REVIEW ARTICLE
Neuroprotection by Ketamine: A Review of the Experimental and Clinical Evidence
Judith A. Hudetz, PhD, and Paul S. Pagel, MD, PhD
N EUROPROTECTION MAY BE DEFINED AS the “pre-
vention or amelioration of neuronal damage evidenced by
abnormalities in cerebral metabolism, histopathology or neuro-
logic function occurring after a hypoxic or an ischemic event.”1
Thus, the prevention of cerebral ischemia and the recovery of
neural tissue that already has sustained an ischemic insult
represent essential goals of neuroprotection. Neuroprotection
may occur as a consequence of reduced O2 demand, enhanced
O2 delivery, or attenuation of pathologic processes that con-
tribute to cellular injury or death. For decades, the dissociative
sedative-hypnotic ketamine has been considered to be rela-
tively contraindicated in the presence of ischemic brain injury
or an intracerebral mass because the drug increases cerebral
metabolic rate for O2 (CMRO2), cerebral blood flow (CBF),
and intracranial pressure (ICP).2 However, this traditionally
held supposition may not be entirely correct because ketamine
also may have the potential to exert important neuroprotective
effects against ischemic damage. Ketamine inhibits N-methyl-
D-aspartate (NMDA) receptor activation and excitotoxic sig-
naling, reduces neuronal apoptosis (programmed cell death),
attenuates the systemic inflammatory response to tissue injury,
and also maintains cerebral perfusion pressure as a result of
sympathetic nervous system activation. These actions of ket-
amine may act to offset its detrimental effect on cerebral blood
flow and metabolism, especially under conditions in which
arterial CO2 tension is controlled during mechanical ventilation. In
the setting of cardiac surgery with or without cardiopulmonary
bypass (CPB), cerebral ischemia may be characterized by global
or regional dysfunction resulting from hypoperfusion and micro-
embolization.
The authors review the current evidence supporting the hy-
pothesis that ketamine may protect the human brain from
ischemic injury. A search of the medical literature was con-
ducted by using several bibliographic databases (PubMed,
CINAHL, Cochrane, and PsychInfo) using the following medical
subject headings: “ketamine,” “neuroprotection,” “neurologic,”
“stroke,” “ischemia,” “clinical,” and “human.” Forty-four arti-
cles were identified, 11 of them in languages other than En-
glish. The review of the 33 articles and the abstracts of the
non-English articles were supplemented by a manual search of
related articles.
O2 DEPRIVATION AND MECHANISMS
OF EXCITOTOXICITY
Cerebral neurons rapidly consume O2 and glucose and de-
pend almost exclusively on these substrates to drive oxidative
phosphorylation for energy production and are extremely sen-
sitive to reductions in the O2 and glucose delivery.3 Restriction
of O2 and glucose delivery to the brain causes a series of events
Journal of Cardiothoracic and Vascular Anesthesia, Vol 24, No 1 (February), 2010: pp 131-142
that rapidly lead to cell death, including excitotoxicity, peri-
infarct depolarization, inflammation, and apoptosis.3 Focal im-
pairment of CBF restricts the delivery of O2 and glucose,
thereby impairing the generation of energy required to maintain
ionic gradients.4 As a result, intracellular energy supplies are
rapidly exhausted, membrane potential is lost, and neurons and
their supporting glial cells depolarize.5 Somatodendritic and
presynaptic voltage-dependent Ca2⫹ channels become activated
under these conditions, and excitatory amino acids (eg, gluta-
mate) are released into the extracellular space. Energy-depen-
dent homeostatic processes, such as presynaptic reuptake of
excitatory amino acids are simultaneously impeded, thereby
further increasing the accumulation of glutamate in the extra-
cellular space. The NMDA-receptor controls an ion channel
that is permeable to Ca2⫹ and glutamate release by ischemic
neurons. The activation of these receptors increases Ca2⫹ influx
and rapidly initiates cell necrosis and apoptosis.6 Cerebral
neurons that are subjected to ischemia-induced glutamate-re-
ceptor activation, Ca2⫹ overload, O2-derived free radicals, or
mitochondrial and DNA damage may be irreversibly damaged
depending on the source and intensity of the injury, the type of
neural cell, and its developmental stage.7 Thus, a potential
therapeutic approach to prevent this sequence of events is the
blockade of NMDA receptors.8 As a result, ketamine may
potentially inhibit neuronal cell death by preventing excitotoxic
injury through this mechanism.9
The intracellular signaling pathways activated during exci-
totoxicity trigger the expression of genes that initiate inflam-
mation, another important contributor to ischemic injury. The
Ca2⫹-induced activation of intracellular second messengers (eg,
ceramide), the release of O2-derived free radicals, and the
presence of hypoxia itself stimulate transcription and transla-
tion of nuclear factor-␬B and hypoxia-inducible factor 1.10,11
Ketamine suppresses nuclear factor-␬B expression12 involved
From the Department of Anesthesiology, Medical College of Wis-
consin and Clement J. Zablocki Veterans Administration Medical Cen-
ter, Milwaukee, WI.
Supported in part by the Medical College of Wisconsin Institutional
Grant RAC 508-3 and by departmental funds.
Address reprint requests to Judith A. Hudetz, PhD, Department of
Anesthesiology, Clement J. Zablocki Veterans Administration Medical
Center, 5000 W National Avenue, Milwaukee, WI 53295. E-mail: judith.
hudetz@va.gov
© 2010 Elsevier Inc. All rights reserved.
1053-0770/10/2401-0025$36.00/0
doi:10.1053/j.jvca.2009.05.008
Key words: ketamine, neuroprotection, neurologic, stroke, ischemia,
clinical, human
131
132
in the transcription of genes encoding the proinflammatory
cytokines tumor necrosis factor ␣ (TNF-␣), interleukin (IL)-6,
and IL-8.13 Although microvascular obstruction by neutrophils
may worsen the degree of ischemia,14-16 the production of toxic
mediators (eg, TNF-␣) by these activated inflammatory cells
and injured neurons also contributes to further exacerbation of
ischemic injury during early reperfusion. For example, isch-
emic neurons produce the proinflammatory cytokine TNF-␣
that has been linked to accelerated ischemic injury through a
“feed-forward” mechanism.17 Thus, ketamine administration
may affect this process by reducing brain injury during early
reperfusion.
NEUROPROTECTIVE EFFECTS OF KETAMINE:
EXPERIMENTAL EVIDENCE
Several experimental studies in vitro and in vivo suggested
that ketamine may be capable of producing neuroprotective
effects.9,18-20 Glutamatergic signaling has been linked to nitric
oxide metabolism.21 Racemic ketamine inhibited nitric oxide
synthesis and nitric oxide-dependent cyclic guanosine mono-
phosphate production stimulated by glutamate and glutamate
analogs (eg, NMDA, quisqualate, and kainite) in primary cul-
tures of cortical neurons and glia.19 These findings suggested
that this ketamine-induced inhibition of glutamate receptors
may contribute not only to anesthesia but also cellular protec-
tion against ischemic injury.
Racemic and (S)- but not (R)-ketamine attenuated injury
after glutamate exposure or axonal transection in rat hippocam-
pal neurons in vitro.9 Neuroregenerative effects also were ob-
served with (S)-ketamine but not racemic or (R)-ketamine.9
Synthesis of a growth-associated protein related to plasticity
and repair were enhanced after glutamate injury by (S)- but not
racemic ketamine in rat hippocampal neurons.18 To determine
the relative neuroprotective activity of (S)-ketamine compared
with its (R)-isomer administered after the ischemic injury in
vivo, the functional and neurohistologic outcomes of rats ex-
posed to global forebrain ischemia were examined.22 (S)- but
not (R)-ketamine significantly reduced neuronal cell loss in the
cerebral cortex. (S)- but not (R)-ketamine also restored the
cortical O2 saturation to preischemic values independent of
CBF. Thus, the (S)-ketamine may reduce cortical neuronal
damage after cerebral ischemia by improving the ratio of O2
supply to consumption during reperfusion.22 (S)-ketamine also
favorably influenced neuronal apoptosis by attenuating in-
creases in expression of the proapoptotic Bax protein produced
by cerebral ischemia and reperfusion in rats compared with
those that did not receive the drug.23 These data emphasize that
the salutary actions of ketamine in models of neuronal injury
appear to be stereoselective.
Ketamine also may decrease the severity of cerebral injury
by interfering with the inflammatory response to ischemia.
Ketamine suppressed lipopolysaccharide-induced TNF-␣, IL-6,
and IL-8 production and inhibited neutrophil adhesion to the
endothelium in vitro.24,25 Racemic ketamine improved the neu-
rologic severity score at 24 and 48 hours and reduced the
volume of hemorrhagic necrosis without altering cerebral
edema after head trauma in rats.26 Ketamine also attenuated
neuronal damage in the caudoputamen of rats exposed to
chronic, hypocapnia-induced cerebral hypoperfusion.27 The ad-
HUDETZ AND PAGEL
ministration of racemic ketamine before the initiation of hypo-
capnia reduced white-matter injury, neuronal damage, and as-
troglial proliferation. These data suggested that racemic
ketamine may be beneficial for preventing brain dysfunction
caused by inadvertent hypocapnia during mechanical ventila-
tion. Racemic ketamine also enhanced neurologic outcome
concomitant with reductions in plasma catecholamine concen-
trations in a rat model of incomplete cerebral ischemia.28 The
beneficial effects of ketamine on cerebral histopathology were
dose-dependent. Ketamine (20 mg/kg) did not affect neuronal
damage in the selectively vulnerable hippocampal CA1 region
in a rat model of near-complete forebrain ischemia, but larger
doses of ketamine administered during the reperfusion pro-
vided significant neuroprotection.29 These results suggested
that NMDA receptor–mediated events may contribute to neu-
ronal damage in selectively vulnerable regions of the central
nervous system after the ischemia insult and further implied
that ketamine may attenuate such damage. Despite the intrigu-
ing nature of these findings, it is important to emphasize that
animal models of cerebral ischemia and their modulation by
NMDA-receptor antagonists may not predict results in humans.
In addition, the wide variation in effective doses of ketamine
reported within and between animal species suggests that the
dose of ketamine required for possible neuroprotection in hu-
mans is not immediately apparent.
CEREBROVASCULAR AND METABOLIC EFFECTS OF
KETAMINE: EXPERIMENTAL FINDINGS
Low doses of ketamine (⬍2 mg/kg) have been reported to
increase30-33 but also not to affect CBF and CMRO2 in exper-
imental animals. These apparently conflicting observations
may be explained at least in part because ketamine may inhibit
metabolism in selected brain regions while simultaneously en-
hancing metabolism in others concomitant with changes in
CBF.30,34,35 Racemic and (S)-ketamine decreased glucose cere-
bral metabolic rate (CMRglu) in cortical, thalamic, cerebellar,
and brainstem regions but increased CMRglu in limbic areas. In
contrast, (R)-ketamine caused less-pronounced reductions in
CMRglu in 11 brain areas, whereas this optical isomer mark-
edly increased CMRglu in the basal ganglia and limbic regions.
This regional specificity of ketamine on CMRglu and CBF was
consistent with the heterogenous effects of the drug on brain
electrical activity.36-38 The actions of ketamine on regional
cerebral perfusion and metabolism appear to be sensitive to
preexisting cerebrovascular tone and the prevalence of other
anesthetics.39-44 The balance between microregional O2 demand
and supply has been shown to be heterogenously distributed.45
The influence of ketamine on regional CBF and microregional
arterial and venous O2 saturation were determined in the ante-
rior cortex, posterior cortex, and pons in rats. In this setting,
ketamine did not substantially affect regional CBF or O2 sup-
ply-demand relations in contrast to enhanced CBF and CMRO2
typically reported.45
Nimkoff et al39 examined the effects of intravenous anes-
thetics on ICP and cerebral perfusion pressure (CPP) in 2
models of brain edema in cats. A space-occupying lesion was
used to mimic vasogenic edema, whereas cytotoxic brain
edema was created by an acute reduction in blood osmolality.
Ketamine reduced ICP caused by space-occupying lesions to a
NEUROPROTECTION BY KETAMINE
similar degree as methohexital and propofol, but the dissocia-
tive anesthetic also increased CPP, in contrast to the other
drugs. However, ketamine, methohexital, and propofol did not
affect ICP or CPP in the cytotoxic brain edema model. These
data suggested that ketamine may attenuate the increase in ICP
caused by space-occupying lesions but may be detrimental
during generalized edema. The authors postulated that some
neurons remain viable and responsive to the effects of ketamine
in the presence of a space-occupying lesion. In contrast, diffuse
intracellular damage occurs in the cytotoxic brain edema,
CMRO2 may be severely depressed, and autoregulation of the
cerebral vasculature may be impaired. As a consequence, the
cytotoxic brain becomes less responsive to the vasoactive ef-
fects of intravenous anesthetics, including ketamine.
The actions of ketamine (10⫺3 to 10⫺7 mol/L) on cerebral
pial arterioles in a closed cranial window model were evaluated
in dogs anesthetized with pentobarbital or isoflurane.40 Neither
topical nor intravenous (1 mg/kg and 5 mg/kg, respectively)
ketamine caused pial arteriolar vasodilation. However, the re-
activity of pial arterioles to hypercapnia was reduced after
intravenous, but not topical, administration of ketamine, sup-
porting the hypothesis that the type of baseline anesthetic
affects the microvascular effects of ketamine. Ketamine was
also shown to differentially modulate the cerebral circulation in
the presence of volatile agents because ketamine reduced
isoflurane- but not sevoflurane-induced cerebral vasodilation.41
NEUROTOXIC EFFECTS OF NMDA-RECEPTOR
ANTAGONISTS: EXPERIMENTAL EVIDENCE
In contrast to the aforementioned data, other evidence sug-
gests that NMDA-receptor antagonists may produce neurotox-
icity under certain experimental conditions. For example, com-
plete inhibition of normal NMDA-receptor activity reduced
brain cell survival and worsened physiologic outcome in ro-
dents because NMDA-mediated signal transduction was re-
quired to express neurotrophins and survival-promoting pro-
teins.46 Similarly, large doses of NMDA-receptor antagonists
caused apoptosis, synaptic deficits, and cognitive impairment in
the developing rat brain, especially during the vulnerable phase
of synaptogenesis.47-50 Ketamine produced acute, albeit tran-
sient, vacuolar changes in posterior cingulate/retrosplenial cor-
tices in adult rats.51-53 The coadministration of ketamine and the
NMDA antagonist nitrous oxide further enhanced vacuole for-
mation, whereas the pretreatment with a ␥-aminobutyric acid
agonist prevented these adverse effects.51,54 Low doses of
NMDA antagonists, including ketamine and phencyclidine,
produced reversible pathomorphologic changes in cerebral cor-
tical neurons of the adult rat brain,55 and higher doses of these
drugs caused irreversible neuronal degeneration in several cor-
tical-limbic brain regions.54-58 In vitro studies showed cell death
in neurons cultured from the rat forebrain after prolonged
exposure to ketamine at concentrations of 10 or 20 ␮mol/L, but
apoptosis did not occur in the presence of 0.1 or 1.0 ␮mol/L of
ketamine.59 Studies conducted with cultured monkey frontal
cortical neurons produced similar results.60 These results
strongly suggested that neurotoxicity produced by NMDA an-
tagonists in vitro may be dose-related.
The mechanism responsible for NMDA-antagonist neurotox-
icity is unclear, but the disinhibition of excitatory neural path-
133
ways that extensively innervate the cerebral cortex may play an
important role in this phenomenon. Whether the NMDA an-
tagonist-induced neurodegeneration observed in rats also oc-
curs in humans is presently unknown. Notably, the doses and
durations of administration of ketamine-implicated neurotoxic-
ity in experimental animals often do not correlate with and
frequently greatly exceed those used to produce sedation or
anesthesia in patients. Thus, the potential clinical relevance of
the data obtained in rats remains to be clarified. Nevertheless,
the results of 1 study suggested that the psychotomimetic
effects of NMDA antagonists in humans may correlate with the
cerebral pathologic changes observed in rats.61 Another crucial
factor that must be considered when extrapolating results from
experimental animals to humans is the presence or absence of
ischemia. Clearly, the pathologic conditions during or after
cerebral ischemic injury are profoundly different from those
present in intact, uninjured tissue. Neural ischemia causes
profound increases in extracellular excitatory transmitter con-
centration.62 This observation indirectly suggests that ketamine
may be capable of causing additional neural excitation and
further damage during ischemia-reperfusion injury, but this
hypothesis has not been examined.
CEREBROVASCULAR AND METABOLIC EFFECTS OF
KETAMINE IN HUMAN VOLUNTEERS
Incremental intravenous doses of ketamine (cumulative total
of 3 mg/kg) increased CBF, CPP, and arterial CO2 tension and
reduced cerebral vascular resistance but did not affect the
CMRO2, CMRglu, and CMRlactate in healthy patients before
elective surgery.2 The actions of racemic ketamine (0.25 or 0.5
mg/kg intravenously) on spontaneous brain electrical activity
and intracranial blood flow velocity were assessed in conscious
volunteers.63 Ketamine modestly increased heart rate and mean
arterial pressure but did not affect end-tidal CO2 tension or
arterial O2 saturation. Ketamine also caused a dose-dependent,
transient shift in the electroencephalogram (EEG) to synchro-
nous, high-voltage slow waves with an increase in total power
concomitant with increases in middle cerebral artery blood flow
velocity. These data suggested that enhanced intracranial blood
flow velocity occurs primarily as a result of increases in neu-
ronal activity and not because of changes in hemodynamics,
ventilation, or oxygenation. Subanesthetic doses of ketamine
also increased EEG theta activity, regional CBF, and metabo-
lism in spontaneously breathing volunteers.63-66 As described
earlier, these metabolic effects were dependent on the optical
isomer examined. Vollenweider et al65 investigated the effects
of (S)- and (R)-ketamine enantiomers on brain energy metab-
olism in healthy volunteers using positron emission tomogra-
phy. Psychotomimetic doses of (S)-ketamine substantially in-
creased regional CMRglu in the frontal cortex and thalamus.
These metabolic changes were associated with egodisintegra-
tion and hallucinations. In contrast, equimolar doses of (R)-
ketamine suppressed regional CMRglu in the temporomedial
cortex and left insula concomitant with a state of relaxation.
Subanesthetic doses of (S) - and (R)-ketamine were shown to
interact differently with the NMDA-and sigma-receptor sites in
the human brain. The sigma receptor was first described as a
novel opioid receptor but later was established as a distinct
pharmacologic receptor distinguished by its unusual ability to
 134
Table 1. Physiologic and Neurocognitive Effects of Ketamine in Humans

Reference Size/Study Group Age Dose, Ketamine Study Setting Outcome

Heart surgery
Tuman et al, 1989 240/345/212/250/47 62/63/63/63/63 3-6 mg/kg Cardiac surgery patients, no NC: neurologic morbidity
FenH/FenM/Sufen/Dia&Ket/Hal cerebral compromise Dia&Ket: D: vasopressors and ECG
evidence of ischemia
Roytblat et al, 1998 14/17 Ket/C 68/65 0.25-mg/kg bolus Cardiac surgery patients, no Ket: D: IL-6 during and post surgery
cerebral compromise
Zilberstein et al, 15/15 Ket/C 64/58 0.25-mg/kg bolus Cardiac surgery patients, no Ket: A: superoxide anion, percentage
2002 cerebral compromise of neutrophils, C: I: superoxide
anion
Nagels et al, 2004 50/56 Ket/Remifen 61/60 2.5-mg/kg bolus and 125 ␮g/kg/ Cardiac surgery patients, no Ket: less D: Trailmaking B test
min cerebral compromise
Smith et al, 2006 21/21 Suf/Ket&Mid 47/47 0.7 mg/kg/min for induction and Cardiac surgery patients, no NC: neurologic morbidity
2 mg/kg/h cerebral compromise Ket&Mid: D: ET-PCO2 Hct and I: MAP
Bartoc et al, 2006 15/18/17 Ket/Ket/C 73/73/69 0.25-, 0.5-mg/kg bolus Cardiac surgery patients, no Ket: D: IL-6 postsurgery in both
cerebral compromise ketamine groups
Ket: D: CRP postsurgery in 0.5 mg/kg
ketamine group
Ket: D: IL-10 postsurgery in both
ketamine groups
Hudetz et al, 2008 24/24 Ket/C 68/67 0.25-mg/kg bolus Cardiac surgery patients, no Ket: less D: delayed figure
cerebral compromise reproduction and delayed word list
recall tests
Hudetz et al, 2009 29/29 Ket/C 68/66 0.25-mg/kg bolus Cardiac surgery patients, no Ket: less delirium
cerebral compromise
Neurology
Mayberg et al, 1995 20 Ket 49 1-mg/kg bolus Neurosurgical patients, NC: MAP, CPP, PaCO2, AVDO2
mildly raised ICP D: VMCA, ICP
Strebel et al, 1995 6/6/6/6 39/43/35/36 2-mg/kg bolus Neurosurgical patients, no C: NC: MAP, VMCA
C/Ket/Ket&Mid/Ket&Esm cerebral compromise Ket: I: VMCA, MAP
Ket&Mid: D:VMCA, NC:MAP
Ket&Esm I: VMCA, NC:MAP
Kolenda et al, 1996 16/17 Ket&Mid/Fen&Mid 38/29 65 mg/kg/d Head-injured patients, Ket&Mid: I: CPP
increased ICP D: vasopressors
Albanese et al, 8 Ket 28 1.5, 3, 5 mg/kg Head-injured patients, NC: CPP, HR VMCA, MAP
1997 increased ICP D: ICP

HUDETZ AND PAGEL

Bourgoin et al, 12/13 Ket&Mid/Suf&Mid 30/27 4.92 ⫾ 1.5 mg Head-injured patients, NC: ICP, CPP
2003 increased ICP Ket&Mid: I: HR
Suf&Mid: I: fluid, vasopressors
 NEUROPROTECTION BY KETAMINE
Grathwohl et al, 46/47 Fen/Sufen&Sevo/Iso 27/27 5-20 ␮g/kg/min Head-injured patients, NC: neurologic outcome, death,
2008 Pro&Ket increased ICP injury severity score lowest
intraoperative SBP
General surgery
Roytblat et al, 1996 11/11 Ket/C 51/52 0.15 mg/kg Surgical patients Ket: D: HR, MAP, IL-6
Sakai et al, 2000 7/7/8 Awake/Pro/Pro&Ket 29/33/32 2 mg/kg/h Surgical patients ProKet: NC: VMCA, MAP, HR
Nagase et al, 2001 15/15 Ket/Pro 40/40 1 mg/kg Surgical patients, no Ket: NC: VMCA
cerebral compromise Pro: D: VMCA
Engelhard et al, 12/12 ProKet/Sevo 52/52 2.5 mg/kg/h Surgical patients, no ProKet: NC: Autoregulatory index
2001 cerebral compromise
Beilin et al, 2007 9/10 Ket/C 39/44 0.15 mg/kg Surgical patients, no Ket: D: IL-6, TNF-␣
cerebral compromise
Volunteers
Takeshida et al, 10 Ket 43 2 mg/kg and 1 mg/kg Volunteers, no cerebral I: MAP, CBF, CPP, PaCO2
1972 compromise D: CVR
NC: CMRO2, CMRglucose
CMRlactate
Kochs et al, 1991 10/10 Ket/Ket 27 0.25 mg/kg/0.5 mg/kg Volunteers, no cerebral I: MAP, HR, EEG theta, CBF
compromise NC: ET-PCO2, SaO2
Vollenweider et al, 10 S-Ket/R-Ket 30 15-mg bolus and 0.84-1.2 mg/ Volunteers, no cerebral S-Ket: I: rCMRGlu in anterior
1997 kg/h compromise cingulate, parietal, left
sensorimotor cortex, thalamus
R-Ket: D: rCMRGlu in temporomedial
cortex, left insula
Holcomb et al, 2001 13/10 Ket/C 31/30 0.3-mg/kg bolus Volunteers, no cerebral Ket: I: rCBF in anterior cingulate,
compromise medial frontal, inferior frontal
cortices
Ket: D: rCBF in cerebellum
Langsjo et al, 2003 9 Ket 26 30/100/300 ng/mL Volunteers, no cerebral I: rCBF in anterior cingulate,
compromise thalamus, putamen frontal cortices
NC: rCMRO2

Abbreviations: NC, no change; D, decrease; Ket, ketamine; Remifen, remifentanil; C, control; ICP, intracranial pressure; IL-6, interleukin 6; CRP, C-reactive protein; IL-10, interleukin 10; MAP, mean
arterial pressure; CPP, cerebral perfusion pressure; AVDO2, arteriovenous difference in oxygen content; VMCA, flow velocity in middle cerebral artery; Esm, esmolol; Mid, midazolam; Fen, fentanyl;
HR, heart rate; Pro, propofol; Sevo, sevoflurane; S-Ket, S-ketamine; R-Ket, R-ketamine; I, increase; rCBF, regional cerebral blood flow; rCMRO2, regional cerebral metabolic rate of oxygen; rCBV,
regional cerebral blood volume; rCMRGlu, regional cerebral metabolic rate of glucose; EEG theta, electroencephalogram theta activity; SaO2, arterial oxygen saturation; ET-PCO2, end-tidal
carbondioxid pressure; CVR, cerebral vascular resistance; PaCO2, arterial carbondioxide pressure; CMRO2, cerebral metabolic rate of oxygen; CMRglucose, cerebral metabolic rate of glucose;
CMRlactate, cerebral metabolic rate of lactate; O2, superoxide anion; TNF-␣, tumor necrosis factor ␣; Sufen, sufentanil; Dia, diazepam; FenH, fentanyl high dose; FenM, fentanyl moderate dose; Hal,
halothane; Hct, hematocrit.

135
136
bind a wide variety of drugs.67 (S)-ketamine was shown to bind
to the phencyclidine binding site of the NMDA receptor with a
4- to 5-fold greater affinity than the (R) enantiomer. In contrast,
(R)-ketamine also had a weak affinity, whereas (S)-ketamine
binds only negligibly to the sigma receptor sites.68 This obser-
vation allowed the investigators to identify the putative sigma
effects of (R)-ketamine on CMRglu and mental state. Such a
distinction was important because sigma receptors may modu-
late glutamatergic neuronal inputs or directly regulate the firing
activity of dopaminergic neurons in schizophrenia.69 Hence, by
modulating the glutamatergic inputs, by directly regulating the
firing activity of dopaminergic neurons, or by both mecha-
nisms, ketamine with its putative effects on the sigma receptors
could affect the treatment of schizophrenia and therefore play a
role in neuroprotection.
The temporal pharmacokinetic actions of racemic ketamine
(0.3 mg/kg) on regional CBF were examined using positron
emission tomography in volunteers.66 As observed in experi-
mental animals, ketamine produced distinctly different tempo-
ral alterations in regional CBF in specific areas of the human
brain. Ketamine increased regional CBF in the anterior cingu-
late, medial frontal, and inferior frontal cortices but reduced
regional CBF in the cerebellum. The peak alteration in regional
CBF occurred 6 to 16 minutes after administration of the drug.
The trend correlations between regional CBF in selected max-
ima in frontal cortex/anterior cingulate and behavior suggested
that these simultaneous measurements may be beneficial to link
regional blood flow to function. Thus, ketamine may provide a
probe to advance an understanding of psychosis from a dy-
namic physiologic perspective70-72 because alterations in re-
gional blood flow change patterns may be associated with the
appearance of the clinical psychotic symptoms.
Langsjo et al64 investigated the neuroprotective effects of
racemic ketamine using 15O-labeled water, O2, and carbon
monoxide as positron emission tomography tracers to quantify
regional CBF, regional CMRO2, and regional cerebral blood
volume, respectively, on selected brain regions in healthy male
volunteers. Intravenous infusions of ketamine (targeted to 30,
100, and 300 ng/mL) increased regional CBF in a dose-depen-
dent manner. Ketamine increased either absolute or relative
regional CBF in the anterior cingulate, thalamus, putamen,
insula, and frontal cortex. Absolute regional CMRO2 was not
changed; only subtle relative increases in the frontal, parietal,
and occipital cortices and decreases in the cerebellum were
detected. The authors concluded that subanesthetic doses of
ketamine increase regional CBF but do not alter regional
CMRO2, leading to a decrease in regional O2 extraction. De-
spite the observed dissociation of CBF and CMRO2, uncou-
pling of cerebral blood flow and metabolism was unlikely
because ketamine previously was shown to increase CMRglu.
Significantly greater increases in regional CBF compared with
regional CMRO2 have been reported in other studies assessing
the effects of focal neuronal stimulation.73,74 Indeed, alterations
in regional CBF may more closely follow changes of regional
CMRglu than regional CMRO2, suggesting that CBF may be
regulated for purposes other than O2 delivery for oxidative
metabolism.74 It may be speculated that the increases in re-
gional CBF in excess of regional CMRO2 requirements may
provide a reserve in O2 supply for conditions with possibly
HUDETZ AND PAGEL
compromised local blood flow. The physiologic effects of
ketamine in human volunteers are summarized in Table 1.
CEREBROVASCULAR AND METABOLIC EFFECTS OF
KETAMINE IN SURGICAL PATIENTS
Early studies suggested that ketamine causes parallel in-
creases in CBF, cerebral blood volume, and CMRO2 and, as a
result, may produce undesirable increases in ICP in surgical
patients.33,75,76 Recent research disputes these long-held suppo-
sitions.77,78 Ventilation was not controlled in many older stud-
ies, and ketamine, especially when combined with propofol or
midazolam, was shown to reduce ICP and CMRO2 in the
presence of mechanical ventilation.79 When changes in anterior
fontanel pressure (a noninvasive indicator of ICP) were com-
pared during ketamine, fentanyl, isoflurane, or halothane anes-
thesia in preterm neonates without neurologic disease during
mechanical ventilation, ketamine caused similar reductions in
anterior fontanel pressure compared with the other drugs.80
Kolenda et al81 examined the effects of ketamine on ICP and
CPP in patients with moderate-to-severe head trauma randomly
assigned to receive ketamine or fentanyl in combination with
midazolam. In the absence of controlled ventilation, patients
sedated with ketamine/midazolam required lower quantities of
vasoactive drugs but also had higher ICP and CPP than those
receiving fentanyl/midazolam. These results suggested that ket-
amine may be deleterious when used for conscious sedation in
patients with intracranial trauma. In contrast, Mayberg et al78
investigated the effects of ketamine on ICP and CBF velocity in
isoflurane/nitrous oxide-anesthetized, mechanically-ventilated
patients undergoing craniotomy for brain tumor resection or
cerebral aneurysm clipping. Ketamine (intravenous bolus of 1
mg/kg) reduced ICP, middle cerebral artery blood flow veloc-
ity, and total EEG power, but CPP, O2 extraction, and arterial
CO2 tension were unaffected.78 Racemic ketamine (1.5, 3, or 5
mg/kg) also significantly decreased ICP in neurosurgical pa-
tients with traumatic brain injury during propofol anesthesia
and mechanical ventilation.79 Again, no differences in CPP,
jugular vein bulb O2 saturation, and middle cerebral artery
blood flow velocity were observed between ketamine- and
placebo-treated patients. Bourgoin et al82 examined and com-
pared the relative safety and efficacy of racemic ketamine and
midazolam in patients with severe head injury during mechan-
ical ventilation. Neither ketamine/midazolam nor sufentanil/
midazolam altered ICP or CPP, but patients randomized to
receive ketamine/midazolam required less aggressive volume
resuscitation early during treatment and also showed a trend
toward reduced use of vasoactive drugs to maintain arterial
pressure compared with those treated with sufentanil/midazo-
lam. Notably, ketamine/midazolam did not produce adverse
effects or contribute to more pronounced morbidity or mortal-
ity. The authors concluded that ketamine/midazolam sedation
compares favorably with sufentanil/midazolam in maintaining
ICP and CPP in this vulnerable patient population. Nagase
et al83 examined the actions of ketamine and propofol on the
cerebrovascular response to CO2 in mechanically ventilated
patients undergoing elective surgery during isoflurane anesthe-
sia. Middle cerebral artery blood flow velocity and pulsatility
index assessed using transcranial Doppler were determined
under hypo-, normo-, and hypercapnic conditions in the pres-
NEUROPROTECTION BY KETAMINE
ence or absence of ketamine (1 mg/kg) or propofol (2 mg/kg
followed by an infusion of 6-10 mg/kg/h). Ketamine, but not
propofol, modestly reduced the cerebrovascular response to
CO2 and prevented increases in middle cerebral artery blood
flow velocity during hypercapnia. Such actions may be bene-
ficial in patients with increased ICP. Taken together, these data
suggest that ketamine may exert beneficial neurologic effects in
anesthetized, mechanically ventilated patients with increased
ICP without causing adverse changes in cerebral hemodynam-
ics. The physiologic effects of ketamine in surgical patients are
summarized in Table 1.
CEREBROVASCULAR AND METABOLIC EFFECTS OF
KETAMINE COMBINED WITH OTHER DRUGS
IN HUMANS
The cerebral hemodynamic and metabolic effects of racemic
ketamine have been shown to be dependent on the presence of
other anesthetics. Strebel et al84 investigated the actions of
ketamine alone or in combination with midazolam or esmolol
in mechanically ventilated patients anesthetized with isoflu-
rane. Ketamine-induced changes in cerebral hemodynamics
were measured by using transcranial Doppler ultrasound. As
expected, ketamine alone increased middle cerebral artery
blood flow velocity and mean arterial pressure compared with
placebo. Ketamine-induced increases in middle cerebral artery
blood flow velocity were unaffected when mean arterial pres-
sure was maintained at baseline values by infusion of intrave-
nous esmolol. In contrast, the deleterious effects of ketamine on
middle cerebral artery blood flow velocity were abolished in
the presence of midazolam. The results suggested that midazo-
lam profoundly affects the cerebrovascular actions of ketamine
in isoflurane-anesthetized patients. The effects of racemic ket-
amine/propofol anesthesia on intracerebral hemodynamics
were compared with those produced by propofol alone using
transcranial Doppler ultrasound.85 Ketamine/propofol anesthe-
sia did not affect heart rate, mean arterial pressure, or middle
cerebral artery blood flow velocity. During normocapnic con-
ditions, middle cerebral artery blood flow velocity was lower in
propofol-anesthetized patients with or without ketamine com-
pared with the conscious state. The cerebral vascular responses
to CO2 in patients receiving propofol/ketamine also were sim-
ilar to propofol alone. These results suggested that racemic
ketamine does not adversely influence middle cerebral artery
blood flow velocity or the cerebrovascular response to CO2
during propofol anesthesia in patients without intracranial pa-
thology. The effects of (S)-ketamine (2.5 mg/kg/h) and propo-
fol (target-controlled plasma concentrations of 1.5-2.5 ␮g/mL)
on cerebrovascular autoregulation were compared with sevo-
flurane (2.0 minimum alveolar concentration) in patients
undergoing elective abdominal surgery.86 Autoregulation was
maintained during (S)-ketamine/propofol anesthesia but was
attenuated during the administration of sevoflurane. Thus, the
addition of (S)-ketamine to propofol anesthesia does not appear
to affect intracranial hemodynamics or autoregulation in surgi-
cal patients.
The effect of anesthetic techniques on neurologic outcomes
in combat-related traumatic brain injury and the potential ben-
efits of total intravenous compared with volatile anesthesia
recently were described in a retrospective study.87 No differ-
137
ences in the lowest intraoperative systolic blood pressure were
observed in patients receiving volatile compared with ket-
amine-propofol anesthesia groups. The neurologic outcome
also was similar between groups. These data suggested that
intravenous propofol-ketamine anesthesia was as efficacious
and safe as volatile anesthesia in these severely injured patients.
The results also confirmed the findings of other studies indi-
cating that the addition of ketamine to propofol anesthesia
attenuates the systemic hypotension associated with propofol
alone by preserving CPP through sympathomimetic effects.88-90
The physiologic effects of ketamine in humans are summarized
in Table 1.
KETAMINE AND NEUROLOGIC IMPAIRMENT AFTER
CARDIAC SURGERY
Postoperative neurologic deterioration is common in cardiac
surgical patients, especially when CPB is used. Reduced per-
fusion pressure during CPB places patients at risk of cerebral
ischemia. Embolization of air or particulate matter during aortic
cannulation or weaning from CPB may produce focal neuro-
logic damage and neuropsychiatric complications.91 CPB also
causes a systemic inflammatory response, which may contrib-
ute to the development of neurologic injury.92,93 This systemic
inflammation may be mediated by surgical trauma, blood con-
tact with the extracorporeal bypass circuit, and lung reperfusion
injury after the discontinuation of CPB. Attenuating this in-
flammatory response is an important therapeutic objective and
is associated with improved outcome.94,95 Pulmonary function
may deteriorate significantly after CPB, and this acute lung
injury also may impair cognitive performance.96 Acute lung
injury after CPB was shown to be related to the activation of
neutrophils and reductions in the body temperature during
CPB.97 Neutrophils and the inflammatory mediators that they
produce play an important role in the pathogenesis of postop-
erative neurologic dysfunction in cardiac surgery patients.97
Lung injury during and after CPB precipitates an accumulation
of activated neutrophils in the pulmonary circulation with the
subsequent release of toxic mediators that contribute to the
injury of other vulnerable tissue, including the brain.98,99 Neu-
trophil elastase may be 1 such mediator of injury.100 Elastase is
a potent protease, capable of damaging intact neurons101 and
elevated plasma concentrations of elastase that occur in patients
after CPB.102-105 Notably, the cellular response to the extracor-
poreal circulation was shown to be delayed after hypothermia,
provoking a delayed onset of neutrophilia and elevated plasma
pulmonary elastase concentrations.97 Thus, the adverse conse-
quences of CPB may affect postoperative neurologic function.
Ketamine may produce neuroprotective effects in part by
inhibiting this systemic inflammatory response. Zilberstein et
al106 showed that the administration of ketamine (0.25 mg/kg)
during anesthetic induction attenuates neutrophil activation in
patients after CPB as indicated by reductions in superoxide
anion production and total postoperative neutrophil count. Ket-
amine also may favorably affect cognitive function and post-
surgical inflammation after CPB. Patients undergoing CABG
surgery using CPB were randomized to receive ketamine (0.25
mg/kg) or 0.9% saline solution during anesthetic induction with
fentanyl.107 In contrast to placebo, ketamine produced a sus-
tained suppression of increases in serum IL-6 concentrations
138
through the 7th postoperative day. Notably, serum IL-6 con-
centrations correlated with the patient’s clinical course after
surgery,107 implying a more beneficial outcome for patients
receiving ketamine pretreatment compared with those who
did not. The degree of the systemic inflammatory response
has been correlated with patient outcome in cardiac surgical
patients.108-110 Inflammation also occurs in the brain after
off-pump coronary artery bypass graft surgery111 or after non-
neurologic, noncardiac surgery, as indicated by increased con-
centrations of proinflammatory cytokines in the cerebrospinal
fluid.112 Notably, inflammatory changes in the hippocampus
may adversely affect learning, memory, and other cognitive
domains.113 The administration of ketamine (0.25 or 0.5 mg/kg)
also attenuated increases of serum C-reactive protein, IL-6, and
IL-10 concentrations during and after cardiac surgery com-
pared with placebo.114 The addition of a single low dose of
ketamine to the other drugs used for anesthetic induction did
not produce adverse hemodynamic effects during induction,
intubation, incision, or sternotomy, nor did this intervention
contribute to postoperative dysphoria. However, the mean ar-
terial pressure and systemic vascular resistance remained
higher at the end of surgery, upon arrival in the intensive care
unit, and during the first postoperative day in patients receiving
ketamine compared with those who did not receive the disso-
ciative anesthetic. In contrast to these intriguing results with
ketamine, opioids alone did not substantially affect serum C-
reactive protein, IL-6, IL-8, and cortisol concentrations when
used as adjuncts to an inhaled anesthetic.115 Quantitative EEG
designed to detect postoperative neurologic injury was similar
between patients receiving a ketamine-midazolam– based anes-
thetic compared with those receiving sufentanil anesthesia in
patients undergoing cardiac surgery with CPB.116 These data
suggested that a ketamine-midazolam anesthetic technique
does not cause cerebral electrical activation or exacerbate post-
operative neurologic injury. The results of this study116 indi-
rectly supported earlier data by Tuman et al117 showing that
ketamine-diazepam anesthesia was associated with decreased
incidences of cerebral ischemia (assessed by EEG) and periop-
erative hypotension requiring vasoactive drug support com-
pared with other anesthetic techniques.
A neuropsychologic test battery was used to examine and
compare the potential neuroprotective effects of ketamine and
remifentanil in patients after cardiac surgery.118 Ketamine im-
proved cognitive performance in only 1 test (the Trailmaking B
test, a measure of executive functions) compared with remifen-
tanil. However, interpretation of these results was complicated
because propofol, a drug with well-known potent anti-inflam-
matory properties, was used as a baseline anesthetic, and many
young patients who are not at risk for long-term postoperative
cognitive dysfunction119-121 were enrolled in the study. In con-
trast to the findings of Nagel et al, the authors recently showed
that the administration of ketamine (0.5 mg/kg) during anes-
thetic induction attenuated short-term postoperative cognitive
dysfunction as indicated by several neuropsychologic tests in
patients anesthetized with isoflurane and fentanyl undergoing
cardiac surgery.122 These findings were accompanied by reduc-
tions in serum C-reactive protein concentrations on the first and
third postoperative days in ketamine- compared with placebo-
treated patients. In this investigation, the preservation of cog-
HUDETZ AND PAGEL
nitive functions concomitant with reduced C-reactive protein
concentrations suggested that the neuroprotective effect of ket-
amine may be caused, in part, by an anti-inflammatory action of
the drug. Hudetz et al123 also showed that the administration of
ketamine (0.5 mg/kg) during anesthetic induction attenuates
postoperative delirium in a similar patient population. The
incidence of postoperative delirium was significantly lower in
patients receiving ketamine (3%) compared with those treated
with placebo (31%). Postoperative C-reactive protein concen-
tration also was significantly lower in the ketamine-compared
with placebo-treated patients, again suggesting that improve-
ment in short-term neurocognition was related to an anti-
inflammatory effect. Whether these ketamine-induced neuro-
protective effects will translate into long-term benefits remains
to be established, but it is clear that perioperative cognitive
dysfunction is an important risk factor for long-term disability.
The physiologic and neurocognitive effects of ketamine in
cardiac surgical patients are summarized in Table 1.
Preoperative depression is a risk factor for postoperative
delirium.124,125 Depression may be precipitated by fear of sur-
gery and its outcome concomitant with unfamiliar environmen-
tal surroundings.126,127 Limited concentration and attention are
among the most commonly reported symptoms, but impairment
in recent verbal and nonverbal memory and impaired executive
functions also have been found in patients with depression.128-131
NMDA-receptor antagonists may be effective for treating de-
pression.132 Ketamine (0.5 mg/kg) significantly improved the
symptoms of patients with depression within 72 hours after
administration.133 Ketamine (1 mg/kg) also improved postop-
erative depression in patients 1 day after orthopedic surgery.134
Thus, alleviating depression symptoms may reduce cognitive
impairment after surgery.
Postoperative delirium and postoperative cognitive dysfunc-
tion occur frequently in elderly patients undergoing cardiac
surgery using CPB. Postoperative delirium often precedes and
may predict the subsequent development of postoperative cog-
nitive dysfunction. To date, few therapeutic options for the
prevention of postoperative cognitive dysfunction have been
shown to be effective. Postoperative cognitive dysfunction may
be observed in as many as three-quarters of cardiac surgical
patients at the time of hospital discharge, and these deficits may
persist in one-third of patients after 6 months.135 Postoperative
cognitive dysfunction is characterized by impaired recent mem-
ory, concentration, language comprehension, and social inte-
gration.121 Patients with postoperative cognitive dysfunction
may experience delayed transfer from the intensive care unit
after surgery, prolonged hospitalization, and a longer recovery
before returning to work.136,137 These patients also may expe-
rience impaired self-care, increased dependency, increased at-
trition from rehabilitation, and higher rates of hospital read-
mission. Thus, identifying treatment interventions that
reduce or eliminate postoperative cognitive dysfunction in
cardiac surgical patients is an essential goal with direct
clinical implications.
CONCLUSION
Ketamine has long been considered contraindicated in
patients with brain injury, but paradoxically this dissociative
anesthetic may provide beneficial effects in neurologically
NEUROPROTECTION BY KETAMINE
impaired patients during controlled ventilation. Ketamine
may exert neuroprotection because the drug inhibits the
NMDA-receptor activation, mediates beneficial changes in
apoptosis-regulating proteins, and interferes with the inflam-
matory response to injury when used in typical sedative or
anesthetic doses. Cardiovascular stimulation by ketamine
may also improve cerebral perfusion, and this action may be
advantageous in patients after brain injury. Conversely,
other laboratory investigations have suggested that ketamine
may cause neurotoxicity when administered in larger doses.
Intriguing recent clinical evidence has emerged, suggesting
that ketamine exerts beneficial short-term actions on post-
operative delirium and cognitive dysfunction in patients
after cardiac surgery. Whether favorable effects also protect
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