Etomidate

Etomidate is a carboxylated imidazole derivative. It consists of two isomers, but only the 11(+)-isomer is the active substance. Like midazolam, which contains an imidazole ring, the drugs undergo intramolecular rearrangement at physiological pH, as a result of which the ring closes and the molecule becomes lipid soluble. Due to its insolubility in water and instability in a neutral solution, the drug is mainly produced as a 2% solution containing propylene glycol by 35% of its volume. Unlike sodium thiopental, etomidate is chemically compatible with muscle relaxants, lidocaine, and vasoactive drugs.

Etomidate: place in therapy

Introduced into clinical practice in 1972, etomidate quickly gained popularity among anesthesiologists due to its favorable pharmacodynamic and pharmacokinetic properties. Later, frequent side effects led to restrictions on its use. However, in recent years, the benefit/side effect ratio has been reconsidered, and etomidate has again come into clinical use because:

• Etomidate causes rapid sleep onset and has minimal effects on hemodynamics
• the likelihood and severity of side effects turned out to be exaggerated;
• rational combination with other drugs neutralizes its side effects;
• The emergence of a new solvent (fat emulsion) has reduced the incidence of side effects.

Currently, it is used mainly when rapid sequence induction and intubation is required in patients with cardiovascular pathology, reactive airway diseases, and intracranial hypertension.

Previously, etomidate was also used at the stage of anesthesia maintenance. Now, due to side effects, it is used for this purpose only in short-term interventions and diagnostic procedures, where the speed of awakening is especially important. The rate of recovery of psychomotor functions is close to that of methohexital. The duration of sleep after a single induction administration is linearly dependent on the dose - every 0.1 mg / kg of the administered drug provides approximately 100 sec of sleep. Although there is no convincing data confirming the anti-ischemic properties of etomidate, it is widely used in neurosurgical vascular interventions. In this case, its ability to reduce elevated intracranial pressure is also taken into account. In patients with trauma against the background of alcohol and / or drug use, etomidate does not cause hemodynamic depression and does not complicate the postoperative assessment of mental status. When used during electroconvulsive therapy, convulsions can be longer than after the administration of other hypnotics.

Sedation by continuous etomidate infusion is currently limited by time limits. Short-term sedation is preferred in cardiac patients with hemodynamic instability.

Etomidate is not recommended for maintenance of anesthesia or prolonged sedation.

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Effect on the central nervous system

Etomidate has a hypnotic effect that is 6 times stronger than methohexital and 25 times stronger than sodium thiopental. It has no analgesic activity. After intravenous administration of an induction dose of the drug, sleep occurs quickly (in one forearm-brain cycle).

Effect on cerebral blood flow

Etomidate has a vasoconstrictor effect on the cerebral vessels and reduces MC (by about 30%) and PMOa (by 45%). Initially elevated intracranial pressure is significantly reduced (up to 50% after the introduction of large doses), approaching normal, and remains so after intubation. BP does not change, therefore CPP does not change or increases. The reaction of vessels to the level of carbon dioxide is preserved. The induction dose of etomidate reduces intraocular pressure (by 30-60%) for the period of hypnotic action of the drug.

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Effect on the cardiovascular system

The minimal effect of etomidate on blood circulation is its main advantage over other induction agents. The main hemodynamic parameters remain unchanged when using conventional induction doses (0.2-0.4 mg/kg) in non-cardiac surgery in cardiac patients. When large doses are administered and in patients with coronary artery disease, hemodynamic changes are minimal. Blood pressure can decrease by 15% due to a decrease in total peripheral vascular resistance. Effects on contractility and conduction function are insignificant. In patients with mitral or aortic valve disease, blood pressure decreases by approximately 20% and tachycardia may occur. In geriatric patients, induction with etomidate, as well as its maintenance infusion, causes a 50% decrease in blood flow and oxygen consumption in the myocardium.

Hemodynamic stability is partly determined by weak stimulation of the sympathetic nervous system and baroreceptors by etomidate. Due to the lack of analgesic properties of the drug, the sympathetic response to laryngoscopy and tracheal intubation is not prevented by etomidate induction.

Effect on the respiratory system

The effect of etomidate on respiration is much weaker than with barbiturates. A short (3-5 min) period of hyperventilation due to tachypnea is observed. Sometimes a short period of apnea is observed, especially with rapid administration of the drug. In this case, PaCO2 increases slightly, but PaO2 does not change. The probability of apnea increases significantly after premedication and coinduction.

Effects on the gastrointestinal tract and kidneys

Etomidate does not affect liver and kidney function even after repeated administration.

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Effect on endocrine response

The data that appeared in the 1980s on the ability of etomidate to inhibit steroid synthesis served as the main reason for skepticism regarding the use of this drug. However, later comparative studies led to the conclusion that:

• after induction with etomidate, adrenocortical suppression is a relatively short-lived phenomenon;
• there is no convincing evidence of adverse clinical outcome associated with etomidate induction;
• Etomidate is safe for use in major traumatic surgeries in terms of the occurrence of infectious complications, myocardial infarction, and hemodynamic disorders.

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Effect on neuromuscular transmission

There is evidence of the effect of etomidate on the neuromuscular block caused by non-depolarizing muscle relaxants.

In particular, the effect of pancuronium is reduced, while that of rocuronium is enhanced.

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Pharmacokinetics

Etomidate is administered intravenously only, after which it is rapidly distributed in the body, binding 75% to plasma proteins. The lipid solubility of the drug is moderate; at physiological blood pH, the drug has a low degree of ionization. The distribution volume at steady state is large and ranges from 2.5 to 4.5 L/kg. The kinetics of etomidate are best described by a three-sector model. In the initial distribution phase, T1/2 is approximately 2.7 min, in the redistribution phase - 29 min, and in the elimination phase - 2.9-3.5 h. Etomidate is metabolized in the liver, mainly by esterase hydrolysis to the corresponding carboxylic acid (the main inactive metabolite), as well as by N-dealkylation. Hypothermia and decreased hepatic blood flow can significantly slow down the metabolism of etomidate.

Due to intensive metabolism, hepatic clearance is quite high (18-25 ml/min/kg). The total clearance of etomidate is approximately 5 times higher than that of sodium thiopental. About 2-3% of the drug is excreted unchanged by the kidneys, the rest is excreted as a metabolite in the urine (85%) and bile (10-13%).

Hypoproteinemia may cause an increase in the free fraction of etomidate in the blood and an increase in the pharmacological effect. In liver cirrhosis, Vdss doubles, but clearance does not change, so T1/2beta increases approximately twofold. With age, the volume of distribution and clearance of etomidate decreases. The main mechanism for the rapid cessation of the hypnotic effect of etomidate is its redistribution to other, less perfused tissues. Therefore, liver dysfunction does not significantly affect the duration of the effect. The accumulation of the drug is insignificant. Intensive metabolism in combination with the already listed features of etomidate allow the drug to be administered in repeated doses or by prolonged infusion.

Electroencephalographic picture

EEG during etomidate anesthesia resembles the effect of barbiturates. The initial increase in alpha wave amplitude is replaced by gamma wave activity. Further deepening of anesthesia is accompanied by periodic bursts of suppression. Unlike sodium thiopental, B waves are not recorded. Etomidate causes a dose-dependent increase in latency and a decrease in the amplitude of early cortical responses to auditory impulses. The amplitude and latency of SSEPs increase, increasing the reliability of their monitoring. Late brainstem responses do not change. The amplitude of MEPs decreases to a lesser extent than with propofol.

Etomidate increases seizure activity in the epileptic focus and can provoke epileptic seizures. This is used for topographic clarification of areas subject to surgical removal. The high frequency of myoclonic movements when using etomidate is not associated with epileptiform-like activity. It is assumed that the cause may be an imbalance in the processes of inhibition and excitation in the thalamocortical interaction, the elimination of the suppressive effect of deep subcortical structures on extrapyramidal motor activity.

Etomidate also reduces the release of glutamate and dopamine in the ischemic zone. Activation of NMDA receptors is involved in ischemic brain damage.

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Interaction

The absence of an analgesic effect of etomidate determines the need for its combined use with other drugs, primarily with opioids. Opioids neutralize some of the undesirable effects of etomidate (pain upon administration, myoclonus), but fentanyl derivatives slow down the elimination of etomidate. BDs also help reduce the likelihood of myoclonus and, unlike opioids, do not increase the risk of PONV. It is possible to enhance the effects of antihypertensive drugs when used together with etomidate.

Combined use of etomidate with ketamine by titrating doses reduces fluctuations in blood pressure, heart rate and coronary perfusion pressure in patients with coronary artery disease. Combined use with other intravenous or inhalation anesthetics, opioids, neuroleptics, tranquilizers changes the time characteristics of recovery towards an increase. Against the background of alcohol intake, the effect of etomidate is potentiated.

Special reactions

Pain when inserted

Pain is felt by 40-80% of patients when etomidate is administered dissolved in propylene glycol (comparable to diazepam). Superficial thrombophlebitis may develop after 48-72 hours. As with other sedative-hypnotic drugs (diazepam, propofol), the likelihood of pain is reduced by using larger veins and preliminary administration of small doses of lidocaine (20-40 mg) or opioids. Accidental intra-arterial administration of etomidate is not accompanied by local or vascular damage.

Signs of agitation and myoclonus

The use of etomidate is accompanied by the appearance of muscle movements at the stage of induction of anesthesia, the frequency of which varies widely (from 0 to 70%). The occurrence of myoclonus is effectively prevented by premedication, including BD or opioids (including tramadol). Premedication also reduces the likelihood of psychomotor agitation and postoperative delirium, which occur more often (up to 80%) with the use of etomidate than after the administration of any other considered intravenous hypnotics. The frequency of myoclonus, pain during administration, and thrombophlebitis are reduced with the infusion technique of etomidate administration. Cough and hiccups are observed in approximately 0-10% of patients.

With propofol, myoclonus occurs less frequently than with etomidate or methohexital, but more frequently than after sodium thiopental. They are observed briefly at the time of induction of anesthesia or during maintenance of anesthesia against the background of preserved spontaneous breathing. Excitation is observed rarely.

Respiratory depression

Etomidate rarely causes apnea and slightly inhibits ventilation and gas exchange.

Apnea with sodium oxybate occurs when the stage of surgical sleep is reached (LS dose 250-300 mg/kg). Due to the slow awakening after short-term interventions, there is a need to maintain the patency of the airways and auxiliary mechanical ventilation.

Hemodynamic shifts

Etomidate has little effect on hemodynamic parameters.

Allergic reactions

When using etomidate, allergic reactions are rare and limited to skin rashes. The drug does not cause histamine release in healthy people or in patients with reactive respiratory diseases. The incidence of cough and hiccups is comparable to that with methohexital induction.

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Postoperative Nausea and Vomiting Syndrome

Traditionally, etomidate was considered a drug that often causes PONV syndrome. According to previous studies, the incidence of this syndrome was 30-40%, which is twice as often as after the use of barbiturates. Combined use with opioids only increased the likelihood of PONV. However, recent studies have cast doubt on the high emetogenicity of etomidate.

Awakening reactions

With etomidate anesthesia, awakening occurs most quickly, with clear orientation, clear restoration of consciousness and mental functions. In rare cases, agitation, neurological and mental disorders, asthenia are possible.

Other effects

Long-term infusion of high doses of etomidate may lead to a hyperosmolar state due to the solvent propylene glycol (the osmolarity of the drug is 4640-4800 mOsm/l). This undesirable effect is much less pronounced in the new dosage form of etomidate (not yet registered in Russia), made on the basis of medium-chain triglycerides, due to which the osmolarity of the drug has decreased to 390 mOsm/l.

Cautions

The following factors must be taken into account:

• age. The duration of action of etomidate may increase slightly with age. In children and elderly patients, the induction dose of etomidate should not exceed 0.2 mg/kg;
• duration of intervention. With prolonged use of etomidate, inhibition of steroidogenesis in the adrenal glands, hypotension, electrolyte imbalance and oliguria are possible;
• concomitant cardiovascular diseases. In patients with hypovolemia and with the introduction of large induction doses of etomidate (0.45 mg/kg), the decrease in blood pressure can be significant and accompanied by a decrease in cardiac output. For cardioversion, etomidate is preferable from the point of view of hemodynamic stability, but it can complicate the assessment of the electrocardiogram (ECG) if myoclonus occurs;
• concomitant respiratory diseases do not have a significant impact on the dosage regimen of etomidate;
• concomitant liver diseases. In cirrhosis, the volume of distribution of etomidate increases, and clearance does not change, so its T1/2 can be significantly increased;
• diseases accompanied by hypoalbuminemia are the cause of increased effects of etomidate. GHB can indirectly increase diuresis;
• There is no data on the safety of etomidate for the fetus. Isolated references indicate its contraindications for use during pregnancy and lactation. Its use for pain relief during labor is inappropriate due to the lack of analgesic activity;
• intracranial pathology. Etomidate should be used with caution in patients with a history of seizures;
• anesthesia in outpatient settings. Despite excellent pharmacokinetic characteristics, the widespread use of etomidate in outpatient settings is limited by the high frequency of excitation reactions. The combined use of opioids and BD prolongs the recovery period. This deprives etomidate of its advantages when used in day hospitals;

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