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.
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.
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.
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.
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).
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).
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.
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).
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.
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.
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.
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.
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.
1. Doppenberg EMR, Choi SC, Bullock R. Clinical trials in traumatic brain injury. J Neurosurg Anesthesiol 2004;16:87–94.
2. Madson JB, Cold GE. The effects of anaesthetics upon cerebral circulation and metabolism: experimental and clinical studies. New York: Springer, 1990.
3. Sakabe T, Nakakimura K. Effects of anesthetic agents and other drugs on cerebral blood flow, metabolism, and intracranial pressure. In: Cottrell JE, Smith DS, eds. Anesthesia and neurosurgery. St. Louis, MO: Mosby, 2001:136–48.
4. Takeshita H, Okuda Y, Sari A. The effects of ketamine on cerebral circulation and metabolism in man. Anesthesiology 1972;36:69–75.
5. Shapiro HM, Wyte SR, Harris AB. Ketamine anesthesia in patients with intracranial pathology. Br J Anaesth 1972;44:1200–4.
6. Chi O, Wei HM, Klein SL, Weiss HR. Effect of ketamine on heterogeneity of cerebral microregional venous O2
saturation in the rat. Anesth Analg 1994;79:860–6.
7. Miyamaoto E, Nakao S, Tomimoto H, et al. Ketamine attenuates hypocapnia-induced neuronal damage in the caudoputamen in a rat model of chronic cerebral hypoperfusion. Neurosci Lett 2004;354:26–9.
8. Langsjö JW, Kaisti KK, Aalto S, et al. Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology 2003;99:614–23.
9. Friesen RH, Honda AT. Changes in anterior fontanel pressure in preterm neonates receiving isoflurane, halothane, fentanyl or ketamine. Anesth Analg 1987;66:431–4.
10. Pfenninger E, Reith A. Ketamine and intracranial pressure. In: Domino EF, ed. Status of ketamine in anaesthesiology. Ann Arbor, MI: NPP Books, 1990:109–18.
11. Mayberg TS, Lam AM, Matta BF, et al. Ketamine does not increase blood flow velocity or intracranial pressure during isoflurane/nitrous oxide anesthesia in patients undergoing craniotomy. Anesth Analg 1995;81:84–9.
12. Strebel S, Kaufman M, Maitre L, Schaefer HG. Effects of ketamine on cerebral blood flow velocity in humans: influence of pre-treatment with midazolam or esmolol. Anaesthesia 1995;50:223–8.
13. Nimkoff L, Quinn C, Silver P, Sagy M. The effects of intravenous anesthetics on intracranial pressure and cerebral perfusion pressure in two feline models of brain edema. J Crit Care 1997;12:132–6.
14. Ohata H, Iida H, Nagase K, Dohi S. The effects of topical and intravenous ketamine on cerebral arterioles in dogs receiving pentobarbital or isoflurane anesthesia. Anesth Analg 2001;93:697–702.
15. Nagase K, Ida H, Dohi S. Effects of ketamine on isoflurane- and sevoflurane-induced cerebral vasodilation in rabbits. J Neurosurg Anesthesiol 2003;15:98–103.
16. Kolenda H, Gremmelt A, Rading S, et al. Ketamine for analgosedative therapy in intensive care treatment of head-injured patients. Acta Neurochir 1996;138:1193–9.
17. Albanese J, Arnaud S, Rey M, Thomachot L, et al. Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology 1997;87:1328–34.
18. Bourgoin A, Albanese J, Wereszcynski N, et al. Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit Care Med 2003;31:711–7.
19. Hardingham GE, Bading H. The Yin and Yang of NMDA receptor signalling. Trends Neurosci 2003;26:81–9.
20. 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.
21. 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.
22. Spandou E, Karkavelas G, Soubasi V, et al. Effect of ketamine on hypoxic-ischemic brain damage in newborn rats. Brain Res 1999;819:1–7.
23. Chang ML, Yang J, Kem S, et al. Nicotinamide and ketamine reduce infarct volume and DNA fragmentation in rats after brain ischemia and reperfusion. Neurosci Lett 2002;322:137–40.
24. Himmelseher S, Pfenninger E, Kochs E, Auchter M. S(+)-Ketamine up-regulates neuronal regeneration associated proteins following glutamate injury in cultured rat hippocampal neurons. J Neurosurg Anesthesiol 2000;12:84–94.
25. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12.
26. Sakai K, Cho S, Fukusaki M, et al. The effects of propofol with and without ketamine on human cerebral blood flow velocity and response. Anesth Analg 2000;90:377–82.
27. Nagase K, Iida H, Ohata H, Dohi S. Ketamine, not propofol, attenuates cerebrovascular response to carbon dioxide in humans with isoflurane anesthesia. J Clin Anesth 2001;13:551–5.
28. Engelhard K, Werner C, Möllenberg O, Kochs E. S(+)-Ketamine/propofol maintain dynamic cerebrovascular autoregulation in humans. Can J Anaesth 2001;48:1034–9.
29. Vollenweider FX, Leenders KL, Oye I, et al. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography. Eur Neuropsychopharmacol 1997;7:25–38.
30. Holcomb HH, Lahti AC, Medorff DR, et al. Sequential regional cerebral blood flow brain scans using PET with H2 15
O demonstrate actions in CNS dynamically. Neuropsychopharmacology 2001;25:165–72.
31. Freo U, Ori C. Effects of anesthesia and recovery from ketamine racemate and enantiomers on regional cerebral glucose metabolism in rats. Anesthesiology 2004;100:1172–8.
32. Wendling WW, Chen D, Daniels FB, et al. The effects of N-methyl-D-aspartate agonists and antagonists on isolated bovine cerebral arteries. Anesth Analg 1996;82:264–8.
33. Shakunaga K, Kojima S, Jomura K, et al. Ketamine suppresses the production and release of endothelin 1 from cultured bovine endothelial cells. Anesth Analg 1998;86:1098–102.
34. Nagase K, Ida H, Dohi S. L-Arginine and nitroglycerin restore hypercapnia-induced cerebral vasodilation in rabbits after its attenuation by ketamine. Anesth Analg 2002;94:954–8.
35. Schmidt A, Ryding E, Akeson J. Racemic ketamine does not abolish cerebrovascular autoregulation in the pig. Acta Anaesthesiol Scand 2003;47:569–75.
36. 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.
37. Paquet-Durand F, Bicker G. Hypoxic/ischemic cell damage in cultured human NT-2 neurons. Brain Res 2004;1011:33–47.
38. Ozden S, Isenmann S. Neuroprotective properties of different anesthetics on axotomized rat retinal ganglion cells in vivo. J Neurotrauma 2004;1:73–82.
39. Mathews KS, Toner CC, McLaughlin DP, Stamford JA. Comparison of ketamine stereoisomers on tissue metabolic activity in an in-vitro model of global cerebral ischaemia. Neurochem Int 2001;38:367–72.
40. Zhan RZ, Wu C, Fujihara H, et al. Intravenous anesthetics differentially reduce neurotransmission damage caused by oxygen-glucose deprivation in rat hippocampal slices in correlation with N-methyl-D-aspartate receptor inhibition. Crit Care Med 2001;29:808–13.
41. Tso MM, Blatchford KL, Callado LF, et al. Stereoselective effects of ketamine on dopamine, serotonin and noradrenaline release and uptake in rat brain slices. Neurochem Int 2004;44:1–7.
42. Xue QS, Yu BW, Wang ZJ, Chen HZ. Effects of ketamine, midazolam, thiopental, and propofol on brain ischemic injury in rat cerebral cortical slices. Acta Pharmacol Sin 2004;25:115–20.
43. Lin SZ, Chiou AL, Wang Y. Ketamine antagonizes nitric oxide release from cerebral cortex after middle cerebral artery ligation in rats. Stroke 1996;27:747–52.
44. Liu Y, Zhang G, Gao C, Hou X. NMDA receptor activation results in tyrosine phosphorylation of NMDA receptor subunit 2A (NR2A) and interaction of Pyk2 with NR2A after transient cerebral ischemia and reperfusion. Brain Res 2001;909:51–8.
45. Zhang C, Shen W, Zhang G. N-methyl-D-aspartate receptor and L-type voltage-gated Ca channel antagonists suppress the release of cytochrome c and the expression of procaspase-3 in rat hippocampus after global brain ischemia. Neurosci Lett 2002;328:265–8.
46. Hou XY, Zhang GY, Yan JZ, et al. Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient cerebral ischemia. Brain Res 2002;955:123–32.
47. Shen W, Zhang C, Zhang G. Nuclear factor κB activation is mediated by NMDA and non-NMDA receptor and L-type voltage-gated Ca2+
channel following severe global ischemia in rat hippocampus. Brain Res 2002;933:23–30.
48. Li H, Zhang Q, Zhang G. Signal transducer and activator of transcription-3 activation mediated by N-methyl-D-aspartate receptor and L-type voltage gated Ca2+
channel during ischemia in rat hippocampus. Neurosci Lett 2003;345:61–4.
49. Shen WH, Zhang CY, Zhang GY. Modulation of Ik
B kinase autophosphorylation and activity following brain ischemia. Acta Pharmacol Sin 2003;24:311–5.
50. Fujikawa DG. Neuroprotective effect of ketamine administered after status epilepticus onset. Epilepsia 1995;36:186–95.
51. Borowicz KK, Czuczwar SJ. Effects of etomidate, ketamine or propofol, and their combinations with conventional antiepileptic drugs on amygdala kindled convulsions in rats. Neuropharmacology 2003;45:315–24.
52. Fournier NM, Persinger MA. The neuromatrix and the epileptic brain: behavioral and learning preservation in limbic epileptic rats treated with ketamine but not acepromazine. Epilepsy Behav 2004;5:119–27.
53. Juvonen T, Biancari F, Rimpilainen J, et al. Determinants of mortality after hypothermic circulatory arrest in a chronic porcine model. Eur J Cardiothorac Surg 2001;20:803–10.
54. Keilhoff G, Bernstein HG, Becker A, et al. Increased neurogenesis in a rat model of schizophrenia. Biol Psychiatry 2004;56:317–22.
55. Uchida K, Nakakimura K, Kuroda Y, et al. Dizocilpine, but not ketamine reduces the volume of ischaemic damage after subdural haematoma in the rat. Eur J Anaesthesiol 2001;18:295–302.
56. Lupp A, Kest S, Karge E. Evaluation of possible pro- or antioxidative properties and of interaction capacity with the microsomal cytochrome P450 system of different NMDA-receptor ligands and of taurine in vitro. Exp Toxicol Pathol 2003;54:441–8.
57. Orser BA, Pennefather PS, MacDonald JF. Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology 1997;86:903–17.
58. Engelhard K, Werner C, Eberspächer E, et al. The effect of the α2
-agonist dexmedetomidine and the N-methyl-D-aspartate antagonist S(+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats. Anesth Analg 2003;96:524–31.
59. Xu Y, Zhang B, Hua Z, et al. Targeted disruption of PSD-93 gene reduces platelet-activation factor-induced neurotoxicity in cultured cortical neurons. Exp Neurol 2004;189:16–24.
60. Storvik M, Linden AM, Kontkanen O, et al. Induction of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) expression in rat brain by uncompetitive N-methyl-D-aspartate receptor antagonists. J Pharmacol Exp Ther 2000;294:52–60.
61. Bernstein HG, Becker A, Keilhoff G, et al. Brain region-specific changes in the expression of calcium sensor proteins after repeated applications of ketamine to rats. Neurosci Lett 2003;339:95–8.
62. Miura Y, Grocott HP, Bart RD, et al. Differential effects of anesthetic agents on outcome from near-complete but not incomplete global ischemia in the rat. Anesthesiology 1998;89:391–400.
63. Adams HA. S(+)-ketamine: circulatory interactions during total intravenous anesthesia and analgosedation. Anaesthesist 1997;46:1081–7.
64. Adams HA, Brausch M, Schmitz CS, et al. Analgosedation with (S)-ketamine/propofol vs. (S)-ketamine/midazolam: control and quality of sedation, stress response and haemodynamic reactions. Anaesthesiol Intensivmed Notfallmed Schmerzther 2001;36:417–24.
65. Botero CA, Smith CE, Holbrook C, et al. Total intravenous anesthesia with a propofol-ketamine combination during coronary artery surgery. J Cardiothorac Vasc Anesth 2000;11:409–15.
66. Kolbel CB, Rippel K, Klar H, et al. Esophageal motility disorders in critically ill patients: a 24-hour manometric study. Intensive Care Med 2000;26:1421–7.
67. Köppel C, Arndt I, Ibe K. Effects of enzyme induction, renal and cardiac function on ketamine plasma kinetics in patients with ketamine long-term analgosedation. Eur J Drug Metab Pharmacokinet 1990;15:259–63.
68. Tsubo T, Sakai I, Okawa H, et al. Ketamine and midazolam kinetics during continuous hemodiafiltration in patients with multiple organ dysfunction syndrome. Intensive Care Med 2001;27:1087–90.
69. Guillou N, Tanguy M, Seguin P, et al. The effects of small dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg 2003;97:843–7.
70. Christ G, Mundigler G, Merhaut C, et al. Adverse cardiovascular effects of ketamine infusion in patients with catecholamine-dependent heart failure. Anaesth Intensive Care 1997;25:255–9.
71. Hijazi Y, Bodonian C, Bolon M, et al. Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury. Br J Anaesth 2003;90:155–60.
72. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002;5:405–14.
73. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70–4.
74. Jevtovic-Todorovic V, Benshoff N, Olney JW. Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats. Br J Pharmacol 2000;130:1692–8.
75. Jevtovic-Todorovic V, Wozniak DF, Benshoff N, Olney JW. A comparative evaluation of the neurotoxic properties of ketamine and nitrous oxide. Brain Res 2001;895:264–7.
76. Nakao S, Miyamoto E, Masuzawa M, et al. Ketamine-induced c-fos expression in the mouse posterior cingulate and retrosplenial cortices is mediated not only via NMDA receptors but also sigma receptors. Brain Res 2002;926:191–6.
77. Hayashi H, Dikkes P, Soriano SG. Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain. Paediatr Anaesth 2002;12:770–4.
78. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetics agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876–82.
79. Scallet AC, Schmued LC, Slikker W Jr, et al. Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol Sci 2004;81:364–70.
80. Bornscheuer A, Lubbe N, Mahr KH, et al. Endocrine reactions, circulatory and resuscitation behaviour after ketamine-midazolam anesthesia: a comparative study of ketamine racemate vs. (S)-ketamine in knee surgery. Anaesthesist 1997;46:1043–9.
81. Engelhardt W, Stahl K, Marouche A, Hartung E. Recovery time after (S)-ketamine or ketamine racemate after short term anesthesia in volunteers. Anaesthesist 1998;47:184–92.
82. Kienbaum P, Heuter T, Pavlakovic G, et al. S(+)-Ketamine increases muscle sympathetic activity and maintains the neural response to hypotensive challenges in humans. Anesthesiology 2001;94:252–6.
83. Pfenninger EG, Durieux ME, Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology 2002;96:357–66.
84. Nagels W, Demeyere R, van Hemelrijck J, et al. Evaluation of the neuroprotective effects of S(+)-ketamine during open-heart surgery. Anesth Analg 2004;98:1595–603.
85. Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of consensus on assessment of neurobehavioral outcome after cardiac surgery. Ann Thorac Surg 1995;59:1289–95.
86. Kunst G, Martin E, Graf BM, et al. Actions of ketamine and its isomers on contractility and calcium transients in human myocardium. Anesthesiology 1999;90:1363–71.
87. Kanellopoulos A, Lenz G, Mühlbauer B. Stereoselective differences in the vasorelaxing effects of S(+) and R(−) ketamine on rat isolated aorta. Anesthesiology 1998;88:718–24.
88. Müllenheim J, Rulands R, Wietschorke T, et al. Late preconditioning is blocked by racemic ketamine, but not by S(+)-ketamine. Anesth Analg 2001;93:265–70.
89. Proescholdt M, Heimann A, Kempski O. Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res 2001;904:245–51.
90. Reeker W, Werner C, Möllenberg O, et al. High-dose S(+)-ketamine improves neurological outcome following incomplete cerebral ischemia. Can J Anaesth 2000;47:572–8.
91. Arundine M, Thymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci 2004;61:657–68.
92. Bullock R, Zauner A, Woodward JJ, et al. Factors affecting excitatory amino acid release following severe head injury. J Neurosurg 1998;89:507–18.
93. Sarrafzadeh AS, Kiening KL, Callsen TA, Unterberg AW. Metabolic changes during impending and manifest cerebral hypoxia in traumatic brain injury. Br J Neurosurg 2003;17:340–6.
94. Narayan RK, Michel ME, and The Clinical Trials in Head Injury Study Group. Clinical trials in head injury. J Neurotrauma 2002;19:503–18.
95. Cohen ML, Chan SL, Way WL, et al. Distribution in the brain and metabolism of ketamine in the rat after intravenous administration. Anesthesiology 1973;39:370–6.
96. Marietta MP, Way WL, Castagnoli N, et al. On the pharmacology of the ketamine enantiomorphs in the rat. J Pharmacol Exp Ther 1977;202:157–65.
97. Livingston A, Waterman AE, Goodrich JE, et al. The development of tolerance to ketamine in rats and the significance of hepatic metabolism. Br J Pharmacol 1978;64:63–9.
98. Domino EF, Zsigmond EK, Domino LE, et al. Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay. Anesth Analg 1982;61:87–92.
99. Hartvig P, Valtysson J, Lindner KH, et al. Central nervous system effects of subdissociative doses of S(+)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers. Clin Pharmacol Ther 1995;58:165–73.
100. Elsersy H, Sheng H, Lynch JR, et al. Effects of isoflurane versus fentanyl-nitrous oxide anesthesia in long-term outcome from severe forebrain ischemia in the rat. Anesthesiology 2004;100:1160–6.
101. Arrowsmith JE, Harrison MJ, Newman SP, et al. Neuroprotection of the brain during cardiopulmonary bypass: randomized trial of remacemide during coronary artery bypass in 171 patients. Stroke 1998;29:2357–62.
102. Morris GF, Bullock R, Marshall SB, et al. Failure of the competitive N-methyl-D-aspartate antagonist selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The selfotel investigators. J Neurosurg 1999;91:737–43.
103. Albers GW, Goldstein LB, Hall D, et al. Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 2001;286:2673–82.
104. Lepeintre JF, D’Arbigny P, Mathe JF, et al. Neuroprotective effect of gacyclidine: a multicenter double-blind pilot trial in patients with acute traumatic brain injury. Neurochirurgie 2004;50:83–95.
105. Biegon A, Fry PA, Paden CM, et al. Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci USA 2004;101:5117–22.
106. Anand KJS, Soriano SG. Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology 2004;101:527–30.