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Revising a Dogma: Ketamine for Patients with Neurological Injury?

Himmelseher, Sabine MD; Durieux, Marcel E. MD, PhD

doi: 10.1213/01.ANE.0000160585.43587.5B
Neurosurgical Anesthesia: Review Article

We evaluated reports of randomized clinical trials in the perioperative and intensive care setting concerning ketamine’s effects on the brain in patients with, or at risk for, neurological injury. We also reviewed other studies in humans on the drug’s effects on the brain, and reports that examined ketamine in experimental brain injury. In the clinical setting, level II evidence indicates that ketamine does not increase intracranial pressure when used under conditions of controlled ventilation, coadministration of a γ-aminobutyric acid (GABA) receptor agonist, and without nitrous oxide. Ketamine may thus safely be used in neurologically impaired patients. Compared with other anesthetics or sedatives, level II and III evidence indicates that hemodynamic stimulation induced by ketamine may improve cerebral perfusion; this could make the drug a preferred choice in sedative regimes after brain injury. In the laboratory, ketamine has neuroprotective, and S(+)-ketamine additional neuroregenerative effects, even when administered after onset of a cerebral insult. However, improved outcomes were only reported in studies with brief recovery observation intervals. In developing animals, and in certain brain areas of adult rats without cerebral injury, neurotoxic effects were noted after large-dose ketamine. These were prevented by coadministration of GABA receptor agonists.

IMPLICATIONS: Ketamine can be used safely in neurologically impaired patients under conditions of controlled ventilation, coadministration of a γ-aminobutyric acid receptor agonist, and avoidance of nitrous oxide. Its beneficial circulatory effects and preclinical data demonstrating neuroprotection merit further animal and patient investigation.

*Klinik fuer Anaesthesiologie, Klinikum rechts der Isar, Technische Universität, München, Germany; and †Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia

Accepted for publication February 9, 2005.

Address correspondence and reprint requests to Marcel E. Durieux, MD, PhD, Department of Anesthesiology, University of Virginia Health System, PO Box 800710, Charlottesville, VA 22908-0710. Address e-mail to

Pharmacological modulation of excessive N-methyl-d-aspartate (NMDA) receptor stimulation may be used as part of a multi-targeted approach to ameliorate secondary brain injury (1). The benefits—if any—of the NMDA receptor antagonist ketamine, however, remain undefined in this setting, in part because of the persisting dogma that the drug not be used in patients at risk for increases in intracranial pressure (ICP) (2,3). Thirty years ago, increases in cerebral oxygen consumption, cerebral blood flow (CBF), and ICP were indeed reported during anesthesia with ketamine (4,5).

Advances in our knowledge of ketamine’s cerebral effects and progress in therapeutic interventions for brain injury warrant a reevaluation of this verdict. First, preclinical and clinical data show that the cerebral hemodynamic and metabolic effects of ketamine depend on study setting (4–8), the absence or presence of controlled ventilation (8–10), background anesthetics, and other drugs (11–15). In patients with intracranial pathology, ketamine has been used safely under appropriate conditions (16–18). Second, as the important role of NMDA receptor signaling in pathways inducing neuronal death has been defined (19), interest in clinically available NMDA antagonists has been renewed. Because preclinical studies report neuroprotective effects for racemic ketamine in cell and animal models (20–23), and additional regenerative effects for S(+)-ketamine in cultured neurons (20,24), the drug may potentially be of benefit for patients with brain injury.

This review will provide an update on ketamine’s cerebral effects, and will attempt to answer the question whether use of ketamine in the neurosurgical patient is acceptable, and whether potential benefits should be further investigated.

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The early literature on ketamine’s cerebral effects has been discussed previously (2,3), and will not be extensively repeated. We will focus on data from the last decade. Actually, almost all of the early reports do not meet current quality criteria for randomized, controlled trials: the studies often were unblinded observations, and without randomization.

Computer literature searches in the electronic databases MEDLINE and EMBASE from 1994 to October 2004 were performed using the following terms: ketamine, NMDA receptor antagonist, hemodynamics, ICP, (neuro)anesthesia, sedation, emergence, psychic, adverse/side effects, neuroprotection, brain, cerebral, injury, ischemia, and (neuro)toxicity. Searches were conducted without language restriction, but limited to items with English abstracts. After abstract screening, only articles deemed relevant were obtained. A manual search for additional reports in reference lists was performed. A systematic review filter was applied. Abstracts, letters, case reports, or unpublished data were not included. Authors were not contacted. If a preclinical study reported effects similar to those reported in a clinical trial, the preclinical study was not included because of space limitations. Literature from the veterinary field was not considered.

Reports of randomized, controlled trials, and nonrandomized controlled or cohort trials in adults were included. Where applicable, trials were scored using a 3-item, 1–5 quality scale (25). Trial evidence was stratified according to accepted level of evidence ratings (level I–level IV), and conclusions were based on this evidence. Specific trial evidence levels are indicated in the text as appropriate. In view of the heterogeneity in study design and settings, and the small number of trials with comparable objectives, meta-analyses were not possible.

For preclinical human studies, a methodological quality of randomized, controlled investigation with allocation concealment and blinding of study assessment was deemed necessary. In laboratory work, studies had to model a clinical scenario, and the primary outcome measure had to be relevant for or represent a measure of neuroprotection.

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Identification of Studies

The literature searches identified 246 articles that examined the use of ketamine in brain insults or the setting of neuroanesthesia. Seventy-nine studies were included. There were 5 volunteer and 16 patient trials (with >500 patients). Frequent reasons for study exclusion were use of ketamine as anesthetic in brain injury experiments or description of pathophysiological phenomena only, and flawed study design, such as lack of blinding or randomization. Many narrative reviews were found, but no systematic review on any aspect of this work was available.

We will discuss evidence for cerebral hemodynamic effects and neuroprotection separately. In addition, we will review evidence for additional beneficial and detrimental effects of the compound, and briefly discuss the potential role for S(+)-ketamine.

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Cerebral Hemodynamics

Study details are presented in Table 1. The effect of ketamine on ICP was studied in patients with intracranial compromise under controlled normocapnic ventilation during brain tumor or aneurysm surgery (11), and in severe head injury in the intensive care unit (ICU) (16–18). When applied as 1 mg/kg bolus to neurosurgical patients during isoflurane/nitrous oxide (N2O) anesthesia, ketamine reduced ICP and middle cerebral artery flow velocity (VMCA), but did not affect mean arterial blood pressure (MAP) (11). After administration of a 1, 3, or 5 mg/kg bolus to head-injured patients with increased ICP under propofol sedation, the drug reduced ICP, but had no effect on either VMCA or MAP (17) (level III evidence). In sedative regimens for severely head-injured patients, ICP was similar during sedation with either ketamine/midazolam or with fentanyl/midazolam. With ketamine/midazolam, however, less vasopressors were needed and greater cerebral perfusion pressures (CPP) were found (16) (level II evidence). In another study, the combination of ketamine and midazolam versus sufentanil and midazolam did not result in a different ICP or CPP (18). The sufentanil-treated patients, however, required more fluids on the first day and showed a trend to need more vasopressors (level II evidence). During the 4-day study, ketamine was associated with more rapid heart rates on 2 days. In normocapnic, ventilated patients without cerebral compromise, ketamine increased VMCA during air/oxygen/isoflurane anesthesia when used alone or in the presence of esmolol; after midazolam, VMCA decreased (12). During propofol anesthesia and hypo- or hyperventilation, ketamine did not affect the VMCA (26). During air/oxygen/isoflurane anesthesia and hypoventilation, it also did not reduce VMCA, but pulsatility index decreased (27) (level III evidence). Importantly, during propofol anesthesia, S(+)-ketamine did not impair dynamic cerebrovascular autoregulation in patients without cerebral compromise (28) (level III evidence). Early work showed that in the presence of N2O, ketamine may increase CBF even under controlled ventilation (4). In spontaneously breathing volunteers, a subanesthetic dose of ketamine given as bolus (29), infusion (8), or a combination of both (30), increased regional CBF and metabolism (8,29) (level III evidence). In spontaneously breathing patients, an increase in arterial Paco2 was identified as a major factor responsible for an increase in CBF or ICP (4,14).

Laboratory data confirm ketamine’s known inhibition of metabolism in certain brain areas and simultaneous stimulation of others, which is partially reflected in decreased CBF in regions with reduced metabolism and vice versa (6,31). The effects were dependent on preexisting cerebrovascular tone and its modulation by background anesthetics (13–15,32–34). Concomitant use of ketamine and anesthetics may stimulate regional metabolism, impair autoregulation, or induce direct vasodilation (32–34). In the presence of anesthetics that depress brain metabolism (i.e., γ-aminobutyric acid [GABA] receptor agonists), global ICP is not increased by ketamine (16–18). In normocapnic, ventilated pigs, racemic ketamine did not impair CBF autoregulation when used alone (35).

In summary, the clinical evidence can be assessed as follows. Ketamine increases CBF and metabolism in spontaneously breathing volunteers (level III evidence). However, under conditions of controlled ventilation and sedation, the drug does not increase ICP (level III evidence). Instead, a greater CPP is maintained when ketamine is used for sedation than when opiates are administered (level II evidence) and need for vasopressors is reduced (level II evidence). During anesthesia, ketamine does not reduce VMCA (level III evidence) or impair autoregulation (level III evidence). This may, however, not be true in the presence of N2O.

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Trials that compared ketamine with fentanyl (16) or sufentanil (18) for sedation after head injury did not find a different 6-mo outcome after 10- (16) or 4-day (18) ketamine use (level II evidence). The drug doses used were adjusted to maintain ICP <25 mm Hg in resting patients.

In vitro and animal studies with a duration of up to 7 days reported neuroprotective effects when ketamine was used before, during, or after induction of various brain insults. In neurons in culture (20,24,36–38), and in brain slices (39–42), ketamine protected against hypoxic, ischemic, mechanical, and chemical neuronal damage. When used at subanesthetic doses and postinjury in cultured neurons, neuroprotective effects were found (20,24). In whole-animal rat models, ketamine use before insult or as anesthesia during regional ischemia attenuated injury from permanent (43) or transient cerebral artery occlusion (23), and from global ischemia (four-vessel occlusion) and reperfusion (44–49). After fluid-percussion brain trauma in rats, ketamine administered postinjury improved behavioral functions and outcome over 48 h (21). The drug reduced hippocampal damage in the immature rat brain when injected after hypoxia-ischemia (22). After seizure onset, ketamine terminated convulsions and reduced cognitive decline (50–52). Anesthesia with ketamine decreased mortality after hypothermic circulatory arrest in pigs (53). In a schizophrenia model in adult rats, repeated subanesthetic ketamine doses evoked neurogenesis, but the new neurons did not functionally integrate (54). Ketamine showed a trend to reduce ischemic injury when applied after simulation of a subdural hematoma with clotted blood (55).

Most investigators related the observed decrease in necrosis to a reduction in glutamate neurotoxicity (20–22,38–40,42,44–49,52,56) resulting from NMDA receptor blockade by ketamine (57). A decrease in DNA fragmentation and apoptotic protein activation after racemic or S(+)-ketamine was also found (23,45,58). Although there is still a lack of data on the molecular machinery behind ketamine neuroprotection, some consequences of the prevention of pathological NMDA receptor up-regulation were reported: At brain synapses, postsynaptic density (PSD) proteins bind and cluster NMDA receptors to the cytoskeleton and sets of signaling proteins, such as nitric oxide synthase (59,60), or calcium sensors (61). Increased excitatory NMDA receptor input activates protein kinase C isoforms and tyrosine kinase cascades, which facilitate assembly of signaling molecules with PSD proteins in the NMDA receptor. This leads to further kinase activation, NMDA receptor phosphorylation, and up-regulation of NMDA currents. In this vicious circle, enhanced downstream signals enhance NMDA receptor function, and finally, induce cell injury (44,59). In studies of postischemic brain tissue, ketamine reduced the injury-related increase in NMDA receptor-PSD-protein kinase assembly (44,46), decreased subsequent transcription factor activation (47–49,61), and apoptotic processing (45) (Fig. 1). The reduction of harmful interactions of NMDA receptors with cascades that transduce signals to destructive intracellular mechanisms may thus represent one effect underlying ketamine neuroprotection.

One study demonstrated no reduction in cellular death when ketamine was used for anesthesia in a rat model of incomplete, and near-complete ischemia, whereas isoflurane anesthesia was neuroprotective in near-complete ischemia in the same study (62). Both compounds improved motor function after near-complete injury. It is conceivable that only repeated ketamine injections which are extended into the postischemic period, i.e., into the phase of delayed injury evolution, may prevent neuronal death. It is also possible that, especially in the rat, ketamine must be combined with other drugs such as GABA-mimetics to prevent unfavorable neuronal effects from blockade of synaptic transmission by ketamine anesthesia (see below).

Particularly important in this area would be studies investigating long-term outcomes after cerebral injury in the presence of ketamine, because studies using other presumed protectants (such as isoflurane) have shown that early benefits may not be sustained.

In summary, although a wealth of animal and cellular studies demonstrate neuroprotective effects of ketamine in various settings, virtually no clinical trial data are available. It is essentially impossible to extrapolate the available animal data to human brain injury. We do know, however, that outcome is no worse when ketamine, rather than sufentanil or fentanyl, is used for sedation of head-injured patients (level II evidence).

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Other Beneficial Effects

The stimulation of the cardiovascular system by racemic or S(+)-ketamine combined with other anesthetics and sedatives was described previously (63). Maintenance of hemodynamic stability and potential vasopressor-sparing effects are of special interest within settings where circulatory depression should be avoided, such as with head injury (level II evidence). Two trials (reported above) found sufficient and comparable sedative levels when midazolam was combined with either ketamine, or with fentanyl (16) or sufentanil (18), in head-injured patients (level II evidence). When sedation was stopped in the second trial (18), ketamine was associated with a slightly longer recovery period, but no prolonged ICU stay. In the first study (16), improved food intake was found with ketamine. Both studies did not report differences in adverse effects. In the non-neurosurgical critically ill patient population, several trials described advantages of ketamine for sedation and analgesia: prevention of hemodynamic depression and a reduced need for catecholamines (64,65), better tolerance of enteral nutrition because of improved gastrointestinal motility as compared with opioids (66), less tachyphylaxis and withdrawal phenomena (67,68), and improved pain control (69) (level II and III evidence). However, ketamine must be used cautiously in long-term sedation of cardiac patients with left heart failure. One study reported a decrease in cardiac index after sufentanil was replaced by ketamine following sedation with sufentanil and midazolam for several days (70). After brain injury, pharmacokinetic analyses of ketamine and its active metabolites found a larger increase in the distribution volume than in total clearance, so that a drug half-life longer than estimated must be considered (71). This could be less relevant with S(+)-ketamine (see below). The trials did not report differences in emergence reactions or other side effects regardless of ketamine use.

In summary, ketamine provides adequate and controllable sedation in critically ill patients (level II evidence), and, when compared with opiates, provides better hemodynamic stability, better tolerance of enteral nutrition, less withdrawal phenomena, and better pain control (level II and III evidence).

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In rodents, profound blockade of normal NMDA receptor activity led to poor brain cell survival and physiological outcome, because signal transduction via NMDA receptors is necessary to express neurotrophins and survival-promoting proteins (72). In rats, physiological signals were reduced directly by NMDA receptor antagonists, such as ketamine, and indirectly by GABA-mimetics, such as volatile anesthetics and barbiturates (73–78). In the developing rat brain, a combination of anesthetics or large-dose NMDA receptor antagonists caused apoptosis, synaptic deficits, and cognitive impairment, especially during the vulnerable phase of synaptogenesis (73,76–79). In adult rats without brain injury, ketamine induced acute, but usually transient, vacuolar changes in posterior cingulate/retrosplenial cortices (74–76). The effect was dose-, age-, and sex-dependent, with younger rats being essentially resistant, and females being more sensitive than males. The latter was likely attributable to sex differences in drug metabolism with more efficient hepatic biotransformation in males. After coadministration of ketamine and the NMDA antagonist N2O, increased vacuolization occurred, whereas the combination with a GABA-agonist completely prevented these changes (74). Although the mechanisms presumed to underlie these phenomena are as yet unclear, they likely involve a disinhibition of excitatory pathways which heavily innervate cerebrocortical neurons (Fig. 2).

In summary, animal data suggest that under some conditions, ketamine (and N2O) may induce neurotoxicity. This has only been demonstrated in rats.

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Several advantages of S(+)- over racemic ketamine with regard to its cardiovascular profile and neuroprotective effects have been reported. At a comparable depth of anesthesia [which requires approximately half the dose of S(+)-ketamine as compared with the racemate], S(+)-ketamine caused similar cardiovascular stimulation as racemic ketamine (80,81) (level II evidence). When combined with midazolam for ICU sedation, racemic or S(+)-ketamine (at a dose of 55%–75% of the racemate) provided hemodynamic stability, and sometimes allowed reduced vasopressor support. S(+)-Ketamine combined with propofol had minimal effects on the systemic circulation (63,64) (level II evidence). In contrast to the racemate, the S(+)-isomer maintained muscle sympathetic activity during a hypotensive challenge in volunteers (82). S(+)-Ketamine showed a shorter half-life than the racemic mixture (80,81), which is favorable for a rapid neurological assessment. However, no different incidence of side effects after S(+)- or racemic ketamine was found (80,83) (level II evidence). A recent study compared a combined anesthetic regimen of S(+)-ketamine and propofol with remifentanil and propofol for open-heart surgery (84). In a neuropsychological test evaluation 10 wk after the procedure, the overall test performance was not different. Unfortunately, by the standards of the consensus statement on assessment of neurobehavioral outcome in cardiac surgery trials (85), this study was greatly underpowered, and the inability to find a difference between the approaches is therefore not surprising.

Laboratory data indicate a better cardiovascular profile for the S(+)-isomer with less myocardial depression (86) and less vasorelaxation of the aorta (87) than induced by the racemate. In contrast to the racemate, S(+)-ketamine did not reverse late cardiac preconditioning (88). S(+)-Ketamine showed better protective and even regenerative efficacy in rat brain slices (39,41) and neuronal cultures (20,24). In contrast to the racemate, it preserved neuronal metabolism, and increased the expression of proteins related to plasticity and repair in the adult brain (20,24). In a rat model of global brain ischemia, S(+)-ketamine, injected postinjury, maintained cortical oxygen saturation and neuronal survival as compared with R(−)-ketamine (89), and in incomplete brain ischemia, anesthesia with S(+)-ketamine improved behavioral outcome 3 days after injury (90).

In summary, although preclinical data suggest benefits of S(+) over racemic ketamine in cardiovascular and neuroprotective profiles, clinical evidence at this time only supports equal hemodynamic and side effect profile (level II evidence).

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From the standpoint of cerebral hemodynamics, the available information demonstrates that ketamine does not increase ICP in neurologically impaired patients during controlled ventilation and coadministration of a GABA receptor agonist. Coadministration with N2O is to be avoided. Thus, the drug can safely be used. Ketamine has been considered unsuitable in neurosurgical patients because of its cataleptic actions and psychotomimetic adverse effects. However, clinical studies did not report an increase in adverse reactions or emergence delirium when ketamine and GABA-mimetics were used as compared with regimens without ketamine. Likely, the coadministration of GABA-agonists prevented these effects.

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Ketamine’s interaction with regional cerebral hemodynamics and metabolism is complex. We know that the drug’s global action on CBF, brain metabolism, and ICP is determined by a combination of effects on cerebral and systemic hemodynamics, although we do not know what this means in case of a brain insult on a regional level. Even if “optimal CPP” is still a matter of debate, it is beyond doubt that systemic hypotension is detrimental in brain injury. Ketamine’s stimulation of the cardiovascular system may prevent hypotension and thus maintain the CPP, which—together with its other advantages over opiate-based sedation—could make the drug a first choice in sedative regimens for patients with brain insults.

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The renewed interest in ketamine as a clinically available neuroprotectant has been fostered by a shift in thinking about neuroprotection by anesthetics: from suppression of brain metabolism to inhibition of excitotoxicity. A key role in the injury cascade seems to be played by the unbalanced activation of NMDA receptors by toxic glutamate concentrations with subsequent cell death (19,91). Cerebral microdialysis in patients confirmed increased glutamate concentrations in the extracellular space during and after critical periods of brain injury (92,93). This prompted therapeutic approaches with NMDA receptor antagonists. Drug regimens used early after insults may especially target secondary injury processes within the therapeutic window of opportunity (94). Ketamine acts at many different signal transduction sites, but its neuroprotective effects seem at least for the most part to be explained by blockade of NMDA receptor activation. It binds noncompetitively to the phencyclidine site in the receptor channel, and additionally acts through allosteric modification (57).

There is a large body of experimental data indicating that racemic ketamine is neuroprotective; S(+)-ketamine may have protective and neuroregenerative effects that exceed those of the racemic mixture. With regard to the drug doses used, the experimental data cannot readily be extrapolated to the clinical setting, but comparisons can be made. Ketamine injected IV is rapidly distributed to the brain, and concentrations in rat and human brain are approximately five times more than blood values (95–99). For anesthesia, rats need 10 times larger ketamine doses than humans (31), and many studies in whole-animal models used rat anesthetic-dose ketamine (95–97). In vitro, drug concentrations several-fold (approximately 5–1000 times) lower than those reached in rat brain tissue after anesthesia induction (peak level 400 μM) were used (95). Ketamine is significantly plasma protein bound (95–99) and because plasma concentrations larger than 0.5 μM racemate were reached in surgical anesthesia in humans, the doses effective for experimental neuroprotection seem to be within a range relevant for clinical use. Nevertheless, limitations other than the drug doses used have to be considered for the available animal data. First, the major caveat is that almost all of the studies were performed in small animal models, and the past decade has seen a series of high-profile failures in clinical trials of drugs that were highly effective in these models. No trial has yet reported neuroprotective efficacy of ketamine after human brain injury. Second, we have no long-term outcome data demonstrating persistent benefit of neuroprotection after ketamine anesthesia or ketamine administration after onset of brain insults. This appears to be very important, because in a rat model of near-complete ischemia, it was recently found that the neuroprotection provided by isoflurane had dissipated three months after cerebral injury (100). Last, but not least, we lack investigations that examine prolonged ketamine treatment after brain injury. It is unlikely that one injection of a short-acting drug will completely prevent delayed inflammation or other injury-related signals associated with NMDA receptor-mediated transduction during the evolution of brain insults. Thus, further study in higher animal species with ketamine use beyond initial brain insults, evaluation of drug combinations, and longer-term outcome studies appear to be indicated. Even if previous clinical trials with NMDA antagonists reported only minor benefit on outcome after cardiopulmonary bypass (101) or were stopped after head trauma (102) or stroke (103), it is not time to conclude that NMDA antagonists failed to provide clinical neuroprotection. All of these studies applied competitive NMDA blockers only, which cause a sustained transmission blockade and thus, probably unfavorable, effects on the brain. In contrast, a recent prospective, randomized, placebo-controlled, double-blind, multicenter pilot trial demonstrated improved patient outcome after use of a noncompetitive NMDA receptor antagonist after traumatic brain injury (104). Similar to ketamine, the drug applied had a lower binding affinity to the phencyclidine site in the NMDA receptor channel than dizocilpine. A recent study demonstrated that, in mice, hyperactivation of NMDA receptors after injury is short-lived, and is followed by a profound and long-lasting loss of function (105). In fact, administration of NMDA 24 and 48 h postinjury significantly attenuated neurological deficits. Thus, appropriate timing and duration of NMDA receptor blockade is likely to be critical.

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Whether the NMDA antagonist-induced neurodegeneration observed in rats could occur in humans is not known. The potential clinical relevance of the rat data remains to be clarified, although psychotomimetic effects after NMDA antagonists may represent a correlate to the changes observed in rat brain (106). However, the pathological conditions after brain injury are profoundly different from the physiological state of intact, uninjured tissue. Cerebral insults cause massive increases in extracellular excitatory transmitter concentration and brain ischemia induces GABA release (91). During these periods, it seems unlikely that ketamine would be able to induce an over-inhibition of NMDA receptor signaling.

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Several clinical trials addressed the use of ketamine as a sedative drug in the ICU, and based on this evidence, the drug seems appropriate for that setting. The major perceived contraindications for ketamine use in neurologically impaired patients have been refuted. Ketamine’s circulatory effects and preclinical data indicating neuroprotection merit further animal and patient investigation, but we do not yet have evidence of ketamine neuroprotection in humans. Based on the known pathological responses of the brain to injury and extrapolation of knowledge from pain therapy using ketamine, it is our bias that human trials will only be successful if ketamine will be present during the whole period of NMDA receptor overstimulation after and during the evolution of brain injuries.

We gratefully acknowledge the expert assistance of David Alpern in the preparation of the manuscript.

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