Etomidate (Systemic)


VA CLASSIFICATION
Primary: CN203
Secondary: CN206

Commonly used brand name(s): Amidate.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Anesthetic, general—

anesthesia adjunct—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Anesthesia, general or
Anesthesia, general, adjunct—Etomidate is indicated for the induction of general anesthesia {02} {16} {18}. It is also indicated to supplement low-potency anesthetics, such as nitrous oxide and oxygen, during maintenance of anesthesia for short operative procedures such as dilation and curettage or cervical conization {02}.
—Etomidate may be especially useful in patients with compromised cardiopulmonary function because of its minimal cardiovascular and respiratory depressant effects and lack of histamine release at usual doses {15} {19} {21}.
—Etomidate is a sedative-hypnotic without analgesic action {02} {05}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Etomidate: 244.29 {01}

Mechanism of action/Effect:

Etomidate is a short-acting hypnotic, which appears to have gamma-aminobutyric acid (GABA)–like effects. Unlike the barbiturates, etomidate reduces subcortical inhibition at the onset of hypnosis while inducing neocortical sleep. Studies in animals suggest that a part of the action of etomidate consists of a depression of the activity and reactivity of the brain stem reticular formation.


Other actions/effects:

Etomidate does not cause significant cardiovascular or respiratory depression {02} {03} {15} {19}, but may cause a brief period of apnea {08} {12}. Also, it does not appear to elevate plasma histamine or cause histamine release when administered in recommended doses {15} {21}. The decrease in cerebral blood flow produced by etomidate is approximately the same as that produced by thiopental and methohexital {02}; this reduction appears to be uniform in the absence of intracranial tumors. Etomidate slightly lowers intracranial pressure and it usually causes a moderate decrease in intraocular pressure {07} {10} {11}. Also, etomidate (at induction doses of 0.3 mg per kg of body weight [mg/kg]) has been reported to reduce plasma cortisol concentrations {05} {06}; this effect persists for 6 to 8 hours and appears to be unresponsive to adrenocorticotropic hormone (ACTH) {02}.

Protein binding:

High (76%), primarily to serum albumin {13}.

Biotransformation:

Hepatic; rapidly metabolized by ester hydrolysis to inactive metabolites {02} {14}.

Half-life:

About 75 minutes {02}.

Onset of action:

Rapid, usually within 1 minute {02}.

Plasma concentration

Minimal hypnotic plasma concentrations of unchanged drug are equal to or higher than 0.23 mcg per mL; they decrease rapidly for up to 30 minutes following injection and more slowly thereafter {02}.

Duration of action:

Dose-dependent, but usually 3 to 5 minutes with an average dose of 0.3 mg/kg; may be prolonged by a sedative premedication or by repeated injections of etomidate {02}.

Time to recovery

As rapid as, or slightly faster than, immediate recovery after similar use of thiopental. The immediate recovery period will usually be shortened in adults by intravenous administration of approximately 0.1 mg of fentanyl 1 or 2 minutes before induction of anesthesia, possibly because less etomidate is generally required {02}.

Elimination:
    Renal; approximately 75% of a dose excreted in the urine the first day after injection. The major inactive acid metabolite accounts for approximately 80% of the urinary excretion {02}.


Precautions to Consider

Carcinogenicity/Mutagenicity

Studies have not been done {02}.

Pregnancy/Reproduction
Fertility—
Reproduction studies showed no impairment of fertility in male and female rats when etomidate was administered prior to pregnancy at 0.31, 1.25, and 5 mg per kg of body weight (mg/kg) (approximately 1, 4, and 16 times the human dose, respectively) {02}.

Pregnancy—
Studies in humans have not been done. However, studies in animals have shown that etomidate causes an embryocidal effect in rats when given in doses 1 and 4 times the human dose; decreases pup survival in rats at doses of 0.3 and 5 mg per kg (approximately 1 and 16 times the human dose) and in rabbits at doses of 1.5 and 4.5 mg per kg (approximately 5 and 15 times the human dose); slightly increases the incidence of stillborn fetuses in rats at doses of 0.3 and 1.25 mg per kg (approximately 1 and 4 times the human dose); and causes maternal toxicity with deaths in 6 out of 20 rats at a dose of 5 mg per kg (approximately 16 times the human dose) and in 6 out of 20 rabbits at a dose of 4.5 mg per kg (approximately 15 times the human dose). However, studies in animals have not shown that etomidate causes teratogenic effects. {02}

FDA Pregnancy Category C {02}.


Labor and delivery—

Use of etomidate is not recommended since data are insufficient to support its use in obstetrics, including cesarean section deliveries {02}.

Breast-feeding

It is not known whether etomidate is distributed into breast milk. However, problems in humans have not been documented {02}.

Pediatrics

Appropriate studies with etomidate have not been performed in children up to 10 years of age {02}. Safety and efficacy have not been established {02}.


Geriatrics


Elderly patients are more sensitive to the effects of etomidate than are younger patients. In addition, geriatric patients are more likely to have age-related hepatic function impairment, which may require reduction of dosage in patients receiving etomidate {09}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or
» Central nervous system (CNS) depression–producing medications, other (see Appendix II )    (concurrent use may increase the CNS depressant effects of either these medications or etomidate; dosage adjustment of etomidate may be necessary)


Hypotension-producing medications, other (see Appendix II )    (concurrent use may potentiate the hypotensive effect of etomidate; dosage adjustments may be necessary)

    (caution is advised during titration of calcium channel blocker dosage for those patients taking medication, such as etomidate, known to promote hypotension, since the combination may result in excessive hypotension)

    (concurrent use of diazoxide with etomidate may result in an additive hypotensive effect, which may be severe; dosage adjustments may be necessary, and patient should be continuously observed for excessive fall in blood pressure for several hours after concurrent use)

    (concurrent use of mecamylamine or trimethaphan with etomidate may potentiate the hypotensive response, with increased risk of severe hypotension, shock, and cardiovascular collapse during surgery)


Ketamine    (concurrent use of ketamine, especially in high doses or when rapidly administered, with etomidate may increase the risk of hypotension and/or respiratory depression)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Immunosuppression or
Sepsis or
Transplantation    (potential effects on adrenal function)


Sensitivity to etomidate{22}


Side/Adverse Effects

Note: Etomidate can block the adrenal gland's production of cortisol and other steroid hormones, possibly resulting in temporary adrenal gland failure. This may cause abnormal salt and water balance, lowered blood pressure, and, ultimately, shock. Postoperative or critically ill patients may require adrenocorticoid supplementation {02}.
Etomidate may cause brief periods of apnea {02}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Nausea and/or vomiting {04}
Note: Incidence of postoperative nausea and vomiting are more frequent than with thiopental when etomidate is used for both induction and maintenance of anesthesia in short procedures or when analgesia is insufficient {02}.



Incidence less frequent or rare {02}
    
Fast or slow breathing
    
increase or decrease in blood pressure
    
irregular or fast or slow heartbeat



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—less frequent when fentanyl is given immediately before induction    
Involuntary muscle movements, temporary —reported incidence 22.7 to 63% {02}
    
pain, temporary, at injection site —reported incidence 1.2 to 42% {02}
Note: Pain may last for less than 1 minute; it is self-limiting without residual effects; pain at injection site appears to be more frequent with occurrence of venous injection.
Bilateral movements are possibly a manifestation of disinhibition of cortical activity; unilateral movements sometimes resemble localized response to stimuli such as venous pain on injection {02}.
Pain at injection site occurs immediately and appears to be less frequent when larger, more proximal arm veins are used {02}.



Incidence less frequent or rare
    
Hiccups {02}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Recommended treatment for suspected or apparent overdosage of etomidate includes the following:

Discontinuation of medication.

Supportive care—Supportive measures such as establishing and maintaining a patent airway (intubating, if necessary) and administering oxygen with assisted ventilation, if necessary. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anesthetics, General (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medicine
»   Conditions affecting use, especially:
Sensitivity to etomidate

Pregnancy—Studies in animals have shown etomidate to cause embryocidal effects in rats, decrease pup survival in rats, slightly increase incidence of stillborn fetuses in rats, and cause maternal toxicity in rats and rabbits

Labor and delivery—Use of etomidate is not recommended since data are insufficient to support its use in obstetrics
Other medications, especially alcohol or other CNS depression–producing medications

Proper use of this medication

Proper dosing

Precautions after receiving this medication
» Possibility of psychomotor impairment following use of anesthetics; using caution in driving or performing other tasks requiring alertness and coordination for about 24 hours following anesthesia

» Avoiding use of alcohol or other CNS depressants within 24 hours following anesthesia except as directed by physician or dentist


Side/adverse effects
Signs of potential side effects, especially nausea and/or vomiting, fast or slow breathing, increase or decrease in blood pressure, and irregular, fast, or slow heartbeat


General Dosing Information
Etomidate injection is for intravenous administration only. It is not intended for administration by prolonged infusion because of potential prolonged suppression of endogenous cortisol and aldosterone production {02}.

Although clinical experience and animal studies have shown that inadvertent intra-arterial injection of etomidate usually will not cause necrosis of tissue, intra-arterial injection of etomidate is not recommended {02}.

Intravenous etomidate should be administered only by individuals trained in the administration of general anesthetics and in the management of complications encountered during general anesthesia {02}.

Dosage of etomidate must be individualized for each patient {02}.

Etomidate injection is compatible with commonly administered preanesthetics, which may be used as indicated {02}.

Immediately before anesthesia induction with etomidate, narcotic analgesics (e.g., fentanyl) may be administered to provide analgesia and to minimize pain on injection and involuntary muscle movements. Diazepam also may be used to reduce the incidence and magnitude of involuntary muscle movements {02}.

Concurrent use of etomidate with neuromuscular blocking agents does not significantly alter the usual dosage requirements of these agents when used for endotracheal intubation or other procedures shortly after induction of anesthesia {02}.


Parenteral Dosage Forms

ETOMIDATE INJECTION

Usual adult and adolescent dose
Anesthesia, general (induction of anesthesia)
Dosage must be individualized by physician; however, as a general guideline: Intravenous, 300 mcg (0.3 mg) (range, 200 to 600 mcg [0.2 to 0.6 mg]) per kg of body weight, administered over a period of thirty to sixty seconds {02}.


Note: Smaller increments of etomidate may be administered during short operative procedures to supplement low-potency anesthetics, such as nitrous oxide and oxygen. Although the dosage is usually much smaller than the initial induction dose, it must be individualized {02}.


Usual pediatric dose
Anesthesia, general (induction of anesthesia)
Children up to 10 years of age: Safety and efficacy have not been established {02}.

Children 10 years of age and over—See Usual adult and adolescent dose. {02}


Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


2 mg per mL (Rx) [Amidate (propylene glycol 35% v/v)]{02}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Any unused portion should be discarded. {02}



Revised: 06/01/1999



References
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 293-4.
  1. Amidate package insert (Abbott—US), Rev 5/97, Rec 4/99.
  1. Gooding JM, Weng JT, Smith RA, et al. Cardiovascular and pulmonary responses following etomidate induction of anesthesia in patients with demonstrated cardiac disease. Anesth Analg 1979; 58: 40-1.
  1. Zacharias M, Dundee JW, Clarke RS, et al. Effect of preanaesthetic medication on etomidate. Br J Anaesth 1979; 51: 127-33.
  1. Fragen RJ, Shanks CA, Molteni A, et al. Effects of etomidate on hormonal responses to surgical stress. Anesthesiology 1984; 61: 652-6.
  1. Wagner RL, White PF. Etomidate inhibits adrenocortical function in surgical patients. Anesthesiology 1984; 61: 647-51.
  1. Renou AM, Vernhiet J, Macrez P, et al. Cerebral blood flow and metabolism during etomidate anaesthesia in man. Br J Anaesth 1978; 50: 1047-51.
  1. Kay B. The measurement of occlusion pressure during anaesthesia. A comparison of the depression of respiratory drive by methohexitone and etomidate. Anaesthesia 1979; 34: 543-8.
  1. Arden JR, Holley FO, Stanski DR. Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response. Anesthesiology 1986; 65: 19-27.
  1. Thomson MF, Brock-Utne JG, Bean P, et al. Anaesthesia and intra-ocular pressure: a comparative of total intravenous anaesthesia using etomidate with conventional inhalation anaesthesia. Anaesthesia 1982; 37: 758-61.
  1. Modica PA, Tempelhoff R. Intracranial pressure during induction of anaesthesia and tracheal intubation with etomidate-induced EEG burst suppression. Can J Anaesth 1992; 39: 236-41.
  1. Morgan M, Lumley J, Whitwam JG. Respiratory effects of etomidate. Br J Anaesth 1977; 49: 233-6.
  1. Meuldermans WE, Heykants JJ. The plasma protein binding and distribution of etomidate in dog, rat and human blood. Arch Int Pharmacodyn Ther 1976; 221: 150-62.
  1. Van Hamme MJ, Ghoneim MM, Ambre JJ. Pharmacokinetics of etomidate, a new intravenous anesthetic. Anesthesiology 1978; 49: 274-7.
  1. Haessler R, Madler C, Klasing S, et al. Propofol/fentanyl versus etomidate/fentanyl for the induction of anesthesia in patients with aortic insufficiency and coronary artery disease. J Cardiothorac Vasc Anesth 1992; 6: 173-80.
  1. Fuchs-Buder T, Sparr HJ, Ziegenfuss T. Thiopental or etomidate for rapid sequence induction with rocuronium Br J Anaesth 1998; 80: 504-6.
  1. Hoffman WE, Charbel FT, Edelman G, et al. Comparison of the effect of etomidate and desflurane on brain tissue gases and pH during prolonged middle cerebral artery occlusion. Anesthesiology 1998; 88: 1188-94.
  1. Bergen JM, Smith DC. A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med 1997; 15: 221-30.
  1. Gelissen HP, Epema AH, Henning RH, et al. Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle. Anesthesiology 1996; 84: 397-403.
  1. Van de Wiele B, Rubinstein E, Peacock W, et al. Propylene glycol toxicity caused by prolonged infusion of etomidate. J Neurosurg Anesthesiol 1995; 7: 259-62.
  1. Doenicke A, Lorenz W, Hoernecke R, et al. Histamine release after injection of benzodiazepines and of etomidate. A problem associated with the solvent propylene glycol. Ann Fr Anesth Reanim 1993; 12: 166-8.
  1. Sold M, Rothhammer A. Life-threatening anaphylactoid reaction following etomidate. Anaesthesist 1985; 34: 208-10.
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