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REVIEW

Ketamine and Peripheral Inflammation

Marc De Kock,1 Sebastien Loix2 & Patricia Lavand’homme1
1 Department of Anesthesia, Perioperative Medicine, Institute of Neurosciences, Catholic University of Louvain, Brussels, Belgium
re, Belgium
2 Intensive care unit, Jolimont Hospital, La Louvie

Keywords SUMMARY
Immune system; Inflammation; Ketamine;
Peripheral. The old anesthetic ketamine has demonstrated interactions with the inflammatory
response. This review intends to qualify the nature and the mechanism underlying this
Correspondence interaction. For this purpose, preclinical data will be presented starting with the initial
Marc De Kock, M.D., Ph.D., Department of works, and then, the probable mechanisms will be discussed. A summary of the most rele-
Anesthesia, Clin Univ St Luc, 10-1821 av vant clinical data will be presented. In conclusion, ketamine appears as a unique “homeo-
Hippocrate, 1200 Brussels, Belgium. static regulator” of the acute inflammatory reaction and the stress-induced immune
Tel.: +32-2-7641821; disturbances. This is of some interest at a moment when the short- and long-term deleteri-
Fax: +32-2-7643699; ous consequences of inadequate inflammatory reactions are increasingly reported. Large-
E-mail: [email protected] scale studies showing improved patient’s outcome are, however, required before to defini-
Received 29 November 2012; revision tively assert the clinical reality of this positive effect.
1 March 2013; accepted 1 March 2013.

doi: 10.1111/cns.12104

presented starting with the initial works demonstrating a keta-

Introduction mine/immune interaction, and then, the probable mechanisms
This work will focus on the effects of ketamine on peripheral will be discussed. Finally, a summary of the most relevant clinical
inflammation. This old anesthetic is a particular substance charac- data will be presented.
terized by interactions with numerous receptor systems. For
example, it is best known as a competitive antagonist of the excit-
atory neurotransmission (N-methyl-D-aspartate NMDA receptor,
A “Successful” Inflammatory Reaction
Nr2b subtype) [1]. It is able to recruit the cathecholaminergic, Inflammatory reaction is capital for the maintenance of body
cholinergic and opioid systems [2,3]. It acts directly on some ionic homeostasis and survival [10]. Its role is to fight infection and tis-
channels receptors (Na+, Ca++) [4] and is ligand at the sigma sue injury by promoting healing. It is based on multiple step reac-
receptors and the trace amine-associated receptors (N,N-Dimeth- tions each under the influence of several positive (pro-
yltryptamine, 5-methoxy-N,N-dimethyltryptamine) [5]. These inflammatory) or negative (anti-inflammatory) retro-controls. On
multiple interactions probably account for its various clinical this fine tuning, depends on the success of this reaction, it is note-
effects such as anesthesia, analgesia, antihyperalgesia, induction worthy that an inadequate inflammatory response either exces-
of psychiatric symptoms compatible with schizophrenia, or posi- sive or insufficient is deleterious for the organism [11].
tive effects on depressive mood [6,7]. Moreover, it is known that To make an overcomplicated story short, the critical steps of the
ketamine influences the immune system particularly the inflam- inflammatory reaction may be summarized as follows:
matory reaction an immune response that largely derives from This reaction is triggered when the resident innate immune or
activation the “innate” immune mechanisms. A close consider- immune-assimilated cells such as macrophages, fibroblasts, mast
ation of this property is of particular interest at a moment where cells, and dendritic cells or circulating leucocytes detect pathogen
successful completion of the inflammatory reaction appears as an invasion or cell damage [12]. Detection mechanisms involve
important determinant for positive outcome in patients undergo- intracellular and surface-expressed pattern recognition receptors,
ing surgery or critical care patients [8,9]. In this field, ketamine that is, the Toll receptors (TLRs) that have a central role to activate
appears as a unique homeostatic regulator of the acute inflamma- innate immunity [13–16]. As a consequence of the reaction initi-
tory reaction and the stress-induced immune disturbances. This ated, transcription factors (NF-jB, AP1, CREB, c/EBP, and IRF)
review intends to qualify the nature and the mechanism underly- will be activated. Accordingly, genes encoding for cytokines,
ing this interaction. For this purpose, preclinical data will be chemokines, adhesion molecules and regulators of the extracellu-

ª 2013 John Wiley & Sons Ltd CNS Neuroscience & Therapeutics 19 (2013) 403–410 403
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Ketamine and Peripheral Inflammation M. De Kock et al.

lar matrix will be expressed [17]. At this moment, the inflamma-

tory reaction become florid, circulating leukocytes are recruited to
Ketamine as a “Regulator” of the
the region. In this regard, alterations of the vascular walls close to Inflammatory Reaction: Preclinical
the site are of primary importance. Mediators such as histamine, Studies
prostaglandins and nitric oxide cause local vasodilation which
Direct Effect on the Local Effectors of the
increase blood flow and the amount of recruited leukocytes.
Inflammatory Reaction
Under the influence of histamine and leukotrienes, vascular per-
meability is increased allowing plasma proteins and leukocytes to Which Steps of the Inflammatory Reaction are
exit the circulation. Additionally, the released cytokines (TNF, IL- Concerned by Ketamine?
1) promote the leukocytes extravasation. All the immune-compe-
The notion that ketamine interferes with immunity comes from
tent cells present at the site of infection or injury will remove
the early observations of improved outcome in critically ill
foreign bodies and injured materials by phagocytosis. At the same
patients [25] and in experimental septic shock [26]. This
time, they release cytokines and other mediators that will shape
prompted numerous laboratory investigations to uncover the
the adaptative immune response and initiate the active process of
mechanisms accounting for this beneficial effect [27–31].
inflammation resolution and healing.
To summarize all these works, we can state that ketamine is
As previously mentioned, the inflammatory reaction is a highly
able to regulate the local inflammatory process very early in its
regulated process [18]. This is mandatory because it is potentially
course by direct action on the key players of the innate immunity
so potent that it can definitively disrupt the homeostasis and com-
(Table 1). Ketamine affects the functioning of numerous cellular
promise survival. The regulation of this reaction occurs at two lev-
effectors of the inflammatory reaction. The first investigations
els: a local and a central one. At the local level: very early, anti-
have focused mainly on the production of cytokines by immune
inflammatory cytokines (i.e., IL-1receptor antagonist, IL-4, IL-10,
cells consecutive to an inflammatory challenge. Results obtained
Interferon a), are released by the immune cells that oppose to the
after these in vitro and/or ex vivo experimentations clearly demon-
action of the inflammatory ones (i.e., IL-1, IL-6, TNF-a) by pro-
strate that ketamine significantly reduces the amount of pro-
moting, among others, the early apoptosis of the inflammatory
inflammatory cytokines without affecting the production of the
cells [14]. Lipid mediators are other important actors in the active
anti-inflammatory ones. In other words, ketamine helps to avoid
resolution process. At the moment of aggression (viral, bacterial,
exacerbated pro-inflammatory reaction [32–37]. Two findings
tissue destruction) under the influence of the COX-2 enzyme,
deserve attention. First: ketamine has no effect on the immune
pro-inflammatory lipid mediators are released such as arachidonic
cells producing inflammatory cytokines in the absence of an
acid-derived leukotriens and prostaglandins. At a particular
inflammatory stimulus. Second, its regulatory action is more pro-
moment and under not yet exactly known influences (reduction
nounced when this drug is administered before the inflammatory
of inflammatory cells, release of pro-inflammatory cytokines),
challenge [36]. This is of particular interest knowing that keta-
using the same COX-2 enzyme, the host will shift to the synthesis
mine is mostly given at the induction of anesthesia before surgery.
of lipid mediators active in the resolution, that is, the lipoxins, re-
Early experimental studies have mainly focused on cytokines
solvins, and protectins [19–21].
production because it was, at that time, an inflammatory marker
At the central level, during peripheral inflammation, it is note-
easy to measure. Inflammatory reaction is also under the influ-
worthy that there exist bilateral communication between the
ence of other soluble mediators such as chemokines and various
immune and the nervous systems. The central nervous system
growth factors released by the effector cells. At the present time,
(CNS) is informed that “something” is happening in the periphery
little is known about any specific effect of ketamine on these types
by the peripheral nervous system and by the immune system (i.e.,
of inflammatory mediators. In contrast, other modulatory effects
glial hyperactivity consecutive to peripheral inflammation [22]).
of ketamine on specific actions of the inflammatory cells are
It will adapt behavior and physiologic responses to maintain
described [38–42]. For example, the oxidative potency and NO
homeostasis during this stress situation. Additionally, the CNS
production by the macrophages are reduced [32,43]. The effect of
exerts a potent modulatory action on the inflammation through
ketamine on NO production deserves some attention: Nitric oxide
efferent hormonal (the hypothalamo-pituitary axis [HPA]) and
acts as a mediator and an effector of the inflammatory reaction.
the autonomic neuronal pathways both sympathetic (noradrener-
Nitric oxide is cytotoxic on the microorganisms and the tumor
gic nerves) and parasympathetic (the vagus nerve) [23]. This is
cells. Its production is under the dependence of the inducible form
done to keep the inflammatory reaction as local as possible and
of NO synthase (iNOS) which is stimulated by pro-inflammatory
locally as efficient as possible. The immune translation of this is
cytokines [44,45]. The inhibition produced by ketamine is time-
best described as a predominance of the Th2 (anti-inflammatory)
and dose-dependent. Interestingly, it is not an NMDA-related
upon the Th1 (pro-inflammatory) type of reaction. Nevertheless,
property because another NMDA antagonist (MK-801) failed to
excessive decrement of Th1/Th2 ratio by exaggerated repression
decrease NO production. Inflammatory-induced NO production
of the Th1 type of reaction is also particularly deleterious for the
reduces the release of pro-inflammatory cytokines by immune
organism. This state of “immunoparalysis” is associated with
competent cells [46,47]. It is part of the multiple feedback loops
increased mortality and complications rates (i.e., secondary infec-
aiming to regulate the inflammatory reaction. These apparently
tions) [8,11,24]. Consequently, to maintain an adequate equilib-
contradictory effects of ketamine perfectly illustrate its immune
rium between pro- and anti-inflammatory influences is of critical
“regulatory” properties. In fact, this drug reduces the production
importance for a successful recovery after an inflammatory
of NO, this is an anti-inflammatory effect and consequently
challenge.

404 CNS Neuroscience & Therapeutics 19 (2013) 403–410 ª 2013 John Wiley & Sons Ltd
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M. De Kock et al. Ketamine and Peripheral Inflammation

Table 1 Summary of the early experimentation demonstrating an “anti-inflammatory” effect of ketamine

Conditions Endpoints Results: inflammatory Results: others Additional informations References

In vivo TNF-a ↓ TNF-a ↓ Acidosis 27

Rats + lipopolysaccharides MABP ↓ Hepatic insult
(LPS) Acidosis ↑ Survival
Ketamine IM Hepatic insult
100 mg/kg Survival
In vivo TNF-a ↓ TNF-a ↑ Survival 28
Rats + Escherichia coli IL-6 ↓ IL-6
Ketamine IP Survival
50 mg/kg
In vivo IL-6 ↓ IL-6 ↑ Survival 29
Rats +E. coli + Burns Survival
Ketamine IP
10 mg/kg
In vivo Survival ↑ Survival Heat shock response improved 30
Rats + Burns In comparison with
Ketamine midazolam/fentanyl
“anesthetic dose” anesthesia
In vivo Acidosis ↓ Acidosis Effects at 10 mg/kg 31
Rats + E. coli Survival ↑ Survival
Ketamine IV
Dose/response curve
3 doses 5, 10 and 20
mg/kg
In vivo IL-6/IL-10 Ratio improved Better than propofol 34
Rats + E. coli
Ketamine IV
10 mg/kg /h
In vivo TNF-a ↓ TNF-a ↑ Survival Preventive effect 36
Rats + E. coli IL-6 ↓ IL-6 Curative effect: less
Ketamine IV Acidosis pronounced but
10 mg/kg/h Survival still present
In vitro TNF-a ↓ TNF-a 33
Peritoneal macrophages of
mices + LPS and ketamine
In vitro TNF-a ↓ TNF-a Concentrations No effect if no immunostimulation 32
Human whole blood + LPS IL-6, IL-8 ↓ IL-6, IL-8  20 lg/mL
 100 lg/mL
In vitro TNF-a ↓ TNF-a Concentrations Both ketamine isomers are 35
Human whole blood + IL-6, IL-8 ↓ IL-6  50 lM immune active
Staph endotoxin ↓ IL-8  100 lM
 500 lM

In vitro TNF-a ↓ TNF-a Concentrations 37

Equine Macrophages IL-6 ↓ IL-6  1.8 lM
cell lines + LPS  1.8 lM
Ketamine concentrations
0, 0.36, 1.8, 3.6, 18, 36 lM
In vitro TNF-a ↓ TNF-a Original effect of ketamine compared 42
Human whole blood + LPS IL-1b ↓ IL-1b with midazolan, thiopental, fentanyl
Ketamine concentrations
5.8910 5 M

suppresses the NO-induced inhibition of pro-inflammatory cyto- expressed on the surface of the immune cell [51] and not an inter-
kines production, a pro-inflammatory effect. action with the inflammatory endothelial function [48]. This is of
Additionally, ketamine significantly limits the diapedesis of the some interest because preservation of an intact endothelial func-
neutrophils to the site of inflammation [48–50]. The underlying tion is correlated with positive outcome after ischemia/reperfu-
mechanism appears to be a reduction in adhesion molecules sion injury [52]. These observations do not exclude any action of

ª 2013 John Wiley & Sons Ltd CNS Neuroscience & Therapeutics 19 (2013) 403–410 405
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Ketamine and Peripheral Inflammation M. De Kock et al.

ketamine on the other determinants of inflamed tissue penetra- Whether the interaction of ketamine with TLR-derived
tion of leukocytes (i.e., chemokines as suggested by the work of mechanisms is the consequence of antagonism at NMDA
Dhote et al. in the CNS [53]) but no specific data can be found in receptor system is not yet determined. Nevertheless, it is
the literature. firmly established that the NMDA glutaminergic transmission
Recently attention was drawn on a particular population of system participate directly to the inflammatory cascade and
cytotoxic lymphocytes: the Natural Killer (NK) cells. These are a its consequences, that is, pain by mechanisms including
major component of the innate immunity. They significantly con- peripheral nerve, spinal cord sensitization, glial activation
tribute to the first line defense against viral infection and tumor and dorsal root reflexes [66–69].
cells growth [54]. Consequently, impairment of their cytotoxic Second: the adenosine receptor system. Adenosine is a metabo-
properties, for example, in the perioperative period, is suspected lite of adenosine triphosphate (ATP). This purine nucleoside
to favor postoperative infections and metastatic cancer cells prolif- has been described as a “retaliatory metabolite” because of
eration in the case of surgery for the resection of a primary tumor. its ability to function in an autocrine manner and to modify
It is known that opioids used as ketamine during anesthesia the activity of a wide range of cells following its extracellular
potently reduce NK activity in vitro. In contrast, ketamine did not accumulation during cell stress or injury. To summarize its
significantly affect the functioning of NK cells [55]. actions, it functions as a local homeostatic modulator by
Finally, ketamine favor the resolution of inflammation by pre- interacting with four cell surface receptors (A1, A2a, A2b,
cipitating the apoptosis of the inflammatory cells [56]. The active A3) [70]. The A2a receptors are mainly involved in the mod-
process of resolution involves several cellular mechanisms. ulation of inflammatory and immune responses. Their critical
Among these, the clearance of inflammatory cells is of critical role is to maintain tissue integrity by down-regulating phlo-
importance [57]. This is obtained both by apoptosis (cell suicide) gistic reactions, repression of the synthesis of pro-inflamma-
and/or egress from the tissues. Once again, the regulatory effect of tory cytokines, inhibition of neutrophil adhesion,
ketamine has to be noted. On the one hand, it promotes apoptosis degranulation and anti-oxidant activity [71]. Mazar and
by specific mitochondrial pathway in human lymphocytes [56], coworkers [72] demonstrated that the ketamine-induced
and on the other; it reduces the release by the inflammatory cells anti-inflammatory effects (including the inhibition of the
of the pro-inflammatory cytokine TNF-a, the major activator of NFj-b [73]) also result from the activation of this endoge-
the apoptotic pathways [58]. This is another example of ketamine nous A2a-mediated homeostatic protector system [74]. Inter-
being a regulator of inflammation, having sometimes opposite esting to point out, ketamine interferes with the functioning
effects. of the COX-2 enzyme through recruitment of the adenosine
2a receptor system altering the production of lipid inflamma-
tory mediators without affecting the lipid-induced resolution
By Which Mechanisms Ketamine Interferes with the
process [75–77]. There is, however, at the present time, no
Local Inflammatory Reaction?
evidence that ketamine experimentally promotes the active
As evidenced previously, ketamine shows pleiotropic anti-inflam- resolution process.
matory effects. This is a strong argument for a very early interac- Third: NMDA receptors activation was recently demonstrated
tion in the time-course of the inflammatory cascade. In this to directly activate Wnt5a signaling pathways, a “nonclassical”
regard, more precise idea on the mechanisms involved are to be activator of the NFj-b [78]. Consequently, ketamine blocks
found in the repression of the nuclear factor NFj-b [59,60]. The this alternative route recognized as critical for endothelium
NFj-b is an intracellular protein that activates the transcription of activation during inflammation [79].
genes coding for cytokines in immune competent cells. It is a key
Finally, several other mechanisms are described that partici-
transcriptional regulator playing a central role in the onset of
pates to the anti-inflammatory effects of ketamine. For exam-
inflammation [61]. How is this factor controlled? Typically, the
ple, ketamine interacts directly with some ion channels such as
NFj-b is activated by prototype inflammatory mediators such as
the large conductance Ca++-activated K+ channels. Although
IL-1b and TNFa [62] released by the resident immune cells facing
no direct action on peripheral inflammation were reported,
an inflammatory stimulus. Other regulators are described such as
blockade of these channels is demonstrated to prevent the
the adenosine receptors system [63] and the recently described
inflammatory signals arising from the periphery to activate the
Wnt5a-signaling pathways.
microglia by suppressing the pro-inflammatory cytokines pro-
By which of these mechanisms ketamine is acting?
duction of the immune cells in the CNS. The dose used in this
First: the release of the prototype inflammatory mediators. Some experimentation were, however, particularly high [4]. More-
experimental works using a rodent model of endotoxic shock over, ketamine activates another important anti-inflammatory
suggests that ketamine may interfere with the early detection pathway, the heme oxygenase enzyme system. The anti-
mechanisms such as the Toll-like receptors (TLRs) [64,65]. inflammatory properties of this system are secondary to the
The fact that ketamine is able to interact with TLR-derived production of metabolites generated during the catabolism of
mechanisms is of some interest. Remember that most of the heme. These include biliverdin, free iron, and CO. This system
in vitro anti-inflammatory properties of ketamine were provides powerful protective effects during sepsis and ischemia/
demonstrated using a lipopolysaccharides (LPS) challenge. reperfusion insults [80]. To which extent these mechanisms
These LPS are a major constituent of gram negative bacteria account for the inflammatory “protective” effects of ketamine
and are recognized as specific agonists of the TLRs type 4. remains to be elucidated.

406 CNS Neuroscience & Therapeutics 19 (2013) 403–410 ª 2013 John Wiley & Sons Ltd
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M. De Kock et al. Ketamine and Peripheral Inflammation

observation in patients receiving an IV bolus of ketamine (either

Effects of Ketamine on the Systemic Regulators
0.25 or 0.5 mg/kg) at induction of the anesthesia. These authors
of the Inflammatory Reaction
reported reduced biological inflammatory markers (IL-6 in both
Facing a localized inflammatory process, the organism will react ketamine groups at arrival in the ICU. C-reactive protein and IL-
by promoting a systemic protective anti-inflammatory effect. In 10 only in the 0.5 mg/kg group at the first postoperative day)
other words, a predominance of the Th2 (anti-inflammatory) when compared to the placebo group. Interestingly, patients trea-
upon the Th1 (pro-inflammatory) type of reaction will be ted with ketamine presented with les post ECC vasoplegia during
observed. Does ketamine interferes with this important immune the entire observation period [88]. Another study conducted in a
ratio? Experimental in vitro data using CD4-positive lymphocytes pediatric cardiac surgery population failed to demonstrate any
separated from healthy volunteers clearly show that ketamine anti-inflammatory action of ketamine after ECC. The administra-
used at concentration of 10 lg/mL (a concentration comparable tion of steroids in both the control and the ketamine groups prob-
with the one obtained after an IV bolus of 0.5 mg/kg) significantly ably explains this negative result [89]. In patients undergoing
increased the Th1/Th2 ratio and might consequently be benefit to liver transplantation, ketamine administration was associated
the patient’s global immune function [81]. In comparison with with reduced levels of circulating TNF-a and IL-6 [90].
morphine (used in the same model at human analgesic concentra- A recent meta-analysis by Dale et al. [91] considered the effects
tion), both drugs reduce the rate of Th cell differentiation and sub- of ketamine on IL-6 production in patients undergoing surgery.
sequent cytokines production simulation. However, morphine Concentrations of this major pro-inflammatory cytokine were
potently decreases the Th1/Th2 ratio in comparison with keta- used as a biomarker of the inflammatory reaction. Of the 14 stud-
mine [82]. ies eligible for evaluation (684 patients from cardiopulmonary
In contrast with the above-described effect on Th1/Th2 differen- bypass operations, abdominal, thoracic and cataract surgeries), six
tiation, ketamine may potentially participate to the stress reac- studies (331 patients) were included in the meta-analysis. It was
tion-induced anti-inflammatory effect (Th-1 repression). These concluded that ketamine, given at an IV bolus dose of at least
are consecutive to the activation of the sympathetic system and 0.15 mg/kg before surgery significantly inhibits the early postop-
the HPA resulting in increased adrenal activity and corticosteroid erative IL-6 inflammatory response. This effect is at least as impor-
production. Studies on human volunteers clearly show that keta- tant as the one obtained after pre-treatment with one of the most
mine stimulates both systems [83,84]. Nevertheless, no data are potent anti-inflammatory medication, that is, methylprednisolone
available on the possible immune consequences of this interac- (30 mg/kg) in cardio-pulmonary bypass surgery [92]. Neverthe-
tion. less, the effect of methylprednisolone was short-lived (approxi-
Ketamine promotes potentially both anti- and pro-inflamma- mately 1 h) in comparison with ketamine where durations of up
tory reactions. In this regard, it has to be considered more as a reg- to 6 h were documented [91].
ulator, a drug that promotes immune homeostasis during stress Although there is no study that specifically considers clinical
conditions. This is exemplified by the following observation: Keta- outcome, it is supposed to be improved. Indeed, elevated levels of
mine used for recreational purposes is often associated with IL-6 in the postoperative period were regularly reported to be
cocaine. Cocaine stimulates ACTH and cortisol production result- associated with poor outcome [93–95].
ing in an exacerbated systemic anti-inflammatory effect. When Another way to get some information about the consequences
ketamine is associated with cocaine in an animal model of addic- of immune regulatory properties of the ketamine is to consider
tion, the cocaine-induced surge in ACTH and cortisol is blunted by the effects of this drug on the deleterious postoperative events
ketamine promoting in this particular circumstance a pro-inflam- usually ascribed to exacerbated pro-inflammatory reactions.
matory effect [85,86].

Hyperalgesia
Ketamine as a “Regulator” of the
Ketamine alleviates postoperative pain syndrome related to exag-
Inflammatory Reaction: Clinical Evidence gerated pro-inflammatory reaction. Ketamine significantly
Ketamine is regularly used in the perioperative period for anes- reduces trauma-induced hyperalgesia, a phenomenon that can be
thetic (high doses 2–3 mg/kg IV bolus) or more recently for anti- ascribed to both its NMDA antagonist effect and its anti-inflamma-
hyperalgesic purposes (low dose 0.5–0.25 mg/kg IV bolus). tory properties. Positive consequences were noted on the develop-
Surgery implies tissue destruction and elicits a significant inflam- ment of chronic postsurgical pain in limited series of patients
matory reaction. Is ketamine given before and/or during surgery [6,96–98].
associated with a more adequate inflammatory reaction and con- Moreover, ketamine is highly efficient to prevent opiate-
sequently a more favorable postoperative outcome? induced hyperalgesia. This action is usually ascribed to the block-
In patients undergoing cardiac surgery under extracorporeal cir- ade of excitatory (NMDA) transmission induced by the activation
culation (ECC) (a circumstance known to strongly activate the of l-opiate excitatory receptors [99]. Nevertheless, some data sup-
inflammatory cascade), the administration of a single IV low dose port the involvement of inflammatory mechanisms in opiate-
of ketamine (0.25 mg/kg) at induction of anesthesia significantly induced analgesia. It is demonstrated, for example, that glia can
reduced the production of IL-6 a pro-inflammatory cytokine. exhibit pro-inflammatory responses to opioids, contributing to
Interesting to note this reduction was still present at the seventh opioid-induced hyperalgesia and the development of tolerance
postoperative day, long time after ketamine has disappeared from and dependence [100]. Interestingly, the mechanism contributing
patients’ blood [87]. Bartoc and coworkers reproduced this to opioid-induced pro-inflammatory actions is probably the

ª 2013 John Wiley & Sons Ltd CNS Neuroscience & Therapeutics 19 (2013) 403–410 407
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Ketamine and Peripheral Inflammation M. De Kock et al.

activation by the opioids of the TLR-4 receptors system [101]. It surgery under ECC [104]. Consequently, it can be hypothesized
may explain why a drug such as ketamine that reduces the activa- that the inflammatory regulatory properties of ketamine this
tion of the TLR-4 opposes to the pro-inflammatory effects of the positive effect on postoperative outcome. Interestingly, a recent
opioids and reduce opioid-induced hyperalgesia. experimental study by Wang et al. [105] pointed out a probable
link between activation of TLR-4 signaling on microglia and
postoperative cognitive dysfunction.
Postoperative Cognitive Dysfunction
Postoperative cognitive dysfunction is a complication following
surgery and particularly cardiac surgery. It was observed that
Conclusions
patients undergoing cardiac procedures where ketamine was asso- Ketamine appears as a drug promoting the inflammatory homeo-
ciated (on iv bolus of 0.5 mg/kg at induction of anesthesia) pre- stasis. Locally, ketamine interferes very early on the determinants
sented a significantly reduced incidence of this complication of primary immunity. It prevents the exacerbation and the
compared with controls as assessed by improved recent verbal and extension of local inflammation without blunting the local process
nonverbal memories and executive functions at 1 week after sur- and delaying inflammatory resolution. Ketamine also prevents
gery. Additionally, the inflammatory marker CRP was signifi- the general anti-pro-inflammatory mechanisms to excessively
cantly reduced in the ketamine group [102]. The exact overcome the pro-inflammatory influences. In other words,
mechanisms underlying postoperative cognitive dysfunctions are ketamine is immunomodulatory rather than immunosuppressive.
not fully understood [103]. Nevertheless, the inflammatory reac- These quite interesting properties deserve, however, confirmation
tion consecutive to the surgical trauma is incriminated. Peripheral in large prospective human studies considering not only some
inflammatory cytokines can takes effects on the CNS. This occurs inflammatory markers but also clinical outcome parameters.
directly, cytokines bind their receptors in the CNS and activate mi-
croglial cells but also indirectly by activation of vascular endothe-
lial cells. Indeed, perioperative increased levels of CRP and
Conflict of Interest
inflammatory cytokines are associated with the occurrence of The authors declare no conflict of interest.
postoperative cognitive dysfunction in patients undergoing

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