Etomidate

20mg/10ml ampoules (IV)

Emergency Medicine Executive Summary

(Extended version, updated November 2021. Author: José Pedro Sepúlveda, MD. Editor: Cristóbal Sáa, MD)

Etomidate is one of the most used and preferred hypnotic agents in the Emergency Department (ED) for Rapid Sequence Intubation (RSI)(29), despite the US-FDA pending label for this indication.

  • Etomidate acts on GABA receptors moderating the activity of chloride channels; it makes neurons less excitable without any major cardiovascular impact. This feature suits etomidate for the great majority of emergency scenarios in which advanced airway management is required.

  • Its use in sepsis has been challenged because of the dose-dependent adrenal inhibition of corticosteroid synthesis, therefore only a single bolus dose is recommended for induction –not as a maintenance infusion– but to minimize adrenal suppression.

  • Myoclonic movements are a common adverse effect; they are observed for 1 to 3 minutes and cease spontaneously. In practice, the movements usually stop shortly after neuromuscular blockage and lack any clinical significance.

Pharmacology for a single bolus administration (23,28,29):

  • Onset: 15-45 seg

  • Time to Peak Effect: 45 seg

  • Duration of hypnotic effect: 3-12 min

  • Half life: 2-5h

Dosing

  • Adult dose for rapid sequence intubation:
    0.3mg/kg IV (total body weight).
    Consider a lower dose of 0.2mg/kg in profound shock.

Mechanism of Action and Usage

Etomidate is an imidazole derivative, with agonist activity to the β2 and β3 subunits of the GABA receptor (11) increasing its activity by moderating chloride channels, inhibiting neuronal action by decreasing the action potential threshold (16, 23, 28, 29).

  • In the adult and pediatric population, it has almost no hemodynamic repercussions. Only a slight reflex tachycardia with an absent to minimal decrease in blood pressure may be observed. It has a mild effect on increasing coronary blood flow, and reduces myocardial oxygen consumption along with no impact on cerebral blood flow or cerebral metabolic rate of oxygen consumption (CMRO2) (1, 3, 10, 25). These characteristics make etomidate the drug of choice in most situations where RSI is required in the ED.

  • It lacks analgesic effects and does not increase histamine release (16, 23).

  • It has an inhibitory effect in the adrenal cortex, reversibly inhibiting 11-𝛃-hydroxylase, an adrenal enzyme necessary for 11-deoxycortisol to cortisol conversion, decreasing cortisol and aldosterone synthesis (14, 15, 17, 35). Cortisol is well known to be one of the most important corticosteroids related to our stress response, making its suppression a potential threat to the inflammatory response presented by our immune system; thereby etomidate has been challenged in sepsis and its usage is still controversial in this setting (18, 19, 20, 24, 26). More details in the “Adverse Effects and Warnings” section.

Indications

US-FDA Labeled (34):

  • Induction of general anesthesia
    (approved in 1983)(4)


Non-US-FDA Labeled:

  • Inductor for rapid sequence intubation in the ED

  • Procedural sedation

Adult dose

  • Inductor for rapid sequence intubation
    0.3mg/kg IV.
    Consider a lower dose of 0.2mg/kg IV in profound shock (23, 29).

Calculate with total body weight (special consideration of TBW-adjusted dose in obese patients).

Pediatric dose

  • Inductor for rapid sequence intubation
    0.3 mg/kg IV.
    Calculate with total body weight.

Renal, hepatic, or other adjustments

No renal or hepatic adjustments needed.

  • Etomidate is metabolized in the liver into inactive metabolites, thus liver insufficiency could prolong its t ½, increasing the duration of its effect (23, 28, 29). From a physiopathological point of view; this could be potentially beneficial given that subtherapeutic dosing can lead to complications during RSI.

Dosage Forms and brand names

  • Etomidate (worldwide generic formulation) 20mg/10ml, IV use.

  • Amidate™ (US) 20mg/10ml, IV use.

  • Hypnomidate® (Europe) 20mg/10ml, IV use.

Cautions, Contraindications, Adverse effects, and Major drug interactions

Bottom line:

  1. Etomidate is contraindicated only in patients with known hypersensitivity.

  2. Use with caution in sepsis and other hyperadrenergic states where corticosteroid response is relevant, consider administering IV corticosteroids if etomidate is used in these settings (29).

  3. Myoclonic events are not provoked by seizure activity and they do not have clinical significance.

  4. In profound shock or hemodynamic instability, some experts suggest using a lower dose of 0.2mg/kg IV for RSI* (23, 29).


  • Cautions:

    • Profound sedation, coma and respiratory depression:
      Particularly caution should be taken when combined with other CNS depressants and/or opioids. This warning should be considered mostly if etomidate is used for procedural sedation, although EMDrugs suggests other sedative alternatives for this indication. In any case, etomidate is a potent sedative that always requires continuous monitoring during administration.

    • Weight-based dosing:
      Always calculate induction dose with total body weight, with special consideration in obese patients as subtherapeutic dosing can lead to significant complications (31, 33).


  • Contraindications:
    Hypersensibility to etomidate.


  • Adverse Effects and Warnings

  1. Myoclonic Movements:
    Etomidate induced-myoclonus (EMc) is a very notorious adverse effect commonly observed during RSI. Those can be observed from minor finger movements to intense generalized myoclonic movements.

  • The incidence of it occurring without any premedication may vary between 30% to 80% of patients (8, 22), and decreases with the use of premedication up to 30% approximately (8, 13, 22, 27, 32).

  • EMc could mimic seizures (29), but with no seizure-like activity on EEG. The possible causing mechanism is thought to be subcortical desinhibition. Unlike seizures, EMc does not produce excitotoxicity. However, intense clonic movements could lead to injuries to the patient (muscular damage, hiperkalemia) and complications for the staff (loss of vascular access, monitoring devices). Nonetheless, those events are extremely unlikely to happen.

  • The movements resolve spontaneously within 1-3 minutes, but during RSI they disappear shortly after NMB administration. The premedication dose of fentanyl during RSI can diminish the incidence of these movements and there are several agents (other opioids, benzodiazepines, NMDAr block, other sedatives)(8, 13, 22, 27, 32) that have been studied for treating EMc during premedication in RSI, however, there is no a established recommendation to prevent or treat EMc.

  1. Cortisol and aldosterone level reductions, considerations in sepsis and other hyperadrenergic states:
    As etomidate blocks 11-B-Hydroxylase, levels of cortisol and aldosterone decrease after the administration of etomidate. It is demonstrated that it can produce adrenal insufficiency after a single bolus administration and cortisol levels have been shown to decrease after 1 hour administration (15). Adrenal steroidogenesis blockage can last up to 24-48h (14, 15, 16, 17, 23, 28, 35).
    Taking advantage of this effect, etomidate has been studied to treat Cushing Syndrome (off-label), but this is irrelevant to the emergency medicine setting.

  • The “sepsis crossroads”:

  • Conflicting evidence is available in this matter. Studies have associated etomidate use in sepsis with increased mortality (17, 19), but this information has been seriously questioned (20, 24, 26). On the other hand, the latest available data shows no association between etomidate and increased mortality in sepsis (26, 35).

  • Some experts and the manufacturer recommend considering a single dose of corticosteroids (eg. hydrocortisone 200mg IV for a 70kg adult) to compensate for this potential risk (29, 34), without having evidence of improved outcomes to support this recommendation routinely (29).

  • In critically-ill septic children it has also been associated with an increased mortality when used as a maintenance sedative drug (12, 25).

    • Miscellaneous hyperadrenergic states:
      Blocking 11-B-hydroxylase in hyperadrenergic states could have a deleterious effect on the patients stress response (cortisol levels), It should only be used as an induction drug; and, as well as with sepsis, other induction agents should always be considered.

  1. Epilepsy and seizures:
    Etomidate accelerates EEG on epileptogenic focus (6, 21). Data shows that some patients may present convulsions during etomidate induction, its use in patients with epilepsy should be strictly monitored. Other induction agents with direct anticonvulsivant activity should be preferred, such as propofol or ketamine.

  • Major drug interactions:
    Etomidate has pharmacological synergism with other hypnotic/induction agents, benzodiazepines, barbiturates, CNS depressants. Caution with profound sedation, coma and respiratory depression.

Pregnancy and Lactation

  • Pregnancy Risk Factor Category (US-FDA): C.
    Data shows that the use of general anaesthetics (GABA enhancers, NMDA blockers, other sedatives) in the third trimester of pregnancy could lead to long-term brain damage in the fetus (30). There are no available controlled studies of etomidate use in pregnant women. Its use in pregnancy should be evaluated with caution and always as a single dose if elected among other inductor agents.
    Consider use of propofol for induction in pregnant women (US-FDA Pregnancy Risk Factor Category B).

  • Lactation:

Amounts of etomidate in milk are small and decrease rapidly (7). Available data indicate that no waiting period is required before resuming breastfeeding after etomidate anesthesia. Breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia.


Pharmacology

(2, 4, 5, 9, 16, 23, 28, 29).

  • Onset of action: 15-45s.

  • Time to Peak Effect: 45s.

  • Duration of hypnotic effect: 3-12m.

  • Half-life elimination: 2-5h (2.9h - 4.6h).

  • Tricompartimental model behaviour:
    Etomidate distributes rapidly into highly perfused tissue (brain), then intermediately into peripheral tissue (muscle), and terminal metabolism ( ≈7% etomidate stays in blood plasma for elimination). Shock does not alter it’s pharmacokinetics (distribution, metabolism and excretion).

  • Hepatic metabolism into inactive metabolites.

  • Renal elimination: 75-78%, biliary elimination: 20-25%.

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