Rev. Bras. Anestesiol. vol.65 número2

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

Effect

of

intraoperative

intravenous

lidocaine

on

pain

and

plasma

interleukin-6

in

patients

undergoing

hysterectomy

夽

Caio

Marcio

Barros

de

Oliveira

_,

_Rioko

_Kimiko

_Sakata

_,

_Alexandre

_Slullitel

_,

Reinaldo

Salomão

_,

_Vera

_Lucia

_Lanchote

_,

_Adriana

_Machado

_Issy

a_{UniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,Brazil} b_{PainService,HospitalSãoDomingos(HSD),SãoLuís,MA,Brazil}

c_{SociedadedeAnestesiologiadoEstadodoMaranhão(SAEM),SãoLuís,MA,Brazil}

d_{PainDivisionoftheDepartmentofAnesthesiology,PainandIntensiveCareoftheUniversidadeFederaldeSãoPaulo(UNIFESP),}

SãoPaulo,SP,Brazil

e_{DepartmentofAnesthesiology,Associac¸ãoPaulistadeMedicina,SãoPaulo,SP,Brazil}

f_{DepartmentofInfectiousDiseases,UniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,Brazil}

g_{FaculdadedeCiênciasFarmacêuticasdeRibeirãoPreto,UniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil}

Received27April2013;accepted15July2013

Availableonline2January2015

KEYWORDS

Lidocaine; Intravenously; Postoperativepain; Hysterectomy; Interleukin-6

Abstract

Backgroundandobjectives: Interleukin-6 is a predictor of trauma severity. The purpose of

thisstudy was to evaluatethe effectofintravenous lidocaineonpain severity andplasma

interleukin-6afterhysterectomy.

Method: Aprospective,randomized,comparative,double-blindstudywith40patients,aged

18---60years.G1receivedlidocaine(2mgkg−1_h−1_{)orG2received0.9%salinesolutionduring}

theoperation.AnesthesiawasinducedwithO2/isoflurane.Painseverity(T0:awakeand6,12,

18and24h),firstanalgesicrequest,anddoseofmorphinein24hwereevaluated.Interleukin-6

wasmeasuredbeforestartingsurgery(T0),5hafterthestart(T5),and24haftertheendof

surgery(T24).

Results:Therewas nodifference inpain severitybetweengroups.Therewas adecreasein

painseveritybetweenT0andothermeasurementtimesinG1.Timetofirstsupplementation

wasgreaterinG2(76.0±104.4min)thaninG1(26.7±23.3min).Therewasnodifferencein

supplementaldoseofmorphinebetweenG1(23.5±12.6mg)andG2(18.7±11.3mg).There

wereincreasedconcentrations ofIL-6 inbothgroupsfromT0 toT5andT24.There wasno

differenceinIL-6dosagebetweengroups.Lidocaineconcentrationwas856.5±364.1ngmL−1

inT5and30.1±14.2ngmL−1_inT24.

夽 _{StudyperformedattheUniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,Brazil.}

∗_{Correspondingauthor.}

E-mail:[email protected](R.K.Sakata).

http://dx.doi.org/10.1016/j.bjane.2013.07.017

Conclusion: Intravenouslidocaine(2mgkg−1_h−1_{)didnotreducepainseverityandplasmalevels}

ofIL-6inpatientsundergoingabdominalhysterectomy.

© 2014SociedadeBrasileirade Anestesiologia.Publishedby ElsevierEditoraLtda.Allrights

reserved.

PALAVRAS-CHAVE

Lidocaína; Viavenosa; Dorpós-operatória; Histerectomia; Interleucina-6

Efeitodalidocaínavenosaintraoperatóriasobredoreinterleucina-6plasmáticaem

pacientessubmetidasahisterectomia

Resumo

Justificativaeobjetivos: Ainterleucina-6(IL-6)épreditoradeintensidadenotrauma.O

obje-tivodesteestudofoiavaliaroefeitodalidocaínaporviavenosasobreaintensidadedadore

IL-6apóshisterectomia.

Método: O estudo foi prospectivo, randomizado, comparativo e duplo-encoberto em 40

pacientes, entre18e60 anos.Foi administradalidocaína (2mg.kg−1_.h−1_{)noG1ousoluc¸ão}

salina a0,9%noG2 duranteaoperac¸ão.A anestesia foicom O2/isoflurano.Foi avaliada a

intensidadedador(T0:despertareseis,12,18e24horas),aprimeirasolicitac¸ãode

anal-gésico,adosedemorfinanas24horas.AIL-6foimedidaantesdoiníciodaoperac¸ão(T0),após

cincohorasdoinício(T5)e24horasapósotérmino(T24).

Resultados: Nãohouvediferenc¸anaintensidadedadorentreosgrupos.Ocorreudiminuic¸ão

daintensidadedadorentreT0eosoutrosmomentosavaliadosnoG1.Otempoparaprimeira

complementac¸ãofoimaiornoG2(76,0±104,4min)doquenoG1(26,7±23,3min).Nãohouve

diferenc¸anadosedemorfinacomplementarentreG1(23,5±12,6mg)eG2(18,7±11,3mg).

Houveaumentodasconcentrac¸õesdeIL-6emambososgruposdeT0paraT5eT24.Nãohouve

diferenc¸anadosagemdeIL-6entreosgrupos.Aconcentrac¸ãodelidocaínafoi856,5±364,1

ng.mL−1_{emT5e30,1±14,2ng.mL}−1_emT24.

Conclusão:A lidocaína(2mg.kg−1_.h−1_{)porviavenosanão promoveureduc¸ãodaintensidade}

dadoredosníveisplasmáticosdeIL-6empacientessubmetidasahisterectomiaabdominal.

©2014SociedadeBrasileira deAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos

direitosreservados.

Introduction

Both the dose and duration of lidocaine infusion remain controversial. Moreover, its effectiveness has not yet been determined. Surgical trauma results in the release of cytokines that are responsible for local inflammatory responsesandpromotetissuehealing.1_{Interleukin-6(IL-6)is}

acytokinethatisearlydetectedinresponsetoinjuryandits increaseiscorrelatedwiththedegreeoftissuedamage.1,2

Some authorshave reportedthatintravenous lidocaine promotesreductionofcytokines,3,4_{inhaledanesthetics}5_and

opioidsconsumption,6,7_{andpostoperativepainseverity.}3,6,7

Furthermore, low doses of intravenous lidocaine (plasma concentrations less than 5␮gmL−1) do not interfere with

normal nerveconduction andare associatedwitha lower incidenceofopioid-relatedadverseeffects.3,6,8

Lidocainehasanalgesic,6_{anti-hyperalgesic,}6,9_and

anti-inflammatory effects.4,10 _{Analgesia maypersist evenafter}

plasmaconcentrationreduction.10,11

The voltage-gated sodiumchannels arethe classic tar-gets of lidocaine.12 _{The analgesic and anti-inflammatory}

action also occurs through calcium and potassium chan-nelsandreceptorscoupledtoGprotein.13,14_{The neuronal}

transmissionblockadeandreducedneurogenicresponseare

causedbytheactiononsodiumandpotassiumchannels.13,15

Lidocaine metabolite, monoethylglycinexylidide (MEGX), may also exert analgesic effect.16 _{Unlike MEGX,}

lido-cainereducesglycineuptakeonlyattoxicconcentrations. However, other studies reported no analgesic effect of lidocaine.17,18

Thus, theprimary objective of thisstudy wasto eval-uatetheeffectof intraoperativeintravenous lidocaineon postoperativepainseverityandplasmalevelsofIL-6after abdominalhysterectomy.

Methods

AfterapprovalbytheResearchEthicsCommitteeofthe Fed-eralUniversityofSãoPauloandobtainingwritteninformed consent,40patients,ASA1or 2,agedbetween18and60 years, undergoing elective total hysterectomy by laparo-tomythroughaPfannenstielincisionwereincluded.

surgeryorreceivedbloodproductsduringthestudyperiod wereexcluded.

This was a prospective, double blind and randomized study.Patientswererandomlyallocatedintotwogroupsof equalsize by lottoreceive either lidocaineinfusion (G1) or 0.9% saline infusion (G2/control). Randomization was performed using G1 and G2 registers, which were placed in sealed envelopes prior to study initiation and opened approximately30minpriortoanesthesiabyaphysicianwho preparedtheintravenoussolutionandidentifieditwiththe patientnumber,accordingtotheenvelopedrawn.The solu-tionwashandedtoanotherphysician,blindtotheprepared solutions’content,whowasresponsiblefortheanesthesia. Thesolutionvolumewasequal.The responsible investiga-torremainedblindtothechosengroupuntiltheendofthe study.

G1 patients (n=20) received 2mgkg−1_h−1 _{of lidocaine}

andG2patients(n=20)receivedan equalvolumeof0.9% saline,whoseinfusionwasinitiatedatthetimeofinduction ofanesthesiaandcontinueduntiltheendoftheoperation. Midazolamwasadministeredatadoseof15mgorally1h beforeanesthesia.Patientsweremonitoredwithcontinuous electrocardiography and pulse oximetry and intermittent noninvasive blood pressure measurements every 5min. Induction of anesthesia was performed with fentanyl (5␮gkg−1)andpropofol (2mgkg−1);neuromuscular

block-adewasachievedwithatracurium(0.5mgkg−1_).Anesthesia

was maintained with O2/isoflurane at sufficient dose to

maintainsystolicbloodpressurewithinthelimitof20% base-line value. Neuromuscular blockade was maintained with atracurium(0.2mgkg−1_{)administeredevery30min.During}

surgery,additionaldosesofopioidsorotheranalgesicswere notused.Therewasnoprophylaxisforpostoperativenausea andvomiting.

Aftersurgery, patientswere monitoredin therecovery room and later taken to the ward. Morphine (5mg) was administeredsubcutaneouslyusinga 23Gscalp,as neces-sary.

Bloodsampleswerecollectedinethylenediaminetetra acetate(EDTA)tubesimmediatelyaftercontralateralupper limbvenipuncture,beforetheoperation(T0),5hafterthe startofsurgery(T5),and24haftersurgery(T24).Blood sam-pleswerecentrifugedandplasmawasseparatedandstored at−70◦_{Cup toanalysis.The levelsofIL-6wereanalyzed}

using the enzyme-linked immunoassay (ELISA). Lidocaine anditsmetabolite MEGXwereanalyzed usinghigh perfor-manceliquidchromatography(HPLC)5hafterthestartof surgeryand24haftersurgery.

Painseveritywasassessedatrestusingaverbalnumeric scale(VNS)fromzeroto10(where0=nopainand10=most severepainpossible).Averbaldescriptivescale (VDS)was also used: 0=no pain, 1=mild pain, 2=moderate pain, and 3=severe pain. The scores were recorded at the following times: T0=immediately at awakening; T6=6h afterawakening;T12=12hafterawakening;T18=18hafter awakening;T24=24hafterawakening.

Forpostoperative analgesia, morphine (5mg) was sub-cutaneouslyadministeredby anurse,asneeded. Thefirst analgesicrequest,thesupplementaldoseofmorphine nec-essary for the first 24h, and the dose of isoflurane used intraoperatively were recorded; side effects were also recorded.

Statisticalanalysis

Sample size calculation was performed with GraphPadInstat® _{program (GraphPad Software Inc., San}

Diego, CA, USA). For such, we considered the reduction of pain severity caused by lidocaine. Based on a pilot studyconductedbythesameresearchgroup,thestandard deviation(SD)wasestimatedat2.2.Adifferenceofatleast 3inVNS(0---10)wasconsideredclinicallyrelevant.Because painissubjectiveandindividual,threelevelsofdifference were considered a significant pattern of change or an improvementfactoror asignificantworsening.Confidence interval was 95%. Thus, a sample with a minimum of 20 patientspergroupwascalculated.Thefollowingtestswere used: Mann---Whitneytest tocompare age and body mass index (BMI); Student t-test to compare weight, height, duration of anesthesia, duration of surgery, time to first analgesicsupplementation,totalmorphineconsumption in 24h, painintensity,totalisofluraneconsumption,andIL-6 plasmalevels.Datawereexpressedasmean±SD.

Results

Fig.1shows the studyflowchart.19 _{Thegroups were}

simi-larregardingdemographicdataanddurationofsurgeryand anesthesia(Table1).

Therewasnodifferencebetweenthetwogroupsinthe timepointsevaluated(Table2).Therewasnostatistically significantdifferenceinIL-6concentrationbetweengroups (Table3).

The postoperative timeto firstmorphine dose request for analgesia was higher in G2 (76±104.4) than in G1 (26.7±23.3) (Table 4). Therewas nodifference between groupsregardingsupplementarymorphinedoseandvolume of isoflurane (Table 4). Table 5 shows the concentrations oflidocaineanditsmetabolite,MEGX.Nauseaoccurredin sevenpatientsineachgroup.

Discussion

There was no analgesic effect with intravenous lidocaine infusion andalso noreductionin plasmaconcentration of IL-6.

Inthisstudy,theopenhysterectomywaschosenbecause it is associated with severe postoperative pain, with a greatchanceof changesintheneuronalprocessingofthe spinal dorsal horn, which would allow us to compare the groups.20

Previousstudieshave usedlargerdosesoflidocainefor intravenousinfusionandsomeusedinitialbolus,whichmay explainthelackofanalgesiceffectinthisstudy.3,5---7

Inonestudy,3_{lidocaine(2mgkg}−1_{)wasadministeredas}

a bolus and maintained with infusion of 3mgkg−1_h−1_{. In}

anotherstudy,6_{theanalgesicandsparingeffectofmorphine}

wasmost evidentonthe thirdpostoperativeday, but this studywaslimitedto24h.

Itmust beremembered that the dose and duration of lidocainevenous infusion, withthe objectiveof obtaining postoperativeanalgesia,havenotbeenwelldefined.21

Evaluated for the study (n=80)

Excluded (n=34)

• No inclusion criteria (n=34)

• Refused to participate (n=0)

Randomized (n=46)

Allocated to G2 (n=22)

• Submitted to placebo (n=22)

• Not submitted to placebo (n=0) Allocated to G1 (n=24)

• Submitted to lidocaine (n=24)

• Not submitted to lidocaine (n=0)

Loss to follow-up (n=4)

Discontinued (n=0)

Loss to follow up (n=2)

Discontinued (n=0)

Analyzed (n=20)

Excluded from analysis (n=0)

Analyzed (n=20)

Excluded from analysis (n=0)

Enrollment

Allocation

Follow-up

Analysis

Figure1 FlowchartbasedonConsort.19

Table1 Demographicdata,operationandanesthesiatimes.

G1 G2 p

Age(years) 44.1±6.6 42.9±5.7 0.646a

Weight(kg) 72.2±13.7 74.2±12.6 0.379b

Height(cm) 159.12±6.5 158.0±6.6 0.343b

BMI(kgm−2_{) 28.5±5.4 29.7±5.3 0.133}a

Operationtime(min) 102.6±49.4 93.0±48.2 0.122b

Anesthesiatime(min) 145.1±51.8 124.0±43.8 0.172b

G1,lidocaine;G2,salinesolution;BMI,bodymassindex.

a_{Mann---Whitneytest.} b_{Student’st-test.}

Table2 Painintensitybynumericalratingscale.

Times(h) G1(n=20) G2(n=20) p

Scores IC95% Scores CI95%

T0 3.2±3.9 1.3---5 2.5±3.7 0.7---4.2 0.602

T6 1.4±1.8 0.5---2.3 1.8±1.6 1---2.5 0.307

T12 0.8±1.5 0---1.4 1.3±1.8 0.4---2.1 0.307

T18 0.9±1.5 0.1---1.5 1±1 0.5---1.5 0.476

T24 1±1.6 0.3---1.8 1.3±1.6 0.5---2 0.602

G1,lidocaine;G2,salinesolution;CI 95%,95%confidenceinterval;T0,awakening;T6,T12,T18 andT24,6,12,18and 24hafter awakening.

Because themeasurementof plasma lidocainewasnot partof thepurposeofthisstudy andserved onlyas addi-tionalinformation,itsanalysiswasmadeatthesamedosage timesof IL-6: beforebeginningsurgery(T0),5hafter the

Table3 PlasmaconcentrationofIL-6(pcgmL−1_).

Times(h) G1(n=20) G2(n=20) p

T0 0.95±4.25 2.56±7.55 0.602

T5 20.34±17.83 19.44±17.88 0.841

T24 24.95±14.82 34.73±15.62 0.056

G1,lidocaine;G2,salinesolution;T0,beforesurgicalincision;T5,5haftertheincision;T24,24hafterskinsuture.

Table4 Volume ofisoflurane used, time to first analgesic request, and additional analgesic dose of morphine over24h

(mean±SD).

G1(n=20) G2(n=20) p

Timetofirstsupplementation(min) 26.7±23.3 76.0±104.4 0.046

Additionaldoseofmorphinein24h(mg) 23.5±12.6 18.7±11.3 0.217

Volumeofisofluraneused(mL) 25.2±8.9 26.5±10.6 0.679

G1,lidocaine;G2,salinesolution;Student’st-test.

tomeasurethepeakconcentrationoflidocaine.AtT5and T24,themeasurementof lidocaineaveraged0.86␮gmL−1 and0.55␮gmL−1,respectively.Theseresultsarewellbelow concentrations considered effective, which range from 2 to 10␮gmL−1.22 In this study, intravenous lidocaine did

not reduce postoperative pain severity, similar to some studies,16---18_{probablybecauseoftheshortinfusiontimeand}

absenceofinitialbolusdose.

Although it has been reported that there would be a higher analgesic effect that would increase the infusion time,insteadoflidocainedose,thestudyofKoppertetal.,6

using low dose infusion of lidocaine for up to 1h after surgery, showedpositive prolonged results for upto 72h. Inourstudy,lidocaineinfusionwasdiscontinuedattheend ofsurgery,asinother studies.3,5,8,23-26 _{Lidocainedose was}

based on the study by Lauwick et al.5 _{Indeed, lidocaine}

boluswasnot usedbeforeinfusionbecause insome stud-iestherewasa reductionin postoperative painwithonly theinfusion.23,27

In thisstudy, patients whoreceivedlidocaine required theirfirstanalgesicsupplementation earlierthanthe con-trolgroup.Onepossibleexplanationforthisresultmaybea greatindividualvariabilityinpainthresholdsandpatients’ responsetoanalgesics.Becausetherewasconsiderable dis-crepancyinthefirstanalgesicrequesttimeamongpatients inG2, the groupstandard deviation wasgreater thanthe mean.

Interleukin-6(IL-6)isan earlymarkeroftissuedamage anditsexcessiveandprolongedincreaseisrelatedtogreater postoperativemorbidity.2 _{Inour study,IL-6wasmeasured}

beforethestartofsurgery(T0),5hfromthestartofsurgery

Table 5 Plasma levels of lidocaine and

monoethyl-glycinexylidide(MEGX)(ngmL−1_)inG1.

Times(h) Lidocaine MEGX

T5 856.5±364.1 545.6±212.9

T24 30.1±14.2 ND

G1,lidocaine;T5,5haftertheincision;T24, 24hafterskin suture;ND,notdetectable.

(T5),and24haftertheendofanesthesia(T24),according totheplasmapeakdescribedintheworkbyHongetal.,28

inwhichIL-6isdetectedin60minwithbloodpeakbetween 4and6handmaypersistfor10days.

Therewasastatisticallysignificantprogressiveincrease in IL-6 dosage in each group. The highest value was at the last collection time (24h after surgical suture). This factcontrastswiththeworksbyLinetal.1 _andHerroeder

etal.,4_{withIL-6peakbetween4and6hinthe}

postopera-tiveperiod,andKuoetal.,3_{withIL-6peak10and12hafter}

surgery. Therewasan increasingtrendinthe lastdose of IL-6 in G2 compared to G1, which shows a possible anti-inflammatory effectof lidocaine or itsactive metabolite, MEGX,evenaftertheendofinfusionandbeyondthehalf-life of elimination. Probably, a statistically significant differ-encewouldbeshownbetweengroupsifthesamplesizewas increased.

Experimental studies have shown that MEGX, but not lidocaine,increasedtheglycinergicactivity(inhibitory neu-rotransmission)throughGlyT1blockade(glycine transporter-1) in central nervous system in clinically relevant concentrations.16,29,30_{Inourstudy,themeanconcentration}

of MEGX reached was 0.55␮gmL−1 5h after the start of

surgery,similartothelevelwhichleadstotheinvitro inhi-bitionofglycinetransport,whichwasobservedduringthe continuousinfusionoflidocaine.29

Unlike some previous studies,6,7 _{lidocaine showed no}

isoflurane and morphine-sparing effect in our study. Fur-thermore, there was no difference in total morphine consumptionbetweengroups.Similarly, somestudieshave reportedanalgesic effectwithlidocaine.17,18 _{It is possible}

thatthesefindingsarerelatedtouniquepatternsof periph-eraland centralsensitizationthat varywiththedifferent typeandlocationofsurgeries.23

Theanalgesiceffectsoflidocainearemorepronounced when it is infusedintraoperatively6 _{and maycontinue for}

days or weeks, that is, beyond infusion time and plasma half-life,11,31 _{indicating its action on other targets, not}

decreasedthedurationofparalyticileus,postoperativepain severity,andopioidconsumption.32---34

A clinically significant reduction in pain severity was observedin theawakeningtimein relationtoother mea-suredtimewithlidocaine,butnotinG2,whichmayreflect thebeneficialeffectoflidocaineoranalgesiceffectof mor-phine.

Noother differenceswereobservedbetween groupsat any assessment time. In this study,intravenous lidocaine infusionduringsurgery(2mgkg−1_h−1_{)withoutinitialbolus}

did not improve postoperative analgesia or reduce IL-6 plasma levelsinpatients undergoingopen abdominal hys-terectomy.

More studies are needed to confirm these results and evaluate the beneficial effects of lidocaine in patients undergoingothertypesofsurgery.Moreover,theappropriate dose, the onset time,and the durationof lidocaine infu-sionrequiredtoreducethepostoperativepainremaintobe determined.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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