A drug review

REVIEW ARTICLE
Ketamine: Teaching an Old Drug New Tricks
Rainer Kohrs, MD, and Marcel E. Durieux, MD
Department of Anesthesiology, University of Virginia Health Center, Charlottesville, Virginia
K
etamine 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, am-
nesia, 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 pa-
tients, particularly children; supplementation of in-
complete 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 indica-
tions. 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 ket-
amine anesthesia, the pharmacologic properties of its
stereoisomers, and the potential uses of ketamine for
preemptive analgesia and neuroprotection. Several as-
pects discussed herein have been reviewed previously
(l-4).
Clinical Pharmacology
Commercial ketamine is a racemic mixture consisting
of two optical enantiomers, R( -) and S( +) (Fig. l), and
the preservative benzethonium chloride. Pharmacoki-
netically, ketamine has relatively short distribution
and elimination half-lives: the a-elimination phase
lasts only a few minutes, and the p-elimination half
life is 2-3 h. The compound is metabolized extensively
This work was supported in part by National Institutes of Health
Grant GMS52387 to MED.
Accepted for publication July 31, 1998.
Address correspondence to Marcel E. Durieux, MD, Department
of Anesthesiology, University of Virginia Health Center, PO Box
10010, Charlottesville, VA 22906-0010.
1186 An&h Analg 1998;87:1186-93
by the hepatic cytochrome ~450 system; its primary
metabolite norketamine is only one-third to one-fifth
as potent as the original compound but may be in-
volved in the prolonged analgesic actions of ketamine.
The metabolites of norketamine are excreted by the
kidneys.
Classic ketamine anesthetic effects are best de-
scribed as a dose-dependent central nervous system
(CNS) depression that leads to a so-called dissociative
state, characterized by profound analgesia and amne-
sia 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 lim-
bit system.
Ketamine has other effects besides analgesia and
amnesia. Effects on the respiratory system are gener-
ally 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 pre-
served than with other IV anesthetics. However, in-
creased oral secretions can occur. Ketamine often pro-
duces significant increases in blood pressure and heart
rate (7), and increases in pulmonary artery pressure
have been reported, especially in patients with preex-
isting heart disease (8,9). These effects are due to sym-
pathetic 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 (hallucina-
tions, 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 com-
pound interacts with multiple binding sites, including
01998 by the International Anesthesia Research Society
0003.ZYY9/98/$5.00
ANESTH ANALG
1998;87:1186-93
REVIEW ARTICLE KOHRS AND DURIEUX 1187
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HN-CH,
H,C -NH
0
0
R (-) - ketamine S (+) - ketamine
Figure 1. Structural formulas of the two enantiomers of ketamine.
N-methyl-D-aspartate (NMDA) and non-NMDA glu-
tamate 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 de-
scribed. 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 ket-
amine’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 (ligand-
gated ion channel) that is activated by glutamate, the
most abundant excitatory neurotransmitter in the CNS
(Fig. 2). The channel is permeable to Ca and, to a lesser
degree, to Na and K. It requires glycine as an obliga-
tory 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.
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 gluta-
mate activation of the channel in a noncompetitive man-
ner. 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 re-
ceptors are still being elucidated (21), enough evidence
suggests a relation between ketamine’s analgesic and
anesthetic properties and NMDA channel blockade
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 antago-
nists 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.
(21-23) to consider the NMDA receptor ketamine’s pri-
mary site of anesthetic action. However, there are inter-
actions 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 ef-
fects are probably mediated through the glutamate/
NO/cGMP system. Not only NMDA receptor activa-
tion 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 anal-
gesic 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 an-
tinociceptive response. Other analgesic substances
(acetaminophen and other nonsteroidal antiinflamma-
tory drugs) similarly interact with NO metabolism
(29). These findings may partly explain some proper-
ties of ketamine not caused by NMDA interaction
alone.
1188 REVIEW ARTICLE KOHRS AND DURIEUX
NEW USES FOR KETAMINE
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 ket-
amine may be explained by the interaction with K
opioid receptors, because K-agonists induce similar
effects. Several investigations show likely interactions
between ketamine and opioid receptors (31,32). Its
affinity for these receptors ranks p > K > 6 (32). S(+)
ketamine binds approximately two- to fourfold stron-
ger to TV and K-receptors than does R(-). Still, the
affinity of ketamine for these receptors is 10 (p) to 20
(K) times less than for the NMDA channel, which
suggests that the interaction is not of major clinical
importance. This is confirmed by findings that nalox-
one does not reverse the analgesic effect of ketamine
in humans (30). However, in an animal study,
ketamine-induced small bowel smooth muscle con-
traction could be partially reversed by naloxone (33).
ANESTH ANALG
1998;87:1186-93
GABA, Signaling
Cholinergic and Advenergic Signaling
Both nicotinic and muscarinic acetylcholine receptors
are affected by ketamine (34), and, in clinical concen-
trations, ketamine inhibits NMDA receptor-mediated
acetylcholine release. The postsynaptic inhibitory ef-
fect of ketamine on nicotinic acetylcholine receptors in
skeletal muscle is not necessarily noticeable clinically,
as ketamine increases muscle tone by central mecha-
nisms. However, the additional administration of
muscle relaxants can uncover this ketamine effect (34).
Muscarinic receptors are also inhibited (35). S(+) ket-
amine shows a twofold greater affinity for the musca-
rinic receptor than does R(-) (30), although this was
not confirmed in functional studies (36). Overall, how-
ever, affinity for the muscarinic receptor is lo- to
20-fold less than NMDA receptor binding (37). Emer-
gence side effects may be partly related to inhibition of
cholinergic transmission.
R(-) ketamine inhibits the neuronal uptake of nor-
epinephrine, and S( +) ketamine additionally inhibits
extraneural uptake, thus inducing a prolonged synap-
tic response and increased transfer of norepinephrine
into the systemic circulation (34). The uptake of dopa-
mine 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, influ-
ences 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 neurotransmit-
ter in the CNS, and GABA signaling neurons account
for approximately 30% of all synaptic connections in
the CNS. Investigations using GABA, receptors ex-
pressed recombinantly in Xenopus laevis oocytes re-
vealed a significant increase of GABA-induced Cl cur-
rent 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 appro-
priate attention in commercial drug development and
that, despite technical difficulties and high cost, focus-
ing on this issue could open new horizons in thera-
peutics. The isomers of ketamine are a good example.
It has been known since the late 1970s that the ket-
amine 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. Nor-
epinephrine release is inhibited in a nonstereoselective
manner at clinically relevant concentrations. How-
ever, its uptake is influenced stereoselectively: both
isomers inhibit neuronal uptake, whereas S(+) ket-
amine 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 phar-
macokinetic 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 signifi-
cantly higher elimination rate was observed for S(+)
ketamine compared with the racemate (44).
The increased inhibitory potency at the NMDA re-
ceptor combined with similar pharmacokinetics sug-
gest that S(+) ketamine may be an interesting clinical
drug, and its pharmacological properties have been
studied in some detail. Table 1 summarizes the clini-
cally relevant differences between the isomers.
Anesthetic/Hypnotic/Analgesic Effects
In rats and mice, S(+) ketamine exhibits 1.5- to 3-fold
greater hypnotic and 3-fold greater analgesic potency
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Table 1. Effects of S( +) and R( -) Ketamine
Variable
SC+) WI
NMDA receptor 4 1
affinity
Plasma concentration 1 1
Cerebral concentration 1 2-3
Elimination rate 1 0.8-l
Side effect profile Similar to racemic ketamine
LDs,/ED,o
2.5 1
Anesthetic potency 3 1
Data are expressed as relative effects.
NMDA = N-methyl-D-aspartate, LD,,, = 50% lethal dose, ED,,, = 50%
effective dose.
than the R( -) compound. Compared with the racemic
mixture, S(+) ketamine is twice as potent. The calcu-
lated 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) rein-
forced 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 explana-
tion may be that, whereas plasma levels are equal after
administration of S( +) or R( -) ketamine, cerebral lev-
els of R(-) norketamine are two- to threefold greater
than those of S( +) norketamine. In mice, R( -) induces
more prominent CNS stimulation than does S( +) ket-
amine, thus making spontaneous movements more
likely.
As to hemodynamic response, no significant differ-
ences between the compounds could be demon-
strated, 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 po-
tency ratio of approximately 2:l. Thus, only one-half
the dose of S(+) ketamine should suffice for the in-
duction of anesthesia, possibly affecting recovery
time. Several clinical studies have assessed the dura-
tion 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 (am-
nesia, 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 inci-
dence 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 inci-
dence of psychotomimetic side effects after S(+) ket-
amine 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”/0 vs 65%),
mainly because of decreased agitation, disorientation,
and anxiety (19). The additional administration of a
benzodiazepine provided both drugs with a signi-
ficantly higher rate of acceptance, but the duration
of recovery also increased significantly with this
regimen.
Taken together, these data suggest that S(+) ket-
amine 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; there-
fore, additional clinical experience will soon be
available.
Ketamine and Preemptive Analgesia
At small doses (0.1-0.5 mg/kg), ketamine has a no-
ticeable analgesic action, which can be used to supple-
ment regional or local anesthesia. A number of studies
have suggested that administration of ketamine be-
fore the noxious stimulus occurs is even more effec-
tive (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 less-
ening 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 pre-
vention 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 pre-
emptive administration of small doses of ketamine on
1190 REVIEW ARTlCLE KOHRS AND DURIEUX
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lYY8;87:1186-93
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 pro-
longed period of time (~6 h). For example, patients
undergoing gallbladder surgery who received ket-
amine were found to have diminished analgesic re-
quirements after a single dose of 0.25 mg/kg IV ket-
amine versus patients who did not receive ketamine
(58). When presurgery versus postsurgery administra-
tion was compared, ketamine administered before
skin incision (0.5 mg/kg bolus followed by continuous
rate of 10 PLg * kg-’ * mini’) provided better pain
control than ketamine given after wound closure (57).
Although the administration schedule and dose var-
ies among studies, preoperatively (preemptively) ad-
ministered ketamine seems to reduce the amount of
narcotics required postoperatively for pain control.
Opioid requirements were reduced 40%60% on av-
erage (57,58). Whether this translates to a lower inci-
dence of opioid-related adverse effects is as yet un-
known, although it seems likely. Psychotomimetic
responses to these small ketamine doses have not been
found troublesome. The role of S(+) ketamine in pre-
emptive analgesia has not yet been studied.
Ketamine and Neurosurgery
Historically, ketamine has been felt to be contraindi-
cated in patients at risk of increases in intracranial
pressure (ICI’). However, reports about its neuropro-
tective actions have led to a reevaluation of this issue.
Effects on ICP
ICI’ can increase after the administration of racemic
ketamine (no data are available yet for S( +) ketamine).
This is especially true when the ICI’ is already in-
creased before ketamine administration and when the
drug is given at doses >l mg/kg IV. Two reasons are
provided for the effect on ICI’: cerebral blood volume
may increase passively, caused by increased arterial
pressure during a period of impaired cerebrovascular
autoregulation; and (probably more important) in-
creases in arterial Pco,, due to ketamine-induced ven-
tilatory depression, may contribute (59). It could be
shown that, independent of the preexisting ICI’, ket-
amine administration (0.5-5 mg/kg) did not increase
ICI’ when normocapnia was maintained with con-
trolled ventilation (60). Although some studies show
an ICI’ increase during normocapnia after the admin-
istration of 2 mg/kg ketamine, this increase could be
avoided by mild hyperventilation or the administra-
tion of benzodiazepines. This is not different from the
situation with most volatile drugs, which are used
routinely in patients with increased ICI’. It has been
shown that neither 1.5, 3, nor 5 mg/kg IV ketamine
increased ICI’ in patients with head trauma during
controlled ventilation and sedation with propofol; in-
stead, the ICI’ decreased after ketamine administra-
tion (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 N,O. In contrast, other animal
studies using barbiturates as a background anesthetic
showed a decrease in CBF after ketamine administra-
tion. This suggests that the cerebrovascular effects of
ketamine are related to the preexisting cerebrovascu-
lar tone. When ventilation is not controlled, part of the
vasodilatory effect may result from increased Pco,.
However, ICI’ can increase even when the Pco, 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 me-
tabolism and increased CBF in areas with higher me-
tabolism (62). The net balance of these determines the
total effect on CBF. In addition, ketamine acts in zlitvo
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, region-
ally specific stimulation and inhibition of cerebral me-
tabolism, 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 sei-
zures by NMDA receptor antagonism.
Neuvopvotection and Neuroregeneration
Cerebral hypoxia/ischemia initiates a pathophysio-
logic cascade that leads to membrane and cell destruc-
tion and neuronal death (Fig. 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 result-
ant transmembrane flux and intracellular accumula-
tion of Na and Ca leads to cell swelling and activation
of cellular pathways, eventually inducing cell death.
In particular, NMDA receptor antagonists have re-
ceived 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
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lipids
VGCC
3
FL
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-o-aspartate (NMDA) re-
ceptor, 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 intracellu-
lar Ca induces extracellular release of glutamate from storage ves-
icles, 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 gener-
ation, and lead to additional FR formation. The noint at which
ketamine can beneficially inhibit this cascade is indicated.
studies, ketamine, given in large doses before the in-
sult and continuously infused thereafter, reduced the
hypoxic/ischemic neurodeficit (63). In contrast, small-
dose bolus application or administration after the isch-
emit 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 hemi-
spheric ischemia. S( +) ketamine in large doses (1 mg *
kg-’ . min-‘) minimized neurologic deficits to a
greater extent than did smaller doses (0.25 mg * kg-i *
min-‘) and was also more protective than fentanyl/
N,O. The neurologic deficit correlated closely and
positively with the plasma levels of dopamine and
norepinephrine. The literature on the subject is con-
fusing because of differences in experimental models,
doses, initiation, duration of therapy, and other fac-
tors. Whereas virtually complete hippocampal protec-
tion after pretreatment with ketamine has been re-
ported (65), other investigations show that ketamine
can intensify neuronal damage during very brief isch-
emit 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. Neu-
rons in the cerebral cortex of rats were found to be
morphologically damaged after phencyclidine or ket-
amine application; this, however, could be prevented
by the administration of anticholinergic drugs, diaze-
pam, or barbiturates (68,69). Of interest is a report (70)
that anesthesia with halothane inhibits the protective
effect of ketamine on hippocampal cells after applica-
tion of the NMDA agonist ibotenic acid.
Using ketamine during cerebral ischemia is incon-
sistent with current clinical dogma and with the con-
cept that metabolic suppression is the mainstay of
cerebral protection. However, studies showing pro-
found protective effects of very small decreases in
temperature have cast doubt on the metabolic sup-
pression theory (71,72). Current thinking instead fo-
cuses on the key role of glutamate signaling in the
neuronal injury cascade (73-75) and suggests that ket-
amine may therefore be appropriate therapy in pa-
tients with acute cerebral ischemia/hypoxia. How-
ever, it is too early to recommend it for clinical
practice.
The literature (76) suggest that S(+) ketamine espe-
cially may have neuroregenerative properties. Dam-
aged 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 un-
treated control group (77).
Conclusions
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 mod-
ern IV anesthesia. S( +) ketamine has been found to be
a very potent and effective anesthetic with less prom-
inent side effects (more rapid emergence from anes-
thesia and fewer unpleasant psychotomimetic emer-
gence 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).
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K&amine may have neuroprotective and even neu-
roregenerative effects (76,77). Some authors are re-
served or even skeptical, others see the results ob-
tained thus far more positively (79) and even propose
new indications (80). Although many issues (such as
time of administration and dose) remain to be re-
solved, the preponderance of evidence favors a neu-
roprotective action. Inconsistencies among studies
probably arise from the complexity of the injury cas-
cade 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 sec-
ondary injury be effectively limited. It seems con-
firmed that ketamine does not increase ICI’ 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 ket-
amine have been rediscovered. Current data strongly
suggest that the preemptive administration of ket-
amine 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 peri-
operative pain.
We thank John C. Rowlingson, MD, for his critical review of the
manuscript.
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