Ketamine has a special position among anesthetic drugs. It was introduced into clinical practice >30 yr ago with the hope that it would function as a "monoanesthetic" drug: inducing analgesia, amnesia, loss of consciousness, and immobility. This dream was not fulfilled because significant side effects were soon reported. With the introduction of other IV anesthetic drugs, ketamine's role diminished rapidly. However, it is still used clinically for indications such as induction of anesthesia in patients in hemodynamic shock; induction of anesthesia in patients with active asthmatic disease; IM sedation of uncooperative patients, particularly children; supplementation of incomplete regional or local anesthesia; sedation in the intensive care setting; and short, painful procedures, such as dressing changes in burn patients.
However, recent insights into ketamine's anesthetic mechanism of action and its neuronal effects, as well as a reevaluation of its profound analgesic properties, offer the potential of expanding this range of indications. In addition, studies with the S(+) ketamine isomer suggest that its use may be associated with fewer side effects than the racemic mixture. In this article, we review the mechanism of action of ketamine anesthesia, the pharmacologic properties of its stereoisomers, and the potential uses of ketamine for preemptive analgesia and neuroprotection. Several aspects discussed herein have been reviewed previously [1-4].
Commercial ketamine is a racemic mixture consisting of two optical enantiomers, R(-) and S(+) (Figure 1), and the preservative benzethonium chloride. Pharmacokinetically, ketamine has relatively short distribution and elimination half-lives: the alpha-elimination phase lasts only a few minutes, and the beta-elimination half life is 2-3 h. The compound is metabolized extensively by the hepatic cytochrome p450 system; its primary metabolite norketamine is only one-third to one-fifth as potent as the original compound but may be involved in the prolonged analgesic actions of ketamine. The metabolites of norketamine are excreted by the kidneys.
Classic ketamine anesthetic effects are best described as a dose-dependent central nervous system (CNS) depression that leads to a so-called dissociative state, characterized by profound analgesia and amnesia but not necessarily loss of consciousness. Although not asleep, the subject seems completely unaware of the environment. Suggested mechanisms for this form of catalepsy include electrophysiologic inhibition of thalamocortical pathways and stimulation of the limbic system.
Ketamine has other effects besides analgesia and amnesia. Effects on the respiratory system are generally beneficial: it is a well documented bronchodilator , it causes minimal respiratory depression with only mild hypercapnia  in clinically relevant doses, and protective airway reflexes are more likely to be preserved than with other IV anesthetics. However, increased oral secretions can occur. Ketamine often produces significant increases in blood pressure and heart rate , and increases in pulmonary artery pressure have been reported, especially in patients with preexisting heart disease [8,9]. These effects are due to sympathetic stimulation; ketamine's direct effect on the heart is depressant, S(+) less than R(-) . Recovery time is dose-dependent, and emergence is, at times, complicated by psychotomimetic reactions (hallucinations, vivid dreams), which can be highly unpleasant. The manufacturer lists the presence of uncontrolled arterial hypertension or hypersensitivity to the drug as contraindications to the use of ketamine. However, caution has also been suggested when the drug is used in patients with coronary artery disease  or right heart failure .
Mechanisms of Action
Ketamine's neuropharmacology is complex. The compound interacts with multiple binding sites, including N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic, and monoaminergic and opioid receptors. In addition, interactions with voltage-dependent ion channels such as Na and L-type Ca channels have been described. Inhibition of neuronal Na channels provides a modest local anesthetic effect of the compound, whereas Ca channel blockade may be responsible for cerebral vasodilation .
All of these interactions may play a role in ketamine's pharmacological and clinical properties. However, NMDA receptor antagonism accounts for most of the analgesic, amnestic, psychotomimetic, and neuroprotective effects of the compound.
NMDA Glutamate Receptors
The NMDA receptor is an ionotropic receptor (ligandgated ion channel) that is activated by glutamate, the most abundant excitatory neurotransmitter in the CNS (Figure 2). The channel is permeable to Ca and, to a lesser degree, to Na and K. It requires glycine as an obligatory co-agonist and is inhibited by Mg in a voltage-dependent manner. NMDA receptors are, among many other functions, involved in the so called wind-up phenomenon , which plays a major role in the development of chronic pain.
The NMDA receptor is the postsynaptic site of action in ketamine's reduction of polysynaptic stimulation in the CNS [15-17]. Ketamine binds to the phencyclidine receptor in the NMDA channel and thus inhibits glutamate activation of the channel in a noncompetitive manner. The phencyclidine binding site partly overlaps with a binding site for Mg. The blockade is time-, concentration- and stimulation frequency-dependent (use-dependent) . The S(+) enantiomer has a three-to fourfold greater affinity for the receptor than the R(-) form, as reflected in the observed differences in their analgesic and anesthetic [19,20] potencies. Although the precise interactions between ketamine and NMDA receptors are still being elucidated , enough evidence suggests a relation between ketamine's analgesic and anesthetic properties and NMDA channel blockade [21-23] to consider the NMDA receptor ketamine's primary site of anesthetic action. However, there are interactions with other systems that may also be relevant.
Non-NMDA Glutamate Receptors
Non-NMDA glutamate receptors exist in several classes, which are activated selectively by the agonists quisqualate, AMPA, or kainate. These receptors were previously thought not to interact with ketamine, but this was disproved in recent animal studies , which demonstrated inhibition by ketamine. The effects are probably mediated through the glutamate/NO/cGMP system. Not only NMDA receptor activation stimulates NO synthesis (which then increases intracellular cGMP production) , but non-NMDA receptor activation does so as well [26,27]. Besides playing a possible role in ketamine's neuroprotective and sympathetic activating actions, ketamine-induced NO synthase inhibition may be involved in its analgesic effects . NO is known to play a role as a neurotransmitter, centrally as well as peripherally, and pain perception and NO are connected at least at the spinal level. In an animal model, the intrathecal administration of the NO-synthase inhibitor L-N-monomethylarginine induced a dose-dependent antinociceptive response. Other analgesic substances (acetaminophen and other nonsteroidal antiinflammatory drugs) similarly interact with NO metabolism . These findings may partly explain some properties of ketamine not caused by NMDA interaction alone.
Agonist actions of ketamine on opioid receptors, members of the G-protein-coupled receptor class, seem to play a minor role in its analgesic effects . However, the psychotomimetic side effects of ketamine may be explained by the interaction with kappa opioid receptors, because kappa-agonists induce similar effects. Several investigations show likely interactions between ketamine and opioid receptors [31,32]. Its affinity for these receptors ranks [micro sign] > kappa > delta . S(+) ketamine binds approximately two- to fourfold stronger to [micro sign] and kappa-receptors than does R(-). Still, the affinity of ketamine for these receptors is 10 ([micro sign]) to 20 (kappa) times less than for the NMDA channel, which suggests that the interaction is not of major clinical importance. This is confirmed by findings that naloxone does not reverse the analgesic effect of ketamine in humans . However, in an animal study, ketamine-induced small bowel smooth muscle contraction could be partially reversed by naloxone .
Cholinergic and Adrenergic Signaling
Both nicotinic and muscarinic acetylcholine receptors are affected by ketamine , and, in clinical concentrations, ketamine inhibits NMDA receptor-mediated acetylcholine release. The postsynaptic inhibitory effect of ketamine on nicotinic acetylcholine receptors in skeletal muscle is not necessarily noticeable clinically, as ketamine increases muscle tone by central mechanisms. However, the additional administration of muscle relaxants can uncover this ketamine effect . Muscarinic receptors are also inhibited . S(+) ketamine shows a twofold greater affinity for the muscarinic receptor than does R(-) , although this was not confirmed in functional studies . Overall, however, affinity for the muscarinic receptor is 10- to 20-fold less than NMDA receptor binding . Emergence side effects may be partly related to inhibition of cholinergic transmission.
R(-) ketamine inhibits the neuronal uptake of norepinephrine, and S(+) ketamine additionally inhibits extraneural uptake, thus inducing a prolonged synaptic response and increased transfer of norepinephrine into the systemic circulation . The uptake of dopamine and 5-HT is inhibited similarly , which could lead to an increase in central dopaminergic activity. The 5-HT antagonist methysergide antagonizes the analgesic effects of intrathecal ketamine, implicating serotonergic mechanisms in ketamine analgesia . These mechanisms may also be involved in ketamine-related emesis, as ondansetron inhibits ketamine-induced currents through 5-HT receptors. Thus, influences of ketamine on monoaminergic transmission seem very likely, although their role in the clinical effects of the compound are not yet clear.
GABA is the most common inhibitory neurotransmitter in the CNS, and GABA signaling neurons account for approximately 30% of all synaptic connections in the CNS. Investigations using GABAA receptors expressed recombinantly in Xenopus laevis oocytes revealed a significant increase of GABA-induced Cl current after ketamine application . Similar effects were observed in olfactory cortex and hippocampal slices . Although an effect of ketamine on GABA signaling seems established , the concentrations used were higher than those used clinically. Based on current knowledge, this interaction seems to be of minor importance for clinical practice .
In 1992, the Food and Drug Administration stated that separation of stereoisomers had not received appropriate attention in commercial drug development and that, despite technical difficulties and high cost, focusing on this issue could open new horizons in therapeutics. The isomers of ketamine are a good example. It has been known since the late 1970s that the ketamine enantiomers exhibit pharmacologic and clinical differences. Receptor studies in animal models show that S(+) ketamine has approximately fourfold greater affinity at phencyclidine binding sites on the NMDA receptor than does R(-) ketamine.
Not all of ketamine's effects are stereoselective. Norepinephrine release is inhibited in a nonstereoselective manner at clinically relevant concentrations. However, its uptake is influenced stereoselectively: both isomers inhibit neuronal uptake, whereas S(+) ketamine additionally inhibits extraneuronal uptake. Muscarinic receptors  and Ca channels  are inhibited nonstereoselectively. Interestingly, serotonin transport is inhibited twofold more potently by R(-) ketamine.
Animal studies have not revealed significant pharmacokinetic differences between the enantiomers and the racemic mixture. After subcutaneous application, similar plasma and brain concentration curves have been found. In a clinical study, however, a significantly higher elimination rate was observed for S(+) ketamine compared with the racemate .
The increased inhibitory potency at the NMDA receptor combined with similar pharmacokinetics suggest that S(+) ketamine may be an interesting clinical drug, and its pharmacological properties have been studied in some detail. Table 1 summarizes the clinically relevant differences between the isomers.
In rats and mice, S(+) ketamine exhibits 1.5- to 3-fold greater hypnotic and 3-fold greater analgesic potency than the R(-) compound. Compared with the racemic mixture, S(+) ketamine is twice as potent. The calculated therapeutic index of S(+) ketamine seems to be 2.5-fold greater than that of the mixture or R(-) alone . A double-blind study with 60 patients  reinforced these findings: S(+) ketamine was 3.4-fold more potent an anesthetic than R(-) and 2-fold more potent than the racemate.
Studies in rats and mice show that S(+) ketamine induces less spontaneous movement than does R(-) ketamine in comparable anesthetic doses. An explanation may be that, whereas plasma levels are equal after administration of S(+) or R(-) ketamine, cerebral levels of R(-) norketamine are two- to threefold greater than those of S(+) norketamine. In mice, R(-) induces more prominent CNS stimulation than does S(+) ketamine, thus making spontaneous movements more likely.
As to hemodynamic response, no significant differences between the compounds could be demonstrated, despite the fact that catecholamine plasma levels are significantly lower after S(+) than R(-) ketamine anesthesia [46,47].
Emergence from Anesthesia and Psychotomimetic Effects
S(+) ketamine and R(-) ketamine have a clinical potency ratio of approximately 2:1. Thus, only one-half the dose of S(+) ketamine should suffice for the induction of anesthesia, possibly affecting recovery time. Several clinical studies have assessed the duration of recovery after administration of the racemic mixture or S(+) ketamine. R(-) was excluded because its clinical potency is insufficient . In virtually every study, the recovery phase was clearly shortened when S(+) ketamine was used compared with racemic ketamine. This was true regardless of whether the compounds were administered as a single IV bolus, as a bolus followed by continuous infusion, or by IM injection [46,48,49].
Classical side effects after ketamine anesthesia (amnesia, altered short-term memory, decreased ability to concentrate, decreased vigilance, altered cognitive performance, hallucinations, nightmares, nausea and vomiting) were observed with similar incidence after S(+) or racemic mixture administration . At least for the racemic mixture, it was found that the incidence of these effects is clearly related to the ketamine plasma concentration , making psychedelic effects less likely (although still possible) at lower drug concentrations. Convincing evidence for a lower incidence of psychotomimetic side effects after S(+) ketamine administration could not be documented. Nonetheless, the patients felt more comfortable after S(+) ketamine , and a larger proportion of patients would be willing to have a repeat anesthetic with S(+)compared with the racemic mixture (85% vs 65%), mainly because of decreased agitation, disorientation, and anxiety . The additional administration of a benzodiazepine provided both drugs with a significantly higher rate of acceptance, but the duration of recovery also increased significantly with this regimen.
Taken together, these data suggest that S(+) ketamine allows the use of significantly smaller doses, with a resultant faster recovery and (possibly) some diminution in side effects. As a result, the compound has been approved for clinical use in Europe; therefore, additional clinical experience will soon be available.
Ketamine and Preemptive Analgesia
At small doses (0.1-0.5 mg/kg), ketamine has a noticeable analgesic action, which can be used to supplement regional or local anesthesia. A number of studies have suggested that administration of ketamine before the noxious stimulus occurs is even more effective [51-53]. This effect is referred to as preemptive analgesia.
The goal of preemptive analgesia is to prevent or reduce the development of a "memory" of the pain stimulus in the nervous system [54,55], thereby lessening postoperative analgesic requirements. When a massive barrage of afferent nociceptive impulses reaches the spinal cord, a hyperexcitable state of CNS sensitization known as wind-up results . NMDA receptors seem to be responsible for pain memory (as they are responsible for other forms of memory), and their blockade can contribute significantly to the prevention of pain . NMDA antagonists prevent the induction of central sensitization and even abolish hypersensitivity once it is established . Ketamine is the only NMDA antagonist approved by the Food and Drug Administration (although magnesium also has significant NMDA receptor-blocking properties), and several studies have demonstrated the effect of preemptive administration of small doses of ketamine postoperative pain, measured as a reduction in opioid requirements [57,58]. These effects require remarkably small doses of the drug and last for a relatively prolonged period of time (>or=to6 h). For example, patients undergoing gallbladder surgery who received ketamine were found to have diminished analgesic requirements after a single dose of 0.25 mg/kg IV ketamine versus patients who did not receive ketamine . When presurgery versus postsurgery administration was compared, ketamine administered before skin incision (0.5 mg/kg bolus followed by continuous rate of 10 [micro sign]g [center dot] kg-1 [center dot] min-1) provided better pain control than ketamine given after wound closure .
Although the administration schedule and dose varies among studies, preoperatively (preemptively) administered ketamine seems to reduce the amount of narcotics required postoperatively for pain control. Opioid requirements were reduced 40%-60% on average [57,58]. Whether this translates to a lower incidence of opioid-related adverse effects is as yet unknown, although it seems likely. Psychotomimetic responses to these small ketamine doses have not been found troublesome. The role of S(+) ketamine in preemptive analgesia has not yet been studied.
Ketamine and Neurosurgery
Historically, ketamine has been felt to be contraindicated in patients at risk of increases in intracranial pressure (ICP). However, reports about its neuroprotective actions have led to a reevaluation of this issue.
Effects on ICP
ICP can increase after the administration of racemic ketamine (no data are available yet for S(+) ketamine). This is especially true when the ICP is already increased before ketamine administration and when the drug is given at doses >1 mg/kg IV. Two reasons are provided for the effect on ICP: cerebral blood volume may increase passively, caused by increased arterial pressure during a period of impaired cerebrovascular autoregulation; and (probably more important) increases in arterial PCO2, due to ketamine-induced ventilatory depression, may contribute . It could be shown that, independent of the preexisting ICP, ketamine administration (0.5-5 mg/kg) did not increase ICP when normocapnia was maintained with controlled ventilation . Although some studies show an ICP increase during normocapnia after the administration of 2 mg/kg ketamine, this increase could be avoided by mild hyperventilation or the administration of benzodiazepines. This is not different from the situation with most volatile drugs, which are used routinely in patients with increased ICP. It has been shown that neither 1.5, 3, nor 5 mg/kg IV ketamine increased ICP in patients with head trauma during controlled ventilation and sedation with propofol; instead, the ICP decreased after ketamine administration .
Effects on Cerebral Blood Flow
Studies in dogs have shown that racemic ketamine increases cerebral blood flow (CBF) in the presence of the cerebral vasodilator N2 O. In contrast, other animal studies using barbiturates as a background anesthetic showed a decrease in CBF after ketamine administration. This suggests that the cerebrovascular effects of ketamine are related to the preexisting cerebrovascular tone. When ventilation is not controlled, part of the vasodilatory effect may result from increased PCO (2). However, ICP can increase even when the PCO2 is constant, and stimulation of cerebral metabolic rate by ketamine has been suggested to explain the increase in CBF. Ketamine inhibits certain cerebral regions and stimulates others at the same time, changes which are reflected as decreased CBF in areas with reduced metabolism and increased CBF in areas with higher metabolism . The net balance of these determines the total effect on CBF. In addition, ketamine acts in vitro as a Ca channel antagonist and increases blood flow by direct vasodilation.
In summary, racemic ketamine can increase CBF dependent on preexisting vascular resistance. The mechanisms most likely involve hypercapnia, regionally specific stimulation and inhibition of cerebral metabolism, and direct vasodilation by Ca channel block. The response of the cerebral autoregulation to racemic ketamine has not been systemically studied yet, but S(+) ketamine does not affect this autoregulation. It also has been proven that ketamine does not trigger seizure activity but, much more likely, prevents seizures by NMDA receptor antagonism.
Neuroprotection and Neuroregeneration
Cerebral hypoxia/ischemia initiates a pathophysiologic cascade that leads to membrane and cell destruction and neuronal death (Figure 3). In this cascade, the activation of NMDA and non-NMDA receptors plays an important role. If these receptors are stimulated by very high levels of glutamate or aspartate, the resultant transmembrane flux and intracellular accumulation of Na and Ca leads to cell swelling and activation of cellular pathways, eventually inducing cell death. In particular, NMDA receptor antagonists have received attention as neuroprotective drugs, although neuronal degeneration correlates more closely with the distribution of AMPA than of NMDA receptors, and AMPA antagonists prevent the degeneration at least as effectively as NMDA antagonists. In animal studies, ketamine, given in large doses before the insult and continuously infused thereafter, reduced the hypoxic/ischemic neurodeficit . In contrast, small-dose bolus application or administration after the ischemic event did not show an effect. However, in a study using a standardized head trauma model in rats, it was shown that the administration of ketamine 180 mg/kg intraperitoneally can reduce infarct size and neurologic deficit when given 2 h postinjury . The protective properties of S(+) ketamine have been studied in a rat model of incomplete cerebral hemispheric ischemia. S(+) ketamine in large doses (1 mg [center dot] kg-1 [center dot] min-1) minimized neurologic deficits to a greater extent than did smaller doses (0.25 mg [center dot] kg-1 [center dot] min-1) and was also more protective than fentanyl/N2 O. The neurologic deficit correlated closely and positively with the plasma levels of dopamine and norepinephrine. The literature on the subject is confusing because of differences in experimental models, doses, initiation, duration of therapy, and other factors. Whereas virtually complete hippocampal protection after pretreatment with ketamine has been reported , other investigations show that ketamine can intensify neuronal damage during very brief ischemic episodes and exerts a beneficial effect only after prolonged ischemia . Some found ketamine to lack an effect in global ischemia, others found positive effects . Ketamine itself can be neurotoxic. Neurons in the cerebral cortex of rats were found to be morphologically damaged after phencyclidine or ketamine application; this, however, could be prevented by the administration of anticholinergic drugs, diazepam, or barbiturates [68,69]. Of interest is a report  that anesthesia with halothane inhibits the protective effect of ketamine on hippocampal cells after application of the NMDA agonist ibotenic acid.
Using ketamine during cerebral ischemia is inconsistent with current clinical dogma and with the concept that metabolic suppression is the mainstay of cerebral protection. However, studies showing profound protective effects of very small decreases in temperature have cast doubt on the metabolic suppression theory [71,72]. Current thinking instead focuses on the key role of glutamate signaling in the neuronal injury cascade [73-75] and suggests that ketamine may therefore be appropriate therapy in patients with acute cerebral ischemia/hypoxia. However, it is too early to recommend it for clinical practice.
The literature  suggest that S(+) ketamine especially may have neuroregenerative properties. Damaged neurons showed significantly increased survival and axonal growth in rats when treated with S(+) ketamine, and the growth-associated protein GAP-43, involved in neuronal regeneration, was expressed at significantly increased levels compared with an untreated control group .
The indications for ketamine may have to be revised based on current knowledge. The separation of the enantiomers S(+) and R(-) has revealed the S(+) enantiomer to be a potentially valuable drug for modern IV anesthesia. S(+) ketamine has been found to be a very potent and effective anesthetic with less prominent side effects (more rapid emergence from anesthesia and fewer unpleasant psychotomimetic emergence reactions) than racemic ketamine. Its recent commercial introduction on the European market may lead to widespread use and will undoubtedly provide much insight into its pharmacological properties and indications .
Ketamine may have neuroprotective and even neuroregenerative effects [76,77]. Some authors are reserved or even skeptical, others see the results obtained thus far more positively  and even propose new indications . Although many issues (such as time of administration and dose) remain to be resolved, the preponderance of evidence favors a neuroprotective action. Inconsistencies among studies probably arise from the complexity of the injury cascade initiated after brain injury. It seems likely that neither racemic nor S(+) ketamine will be clinically successful if used as sole therapy; only when used in combination with other drugs and treatments can secondary injury be effectively limited. It seems confirmed that ketamine does not increase ICP when the blood pressure is controlled and mild hypocapnia is achieved. Thus, the contraindication for ketamine use in neurosurgical patients is only a relative one, and when further preclinical and clinical studies confirm a neuroprotective effect of the compound, ketamine and, more likely, S(+) ketamine may well find a place in the neuroanesthesiology drug cart.
Finally, the analgesic properties of small-dose ketamine have been rediscovered. Current data strongly suggest that the preemptive administration of ketamine can have profound effects on postoperative analgesic requirements [57,58] with minimal risk and side effects. This provides the anesthesia practitioner with another useful tool in the management of perioperative pain.
We thank John C. Rowlingson, MD, for his critical review of the manuscript.
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