Does Intraoperative Ketamine Attenuate Inflammatory Reactivity Following Surgery

Pain Medicine

Section Editor: Spencer S. Liu

Does Intraoperative Ketamine Attenuate InflammatoryReactivity Following Surgery? A Systematic Reviewand Meta-AnalysisOla 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 theinflammatory response to surgery are conflicting. In this systematic review we examined theeffect of perioperative ketamine administration on postoperative inflammation as assessed byconcentrations of the biomarker interleukin-6 (IL-6).METHODS: This study was based on a systematic search in PubMed, Scopus, Web ofKnowledge, and the Cochrane Library. English written randomized controlled trials conducted inhumans were eligible. To be included in the analysis, outcome had to relate to inflammation orimmune modulation. Each study was reviewed independently by 2 assessors. Data wereanalyzed according to the GRADEs approach and reported in compliance with the PRISMArecommendations.RESULTS: Fourteen studies were eligible for evaluation (684 patients). Surgery was performedunder general anesthesia, and ketamine was given before or during the surgery in varied dosesEight studies involved cardiopulmonary bypass operations, 4 were for abdominal surgery, 1thoracic surgery, and 1 cataract surgery. Three studies were deemed of low quality. Nine studiesmeasured IL-6 concentrations within the first 6 hours postoperatively; but in 3 studies, otherpotent anti-inflammatory drugs were used as premedication or during the operation; thus 6studies (n 331) were included in the meta-analysis. Using postoperative IL-6 concentrationsas an outcome, ketamine had an anti-inflammatory effect; the meta-analysis showed a meanpreoperativepostoperative IL-6 concentration difference (95% confidence interval) of 71(101 to 41) pg/mL.CONCLUSIONS: It can be concluded that intraoperative administration of ketamine significantlyinhibits the early postoperative IL-6 inflammatory response. Future studies should furtherexamine the anti-inflammatory effect of ketamine during major surgery, determine whether ketaminetreatment alters functional outcomes, elucidate the mechanisms of its anti-inflammatory effect, andsuggest an appropriate dosing regimen. (Anesth Analg 2012;115:93443)

Major surgery invariably evokes the inflammatoryresponse. It has been shown that the extent ofsystemic inflammatory response in cardiac sur-gery 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 associatedwith postoperative left ventricular wall motion abnormalities

and myocardial ischemic episodes,3 perioperative compli-cations,3 and postoperative hyperdynamic instability.1 IL- 6concentrations were correlated with postoperative morbid-ity and mortality in children after an open-heart surgery,4

as well as with the severity of adult respiratory distresssyndrome.5 It has become increasingly appreciated that inthe perioperative period, circulating concentrations of cy-tokines may play an important role in surgery outcome andtherefore should be controlled. Indeed, several tactics havebeen used by clinicians to curb perioperative cytokineresponse.6

Strategies used in the past to reduce the systemiccytokine response include treatment with glucocorticoidsor with the serine protease inhibitor aprotinin.2,6 Anotherstrategy is to use anesthetic or subanesthetic doses ofgeneral anesthetics or opioids with potential anti-inflammatory effects.712 The results of multiple studies onthe systemic anti-inflammatory effects of fentanyl79 ormorphine10 are conflicting, and single studies on sevoflu-rane11 or propofol12 indicate anti-inflammatory effects atanesthetic doses of these drugs. Notably, local anesthetics(LA) are the most widely studied anesthetic drugs withclinically relevant endpoints. Hollmann and Durieux13

From *Discipline of Pharmacology, Faculty of Health Sciences, University ofAdelaide, Adelaide, Australia; Department of Circulation and MedicalImaging, Pain and Palliation Research Group, Norwegian University ofScience and Technology, Trondheim, Norway; Department of Anaesthesiaand Emergency Medicine, St. Olavs University Hospital, Trondheim, Nor-way; Discipline of Public Health, Faculty of Health Sciences, University ofAdelaide, Adelaide, Australia; Department of Psychology, Hebrew Univer-sity, 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 Circulationand Medical Imaging, NTNU, Box 8095 MTFS, N_7491 Trondheim, Norway.Address e-mail to [email protected].

Copyright 2012 International Anesthesia Research SocietyDOI: 10.1213/ANE.0b013e3182662e30

934 www.anesthesia-analgesia.org October 2012 Volume 115 Number 4

reviewed the anti-inflammatory effects of LA, and Herroe-der et al.14 provided evidence that the frequently shownbeneficial effects of LA on gastrointestinal recovery aftersurgery are most likely due to a potent modulatory effect ofthe proinflammatory response.

Among the general anesthetics, ketamine is the mostwidely studied in the search for strategies to modulatesystemic perioperative cytokine response. Ketamine is apotent anesthetic and analgesic drug. When administeredIV during anesthesia in adults, ketamine decreased postop-erative pain intensity for up to 48 hours, decreased cumu-lative 24-hour morphine consumption, and delayed thetime to first request of rescue analgesic.15 On the basis ofcurrent recommendations for ketamine, there is level Ievidence for an opioid- sparing effect and level II evidencefor antihyperalgesic and opioid toleranceprotecting effectsand for reduction in chronic postsurgical pain.16

The effect of ketamine on perioperative inflammatoryresponses has been studied in patients undergoing cardiacoperations under cardiopulmonary bypass (CPB), off-pump cardiac surgery, hysterectomies, and abdominal sur-gery. Doses ranged from a small supplemental single bolusdose and up to full ketamine anesthetic doses, either withracemic drug or the pharmacologically more active S-()-ketamine. Ketamine has been found to act as an immunemodulator. Furthermore, it has been argued that ketamineis a unique, specific anti-inflammatory drug,17 which inhib-its the systemic response without affecting local healingprocesses.

It has been suggested that ketamines anti-inflammatoryactivity might be mediated by suppression of microgliaactivation, as demonstrated by inhibition of extracellularsignal-regulated kinase 1/2 phosphorylation in primarycultured microglia,18 or by inhibition of large-conductanceCa2-activated K channels in microglia.19 Taken togetherwith the findings that microglia respond to endogenous(e.g., heat shock protein) and exogenous (e.g., stress, infec-tion, drugs) inflammation signals by producing proinflam-matory cytokines (e.g., IL-1, IL-6, tumor necrosis factor[TNF]) and thus inducing hyperalgesia,20 this provokedrenewed interest in the potential anti-inflammatory effectsof ketamine. Although it is generally believed that ket-amine has anti-inflammatory action in humans, the evi-dence has not been critically evaluated.

The aim of this systematic review was to evaluate theanti-inflammatory effect of ketamine in surgical patients inthe early postoperative period based on randomized con-trolled trials (RCT) in which ketamine was used as part ofthe intervention. The effect of ketamine on systemic expo-sure of the cytokine IL-6 was of special interest because itsplasma concentration serves as a useful and reliable bio-marker of systemic inflammation.21

METHODSA systematic search was performed in PubMed, Scopus,Embase, Web of Science, and the Cochrane Central Registerof Controlled Trials (CENTRAL) up to October 13, 2011. Inaddition the reference lists of the retrieved full articles weresearched.

The following search strategy combining free text andMeSH terms (ME) was set up for PubMed:

(ketamine[tw] OR ci 581[tw] OR ci581[tw] OR keta-set[tw] OR ketanest[tw] OR kalipsol[tw] OR calyp-sol[tw] OR ketalar[tw]) AND (Anti-inflammatoryagents[mh] OR inflammat*[tw] OR antiinflammat*[tw]OR nsaid*[tw] OR antirheumatic*[tw] OR antirheumatic*[tw] OR cyclooxygenase inhibitor*[tw] ORcyclo oxygenase inhibitor*[tw] OR cyclooxygenase 2inhibitor*[tw] OR cyclo oxygenase 2 inhibitor*[tw] ORcox 2 inhibitor*[tw] OR coxib*[tw] OR neutrophil*[tw]OR interleukin*[tw] OR tumor necrosis factor*[tw] ORtumor necrosis factor*[tw] OR ((Receptors, N-Methyl-d-Aspartate[Mesh] OR NMDA-receptor*) AND (an-tagonis* OR inhibitor* OR inhibiting OR blocking)) ORproinflammat* OR antiproinflammat* OR Cytokines-[mesh:noexp]) AND (ex vivo[tw] OR in vivo[tw] ORdouble-blindmethod[mh] OR single-blindmethod[mh]OR clinical trial[pt] OR trial[tiab] OR ((singl*[tiab] ORdoubl*[tiab] OR trebl*[tiab] OR tripl*[tiab]) AND(mask*[tiab] OR blind*[tiab])) OR placebos[mh] ORplacebo*[tiab] OR random*[tw] OR research design[mh:noexp] OR comparative study[pt] OR evaluationstudies as topic[mh] OR Evaluation Studies [pt] ORfollow-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] ORsystematic[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 specificterminology and indexing characteristics. In the updatingsearch MarchOctober 2011 Embase was used instead ofScopus. A detailed account of the searches can be obtainedfrom O. Dale.

Inclusion criteria included the following: English writ-ten RCT conducted in humans were eligible. Ketamine hadto be part of the intervention, and study outcomes had torelate to inflammation/immune modulation. If the primaryoutcome was not a clinical measure, any surrogate out-comes 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 thetitle of the study or its abstract, the full paper was retrieved.During the search process, several relevant publicationsin Chinese were identified. These were preliminarily re-viewed by one of the authors (Y.L.) with native knowledgeof Chinese.

The following were summarized in a data extractionform: publication details, study design and limitations,patient population details, settings, interventions, validityof methods for assessing outcomes, results, internal andexternal validity, and narrative summary of the mainfindings. Each study was reviewed and rated indepen-dently by 2 assessors (O.D. and Y.S.). The internal validityof each RCT was assessed using a checklist adapted fromthe criteria recommended in the National Health ServiceCentre for Reviews and Dissemination guidance document,22

as described earlier.23 Data were analyzed in accordance withthe GRADEs approach,24 which includes reporting of anevidence profile for the outcome. This profile consists of thenumber and type of eligible studies, number of participants,

October 2012 Volume 115 Number 4 www.anesthesia-analgesia.org 935

study limitations, consistency, directness, precision, publica-tion bias, and factors that might increase quality of evidence.On this basis a recommendation was given. Finally, theprocesswas reported in accordancewith the PRISMA require-ments (www.prisma-statement.org/), although the reviewprotocol was not registered as recommended.

On the basis of the evaluation process, we conducted ameta-analysis on the most consistently reported outcome,plasma concentrations of IL-6 within the first 6 postopera-tive hours. Pre- to postoperative changes in plasma orserum IL-6 concentrations were extracted for each random-ized group within each study. The precise data for postop-erative IL-6 concentration were not reported by Zeynelogluet al.,25 Bartoc et al.,26 and Cho et al.27 but were collected byconsulting the authors by e-mail. Differences betweengroups (ketamine vs control treated) were then pooledusing a random effects meta-analysis model according tothe DerSimonianLaird method.28 Heterogeneity in meandifferences was assessed using the I-squared statistic29 anda 2 test of goodness of fit. Publication bias in the meta-analysis was assessed visually using a funnel plot.30

RESULTSKetamine had an anti-inflammatory effect based on the 6studies included in the meta-analysis (Table 1, Figs. 1 and2) when using postoperative plasma/serum IL-6 as anoutcome. The overall mean (95% confidence interval [CI])difference was 71 (101 to 41) pg/mL (P 0.001). Nodose response was observed. The degree of heterogeneitywas 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 publi-cation bias. Including the studies in which a potent anti-inflammatory 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 to50 (75 to 25) pg/mL.

In total, the search for relevant studies yielded 1187 136 (original additional search, respectively) records asfollows: PubMed (148 28), Scopus/Embase (925 82),CENTRAL (0), and Web of Science (114 26) (Fig. 1). Noadditional records were identified through other sources,and 1033 113 records remained after removing dupli-cates. Removing 10 records (articles written in non-EnglishlanguagesChinese [6], German [2], Spanish [1], and Japa-nese [1]), left 1136 records for screening. A total of 1083 13 records were removed on the basis of their titles or afterreading the abstract when deemed necessary. Forty full-text articles were retrieved, and 26 were not rated eligiblefor further analysis.

Since one of the authors (Y.L.) is native Chinese, andsince 5 of the Chinese publications were relevant to the aimof this review, these publications underwent a separateevaluation (was not included in the primary evaluation, butas a supplement), as described under Methods.

The 14 studies eligible for evaluation included 684patients. In all (except for 2 studies including 3 groups26,33),2 groups were compared. Ten studies were double-blind, 2single-blinde34,35 (one did not report this originally,35 butconfirmed single-blinding upon request), and 2 of the

studies were open.25,33 Three studies31,34,36 reported pa-tient flow according to CONSORT agreement. All but 2studies25,32 were conducted in adults. In 7 studies, CPBwas used; in another, cardiac surgery was conductedoff-pump27; 4 studies included major abdominal opera-tions35,37,38; 1 thoracic surgery36; and in 1,33 cataract sur-gery was performed. All patients underwent surgery undergeneral anesthesia, except one group in Tu et al.s study,33

and a varying number of patients who received epiduralanesthesia in the control and interventions groups inDAlonzo et al.s study.36 Total subject numbers variedfrom 24 to 142 patients, with the sample size justified in 6studies.2527,31,34,36 One of the studies had a clinical pri-mary outcome (neurodevelopment),32 12 measured surro-gate outcomes such as markers of inflammations directly inblood samples, and 2 measured similar outcome in stimu-lated blood samples (ex vivo).35,39 All studies (except forAkhlag 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 racemicketamine. The intervention varied from an anesthesiabased entirely on (S)-ketamine (single dose of 2 to 4 mg/kgfollowed by 2 to 4 mg/kg/h34), racemic ketamine singledose (1 to 2 mg/kg) followed by infusion (1.5 to 3.5mg/kg/h),25 low dose (S)-ketamine infusion (0.075mg/kg/h),40 or low (0.15 to 0.5/mg/kg) single doses. In Tuet al.s study33 one group received ketamine 1 mg/kg infusedover the duration of surgery. In all studies, ketamine wasgiven at induction of anesthesia, except Bhutta et al.,32 inwhich ketamine was administered just before CPB.

Of the 14 eligible studies, 2 were deemed high quality(),26,34 9 were of medium quality (),25,27,31,32,35,3841

and 3 were of low () quality and therefore excluded fromthe qualitative analysis: Mostafa et al.37 because of lack ofpreoperative sampling, Tu et al.33 because of large losses tofollowup, and DAlonzo et al.36 primarily because ofheterogeneity of study groups, and also lack of control ofpreoperative use of nonsteroidal anti-inflammatory drugs.One study reported regular use of nonsteroidal anti-inflammatory drugs before the operation that was similarin the study groups.26 Thus, 11 studies were included in thequalitative analysis. Of these, drugs with significant anti-inflammatory effects (methyl prednisolone, dexametha-sone, and ibuprofen) were administered as premedicationor during the operations in 3 studies,25,31,32 respectively;this fact may cancel the effects of ketamine on inflamma-tory biomarkers. Three of the studies used questionablestatistics, such as failing to consider the fact that repeatedmeasures were conducted, or not compensating for mul-tiple comparisons.38,40,41 Primary endpoints were statedclearly in 2 studies,34,36 but could be anticipated in 4studies.2527,31 The primary endpoints chosen in the in-cluded studies were all different, and only Welters et al.34

and DAlonzo et al.36 reported their primary endpoint in aprecise manner.

Five of the studies (Table 1) reported that racemic or(S)-ketamine significantly reduced the inflammatory re-sponse after surgery,26,34,35,38,41 as measured by plasma/serum IL-6 concentrations (Table 1). Effect size was largerand lasted for a longer time period in early studies38,41 incomparison with the later studies by Bartoc et al. and

Perioperative Ketamine and Cytokines

936 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

Table1.Des

cription

ofStudies

Eligible

forQua

litativeAna

lysis

Study

/de

sign

Participa

nts

Interven

tion

/statistics

laban

alysis

Outco

memea

sures

Outco

mes

Bar

toc

etal

.,2006

26

Ara

ndom

ized

,do

uble

-blin

d,pl

aceb

o-co

ntro

lled

stud

yas

sess

ing

the

anti-

infla

mm

ator

yef

fect

ofke

tam

ine

inca

rdia

csu

rgic

alpa

tient

s.JCardiotho

racVa

scAn

esth

Dou

ble

blin

dS

ingl

e-ce

nter

stud

yC

onso

rtfo

rmno

tre

port

ed

Elec

tive

card

iac

surg

ery

(CAB

G,

valv

ere

plac

emen

ts,

and

com

bina

tions

)w

ithC

PB(3

2C

),m

eetin

gat

leas

t1

offo

llow

ing

crite

ria:

age

70

year

s,re

cent

(14

days

)M

I,el

evat

edcr

eatin

ine

(1.3

mg/

dL),

prev

ious

stro

ke,

prev

ious

card

iac

surg

ery.

Anes

thes

iaat

the

disc

retio

nof

the

anes

thet

ist.

Preo

pera

tive

NS

AID

seq

uali

nst

udy

grou

ps.

Sam

ple

size

:30

(15

pair

keta

min

egr

oups

).50

incl

uded

,15

and

18

toke

tam

ine

grou

ps,

17

topl

aceb

o.R

ando

miz

atio

n:se

aled

enve

lope

byan

inve

stig

ator

not

invo

lved

inpa

tient

care

the

day

ofsu

rger

y.

Rac

emic

keta

min

e0.2

5m

g/kg

.R

acem

icke

tam

ine

0.5

mg/

kgat

indu

ctio

nas

anad

juva

ntto

anes

thet

icpr

oced

ure.

Con

trol

sre

ceiv

edsa

line.

ANO

VAfo

llow

edby

Tuke

yte

stfo

rpa

irwis

eco

mpa

rison

ofm

eans

orD

unne

tfo

rbe

twee

nke

tam

ine

grou

ps.

Qua

ntik

ine

IL-6

;R

DS

yste

ms.

Sam

plin

gun

tilPO

D1.

Prim

ary

outc

ome:

differ

ence

betw

een

keta

min

egr

oups

inIL

-6on

POD

1(in

vivo

).S

econ

dary

outc

ome:

differ

ence

sbe

twee

nke

tam

ine

grou

psan

dpl

aceb

oan

ytim

e.Al

soC

RP,

IL8

and

10.

Dat

aal

soat

ICU

arriv

al.

Prim

ary

outc

ome:

nost

atis

tical

lysi

gnifi

cant

differ

ence

betw

een

keta

min

egr

oups

inIL

-6on

POD

1.

Sec

onda

ryou

tcom

e:ke

tam

ine

low

ered

IL-6

inco

mpa

rison

with

plac

ebo

upon

arriv

alat

the

ICU

and

POD

1,

whi

leIL

-10

was

low

erfo

rke

tam

ine

POD

1.

No

chan

ges

obse

rved

for

IL-8

.C

RP

low

erin

the

0.5

mg/

kggr

oup

POD

1.

Writ

ten

toau

thor

for

data

:IL

-6pg

/L,

atIC

U,

mea

n(S

D):

Con

trol

:152

(114).

Ket

amin

e(0

.25):

59

(53).

Ket

amin

e(0

.5):

53

(38).

MAP

and

SVT

high

erfo

rke

tam

ine.

Wel

ters

etal

.,2011

34

Con

tinuo

usS

-()-k

etam

ine

adm

inis

trat

ion

durin

gel

ectiv

eC

ABG

surg

ery

atte

nuat

espr

oinfl

amm

ator

ycy

toki

nere

spon

sedu

ring

and

afte

rCPB

.BJA

Sing

lebl

ind

Sing

le-c

ente

rstu

dy?

Cons

ortf

orm

repo

rted

Elec

tive

CAB

Gw

ithC

PB(t

pno

tgi

ven)

.Ex

clus

ions

:C

K

170

U/L

,re

peat

card

iac

surg

ery

and

com

bine

dop

erat

ions

,he

patic

(AS

AT/A

LAT

150

U/L

)an

dre

nal(

crea

tinin

e

132

M)

dise

ase,

imm

unos

uppr

essi

vem

edic

atio

ns,

imm

unod

efici

ency

synd

rom

es,

neur

olog

icor

psyc

hiat

ricdi

seas

e.Pa

tsw

ithC

RP

16

mg/

L,IL

-6

24

pg/m

Lin

the

mor

ning

wer

eex

clud

ed.

Anes

thes

iaw

ellc

ontr

olle

d.C

PB32

Sam

ple

size

:50

inea

chgr

oup,

incr

ease

dby

16%

toco

mpe

nsat

efo

rlo

ss.

142

pats

rand

omiz

ed,

70

toin

terv

entio

n,72

toco

ntro

l,60

and

68

com

plet

edth

est

udy

inth

ere

spec

tive

grou

ps.

Excl

usio

nsdu

eto

too

high

CR

Por

IL-6

,or

inco

mpl

ete

data

.

S-k

etam

ine-

base

dan

esth

esia

(13

mg/

kg,

24

mg/

kg/h

).C

ontr

ol:

sufe

ntan

ilba

sed

(0.2

51

g/

kg,

0.5

2

g/kg

/h).

Ran

dom

izat

ion:

com

pute

rge

nera

ted.

Nor

mal

dist

ribut

ion

chec

ked.

Rep

eate

d-m

easu

res

ANO

VAw

ithG

reen

hous

eG

eiss

erE

psilo

nad

just

men

t,ot

herw

ise

Man

nW

hitn

ey.

Cat

egor

ical

bych

i-squ

are.

Cyt

oset

s,B

ioso

urce

BD

Opt

EIA,

BD

Bio

scie

nces

Sam

plin

gfo

r24

hour

s.

Prim

ary

outc

ome:

IL-6

6ho

urs

afte

rao

rtic

uncl

ampi

ngin

vivo

.S

econ

dary

:IL

-8,

10.

TNF

,TN

F-R

I(T

NF-

rece

ptor

1,

sFAS

(pro

apto

pic

prot

ein

solu

ble

FAS

),C

RP.

Prim

ary

outc

ome:

IL-6

pg/L

,m

ean

(SD

):K

etam

ine:

56.8

(46.3

).S

ufen

tani

l:172.6

(149.9

).P

0.0

1S

econ

dary

:IL

-8al

sode

crea

sed

at6

hour

s.IL

-10

incr

ease

dat

1ho

ur.

No

chan

ges

for

TNF

,TN

F-R

I,sF

AS,

CR

P.

Bei

linet

al.,

2007

35

Low

-dos

eke

tam

ine

affe

cts

imm

une

resp

onse

sin

hum

ans

durin

gth

eea

rlypo

stop

erat

ive

perio

d;B

JAS

ingl

ebl

indi

ngac

cord

ing

toau

thor

.S

ingl

e-ce

nter

stud

yC

onso

rtfo

rmno

tre

port

ed

Patie

nts

unde

rgoi

ngab

dom

inal

surg

ery

(hys

tere

ctom

yan

dga

stro

plas

ty).

Oth

erin

clus

ion/

excl

usio

ncr

iteria

not

give

n.S

ampl

esi

ze:

not

estim

ated

36

pats

rand

omiz

ed,

17

toke

tam

ine,

19

tois

oton

icsa

line

(con

trol

).

0.1

5m

g/kg

race

mic

keta

min

e5

min

utes

befo

rein

duct

ion

asan

adju

vant

toan

esth

etic

proc

edur

e.C

ontr

ols:

isot

onic

salin

e.R

epea

ted-

mea

sure

sAN

OVA

(for

time

perio

dbe

fore

Stu

dent

tte

stpo

stho

c.EL

ISA

kits

:R

DS

yste

ms,

Bio

sour

ceIn

tern

atio

nal,

Phar

min

gen.

Sam

plin

gfo

r72

hour

s.

Prim

ary

out

com

e.N

otgi

ven.

IL-b

eta,

IL-2

,IL

-6,

TNF-

alph

a,m

itoge

nre

spon

se,

NK

CC

,ex

vivo

.

Out

com

e(a

ll-ov

er).

IL-6

pg/L

,m

ean

(SEM

).4

hour

spo

stop

erat

ive.

Ket

amin

e:68.3

(10.6

).Pl

aceb

o:114.4

(16.7

).P

0.0

5M

oder

ate

effe

ctof

keta

min

e,lo

wer

IL-6

TNF-

alfa

(sm

all)

at4

hour

s.IL

2w

asm

aint

aine

d(a

ndno

tre

duce

das

for

cont

rols

)in

stud

ype

riod.

(Con

tinue

d)


Table1.(Continued

)Study

/de

sign

Participa

nts

Interven

tion

/statistics

laban

alysis

Outco

memea

sures

Outco

mes

Cho

etal

.,2009

27

Effe

ctof

low

-dos

eke

tam

ine

onin

flam

mat

ory

resp

onse

inof

f-pum

pco

rona

ryar

tery

bypa

ssgr

aft

surg

ery.

BJA

Dou

ble

blin

dS

ingl

e-ce

nter

stud

y.C

onso

rtno

tre

port

ed.

Patie

nts

unde

rgoi

ngel

ectiv

e,m

ultiv

esse

lOPC

AB.

Excl

usio

ncr

iteria

i:ag

e

75

year

s,re

cent

(14

days

)m

yoca

rdia

linf

arct

ion,

unst

able

angi

naw

ithel

evat

edcr

eatin

eki

nase

-MB

(CK

-MB

),el

evat

edse

rum

crea

tinin

e(.1.3

mg/

dL)

befo

reop

erat

ion,

EF

40%

,pr

evio

usca

rdia

csu

rger

y,pr

evio

usst

roke

orpu

lmon

ary

dise

ase,

and

hist

ory

oftr

eatm

ent

with

ster

oid

orno

nste

roid

alan

ti-in

flam

mat

ory

drug

sw

ithin

am

onth

(nor

mot

herm

ia).

Anes

thes

iaw

ellc

ontr

olle

d(s

ufen

tani

l-sev

oflur

ane

base

d).

One

surg

eon.

Sam

ple

size

estim

ated

.(C

RP

POD

1?)

50

patie

nts

rand

omiz

ed,

2

25

com

pute

r-ge

nera

ted

rand

omiz

atio

n.

0.5

mg/

kgra

cem

icke

tam

ine

atin

duct

ion

asan

adju

vant

toan

esth

etic

proc

edur

e.C

ontr

ols

rece

ived

salin

e.t

test

and

repe

ated

-mea

sure

sAN

OVA

;po

stho

cD

unne

ttte

st.

Wilc

oxon

rank

-sum

(bet

wee

ngr

oups

),Fr

iedm

ante

st(w

ithin

grou

p)fu

rthe

rin

vest

igat

edby

Man

nW

hitn

eyw

ithB

onfe

rron

i.be

twee

nth

egr

oups

:

2te

stor

byFi

sher

exac

tte

st.

CR

P:in

stitu

tiona

llab

.Q

uant

ikin

ehi

gh-s

enso

ryim

mun

oass

ay;

R

DS

yste

ms.

Sam

plin

gto

POD

2

Prim

ary

outc

ome:

not

give

n,bu

tac

cord

ing

tosa

mpl

esi

zeC

RP

POD

1.

Oth

er:

IL-6

,TN

F-al

fa,

bloo

dco

unts

,m

yoca

rdia

linj

ury

mar

kers

.

No

spec

ific

data

give

n.N

odi

ffer

ence

betw

een

grou

ps.

CR

Pan

dIL

-6in

crea

sed

post

oper

ativ

e(m

axim

umat

2da

ys(a

bout

15

mg/

dL)

and

4ho

urs

(abo

ut300

pg/m

L),

resp

ectiv

ely)

.TN

F-al

fast

able

.W

ritte

nto

auth

orfo

rda

ta.

Il-6

(pg/

mL)

4-h

our

post

anas

tom

oses

:m

ean

(SD

):K

etam

ine:

(163).

Con

trol

:95

(82).

Roy

tbla

tet

al.,

19

96

38

Preo

pera

tive

low

-dos

eke

tam

ine

redu

ces

seru

min

terle

ukin

-6re

spon

seaf

ter

abdo

min

alhy

ster

ecto

my.

Pain

Clin

Dou

ble

blin

d.S

ingl

e-ce

nter

stud

y.C

onso

rtno

tre

port

ed.

ASA

12

wom

en,

unde

rgoi

ngel

ectiv

eab

dom

inal

hyst

erct

omia

.Ex

clus

ion

crite

ria:

60

year

s,m

alig

nant

orch

roni

cin

flam

mat

ory

orse

vere

resp

irato

ryor

card

iova

scul

ardi

seas

e,al

read

yre

ceiv

ing

opio

ids.

Sam

ple

size

not

estim

ated

.22

enro

lled,

11

inea

chst

udy

grou

p.R

ando

miz

atio

npr

oced

ure

not

desc

ribed

.

Ket

amin

e0.1

5m

g/kg

befo

rein

cisi

on.

Con

trol

ssa

line.

Anes

thes

iaba

sed

onis

oflur

ane

and

fent

anyl

(5

g/kg

).Tw

ow

ayAN

OVA

follo

wed

bym

ultip

leco

mpa

rison

s.IL

-6im

mun

oass

ayki

t,B

ioso

urce

Inte

rnat

iona

l.S

ampl

ing

preo

pera

tive,

uter

usm

obili

zatio

n,4,

24,

48,

and

72

hour

s.

Prim

ary

outc

ome:

not

give

n,bu

t4-h

our

IL-6

isac

cura

tely

repo

rted

.C

ircul

ator

yva

riabl

es.

IL-6

at4-h

our

pg/m

L,m

ean

(SD

).K

etam

ine:

9.3

(12.6

).C

ontr

ol:

43.8

(9.5

).Al

love

r:IL

-6in

crea

sed

at4,

and

24h

for

both

grou

ps,c

ontro

lals

oat

48hr

.Co

ntro

lshi

gher

than

keta

min

egr

oup

atth

ese

time

poin

ts.

Cont

rolg

roup

had

high

erm

ean

arte

rial

bloo

dpr

essu

rean

dhe

artr

ate

than

the

keta

min

egr

oup.

Roy

tbla

tet

al.,

19

98

41

Ket

amin

eat

tenu

ates

the

inte

rleuk

in-6

resp

onse

afte

rca

rdio

pulm

onar

yby

pass

;An

esth

Analg

Dou

ble

blin

d.S

ingl

e-ce

nter

stud

y.C

onso

rtfo

rmno

tre

port

ed.

Elec

tive

CAB

Gpo

ints

with

EF

0.4

.U

ncon

trol

led

syst

emic

dise

ase

(hyp

erte

nsio

n,di

abet

es,

rena

lfa

ilure

)an

dre

quire

men

tfo

rao

rtic

ballo

onpu

mp

lead

toex

clus

ion.

Aspi

rinan

dN

SAI

DS

stop

ped

10

days

befo

resu

rger

y.S

tand

ard

oper

ativ

e/an

esth

etic

(hig

h-do

sefe

ntan

yl)

proc

edur

es.

Anes

thes

iaw

ellc

ontr

olle

d.Tw

osu

rgeo

nson

ly.

CPB

:32C

Sam

ple

size

:no

tes

timat

ed.

31

patie

nts

rand

omiz

ed14

toin

terv

entio

n,17

toco

ntro

l.3

patie

nts

inco

ntro

lgro

upex

clud

edbe

caus

eof

hem

odyn

amic

inst

abili

ty/l

ow-o

utpu

tsy

ndro

me.

0.2

5m

g/kg

race

mic

keta

min

eat

indu

ctio

nas

anad

juva

ntto

anes

thet

icpr

oced

ure.

Con

trol

sre

ceiv

edsa

line.

Ran

dom

izat

ion:

not

desc

ribed

.Tw

o-w

ayAN

OVA

with

mul

tiple

post

hoc

test

ing.

Qua

ntik

ine

IL-6

;R

DS

yste

ms.

Sam

plin

gfo

r8

days

.

Prim

ary

outc

ome:

No.

Rep

orte

d.D

iffer

ence

sin

IL-6

seru

mco

ncen

trat

ion

post

-CPB

,4,

24,

48,

and

days

38

(invi

vo).

And

at4

hour

s.

Sta

tistic

ally

sign

ifica

ntlo

wer

IL-6

conc

entr

atio

nat

allm

easu

ring

poin

tsun

tilre

turn

toba

selin

eat

day

8.

Prec

ise

figur

esno

tgi

ven

(onl

ygr

aphi

c).

IL-6

pg/L

,m

ean

(SD

)4

hour

saf

ter

CPB

:K

etam

ine:

70

(38).

Con

trol

:200

(44).

CAB

G

coro

nary

arte

ryby

-pas

sgr

aft;

CPB

card

iopu

lmon

ary

bypa

ss;E

F

ejec

tion

frac

tion;

MAP

mea

nar

teria

lblo

odpr

essu

re;O

PCAB

off-p

ump

coro

nary

arte

ryby

pass

;SVT

syst

emic

vasc

ular

resi

stan

ce;A

SA

Amer

ican

Soc

iety

ofAn

esth

esio

logi

sts

phys

ical

clas

sific

atio

nsy

stem

;Tp

tem

pera

ture

;ALA

T(A

LT)

alan

ine

amin

otr

ansf

eras

e;AS

AT(A

ST)

aspa

rtat

eam

ino

tran

sfer

ase;

CK

crea

tine

kina

se;C

RP

C-re

activ

epr

otei

n;Il

inte

rleuk

in;

TNF

tum

orne

cros

isfa

ctor

;AN

OVA

anal

ysis

ofva

rianc

e;IT

T

inte

ntio

nto

trea

t;S

EM

stan

dard

erro

rof

the

mea

n;PO

D1

post

oper

ativ

eda

y;C

PB

card

iopu

lmon

ary

bypa

ss;

MI

myo

card

ial

infa

rctio

n;N

SAI

Ds

nons

tero

idal

anti-

infla

mm

ator

yst

eroi

ds;

ICU

inte

nsiv

eca

reun

it;N

KC

C

natu

ralk

iller

cell

cyto

toxi

city

.



Welters et al.,26,34 all conducted in patients undergoingCPB. The study of off-pump cardiac surgery patients didnot show ketamines effect.27 Moreover, effect size wassmaller and duration was shorter in patients undergoingmajor abdominal surgery.35,38

Overall, plasma/serum C-reactive protein, IL-8, orTNF- concentrations either did not show differences ordecreased in a fashion similar to IL-6 in ketamine-treatedpatients,26,34,35,40 while IL-10 concentrations increased in

the 2 high-quality studies.26,34 Zilberstein et al. have re-ported that the addition of low-dose ketamine to generalanesthesia attenuated postoperative neutrophil activationup to 6 days after CPB.39

Among the 5 papers in Chinese, 1 was excluded becauseit could not be asserted whether it was an RCT,42 andanother because the reported baseline IL-6 concentrationsdeviated significantly from all other studies.43 Two of theremaining studies included abdominal operations44,45 and

Figure 1. PRISMA 2009 flow diagram.

Figure 2. Forest plot of early postopera-tive IL-6 serum/plasma concentrations.The designation of the abscissa is inpg/mL.


1, acute burn patients given analgesia.46 Neither of the ab-dominal 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). Itshould be noted that the ketamine intervention started afterthe trauma (burn); thus this study had starting IL-6 con-centrations of about 120 pg/mL, which increased over 48hours in the control group but decreased in the ketamine-exposed groups.

The overall evidence profile as rated according to theGRADE recommendation24 for intraoperative ketamine onthe postoperative Il-6 response was considered high.

DISCUSSIONThis systematic review substantiates the notion that intra-operative ketamine has an anti-inflammatory effect, asindicated by the meta-analysis showing a considerablereduction in circulating concentrations of the proinflamma-tory cytokine IL-6 during the first 6 hours after surgery.

IL-6 concentration in the first 6 postoperative hours waschosen as a representative outcome for the inflammatoryresponse for several reasons. First, IL-6 was the mostconsistently reported inflammation biomarker in the stud-ies included in this review, and most studies provided datain the early postoperative phase. Second, it has a proinflam-matory action, and ketamine has been suggested to act asan anti-inflammatory drug.17 Third, any action of ketaminegiven intraoperatively should last into the early postopera-tive phase to have any potential clinical relevance, andpossibly even be more prominent at this stage than later.Numerous studies have indicated the importance of IL-6 asa reliable and particularly sensitive biomarker of inflam-matory activation and a predictor of subsequent organdysfunction and death.47,48 For example, higher plasma/serum concentrations of IL-6 have been associated withincreased risk for major cardiopulmonary complicationsafter general thoracic surgery,49 postoperative morbidityafter cardiac surgery,13,50 postoperative complications,51,52

cognitive dysfunction after coronary artery surgery,53

increased risk of coronary heart disease,54 adverse postop-erative outcome (mortality and complications) in elderlypatients undergoing hip fracture surgery,55 and poor out-come and death after stroke.21

The overall effect size of ketamine on IL-6 was largeeven when including, in a separate meta-analysis, the 3studies using potent anti-inflammatory drugs in theperioperative period.25,31,32 This was especially true for sur-geries with CPB in which ketamine reduced IL-6 concen-trations to about one third of those of the controlgroup.26,34,41 This effect size was of the same magnitude (orlarger) as reported for pretreatment with methylprednisolone(30 mg/kg) in which IL-6 was measured at declamping of theaorta during CPB surgery,56 or 60minutes later.57 The effect ofmethylprednisolone in the former study, however, was short-lived and did not last beyond 1 hour after termination of theextracorporal circulation.

According to the GRADE approach the evidence level israted high because it is based upon RCTs.24 Studies withquestionable quality did not enter the qualitative analysis,while studies that included potent anti-inflammatory drugsdid not enter the quantitative analysis. The meta-analysis

showed consistent data for the chosen endpoint. The data,however, were inconsistent with regard to the duration ofaction of intraoperative ketamine. There are no signs ofpublication bias. Perhaps the weakest of the GRADE evidenceelements is related to directness, because IL-6 may be anarrow or rather indirect measure of inflammation and itsclinical consequences.

According to GRADE, a doseresponse associationwould strengthen the evidence.24 In the present reviewneither a more pronounced effect nor a longer duration ofaction was seen, although the doses ranged from a singlesubanesthetic dose up to doses required for full ketamine-based anesthesia. This lack of dose response is difficult tounderstand, but the studies all have in common the factthat a bolus dose of at least 0.15 mg/kg ketamine was givenbefore the surgical intervention. If this bolus dose is at thetop of the dose-response curve for ketamines anti-inflammatory effect, higher bolus doses or infusion may befutile. However, the study of Welters34 comparing ket-amine anesthesia with sufentanil-based anesthesia presentsimportant evidence that ketamine itself has an anti-inflammatory effect.

Although not derived from the meta-analysis, it isnoteworthy that the duration of action of intraoperativeketamine differed substantially among studies. Duration ofup to 6 hours postoperatively was documented in thepresent review. Furthermore, some of the studies reportedduration of action of up to 24 hours,26 or even up to 8days.38,39,41 Although there are statistical concerns with thelast 3 studies, the findings are corroborated by other reports(not included in this review), showing long-term effects (5to 7 days) after short-duration infusions (4 hours or less) ofketamine in both depression58 and pain relief in patientswith critical limb ischemia.58,59

Most of the studies included other measures of inflam-mation in addition to IL-6. Among these were C-reactiveprotein, IL-8, IL-10, and TNF. Only the data for IL-10 wereconsistent, showing that ketamine increased the concentra-tions of this anti-inflammatory cytokine, providing furtherevidence to the main observation of this review, i.e., thatketamine plays an anti-inflammatory role. Moreover, sincethe most consistent finding was related to IL-6, this reviewlends credibility to the suggestion that ketamine primarilyacts as an antiinflammatory drug.17

Several potentially interesting studies written in Chinesewere identified. Since one of the authors (Y.L.) is a nativeChinese, it was decided to do a preliminary evaluation ofthese studies in addition to the primary papers written inEnglish. These studies for reasons stated above added little.However, the study comparing the effect of ketamine onIL-6, as a part of the acute pain control regimen in burnpatients,46 attracted attention, since evidence suggests arole for inflammation as an inducer of microglial-mediatedhyperalgesia.20 Interestingly, the effect size reported by Xiaet al.46 for IL-6 was of the same magnitude as that afterCPB.26,34,41 The study also indicated that ketamine maypotentially reduce the inflammatory response even whengiven after a trauma, at a time when biomarkers such asIL-6 are already increased.

Various studies, including clinical and preclinical re-search, in vivo and in vitro, have shown that in addition to



its anesthetic activity, ketamine has an anti-inflammatoryeffect (for a recent review, see Loix et al.17). The mecha-nisms by which ketamine produces its anti-inflammatoryactions needs to be elucidated. The acute analgesic effectsof ketamine are generally believed to be mediated throughthe blockade of phencyclidine binding site of N-methyl-d-aspartate (NMDA) receptors of the nociceptive neurons;this mechanism could also partly account for the anti-inflammatory effects of ketamine. However, ketamine hasalso been reported to interact with opioid, monoamine,cholinergic, purinergic, and adenosine receptor systems.The functional anti-inflammatory effects of ketamine with-out affecting local healing processes (blunting neutrophilactivation but sparing endothelial production of cytokines)shares similarities to those of LAs,13 which is consideredto be due to their effect on G-protein-coupled-receptorsignaling, specifically Gq downregulation.60 Because ket-amine also has local anesthetic effects,60 it remainsspeculative as to whether they share a common anti-inflammatory mechanism.

Moreover, numerous mechanisms in addition to thosediscussed above have been shown to mediate the anti-inflammatory effects of ketamine. A nonexhaustive list ofproposed mechanisms include inhibition of transcriptionfactors nuclear factor-B and activator protein 1,61 inhibi-tion of proinflammatory cytokine production (IL-6 andTNF),6264 inhibition of neutrophil functions,65 the releaseof adenosine,66 the blockade of large-conductance KCachannels on microglia (BK channels),19 or the inhibition ofnitric oxide production in macrophages.67 Ketamine hasbeen shown to downregulate the proinflammatory enzymescyclooxygenase 2 and inducible nitric oxide synthase, whilepreserving expression of the anti-inflammatory enzymeheme-oxygenase-1.68 This review does not shed light on themechanisms of the anti-inflammatory action of ketamine inthe perioperative period. Whether it is mediated by NMDAor non-NMDA mechanisms remains to be elucidated, butthe finding of this review should certainly stimulate basicresearchers to clarify these aspects.

In this systematic search, no studies examining anyclinical outcome were found. Although there are someindications that IL-6 is associated with a clinical out-come,15,5154,69 the bulk of evidence seems weak. Therefore,clinical outcome studies are warranted, and the evidencepresented in this review suggests that subanesthetic singledoses should be examined first. It is also intriguing toexamine whether the anti-inflammatory effect of ketaminemay have an impact on postoperative pain management.

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

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 pa-pers independently, analyze the overall data, and write themanuscript.This manuscript was handled by: Spencer S. Liu, MD.

ACKNOWLEDGMENTSThe authors greatly appreciate the support for the searchesprovided by Mr. Michael Draper, Research Librarian, Univer-sity of Adelaide, Adelaide, Australia, and Ingrid RiphagenMSc, AKF, Norwegian University of Science and Technology,Trondheim, Norway. This work was facilitated by the Leonand Clara Sznajderman Chair of Psychology (to Y.S.). We arealso 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.

REFERENCES1. Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T,

Haverich A, Schlag G, Borst HG. Systemic inflammatoryresponse syndrome after cardiac operations. Ann Thorac Surg1996;61:171420

2. Hill GE, Whitten CW, Landers DF. The influence of cardiopul-monary bypass on cytokines and cell-cell communication.J Cardiothorac Vasc Anesth 1997;11:36775

3. Hennein HA, Ebba H, Rodriguez JL, Merrick SH, Keith FM,Bronstein MH, Leung JM, Mangano DT, Greenfield LJ, RankinJS. Relationship of the proinflammatory cytokines to myo-cardial ischemia and dysfunction after uncomplicated coro-nary revascularization. J Thorac Cardiovasc Surg 1994;108:62635

4. Deng MC, Dasch B, Erren M, Mollhoff T, Scheld HH. Impactof left ventricular dysfunction on cytokines, hemodynamics,and outcome in bypass grafting. Ann Thorac Surg1996;62:18490

5. Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, UmbergerR, Leeper K. Persistent elevation of inflammatory cytokinespredicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6levels are consistent and efficient predictors of outcome overtime. Chest 1995;107:106273

6. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatoryresponse to cardiac surgery: implications for the anesthesiolo-gist. Anesthesiology 2002;97:21552

7. Taylor NM, Lacoumenta S, Hall GM. Fentanyl and theinterleukin-6 response to surgery. Anaesthesia 1997;52:1125

8. Winterhalter M, Brandl K, Rahe-Meyer N, Osthaus A, HeckerH, Hagl C, Adams HA, Piepenbrock S. Endocrine stressresponse and inflammatory activation during CABG surgery.A randomized trial comparing remifentanil infusion to inter-mittent fentanyl. Eur J Anaesthesiol 2008;25:32635

9. Brix-Christensen V, Tonnesen E, Sorensen IJ, Bilfinger TV,Sanchez RG, Stefano GB. Effects of anaesthesia based on highversus low doses of opioids on the cytokine and acute-phaseprotein responses in patients undergoing cardiac surgery. ActaAnaesthesiol Scand 1998;42:6370

10. Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS.The effects of morphine and fentanyl on the inflammatoryresponse to cardiopulmonary bypass in patients undergoingelective coronary artery bypass graft surgery. Anesth Analg2007;104:133442

11. Kawamura T, Kadosaki M, Nara N, Kaise A, Suzuki H, Endo S,Wei J, Inada K. Effects of sevoflurane on cytokine balance inpatients undergoing coronary artery bypass graft surgery.J Cardiothorac Vasc Anesth 2006;20:5038

12. Corcoran TB, Engel A, Sakamoto H, OShea A, OCallaghan-Enright S, Shorten GD. The effects of propofol on neutrophilfunction, lipid peroxidation and inflammatory response dur-ing elective coronary artery bypass grafting in patients withimpaired ventricular function. Br J Anaesth 2006;97:82531


13. Hollmann MW, Durieux ME. Local anesthetics and the inflam-matory response: a new therapeutic indication? Anesthesiol-ogy 2000;93:85875

14. Herroeder S, Pecher S, Schonherr ME, Kaulitz G, HahnenkampK, Friess H, Bottiger BW, Bauer H, Dijkgraaf MG, Durieux ME,Hollmann MW. Systemic lidocaine shortens length of hospitalstay after colorectal surgery: a double-blinded, randomized,placebo-controlled trial. Ann Surg 2007;246:192200

15. Elia N, Tramer MR. Ketamine and postoperative painaquantitative systematic review of randomised trials. Pain2005;113:6170

16. Hocking G, Cousins MJ. Ketamine in chronic pain manage-ment: an evidence-based review. Anesth Analg 2003;97:17309

17. Loix S, De Kock M, Henin P. The anti-inflammatory effects ofketamine: state of the art. Acta Anaesthesiol Belg 2011;62:4758

18. Chang Y, Lee JJ, Hsieh CY, Hsiao G, Chou DS, Sheu JR. Inhibitoryeffects of ketamine on lipopolysaccharide-induced microglialactivation. Mediators Inflamm 2009;2009:705379 [Epub]

19. Hayashi Y, Kawaji K, Sun L, Zhang X, Koyano K, Yokoyama T,Kohsaka S, Inoue K, Nakanishi H. Microglial Ca(2)-activatedK() channels are possible molecular targets for the analgesiceffects of S-ketamine on neuropathic pain. J Neurosci 2011;31:1737082

20. Watkins LR, Hutchinson MR, Johnston IN, Maier SF. Glia:novel counter-regulators of opioid analgesia. Trends Neurosci2005;28:6619

21. Whiteley W, Jackson C, Lewis S, Lowe G, Rumley A, SandercockP, Wardlaw J, Dennis M, Sudlow C. Inflammatory markers andpoor outcome after stroke: a prospective cohort study and sys-tematic review of interleukin-6. PLoS Med 2009;6:e1000145

22. NHS Centre for Reviews and Dissemination. UndertakingSystematic Reviews of Research on Effectiveness. CRDs Guid-ance for Those Carrying Out or Commissioning Reviews. 2nded. York: University of York, 2001

23. Mayyas F, Fayers P, Kaasa S, Dale O. A systematic review ofoxymorphone in the management of chronic pain. J PainSymptom Manage 2010;39:296308

24. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S,Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, JaeschkeR, Leng G, Liberati A, Magrini N, Mason J, Middleton P,Mrukowicz J, OConnell D, Oxman AD, Phillips B, Schun-emann HJ, Edejer TT, Varonen H, Vist GE, Williams JW Jr.,Zaza S. Grading quality of evidence and strength of recom-mendations. BMJ 2004;328:1490

25. Zeyneloglu P, Donmez A, Bilezikci B, Mercan S. Effects ofketamine on serum and tracheobronchial aspirate interleukin-6levels in infants undergoing cardiac surgery. J CardiothoracVasc Anesth 2005;19:32933

26. Bartoc C, Frumento RJ, JalboutM,Nett-Guerrero E, DuE,NishanianE. A randomized, double-blind, placebo-controlled study assessingthe anti-inflammatory effects of ketamine in cardiac surgical patients.J Cardiothorac Vasc Anesth 2006;20:21722

27. Cho JE, Shim JK, Choi YS, Kim DH, Hong SW, Kwak YL. Effect oflow-dose ketamine on inflammatory response in off-pump coronaryartery bypass graft surgery. Br J Anaesth 2009;102:238

28. DerSimonian R, Laird N. Meta-analysis in clinical trials. Con-trol Clin Trials 1986;7:17788

29. Higgins JPT, Thompson SG. Quantifying heterogeneity inmeta-analysis. Stat Med 2002;21:153958

30. Egger M, Davey Smith G, Schneider M, Minder C. Bias inmeta-analysis detected by a simple graphical test. BMJ1997;315:62934

31. Bonofiglio FC, Molmenti EP, de Santibanes E. Ketamine doesnot inhibit interleukin-6 synthesis in hepatic resections requir-ing a temporary porto-arterial occlusion (Pringle manoeuvre):a controlled, prospective, randomized, double-blinded study.HPB (Oxford) 2011;13:70611

32. Bhutta AT, Schmitz ML, Swearingen C, James LP, Wardbeg-noche WL, Lindquist DM, Glasier CM, Tuzcu V, Prodhan P,Dyamenahalli U, Imamura M, Jaquiss RD, Anand KJ. Ket-amine as a neuroprotective and anti-inflammatory agent inchildren undergoing surgery on cardiopulmonary bypass: apilot randomized, double-blind, placebo-controlled trial. Pedi-atr Crit Care Med 2012;13:32837

33. Tu KL, Kaye SB, Sidaras G, Taylor W, Shenkin A. Effect ofintraocular surgery and ketamine on aqueous and serumcytokines. Mol Vis 2007;13:11307

34. Welters ID, Feurer MK, Preiss V, Muller M, Scholz S, KwapiszM, Mogk M, Neuhauser C. Continuous S-()-ketamine admin-istration during elective coronary artery bypass graft surgeryattenuates pro-inflammatory cytokine response during andafter cardiopulmonary bypass. Br J Anaesth 2011;106:1729

35. Beilin B, Rusabrov Y, Shapira Y, Roytblat L, Greemberg L,Yardeni IZ, Bessler H. Low-dose ketamine affects immuneresponses in humans during the early postoperative period.Br J Anaesth 2007;99:5227

36. DAlonzo RC, Bennett-Guerrero E, Podgoreanu M, DAmicoTA, Harpole DH, Shaw AD. A randomized, double blind,placebo controlled clinical trial of the preoperative use ofketamine for reducing inflammation and pain after thoracicsurgery. J Anesth 2011;25:6728

37. Mostafa H, Ela AMA, El-Tweel N. S () ketamine suppressesTNF-, IL-6 and IL-8 production in blood in major abdominalsurgery under combined epidural-general anesthesia. J MedSci 2010;8:13742

38. Roytblat L, Roy-Shapira A, Greemberg L, Korotkoruchenko A,Schwartz A, Peizer J, Douvdevani A. Preoperative low doseketamine reduces serum interleukin-6 response after abdomi-nal hysterectomy. Pain Clinic 1996;9:32734

39. Zilberstein G, Levy R, Rachinsky M, Fisher A, Greemberg L,Shapira Y, Appelbaum A, Roytblat L. Ketamine attenuatesneutrophil activation after cardiopulmonary bypass. AnesthAnalg 2002;95:5316

40. Akhlagh AH, Zeighami D, Koshravi MB, Maghsoodi B, Aze-mati S, Alipour A. The effect of low dose of ketamine infusionon stress responses in coronary bypass graft surgery. IranianCardiovasc Res J 2008;4:2832

41. Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A,Appelbaum A, Gurman GM, Shapira Y, Duvdenani A. Ket-amine attenuates the interleukin-6 response after cardiopulmo-nary bypass. Anesth Analg 1998;87:26671

42. Cao DQ, Chen YP, Zou DG. Effects of ketamine on cardiopul-monary bypass induces interleukin-6 and interleukin-8 re-sponse and its significance. Bull Hunan Med Univ 2001;26:3502

43. Huang C, Liu A. Effect of preemptive analgesia by intravenoussmall-dose ketamine on cytokine response to upper abdominalsurgery. Med J Wuhan Univ 2006;27:6824

44. Yang Z, Chen ZQ, Jiang XQ. Effects of subanesthetic dose ofketamine on perioperative serum cytokines in orthoptic livertransplantation. J South Med Univ 2006;26:8024

45. Xin MG, Ye H, Zhang YZ, Be FH. Effects of ketamine andpropofol on levels of perioperative plasma cytokines in gastriccancer patients underwent radical gastrectomy. J Jilin UnivMed Ed 2007;33:10702

46. Xia JG, Peng J, Xiao H, Sun JB. Effect of intravenous patient-controlled intravenous analgesia with a small dose of ketamineduring shock stage on cytokine balance in patients with severeburn. Chin Crit Care Med 2006;18:325

47. Kanda T, Takahashi T. Interleukin-6 and cardiovascular dis-eases. Jpn Heart J 2004;45:18393

48. Cruickshank AM, Fraser WD, Burns HJ, Van DJ, Shenkin A.Response of serum interleukin-6 in patients undergoing elec-tive surgery of varying severity. Clin Sci (London) 1990;79:1615

49. Amar D, Zhang H, Park B, Heerdt PM, Fleisher M, Thaler HT.Inflammation and outcome after general thoracic surgery. EurJ Cardiothorac Surg 2007;32:4314

50. Rallidis LS, Zolindaki MG, Manioudaki HS, Laoutaris NP,Velissaridou AH, Papasteriadis EG. Prognostic value ofC-reactive protein, fibrinogen, interleukin-6, and macrophagecolony stimulating factor in severe unstable angina. ClinCardiol 2002;25:50510

51. Oka Y, Murata A, Nishijima J, Yasuda T, Hiraoka N, OhmachiY, Kitagawa K, Yasuda T, Toda H, Tanaka N. Circulatinginterleukin 6 as a useful marker for predicting postoperativecomplications. Cytokine 1992;4:298304



52. Holmes JH, Connolly NC, Paull DL, Hill ME, Guyton SW,Ziegler SF, Hall RA. Magnitude of the inflammatory responseto cardiopulmonary bypass and its relation to adverse clinicaloutcomes. Inflamm Res 2002;51:57986

53. Hudetz JA, Gandhi SD, Iqbal Z, Patterson KM, Pagel PS.Elevated postoperative inflammatory biomarkers are associ-ated with short- and medium-term cognitive dysfunction aftercoronary artery surgery. J Anesth 2011;25:19

54. Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, AnglemanSB, Wensley F, Higgins JP, Lennon L, Eiriksdottir G, Rumley A,Whincup PH, Lowe GD, Gudnason V. Long-term interleukin-6levels and subsequent risk of coronary heart disease: two newprospective studies and a systematic review. PLoS Med2008;5:e78

55. Sun T, Wang X, Liu Z, Chen X, Zhang J. Plasma concentrationsof pro- and anti-inflammatory cytokines and outcome predic-tion in elderly hip fracture patients. Injury 2011;42:70713

56. Inaba H, Kochi A, Yorozu S. Suppression by methylpred-nisolone of augmented plasma endotoxin-like activity andinterleukin-6 during cardiopulmonary bypass. Br J Anaesth1994;72:34850

57. Kawamura T, Inada K, Okada H, Okada K, Wakusawa R.Methylprednisolone inhibits increase of interleukin 8 and 6during open heart surgery. Can J Anaesth 1995;42:399403

58. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R,Luckenbaugh DA, Charney DS, Manji HK. A randomized trialof an N-methyl-d-aspartate antagonist in treatment-resistantmajor depression. Arch Gen Psychiatry 2006;63:85664

59. Mitchell AC, Fallon MT. A single infusion of intravenousketamine improves pain relief in patients with critical limbischaemia: results of a double blind randomised controlledtrial. Pain 2002;97:27581

60. Hollmann MW, Herroeder S, Kurz KS, Hoenemann CW,Struemper D, Hahnenkamp K, Durieux ME. Time-dependentinhibition of G protein-coupled receptor signaling by localanesthetics. Anesthesiology 2004;100:85260

61. Welters ID, Hafer G, Menzebach A, Muhling J, Neuhauser C,Browning P, Goumon Y. Ketamine inhibits transcriptionfactors activator protein 1 and nuclear factor-kappaB,interleukin-8 production, as well as CD11b and CD16 expres-sion: studies in human leukocytes and leukocytic cell lines.Anesth Analg 2010;110:93441

62. Shaked G, Czeiger D, Dukhno O, Levy I, Artru AA, Shapira Y,Douvdevani A. Ketamine improves survival and suppressesIL-6 and TNFalpha production in a model of gram-negativebacterial sepsis in rats. Resuscitation 2004;62:23742

63. Lankveld DP, Bull S, Van DP, Fink-Gremmels J, HellebrekersLJ. Ketamine inhibits LPS-induced tumour necrosis factor-alpha and interleukin-6 in an equine macrophage cell line. VetRes 2005;36:25762

64. Wu GJ, Chen TL, Ueng YF, Chen RM. Ketamine inhibits tumornecrosis factor-alpha and interleukin-6 gene expressions inlipopolysaccharide-stimulated macrophages through suppres-sion of toll-like receptor 4-mediated c-Jun N-terminal kinasephosphorylation and activator protein-1 activation. ToxicolAppl Pharmacol 2008;228:10513

65. Weigand MA, Schmidt H, Zhao Q, Plaschke K, Martin E,Bardenheuer HJ. Ketamine modulates the stimulated adhesionmolecule expression on human neutrophils in vitro. AnesthAnalg 2000;90:20612

66. Mazar J, Rogachev B, Shaked G, Ziv NY, Czeiger D, Chaimo-vitz C, Zlotnik M, Mukmenev I, Byk G, Douvdevani A.Involvement of adenosine in the antiinflammatory action ofketamine. Anesthesiology 2005;102:117481

67. Li CY, Chou TC, Wong CS, Ho ST, Wu CC, Yen MH, Ding YA.Ketamine inhibits nitric oxide synthase in lipopolysaccharide-treated rat alveolar macrophages. Can J Anaesth 1997;44:98995

68. Ward JL, Adams SD, Delano BA, Clarke C, Radhakrishnan RS,Weisbrodt NW, Mercer DW. Ketamine suppresses LPS-induced bile reflux and gastric bleeding in the rat. J Trauma2010;68:6975

69. Hauser GJ, Ben-Ari J, Colvin MP, Dalton HJ, Hertzog JH, BearbM, Hopkins RA, Walker SM. Interleukin-6 levels in serum andlung lavage fluid of children undergoing open heart surgerycorrelate with postoperative morbidity. Intensive Care Med1998;24:4816


Documents

Does Intraoperative Ketamine Attenuate Inflammatory Reactivity Following Surgery