Ketamine

Ketamine is the only of almost 200 derivatives of phencyclidine, which is used in the clinic. The rest were rejected because of the large number of side effects of psychomimetic effects. Ketamine is available in the form of a weakly acid solution with a stabilizer benzethonium chloride.

[1], [2], [3], [4]

Ketamine: a place in therapy

Ketamine is a special drug not only in terms of unique hemodynamic effects, but also because it can be used for premedication (in children), and it should be injected / m. The use of ketamine for the induction of anesthesia is most preferable in patients at high risk of perioperative complications (above grade III ASA), when sympathomimetic and bronchodilating action of ketamine is desired. Ketamine is indicated for anesthesia in patients with:

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

Ketamine is the drug of choice for conducting rapid sequential induction and intubation of the trachea. It can be used for anesthesia of childbirth. Propofol, ketamine and etomidate are safe in patients at risk of malignant hyperthermia, acute intermittent porphyria.

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

Combination with DB (midazolam, diazepam) and / or opioids (alfentanil, remifentanil) softens or eliminates unwanted tachycardia and hypertension. This expands the indications for the use of ketamine in patients with valvular and ischemic heart lesions. In addition, awakening reactions are prevented. The possibility of creating high concentrations of oxygen is desirable in thoracic surgery and in patients with concomitant COPD.

Ketamine in combination with DB and / or opioids is successfully used for sedation during conductive and regional anesthesia, as well as in the postoperative period. He proved his exceptional usefulness in pediatric practice. In children, ketamine less often causes side psychomimetic reactions. Therefore, it is used not only for induction, maintenance of anesthesia and sedation, but also in the performance of regional blockades and for providing procedures outside the operating room:

• angiosurgical, diagnostic and therapeutic interventions;
• radiological research;
• treatment of wounds and bandages;
• dental procedures;
• radiation therapy, etc.

When bandaging, usually used subaneesthetic (analgesic) doses of ketamine. This, along with rapid recovery of consciousness, contributes to early eating, which is extremely important for patients with burns. Due to the low oppression of self-breathing and good analgesia, ketamine is indispensable in patients with burns of the face and respiratory tract.

When providing the probing of the heart cavities in children, when interpreting the obtained data, it is necessary to take into account the own stimulating effects of ketamine.

Ketamine is usually given IV. In pediatrics, he can be administered in / m, orally, intranasally or rectally. With the / m introduction, higher doses are needed, which is explained by the effect of the first passage of the drug through the liver.

In a number of countries, epidural and subarachnoid routes of administration of ketamine are of limited use. With these routes of administration, analgesia is not accompanied by depression of respiration. However, the effectiveness of epidural anesthesia with ketamine is being questioned, since its affinity for opioid receptors in the spinal cord is thousands of times smaller than that of morphine. Probably, LS 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 has its main effects at the thalamocortical level. Its complex effect includes selective inhibition of neuronal transmission in the cerebral cortex, especially in associative sites, and the thalamus. Simultaneously, parts of the limbic system, including the hippocampus, are stimulated. As a result, there is a functional disorganization of nonspecific connections in the middle brain and thalamus. In addition, the transfer of impulses in the reticular formation of the medulla oblongata is inhibited, afferent nociceptive stimuli from the spinal cord are blocked in higher cerebral centers

It is assumed that the hypnotic and analgesic mechanisms of ketamine action are due to the effect on various types of receptors. The general anesthetic and partly analgesic effects are associated with the postsynaptic non-competitive blockade of NMDA receptors permeable to Ca2 + ions. Ketamine occupies opioid receptors in the cephalic and posterior horns of the spinal cord. It also enters into antagonistic relations with monoaminergic, muscarinic receptors and calcium channels. Anticholinergic effects are manifested by bronchodilation, sympathomimetic action, delirium and partially eliminated by anticholinesterase drugs. The effects of ketamine are not associated with exposure to GABA receptors and blockade of sodium channels in the central nervous system. A greater activity with respect to the cortex than the thalamus seems to be due to the uneven distribution of NMDA receptors in the central nervous system.

Influence on the central nervous system

Anesthesia with ketamine is fundamentally different from that caused by other anesthetics. First of all, this cataleptic state differs from normal sleep. The patient's eyes can be open, pupils dilate moderately, nystagmus is observed. Many reflexes persist, but should not be considered protective. Thus, corneal, cough and swallowing reflexes are not completely oppressed. Typical increased tone of skeletal muscles, lacrimation and salivation. Possible uncontrolled movements of limbs, trunk and head, independent of surgical stimulation. To provide 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, in contrast to other intra / sedative hypnotic drugs, causes a rather pronounced analgesia. Moreover, analgesia is observed at significantly lower concentrations of drugs in plasma than loss of consciousness. Because of this, the analgesic effect is exerted by subaneesthetic doses, and there is also a significant period of analgesia after ketamine anesthesia. Analgesia affects a more somatic than visceral component of pain.

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

Effects on cerebral blood flow

Ketamine is a cerebral vasodilator, increases MC (approximately 60%), PMO2 and increases intracranial pressure. The sensitivity of the blood vessels to the carbon dioxide is maintained, so hypercapnia weakens the increase in intracranial pressure caused by ketamine. 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.

[5], [6], [7], [8], [9], [10], [11], [12]

Electroencephalographic picture

In the application of ketamine, the EEG is largely specific. In the absence of an alpha-rhythm, generalized hypersynchronous 9-activity dominates, which reflects the excitation of the CNS and epileptiform activity in the thalamus and limbic system (but not in the cortex). In addition, 6-waves indicate an analgesic activity, while alpha waves - about its absence. The appearance of 5-activity coincides with the loss of consciousness. In high doses, ketamine is able to cause suppression outbreaks. Determination of the depth of ketamine anesthesia on the basis of EEG analysis and its transformation presents certain difficulties due to low information content. This is also not conducive to the possibility of nystagmus when used. Ketamine increases the amplitude of cortical responses to SSEP and, to a lesser extent, their latency. Responses to stem SVP are suppressed.

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

[13], [14], [15], [16], [17], [18],

Influence on the cardiovascular system

Ketamine is a unique intravenous anesthetic with regard to the effects on the cardiovascular system. Its use is usually accompanied by an increase in blood pressure (an average of 25%), increased heart rate (an average of 20%) and CB. This is accompanied by an increase in the work and consumption of oxygen by the myocardium. In a healthy heart, the increased oxygen demand is compensated by the increase in CB and the decrease in the resistance of coronary vessels. Ketamine can significantly increase the pressure in the pulmonary artery, pulmonary vascular resistance, intrapulmonary shunt.

Interestingly, hemodynamic effects of ketamine do not depend on the dose used, and repeated administration of the drug causes less or even opposite effects. Ketamine has a similar stimulating effect on hemodynamics and heart disease. With initially elevated pulmonary arterial pressure (as with mitral or some congenital malformations), the degree of increase in pulmonary vascular resistance is higher than that of the systemic one.

The mechanism of the stimulating effect of ketamine on blood circulation is not clear. There are reasons to believe that this is not a peripheral, but rather central, influence through the NMDA receptors in the nuclei of a single pathway. Thus, the central sympathetic stimulation prevails over the direct negative inotropic effect of ketamine on the myocardium. There is also a sympathetic neuronal release of epinephrine and norepinephrine.

Influence 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 MOD after an induction dose is possible. Excessively high doses, rapid administration or combined administration of opioids can cause apnea. In most cases, the arterial blood gases do not change significantly (an increase in RaCO2 within 3 mm Hg). When combined with other anesthetics or analgesics, severe respiratory depression can occur. In children, the depressing effect of ketamine on respiration is more pronounced.

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

It is important to consider (especially in children) an increase in salivation against the background of ketamine and the associated risk of airway obstruction and laryngospasm. In addition, there are cases of inconspicuous aspiration during ketamine anesthesia, despite the persistence of swallowing, cough, sneezing and vomiting reflexes.

Effects on the gastrointestinal tract and kidneys

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

[19], [20], [21], [22], [23], [24],

Effect on the 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 of the central mechanism of these cardiovascular reactions appeared. After the induction of ketamine, the levels of prolactin and luteinizing hormone are also increased.

[25], [26], [27], [28], [29], [30], [31], [32],

Effect on neuromuscular transmission

Ketamine increases muscle tone. But it is believed that it potentiates the action of nondepolarizing muscle relaxants. The mechanism of such interaction is not established. It is suggested that it interferes with binding to calcium ions or their transport, as well as a decrease in the sensitivity of the postsynaptic membrane to the relaxants. The duration of apnea caused by suxamethonium increases, probably reflecting the ketamine suppression of plasma cholinesterase activity.

[33], [34], [35], [36]

Tolerance and dependence

Chronic administration of ketamine stimulates enzymatic activity. This partly explains the development of tolerance to the analgesic effect in patients receiving repeated doses of drugs. A similar condition is observed, for example, in patients with burns with frequent dressings under ketamine anesthesia. There is currently no reliable data on the safety limits of repeated use of ketamine. The development of tolerance also agrees with reports of ketamine dependence. Ketamine refers to drugs for which abuse occurs for non-medical purposes.

Pharmacokinetics

The pharmacokinetics of ketamine has not been studied as carefully as many other intravenous anesthetics. Ketamine has a high solubility in fats (5-10 times higher than that of sodium thiopental), which is reflected in a rather large volume of distribution (about 3 l / kg). Due to its fat solubility and low molecular weight, it easily penetrates through the BBB and has a quick effect. Peak plasma concentrations are achieved 1 min after IV and 20 min after IM injection. When administered sedative effect develops after 20-45 minutes (depending on the dose). Binding to plasma proteins is negligible.

The kinetics of LS is described by a two-sector model. After bolus administration, the drug is quickly distributed to organs and tissues (11-16 minutes). Metabolism of ketamine occurs in the liver with the participation of microsomal enzymes of cytochrome P450. In this case, several metabolites are formed. N-demethylation mainly takes place with the formation of norketamina, which is then hydroxylated to hydroxynorquetamine. Norketamine is about 3-5 times less active than ketamine. The activity of other metabolites (hydroxyketamines) has been little studied. In the future, in the form of inactive glucuronide derivatives, metabolites are excreted by the kidneys. Less than 4% of unchanged ketamine is excreted in the urine, less than 5% - with 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 LS in the elimination phase - from 2 to 3 hours.

Contraindications

The use of the racemic mixture of ketamine and the S-enantiomer is contraindicated in patients with intracranial lesion and elevated ICP due to the danger of further enhancement and apnea. Because of the risk of hypertension, tachycardia and increased oxygen consumption by myocardium, it should not be used as the only anesthetic in patients with IHD, paroxysmal ventricular tachycardia, in patients with vascular aneurysms, arterial hypertension and symptomatic hypertension, and pulmonary hypertension. Ketamine is contraindicated in patients who do not want an increase in intraocular pressure (in particular, with open eye injuries). It is contraindicated also in mental illness (for example, schizophrenia), as well as with adverse reactions to ketamine or its analogs in the past. It is undesirable to use ketamine at the risk of postoperative delirium (in alcoholics, drug addicts), the probability of head trauma, the need for differential evaluation of the psychoneurological status.

[37], [38],

Tolerance and side effects

There are data on the neurotoxicity of the stabilizer of ketamine chlorbutanol for subarachnoid and epidural administration. It is believed that the likelihood of such toxicity is low for the S - (+) isomer of ketamine.

Pain when administered

With the introduction of ketamine, there is practically no reaction from the venous wall.

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

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

Inhibition of respiration

Ketamine in most cases has a short-term respiratory depression. But with rapid administration, use of large doses, combination with opioids, weakened patients usually need respiratory support. Also important are the mediated effects of ketamine - an increase in the tone of the masticatory muscles, the sinking of the root of the tongue, the hyperproduction of saliva and bronchial mucus. To prevent coughing and laryngospasm associated with hypersalivation, the use of gli-coprolrolate is indicated. It is preferable to atropine or scopolamine, which easily penetrate the BBB and may increase the likelihood of delirium.

Hemodynamic changes

Stimulation of the cardiovascular system is a side effect of ketamine and is not always desirable. Such effects are best prevented by the DB, as well as barbiturates, droperidol, inhalation anesthetics. Effective use of adrenoblockers (and alpha, and beta), clonidine or other vasodilators. In addition, a smaller tachycardia and hypertension is observed with the infusion technique of introducing ketamine (with or without DB).

It should be taken into account that the hyperdynamic effect of ketamine in patients with severe hypovolemia in case of untimely completion of BCC and inadequate anti-shock therapy may lead to depletion of compensatory possibilities of the myocardium. With a prolonged course of shock, the regulation of cardiac activity at the level of the structures of the medulla and the medulla oblongata is disturbed, therefore, there is no stimulation of circulation on the background of the use of ketamine.

Allergic reactions

Ketamine is not a histaminolyzer and usually does not cause allergic reactions.

[39], [40], [41]

Postoperative nausea and vomiting syndrome

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

Among intravenous sedative hypnotics for the ability to provoke POTR ketamine is comparable only with etomidate. However, this effect of drugs in most cases can be prevented by appropriate prevention.

Reaction of awakening

Although, according to the literature, the frequency of awakening reactions with ketamine as the sole or basic anesthetic varies between 3 and 100%, clinically significant reactions in adult patients are found in 10-30% of cases. The frequency of awakening reactions is influenced by age (over 15 years), dose (> 2 mg / kg IV), sex (more often in women), psychic susceptibility, personality type and use of other drugs. Dreams are more likely in individuals who usually see vivid dreams. Music during anesthesia does not reduce the frequency of psychomimetic reactions. In children of both sexes, awakening reactions are less common. Psychological changes in children after the application of ketamine and inhalational anesthetics do not differ. Expressed wake-up reactions are less common with repeated use of ketamine. For example, they are rare after three ketamine anesthesia and more. Ketamine does not have specific antagonists. Various drugs, including barbiturates, antidepressants, DB, antipsychotics, were used to weaken and treat the awakening reactions, although, according to some sources, droperidol may increase the likelihood of delirium. The best effectiveness was shown by DB, especially midazolam. The mechanism of this effect is unknown, but it is probably due to the sedative and amnestic effects of the DB. Effective prophylaxis was achieved by administering piracetam at the end of the operation.

The reason for the occurrence of the awakening reactions is a violation of perception and / or interpretation of auditory and visual stimuli as a result of depression of auditory and visual relay nuclei. The loss of cutaneous and musculoskeletal sensitivity reduces the ability to sense gravity.

Influence on immunity

Ketamine not only does not inhibit immunity, but even slightly increases the content of T- and B-lymphocytes.

Interaction

Ketamine is not recommended for use without other drugs for anesthesia. First, psychomimetic reactions are prevented upon awakening. This outweighs the inconvenience associated with some slowdown in the recovery period. Secondly, it helps to reduce other side effects of each drug. Thirdly, the analgesic effect of ketamine is not enough to perform traumatic cavity 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 propofolovuyu anesthesia. Their interaction is additive, so the dose of each drug should be reduced by about half.

Depression of the central nervous system caused by inhalation anesthetics and DB, prevents unwanted central sympathetic influences. Therefore, their combined use with ketamine may be accompanied by hypotension. In addition, volatile anesthetics themselves can cause auditory, visual, propriosensitive hallucinations and confusion. Probably, the risk of occurrence of awakening reactions increases. Thiopental sodium and diazepam block the ketamine-induced increase in MC. The combined use of ketamine with atropine can lead to excessive tachycardia and rhythm disturbances, especially in elderly patients. In addition, atropine can increase the likelihood of postoperative delirium. Pancuronium can enhance the cardiostimulatory effects of ketamine. Verapamil reduces the ketamine-induced hypertension, but does not moderate the heart rate.

The use of drugs that reduce hepatic blood flow can lead to a decrease in ketamine clearance. This effect can, in particular, volatile anesthetics. Diazepam and lithium preparations also slow down the elimination of ketamine. The combined use of ketamine and euphyllin reduces the incidence of seizures. Mixing ketamine and barbiturates in the same syringe results in a precipitate.

Caveats

Despite the obvious separate advantages and relative safety of non-barbituric sedative-hypnotic drugs, it is necessary to consider the following factors:

• age. In elderly patients and depleted 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. With prolonged intervention against the background of ketamine anesthesia, difficulties in assessing the depth of anesthesia and determining the dosage regimen of drugs can occur;
• concomitant cardiovascular diseases. Ketamine should be used with caution in patients with systemic or pulmonary hypertension because of the danger of an even greater increase in blood pressure. The cardiodepressor effect of ketamine may appear in patients with depletion of catecholamine stocks against traumatic shock or sepsis. In such cases, preoperative training is required to recover BCC;
• Concomitant kidney disease does not significantly alter the pharmacokinetics and dosage regimen of ketamine;
• anesthesia in childbirth, the effect on the fetus, GHB is harmless to the fetus, does not depress the uterine contractility, facilitates the opening of its cervix, so it can be used to anesthetize labor. Ketamine is considered safe for the fetus if it is extracted within 10 minutes after induction. Neurophysiological status of newborns after birth through natural pathways is higher after application of ketamine compared with the combination of sodium thiopental with dinitrogen oxide, although in both cases it is lower than after epidural anesthesia. 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. The use of ketamine in patients with intracranial injury and increased intracranial pressure is contraindicated, it should be borne in mind that many early studies on the effect of drugs on ICP were performed against the background of self-breathing 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 thiopental sodium does not lead to a pronounced increase in intracranial pressure and makes the use of ketamine even safer;
• anesthesia on an outpatient basis. It should take into account increased salivation on the background of the use of ketamine, as well as the likelihood of mental reactions during awakening;

[42], [43], [44], [45], [46]