Ketamine

Ketamine is the only one of nearly 200 phencyclidine derivatives that is used clinically. The others were rejected due to a large number of psychomimetic side effects. Ketamine is available as a weakly acidic solution with the stabilizer benzethonium chloride.

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Ketamine: a place in therapy

Ketamine is a special drug not only in terms of its unique hemodynamic effects, but also because it can be used for premedication (in children), and administered intramuscularly. The use of ketamine for induction of anesthesia is most preferable in patients with a high risk of perioperative complications (above ASA class III), when the sympathomimetic and bronchodilating effects of ketamine are desirable. Ketamine is indicated for anesthesia in patients with:

• hypovolemia;
• cardiomyopathy (without concomitant coronary artery disease);
• hemorrhagic and infectious-toxic shock;
• cardiac tamponade;
• compressive pericarditis;
• congenital heart defect with right-to-left shunt;
• bronchospastic diseases
• respiratory tract (eg, asthma).

Ketamine is the drug of choice for rapid sequence induction and tracheal intubation. It can be used for labor pain relief. Propofol, ketamine, and etomidate are safe in patients at risk for malignant hyperthermia and acute intermittent porphyria.

In all the above cases, ketamine is indicated for maintaining anesthesia. It can be administered by prolonged infusion or boluses as a monoanesthetic or in combination with other intravenous or inhalation drugs. It should be noted that when using ketamine without opioids in traumatic abdominal surgeries, large doses are required, which significantly slows down recovery. Ketamine is the anesthetic of choice in obstetrics and gynecology, for short-term diagnostic and therapeutic interventions.

Combination with BD (midazolam, diazepam) and/or opioids (alfentanill, remifentanill) alleviates or eliminates unwanted tachycardia and hypertension. This expands the indications for the use of ketamine in patients with valvular and ischemic heart disease. In addition, awakening reactions are prevented. The ability to create high oxygen concentrations is desirable in thoracic surgery and in patients with concomitant COPD.

Ketamine in combination with BD and/or opioids is successfully used for sedation during conduction and regional anesthesia, as well as in the postoperative period. It has proven its exceptional usefulness in pediatric practice. In children, ketamine is less likely to cause psychomimetic side effects. Therefore, it is used not only for induction, maintenance of anesthesia and sedation, but also for regional blockades and for procedures outside the operating room:

• angiosurgical, diagnostic and therapeutic interventions;
• radiological studies;
• treating wounds and changing dressings;
• dental procedures;
• radiation therapy, etc.

Subanesthetic (analgesic) doses of ketamine are usually used for dressings. This, along with rapid recovery of consciousness, facilitates early food intake, which is extremely important for burn patients. Due to its minor suppression of spontaneous breathing and good analgesia, ketamine is indispensable for patients with burns of the face and respiratory tract.

When performing cardiac catheterization in children, the intrinsic stimulating effects of ketamine must be taken into account when interpreting the data obtained.

Ketamine is usually administered intravenously. In pediatrics, it can be administered intramuscularly, orally, intranasally, or rectally. When administered intramuscularly, larger doses are required due to the first-pass effect of the drug through the liver.

In some countries, the epidural and subarachnoid routes of ketamine administration are used to a limited extent. With these routes of administration, analgesia is not accompanied by respiratory depression. However, the effectiveness of epidural anesthesia with ketamine is questionable, since its affinity for opioid receptors of the spinal cord is thousands of times less than that of morphine. The drug probably has not only spinal but also systemic effects. Intrathecal administration causes variable and short-term analgesia. Addition of the S-(+) isomer of ketamine to bupivacaine increases the duration, but not the intensity of the epidural block.

Mechanism of action and pharmacological effects

Ketamine exerts its main effects at the thalamocortical level. Its complex action involves selective inhibition of neuronal transmission in the cerebral cortex, especially in the associative areas, and the thalamus. At the same time, parts of the limbic system, including the hippocampus, are stimulated. As a result, functional disorganization of non-specific connections in the midbrain and thalamus occurs. In addition, impulse transmission in the reticular formation of the medulla oblongata is inhibited, and afferent nociceptive stimuli from the spinal cord to higher brain centers are blocked.

It is assumed that the hypnotic and analgesic mechanisms of ketamine action are due to the effect on various types of receptors. General anesthetic and partly analgesic effects are associated with postsynaptic non-competitive blockade of NMDA receptors permeable to Ca2+ ions. Ketamine occupies opioid receptors in the brain and dorsal horns of the spinal cord. It also enters into antagonistic relationships with monoaminergic, muscarinic receptors and calcium channels. Anticholinergic effects are manifested by bronchodilation, sympathomimetic action, delirium and are partially eliminated by anticholinesterase drugs. The effects of ketamine are not associated with the effect on GABA receptors and blockade of sodium channels in the CNS. Greater activity in relation to the cortex than the thalamus is apparently associated with the uneven distribution of NMDA receptors in the CNS.

Effect on the central nervous system

Anesthesia with ketamine differs fundamentally from that caused by other anesthetics. First of all, this state, similar to cataleptic, differs from normal sleep. The patient's eyes may be open, the pupils are moderately dilated, nystagmus is observed. Many reflexes are preserved, but should not be considered protective. Thus, the corneal, cough and swallowing reflexes are not completely suppressed. Increased skeletal muscle tone, lacrimation and salivation are typical. Uncontrolled movements of the limbs, trunk and head are possible, independent of surgical stimulation. To ensure anesthesia, plasma concentrations are individually variable: from 0.6 to 2 μg/ml for adults and from 0.8 to 4 μg/ml for children.

In addition, ketamine, unlike other intravenous sedative-hypnotic drugs, causes quite pronounced analgesia. Moreover, analgesia is observed at significantly lower concentrations of the drug in the plasma than loss of consciousness. Due to this, subanesthetic doses have an analgesic effect, and there is a significant period of analgesia after anesthesia with ketamine. Analgesia affects the somatic component of pain to a greater extent than the visceral one.

After intravenous administration of an induction dose of ketamine (2 mg/kg), awakening occurs after 10-20 minutes. However, full restoration of orientation in person, place and time occurs after another 15-30 minutes, sometimes after 60-90 minutes. During this time, anterograde amnesia persists, but not as pronounced as with benzodiazepines.

Effect on cerebral blood flow

Ketamine is a cerebral vasodilator, increases MBF (by about 60%), PMO2, and increases intracranial pressure. The sensitivity of cerebral vessels to carbon dioxide is preserved, so hypercapnia attenuates the ketamine-induced increase in intracranial pressure. At present, however, there is no consensus on the ability of ketamine to increase intracranial pressure, particularly in patients with brain and spinal cord injuries.

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Electroencephalographic picture

When using ketamine, the EEG is largely specific. In the absence of the alpha rhythm, generalized hypersynchronous 9-activity dominates, which reflects CNS excitation and epileptiform activity in the thalamus and limbic system (but not in the cortex). In addition, 6-waves indicate analgesic activity, while alpha waves indicate its absence. The appearance of 5-activity coincides with loss of consciousness. In high doses, ketamine can cause bursts of suppression. Determining the depth of ketamine anesthesia based on EEG analysis and its transformations presents certain difficulties due to low information content. This is also not facilitated by the possibility of nystagmus when using it. Ketamine increases the amplitude of cortical SSEP responses and, to a lesser extent, their latency. Responses to brainstem SEPs are suppressed.

Ketamine does not change the seizure threshold in patients with epilepsy. Despite the possibility of myoclonus even in healthy patients, the drug does not have seizure activity.

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Effect on the cardiovascular system

Ketamine is a unique intravenous anesthetic in terms of its effect on the cardiovascular system. Its use is usually accompanied by an increase in blood pressure (by an average of 25%), heart rate (by an average of 20%) and cardiac output. This is accompanied by an increase in the work and oxygen consumption of the myocardium. In a healthy heart, increased oxygen requirements are compensated by an increase in cardiac output and a decrease in coronary vascular resistance. Ketamine can significantly increase pulmonary artery pressure, pulmonary vascular resistance, and intrapulmonary shunt.

Interestingly, the hemodynamic effects of ketamine are independent of the dose used, and repeated administration of the drug causes smaller or even opposite effects. Ketamine has a similar stimulating effect on hemodynamics in heart disease. With initially elevated pulmonary arterial pressure (as in mitral or some congenital defects), the degree of increase in pulmonary vascular resistance is higher than that of systemic.

The mechanism of ketamine's stimulating effect on blood circulation is unclear. There is reason to believe that it is not a peripheral effect, but rather a central effect via NMDA receptors in the nuclei of the solitary tract. Thus, central sympathetic stimulation prevails over the direct negative inotropic effect of ketamine on the myocardium. Sympatho-neuronal release of adrenaline and noradrenaline also occurs.

Effect on the respiratory system

The effect of ketamine on the sensitivity of the respiratory center to carbon dioxide is minimal. However, a temporary decrease in the MV after an induction dose is possible. Excessively high doses, rapid administration, or combined administration of opioids can cause apnea. In most cases, arterial blood gases do not change significantly (an increase in PaCO2 within 3 mm Hg). When used in combination with other anesthetics or analgesics, severe respiratory depression may occur. In children, the depressing effect of ketamine on respiration is more pronounced.

Ketamine, like halothane or enflurane, relaxes the smooth muscles of the bronchi, reduces pulmonary resistance, and in subanesthetic doses relieves bronchospasm. It is effective even in asthmatic status. The mechanism of ketamine's bronchodilating action is not precisely known. It is assumed that it is associated with the sympathomimetic effect of catecholamines, as well as with direct suppression of postsynaptic nicotinic, muscarinic, or histamine receptors in the bronchi.

It is important to consider (especially in children) the increased salivation associated with ketamine and the associated risk of airway obstruction and laryngospasm. In addition, there are cases of unnoticed aspiration during ketamine anesthesia despite the preservation of the swallowing, cough, sneeze, and gag reflexes.

Effects on the gastrointestinal tract and kidneys

Ketamine does not affect liver or kidney function even after repeated administration. Although there is evidence that ketamine reduces hepatic blood flow by about 20%.

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Effect on endocrine response

The endocrine effects of ketamine are largely contradictory. Hyperdynamics of blood circulation was attributed to activation of the adrenocortical system, release of endogenous norepinephrine, adrenaline. Subsequently, more evidence appeared on the central mechanism of these cardiovascular reactions. After induction administration of ketamine, an increase in prolactin and luteinizing hormone levels is also recorded.

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Effect on neuromuscular transmission

Ketamine increases muscle tone. However, it is believed to potentiate the action of non-depolarizing muscle relaxants. The mechanism of this interaction has not been established. It is thought to interfere with calcium binding or transport, and to reduce the sensitivity of the postsynaptic membrane to relaxants. The duration of apnea induced by suxamethonium is increased, probably reflecting ketamine's suppression of plasma cholinesterase activity.

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Tolerance and dependence

Chronic ketamine use stimulates enzymatic activity. This partly explains the development of tolerance to the analgesic effect in patients receiving repeated doses of the drug. Such a condition is observed, for example, in burn patients with frequent dressing changes under ketamine anesthesia. There are currently no reliable data on the safety limits of repeated use of ketamine. The development of tolerance is also consistent with reports of ketamine addiction. Ketamine is a drug that is subject to abuse for non-medical purposes.

Pharmacokinetics

The pharmacokinetics of ketamine have not been studied as thoroughly as many other intravenous anesthetics. Ketamine has high lipid solubility (5-10 times greater than sodium thiopental), which is reflected in a fairly large distribution volume (about 3 l/kg). Due to its lipid solubility and low molecular weight, it easily penetrates the BBB and has a rapid effect. Peak plasma concentrations are achieved 1 min after intravenous and 20 min after intramuscular administration. When taken orally, the sedative effect develops after 20-45 minutes (depending on the dose). Plasma protein binding is insignificant.

The kinetics of the drug is described by a two-sector model. After bolus administration, the drug is rapidly distributed among organs and tissues (in 11-16 min). Ketamine is metabolized in the liver with the participation of microsomal cytochrome P450 enzymes. Several metabolites are formed. Mainly, N-demethylation occurs with the formation of norketamine, which is then hydroxylated to hydroxynorketamine. Norketamine is approximately 3-5 times less active than ketamine. The activity of other metabolites (hydroxyketamines) has not yet been studied well. The metabolites are then excreted by the kidneys as inactive glucuronide derivatives. Less than 4% of unchanged ketamine is excreted in the urine, less than 5% in the feces.

The total clearance of ketamine from the body is almost equal to the hepatic blood flow (1.4 l/min). Therefore, a decrease in hepatic blood flow entails a decrease in ketamine clearance. High hepatic clearance and a large volume of distribution explain the relatively short T1/2 of the drug in the elimination phase - from 2 to 3 hours.

Contraindications

The use of a racemic mixture of ketamine and the S-enantiomer is contraindicated in patients with intracranial injury and increased ICP due to the risk of further increase and apnea. Due to the risk of hypertension, tachycardia and increased myocardial oxygen consumption, it should not be used as the only anesthetic in patients with coronary artery disease, paroxysmal ventricular tachycardia, in patients with vascular aneurysms, arterial hypertension and symptomatic hypertension, as well as pulmonary hypertension. Ketamine is contraindicated in patients in whom an increase in intraocular pressure is undesirable (in particular, in case of open eye injuries). It is also contraindicated in mental illnesses (e.g. schizophrenia), as well as in case of an adverse reaction to ketamine or its analogues in the past. It is undesirable to use ketamine in case of risk of postoperative delirium (in alcoholics, drug addicts), probability of head injury, the need for differential assessment of psychoneurological status.

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Tolerability and side effects

There is evidence of neurotoxicity of the ketamine stabilizer chlorobutanol when administered subarachnoidally and epidurally. The likelihood of such toxicity is considered low for the S-(+) isomer of ketamine.

Pain when inserted

When ketamine is administered, there is virtually no reaction from the venous wall.

During induction and even during maintenance of ketamine anesthesia (without muscle relaxants), muscle tone increases, fibrillary twitching of skeletal muscles and involuntary movements of the limbs are possible. More often, this is not a sign of inadequate anesthesia, but a consequence of stimulation of the limbic system.

Compared with other steroid anesthetics, pregnenolone does not cause excitation during induction.

Respiratory depression

Ketamine in most cases causes short-term respiratory depression. However, with rapid administration, use of large doses, combination with opioids, in weakened patients there is usually a need for respiratory support. Indirect effects of ketamine are also important - increased tone of the masticatory muscles, retraction of the root of the tongue, hyperproduction of saliva and bronchial mucus. To prevent cough and laryngospasm associated with hypersalivation, glycopyrrolate is indicated. It is preferable to atropine or scopolamine, which easily penetrate the BBB and can increase the likelihood of delirium.

Hemodynamic shifts

Cardiovascular stimulation is a side effect of ketamine and is not always desirable. Such effects are best prevented by BD, as well as barbiturates, droperidol, and inhalation anesthetics. Adrenergic blockers (both alpha and beta), clonidine, or other vasodilators are effective. In addition, less tachycardia and hypertension are observed with the infusion technique of ketamine administration (with or without BD).

It should be taken into account that the hyperdynamic effect of ketamine in patients with severe hypovolemia with untimely replenishment of the circulating blood volume and inadequate anti-shock therapy can lead to depletion of the compensatory capabilities of the myocardium. With prolonged shock, the regulation of cardiac activity at the level of the structures of the midbrain and medulla oblongata is disrupted, therefore, against the background of the use of ketamine, stimulation of blood circulation does not occur.

Allergic reactions

Ketamine is not a histamine liberator and does not usually cause allergic reactions.

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Postoperative Nausea and Vomiting Syndrome

Ketamine and, to a lesser extent, sodium oxybate are highly emetogenic drugs.

Among intravenous sedative-hypnotic agents, ketamine is comparable in its ability to provoke PONV only to etomidate. However, this effect of the drug can be prevented in most cases by appropriate prophylaxis.

Awakening reactions

Although the literature reports that the incidence of awakening reactions with ketamine as the sole or primary anesthetic varies from 3 to 100%, clinically significant reactions in adult patients occur in 10-30% of cases. The incidence of awakening reactions is influenced by age (over 15 years), dose (> 2 mg/kg IV), gender (more common in women), mental susceptibility, personality type, and use of other drugs. Dreams are more likely in individuals who usually have vivid dreams. Music during anesthesia does not reduce the incidence of psychomimetic reactions. Awakening reactions are less common in children of both sexes. Psychological changes in children after ketamine and inhalation anesthetics do not differ. Severe awakening reactions are less common with repeated uses of ketamine. For example, they are rare after three or more ketamine anesthetics. Ketamine has no specific antagonists. Various drugs have been used to reduce and treat awakening reactions, including barbiturates, antidepressants, BD, and neuroleptics, although, according to some data, droperidol may increase the likelihood of delirium. BD, especially midazolam, have shown the best effectiveness. The mechanism of this effect is unknown, but it probably occurs due to the sedative and amnestic effects of BD. Prevention by administering piracetam at the end of the operation has proven effective.

The cause of awakening reactions is considered to be a disturbance in the perception and/or interpretation of auditory and visual stimuli as a result of depression of the auditory and visual relay nuclei. Loss of cutaneous and musculoskeletal sensitivity reduces the ability to sense gravity.

Impact on immunity

Ketamine not only does not suppress the immune system, but even slightly increases the content of T- and B-lymphocytes.

Interaction

Ketamine is not recommended for use without other drugs for anesthesia. Firstly, it prevents psychomimetic reactions upon awakening. This outweighs the inconvenience associated with some slowing down of the recovery period. Secondly, it helps to reduce other side effects of each drug. Thirdly, the analgesic effect of ketamine is insufficient for performing traumatic abdominal interventions, and the administration of large doses significantly prolongs the recovery period.

Ketamine neutralizes the depressant effect of sodium thiopental and propofol on hemodynamics during induction and maintenance of anesthesia. In addition, it significantly reduces the cost of propofol anesthesia. Their interaction is additive, so the dose of each drug should be reduced by about half.

CNS depression caused by volatile anesthetics and BD prevents unwanted central sympathetic effects. Therefore, their combined use with ketamine may be accompanied by hypotension. In addition, volatile anesthetics themselves can cause auditory, visual, proprioceptive hallucinations and confusion. The risk of awakening reactions is probably increased. Sodium thiopental and diazepam block the ketamine-induced increase in MBF. The combined use of ketamine with atropine may lead to excessive tachycardia and rhythm disturbances, especially in elderly patients. In addition, atropine may increase the likelihood of postoperative delirium. Pancuronium may enhance the cardiostimulatory effects of ketamine. Verapamil reduces ketamine-induced hypertension, but does not slow the heart rate.

The use of drugs that reduce hepatic blood flow may lead to a decrease in ketamine clearance. Volatile anesthetics may have this effect. Diazepam and lithium preparations also slow down the elimination of ketamine. The combined use of ketamine and aminophylline lowers the threshold for seizures. Mixing ketamine and barbiturates in one syringe leads to sediment formation.

Cautions

Despite the obvious individual advantages and relative safety of non-barbiturate sedative-hypnotic drugs, the following factors must be taken into account:

• age. In elderly and debilitated patients, it is advisable to reduce the dosages of pregnenolone and ketamine recommended for adults. In children, induction bolus doses of ketamine may cause respiratory depression and require respiratory support;
• duration of intervention. During a long intervention with ketamine anesthesia, difficulties may arise in assessing the depth of anesthesia and determining the dosage regimen of the drug;
• concomitant cardiovascular diseases. Ketamine should be used with caution in patients with systemic or pulmonary hypertension due to the risk of further increase in blood pressure. The cardiodepressor effect of ketamine may occur in patients with depletion of catecholamine stores due to traumatic shock or sepsis. In such cases, preoperative preparation for volume replenishment is necessary;
• concomitant kidney diseases do not significantly alter the pharmacokinetics and dosing regimen of ketamine;
• pain relief during labor, effect on the fetus, GHB is harmless to the fetus, does not inhibit uterine contractility, facilitates cervical dilation, and can therefore be used to relieve pain during labor. Ketamine is considered safe for the fetus if it is removed within 10 minutes after induction. The neurophysiological status of newborns after vaginal delivery is higher after ketamine use compared to a combination of sodium thiopental and dinitrogen oxide, although in both cases it is lower than after epidural anesthesia. There are no data on the safety of etomidate for the fetus. Isolated reports 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. The use of ketamine in patients with intracranial damage and increased intracranial pressure is considered a contraindication, it should be borne in mind that many early studies on the effect of drugs on ICP were performed against the background of spontaneous breathing of patients. In the same category of patients, the use of ketamine against the background of mechanical ventilation is accompanied by a decrease in intracranial pressure. Preliminary administration of midazolam, diazepam or sodium thiopental does not lead to a significant increase in intracranial pressure and makes the use of ketamine even safer;
• anesthesia in outpatient settings. Increased salivation during the use of ketamine should be taken into account, as well as the likelihood of mental reactions upon awakening;

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