Etomidate: Anesthetic Properties & Uses PDF

Propofol does not trigger malignant hyperthermia and has been administered to patients with hereditary coproporphyria without incident.105–107 Secretion of cortisol is not influenced by propofol, even when administered for prolonged periods in the ICU. Temporary abolition of tremors in patients with...

Propofol does not trigger malignant hyperthermia and has been administered to patients with hereditary coproporphyria without incident.105–107 Secretion of cortisol is not influenced by propofol, even when administered for prolonged periods in the ICU. Temporary abolition of tremors in patients with Parkinson disease may occur after the administration of propofol.108 For this reason, propofol may not be ideally suited for patients undergoing stereotactic neurosurgery during which the symptom is required to identify the correct anatomic location. Etomidate Etomidate is a carboxylated imidazole–containing compound that is chemically unrelated to any other drug used for the IV induction of anesthesia.109 The imidazole nucleus renders etomidate, like midazolam, water-soluble at an acidic pH and lipid-soluble at physiologic pH. Commercial Preparation The original formulation of etomidate included 35% propylene glycol (pH 6.9) contributing to a high incidence of pain during IV injection and occasional venous irritation. This has been changed to a fat emulsion, which has virtually abolished pain on injection and venous irritation, whereas the incidence of myoclonus remains unchanged. An oral formulation of etomidate for transmucosal delivery has been shown to produce dose-dependent sedation.110 Administration through the oral mucosa results in systemic absorption while bypassing hepatic metabolism. As a result, higher blood concentrations are achieved more rapidly compared with drug that is administered by mouth. Mechanism of Action Etomidate is unique among injected and inhaled anesthetics in being administered as a single isomer.109 The anesthetic effect of etomidate resides predominantly in the R(+) isomer, which is approximately 5 times as potent as the S(−) isomer. In contrast to barbiturates, etomidate appears to be relatively selective as a modulator of GABAA receptors. Stereoselectivity of etomidate supports the concept that GABAA receptors are the site of action of etomidate. Etomidate exerts its effects on GABAA receptors by binding directly to a specific site or sites on the protein and enhancing the affinity of the inhibitory neurotransmitter (GABA) for these receptors.109 Antagonism of steroid-induced psychosis by etomidate is consistent with enhancement of GABA receptor function by this anesthetic drug.111 Etomidate is not known to modulate other ligand-gated ion channels in the brain at clinically relevant concentrations. Pharmacokinetics The Vd of etomidate is large, suggesting considerable tissue uptake (see Table 5.1). Distribution of etomidate throughout body water is favored by its moderate lipid solubility and existence as a weak base (pK 4.2, pH 8.2, 99% unionized at physiologic pH). Etomidate penetrates the brain rapidly, reaching peak levels within 1 minute after IV injection. About 76% of etomidate is bound to albumin independently of the plasma concentration of the drug. Decreases in plasma albumin concentrations result in dramatic increases in the unbound pharmacologically active fraction of etomidate in the plasma. Prompt awakening after a single dose of etomidate principally reflects the redistribution of the drug from brain to inactive tissue sites. Rapid metabolism is also likely to contribute to prompt recovery. Metabolism Etomidate is rapidly metabolized by hydrolysis of the ethyl ester side chain to its carboxylic acid ester, resulting in a water-soluble, pharmacologically inactive compound. Hepatic microsomal enzymes and plasma esterases are responsible for this hydrolysis. Hydrolysis is nearly complete, as evidenced by recovery of less than 3% of an administered dose of etomidate as unchanged drug in urine. About 85% of a single IV dose of etomidate can be accounted for as the carboxylic acid ester metabolite in urine, whereas another 10% to 13% is present as this metabolite in the bile. Overall, the clearance of etomidate is somewhat slower than that for propofol (18-25 mL/kg/minute vs 20-30 m L/kg/minute, respectively). The Vd for etomidate is about half that of propofol (2.5-4.5 L/kg vs 2-10 L/kg, respectively).112–114 Slower clearance will delay elimination, while a small Vd will result in more rapid elimination. In the case of etomidate, the effect of volume dominates, and etomidate has a shorter terminal elimination half-life (3-5 hours) than propofol (4-7 hours). Likewise, the context-sensitive half-time (the time for the plasma level of the drug to drop 50% after cessation of infusion) of etomidate is less likely to be increased by continuous infusion as compared with propofol. Cardiopulmonary Bypass Institution of hypothermic cardiopulmonary bypass causes an initial decrease of about 34% in the plasma etomidate concentration that then returns to within 11% of the pre-bypass value only to be followed by a further decrease with rewarming.26 The return of the plasma concentration toward pre-bypass levels is attributed to decreased metabolism, and the subsequent decrease on rewarming is attributed to increased metabolism. In addition, hepatic blood flow changes during cardiopulmonary bypass may alter metabolism, as etomidate is a high–hepatic extraction drug. Clinical Uses Etomidate may be viewed as an alternative to propofol or barbiturates for the IV induction of anesthesia, especially in the presence of an unstable cardiovascular system. After a standard induction dose of 0.2 to 0.4 mg/kg IV, the onset of unconsciousness occurs within one arm-to-brain circulation time. Involuntary myoclonic movements are common during the induction period as a result of alteration in the balance of inhibitory and excitatory influences on the thalamocortical tract. The frequency of this myoclonic-like activity can be attenuated by prior administration of an opioid. Awakening after a single IV dose of etomidate is more rapid than after barbiturates and similar to that of propofol. This has been tested in numerous settings, including induction of anesthesia for electroconvulsive therapy36 and for cardioversion,115 where awakening occurs within 5 to 15 minutes after doses of etomidate ranging from 0.1 to 0.3 mg/kg and propofol ranging from 0.75 to 1.5 mg/kg,115 and there is little or no evidence of a hangover or cumulative drug effect. Full recovery of psychomotor function after administration of etomidate is somewhat slower than following use of propofol. The duration of action is prolonged by increasing the dose of etomidate or administering the drug as a continuous infusion. As with barbiturates and propofol, analgesia is not produced by etomidate. For this reason, administration of an opioid before induction of anesthesia with etomidate may be useful to blunt the hemodynamic responses evoked by direct laryngoscopy and tracheal intubation. Etomidate, 0.15 to 0.3 mg/kg IV, has minimal effects on the duration of electrically induced seizures and thus may serve as an alternative to drugs that decrease the duration of seizures (propofol, thiopental) in patients undergoing electroconvulsive therapy.38 The principal limiting factor in the clinical use of etomidate for induction of anesthesia is the ability of this drug to transiently depress adrenocortical function (see the “Adrenocortical Suppression” section). It is widely viewed that postoperative nausea and vomiting is increased in patients receiving etomidate for induction of anesthesia.116 Nevertheless, comparison of etomidate with propofol did not document an increased incidence of nausea and vomiting in the first 24 hours after surgery in patients receiving etomidate.117 Side Effects Central Nervous System Etomidate is a potent direct cerebral vasoconstrictor that decreases cerebral blood flow and CMRO2 35% to 45%.118 As a result, previously increased ICP is lowered by etomidate. These effects of etomidate are similar to those changes produced by comparable doses of propofol. Suppression of adrenocortical function limits the clinical usefulness for long-term treatment of intracranial hypertension (see the “Adrenocortical Suppression” section). Etomidate produces a pattern on the EEG that is similar to thiopental and propofol. However, the frequency of excitatory spikes on the EEG is greater with etomidate than with propofol, thiopental, and methohexital, suggesting caution in administration of etomidate to patients with a history of seizures.88 Like methohexital, etomidate may activate seizure foci, manifesting as fast activity on the EEG.119 For this reason, etomidate should also be used with caution in patients with focal epilepsy. Conversely, this characteristic has been observed to facilitate localization of seizure foci in patients undergoing cortical resection of epileptogenic tissue. Etomidate also possesses anticonvulsant properties and has been used to terminate status epilepticus. Etomidate has been observed to augment the amplitude of somatosensory evoked potentials, making monitoring of these responses more reliable.120 Cardiovascular System Cardiovascular stability is characteristic of induction of anesthesia with 0.3 mg/kg IV of etomidate. After this dose of etomidate, there are minimal changes in heart rate, stroke volume, or cardiac output, whereas mean arterial blood pressure may decrease up to 15% because of decreases in systemic vascular resistance. The decrease in systemic blood pressure in parallel with changes in systemic vascular resistance suggests that administration of etomidate to acutely hypovolemic patients could result in sudden hypotension. When an induction dose of etomidate is 0.45 mg/kg IV, significant decreases in systemic blood pressure and cardiac output may occur.121 During induction of patients undergoing elective cardiac surgery, propofol caused a significantly greater decline in mean arterial pressure (MAP) than etomidate, while changes in other hemodynamic parameters were not significantly changed.122 Effects of etomidate on myocardial contractility are important to consider, as this drug has been proposed for induction of anesthesia in patients with little or no cardiac reserve. It is difficult to document anesthetic-induced negative inotropic effects in vivo because of concurrent changes in preload, afterload, sympathetic nervous system activity, and baroreceptor reflex activity. Therefore, direct effects of anesthetics on intrinsic myocardial contractility may be more accurately assessed in vitro. Etomidate causes dose-dependent decreases in developed tension in isolated cardiac muscle obtained from patients undergoing coronary artery bypass graft operations or cardiac transplantation (Figure 5.8).123 This depression was reversible with β-adrenergic stimulation. Nevertheless, concentrations required to produce these negative inotropic effects are in excess of those achieved with clinical use. Thus, etomidate may differ from most other IV anesthetics in that depressive effects on myocardial contractility are minimal at concentrations needed for the production of anesthesia. Hepatic and renal functions tests are not altered by etomidate. Intraocular pressure is decreased by etomidate to a similar degree as by propofol. Etomidate does not result in detrimental effects when accidentally injected into an artery. FIGURE 5.8 Effects of etomidate on maximal rate of contraction (+dT/dt) in nonfailing atrial muscle (A) and in failing atrial and ventricular muscle (B). Mean ≠ standard deviation. *P < .05 versus vehicle. Reprinted with permission from Sprung J, Ogletree-Hughes ML, Moravec CS. The effects of etomidate on the contractility of failing and nonfailing human heart muscle. Anesth Analg. 2000;91(1):68-75. Copyright © 2000 International Anesthesia Research Society. Ventilation The depressant effects of etomidate on ventilation seem to be less than those of barbiturates and propofol, although apnea may occasionally accompany a rapid IV injection of the drug.124 In the majority of patients, etomidateinduced decreases in tidal volume are offset by compensatory increases in the frequency of breathing. These effects on ventilation are transient, lasting only 3 to 5 minutes. Etomidate may stimulate ventilation independently of the medullary centers that normally respond to carbon dioxide. For this reason, etomidate may be useful when maintenance of spontaneous ventilation is desirable. However, careful analysis of the impact of equipotent doses of etomidate on respiration in comparison to other sedative-hypnotics has not been conducted. A recent Cochrane Database review of 23 trials comparing various anesthetic and sedative agents for cardioversion concluded that there were no discernible differences among agents or combinations of agents using in this common setting.125 Depression of ventilation may be exaggerated when etomidate is combined with inhaled anesthetics or opioids during continuous infusion techniques. Pain on Injection Pain on injection and venous irritation has been virtually eliminated with use of etomidate in a lipid emulsion vehicle rather than propylene glycol. Myoclonus Commonly administered IV anesthetics can cause excitatory effects that may manifest as spontaneous movements, such as myoclonus, dystonia, and tremor. These spontaneous movements, particularly myoclonus, occur in 50% to 80% of patients receiving etomidate in the absence of premedication.88 In one report, 87% of patients receiving etomidate developed excitatory effects, of which 69% were myoclonic. Multiple spikes appeared on the EEG of 22% of these patients.88 In this same report, the frequency of excitatory effects was 17% after thiopental, 13% after methohexital, and 6% after propofol, and none of the patients treated with other drugs developed myoclonus with spike activity on the EEG.88 Inclusion of atropine in the preoperative medication may suppress spike activity on the EEG associated with the administration of etomidate. Prior administration of an opioid (fentanyl, 1-2 μg/kg IV) or a benzodiazepine may decrease the incidence of myoclonus associated with administration of etomidate. Furthermore, the incidence and intensity of myoclonus following the administration of etomidate is dose related and suppressed by pretreatment with small doses of etomidate (0.03-0.075 mg/kg IV) before administration of the induction dose.126 The mechanism of etomidate-induced myoclonus appears to be disinhibition of subcortical structures that normally suppress extrapyramidal motor activity. In many patients, excitatory movements are coincident with the early slow phase of the EEG, which corresponds to the beginning of deep anesthesia.88 It is possible that myoclonus could occur on awakening if the extrapyramidal system emerged more quickly than the cortex that inhibits it.127 Others have not documented seizure-like activity on the EEG in association with etomidate-induced myoclonus.126 Adrenocortical Suppression Etomidate causes adrenocortical suppression by producing a dose-dependent inhibition of the conversion of cholesterol to cortisol (Figure 5.9).128,129 The specific enzyme inhibited by etomidate appears to be 11-β-hydroxylase as evidenced by the accumulation of 11-deoxycorticosterone.130 This enzyme inhibition lasts 4 to 8 hours after an induction dose of etomidate. Conceivably, patients experiencing sepsis or hemorrhage and who might require an intact cortisol response would be at a disadvantage should etomidate be administered.131 Conversely, suppression of adrenocortical function could be considered desirable from the standpoint of “stress-free” anesthesia. Nevertheless, in at least one report, it was not possible to demonstrate a difference in the plasma concentrations of cortisol, corticosterone, or adrenocorticotrophic hormone in patients receiving a single dose of etomidate or thiopental.132 In a retrospective study of almost 1,700 trauma patients receiving a single induction dose of etomidate or another induction agent, use of etomidate had no impact on mortality, length of ICU stay, or duration of mechanical ventilation.133 In a retrospective study of more than 3,000 cardiac surgical patients who received etomidate for induction of anesthesia, there was no evidence to suggest that etomidate exposure was associated with severe hypotension, longer mechanical ventilation hours, longer length of hospital stay, or in-hospital mortality.134 In contrast, another large-scale retrospective study demonstrated that anesthetic induction with etomidate, rather than propofol, was associated with increased 30-day mortality and cardiovascular morbidity after noncardiac surgery.135 The clinical benefit of minimizing cardiac suppression should be carefully weighed against the potential for worsened long-term outcomes when using propofol in high-risk patients. FIGURE 5.9 Etomidate, but not thiopental, is associated with decreases in the plasma concentrations of cortisol. Mean ± standard deviation. *P < .05 compared with thiopental. Reprinted with permission from Fragen RJ, Shanks CA, Molteni A, et al. Effects of etomidate on hormonal responses to surgical stress. Anesthesiology. 1984;61(6):652-656. Copyright © 1984 American Society of Anesthesiologists, Inc. Allergic Reactions The incidence of allergic reactions following administration of etomidate is very low.136 When reactions have occurred, it is difficult to separate the role of etomidate from other concomitantly administered drugs (neuromuscular blocking drugs) that are more likely to evoke histamine release than etomidate. Benzodiazepines Benzodiazepines are drugs that exert, in slightly varying degrees, five principal pharmacologic effects: anxiolysis, sedation, anticonvulsant actions, spinal cord–mediated skeletal muscle relaxation, and anterograde amnesia (acquisition or encoding of new information).137 The amnestic potency of