Pain Medicine

Section Editor: Spencer S. Liu

Does Intraoperative Ketamine Attenuate Inflammatory

Reactivity Following Surgery? A Systematic Review
and Meta-Analysis
Ola Dale, MD, PhD,* Andrew A. Somogyi, MSc, PhD,* Yibai Li, BHSc (Hon),*
Thomas Sullivan, BMa, CompSc (Hon), and Yehuda Shavit, PhD*
BACKGROUND: Reports regarding the ability of the anesthetic drug ketamine to attenuate the
inflammatory response to surgery are conflicting. In this systematic review we examined the
effect of perioperative ketamine administration on postoperative inflammation as assessed by
concentrations of the biomarker interleukin-6 (IL-6).
METHODS: This study was based on a systematic search in PubMed, Scopus, Web of
Knowledge, and the Cochrane Library. English written randomized controlled trials conducted in
humans were eligible. To be included in the analysis, outcome had to relate to inflammation or
immune modulation. Each study was reviewed independently by 2 assessors. Data were
analyzed according to the GRADEs approach and reported in compliance with the PRISMA
recommendations.
RESULTS: Fourteen studies were eligible for evaluation (684 patients). Surgery was performed
under general anesthesia, and ketamine was given before or during the surgery in varied doses
Eight studies involved cardiopulmonary bypass operations, 4 were for abdominal surgery, 1
thoracic surgery, and 1 cataract surgery. Three studies were deemed of low quality. Nine studies
measured IL-6 concentrations within the first 6 hours postoperatively; but in 3 studies, other
potent anti-inflammatory drugs were used as premedication or during the operation; thus 6
studies (n 331) were included in the meta-analysis. Using postoperative IL-6 concentrations
as an outcome, ketamine had an anti-inflammatory effect; the meta-analysis showed a mean
preoperativepostoperative IL-6 concentration difference (95% confidence interval) of 71
(101 to 41) pg/mL.
CONCLUSIONS: It can be concluded that intraoperative administration of ketamine significantly
inhibits the early postoperative IL-6 inflammatory response. Future studies should further
examine the anti-inflammatory effect of ketamine during major surgery, determine whether ketamine
treatment alters functional outcomes, elucidate the mechanisms of its anti-inflammatory effect, and
suggest an appropriate dosing regimen. (Anesth Analg 2012;115:934 43)

ajor surgery invariably evokes the inflammatory

response. It has been shown that the extent of
systemic inflammatory response in cardiac surgery is associated with the outcome of the intervention.13
For instance, increased serum concentration of interleukin 6
(IL-6, a major proinflammatory cytokine) has been associated
with postoperative left ventricular wall motion abnormalities

From *Discipline of Pharmacology, Faculty of Health Sciences, University of

Adelaide, Adelaide, Australia; Department of Circulation and Medical
Imaging, Pain and Palliation Research Group, Norwegian University of
Science and Technology, Trondheim, Norway; Department of Anaesthesia
and Emergency Medicine, St. Olavs University Hospital, Trondheim, Norway; Discipline of Public Health, Faculty of Health Sciences, University of
Adelaide, Adelaide, Australia; Department of Psychology, Hebrew University, Jerusalem, Israel.
Accepted for publication June 4, 2012.
Funding: Departmental funds.
The authors declare no conflict of interest.
Reprints will not be available from the authors.
Address correspondence to Ola Dale, MD, PhD, Department of Circulation
and Medical Imaging, NTNU, Box 8095 MTFS, N_7491 Trondheim, Norway.
Address e-mail to Ola.Dale@ntnu.no.
Copyright 2012 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e3182662e30

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and myocardial ischemic episodes,3 perioperative complications,3 and postoperative hyperdynamic instability.1 IL- 6
concentrations were correlated with postoperative morbidity and mortality in children after an open-heart surgery,4
as well as with the severity of adult respiratory distress
syndrome.5 It has become increasingly appreciated that in
the perioperative period, circulating concentrations of cytokines may play an important role in surgery outcome and
therefore should be controlled. Indeed, several tactics have
been used by clinicians to curb perioperative cytokine
response.6
Strategies used in the past to reduce the systemic
cytokine response include treatment with glucocorticoids
or with the serine protease inhibitor aprotinin.2,6 Another
strategy is to use anesthetic or subanesthetic doses of
general anesthetics or opioids with potential antiinflammatory effects.712 The results of multiple studies on
the systemic anti-inflammatory effects of fentanyl79 or
morphine10 are conflicting, and single studies on sevoflurane11 or propofol12 indicate anti-inflammatory effects at
anesthetic doses of these drugs. Notably, local anesthetics
(LA) are the most widely studied anesthetic drugs with
clinically relevant endpoints. Hollmann and Durieux13
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reviewed the anti-inflammatory effects of LA, and Herroeder et al.14 provided evidence that the frequently shown
beneficial effects of LA on gastrointestinal recovery after
surgery are most likely due to a potent modulatory effect of
the proinflammatory response.
Among the general anesthetics, ketamine is the most
widely studied in the search for strategies to modulate
systemic perioperative cytokine response. Ketamine is a
potent anesthetic and analgesic drug. When administered
IV during anesthesia in adults, ketamine decreased postoperative pain intensity for up to 48 hours, decreased cumulative 24-hour morphine consumption, and delayed the
time to first request of rescue analgesic.15 On the basis of
current recommendations for ketamine, there is level I
evidence for an opioid- sparing effect and level II evidence
for antihyperalgesic and opioid toleranceprotecting effects
and for reduction in chronic postsurgical pain.16
The effect of ketamine on perioperative inflammatory
responses has been studied in patients undergoing cardiac
operations under cardiopulmonary bypass (CPB), offpump cardiac surgery, hysterectomies, and abdominal surgery. Doses ranged from a small supplemental single bolus
dose and up to full ketamine anesthetic doses, either with
racemic drug or the pharmacologically more active S-()ketamine. Ketamine has been found to act as an immune
modulator. Furthermore, it has been argued that ketamine
is a unique, specific anti-inflammatory drug,17 which inhibits the systemic response without affecting local healing
processes.
It has been suggested that ketamines anti-inflammatory
activity might be mediated by suppression of microglia
activation, as demonstrated by inhibition of extracellular
signal-regulated kinase 1/2 phosphorylation in primary
cultured microglia,18 or by inhibition of large-conductance
Ca2-activated K channels in microglia.19 Taken together
with the findings that microglia respond to endogenous
(e.g., heat shock protein) and exogenous (e.g., stress, infection, drugs) inflammation signals by producing proinflammatory cytokines (e.g., IL-1, IL-6, tumor necrosis factor
[TNF]) and thus inducing hyperalgesia,20 this provoked
renewed interest in the potential anti-inflammatory effects
of ketamine. Although it is generally believed that ketamine has anti-inflammatory action in humans, the evidence has not been critically evaluated.
The aim of this systematic review was to evaluate the
anti-inflammatory effect of ketamine in surgical patients in
the early postoperative period based on randomized controlled trials (RCT) in which ketamine was used as part of
the intervention. The effect of ketamine on systemic exposure of the cytokine IL-6 was of special interest because its
plasma concentration serves as a useful and reliable biomarker of systemic inflammation.21

METHODS
A systematic search was performed in PubMed, Scopus,
Embase, Web of Science, and the Cochrane Central Register
of Controlled Trials (CENTRAL) up to October 13, 2011. In
addition the reference lists of the retrieved full articles were
searched.
The following search strategy combining free text and
MeSH terms (ME) was set up for PubMed:

October 2012 Volume 115 Number 4

(ketamine[tw] OR ci 581[tw] OR ci581[tw] OR ketaset[tw] OR ketanest[tw] OR kalipsol[tw] OR calypsol[tw] OR ketalar[tw]) AND (Anti-inflammatory
agents[mh] OR inflammat*[tw] OR antiinflammat*[tw]
OR nsaid*[tw] OR antirheumatic*[tw] OR anti
rheumatic*[tw] OR cyclooxygenase inhibitor*[tw] OR
cyclo oxygenase inhibitor*[tw] OR cyclooxygenase 2
inhibitor*[tw] OR cyclo oxygenase 2 inhibitor*[tw] OR
cox 2 inhibitor*[tw] OR coxib*[tw] OR neutrophil*[tw]
OR interleukin*[tw] OR tumor necrosis factor*[tw] OR
tumor necrosis factor*[tw] OR ((Receptors, N-Methyld-Aspartate[Mesh] OR NMDA-receptor*) AND (antagonis* OR inhibitor* OR inhibiting OR blocking)) OR
proinflammat* OR antiproinflammat* OR Cytokines[mesh:noexp]) AND (ex vivo[tw] OR in vivo[tw] OR
double-blind method[mh] OR single-blind method[mh]
OR clinical trial[pt] OR trial[tiab] OR ((singl*[tiab] OR
doubl*[tiab] OR trebl*[tiab] OR tripl*[tiab]) AND
(mask*[tiab] OR blind*[tiab])) OR placebos[mh] OR
placebo*[tiab] OR random*[tw] OR research design
[mh:noexp] OR comparative study[pt] OR evaluation
studies as topic[mh] OR Evaluation Studies [pt] OR
follow-up studies[mh] OR prospective studies[mh]
OR control[tw] OR controlled[tw] OR prospectiv*[tw]
OR volunteer*[tw] OR group[tiab] OR groups[tiab] OR
systematic[sb]) NOT(animals[mh] NOT human[mh])
A similar search strategy was set up for CENTRAL, Scopus,
and Web of Science, with search terms adapted to specific
terminology and indexing characteristics. In the updating
search MarchOctober 2011 Embase was used instead of
Scopus. A detailed account of the searches can be obtained
from O. Dale.
Inclusion criteria included the following: English written RCT conducted in humans were eligible. Ketamine had
to be part of the intervention, and study outcomes had to
relate to inflammation/immune modulation. If the primary
outcome was not a clinical measure, any surrogate outcomes had to be measured directly in a biological sample
(in vivo), or resulting from manipulation of such a sample
(ex vivo). If eligibility could not be determined from the
title of the study or its abstract, the full paper was retrieved.
During the search process, several relevant publications
in Chinese were identified. These were preliminarily reviewed by one of the authors (Y.L.) with native knowledge
of Chinese.
The following were summarized in a data extraction
form: publication details, study design and limitations,
patient population details, settings, interventions, validity
of methods for assessing outcomes, results, internal and
external validity, and narrative summary of the main
findings. Each study was reviewed and rated independently by 2 assessors (O.D. and Y.S.). The internal validity
of each RCT was assessed using a checklist adapted from
the criteria recommended in the National Health Service
Centre for Reviews and Dissemination guidance document,22
as described earlier.23 Data were analyzed in accordance with
the GRADEs approach,24 which includes reporting of an
evidence profile for the outcome. This profile consists of the
number and type of eligible studies, number of participants,

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study limitations, consistency, directness, precision, publication bias, and factors that might increase quality of evidence.
On this basis a recommendation was given. Finally, the
process was reported in accordance with the PRISMA requirements (www.prisma-statement.org/), although the review
protocol was not registered as recommended.
On the basis of the evaluation process, we conducted a
meta-analysis on the most consistently reported outcome,
plasma concentrations of IL-6 within the first 6 postoperative hours. Pre- to postoperative changes in plasma or
serum IL-6 concentrations were extracted for each randomized group within each study. The precise data for postoperative IL-6 concentration were not reported by Zeyneloglu
et al.,25 Bartoc et al.,26 and Cho et al.27 but were collected by
consulting the authors by e-mail. Differences between
groups (ketamine vs control treated) were then pooled
using a random effects meta-analysis model according to
the DerSimonianLaird method.28 Heterogeneity in mean
differences was assessed using the I-squared statistic29 and
a 2 test of goodness of fit. Publication bias in the metaanalysis was assessed visually using a funnel plot.30

RESULTS
Ketamine had an anti-inflammatory effect based on the 6
studies included in the meta-analysis (Table 1, Figs. 1 and
2) when using postoperative plasma/serum IL-6 as an
outcome. The overall mean (95% confidence interval [CI])
difference was 71 (101 to 41) pg/mL (P 0.001). No
dose response was observed. The degree of heterogeneity
was high when all studies were pooled (I-squared
91.1%), but low for the CPB studies (I-squared 0.0%).
Using Eggers funnel plot,30 we observed no sign of publication bias. Including the studies in which a potent antiinflammatory drug was given25,31,32 in the meta-analysis
(results not shown) did not abolish the major finding,
although the mean effect estimate (95% CI) was reduced to
50 (75 to 25) pg/mL.
In total, the search for relevant studies yielded 1187
136 (original additional search, respectively) records as
follows: PubMed (148 28), Scopus/Embase (925 82),
CENTRAL (0), and Web of Science (114 26) (Fig. 1). No
additional records were identified through other sources,
and 1033 113 records remained after removing duplicates. Removing 10 records (articles written in non-English
languagesChinese [6], German [2], Spanish [1], and Japanese [1]), left 1136 records for screening. A total of 1083
13 records were removed on the basis of their titles or after
reading the abstract when deemed necessary. Forty fulltext articles were retrieved, and 26 were not rated eligible
for further analysis.
Since one of the authors (Y.L.) is native Chinese, and
since 5 of the Chinese publications were relevant to the aim
of this review, these publications underwent a separate
evaluation (was not included in the primary evaluation, but
as a supplement), as described under Methods.
The 14 studies eligible for evaluation included 684
patients. In all (except for 2 studies including 3 groups26,33),
2 groups were compared. Ten studies were double-blind, 2
single-blinde34,35 (one did not report this originally,35 but
confirmed single-blinding upon request), and 2 of the

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studies were open.25,33 Three studies31,34,36 reported patient flow according to CONSORT agreement. All but 2
studies25,32 were conducted in adults. In 7 studies, CPB
was used; in another, cardiac surgery was conducted
off-pump27; 4 studies included major abdominal operations35,37,38; 1 thoracic surgery36; and in 1,33 cataract surgery was performed. All patients underwent surgery under
general anesthesia, except one group in Tu et al.s study,33
and a varying number of patients who received epidural
anesthesia in the control and interventions groups in
DAlonzo et al.s study.36 Total subject numbers varied
from 24 to 142 patients, with the sample size justified in 6
studies.2527,31,34,36 One of the studies had a clinical primary outcome (neurodevelopment),32 12 measured surrogate outcomes such as markers of inflammations directly in
blood samples, and 2 measured similar outcome in stimulated blood samples (ex vivo).35,39 All studies (except for
Akhlag et al.40 and Zilberstein et al.39) measured IL-6.
Samples were drawn at a myriad of different time points,
from 4 hours to 8 days. All studies (but 234,40) used racemic
ketamine. The intervention varied from an anesthesia
based entirely on (S)-ketamine (single dose of 2 to 4 mg/kg
followed by 2 to 4 mg/kg/h34), racemic ketamine single
dose (1 to 2 mg/kg) followed by infusion (1.5 to 3.5
mg/kg/h),25 low dose (S)-ketamine infusion (0.075
mg/kg/h),40 or low (0.15 to 0.5/mg/kg) single doses. In Tu
et al.s study33 one group received ketamine 1 mg/kg infused
over the duration of surgery. In all studies, ketamine was
given at induction of anesthesia, except Bhutta et al.,32 in
which ketamine was administered just before CPB.
Of the 14 eligible studies, 2 were deemed high quality
(),26,34 9 were of medium quality (),25,27,31,32,35,38 41
and 3 were of low () quality and therefore excluded from
the qualitative analysis: Mostafa et al.37 because of lack of
preoperative sampling, Tu et al.33 because of large losses to
follow up, and DAlonzo et al.36 primarily because of
heterogeneity of study groups, and also lack of control of
preoperative use of nonsteroidal anti-inflammatory drugs.
One study reported regular use of nonsteroidal antiinflammatory drugs before the operation that was similar
in the study groups.26 Thus, 11 studies were included in the
qualitative analysis. Of these, drugs with significant antiinflammatory effects (methyl prednisolone, dexamethasone, and ibuprofen) were administered as premedication
or during the operations in 3 studies,25,31,32 respectively;
this fact may cancel the effects of ketamine on inflammatory biomarkers. Three of the studies used questionable
statistics, such as failing to consider the fact that repeated
measures were conducted, or not compensating for multiple comparisons.38,40,41 Primary endpoints were stated
clearly in 2 studies,34,36 but could be anticipated in 4
studies.2527,31 The primary endpoints chosen in the included studies were all different, and only Welters et al.34
and DAlonzo et al.36 reported their primary endpoint in a
precise manner.
Five of the studies (Table 1) reported that racemic or
(S)-ketamine significantly reduced the inflammatory response after surgery,26,34,35,38,41 as measured by plasma/
serum IL-6 concentrations (Table 1). Effect size was larger
and lasted for a longer time period in early studies38,41 in
comparison with the later studies by Bartoc et al. and

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937

Participants
Elective cardiac surgery (CABG, valve
replacements, and combinations) with CPB (32
C), meeting at least 1 of following criteria: age
70 years, recent (14 days) MI, elevated
creatinine (1.3 mg/dL), previous stroke,
previous cardiac surgery. Anesthesia at the
discretion of the anesthetist. Preoperative
NSAIDs equal in study groups.
Sample size: 30 (15 pair ketamine groups).
50 included, 15 and 18 to ketamine groups, 17 to
placebo.
Randomization: sealed envelope by an investigator
not involved in patient care the day of surgery.

Elective CABG with CPB (tp not given).

Exclusions: CK 170 U/L, repeat cardiac surgery
and combined operations, hepatic (ASAT/ALAT
150 U/L) and renal (creatinine 132 M)
disease, immunosuppressive medications,
immunodeficiency syndromes, neurologic or
psychiatric disease. Pats with CRP 16 mg/L,
IL-6 24 pg/mL in the morning were excluded.
Anesthesia well controlled. CPB 32
Sample size: 50 in each group, increased by 16%
to compensate for loss.
142 pats randomized, 70 to intervention, 72 to
control, 60 and 68 completed the study in the
respective groups. Exclusions due to too high
CRP or IL-6, or incomplete data.

Patients undergoing abdominal surgery

(hysterectomy and gastroplasty). Other
inclusion/exclusion criteria not given.
Sample size: not estimated 36 pats randomized,
17 to ketamine, 19 to isotonic saline (control).

Study/design
Bartoc et al., 200626
A randomized, double-blind,
placebo-controlled study
assessing the antiinflammatory effect of
ketamine in cardiac
surgical patients.
J Cardiothorac Vasc Anesth
Double blind
Single-center study
Consort form not reported

Welters et al., 201134

Continuous S-()-ketamine
administration during
elective CABG surgery
attenuates proinflammatory
cytokine response during
and after CPB. BJA
Single blind
Single-center study?
Consort form reported

Beilin et al., 200735

Low-dose ketamine affects
immune responses in
humans during the early
postoperative period;
BJA
Single blinding according to
author.
Single-center study
Consort form not reported

0.15 mg/kg racemic ketamine 5 minutes

before induction as an adjuvant to
anesthetic procedure.
Controls: isotonic saline.
Repeated-measures ANOVA (for time period
before Student t test post hoc.
ELISA kits: RD Systems, Biosource
International, Pharmingen.
Sampling for 72 hours.

S-ketamine-based anesthesia (13 mg/kg,

24 mg/kg/h).
Control: sufentanil based (0.251 g/kg,
0.52 g/kg/h).
Randomization: computer generated.
Normal distribution checked.
Repeated-measures ANOVA with
GreenhouseGeisserEpsilon
adjustment, otherwise MannWhitney.
Categorical by chi-square.
Cytosets, Biosource
BD OptEIA, BD Biosciences
Sampling for 24 hours.

Intervention/statistics lab analysis

Racemic ketamine 0.25 mg/kg. Racemic
ketamine 0.5 mg/kg at induction as an
adjuvant to anesthetic procedure.
Controls received saline.
ANOVA followed by Tukey test for pairwise
comparison of means or Dunnet for
between ketamine groups.
Quantikine IL-6; RD Systems.
Sampling until POD 1.

Table 1. Description of Studies Eligible for Qualitative Analysis

Primary out come.

Not given.
IL - beta, IL-2, IL-6, TNFalpha, mitogen response,
NKCC, ex vivo.

Primary outcome: IL-6 6

hours after aortic
unclamping in vivo.
Secondary: IL-8, 10.
TNF , TNF-RI (TNF-receptor
1, sFAS (proaptopic
protein soluble FAS), CRP.

Outcome measures
Primary outcome: difference
between ketamine groups
in IL-6 on POD 1 (in vivo).
Secondary outcome:
differences between
ketamine groups and
placebo any time.
Also CRP, IL 8 and 10. Data
also at ICU arrival.

Outcome (all-over).
IL-6 pg/L, mean (SEM).
4 hours postoperative.
Ketamine: 68.3 (10.6).
Placebo: 114.4 (16.7).
P 0.05
Moderate effect of ketamine, lower
IL-6 TNF-alfa (small) at 4 hours. IL 2
was maintained (and not reduced
as for controls) in study period.
(Continued)

Primary outcome: IL-6 pg/L, mean

(SD):
Ketamine: 56.8 (46.3).
Sufentanil: 172.6 (149.9).
P 0.01
Secondary: IL-8 also decreased at 6
hours.
IL-10 increased at 1 hour.
No changes for TNF, TNF-RI, sFAS,
CRP.

Outcomes
Primary outcome: no statistically
significant difference between
ketamine groups in IL-6 on POD 1.
Secondary outcome: ketamine lowered
IL-6 in comparison with placebo
upon arrival at the ICU and POD1,
while IL-10 was lower for ketamine
POD 1. No changes observed for
IL-8. CRP lower in the 0.5 mg/kg
group POD1.
Written to author for data: IL-6 pg/L,
at ICU, mean (SD):
Control: 152 (114).
Ketamine (0.25): 59 (53).
Ketamine (0.5): 53 (38).
MAP and SVT higher for ketamine.

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0.25 mg/kg racemic ketamine at induction
as an adjuvant to anesthetic procedure.
Controls received saline.
Randomization: not described.
Two-way ANOVA with multiple post hoc
testing.
Quantikine IL-6; RD Systems.
Sampling for 8 days.

Elective CABG points with EF 0.4. Uncontrolled

systemic disease (hypertension, diabetes, renal
failure) and requirement for aortic balloon pump
lead to exclusion. Aspirin and NSAIDS stopped
10 days before surgery. Standard operative/
anesthetic (high- dose fentanyl) procedures.
Anesthesia well controlled. Two surgeons only.
CPB: 32C
Sample size: not estimated.
31 patients randomized 14 to intervention, 17 to
control. 3 patients in control group excluded
because of hemodynamic instability/low- output
syndrome.

Roytblat et al., 199841

Ketamine attenuates the
interleukin-6 response
after cardiopulmonary
bypass; Anesth Analg
Double blind.
Single-center study.
Consort form not reported.

Primary outcome: No.

Reported.
Differences in IL-6 serum
concentration post-CPB,
4, 24, 48, and days 38
(in vivo).
And at 4 hours.

Primary outcome: not given,

but 4-hour IL-6 is
accurately reported.
Circulatory variables.

Outcome measures
Primary outcome: not given,
but according to sample
size CRP POD 1.
Other: IL-6, TNF-alfa, blood
counts, myocardial injury
markers.

Statistically significant lower IL-6

concentration at all measuring
points until return to baseline at day
8. Precise figures not given (only
graphic).
IL-6 pg/L, mean (SD) 4 hours after
CPB:
Ketamine: 70 (38).
Control: 200 (44).

IL-6 at 4-hour pg/mL, mean (SD).

Ketamine: 9.3 (12.6).
Control: 43.8 (9.5).
All over: IL-6 increased at 4, and 24 h for
both groups, control also at 48 hr.
Controls higher than ketamine group at
these time points.
Control group had higher mean arterial
blood pressure and heart rate than the
ketamine group.

Outcomes
No specific data given.
No difference between groups. CRP
and IL-6 increased postoperative
(maximum at 2 days (about 15 mg/
dL) and 4 hours (about 300 pg/mL),
respectively).
TNF-alfa stable.
Written to author for data.
Il-6 (pg/mL)
4-hour postanastomoses: mean (SD):
Ketamine: (163).
Control: 95 (82).

CABG coronary artery by-pass graft; CPB cardiopulmonary bypass; EF ejection fraction; MAP mean arterial blood pressure; OPCAB off-pump coronary artery bypass; SVT systemic vascular resistance; ASA
American Society of Anesthesiologists physical classification system; Tp temperature; ALAT (ALT) alanine amino transferase; ASAT (AST) aspartate amino transferase; CK creatine kinase; CRP C-reactive protein;
Il interleukin; TNF tumor necrosis factor; ANOVA analysis of variance; ITT intention to treat; SEM standard error of the mean; POD 1 postoperative day; CPB cardiopulmonary bypass; MI myocardial
infarction; NSAIDs nonsteroidal anti-inflammatory steroids; ICU intensive care unit; NKCC natural killer cell cytotoxicity.

Ketamine 0.15 mg/kg before incision.

Controls saline.
Anesthesia based on isoflurane and
fentanyl (5 g/kg).
Two way ANOVA followed by multiple
comparisons.
IL-6 immunoassay kit, Biosource
International.
Sampling preoperative, uterus mobilization,
4, 24, 48, and 72 hours.

ASA 12 women, undergoing elective abdominal

hysterctomia. Exclusion criteria: 60 years,
malignant or chronic inflammatory or severe
respiratory or cardiovascular disease, already
receiving opioids.
Sample size not estimated.
22 enrolled, 11 in each study group.
Randomization procedure not described.

Roytblat et al., 199638

Preoperative low-dose
ketamine reduces serum
interleukin-6 response
after abdominal
hysterectomy. Pain Clin
Double blind.
Single-center study.
Consort not reported.

Intervention/statistics lab analysis

0.5 mg/kg racemic ketamine at induction
as an adjuvant to anesthetic procedure.
Controls received saline.
t test and repeated-measures ANOVA; post
hoc Dunnett test. Wilcoxon rank-sum
(between groups), Friedman test (within
group) further investigated by Mann
Whitney with Bonferroni. between the
groups: 2 test or by Fisher exact test.
CRP: institutional lab.
Quantikine high-sensory immunoassay;
RD Systems.
Sampling to POD 2

Participants
Patients undergoing elective, multivessel OPCAB.
Exclusion criteria i: age 75 years, recent (14
days) myocardial infarction, unstable angina
with elevated creatine kinase-MB (CK-MB),
elevated serum creatinine (.1.3 mg/dL) before
operation, EF 40%, previous cardiac surgery,
previous stroke or pulmonary disease, and
history of treatment with steroid or nonsteroidal
anti-inflammatory drugs within a month
(normothermia). Anesthesia well controlled
(sufentanil-sevoflurane based). One surgeon.
Sample sizeestimated. (CRP POD1?)
50 patients randomized, 2 25 computergenerated randomization.

Study/design
Cho et al., 200927
Effect of low-dose ketamine
on inflammatory
response in off-pump
coronary artery bypass
graft surgery. BJA
Double blind
Single-center study.
Consort not reported.

Table 1. (Continued)

Perioperative Ketamine and Cytokines

ANESTHESIA & ANALGESIA

Figure 1. PRISMA 2009 flow diagram.

Figure 2. Forest plot of early postoperative IL-6 serum/plasma concentrations.

The designation of the abscissa is in
pg/mL.

Welters et al.,26,34 all conducted in patients undergoing

CPB. The study of off-pump cardiac surgery patients did
not show ketamines effect.27 Moreover, effect size was
smaller and duration was shorter in patients undergoing
major abdominal surgery.35,38
Overall, plasma/serum C-reactive protein, IL-8, or
TNF- concentrations either did not show differences or
decreased in a fashion similar to IL-6 in ketamine-treated
patients,26,34,35,40 while IL-10 concentrations increased in

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the 2 high-quality studies.26,34 Zilberstein et al. have reported that the addition of low-dose ketamine to general
anesthesia attenuated postoperative neutrophil activation
up to 6 days after CPB.39
Among the 5 papers in Chinese, 1 was excluded because
it could not be asserted whether it was an RCT,42 and
another because the reported baseline IL-6 concentrations
deviated significantly from all other studies.43 Two of the
remaining studies included abdominal operations44,45 and

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1, acute burn patients given analgesia.46 Neither of the abdominal studies showed an effect of ketamine on plasma IL-6,
while the latter supported the findings of the meta-analysis
(120 [156 to 84]) pg/mL (95% CI for the difference). It
should be noted that the ketamine intervention started after
the trauma (burn); thus this study had starting IL-6 concentrations of about 120 pg/mL, which increased over 48
hours in the control group but decreased in the ketamineexposed groups.
The overall evidence profile as rated according to the
GRADE recommendation24 for intraoperative ketamine on
the postoperative Il-6 response was considered high.

DISCUSSION
This systematic review substantiates the notion that intraoperative ketamine has an anti-inflammatory effect, as
indicated by the meta-analysis showing a considerable
reduction in circulating concentrations of the proinflammatory cytokine IL-6 during the first 6 hours after surgery.
IL-6 concentration in the first 6 postoperative hours was
chosen as a representative outcome for the inflammatory
response for several reasons. First, IL-6 was the most
consistently reported inflammation biomarker in the studies included in this review, and most studies provided data
in the early postoperative phase. Second, it has a proinflammatory action, and ketamine has been suggested to act as
an anti-inflammatory drug.17 Third, any action of ketamine
given intraoperatively should last into the early postoperative phase to have any potential clinical relevance, and
possibly even be more prominent at this stage than later.
Numerous studies have indicated the importance of IL-6 as
a reliable and particularly sensitive biomarker of inflammatory activation and a predictor of subsequent organ
dysfunction and death.47,48 For example, higher plasma/
serum concentrations of IL-6 have been associated with
increased risk for major cardiopulmonary complications
after general thoracic surgery,49 postoperative morbidity
after cardiac surgery,13,50 postoperative complications,51,52
cognitive dysfunction after coronary artery surgery,53
increased risk of coronary heart disease,54 adverse postoperative outcome (mortality and complications) in elderly
patients undergoing hip fracture surgery,55 and poor outcome and death after stroke.21
The overall effect size of ketamine on IL-6 was large
even when including, in a separate meta-analysis, the 3
studies using potent anti-inflammatory drugs in the
perioperative period.25,31,32 This was especially true for surgeries with CPB in which ketamine reduced IL-6 concentrations to about one third of those of the control
group.26,34,41 This effect size was of the same magnitude (or
larger) as reported for pretreatment with methylprednisolone
(30 mg/kg) in which IL-6 was measured at declamping of the
aorta during CPB surgery,56 or 60 minutes later.57 The effect of
methylprednisolone in the former study, however, was shortlived and did not last beyond 1 hour after termination of the
extracorporal circulation.
According to the GRADE approach the evidence level is
rated high because it is based upon RCTs.24 Studies with
questionable quality did not enter the qualitative analysis,
while studies that included potent anti-inflammatory drugs
did not enter the quantitative analysis. The meta-analysis

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showed consistent data for the chosen endpoint. The data,

however, were inconsistent with regard to the duration of
action of intraoperative ketamine. There are no signs of
publication bias. Perhaps the weakest of the GRADE evidence
elements is related to directness, because IL-6 may be a
narrow or rather indirect measure of inflammation and its
clinical consequences.
According to GRADE, a doseresponse association
would strengthen the evidence.24 In the present review
neither a more pronounced effect nor a longer duration of
action was seen, although the doses ranged from a single
subanesthetic dose up to doses required for full ketaminebased anesthesia. This lack of dose response is difficult to
understand, but the studies all have in common the fact
that a bolus dose of at least 0.15 mg/kg ketamine was given
before the surgical intervention. If this bolus dose is at the
top of the dose-response curve for ketamines antiinflammatory effect, higher bolus doses or infusion may be
futile. However, the study of Welters34 comparing ketamine anesthesia with sufentanil-based anesthesia presents
important evidence that ketamine itself has an antiinflammatory effect.
Although not derived from the meta-analysis, it is
noteworthy that the duration of action of intraoperative
ketamine differed substantially among studies. Duration of
up to 6 hours postoperatively was documented in the
present review. Furthermore, some of the studies reported
duration of action of up to 24 hours,26 or even up to 8
days.38,39,41 Although there are statistical concerns with the
last 3 studies, the findings are corroborated by other reports
(not included in this review), showing long-term effects (5
to 7 days) after short-duration infusions (4 hours or less) of
ketamine in both depression58 and pain relief in patients
with critical limb ischemia.58,59
Most of the studies included other measures of inflammation in addition to IL-6. Among these were C-reactive
protein, IL-8, IL-10, and TNF. Only the data for IL-10 were
consistent, showing that ketamine increased the concentrations of this anti-inflammatory cytokine, providing further
evidence to the main observation of this review, i.e., that
ketamine plays an anti-inflammatory role. Moreover, since
the most consistent finding was related to IL-6, this review
lends credibility to the suggestion that ketamine primarily
acts as an antiinflammatory drug.17
Several potentially interesting studies written in Chinese
were identified. Since one of the authors (Y.L.) is a native
Chinese, it was decided to do a preliminary evaluation of
these studies in addition to the primary papers written in
English. These studies for reasons stated above added little.
However, the study comparing the effect of ketamine on
IL-6, as a part of the acute pain control regimen in burn
patients,46 attracted attention, since evidence suggests a
role for inflammation as an inducer of microglial-mediated
hyperalgesia.20 Interestingly, the effect size reported by Xia
et al.46 for IL-6 was of the same magnitude as that after
CPB.26,34,41 The study also indicated that ketamine may
potentially reduce the inflammatory response even when
given after a trauma, at a time when biomarkers such as
IL-6 are already increased.
Various studies, including clinical and preclinical research, in vivo and in vitro, have shown that in addition to

ANESTHESIA & ANALGESIA

its anesthetic activity, ketamine has an anti-inflammatory

effect (for a recent review, see Loix et al.17). The mechanisms by which ketamine produces its anti-inflammatory
actions needs to be elucidated. The acute analgesic effects
of ketamine are generally believed to be mediated through
the blockade of phencyclidine binding site of N-methyl-daspartate (NMDA) receptors of the nociceptive neurons;
this mechanism could also partly account for the antiinflammatory effects of ketamine. However, ketamine has
also been reported to interact with opioid, monoamine,
cholinergic, purinergic, and adenosine receptor systems.
The functional anti-inflammatory effects of ketamine without affecting local healing processes (blunting neutrophil
activation but sparing endothelial production of cytokines)
shares similarities to those of LAs,13 which is considered
to be due to their effect on G-protein-coupled-receptor
signaling, specifically Gq downregulation.60 Because ketamine also has local anesthetic effects,60 it remains
speculative as to whether they share a common antiinflammatory mechanism.
Moreover, numerous mechanisms in addition to those
discussed above have been shown to mediate the antiinflammatory effects of ketamine. A nonexhaustive list of
proposed mechanisms include inhibition of transcription
factors nuclear factor-B and activator protein 1,61 inhibition of proinflammatory cytokine production (IL-6 and
TNF),62 64 inhibition of neutrophil functions,65 the release
of adenosine,66 the blockade of large-conductance KCa
channels on microglia (BK channels),19 or the inhibition of
nitric oxide production in macrophages.67 Ketamine has
been shown to downregulate the proinflammatory enzymes
cyclooxygenase 2 and inducible nitric oxide synthase, while
preserving expression of the anti-inflammatory enzyme
heme-oxygenase-1.68 This review does not shed light on the
mechanisms of the anti-inflammatory action of ketamine in
the perioperative period. Whether it is mediated by NMDA
or non-NMDA mechanisms remains to be elucidated, but
the finding of this review should certainly stimulate basic
researchers to clarify these aspects.
In this systematic search, no studies examining any
clinical outcome were found. Although there are some
indications that IL-6 is associated with a clinical outcome,15,5154,69 the bulk of evidence seems weak. Therefore,
clinical outcome studies are warranted, and the evidence
presented in this review suggests that subanesthetic single
doses should be examined first. It is also intriguing to
examine whether the anti-inflammatory effect of ketamine
may have an impact on postoperative pain management.
DISCLOSURES

Name: Ola Dale, MD, PhD.

Contribution: This author helped design the study, collect
data, evaluate the candidate papers independently, analyze the
overall data, and write the manuscript.
Name: Andrew A. Somogyi, MSc, PhD.
Contribution: This author helped design the study, analyze
the overall data, and write the manuscript.
Name: Yibai Li, BHSc (Hon).
Contribution: This author helped analyze the overall data and
write the manuscript.
Name: Thomas Sullivan, BMa, CompSc (Hon).

October 2012 Volume 115 Number 4

Contribution: This author helped conduct the meta analysis,

analyze the overall data, and write the manuscript.
Name: Yehuda Shavit, PhD.
Contribution: This author helped evaluate the candidate papers independently, analyze the overall data, and write the
manuscript.
This manuscript was handled by: Spencer S. Liu, MD.
ACKNOWLEDGMENTS

The authors greatly appreciate the support for the searches

provided by Mr. Michael Draper, Research Librarian, University of Adelaide, Adelaide, Australia, and Ingrid Riphagen
MSc, AKF, Norwegian University of Science and Technology,
Trondheim, Norway. This work was facilitated by the Leon
and Clara Sznajderman Chair of Psychology (to Y.S.). We are
also grateful to Drs. P. Zeyneloglu, C. Bartoc, and Y.L. Kwak,
who gave us access to their original data on IL-6, and to Dr. B.
Beilin for confirming his blinding procedure.
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