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Review Article


Teaching an Old Drug New Tricks

Kohrs, Rainer MD; Durieux, Marcel E. MD

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doi: 10.1213/00000539-199811000-00039
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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].

Clinical Pharmacology

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.

Figure 1:
Structural formulas of the two enantiomers of ketamine.

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 [5], it causes minimal respiratory depression with only mild hypercapnia [6] 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 [7], 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(-) [10]. 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 [11] or right heart failure [12].

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 [13].

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 [14], which plays a major role in the development of chronic pain.

Figure 2:
The N-methyl-D-aspartate (NMDA) receptor. Schematic diagram of the molecular structure of the NMDA glutamate receptor/channel complex. The receptor consists of five subunits surrounding a central ion channel permeable to Ca, K, and Na. Binding sites for the agonist glutamate and the obligatory co-agonist glycine are indicated. Competitive glutamate and glycine antagonists act on these sites. One of the subunits has been removed to allow a view inside the ion channel, in which binding sites for ketamine and Mg are located. These compounds block NMDA receptor functioning noncompetitively. PCP = phencyclidine.

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) [18]. 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 [21], 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 [24], 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) [25], 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 [28]. 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 [29]. These findings may partly explain some properties of ketamine not caused by NMDA interaction alone.

Opioid Receptors

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 [30]. 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 [32]. 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 [30]. However, in an animal study, ketamine-induced small bowel smooth muscle contraction could be partially reversed by naloxone [33].

Cholinergic and Adrenergic Signaling

Both nicotinic and muscarinic acetylcholine receptors are affected by ketamine [34], 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 [34]. Muscarinic receptors are also inhibited [35]. S(+) ketamine shows a twofold greater affinity for the muscarinic receptor than does R(-) [30], although this was not confirmed in functional studies [36]. Overall, however, affinity for the muscarinic receptor is 10- to 20-fold less than NMDA receptor binding [37]. 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 [34]. The uptake of dopamine and 5-HT is inhibited similarly [38], 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 [39]. 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.

GABAA Signaling

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 [40]. Similar effects were observed in olfactory cortex and hippocampal slices [41]. Although an effect of ketamine on GABA signaling seems established [42], the concentrations used were higher than those used clinically. Based on current knowledge, this interaction seems to be of minor importance for clinical practice [34].

S(+) Ketamine

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 [36] and Ca channels [43] 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 [44].

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.

Table 1:
Effects of S(+) and R(-) Ketamine

Anesthetic/Hypnotic/Analgesic Effects

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 [45]. A double-blind study with 60 patients [20] 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 [44]. 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 [19]. At least for the racemic mixture, it was found that the incidence of these effects is clearly related to the ketamine plasma concentration [50], 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 [49], 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 [19]. 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 [55]. 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 [56]. NMDA antagonists prevent the induction of central sensitization and even abolish hypersensitivity once it is established [56]. 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 [58]. 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 [57].

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 [59]. 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 [60]. 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 [61].

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 [62]. 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 [63]. 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 [64]. 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 [65], other investigations show that ketamine can intensify neuronal damage during very brief ischemic episodes and exerts a beneficial effect only after prolonged ischemia [66]. Some found ketamine to lack an effect in global ischemia, others found positive effects [67]. 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 [70] that anesthesia with halothane inhibits the protective effect of ketamine on hippocampal cells after application of the NMDA agonist ibotenic acid.

Figure 3:
The neuronal injury cascade. Schematic and simplified diagram of the main neuronal injury pathways. The critical event after neuronal injury is an increase in intracellular Ca. This is brought about by several means. Depletion of energy stores leads to membrane depolarization. This induces opening of voltage-gated Ca channels (VGCC) and subsequent Ca influx, depolarizing the membrane even more. Depolarization also removes voltage-dependent Mg block from the N-methyl-D-aspartate (NMDA) receptor, which leads to Ca influx and K efflux when stimulated by glutamate. The increased intracellular Ca level has a number of effects. First, there is a positive feedback loop: increased intracellular Ca induces extracellular release of glutamate from storage vesicles, which, in turn, further activates NMDA receptors. Second, Ca activates a number of intracellular processes detrimental to the cell. Activation of phospholipases (PL) converts membrane lipids to free fatty acids (FFA), which damage cell membranes (indicated by the undulating arrow). FFA are further converted to arachidonic acid (AA) and prostaglandin derivatives (PG), which induce further damage. Activation of proteases (Prot) by Ca induces generation of damaging free radical species (FR). Finally, increased Ca levels in mitochondria inhibit their functioning, thus blocking energy generation, and lead to additional FR formation. The point at which ketamine can beneficially inhibit this cascade is indicated.

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 [76] 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 [77].


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 [78].

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 [79] and even propose new indications [80]. 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.


1. Hirota K, Lambert DG. Ketamine: its mechanisms of action and unusual clinical uses. Br J Anaesth 1996;77:441-4.
2. Hudspith MJ. Glutamate: a role in normal brain function, anaesthesia, analgesia and CNS injury. Br J Anaesth 1997;78:731-47.
3. White PF. Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982;56:119-36.
4. Reich DL. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989;36:186-97.
5. Haas DA, Harper DG. Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia. Anesth Prog 1992;39:61-8.
6. Werner C, Reeker W, Engelhard K. Ketamine racemate and S-(+)-ketamine: cerebrovascular effects and neuroprotection following focal ischemia. Anaesthesist 1997;46:55-60.
7. Zielmann S, Kazmaier S, Schnull S, Weyland A. S-(+)-ketamine and circulation. Anaesthesist 1997;46(Suppl 1):43-6.
8. Gutzke GE, Shah KB, Glisson SN. Cardiac transplantation: a prospective comparison of ketamine and sufentanil for anesthetic induction. J Cardiothorac Anesth 1989;3:389-95.
9. Berman W Jr, Fripp RR, Rubler M, Alderete L. Hemodynamic effects of ketamine in children undergoing cardiac catheterization. Pediatr Cardiol 1990;11:72-6.
10. Graf BM, Vicenzi MN, Martin E, et al. Ketamine has stereospecific effects in the isolated perfused guinea pig heart. Anesthesiology 1995;82:1426-37.
11. Folts JD, Afonso S, Rowe GG. Systemic and coronary hemodynamic effects of ketamine in intact anaesthetized and unanaesthetized dogs. Br J Anaesth 1975;47:686-94.
12. Johnstone M. The cardiovascular effects of ketamine in man. Anaesthesia 1976;31:873-82.
13. Wong BS, Martin CD. Ketamine inhibition of cytoplasmic calcium signalling in rat pheochromocytoma (PC-12) cells. Life Sci 1993;53:359-64.
14. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989;63:139-46.
15. Brockmeyer DM, Kendig JJ. Selective effects of ketamine on amino acid-mediated pathways in neonatal rat spinal cord. Br J Anaesth 1995;74:79-84.
16. MacDonald JF, Nowak LM. Mechanisms of blockade of excitatory amino acid receptor channels. Trends Pharmacol Sci 1990;11:167-70.
17. Yamamura T, Harada K, Okamura A, Kemmotsu O. Is the site of action of ketamine anesthesia the N-methyl-D-aspartate receptor? Anesthesiology 1990;72:704-10.
18. MacDonald JF, Milikovic Z, Pennefaher P. Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine. J Neurophysiol 1987;58:251-66.
19. White PF, Ham J, Way WL, Trevor AJ. Pharmacology of ketamine isomers in surgical patients. Anesthesiology 1980;52:231-9.
20. White PF, Schuttler J, Shafer A, et al. Comparative pharmacology of the ketamine isomers: studies in volunteers. Br J Anaesth 1985;57:197-203.
21. Irifune M, Shimizu T, Nomoto M, Fukuda T. Ketamine-induced anesthesia involves the N-methyl-D-aspartate receptor-channel complex in mice. Brain Res 1992;569:1-9.
22. Nasstrom J, Karlsson U, Post C. Anti-nociceptive actions of different classes of excitatory amino acid receptor antagonists in mice. Eur J Pharmacol 1992;212:21-9.
23. Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 1992;260:1209-13.
24. Gonzales JM, Loeb AL, Reichard PS, Irvine S. Ketamine inhibits glutamate-, N-methyl-D-aspartate- and quisqualate-stimulated cGMP production in cultured cerebral neurons. Anesthesiology 1995;82:205-13.
25. Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci 1991;14:60-7.
26. Marin P, Quignard JF, Lafon-Cazal M, Bockaert J. Non-classical glutamate receptors, blocked by both NMDA and non-NMDA antagonists, stimulate nitric oxide production in neurones. Neuropharmacology 1993;32:29-36.
27. Wood PL, Emmett MR, Rao TS, et al. Inhibition of nitric oxide synthase blocks N-methyl-D-aspartate-, quisqualate-, kainate-, harmaline-, and pentylene-tetrazole-dependent increases in cerebellar cyclic GMP in vivo. J Neurochem 1990;55:346-8.
28. Gordh T, Karlsten R, Kristensen J. Intervention with spinal NMDA, adenosine and NO systems for pain modulation. Ann Med 1995;27:229-34.
29. Bjorkman R, Hallman K, Hedner J, et al. Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. Pain 1994;57:259-64.
30. Hustveit O, Maurset A, Oye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, and muscarinic receptors. Pharmacol Toxicol 1995;77:355-9.
31. Finck AD, Ngai SH. Opiate receptor mediation of ketamine analgesia. Anesthesiology 1982;56:291-7.
32. Smith DJ, Bouchal RL, deSanctis CA, et al. Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacology 1982;26:1253-60.
33. Bansinath M, Warner W, Tang CK, et al. On the mechanism of the interaction of ketamine and halothane in vitro. Gen Pharmacol 1992;23:1183-7.
34. Kress HG. Actions of ketamine not related to NMDA and opiate receptors. Anaesthesist 1994;43(Suppl 2):S15-24.
35. Durieux ME. Inhibition by ketamine of muscarinic acetylcholine receptor function. Anesth Analg 1995;81:57-62.
36. Durieux ME, Nietgen GW. Synergistic inhibition of muscarinic signaling by ketamine stereoisomers and the preservative benzethonium chloride. Anesthesiology 1997;86:1326-33.
37. Aronstam RS, Narayanan L, Wenger DA. Ketamine inhibition of ligand binding to cholinergic receptors and ion channels. Eur J Pharmacol 1982;78:367-70.
38. Martin DC, Watkins CA, Adams RJ, Nason LA. Anesthetic effects on 5-hydroxytryptamine uptake by rat brain synaptosomes. Brain Res 1988;455:360-5.
39. Crisp T, Perrotti JM, Smith DL, et al. The local monoaminergic dependency of spinal ketamine. Eur J Pharmacol 1991;194:167-72.
40. Kress HG, Tas PW. Effects of volatile anaesthetics on second messenger Ca2+ in neurones and non-muscular cells. Br J Anaesth 1993;71:47-58.
41. Gage PW, Robertson B. Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells of rat hippocampus. Br J Pharmacol 1985;85:675-81.
42. Lin LH, Chen LL, Zirrolli JA, Harris RA. General anesthetics potentiate y-amino-butyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium. J Pharmacol Exp Ther 1992;263:569-78.
43. Sekino N, Endou M, Hajiri E, Okumura F. Nonstereospecific actions of ketamine isomers on the force of contraction, spontaneous beating rate, and Ca (2+) current in the guinea pig heart. Anesth Analg 1996;83:75-80.
44. Schuttler J, Stanski DR, White PF, et al. Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. J Pharmacokinet Biopharm 1987;15:241-53.
45. Ryder S, Way WL, Trevor A. Comparative pharmacology of the optical isomers of ketamine in mice. Eur J Pharmacol 1978;49:15-23.
46. Adams HA, Bauer R, Gebhardt B, et al. Total i.v. anesthesia with S-(+)-ketamine in orthopedic geriatric surgery: endocrine stress reaction, hemodynamics and recovery. Anaesthesist 1994;43:92-100.
47. Doenicke A, Angster R, Mayer M, et al. The action of S-(+)-ketamine on serum catecholamine and cortisol: a comparison with ketamine racemate. Anaesthesist 1992;41:597-603.
48. Adams HA, Thiel A, Jung A, et al. Studies using S-(+)-ketamine in orthopedic geriatric surgery: endocrine stress reaction, hemodynamics and recovery. Anaesthesist 1992;41:588-96.
49. Doenicke A, Kugler J, Mayer M, et al. Ketamine racemate or S-(+)-ketamine and midazolam: the effect on vigilance; efficacy and subjective findings. Anaesthesist 1992;41:610-8.
50. Bowdle A, Radant A, Cowley D, et al. Psychedelic effects of ketamine in healthy volunteers. Anesthesiology 1998;88:82-8.
51. Tverskoy M, Oz Y, Isakson A, et al. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg 1994;78:205-9.
52. Choe H, Choe YS, Kim YH, et al. Epidural morphine plus ketamine for upper abdominal surgery: improved analgesia from preincisional versus postincisional administration. Anesth Analg 1997;84:560-3.
53. Wong CS, Lu CC, Cherng CH, Ho ST. Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth 1996;21:534-41.
54. McQuay HJ. Pre-emptive analgesia [editorial]. Br J Anaesth 1992;69:1-3.
55. Wall PD. The prevention of postoperative pain [editorial]. Pain 1988;33:289-90.
56. Woolf CJ, Thompson WN. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartate acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:293-9.
57. Fu ES, Miguel R, Scharf JE. Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg 1997;84:1086-90.
58. Roytblat L, Korotkoruchko A, Katz J, et al. Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg 1993;77:1161-5.
59. Gardner AE, Olson BE, Lichtiger M. Cerebrospinal-fluid pressure during dissociative anesthesia with ketamine. Anesthesiology 1971;35:226-8.
60. Pfenninger E, Dick W, Grunert A, Lotz P. Animal experiment study on intracranial pressure, after ketamine administration. Anaesthesist 1984;33:82-8.
61. Albanese J, Arnaud S, Rey M, et al. Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology 1997;87:1328-34.
62. Cavazzuti M, Porro CA, Biral GP, et al. Ketamine effects on local cerebral blood flow and metabolism in the rat. J Cereb Blood Flow Metab 1987;7:806-11.
63. Hoffman WE, Pelligrino D, Werner C, et al. Ketamine decreases plasma catecholamines and improves neurologic outcome from incomplete cerebral ischemia in rats. Anesthesiology 1992;76:755-62.
64. Shapira Y, Lam AM, Engl CC, et al. Therapeutic time window and dose response of the beneficial effects of ketamine in experimental head injury. Stroke 1994;25:1637-43.
65. Marcoux FW, Pobert AW, Weber ML, Boxer PA. Glutamate mediated excitotoxicity and experimental stroke. In: Kempski O, ed. Glutamate-transmitter and toxin. Munich: Zuckschwedt, 1993:76-85.
66. Church J, Zeman S. Ketamine promotes hippocampal CA1 pyramidal neuron loss after a short-duration ischemic insult in rats. Neurosci Lett 1991;123:65-8.
67. Jantzen JP. Cerebral neuroprotection and ketamine. Anaesthesist 1994;43:41-7.
68. Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989;244:1360-2.
69. Olney JW, Labruyere J, Price MT. NMDA antagonist neurotoxicity: mechanism and preventions. Science 1989;254:1515-8.
70. Lees GJ. Halothane anaesthesia reverses the neuroprotective effect of ketamine against ibotenic acid toxicity in the rat hippocampus. Brain Res 1989;502:280-6.
71. Wass CT, Lanier WL. Hypothermia-associated protection from ischemic brain injury: implications for patient management. Int Anesthesiol Clin 1996;34:95-111.
72. Lanier WL. Cerebral metabolic rate and hypothermia: their relationship with ischemic neurologic injury. J Neurosurg Anesth 1995;7:216-21.
73. Farooqui AA, Horrocks LA. Excitatory amino acid receptors, neural membrane phospholipid metabolism and neurological disorders. Brain Res 1991;16:171-91.
74. Dugan LL, Choi DW. Excitotoxicity, free radicals, and cell membrane changes. Ann Neurol 1994;35(Suppl):S17-21.
75. Obrenovitch TP, Urenjak J. Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury? J Neurotrauma 1997;14:677-98.
76. Himmelseher S, Pfenninger E, Georgieff M. The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. Anesth Analg 1996;83:505-12.
77. Himmelseher S, Auchter M, Pfenninger E, Georgieff M. S(+)-ketamine prevents loss of mitochondrial transmembrane potential, increases glucose uptake and induces GAP-43 and MAP-2-expression in hippocampal neurons after glutamate exposure. Anesthesiology 1996;85:A711
78. Hempelmann G, Kuhn DF. Clinical significance of S-(+)-ketamine. Anaesthesist 1997;46(Suppl 1):S3-7
79. Kochs E, Werner C. Neuroprotection: fact or fantasy? Eur J Anaesth 1995;12:67-70.
80. Pfenninger E, Himmelseher S. Neuroprotection by ketamine at the cellular level. Anaesthesist 1997;46:S47-54.
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