This etomidate

This ethomidate is a carboxylated imidazole derivative. It consists of two isomers, but only the 11 (+) - isomer is an active substance. As midazolam containing an imidazole ring, the preparations undergo intramolecular rearrangement at physiological pH, as a result of which the ring is closed and the molecule acquires fat solubility. Due to the insolubility in water and the instability in the neutral solution, the drug is mainly released as a 2% solution containing 35% volume propylene glycol. Unlike thiopental sodium, etomidate is chemically compatible with muscle relaxants, lidocaine, vasoactive drugs.

Etomidate: a place in therapy

Introduced in clinical practice in 1972, etomidate quickly gained popularity among anesthesiologists due to its favorable pharmacodynamic and pharmacokinetic properties. Later, frequent side effects led to a restriction of its use. However, in recent years, there has been a review of the benefit / side effects ratio, and this is again applied in the clinic because:

• etomidate causes a rapid onset of sleep and minimally affects hemodynamics
• the probability and severity of side effects was exaggerated;
• a rational combination with other drugs neutralizes its side effects;
• the appearance of a new solvent (fat emulsion) allowed to reduce the incidence of side effects.

At present, it is used mainly for the need for rapid sequential induction and intubation in patients with cardiovascular pathology, reactive respiratory diseases, intracranial hypertension.

Previously, this etimidate was also used at the stage of maintaining anesthesia. Now, because of side effects for this purpose, it is used only for short-term interventions and diagnostic procedures, where the speed of awakening is especially important. The speed of recovery of psychomotor functions approaches that of methohexital. The duration of sleep after a single induction is linearly dose-dependent - every 0.1 mg / kg of injected drugs provide approximately 100 seconds of sleep. Although there is no conclusive evidence supporting the anti-ischemic properties of etomidate, it is widely used in neurosurgical vascular interventions. At the same time, its ability to reduce increased intracranial pressure is also taken into account. In patients with trauma associated with alcohol and / or drug use, etomidate does not cause depression of hemodynamics and does not complicate post-operative assessment of mental status. If used during electroconvulsive therapy, seizures may be more prolonged than after the administration of other hypnotics.

The sedation by continuous infusion of etomidate is now limited to a time frame. Short-term sedation is preferred in cardiac patients with hemodynamic instability.

This etimidate is undesirable for maintaining anesthesia and prolonged sedation.

[1], [2], [3], [4], [5], [6], [7], [8],

Influence on the central nervous system

Etomidate has a hypnotic effect, which is six times stronger than that of methohexital, and 25 times that of thiopental sodium. Analgesic activity, he does not. After intravenous injection of an induction dose of LS quickly comes to sleep (for one cycle of the forearm - the brain).

Effects on cerebral blood flow

Etomidate has a vasoconstrictive effect on the vessels of the brain and reduces MK (by about 30%) and PMOA (by 45%). Initially, increased intracranial pressure is significantly reduced (to 50% after the administration of large doses), approaching normal, and remains so after intubation. The BP does not change, so the CPU does not change or increase. The reaction of blood 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 drugs.

[9], [10], [11], [12], [13], [14], [15], [16],

Influence on the cardiovascular system

The minimal effect of etomidate on blood circulation is its main advantage over other induction drugs. The main parameters of hemodynamics remain unchanged when using conventional induction doses (0.2-0.4 mg / kg) with noncardiac surgical interventions in cardiac patients. With the introduction of large doses and in patients with ischemic heart disease, hemodynamic changes are minimal. Blood pressure can decrease by 15% due to a decrease in OPSS. Effects on the function of contractility and conductivity are insignificant. In patients with mitral or aortic valve lesions, blood pressure decreases by approximately 20% and tachycardia can occur. In geriatric patients, induction with etomidate, as well as its maintenance infusion, causes a 50% reduction in blood flow and oxygen consumption in the myocardium.

The stability of hemodynamics is partly determined by the weak stimulation of etimidate of the sympathetic nervous system and baroreceptors. Due to the lack of analgesic properties in LS, the sympathetic response to laryngoscopy and intubation of the trachea during induction with etomidate is not prevented.

Influence on the respiratory system

The effect of etomidate on respiration is much weaker than with barbiturates. There is a short (3-5 min) period of hyperventilation due to tachypnea. Sometimes a short period of apnea is observed, especially with the rapid administration of drugs. This slightly increases PaCO2, but PaO2 does not change. The likelihood of apnea increases significantly after premedication and with co-induction.

Effects on the gastrointestinal tract and kidneys

This etimidate does not affect the function of the liver and kidneys even after repeated administration.

[17], [18], [19], [20]

Effect on the endocrine response

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

• after induction by etomidate, adrenocortical suppression is a relatively short-term phenomenon;
• There is no conclusive evidence of an adverse clinical outcome associated with the induction of etomidate;
• etomidate is safe for use in large traumatic operations with respect to the occurrence of infectious complications, myocardial infarction, hemodynamic disorders.

[21], [22]

Effect on neuromuscular transmission

There is evidence of the effect of etomidate on the neuromuscular block caused by nondepolarizing muscle relaxants.

In particular, the effect of pancuronium decreases, and rocuronium - is enhanced.

[23], [24], [25], [26], [27]

Pharmacokinetics

Etomidate is administered only in / in, after which it is quickly distributed in the body, 75% bound to plasma proteins. Fat solubility of drugs is moderate, at a physiological pH value of the blood of the drug has a low degree of ionization. The volume of distribution in the equilibrium state is large and varies from 2.5 to 4.5 l / kg. The kinetics of etomidate is better described by a three-sector model. The phase of the initial T1 / 2 distribution is approximately 2.7 min, in the redistribution phase - 29 min, and in the elimination phase - 2.9-3.5 h. Metabolism of this etomidate occurs 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 greatly slow the metabolism of etomidate.

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

Hypoproteinemia can cause an increase in the free fraction of etomidate in the blood and enhance the pharmacological effect. With cirrhosis of the liver Vdss doubles, but the clearance does not change, so T1 / 2beta increases approximately twice. 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 into other, less perfused tissues. Therefore, liver dysfunction does not have a significant effect on the duration of the effect. Cumulation of drugs is negligible. Intensive metabolism in combination with the already listed features of etomidate allows you to inject the medication with repeated doses or prolonged infusion.

Electroencephalographic picture

EEG in anesthesia with etomidate resembles the effect of barbiturates. The initial increase in the amplitude of alpha waves is replaced by gamma-wave activity. Further deepening of anesthesia is accompanied by the periodic appearance of suppressant outbreaks. Unlike thiopental sodium, B-waves are not detected. This etomidate causes a dose-dependent increase in latency and a decrease in the amplitude of early cortical responses to auditory impulses. Amplitude and latency of SSEP increases, increasing the reliability of their monitoring. Late brain stem response does not change. The amplitude of the MWP decreases to a lesser extent than when using propofol.

This etomidate causes an increase in convulsive activity in the epileptic focus and may provoke epileptic seizures. This is used for topographical refinement of sites subject to operational 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.

This etomidate also reduces the release of glutamate and dopamine in the ischemic zone. Activation of NMDA receptors is implicated in ischemic brain damage.

[28], [29]

Interaction

The lack of analgesic effect in etomidata determines the need for its joint use with other drugs, primarily with opioids. Opioids neutralize some of the undesirable effects of etomidate (pain upon administration, myoclonia), however, fentanyl derivatives slow the elimination of etomidate. OBDs also contribute to reducing the likelihood of myoclonus and, unlike opioids, do not increase the risk of POND. It is possible to intensify the effects of antihypertensive drugs when combined with etomidate.

Combined application of etomidate with ketamine by titration of doses reduces fluctuations in blood pressure, heart rate and coronary perfusion pressure in patients with ischemic heart disease. Sharing with other intravenous or inhalation anesthetics, opioids, antipsychotics, tranquilizers changes the temporal characteristics of recovery upwards. Against the background of alcohol intake, the action of ethomidate is potentiated.

Special reactions

Pain when administered

Pain affects 40-80% of patients with the administration of ethomidate, dissolved in propylene glycol (comparable to diazepam). After 48-72 hours, surface thrombophlebitis may develop. As with other sedative hypnotic drugs (diazepam, propofol), the likelihood of pain decreases with the use of 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 lesions.

Signs of arousal and myoclonus

The use of etomidate is accompanied by the appearance of muscle movements during the induction of anesthesia, the frequency of which varies widely (from 0 to 70%). The occurrence of myoclonium is effectively prevented by premedication, including a DB or opioids (including tramadol). Premedication also reduces the likelihood of psychomotor agitation and postoperative delirium, which occurs more often (up to 80%) when using etomidate than after the administration of any other hypnotics considered in / in. The frequency of myoclonias, pain upon administration and thrombophlebitis decrease with the infusion technique of etomidate administration. Cough and hiccough are observed in about 0-10% of patients.

With the administration of propofol myoclonus occurs less frequently than with the administration of etomidate or metohexital, but more often than after thiopental sodium. They are observed briefly at the time of induction of anesthesia or while maintaining anesthesia against the background of self-contained respiration. Excitation is rare.

Inhibition of respiration

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

Apnea with the use of sodium oxybate occurs when the stage of surgical sleep (dose of the drug is 250-300 mg / kg). Due to delayed awakening after short-term interventions, it becomes necessary to maintain airway patency and assistive ventilation.

Hemodynamic changes

Etomidate slightly affects the parameters of hemodynamics.

Allergic reactions

When using etomidata allergic reactions occur rarely and are limited to skin rashes. The drug does not cause histamine release in either healthy or in patients with reactive respiratory diseases. The frequency of occurrence of cough and hiccoughs is comparable to that of induction by metohexital.

[30], [31]

Postoperative nausea and vomiting syndrome

Traditionally, etomidate was considered a drug that often causes POND syndrome. According to previous studies, the incidence of this syndrome was 30-40%, which is twice as likely as after using barbiturates. Sharing with opioids only increased the likelihood of POT. However, recent studies have questioned the high emetogenicity of etomidate.

Reaction of awakening

In anesthesia with etomidata, awakening occurs most rapidly, with a clear orientation, a clear restoration of consciousness and mental functions. In rare cases, excitation, neurological and mental disorders, asthenia are possible.

Other effects

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

Caveats

It is necessary to consider the following factors:

• age. With age, the duration of action of etomidate may increase slightly. In children and in elderly patients, the induction dose of etomidate should not exceed 0.2 mg / kg;
• duration of intervention. With prolonged use of etomidate oppression of steroidogenesis in the adrenal glands, hypotension, electrolyte imbalance and oliguria are possible;
• concomitant cardiovascular diseases. In patients with hypovolemia and with the administration of large induction doses of etomidate (0.45 mg / kg), the decrease in blood pressure can be significant and accompanied by a decrease in CB. To perform cardioversion, etomidate is preferred from the point of view of hemodynamic stability, but it may make it difficult to evaluate the electrocardiogram (ECG) in the occurrence of myoclonus;
• concomitant diseases of the respiratory system do not have a significant effect on the dosage regimen of etomidate;
• concomitant liver disease. With cirrhosis, the volume of distribution of etomidate increases, and the 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 enhance diuresis;
• data on the safety of etomidata for the fetus are absent. Single references indicate its contraindications to use during pregnancy and lactation. For analgesia in childbirth, its use is impractical due to the lack of analgesic activity;
• intracranial pathology. Care should be taken to use etomidate in patients with a history of convulsive syndrome;
• anesthesia on an outpatient basis. Despite the excellent pharmacokinetic characteristics, the widespread use of etomidate in polyclinic conditions is limited by the high frequency of excitation reactions. Joint use of opioids and DB prolongs the recovery time. This deprives etomidat benefits when using it in hospitals one day;

[32], [33]