Etomidate

Mechanism of Action

Etomidate contains a carboxylated imidazole ring-containing anesthetic compound (R-1-ethyl-1-[a-methylbenzyl] imidazole-5-carboxylate) and is structurally unrelated to other anesthetic agents. The imidazole ring provides water solubility in acidic solutions and lipid solubility at physiological pH. Therefore, etomidate is dissolved in propylene glycol, which often causes pain on injection but can be reduced by prior intravenous injection of lidocaine.

Etomidate has a chiral carbon atom and exists in the form of 2 enantiomers. Only the R (+) isomer is hypnotically active. The S (-) enantiomer has a 20-fold lower hypnotic effect.[2] Etomidate interacts with gamma-Aminobutyric acid type A (GABA) receptors by binding directly to specific sites and increasing the affinity of the inhibitory neurotransmitter GABA (positive modulation of GABA-mediated activity).[6] GABA is the principal inhibitory neurotransmitter within the central nervous system (CNS) and works with the adrenergic neurotransmitter system to counterbalance the action of excitatory neurotransmitters. Etomidate may have disinhibitory effects on the parts of the nervous system that control extrapyramidal motor activity. This disinhibition offers a potential explanation for the 30% to 60% incidence of myoclonus during induction with etomidate.

Pharmacokinetics

The onset of action: 30 to 60 seconds, Peak effect: 1 minute

Distribution: 2 to 4.5 L/kg. Limited pharmacokinetic data in patients with cirrhosis and esophageal varices suggest that the volume of distribution and elimination half-life of etomidate are approximately double that seen in healthy subjects.

Metabolism:  Metabolism is primarily hepatic by ester hydrolysis to inactive metabolites. Minimal anesthetic plasma levels of unchanged drug are equal to or higher than 0.23 mcg/mL; they decrease rapidly up to 30 minutes following injection and more slowly with a half-life value of about 75 minutes.

Excretion: 75% of the administered dose is excreted in the urine on the first day after injection. The chief metabolite is R-(+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, resulting from hydrolysis of etomidate, and accounts for about 80% of the urinary excretion. Another route of excretion is bile. Like most intravenous anesthetics, etomidate is highly protein-bound (77%). Thus, it can achieve a higher concentration in the brain in low albumin states since it will be less bound to albumin, and more free-drug would be available in the brain.[8]

Administration

Etomidate is an agent for IV anesthesia induction, and it offers several advantages:

•  Simple dose regimen
•  Fast onset of action
•  The short duration of effect
•  Rapid metabolism
•  Low risk of histamine release
•  Hemodynamic stability on bolus injection[6]

The dose for induction of anesthesia in adult and pediatric patients above the age of 10 varies between 0.2 and 0.6 mg/kg of body weight. Use is not recommended in patients below ten years old because there is insufficient data to support dosage recommendations for induction of anesthesia. Geriatric patients may require reduced doses of etomidate due to the natural progression of declining renal function. Clinical studies suggest that etomidate may induce cardiac depression in elderly patients with hypertension. A common induction dose of etomidate at 0.2 to 0.3 mg/kg, injected over 30 to 60 seconds, produces rapid onset of anesthesia, usually in less than one minute. Narcotics and other neuroactive drugs utilized during anesthesia may decrease the required etomidate dosage. The duration of action is directly correlated to the dose, with each 0.1 mg/kg providing about 100 seconds of unconsciousness.

Recovery depends on redistribution to inactive tissue sites. Like most intravenous anesthetics, etomidate is highly protein-bound (77%). Thus, it can achieve a higher concentration in the brain in low albumin states since it will be less bound to albumin, and more free-drug would be available in the brain. In addition, larger doses and repeated boluses can safely be administered because of their minimal effects on hemodynamics and short context-sensitive half-time.

Special Population

Hepatic Impairment: No dosage adjustments are provided in the manufacturer's labeling.

Renal Impairment: Etomidate is primarily excreted by the kidney; hence the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, clinicians should take care of dose selection and monitor renal function. 

Pregnancy Considerations: According to the package insert, there are no adequate and well-controlled studies on pregnant women. In animal reproduction studies, fetal deaths and reduced pup survival were noted after intravenous etomidate administration to pregnant rats at doses 0.17 times the human induction dose of 0.3 mg/kg. In addition, there are inadequate data to support intravenous etomidate in obstetrics, including Caesarean section deliveries. Therefore, such use is not recommended. 

Breastfeeding Considerations: Amounts of etomidate in milk are small and decrease rapidly. Current literature indicates that no waiting period is required before resuming breastfeeding after etomidate anesthesia. Mother can resume breastfeeding as soon as she has recovered from general anesthesia. However, caution should be exercised when administering etomidate to a nursing mother.[9]

Adverse Effects

Transient inhibition of adrenal steroid synthesis is considered etomidate's most significant adverse effect. A single bolus dose causes a dose-dependent inhibition of 11-beta-hydroxylase lasting 6 to 12 hours. This enzyme is responsible for converting 11-deoxycortisol to cortisol, which results in adrenocortical suppression. Hence, it poses a theoretical risk of impairing a patient's ability to produce an adequate stress response. 80% of patients were found to have etomidate-induced adrenal inhibition at 12 hours, and most patients' suppression had resolved by 48 hours.[10] Etomidate is no longer administered by continuous infusion because of the risks of sustained suppression of endogenous cortisol and aldosterone production.

The most common adverse reaction associated with etomidate use is transient intravenous pain on injection.[11] The pain appears less frequent when larger, more proximal arm veins are used, or IV lidocaine is given before an etomidate bolus. Transient skeletal muscle movements or myoclonus were observed in about 32% of the patients. Electroencephalographic studies have failed to expose seizure activity and suggest that these muscle movements demonstrate the disinhibition of cortical activity.[12][13] Severe, disturbing movements were decreased when 0.1 mg of fentanyl was given immediately before induction.[14] According to several studies, pretreatment with midazolam, dexmedetomidine, narcotics, propofol, dezocine, or ketamine reduces myoclonus incidence and severity after a bolus dose of etomidate.[15][16]

Postoperative nausea and vomiting with etomidate are comparable to the general frequency of PONV. The incidence of PONV was higher when etomidate was used for both induction and maintenance of anesthesia in short procedures such as dilation and curettage or when analgesia was insufficient.[17]

Contraindications

Etomidate is contraindicated in any patient with a known hypersensitivity reaction.

Adrenal Suppression: Etomidate is a commonly used sedative during rapid sequence intubation (RSI). In some studies, septic patients have an increased risk of developing adrenal suppression, associated with increased mortality.[18] Since etomidate affects cortisol production, its use in septic patients is controversial.[19][20] However, data are still lacking to prove that etomidate should be avoided in this patient population.

Pediatric Neurotoxicity: Published preclinical studies demonstrate that administering anesthetic and sedation drugs that potentiate GABA activity and block NMDA receptors increase neuronal apoptosis in the developing brain and result in cognitive deficits.[21] Decisions regarding the timing of any elective procedures requiring anesthesia should consider the procedure's benefits weighed against the potential risks.[22]

Monitoring

The ASA recommends standard monitoring for all anesthetics, including oxygenation, circulation, ventilation, and temperature. Trained anesthesia personnel must be continually present during all anesthetic cases requiring general anesthesia, monitored anesthesia care, or regional anesthesia.[23]

Cardiovascular Effects

Etomidate has minimal effects on the cardiovascular system and is the major reason for choosing this drug as an induction agent. It causes a mild reduction in peripheral vascular resistance, which is responsible for a decline in arterial blood pressure. Myocardial contractility and cardiac output are usually unchanged. Etomidate does not release histamine. However, etomidate by itself, even in large doses, produces relatively light anesthesia for laryngoscopy, and marked increases in heart rate and blood pressure may be recorded when etomidate is solely used for induction.

Respiratory Effects

Ventilation is not significantly affected. Induction doses do not result in apnea unless opioids have also been administered. The most distinctive effect on the respiratory system is a slight rise in arterial carbon dioxide tension (PaCO2).

Central Nervous System Effects

Etomidate decreases cerebral metabolic rate, cerebral blood flow, and intracranial pressure. Because of minimal cardiovascular effects, cerebral perfusion pressure is well maintained. Etomidate increases the amplitude of somatosensory evoked potentials, making it beneficial for ECT. Postoperative nausea and vomiting are more common with etomidate than propofol or barbiturate induction but appear to have the same frequency as general anesthesia. Etomidate lacks analgesic properties.

Toxicity

According to manufacturer labeling, overdose can occur from too rapid and repeated injections. In addition, the administration of rapid injections is followed by a fall in blood pressure. There is no antidote for etomidate. In a suspected case of overdosage, etomidate should be discontinued, a patent airway established (intubate, if necessary) or maintained, and oxygen administered with assisted ventilation.

Enhancing Healthcare Team Outcomes

Since etomidate is intended to induce general anesthesia, any clinician who administers etomidate must be trained in administering general anesthesia and managing complications encountered. In addition, emergency equipment must be readily available and in good working order. A trained, certified registered nurse anesthetist (CRNA) helps comprehensive perioperative care. Finally, hospital pharmacists should ensure proper dosing as the duration of action is closely related to the dose. In the case of overdose, critical care physician supervision is necessary. This interprofessional approach to etomidate use is crucial for optimal patient outcomes with the fewest adverse events. All clinicians (MDs, DOs, NPs, and PAs), nurses, pharmacists, and other staff involved must alert the rest of the interprofessional team to any changes in patient status, as well as document them in the patient's health record so all team members have access to the same information base. [Level 5]

Clinicians should use the revised Cardiac Risk Index for Pre-Operative Riskto estimate the risk of cardiac complications after noncardiac surgery.[24]

The decision to use etomidate as an induction agent is ultimately up to the clinician based on the physiologic state of their patient. Large, prospective controlled trials are still needed to determine the final role of etomidate, especially in critically ill patients. In the specific case of increasing the seizure duration potential, etomidate is superior to propofol and thiopental.[7] [Level 3]