 2 minutes,, or cardiac arrest) was more common with ketamine (22%) vs etomidate (17%) (NNH 20)
    • Effect was greater in sepsis and in APACHE II >20 patients (NNH = 10)
• Comments and criticisms
  • Excellent, well designed pragmatic trial with excellent internal validity
  • Dosing used is a threat to external validity, as doses used are higher those used in many centers
    • IBW dosing rather than actual body weight  is recommended based on expert consensus and pharmacokinetic principles
    • Many patients were overweight or living with obesity (median BMI was 26)
    • About 25% of patients in both arms were administered doses higher than the maximum dose recommended by the trial nomograms.
• Conclusion:
  • At the doses used in non-trauma critically ill patients,, there was mortality difference between etomidate and ketamine and there was less cardiovascular collapse with etomidate.
  • Confirms etomidate as the most haemodynamically stable induction agent.

Other clinical trials comparing ketamine and etomidate as induction agents for emergency intubation:

• KETASED (2009)
  • French RCT of n=449 ICU adults needing RSI; Etomidate vs Ketamine.
  • Primary outcome: SOFA score at 3 days.
  • Findings: No difference in SOFA score at 3 days (though difference in 95% CI was 0 to 1.1) or mortality. Confirmed etomidate causes adrenal suppression.
• EvK (2021/22)
  • European RCT of n=801 critically ill adults needing emergency intubation; Etomidate vs Ketamine.
  • Primary outcome: 30‑day survival.
  • Findings: No survival benefit of ketamine (though there was a statistically significant 7-day mortality difference in favour of ketamine that did not persist to 30 days). Hemodynamic effects were similar.; Confirmed etomidate causes adrenal suppression.

Systematic reviews and meta-analysis prior to the RSI trial provide mixed conclusions

• Kotani et al (2023)
  • found no clear mortality difference but confirmed etomidate’s adrenal suppression risk. Bayesian analysis suggested that a mortality benefit in favour of ketamine was likely. Confirmed the adrenal suppression effect of etomidate, in comparison with ketamine.
• Greer et al (2025)
  • found that neither ketamine nor etomidate as induction agents improved survival; ketamine may worsen cardiovascular outcomes (arrhythmias and hypotension), while confirming that etomidate impairs adrenal function.

CONTROVERSIES

• Historically, there was concern about the potential for increased mortality with etomidate, especially in patients with sepsis. However, there was no signal for harm from etomidate in the 2025 RSI trial.
• Etomidate boluses commonly cause transient adrenal suppression (<24-72h), but the clinical significance is uncertain
• Etomidate is not available in a number of countries (including Australia) due to historical safety concerns of regulatory bodies.
• Etomidate can be a recreational drug of abuse. It has been used in vaping fluids (“space oil”). Recurrent use can lead to adrenal insufficiency.

PRACTICAL TIPS

• Etomidate has rapid onset and offset. Ensure prompt initiation of post-intubation analgo-sedation to minimise the risk of awareness.
• Never use etomidate infusions for ongoing post-intubation sedation due to the risk of adrenal insufficiency.

REFERENCES

Journal articles

• Casey JD, Seitz KP, Driver BE, et al. Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults. N Engl J Med. Published online December 9, 2025. doi:10.1056/NEJMoa2511420 PMID: 41369227.
• Forman SA. Clinical and molecular pharmacology of etomidate. Anesthesiology. 2011;114(3):695-707. doi:10.1097/ALN.0b013e3181ff72b5 PMID: 21263301 PMCID: PMC3108152
• Greer A, Hewitt M, Khazaneh PT, et al. Ketamine Versus Etomidate for Rapid Sequence Intubation: A Systematic Review and Meta-Analysis of Randomized Trials. Crit Care Med. 2025;53(2):e374-e383. doi:10.1097/CCM.0000000000006515 PMID: 39570063
• Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009;374(9686):293-300. doi:10.1016/S0140-6736(09)60949-1 PMID: 19573904
• Koroki T, Kotani Y, Yaguchi T, et al. Ketamine versus etomidate as an induction agent for tracheal intubation in critically ill adults: a Bayesian meta-analysis. Crit Care. 2024;28(1):48. Published 2024 Feb 17. doi:10.1186/s13054-024-04831-4 PMID: 38368326
• Matchett G, Gasanova I, Riccio CA, et al. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med. 2022;48(1):78-91. doi:10.1007/s00134-021-06577-x PMID: 34904190

FOAM and web resources

• FDA Data sheet for AMIDATE (etomidate)
• EMCrit Wee – The RSI Trial (2025)
• ICU Ed and Todd Cast – CCR Down Under: RSI with Jon Casey (2025)