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Ketamine produces dose-related unconsciousness and analgesia. The anesthetized state has been termed dissociative anesthesia because patients who receive ketamine alone appear to be in a cataleptic state, unlike other states of anesthesia that resemble normal sleep. Ketamine-anesthetized patients have profound analgesia but keep their eyes open and maintain many reflexes. Corneal, cough, and swallow reflexes may all be present but should not be assumed to be protective. [457] Patients have no recall of surgery or anesthesia, but amnesia is not as prominent with ketamine as with the benzodiazepines. Because ketamine has a low molecular weight, a pKa near physiologic pH, and relatively high lipid solubility, it crosses the blood-brain barrier rapidly and therefore has an onset of action within 30 seconds of administration. Maximal effect occurs in about 1 minute. After ketamine administration, pupils dilate moderately and nystagmus occurs. Lacrimation and salivation are common, as is increased skeletal muscle tone, often with coordinated but seemingly purposeless movement of the arms, legs, trunk, and head. Despite great interindividual variability, plasma levels of 0.6 to 2.0 µg/mL are considered the minimum concentrations for general anesthesia,[451] [452] but children may require slightly higher plasma levels (0.8 to 4.0 µg/mL). [458] The duration of ketamine anesthesia after a single administration of a general anesthetic dose (2 mg/kg IV) is 10 to 15 minutes (see Fig. 10-21 ),[459] and full orientation to person, place, and time occurs within 15 to 30 minutes.[460]
The S-(+)-enantiomer enables quicker recovery (by a couple of minutes) than the racemic mixture does.[461] This more rapid recovery is thought to be due to the lower dose necessary to produce an equi-anesthetic effect and the 10% faster hepatic biotransformation.[462]
The duration of ketamine anesthesia is determined by the dose; higher doses produce more prolonged anesthesia,[463] and the concurrent use of other anesthetics also prolongs the time of emergence. Because of reasonably good correlation between blood level of ketamine and CNS effect, it appears that ketamine's relatively short duration of action is due to its redistribution from the brain and blood to other tissues in the body. Thus, termination of effect after a single bolus administration of ketamine is a result of drug redistribution from well-perfused to less well perfused tissues. Concomitant administration of a
Ketamine provides important postoperative analgesia. The plasma level at which pain thresholds are elevated is 0.1 µg/mL or higher,[452] which means that there is a considerable period of postoperative analgesia after ketamine general anesthesia and that subanesthetic doses can be used to produce analgesia. Ketamine has been shown to inhibit nociceptive central hypersensitization.[466] It also attenuates acute tolerance after opiate administration.[467] Ketamine reduces opiate requirements postoperatively when used as a component of a preventive/preemptive analgesia regimen.[468] [469]
The primary site of CNS action of ketamine appears to be the thalamoneocortical projection system.[470] The drug selectively depresses neuronal function in parts of the cortex (especially association areas) and thalamus while simultaneously stimulating parts of the limbic system, including the hippocampus. This process creates what is termed functional disorganization[459] of nonspecific pathways in the midbrain and thalamic areas.[471] [472] There is also evidence that ketamine depresses the transmission of impulses in the medial medullary reticular formation, which is important for transmission of the affective-emotional components of nociception from the spinal cord to higher brain centers.[473] Blockade of CNS sodium channels has been shown to not be the mechanism of action by which ketamine produces anesthesia.[474] Some evidence indicates that ketamine occupies opiate receptors in the brain and spinal cord, and this property could account for some of the analgesic effects.[285] [444] [475] [476] The S(+)-enantiomer has been shown to have some opioid μ-receptor activity, which accounts for part of its analgesic effect.[477] NMDA receptor interaction may mediate the general anesthetic effects as well as some analgesic actions of ketamine.[478] [479] [480] The spinal cord analgesic effect of ketamine is postulated to be due to inhibition of dorsal horn, wide-dynamic range neuronal activity.[481] Although some drugs have been used to antagonize ketamine, no specific receptor antagonist is yet known that reverses all the CNS effects of ketamine.
Ketamine increases cerebral metabolism, CBF, and ICP. Because of its excitatory CNS effects, which can be detected by generalized EEG development of theta-wave activity,[463] as well as by petit mal seizure-like activity in the hippocampus,[482] ketamine increases CMRO2 . Whereas theta-wave activity signals the analgesic activity of ketamine, alpha waves indicate its absence. There is an increase in CBF that appears to be higher than the increase in CMRO2 would mandate. With the increase in CBF as well as the generalized increase in sympathetic nervous system response, there is an increase in ICP after ketamine administration.[483] [484] The increase in CMRO2 and CBF can be blocked by the use of thiopental[485] or diazepam. [484] [486] Cerebrovascular responsiveness to carbon dioxide appears to be preserved with ketamine; therefore, reducing PaCO2 attenuates the rise in ICP after ketamine.[484]
Ketamine has also been shown in animal model of incomplete cerebral ischemia and reperfusion to reduce necrosis and improve neurologic outcome.[487] Decreased sympathetic tone and inhibition of NMDA receptor-mediated ion currents were believed to mediate the reduction in necrotic cell death. Recently, S-(+)-ketamine has been shown to influence the expression of apoptosis-regulating proteins in rat brains 4 hours after cerebral ischemia/reperfusion.[488] Thus, the neuroprotection observed with ketamine may involve antiapoptotic mechanisms in addition to reducing necrotic cell death.
Ketamine, like other phencyclidines, produces undesirable psychological reactions during awakening from anesthesia that are termed emergence reactions. Common manifestations of these reactions, which vary in severity and classification, are vivid dreaming, extracorporeal experiences (sense of floating out of one's body), and illusions (misinterpretation of a real, external sensory experience).[489] These incidents of dreaming and illusion are often associated with excitement, confusion, euphoria, and fear.[285] They occur in the first hour of emergence and usually abate within 1 to several hours. It has been postulated that psychic emergence reactions occur secondary to ketamine-induced depression of auditory and visual relay nuclei and thus lead to misperception or misinterpretation (or both) of auditory and visual stimuli.[444] Their incidence ranges from as low as 3% to 5%[285] [444] to as high as 100%.[489] A clinically relevant range is probably 10% to 30% of adult patients who receive ketamine as a sole or major part of the anesthetic technique.
Factors that affect the incidence of emergence reactions are age, [490] dose,[285] gender,[491] psychological susceptibility,[492] and concurrent drugs. Playing music during anesthesia does not attenuate the incidence of psychotomimetic reactions.[493] Pediatric patients do not report as high an incidence of unpleasant emergence reactions as adult patients do, nor do men as compared with women. Larger doses and rapid administration of large doses seem to predispose patients to a higher incidence of adverse effects. [494] [495] Finally, certain personality types seem to be prone to the development of emergence reactions. Patients who score high in psychoticism on the Eysenck Personality Inventory have a propensity for the development of emergence reactions,[492] and people who commonly dream at home are more likely to have postoperative dreams in the hospital after ketamine.[494] Numerous drugs have been used to reduce the incidence and severity of postoperative reactions to ketamine,[285] [444] [496] and the benzodiazepines seem to be the most effective group of drugs to attenuate or treat ketamine emergence reactions. Midazolam, [444] lorazepam,[497] and diazepam[498] are useful in reducing reactions to ketamine. The mechanism is not known, but it is probable that both the sedative and amnesic actions of the benzodiazepines make them superior to other sedative-hypnotics. Midazolam has also been shown to reduce the psychotomimetic effect of the S-(+)-enantiomer. [499]
Ketamine has minimal effect on the central respiratory drive as reflected by an unaltered response to carbon dioxide.[500] A transient (1- to 3-minute) decrease in minute
Ketamine is a bronchial smooth muscle relaxant. When given to patients with reactive airway disease and bronchospasm, pulmonary compliance is improved. [506] [507] Ketamine is as effective as halothane or enflurane in preventing experimentally induced bronchospasm. [508] The mechanism for this effect is probably a result of the sympathomimetic response to ketamine, but isolated bronchial smooth muscle studies have shown that ketamine can directly antagonize the spasmogenic effects of carbachol and histamine.[509] Because of its bronchodilating effect, ketamine has been used to treat status asthmaticus unresponsive to conventional therapy.[510]
A potential respiratory problem, especially in children, is the increased salivation that follows ketamine administration (also see Chapter 60 ). Such salivation can produce upper airway obstruction, which can be further complicated by laryngospasm. The increased secretions may also contribute to or may further complicate laryngospasm. In addition, although the swallow, cough, sneeze, and gag reflexes are relatively intact after ketamine administration, there is evidence that silent aspiration can occur during ketamine anesthesia.[457]
Ketamine also has unique cardiovascular effects; it stimulates the cardiovascular system and is usually associated with increases in blood pressure, heart rate, and cardiac output (see Table 10-2 ). Other anesthetic induction drugs either cause no change in hemodynamic variables or produce vasodilation with cardiac depression. The S-(+)-enantiomer, despite hope that reducing the dose by half (equi-anesthetic potency) would attenuate its side effects, is equivalent to the racemic mixture regarding hemodynamic response. [499] The increase in hemodynamic variables is associated with increased work and myocardial oxygen consumption. A healthy heart is able to increase oxygen supply by increasing cardiac output and decreasing coronary vascular resistance so that coronary blood flow is appropriate for the increased oxygen consumption. [511] The hemodynamic changes are not related to the dose of ketamine (i.e., there is no hemodynamic difference between the administration of 0.5 and 1.5 mg/kg IV).[512] It is also interesting that a second dose of ketamine produces hemodynamic effects less than or even opposite those of the first dose.[513] The hemodynamic changes after induction of anesthesia with ketamine tend to be the same in healthy patients and those with a variety of acquired or congenital heart diseases.[502] [512] [514] [515] [516] Patients with congenital heart disease do not have any significant changes in shunt direction or fraction[517] or in systemic oxygenation after ketamine induction of anesthesia.[518] In patients who have elevated pulmonary artery pressure (as with mitral valvular and some congenital lesions), ketamine seems to cause a more pronounced increase in pulmonary than systemic vascular resistance.[516] [517] [519] [520]
The mechanism by which ketamine stimulates the circulatory system remains enigmatic. It does not appear to be a peripheral mechanism such as baroreflex inhibition,[521] [522] but rather seems to be central.[523] [524] [525] Some evidence indicates that ketamine attenuates baroreceptor function through an effect on NMDA receptors in the nucleus tractus solitarius.[526] Ketamine injected directly into the CNS produces an immediate sympathetic nervous system hemodynamic response.[527] Ketamine also causes the sympathoneuronal release of norepinephrine, which can be detected in venous blood.[528] Blockade of this effect is possible with barbiturates, benzodiazepines, and droperidol.[525] [527] [528] [529] Ketamine in vitro probably has negative inotropic effects. Myocardial depression has been demonstrated in isolated rabbit hearts,[530] intact dogs,[531] chronically instrumented dogs, [532] and isolated canine heart preparations.[533] However, in isolated guinea pig hearts, ketamine was the least depressant of all the major induction drugs.[534] The finding that ketamine may exert its myocardial effects by acting on myocardial ionic currents (which may exert different effects from species to species or in diverse tissue types) may explain the tissue and animal model variance in direct myocardial action.[535]
The centrally mediated sympathetic responses to ketamine usually override the direct depressant effects of ketamine. Some peripheral nervous system actions of ketamine play an undetermined role in the hemodynamic effects of the drug. Ketamine inhibits intraneuronal uptake of catecholamines in a cocaine-like effect, [536] [537] as well as extraneuronal norepinephrine uptake.[538] [539]
Stimulation of the cardiovascular system is not always desirable, and certain pharmacologic methods have been used to block ketamine-induced tachycardia and systemic hypertension. Successful methods include the use of adrenergic antagonists (both α and β), as well as a variety of vasodilators[540] and clonidine.[541] However, probably the most fruitful approach has been the administration of benzodiazepines. Modest doses of diazepam, flunitrazepam, and midazolam all attenuate the hemodynamic effects of ketamine. It is also possible to lessen the tachycardia and hypertension caused by ketamine by using a continuous infusion technique with or without a benzodiazepine.[542] Other general anesthetics, particularly the inhaled anesthetics,[543] blunt the hemodynamic effect of ketamine. Ketamine can produce hemodynamic depression in the setting of deep anesthesia when sympathetic responses do not accompany its administration.
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