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EfficacyandSafetyofIntravenousLidocaineforPostoperativeAnalgesiaand
RecoveryAfterSurgery
ASystematicReviewWithTrialSequentialAnalysis
S.WeibelJ.JokinenN.L.PaceA.SchnabelM.W.HollmannK.HahnenkampL.H.J.EberhartD.M.PoeppingA.AfshariP.Kranke
BrJAnaesth.2016116(6):770783.

AbstractandIntroduction
Abstract

Background:Improvementofpostoperativepainandotherperioperativeoutcomesremainasignificantchallengeandamatterofdebateamongperioperativeclinicians.This
systematicreviewaimstoevaluatetheeffectsofperioperativei.v.lidocaineinfusiononpostoperativepainandrecoveryinpatientsundergoingvarioussurgicalprocedures.

Methods:CENTRAL,MEDLINE,EMBASE,andCINAHLdatabasesandClinicalTrials.gov,andcongressproceedingsweresearchedforrandomizedcontrolledtrialsuntilMay2014,
thatcomparedpatientswhodidordidnotreceivecontinuousperioperativei.v.lidocaineinfusion.

Results:Fortyfivetrials(2802participants)wereincluded.Metaanalysissuggestedthatlidocainereducedpostoperativepain(visualanaloguescale,0to10cm)at14h(MD
0.84,95%CI1.10to0.59)andat24h(MD0.34,95%CI0.57to0.11)aftersurgery,butnotat48h(MD0.22,95%CI0.47to0.03).Subgroupanalysisandtrial
sequentialanalysissuggestedpainreductionforpatientsundergoinglaparoscopicabdominalsurgeryoropenabdominalsurgery,butnotforpatientsundergoingothersurgeries.
Therewaslimitedevidenceofpositiveeffectsoflidocaineonpostoperativegastrointestinalrecovery,opioidrequirements,postoperativenauseaandvomiting,andlengthofhospital
stay.Therewerelimiteddataavailableontheeffectofsystemiclidocaineonadverseeffectsorsurgicalcomplications.Qualityofevidencewaslimitedasaresultofinconsistency
(heterogeneity)andindirectness(smallstudies).

Conclusions:Thereislimitedevidencesuggestingthati.v.lidocainemaybeausefuladjuvantduringgeneralanaesthesiabecauseofitsbeneficialimpactonseveraloutcomes
aftersurgery.

Introduction

Commonproblemsimmediatelyaftersurgeryincludepostoperativepain,nauseaandvomiting,ileus,hypercoagulation,andpostoperativecognitivedysfunction. [2]Evidencesuggests
thatpainandileuscausingaprolongedhospitalstayaremajorcostdriversinthepostoperativeperiod. [3]Fasttrackprotocolsaimtopreventorreducethesecomplicationsand
speedupearlyrecovery.Opioidmedicationsthataregiveneitheri.v.(systemicanalgesia)orviaepiduralcatheters(epiduralanalgesia)toreducepostoperativepaincanprovoke
sideeffectsincludingnauseaandconstipation,slowingpostoperativerecovery.Inaddition,recentevidencequestionsthebenefitofepiduralanalgesiaforsomepatientsandtypesof
surgery(e.g.laparoscopicprocedures,lowerabdominalsurgeryorpatientswithoutpreexistinglungdisease),asseriousneurologiccomplicationsafterplacementofanepidural
catheter,seemtooccurmorefrequentlythanoriginallythought. [46]Therefore,alternativetherapeuticinterventionsforoptimalperioperativecarearedesirableandmayaddtothe
existinganalgesicarmamentarium.

Postoperativepaincanbeamixtureofinflammatoryandneuropathicpain,oftenpresentingasanincreasedsensitivitytopain.Thesearetargetsofi.v.lidocaine.Numerousother
clinicalrelevantoutcomesarethoughttobeinfluencedbytheadministrationoflidocaine,includingwoundhealing,analgesia,coagulation,postoperativecognitivedysfunction,and

ileus. [7]Bycharacterizingthebeneficialeffectsofi.v.lidocaineintheperioperativesetting,lidocainemayofferasafeandalternativestrategytoepiduralanalgesiaforimproving
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ileus. [7]Bycharacterizingthebeneficialeffectsofi.v.lidocaineintheperioperativesetting,lidocainemayofferasafeandalternativestrategytoepiduralanalgesiaforimproving
perioperativeoutcome.

Theobjectiveofthisreviewwastosystematicallyevaluatethebenefitsandrisksofsystemicperioperativelidocaineinfusionforanenhancedpostoperativerecovery,intermsof
postoperativepain,gastrointestinalrecovery,postoperativeopioidconsumption,andopioidrelatedsideeffectssuchaspostoperativenauseaandvomiting(PONV).Thisco
publicationaimstodisplayanabridgedsummaryofthemainresearchresultoftheCochraneReviewandintendstodisseminatetheresearchfindingsamongstanaesthetists.In
addition,wehaveexploredthereliabilityoftheestimated(positive)treatmenteffectsbyinformationsizeconsiderationsandadjustedsignificancethresholds(trialsequential
analysis).

Methods
ProtocolandRegistration

ThepresentreviewisbasedonareviewprotocolpreviouslypublishedintheCochraneDatabaseofSystematicReviews. [8]Differencesbetweenprotocolandreviewarelistedinthe
webAppendix(supportinginformation1).

WehavepreparedthecurrentmanuscriptaccordingtotheguidelinespublishedbyTheCochraneCollaboration, [9]thePRISMAstatementforsystematicreviewsandmetaanalysis,
[10]andtheBJAguidelines.

EligibilityCriteria

Weincludedrandomizedcontrolledtrialswhichevaluatetheeffectofi.v.lidocaineinfusiononpostoperativepainandrecovery,inadultpatientsundergoingsurgeryonanybody
part(s)undergeneralanaesthesia.Eligiblecomparatorswereeitherplacebo,ornotreatment,orepiduralanalgesia.Thelidocaineinfusionhadtobestartedintraoperativelybefore
incisionandcontinuedatleastuntiltheendofthesurgicalprocedureorduringthepostoperativeperiod.Studyspecificoutcomeswerenotconsideredascriteriaforinclusionor
exclusionintothecurrentsystematicreview.

InformationSource

WesearchedtheCochraneCentralRegisterofControlledTrials(CENTRAL,Issue52014),MEDLINE(January1966toMay2014),EMBASE(1980toMay2014),CINAHL(1982to
May2014)andreferencelistsofarticles.Wesearchedthetrialregistrydatabaseclinicaltrials.gov,contactedresearchersinthefield,andhandsearchedjournalsandcongress
proceedings.Wedidnotapplyanylanguagerestrictions.

Search

ThesearchstrategywasdevelopedbytheCochraneAnaesthesia,CriticalandEmergencyCareGroup(ACE).ThesearchstrategyusedforMEDLINEispresentedintheweb
Appendix(supportinginformation2).

StudySelection

Threeauthorsscannedthetitlesoftheinitialsearchtoexcludeirrelevanttrials.TwoauthorsindependentlycheckedforeligibilityoftheidentifiedstudiesaccordingtothePICO
(patient,intervention,comparison,andoutcome)framework.

DataCollectionProcess

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Authorsindependentlyextractedthedataoftheincludedstudiesastandems.Ifthereweremissingdatasuchasstandarddeviations,wecontactedtheauthorsoftherelevantstudy.

DataItems

DatawereextractedusingastandardizeddataextractionformbasedonPICOcontaininginclusionandexclusioncriteria,patient'scharacteristics,typeofsurgery,detailson
lidocaineadministrationandtheinvestigatedcomparator,anaesthesiaregimen,followup,concomitantmedication,funding.Dataonthefollowingrelevantclinicaloutcomeswere
extracted:

PrimaryOutcomes

1.Painscore(010cm,0100mmVAS,numericratingscale(NRS),verbalratingscale(VRS))

2.Postoperativeileus(dichotomous).

3.Functionalgastrointestinalrecovery(eithertimetodefecation,timetofirstflatus,ortimetofirstbowelmovement/sounds).

SecondaryOutcomes

1.Lengthofhospitalstay

2.Surgicalcomplication(postoperativeinfections,thromboembolism,woundbreakdown,etc.)

3.Adverseevents(e.g.death,arrhythmias,otherheartratedisorders,signsoflidocainetoxicity)

4.Postoperativenauseaandvomiting(PONV)

5.Intraandpostoperativeopioidrequirements

6.Functionalpostoperativeneuropsychologicalstatusscale

7.Patientsatisfaction

8.Cessationoftheintervention

Inthecurrentversionofthissystematicreviewonlytheresultsofthoseoutcomesthatcouldbeanalysedinaquantitativemetaanalysiswereincluded.Criteriaforperforminga
metaanalysiswereclinicalcombinabilityofdataandatleasttworeportingstudies.Further,inthecurrentmanuscriptemphasiswasputonmeaningfulresultstoguideclinical
decisionmaking.ThefullrangeofanalysedoutcomeswasdescribedinthefullreportoftheCochranereview. [1]

RiskofBiasinIndividualStudies

TwoauthorsindependentlyassessedthemethodologicalqualityoftheindividualstudiesaccordingtothecriteriaoftheCochraneCollaboration. [9]Thestandardriskofbiasdomains
includedrandomsequencegeneration,allocationconcealment,blindingofparticipants,personnelandoutcomeassessors,incompleteoutcomedata,andselectivereporting.We
classifiedeachdomainonthestudylevelasbeingeither:lowriskofbias,highriskofbiasorunclearriskofbias.

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SummaryMeasuresandSynthesisofResults

DatawereanalysedusingReviewManager,version5.3.5(RevMan,TheCochraneCollaboration,Oxford,UnitedKingdom).Wepooledstudiesformetaanalysiswhichcomparedi.v.
perioperativelidocaineeitherwithnotreatment,orplacebo,orwithanactivecomparator,namelyepiduralanalgesia.

FortheoutcomepainwecombinedalldatapresentedoneitherVAS010cm,VAS0100mm,NRS010,andVRS010andtransformedallintoVAS010cmandpresented
theeffectestimatesasmeandifferences(MD).

Fortheoutcomesintraandpostoperativeopioidrequirementsalldifferentopioidquantitiesweretransformedintoi.v.MorphineEquivalents(MEQinmg)asdescribedindetail
elsewhere(http://www.whocc.no/atc_ddd_index).

Dichotomousdatawereextractedasreportedintheoriginaltrialsandtherelativerisk(RR)with95%confidenceintervals(CI)werecalculatedatthestudylevel,fromthe
interventionandcontroleventratesandcombinedusingtheinversevarianceapproachasstatisticalmethod.Continuousdatawereextractedasmeanswithstandarddeviations(sd)
orstandarderrors(SE)andmedianwithinterquartilerange(IQR).Themedianwithinterquartilerange(IQR)wastransformedintomeanwithsdandSEwastransformedintosd
accordingtotherecommendationspublishedbyHiggins. [9]MDswerecalculatedatthestudylevelandpooledintoweighted(accordingtotheinverseofthereportedvariance)MDs
with95%CI.RRswiththerangeofthelowerandupperboundsofthe95%CInotcrossingoneandMDswiththerangeofthelowerandupperboundsofthe95%CInotcrossing
zerowereconsideredasstatisticallysignificanteffectsizes.

Weusedtherandomeffectsmodeltoanalysethedataaccordingtotheassumptionthatclinicalheterogeneityexistedbetweentheanalysedpatientpopulations,interventionsand
clinicalsettings. [11]

Weassessedclinicalandmethodologicalheterogeneityofincludedstudiestodecidewhetherthestudiesweresufficientlyhomogenoustobecombined.Furthermore,wereported
statisticalheterogeneityusingtheI 2statistics.HeterogeneitywasclassifiedaccordingtotheinterpretationdescribedwithintheCochraneHandbookofSystematicReviewsof
Interventions. [9]

AdditionalAnalysesAssessmentoftheEvidence

Weperformedsubgroupanalysistoconsiderthemagnitudeofclinicalheterogeneity.DatawereanalysedusingtherandomeffectsmodelheterogeneityI 2statistictocompare
differentsubgroupsofsurgicalprocedures(openabdominal,laparoscopicabdominal,andothersurgery).

Toassesstherobustnessoftheresultsweperformedasensitivityanalysisinvestigatingtheimpactofhighriskofbiasstudies.

Weassessedtheriskofbiasacrossstudies(publicationbias)fortheoutcomespain'early',postoperativeopioidconsumption,andPONV'late'.Wecreatedfunnelplotswhichserved
asavisualtoolfordetectingriskofbiasacrossstudies,whichmayindicatereportingbiasandsmallstudyeffects.Inaddition,therelationoftreatmenteffectandstudysizewas
furtheranalysedbylinearregressionanalysis,bymethodsofmomentsusinganarcsinetransformationforRRandweightedregressionforMD.

Inaposthocanalysis,weappliedtrialsequentialanalysis[12]ascumulativemetaanalysesareatriskofproducingtypeIerrors,asaresultofsparsedataandrepetitivetestingof
accumulatingdata. [1316]Therequiredinformationsize(ISthenumberofparticipantsneededinametaanalysistodetectorrejectacertaininterventioneffect)andthesequential
monitoringboundaries(testingforstatisticalsignificancebeforetheIShasbeenreached)provideduswithrelevantinformationtoestimatethelevelofevidencefortheexperimental
intervention.TherequiredISwasderivedusingtheformulaIS=2(Z 1/2+Z 1)22 2/ 2whereZ 1/2andZ 1arethe(1/2)and(1)standardnormaldistribution
quantiles.Forbinarydata,=P CP Edenotedanestimateforarealisticimportantinterventioneffect(P CandP Ebeingtheproportionwithanoutcomeinthecontrolgroupandinthe

interventiongroup,respectively)and 2istheassociatedvariance.Forcontinuousdata,denotedanestimateoftherealisticdifferencebetweenmeansinthetwointervention
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interventiongroup,respectively)and 2istheassociatedvariance.Forcontinuousdata,denotedanestimateoftherealisticdifferencebetweenmeansinthetwointervention
groupsand 2denotedtheassociatedvariance.ThetrialsequentialmonitoringboundariesalsoknownasO'BrienFlemingmonitoringboundarieswerebasedontheLanDeMets
spendingfunction.

OnthebasisofariskforatypeIerrorof5%andatypeIIerrorof10%(90%power)andthefollowingassumptionsfortheoutcomespain(assumedMDonthebasisofaclinical
relevantestimate:MD=1.0(VAS010cm),sd=2),opioidconsumption(assumedMDonthebasisofthelowriskofbiasstudiesbyBrysonandcolleagues, [17]DeOliveiraand
colleagues,: [18,19]MD=8.97mg(MEQ),sd=25.12),andPONV(clinicallyrelevantestimateofRRR20%andanincidenceof30%inthecontrolarm),weestimatedtherequiredIS
andconstructedthetrialsequentialmonitoringboundaries,usingtheTSAsoftwarev0.9Beta(CopenhagenTrialUnit).Highriskofbiastrials(definedas:highriskatleastinonerisk
ofbiasdomainorunclearriskofbiasinalldomains)wereexcludedfromtheanalysis.AllinformationsizeswereheterogeneityadjustedbyusingtheestimateofdiversityD2
(assumedD2=25%)andmultiplyingtherequiredISby1(1D2)1. [12]Thismaycorrespondtotheheterogeneityadjustmentinamulticentretrial.WeperformedTSAforboththe
pooledmetaanalysisandtheindividualsubgroups(openabdominal,laparoscopicabdominal,andothersurgeries).TSAresultsweregraphicallypresented.ThecumulativeZcurves
(green)wereconstructed,witheachcumulativeZvaluecalculatedaftertheadditionofanewtrialaccordingtopublicationdate.Zvaluesontheupperhalfoftheyaxisindicate
benefitoftheintervention,whereasZvaluesonthelowerhalfindicateharm.CrossingofthetwosidedZ=+1.96andZ=1.96(pinklines)providesatraditionallysignificantresult
(p=0.05).Forthepositivehalfoftheyaxistheredinwardslopinglinesrepresentedthetrialsequentialmonitoringboundariesandtheredupwardslopinglinesdisplayedthefutility
boundaries.Themonitoringboundariesquantifytheriskofrandomerroratanymetaanalyticalstageandareconservativeboundariesatearlystageswhenlargefluctuationsin
metaanalysesoccur,asaresultofrandomerrorandheterogeneity.Crossingofmonitoringboundariesisneededtoobtainreliableevidence.

ToassessthevalidityofTSAresultsbasedonclinicallyrelevantestimatesweperformedasensitivityanalysisandconductedTSAwiththeempiricalpooledestimatesandthe
modelvariancebasedheterogeneitycorrection.

Results
StudySelection

Weidentified4162recordsthroughdatabasesearching(15thofMay2014)and798recordsbysearchingclinicaltrials.govandreferencelistsoftheincludedstudiesandrelated
reviewarticles(Fig.1).Afterremovalofduplicatesweretrieved2883recordsandselected65fulltextarticlesforassessmentofeligibility.Eighteenarticleswereexcludedandthe
remaining45studies(andtwocopublications)wereincludedinthequalitativesynthesisofthisreview,whereby42studiescontributetothequantitativeanalysisofthecurrent
review.

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Figure1.


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Flowchartofsearchstrategy.(RCT)randomizedcontrolledtrials.

Ofthe45includedstudies,onetrialwaspublishedinPersian, [20]allotherswerepublishedinEnglish.Foronestudyweonlyobtainedtheabstract. [21]

StudyCharacteristics

Atotalof45RCTspublishedbetween1985and2014containingdataon2802participantswereincluded.Ofallpatients,1395receivedi.v.lidocaineand1407participantsservedas
acontrol.In41trialspatientsinthecomparatorarmreceivedplacebotreatmentwithsaline,intwotrialspatientsremaineduntreated. [22,23]Theremainingtwotrialsusedthoracic
epiduralanalgesiawithbupivacaineandhydromorphone[24]ormorphine[25]asacomparator.ThecharacteristicsofthetrialsweredescribedinthewebAppendix(supporting
information3)andmoredetailedintheextendedversionofthissystematicreviewintheCochraneDatabaseofSystematicReviews. [1]

Studieswereconductedinpatientsundergoingeitheropenabdominalsurgery, [17,24,2635]orlaparoscopicabdominalsurgery, [18,19,23,25,3644]orvariousothersurgicalprocedures


includingamongstotherscardiac,thoracic,extremityandminorsurgicalprocedures. [2022,4561]

Theperioperativeadministrationofi.v.lidocainestronglyvariedbetweenthestudiesconcerningthedoseofthelidocainebolus(100mgor13mgkg1)andtheinfusion(15mgkg
1h1or2to4mgmin1)andthedurationoftheinfusion(webAppendix,supportinginformation3).

Quantitativemetaanalysiswasperformedformostoftheoutcomesofinterestinthepresentreview.Asaresultofthelackofeitherclinicalcombinabilityoraninsufficientnumber
ofstudiestheprespecifiedsecondaryoutcomes'functionalpostoperativeneuropsychologicalstatusscale','patientsatisfaction',and'cessationoftheintervention'couldnotbepooled
andmetaanalysed.

RiskofBiasWithinStudies

Theoverallriskofbiasconcerningselectionbias(randomsequencegeneration),performancebias(blindingofparticipantsandpersonnel),detectionbias(blindingofoutcome
assessment),andattritionbias(incompleteoutcomedata)revealedlowriskofbiasinmorethan50%oftheincludedstudies(Fig.2).Forallocationconcealmentandselective
reportingthequalityassessmentyieldedlowriskofbiasforonly~20%oftheincludedstudies.

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Figure2.


Riskofbiasgraph.Reviewauthors'judgmentsabouteachriskofbiasitempresentedaspercentageacrossallincludedstudies.

TheresultsofthequalityassessmentsonthestudylevelaccordingtotheCochraneRiskofBiasassessmenttoolaregraphicallypresentedonthestudylevelinthewebAppendix
(supportinginformation4).

SynthesisofResults

Lidocainei.v.vsPlacebo.PrimaryOutcomes:PostoperativePain(atRest):Metaanalysisofpaindatarevealedasignificantlyloweredpainscore(VAS0to10cm)inthe
lidocainegroupcomparedwiththecontrolgroupat14h(MD0.84,95%CI1.10to0.59I 2=86%23RCTsn=1286)[17,23,27,29,30,32,3537,3946,48,50,51,55,58,61]andat24h
(MD0.34,95%CI0.57to0.11I 2=91%25RCTsn=1393)[17,22,23,27,2932,3537,3945,48,50,51,53,55,58,61]aftersurgery().However,at48hsubjectsintheinterventiongroup
didnolongerbenefitfromlidocaineadministrationwhencomparedwithsubjectsinthecontrolgroup(MD0.22,95%CI0.47to0.03I 2=92%19RCTsn=1077)[17,22,2932,35
37,4042,44,45,48,50,51,53,61]().

Table1.Primaryoutcomescomparison:lidocainevscontrol(placebo/untreated).EffectsizeswerereportedasMDorRRwith95%CI.Effectsizes<0forcontinuousdata(MD)and
<1fordichotomousdata(RR)indicate'favourof'lidocainetreatment.Paindatawerepresentedat'early'(14h),'intermediate'(24h),and'late'(48h)timepointspostoperatively.
StatisticalheterogeneitybetweentrialswasreportedusingI2.IV(inversevariance)

Outcome No.ofstudies(participants) Lidocaine(n) Placebo(n) Statisticalmethod Effectsize Heterogeneity(I 2)


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Pain'early',(VAS010) 23(1286) 645 641 MD(IV,Random,95%CI) 0.84[1.10,0.59] 86%

Pain'intermediate',(VAS010) 25(1393) 696 697 MD(IV,Random,95%CI) 0.34[0.57,0.11] 91%

Pain'late',(VAS010) 19(1077) 538 539 MD(IV,Random,95%CI) 0.22[0.47,0.03] 92%

Postoperativeileus(dichotomous) 3(205) 104 101 RR(IV,Random,95%CI) 0.38[0.15,0.99] 0%

Timetofirstdefecation(h) 4(214) 108 106 MD(IV,Random,95%CI) 9.52[23.24,4.19] 85%

Timetofirstflatus(h) 11(566) 283 283 MD(IV,Random,95%CI) 5.49[7.97,3.00] 88%

Timetobowelmovement/sound(h) 6(288) 145 143 MD(IV,Random,95%CI) 6.12[7.36,4.89] 0%


Table1.Primaryoutcomescomparison:lidocainevscontrol(placebo/untreated).EffectsizeswerereportedasMDorRRwith95%CI.Effectsizes<0forcontinuousdata(MD)and
<1fordichotomousdata(RR)indicate'favourof'lidocainetreatment.Paindatawerepresentedat'early'(14h),'intermediate'(24h),and'late'(48h)timepointspostoperatively.
StatisticalheterogeneitybetweentrialswasreportedusingI2.IV(inversevariance)

Outcome No.ofstudies(participants) Lidocaine(n) Placebo(n) Statisticalmethod Effectsize Heterogeneity(I 2)

Pain'early',(VAS010) 23(1286) 645 641 MD(IV,Random,95%CI) 0.84[1.10,0.59] 86%

Pain'intermediate',(VAS010) 25(1393) 696 697 MD(IV,Random,95%CI) 0.34[0.57,0.11] 91%

Pain'late',(VAS010) 19(1077) 538 539 MD(IV,Random,95%CI) 0.22[0.47,0.03] 92%

Postoperativeileus(dichotomous) 3(205) 104 101 RR(IV,Random,95%CI) 0.38[0.15,0.99] 0%

Timetofirstdefecation(h) 4(214) 108 106 MD(IV,Random,95%CI) 9.52[23.24,4.19] 85%

Timetofirstflatus(h) 11(566) 283 283 MD(IV,Random,95%CI) 5.49[7.97,3.00] 88%

Timetobowelmovement/sound(h) 6(288) 145 143 MD(IV,Random,95%CI) 6.12[7.36,4.89] 0%

GastrointestinalRecovery:Postoperativeileusoccurredin4.8%(5:104)ofparticipantsinthelidocainegroupandin13.9%(14:101)ofparticipantsinthecontrolgroup(RR0.38,
95%CI0.15to0.99I 2=0%3RCTsn=205)[30,43,45]().

Table1.Primaryoutcomescomparison:lidocainevscontrol(placebo/untreated).EffectsizeswerereportedasMDorRRwith95%CI.Effectsizes<0forcontinuousdata(MD)and
<1fordichotomousdata(RR)indicate'favourof'lidocainetreatment.Paindatawerepresentedat'early'(14h),'intermediate'(24h),and'late'(48h)timepointspostoperatively.
StatisticalheterogeneitybetweentrialswasreportedusingI2.IV(inversevariance)

Outcome No.ofstudies(participants) Lidocaine(n) Placebo(n) Statisticalmethod Effectsize Heterogeneity(I 2)

Pain'early',(VAS010) 23(1286) 645 641 MD(IV,Random,95%CI) 0.84[1.10,0.59] 86%

Pain'intermediate',(VAS010) 25(1393) 696 697 MD(IV,Random,95%CI) 0.34[0.57,0.11] 91%

Pain'late',(VAS010) 19(1077) 538 539 MD(IV,Random,95%CI) 0.22[0.47,0.03] 92%

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Postoperativeileus(dichotomous) 3(205) 104 101 RR(IV,Random,95%CI) 0.38[0.15,0.99] 0%

Timetofirstdefecation(h) 4(214) 108 106 MD(IV,Random,95%CI) 9.52[23.24,4.19] 85%

Timetofirstflatus(h) 11(566) 283 283 MD(IV,Random,95%CI) 5.49[7.97,3.00] 88%

Timetobowelmovement/sound(h) 6(288) 145 143 MD(IV,Random,95%CI) 6.12[7.36,4.89] 0%

Theadministrationoflidocainei.v.didnotsignificantlyreducethetime(h)tofirstdefecationincomparisonwiththecontrolgroup(MD9.52,95%CI23.24to4.19I 2=85%4
RCTsn=214)[22,30,33,41]().

Table1.Primaryoutcomescomparison:lidocainevscontrol(placebo/untreated).EffectsizeswerereportedasMDorRRwith95%CI.Effectsizes<0forcontinuousdata(MD)and
<1fordichotomousdata(RR)indicate'favourof'lidocainetreatment.Paindatawerepresentedat'early'(14h),'intermediate'(24h),and'late'(48h)timepointspostoperatively.
StatisticalheterogeneitybetweentrialswasreportedusingI2.IV(inversevariance)

Outcome No.ofstudies(participants) Lidocaine(n) Placebo(n) Statisticalmethod Effectsize Heterogeneity(I 2)

Pain'early',(VAS010) 23(1286) 645 641 MD(IV,Random,95%CI) 0.84[1.10,0.59] 86%

Pain'intermediate',(VAS010) 25(1393) 696 697 MD(IV,Random,95%CI) 0.34[0.57,0.11] 91%

Pain'late',(VAS010) 19(1077) 538 539 MD(IV,Random,95%CI) 0.22[0.47,0.03] 92%

Postoperativeileus(dichotomous) 3(205) 104 101 RR(IV,Random,95%CI) 0.38[0.15,0.99] 0%

Timetofirstdefecation(h) 4(214) 108 106 MD(IV,Random,95%CI) 9.52[23.24,4.19] 85%

Timetofirstflatus(h) 11(566) 283 283 MD(IV,Random,95%CI) 5.49[7.97,3.00] 88%

Timetobowelmovement/sound(h) 6(288) 145 143 MD(IV,Random,95%CI) 6.12[7.36,4.89] 0%

Systemiclidocainesignificantlyshortenedthetime(h)tofirstflatus(MD5.49,95%CI7.97to3.00I 2=88%,11RCTsn=566)[22,30,32,33,36,3841,49,51]andthetime(h)tofirst
bowelmovement [31,38,43,49]orsounds[30,44](MD6.12,95%CI7.36to4.89I 2=0%6RCTsn=288)insubjectswhencomparedwithcontrolsubjects().

Table1.Primaryoutcomescomparison:lidocainevscontrol(placebo/untreated).EffectsizeswerereportedasMDorRRwith95%CI.Effectsizes<0forcontinuousdata(MD)and
<1fordichotomousdata(RR)indicate'favourof'lidocainetreatment.Paindatawerepresentedat'early'(14h),'intermediate'(24h),and'late'(48h)timepointspostoperatively.
StatisticalheterogeneitybetweentrialswasreportedusingI2.IV(inversevariance)

Outcome No.ofstudies(participants) Lidocaine(n) Placebo(n) Statisticalmethod Effectsize Heterogeneity(I 2)

Pain'early',(VAS010) 23(1286) 645 641 MD(IV,Random,95%CI) 0.84[1.10,0.59] 86%

Pain'intermediate',(VAS010) 25(1393) 696 697 MD(IV,Random,95%CI) 0.34[0.57,0.11] 91%

Pain'late',(VAS010) 19(1077) 538 539 MD(IV,Random,95%CI) 0.22[0.47,0.03] 92%

Postoperativeileus(dichotomous) 3(205) 104 101 RR(IV,Random,95%CI) 0.38[0.15,0.99] 0%

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Timetofirstdefecation(h) 4(214) 108 106 MD(IV,Random,95%CI) 9.52[23.24,4.19] 85%

Timetofirstflatus(h) 11(566) 283 283 MD(IV,Random,95%CI) 5.49[7.97,3.00] 88%

Timetobowelmovement/sound(h) 6(288) 145 143 MD(IV,Random,95%CI) 6.12[7.36,4.89] 0%

SecondaryOutcomes:LengthofHospitalStay:I.V.lidocaineadministrationledtoasignificantreductionofthelengthofhospitalstayofabout8h(MD0.31,95%CI0.56to
0.07I 2=75%21RCTsn=1424)[19,22,3032,3638,4145,4951,53,54,56,57,59](webAppendix,supportinginformation5).

SurgicalComplicationsPostoperativeInfections:Postoperativeinfectionsoccurredin2.16%(3:139)ofparticipantsinthelidocainegroupandin1.44%(2:139)ofparticipantsin
theplacebotreatedgroup(RR1.19,95%CI0.25to5.67I 2=0%4RCTsn=278)[38,41,43,45](webAppendix,supportinginformation5).

Othersurgicalcomplicationsreportedbytheincludedstudieswereurinaryretention, [43,45]bleeding, [38,45]anastomoticleak, [30,43]thromboembolicdisease, [45,49]woundhealing


disturbances, [30]andneedforpyelonephrostomyafterrenalsurgery. [41]Noneofthestudiesanalysingthosecomplicationsreportedsignificantdifferencesbetweenthelidocaineand
controlgroups.

AdverseEvents:Seventeentrialsreportedthatnosignificantdifferenceintheoccurrenceofadverseeventswasobservedbetweentheinvestigatedgroupsduringthestudy.
[18,19,27,28,31,37,4149,53,58]Fourtrialsincludingpatientsundergoingcardiacsurgeriesreportedthatpatientsdiedduringthestudyperiod. [50,56,57,59]However,noneoftheseevents

couldbeplausiblylinkedtolidocaineadministration.Onestudyreportedbradycardiainthreepatientsofthelidocainegroup[32]andanothermentionedarrhythmiainonepatientfrom
eachgroup. [40]Leeandcolleagues[60]reportedonatrialfibrillationandotherarrhythmiainbothgroupsaftercardiacsurgery,however,withoutsignificantdifferences.Threetrials
reportedneuropsychologicaldisturbancesinpatientsofthelidocainegroup(e.g.lightheadedness)(threepatients), [26]dizzinessandvisualdisturbances(one), [55]anddrowsiness
(two). [34]Theremainingtrialsdidnotcommentonadverseeventsorlidocainerelatedsideeffects.

PostoperativeNauseaandVomiting:AtPACUPON/PONVoccurredin20.1%(45:218)ofparticipantsinthelidocainegroupandin28.4%(63:222)ofparticipantsinthecontrol
group(RR0.72,95%CI0.53to0.99I 2=0%7RCTsn=440)[19,20,23,29,45,46,48](supportinginformation5).PON/PONVwithin72hpostoperativelyoccurredin26.6%(154:545)of
lidocainesubjectsandin35.6%(192:539)ofcontrolsubjects(RR0.82,95%CI0.70to0.97I 2=0%21RCTsn=1084)[22,23,26,27,29,3133,3645,51,55,61](webAppendix,
supportinginformation5).

PostoperativevomitingatPACUappearedin2.6%(4:150)ofparticipantsintheinterventiongroupandin5.8%(9:155)ofparticipantsintheplacebotreatedgroup(RR0.49,95%
CI0.16to1.48I 2=0%4RCTsn=305)[19,20,29,45](webAppendixsupportinginformation5).At'late'timepointsaftersurgeryvomitingoccurredin17.4%(64:367)ofparticipantsin
thelidocainegroupandin20.1%(73:364)ofparticipantsinthecontrolgroup(RR0.92,95%CI0.68to1.24I 2=0%13RCTsn=731)[22,27,29,31,33,39,4145,51,55](webAppendix,
supportinginformation5).

OpioidRequirements:Pooledmetaanalysisrevealedsignificantlyreducedopioidrequirements(MEQ,mg)duringanaesthesiainthelidocainegroupincomparisontothecontrol
group(MD3.30,95%CI6.59to0.02I 2=86%12RCTsn=667)[17,23,3336,39,41,48,55,59,61](webAppendix,supportinginformation5).

Altogether,32trialsreportedpostoperativeopioidconsumption. [1720,22,23,27,2942,44,45,4751,53,55,58,61]Combinedanalysisonopioidconsumptionshowedsignificantlyreduced
opioidconsumptioninthelidocainegroupcomparedwithcontrol,duringstayinPACU(MD4.17mg,95%CI6.40to1.94I 2=94%18RCTsn=1001)andduringthewhole
postoperativeperiod(MD5.36mg,95%CI7.12to3.59I 2=77%29RCTsn=1553)(webAppendix,supportinginformation5).

Lidocainei.v.vsThoracicEpiduralAnalgesia(TEA).Thesecondcomparisonanalysedlidocainei.v.vsTEA.Forthiscomparison,wewereabletoidentifytwostudies. [24,25]
Becauseofthelownumberofidentifiedstudiesanalysingtheeffectofi.v.lidocainecomparedwithTEAthesummarizedeffectsforeachoutcomeinthiscomparisonwereonlyof

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verylowevidence(webAppendix,supportinginformation6).Insummary,wewerenotabletoidentifyanyevidenceofeffectintermsofallanalysedoutcomes(postoperativepain,
functionalgastrointestinalrecovery,lengthofhospitalstay,andintraoperativeopioidrequirements).

AdditionalAnalysesAssessmentoftheEvidence.Furtheranalyseswereconductedtoinvestigate(1)whichpatient'spopulationmaybenefitfromperioperativelidocainei.v.
administration(subgroupanalysis),(2)therobustnessoftheresultsintermsofriskofbiasfromindividualstudies(sensitivityanalysis),(3)theoccurrenceofriskofbiasacross
studies(publicationbias),and(4)therequiredinformationsizeandlevelofevidencereached(TSA).Bythismeansweinvestigatedtheoutcomespain'early',postoperativeopioid
requirements,andPONV'late'toexaminevalidityforthoseoutcomes.

(1)Subgroupanalysis.Subgroupanalysiswasconductedtoexploretheeffectsoflidocainei.v.indifferentsurgicalpopulations(openabdominal,laparoscopicabdominal,
othersurgicalprocedures)andtoanalysetheinfluenceofdifferentsurgicalproceduresonstatisticalheterogeneitybetweenstudies.Fortheoutcomespostoperativepain'early'
(14h)(,Fig.3a),postoperativeopioidrequirements(,Fig.4a),andPONV'late'(,Fig.5a)lidocaineadministrationwasmostbeneficialforpatientsundergoinglaparoscopic
abdominalprocedures.Forpatientsundergoingopenabdominalsurgerylidocaineadministrationwasadvantageousintermsofpain'early'andpostoperativeopioid
requirements.Themixedpopulationothersurgerydidnotbenefitfromperioperativelidocainei.v.infusionintermsofpostoperativepain,opioidconsumption,andPONV.
Thehighstatisticalheterogeneity(I 2)observedfortheoutcomespain'early'(I 2=87%)andpostoperativeopioidrequirements(I 2=77%)wasonlydecreasedforthesubgroup
openabdominalsurgeryto0%and13%,respectively.Heterogeneityforallothersubgroupsremainedsubstantialtoconsiderable.
(2)Sensitivityanalysis.Weexcludedalltrialswhichwereidentifiedashighriskofbias(=judgedashighriskatleastinoneriskofbiasdomainorasunclearriskofbiasinall
domains)andperformedasensitivitymetaanalysistotestrobustnessoftheresults.Thepooledestimatesofthesensitivityanalysisweresimilartotheoriginalmetaanalysis
withrespecttoeffectsizesandCIsfortheoutcomespain'early'(18studies:0.91[1.18,0.63]),postoperativeopioidrequirements(23studies:4.85mg[6.72,2.98]),
andPONV'late'(17studies:0.76[0.62,0.93]).
(3)Riskofbiasacrossstudies:Riskofbiasacrossstudieswasdeterminedusingfunnelplotsandcorrespondinglinearregressiontestsoffunnelplotasymmetry.Forpain
'early',thefunnelplotshowedsymmetryaroundtheYaxiswithbalanceddistributionalongtheYaxis,indicatingnoevidenceofreportingbias(Fig.3b).Noobviousfunnel
asymmetrywasdetectableforopioidconsumption(Fig.4b).FortheoutcomePONV'late'thefunnelplotrevealedasymmetrytotheleftoftheYaxis('significant'studies)with
nostudiesappearingontheright('nonsignificant'studies)(Fig.5b).Further,weanalysedthethreeoutcomesforfunnelplotasymmetryusingalinearregressiontest
(supportinginformation7).ForPONV'late'(t=2.1977,degreesoffreedom(df)=19,P=0.041)wefoundevidenceoffunnelplotasymmetry.
(4)Trialsequentialanalysis(TSA):Tominimizerandomerrorsanddecideonconclusivenessofthepositiveresultsofourmetaanalysis,wecalculatedtherequiredISand
thecorrespondingmonitoringboundariesforthesurgicalsubgroupsandthepooledmetaanalysis.
Trialsequentialanalysisforpain'early'(assumptions:=5%,=10%,MD=1.0,sd=2.0,Heterogeneitycorrection:D 2=25%)revealedarequiredinformationsizeof449
participants.Therefore,TSAofthepooledmetaanalysis(999patientsoflowriskofbiasstudies)showedfirmevidencefortheanticipatedinterventioneffect(Fig.3f).Further,
TSArevealedfirmevidencefortheanticipatedinterventioneffectforthesubgroupsopenabdominalsurgery(Fig.3c)andlaparoscopicabdominalsurgery(Fig.3d).TSAalso
pointedoutthatthelackofsignificanceinthesubgroupothersurgerywasbecauseoftheunderlyingequivalencybetweeninterventionandcontrol(Fig.3e).
Trialsequentialanalysisfor'postoperativeopioidconsumption'(assumptions:=5%,=10%,MD=8.97,sd=25.12,Heterogeneitycorrection:D 2=25%)revealedarequired
informationsizeof880participants.TSAofthepooledmetaanalysis(1208patientsoflowriskofbiasstudies)demonstratedfirmevidencefortheanticipatedintervention
effect(Fig.4f).TSArevealedfirmevidencefortheanticipatedinterventioneffectforthesubgrouplaparoscopicabdominalsurgery(Fig.4d)andabsenceofevidenceforthe
subgroupsopenabdominalsurgery(Fig.4c)andothersurgery(Fig.4e).
Trialsequentialanalysisfor'PONVlate'(assumptions:=5%,=10%,MD=1.0,sd=2.0,Heterogeneitycorrection:D 2=25%)pointeduparequiredinformationsizeof3069
participants.Theanalysisrevealedabsenceofevidencefortheanticipatedinterventioneffectforallsubgroupsandthepooledmetaanalysis(886patientsoflowriskofbias
studies)(Fig.5cf).
TSAusingtheempiricalestimatesandtheappropriatebetweentrialheterogeneitiesofthemetaanalyses(webAppendix,supportinginformation8)largelyconfirmedthe
TSAresultsobtainedbyusingtheclinicallyrelevantestimatessupportingreliabilityoftheanalyses.

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Figure3.


Comparison:lidocainevscontrol(placebo/untreated),outcome:pain'early'(04h,PACU),VAS010cm,atrest.(a)Forestplotwithsubgroupanalysis'openabdominalsurgery',
'laparoscopicabdominalsurgery',and'othersurgery'.Trialsappraisedashighriskofbiasforatleastonedomainorasunclearriskofbiasforalldomainswereexcludedfromthe
analysis.(b)Funnelplotofalltrials.(cf)Trialsequentialanalysis(TSA)wasusedtodemonstrateorrejectananticipatedmeandifference(MD)of1.0(VAS010)andastandard
deviation(sd)of2.0(clinicalrelevantestimate),analphaof5%,andabetaof10%.Theheterogeneityadjusted(H:D 2=25%)requiredinformationsize(IS)is449patients(vertical
blueline).DetailstothegraphicalpresentationofTSAareexplainedwithintheMethods.TSArevealedfirmevidencefortheanticipatedinterventioneffectforthesubgroups'open
abdominalsurgery'(c:NumberofparticipantsdoesnotreachtheIS,buttheZcurve(green)doescrossthemonitoringboundary(blue))and'laparoscopicabdominalsurgery'(d:
NumberofparticipantsdoesreachtheISandtheZcurvedoescrossthemonitoringboundary).TSArevealedfirmevidencethatthelackofsignificanceforthesubgroup'other
surgery'isbecauseoftheunderlyingequivalencybetweeninterventionandcontrol(e:NumberofparticipantsdoesnotreachtheIS,buttheZcurvedoescrossthefutilityboundary
(blue)).TSAofthepooledmetaanalysis(f)revealedfirmevidencefortheanticipatedinterventioneffect.

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Figure4.


Comparison:lidocainevscontrol(placebo/untreated),outcome:postoperativeopioidconsumption(MEQ,mg).(a)Forestplotwithsubgroupanalysis'openabdominalsurgery',
'laparoscopicabdominalsurgery',and'othersurgery'.Trialsappraisedashighriskofbiasforatleastonedomainorasunclearriskofbiasforalldomainswereexcludedfromthe
analysis.(b)Funnelplotofalltrials.(cf)Trialsequentialanalysis(TSA)wasusedtodemonstrateorrejectananticipatedmeandifference(MD)of8.97mgandastandard
deviation(sd)of25.12('lowbiasbased',Bryson2010,DeOliveira2012+2014),analphaof5%,andabetaof10%.Theheterogeneityadjusted(H:D 2=25%)requiredinformation
size(IS)is880patients(verticalblueline).DetailstothegraphicalpresentationofTSAareexplainedwithintheMethods.TSArevealedfirmevidencefortheanticipated
interventioneffectforthesubgroup'laparoscopicabdominalsurgery'(d:NumberofparticipantsdoesnotreachtheIS,buttheZcurve(green)doescrossthemonitoringboundary
(blue)).TSArevealedabsenceofevidenceforthesubgroups'openabdominalsurgery'and'othersurgery'(c,e:NumberofparticipantsdoesnotreachtheISandtheZcurvedoes
notcrossneitherthemonitoringboundarynorthefutilityboundary(blue)).TSAofthepooledmetaanalysis(f)revealedfirmevidencefortheanticipatedinterventioneffect.

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Figure5.


Comparison:lidocainevscontrol(placebo/untreated),outcome:PONV'late'(024h,48h,72h).(a)Forestplotwithsubgroupanalysis'openabdominalsurgery','laparoscopic
abdominalsurgery',and'othersurgery'.Trialsappraisedashighriskofbiasforatleastonedomainorasunclearriskofbiasforalldomainswereexcludedfromtheanalysis.(b)
Funnelplotofalltrials.(cf)Trialsequentialanalysis(TSA)wasusedtodemonstrateorrejectananticipatedrelativeriskreduction(RRR)of20%andanincidenceinthecontrolarm
of30%(clinicalrelevantestimate),analphaof5%,andabetaof10%.Theheterogeneityadjusted(H:D 2=25%)requiredinformationsize(IS)is3069patients(verticalblueline).
DetailstothegraphicalpresentationofTSAareexplainedwithintheMethods.TSArevealedabsenceofevidencefortheanticipatedinterventioneffectforallsubgroupsandthe
pooledmetaanalysis(cf:NumberofparticipantsdoesnotreachtheISandtheZcurve(green)doesnotcrossthemonitoringboundary(blue)).

Discussion
SummaryofEvidence

Thisreviewdemonstratesthatpatientsundergoinganyelectivesurgeryundergeneralanaesthesiawhohavereceivedperioperativei.v.lidocainehaveslightlylowerpainscoresat1
4h(MD0.84,95%CI1.10to0.59)andat24h(MD0.34,95%CI0.57to0.11)aftersurgerycomparedwiththosereceivingacontroltreatment,despitehavingreceivedthe
samepostoperativeaccesstoopioidanalgesia.At48haftersurgerytherewasnobenefitwithrespecttopainreliefassociatedwiththisintervention.Subgroupanalysissuggested
thatbestbenefitintermsofthelevelofpainreductionandthedurationofpainreliefisforpatientsundergoinglaparoscopicabdominalsurgery(MD1.14,95%CI1.510.78)
followedbyopenabdominalsurgery(MD0.72,95%CI0.96to0.47).Furthermoreweshowedthatopioidrequirements(MD5.36mg,95%CI7.12to3.59)andopioidrelated
sideeffects(PON/PONV:RR0.82,95%CI0.70to0.97)duringthepostoperativephase,wereloweramongpatientswhoreceivedi.v.lidocaine.

Strengthofevidencefortheoutcomespainandpostoperativeopioidrequirementswaslimitedbyinconsistency.Atthesametime,conclusivenesswasstrengthenedbyanalysisof
methodologicalstudyqualityandlackofriskofbiasacrossstudiesforthoseoutcomes.Especiallytrialsequentialanalysisresultsrevealedthatwecanbeconfident(atleastinterms
oftherequiredinformationsize)ofthepositiveeffectslidocainehasonthereductionofpostoperativepain,inpatientsundergoingabdominalandlaparoscopicabdominalsurgery
andonreductionofopioidrequirementsinpatientsundergoinglaparoscopicabdominalsurgery.TSAindicatedfurtherthatlidocainehasnobeneficialeffectonearlypostoperative
paininthemixedsubgroup'othersurgery'.Theselectivebenefitofthisinterventionforabdominalsurgerypatientsmaybeasaresultoflidocainerelatedeffectsonthespecific
inflammatoryenvironmentoftheabdominalregion.However,thisisratheraspeculativehypothesiswhichhastobeprovedinfuturetrialsandprimaryresearch.Theresultsfor
PONV'late'shouldbetreatedwithcautionaswecouldidentifyfunnelplotasymmetryandanunderpoweredpatientpopulationsize(TSAresults)underlyingthismetaanalysisto
reachfirmevidence.

Positiveeffectsofsystemiclidocainewerealsorecognizedforreductionofpostoperativeileusandfunctionalgastrointestinalrecovery(timetofirstflatusandbowel
movement/sounds).Fortheoutcome'timetofirstdefecation',thereiscurrentlynoevidenceofpositiveeffectdetectable.Ingeneral,evidenceislimitedforoutcomesconcerning
gastrointestinalrecoverybecauseofimprecision.

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Wealsofoundlimitedevidenceofeffectforlengthofhospitalstay,postoperativenausea(earlytimepointsaftersurgery),intraoperativeopioidconsumption,andpostoperative
opioidrequirements(earlytimepointsaftersurgery).Therewasnoevidenceoftreatmenteffectfoundforthereductionofpostoperativevomitingbecauseoftheintervention,which
maybedependentonthelimitedeventrate.

Intermsofriskofsurgicalcomplicationssuchaspostoperativeinfection,urinaryretention,bleeding,anastomoticleak,thromboembolicdisease,andwoundhealingdisturbances,
therewascurrentlynoevidenceforeitherbenefitorharm.However,thebodyofevidenceislimitedbyimprecisionasaresultofthesmallnumberofstudiesreportingsurgical
complications.

Thisreviewillustratesthattherearenomajoradverseeventsasaresultofsystemiclidocaineadministrationintheperioperativesetting,detectableonthebasisof45small
randomized,controlledtrialsreviewed.However,thisassumptionisbasedonlyonasampleofsmallstudieswithoutasystematicscreeningforadverseevents.Therefore,current
dataarecertainlyunderpoweredtoassessmost(rare)potentialserioussideeffects.

Thesecondcomparisonanalysedinthisreviewwaslidocainei.v.vsthoracicepiduralanalgesia.Forthiscomparison,wewereabletoidentifytwostudies.Asaresultofthelow
numberofidentifiedstudiesanalysingtheeffectofsystemiclidocainecomparedwithTEAthesummarizedeffectsofeachoutcomeforthiscomparisonwereonlyofverylow
evidence.Ingeneral,wewerenotabletoidentifyanyevidenceofeffect,neitherpositivenornegative,intermsofpostoperativepain,functionalgastrointestinalrecovery,ileus,
lengthofhospitalstay,andPONV.

Atthetimeofsubmissionofourprotocol,therewerethreesystematicreviewsaddressingsimilarquestions[6265]andonearticlewaspublishedasareferencedreviewtotheoriginal
ofMcCarthyandcolleagues[65]In2012anothermetaanalysiswaspublishedwhichanalysesperioperativesystemiclidocaineforpostoperativeanalgesiaandrecoveryafter
abdominalsurgery. [66]Itisreassuringthatexistingsystematicreviewswithcomparableorslightlydifferentresearchquestionshavefoundmoreorlesssimilarresultsand
consequentlyconcludedthatthisinterventionshouldbeconsideredinappropriatepatients.However,themoreuptodatesearch,thegreaternumberofincludedtrials,andthe
broaderrangeofincludedsurgerytypesimprovedtheprecisionandtheexternalvalidityofthepresentreview.Inaddition,thepresentreviewhasanalysedpublicationbias,TSA,
andinconsistencyfortheoutcomes'painearly','postoperativeopioidrequirements',and'PONVlate'andprovidessufficientbackgroundinformationtothestudy'sdetails.

Limitations

Amajorlimitationofthisreviewwasthelargeandunexplainedheterogeneitybetweenstudieswhichlimitedthequalityofevidenceformostoftheoutcomesbecauseof
inconsistency.Thepreplannedsubgroupanalysisaccordingtodifferentsurgicalprocedureswasoflimitedsuccesstoexplaintheheterogeneity.Onlyforthesubgroup,open
abdominalsurgeryoftheoutcomespain'early'andpostoperativeopioidconsumptionheterogeneitycouldbedecreasedsignificantly.

Anotherlimitationwasthesmalltrialsizesoftheincludedstudies,assmalltrialstendtooverorunderestimatetheunderlyingtreatmenteffect.Incombinationwithpublicationbias
(preferredpublicationofpositiveresults)thepooledinterventioneffectcanbedramaticallyoverestimated.However,inthecurrentmetaanalysispublicationbiasseemnottoplaya
roleformostoftheoutcomes(symmetricfunnelplots).Nevertheless,evidencewaslimitedbyindirectnessofeffectestimates.Assmalltrialsalsotendtohavelimitedheterogeneity
intheirpatientpopulationand/orimplementedintervention(lowwithinstudyclinicalheterogeneity)theestimatedtreatmenteffectsofmetaanalysesincludingsolelysmalltrials
possesslowerexternalvalidityandgeneralizability.

Sofar,atleast,itisunclear,whichisthebestdoseforanadministeredbolusoflidocaineandforthefollowingcontinuousinfusionoflidocaine.Thisisalsovalidforthelengthof
administrationoflidocaineinfusion.Subgroupanalysiscomparingdifferenttreatmentregimens(dosingoflidocaineanddifferenttimingofadministration)presentedintheCochrane
reviewhavenotrevealedconclusiveresults. [1]

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Finally,assumptionsregardingthemostappropriatedosing,timing(includingthedurationofadministration)andthetypeofsurgeryresultedfromindirectcomparisonsbasedon
differentclinicaltrialswithvaryingclinicalsettings.Forthisreason,clinicaltrialsinvestigatingadoseresponseandmultiplesurgicalcategorieswithinonetrial(e.g.asaclinicaltrials
withfactorialdesign),wouldbewarrantedtofurtherelucidateandgaininsightsintotheseissuesbasedondirectcomparisons.

ImplicationforPractice

Thedescribedeffectsonpostoperativepainscoresweremostobviousandevidentintheimmediatepostoperativeperiod(~0.8NRSpoints),definedasonetofourhpostoperatively
forthepurposeofthisreview.Theeffectwaslesspronouncedandevidentatintermediatetimepoints(definedas24h)withonlyapproximatelyhalfoftheeffect(~0.3NRSpoints)
andtheeffectwasnotsignificantinthelatepostoperativeperiod(48h).

Theresultingclinicalquestionandimplicationiswhethertheseeffectsareworththeeffortsassociatedwiththisintervention.

Toaddressthisquestionitisusefultobearinmindthatunderconditionsofclinicaltrialsandmetaanalyses, [6769]andclinicalaudits, [6,70]thebenefitofneuraxialtechniques(e.g.


epiduralanalgesia)overanopioidbasedpatientcontrolledanalgesiaalthoughusuallyconsideredsuperiorintermsofpainreliefisintherangeof12pointsona0to10visual
analoguescaledependingonthespecifiedpainoutcome.Inthislight,theperioperativeadministrationofi.v.lidocainecouldbeseenasclinicallyrelevantintermsofsuperiorpain
relief,atleastfortheearlypostoperativeperiod,inpatientsundergoinglaparoscopicabdominalsurgery(MD1.14,95%CI1.51to0.78).

Wethinkthatlidocainehasthepotentialtobeanalternativetoepiduralanalgesia(atleastinspecificpopulationsofpatients)especiallybecauseofthebeneficial,evenifsmall,
impactonamultiplicityofclinicalandpatientrelevantoutcomes,suchasgastrointestinalrecovery,PONV,andopioidconsumptionduringpostoperativerecoveryinpatients
undergoingabdominalsurgery.

Asfarastheclinicalapplicabilityoftheseresultsareconcerneditisreassuringthatthisinterventiondidnotproducerelevantclinicalsideeffectsintheinvestigatedcohortof
participantsdespitetheencouragingeffectsoflidocaineadministrationintheadministereddoses(~1.5mgkg1ofbodyweightasbolusand~2mgkg1h1ascontinuousinfusion).
However,wecannotmakeanyconclusionsregardingthetolerabilityinpatientswithcompromisedliverorrenalfunction.

Thus,theeffectsofarelativelysimpleinterventionsuchastheadministrationofi.v.lidocaineshouldbeconsideredrelevantandworthwhiletobediscussedwithpatientsifthesite
ofthesurgicalprocedure(abdominalandlaparoscopicabdominalsurgeries)ortheexpectedpainlevelisappropriate.

Thedescribedeffectsmaybeconsideredespeciallyrelevantifconditionsareprevalentthatworsentherisktobenefitratioofmoreinvasivetreatments,suchas(thoracic)epidural
analgesiaorperipheralregionalanalgesiatechniques.Suchconditionsincludehereditaryoracquiredcoagulationdisordersandtreatmentwithanticoagulants,resultinginabsoluteor
relativecontraindicationstoperformcentralneuraxialblocks.Thismayalsoincludeconditionswithlesspreciselydefinedrisk(e.g.patientsreceivinglowmolecularweightheparin)
(LMWH),inthepresenceofadditionaldrugsinterferingwithcoagulation(e.g.acetylsalicylicacid)orLMWHplusthepresenceofrenalorliverdiseases.Further,itmaybeofvaluein
casesthatturnouttobeamajorsurgicalprocedurebutarenotplannedassuch(e.g.conversionformdiagnosticlaparoscopytomajorlaparoscopicorevenopenabdominal
procedure).

Conclusions

Thereislimitedevidencethatthisintervention,whencomparedwithplacebo,hasanimpactonpainscores,especiallyintheearlypostoperativephase.Thereisalsolimited
evidencethatthishasfurtherimpactonotherrelevantclinicaloutcomes,suchasgastrointestinalrecovery,postoperativenausea,andopioidrequirements.Theanalysesrevealed
thati.v.lidocaineisespeciallyusefulasadjuvantduringgeneralanaesthesia,forpatientsundergoingabdominalsurgery,becauseofitsbeneficialimpactonmultipleoutcomes
duringpostoperativerecovery.Sofarthereisascarcityofstudiesthathavesystematicallyassessedtheincidenceofadverseeffectstheoptimaldosetiming(includingtheduration
oftheadministration)andtheeffectswhencomparedwithepiduralanaesthesia,whichlimitconclusionsonthoseparticularpoints.
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Sidebar
Editor'sKeyPoints

I.V.lidocainemaybeasimpleandsafeadjunctiveanalgesictechniqueforsomesurgeries.

Thiscompleteandcomplexsystematicreviewcollatesallrelevant,reliableevidencetoshowthattherearelikelytobesomebenefitsinperioperativepractice.

Thetrialsequentialanalysisreassuresusthatsufficientevidenceisavailableforsomeoutcomes(butnotothers).

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Funding
Thisworkwasfundedbydepartmentalresourcesonly.

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Acknowledgements
WewouldliketothankKarenHovhannisyan(CochraneAnaesthesiaReviewGroupTrialsSearchCoordinator)forperformingprofessionalliteraturesearchandtheCochrane
AnaesthesiaReviewGroupfortheirsupportinpublishingtheCochraneReview.WefurtherthankBitaMesgarpourfortranslationanddataabstractionoftheincludedPersianstudy
andTaruJokinenforhelpingwiththetranslationofSpanisharticlesduringthesearchprocess.

BrJAnaesth.2016116(6):770783.2016OxfordUniversityPress

Copyright2007TheBoardofManagementandTrusteesoftheBritishJournalofAnaesthesia.PublishedbyOxfordUniversityPress.Allrightsreserved.

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