Optimal Dexmedetomidine Dose to Prevent Emergence ...

Thus, we evaluated the optimal dose (ED95) of dexmedetomidine for preventing EA with sevoflurane and remifentanil anesthesia after pediatric ... Articles JunShi dMedBiopharmaceutical(China),China CarrieA.Vyhlidal Children'sMercyHospital,UnitedStates MeinaT.Tang Genentech,Inc.,UnitedStates Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. AbstractIntroductionMaterialsandMethodsResultsDiscussionConclusionDataAvailabilityEthicsStatementAuthorContributionsConflictofInterestStatementAcknowledgmentsReferences SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData ORIGINALRESEARCHarticle Front.Pharmacol.,19September2019 |https://doi.org/10.3389/fphar.2019.01091 OptimalDexmedetomidineDosetoPreventEmergenceAgitationUnderSevofluraneandRemifentanilAnesthesiaDuringPediatricTonsillectomyandAdenoidectomyYan-zhuoZhang,XueWang,Jia-minWu,Chun-yuSongandXiao-guangCui*DepartmentofAnesthesiology,ChinaandHeilongjiangKeyLaboratoryforAnesthesiaandCriticalCare,TheSecondAffiliatedHospitalofHarbinMedicalUniversity,Harbin,ChinaBackground:Emergenceagitation(EA)isacommonpediatriccomplicationaftersevofluraneanesthesiathatcanbepreventedwithdexmedetomidine.However,aninappropriatedoseofdexmedetomidinecancauseprolongedsedationandcardiovascularcomplications.Thus,weevaluatedtheoptimaldose(ED95)ofdexmedetomidineforpreventingEAwithsevofluraneandremifentanilanesthesiaafterpediatrictonsillectomyandadenoidectomy.Methods:WeenrolledAmericanSocietyofAnesthesiologists(ASA)IandIIchildren3–7yearsofagewhounderwenttonsillectomywithadenoidectomy.Duringinduction,dexmedetomidinewasinfusedfor10min.Anesthesiawasinducedwithsevofluraneandmaintainedwithsevofluraneandremifentanil,resultinginabispectralspectrumindex(BIS)rangefrom40to60.Extubationtime,surgicalandanestheticdurationtime,anddurationtimeinthepostanesthesiacareunit(PACU)staywererecorded.EA[measuredwithPediatricAnaesthesiaEmergenceDelirium(PAED)scores]andpain[measuredwithFace,Legs,Activity,Cry,Consolability(FLACC)scores]wereassessedatextubation(E0),15minafterextubation(E1),and30minafterextubation(E2).IfEAoccurred,thenextsurgicalprocedureincludedincreaseddexmedetomidineby0.1μg/kg,andifnot,thedrugwasreducedby0.1μg/kg.Results:The50%effectivedose(ED50)ofdexmedetomidineforpreventingEAaftersevofluraneandremifentanilanesthesiafortonsillectomyandadenoidectomywas0.13μg/kg,andits95%confidenceintervalis0.09–0.19μg/kg;ED95was0.30μg/kg,andits95%confidenceintervalis0.21–1.00μg/kg.Conclusion:IntravenousdexmedetomidineinfusionatED50(0.13μg/kg)orED95(0.30μg/kg)duringinductionfor10mincanpreventhalforalmostallEAaftersevofluraneandremifentanilanesthesiaduringpediatrictonsillectomyandadenoidectomy.IntroductionEmergenceagitation(EA)isacommonpediatriccomplicationwithsevofluraneanesthesia.EAincidencevariesfrom10%to80%(Aonoetal.,1997;Keaneyetal.,2004;VlajkovicandSindjelic,2007;Dahmanietal.,2010),anditisassociatedwithcomplications,includingincreasedheartrate,elevatedbloodpressure,dissatisfactionandanxiety,andfussybehaviorssuchasfallingoutofbed,removalofsurgicaldressingsandintravenouscatheters,andself-injury,whichweregenerallyassociatedwithincreasedcostsforadditionalmedicalcare(Lermanetal.,1996;Welbornetal.,1996;Picardetal.,2000;Uezonoetal.,2000).EAisdrivenbyage,pain,surgerytype,personality,rapidawakening,preoperativeanxiety,andinhalationagentsthatwereadministered(KurataniandOi,2008;Zhangetal.,2014).Manytechniquesandmedications,whichincluderegionalblock(Aouadetal.,2005;Ghoshetal.,2011;SlinhaandSood,2012),premedication(Kimetal.,2013;Zhangetal.,2013),propofol(Picardetal.,2000;Uezonoetal.,2000;Kimetal.,2012),µ-opioidagonists(Lietal.,2012;Liangetal.,2014),andα2-agonists(Bokuetal.,2016;Linetal.,2016),havebeenusedtoreducepediatricEA.Dexmedetomidine,ahighlyspecificα2-adrenoceptoragonistwithsedative,analgesic,andanxiolyticpropertiesandfewadverseeffects,significantlyreducespediatricEA(Pateletal.,2010;Satoetal.,2010;Kimetal.,2014).Variousdoses(0.15–2.0μg/kg)(SunandGuo,2014)ofdexmedetomidinehavebeenreportedtopreventpediatricEAaftersevofluraneanesthesia,buttheoptimaldoseofdexmedetomidineisnotknown.Dexmedetomidinedoesnotcauserespiratorydepression,butitdoeshavecardiovasculareffects(Kimetal.,2014),souseofthedrugrequiresmonitoring,especiallyforchildren(Buck,2010).Thus,wesoughttoidentifyanoptimaldoseofdexmedetomidinetopreventEAwithoutprolongedsedationandcardiovascularcomplicationsduringtonsillectomyandadenoidectomy.MaterialsandMethodsStudyOversightSubjectsunderwenttonsillectomyandadenoidectomyattheSecondAffiliatedHospitalofHarbinMedicalUniversityatHarbin,HeilongjiangProvince,China.Thisstudywasapprovedbytheinstitutionalethicscommitteeandregisteredatwww.ClinicalTrials.gov(ChiCTR-OIh-17011790).Informedwrittenconsenttoparticipateinthisstudywasobtainedfromtheparentsandguardiansofallofthechildren.ParticipantsThirty-sixchildrenbetween3and7yearsofagewithanAmericanSocietyofAnesthesiologists(ASA)physicalstatusIorIIwhowerescheduledfortonsillectomyandadenoidectomysurgerywereenrolledinthisstudy.SubjectswereselectedusingDixon’sup-and-downsequentialmethod(UDM)ratherthanrandomsequence.Patientswithcardiacdisease,developmentaldelay,abnormalupperairways,asthma,orahistoryofupperrespiratorytractinfectioninthepreceding4weekswereexcluded.Onechildwithcardiacdisease,onechildwithdevelopmentaldelay,onechildwithanabnormalupperairway,twochildrenwithasthma,andtwochildrenwithahistoryofupperrespiratorytractinfectionwereexcluded,and29childrenfinishedtheexperiments.StudyOutcomesWefirstdeterminedtheoptimaldoseofdexmedetomidinetopreventEAafterpediatrictonsillectomyandadenoidectomywithsevofluraneandremifentanilanesthesia.WefoundtheED95andED50.StudyProtocolNopremedicationwasgiven.Monitoringincludedelectrocardiography(ECG),pulseoximetry(SpO2),noninvasivearterialbloodpressure(NIBP),adepthofanesthesiamonitor,andaBIS(VISTAmonitoringsystem,Covidien,Ma).Anesthesiawasinducedwith3%sevofluranewith5L/minofoxygen,lidocaine(1mg/kg),propofol(2–2.5mg/kg),andatracurium(0.3mg/kg).Atthesametimeofinduction,dexmedetomidinewasinfused(iv)for10min,andthestartingdoseforthefirstpatientwas0.5μg/kg.Anesthesiawasmaintainedwith2–3%sevofluraneinapproximately50%oxygenwithtotalinflowof2L/minandremifentanil(10μg/kg/h,iv).SevofluranewasadjustedtoaBISrangeof40–60.Then,a0.5%lidocaineandepinephrinemixture(1:200,000)in3mlwereinjectedintothemucosasurroundingeachtonsillarfossaforlocalanesthesiaandvasoconstriction.Intravenoustramadol(2mg/kg)anddexamethasone(0.1mg/kg)weregivenaftertheinductionofanesthesiaforpostoperativeanalgesiaandtopreventpostoperativenauseaandvomiting.Sevofluranewasdiscontinueduponremovalofmedicalmouthgag,andtrachealextubationwasperformedwhenpatientsbeganbreathingspontaneouslyandcoughingorhadbodymovements.Then,childrenweretransferredtothePACU,andEAwasevaluatedafterextubation.IfEAoccurred,thenextchild’sdoseofdexmedetomidineincreasedby0.1μg/kgcomparedwiththepreviousone,andifnot,itwasloweredby0.1μg/kg.IfsevereEAoccurred,thechildwasgivenpropofol(0.5mg/kg,iv).PostoperativepainwasassessedwiththeFace,Legs,Activity,Cry,Consolability(FLACC)scale(Voepel-Lewisetal.,2010),andthosewithFLACCscoresof4weregiven0.5μg/kgoffentanyl.MeasurementsWerecordedthedurationofsurgeryandanesthesia,end-tidalsevofluraneconcentration,extubationtime,andPACUstay.Extubationtimewasmeasuredfromthecessationofsevofluranetothepointatwhichthepatients’eyesopened.EAseveritywasevaluatedwiththePAED(Table1)scaledevisedbySikich(SikichandLerman,2004),andcriteriaappearinthetable.EAincidenceandseverityweremeasuredatextubation(E0),15minafterextubation(E1),and30minafterextubation(E2).TotalPAEDscoresaresumsforthefivebehaviorslisted.EAwasconfirmedwithanindividualscoreof4points,atotalPAEDscorethatwasnolessthan10,oracomprehensivescorethatwasgreaterthan15(severeEA).DexmedetomidinedosesweredeterminedusingDixon’sUDM(Dixon,1991).PostoperativepainwasassessedwithFLACCatE0,E1,andE2.Rescuepropofolandfentanylwererecordedifused.EAandpostoperativepainwereevaluatedandrecordedbyasingleanesthesiologistblindedtothesequenceofinclusionofpatientsandthedoseofdexmedetomidineadministeredtoeachpatient.TABLE1Table1PediatricAnesthesiaEmergenceDelirium(PAED)scale.StatisticsDixon’sUDMrequiresatleastsixfailure–successpairsforstatisticalanalysis;therefore,patientenrollmentcontinueduntilsixcrossoverpairswereobserved.Inourresearch,weobservedninecrossoverpairs.ED50andED95ofdexmedetomidinewereestimatedbycalculatingamodifiedisotonicestimator(StylianouandFlournoy,2002).TheR3.4.1programwasusedforthiscalculation.The95%confidenceinterval(CI)wasobtainedusingaparametricbootstraproutineandcalculatedbyabias-correctedpercentilemethod(PaceandStylianou,2007).DemographicandrecoverydataforchildrenwithEAandthosewithoutEAwerecomparedwithFisher’sexacttestandaMann–WhitneyUtest.ThePAEDscoreandFLACCscoreforchildrenwithEAandthosewithoutEAwerecomparedwithrepeated-measuresANOVA.StatisticalanalyseswereperformedwithStatisticalProductandServiceSolutions(SPSS)19.0forWindows.Statisticalsignificancewasdefinedasp<0.05.ResultsThirty-sixchildrenunderwenttonsillectomyandadenoidectomyandwereenrolled,and29childrencompletedthisstudy.ChildrenwithandwithoutEAdidnotdiffersignificantlywithrespecttoage,weight,sex,surgerytypeorduration,extubationtime,anestheticduration,andPACUstay(p>0.05).End-tidalsevofluraneconcentrationwasrecorded15,30,and45minaftertheadministrationofdexmedetomidine,andtherewasnosignificantdifferenceinmeanend-tidalsevofluraneconcentrationbetweenthepediatricgroups.TherewasnosignificantdifferenceinmeanFLACCscoresbetweenthegroups.ButPAEDscoresintheEAgrouparesignificantlyhigherthanthoseinthewithout-EAgroup(p<0.05)(Table2).TABLE2Table2DemographicandsurgicalcharacteristicsofchildrenwithandwithoutEA(mean±SD).Dexmedetomidinedosesuccess/failuredataappearinFigure1.Fromthisfigure,theED95andED50ofdexmedetomidinetopreventEAaftersevofluraneandremifentanilanesthesiaare0.30 μg/kg(its95%CIis0.21–1.00μg/kg)and0.13μg/kg(its95%CIis0.09–0.19μg/kg),respectively.FIGURE1Figure1Emergenceagitation(EA)usingDixon’sup-and-downmethod.Crossoverpairsfromsuccess(solidsquare)tofailure(hollowcircle).DiscussionDexmedetomidineisaselectiveα2-agonistthathasashorthalf-life.Becauseofitssedative,analgesic,andanxiolyticproperties,itisusedtopreventpediatricEAduringtonsillectomyandadenoidectomy.AsingledoseorcontinuousinfusionofdexmedetomidinecanreducepediatricEAaftersevofluraneanesthesia(Zhangetal.,2014;Makkaretal.,2016;TBedirlietal.,2017),butanoptimaldosehasnotyetbeendetermined.WereporttheED95andED50fordexmedetomidine(0.30and0.13μg/kg,respectively),determinedusingDixon’sUDM,andthisdoseofferslessEAandlessriskofcomplicationsrelatedtodexmedetomidineoverdose.Dixon’sUDMwasdesignedtoestimatethemedianthreshold,includingtheED50orEC50(Dixon,1991;Oron,2006;PaceandStylianou,2007),ithasmanyadvantagessuchassmallsamplesize,simpleoperation,andrelativelyaccurateresults.AnditcanestimatetheED90/EC90orED95/EC95byextrapolationinaUDMstudy(Leeetal.,2017).Kim’sgroupreportedthatadexmedetomidinebolus(0.38μg/kg)couldprevent95%of2-to12-year-oldpediatricEAcasesaftertonsillectomyandadenoidectomywithdesfluraneanesthesia(Kimetal.,2015).ConsideringthegreaterincidenceofEAaftersevofluraneanesthesiaandthatEAinwiththoseaged3–7yearsisseverethanthatinothers(Aonoetal.,1997;Keaneyetal.,2004;VlajkovicandSindjelic,2007;Dahmanietal.,2010;Choietal.,2015),weselected0.5μg/kgofdexmedetomidineastheinitialdoseandobservednoadversereactions,suchasbradycardia,hypotension,orprolongedrecoverytime(Masonetal.,2009).Atropine(0.02mg/kg)asantisialagogueatthetimeofinductionantagonizedpotentialbradycardiainducedbydexmedetomidine,whichhasahalf-lifeof2handisrapidlymetabolized.InKim’sstudy(Kimetal.,2015),theyselectedadosingincrementofdexmedetomidineof0.1µg/kg.Weincreasedanddecreasedtheincrementinourpreliminaryexperiment,butitisinappropriate,sowealsoselected0.1µg/kgasanincrementdoseofdexmedetomidine.Postoperativepainisacauseofagitation(Lynchetal.,1998);butevenwithanalgesia(Seoetal.,2011),postanestheticEAhasbeenobserved(Weldonetal.,2004),ortherewasanabsenceofpain(Craveroetal.,2000).Toaddressthis,wegavetramadol2 mg/kg(iv)duringtheinductionofanesthesiatominimizepaineffects.Duringsurgery,localanesthesiawith0.5%lidocaineandepinephrine(1:200,000)wasusedtoreducepostoperativepain.TherewerenodifferencesinFLACCscoresbetweenthetwogroups.Duringpediatricanesthesia,sevofluraneisoftenpairedwithketamine,propofol,dexmedetomidine,clonidine,midazolam,fentanyl,remifentanil,orsufentaniltopreventEA(Wangetal.,2017).Remifentanilisanappropriatesyntheticshort-actingopioidcommonlycombinedwithvolatileanesthesiaforpediatricpatients.RemifentanilpreventsEAaftersevofluraneanesthesiaaswell(Dongetal.,2010;Naetal.,2013;Wangetal.,2017).SincewestillobservedEA,weusedprophylacticdexmedetomidinetopreventEAandnotedtheED50andED95values.Thestudyislimitedbyasmallsamplesizealthoughstatisticalpowerwassufficient.Althoughthepvalueofbodyweightbetweentwogroupsis0.12,themeanbodyweightintheEAgroupisslightlybiggerthanthatinthewithout-EAgroup.ThismayhaveaslightimpactonthefinalED50/ED95outcome.Moreresearchisrequiredtoconfirmourpreliminarydataandourdexmedetomidinedose.Andourdexmedetomidinedosemustbeverifiedwithotherpreoperativemedications,sothatitcanbebetterusedinclinicalpractice.ConclusionIntravenousdexmedetomidineinfusionatED50(0.13μg/kg)orED95(0.30μg/kg)duringinductionfor10mincanpreventhalforalmostallEAaftersevofluraneandremifentanilanesthesiaduringpediatrictonsillectomyandadenoidectomy.DataAvailabilityAlldatasetsgeneratedforthisstudyareincludedinthemanuscript/supplementaryfiles.EthicsStatementThestudiesinvolvinghumanparticipantswerereviewedandapprovedbytheinstitutionalethicscommitteeofHarbinMedicalUniversityandregisteredatwww.ClinicalTrials.gov(theethicnumberisChiCTR-OIh-17011790).Writteninformedconsenttoparticipateinthisstudywasprovidedbytheparticipants’legalguardian/nextofkin.Writteninformedconsentwasobtainedfromtheindividual(s),andminor(s)’legalguardian/nextofkin,forthepublicationofanypotentiallyidentifiableimagesordataincludedinthisarticle.AuthorContributionsAlloftheauthorshadaccesstothedataandguaranteetheintegrityandaccuracyofthedataandanalyses.Thefirstauthorwrotethefirstdraftofthemanuscript,andalloftheauthorsparticipatedinthesubsequentdrafts.Alloftheauthorsagreedonsubmittingthepaper,andtherewasnocommercialsupportforthestudy.ConflictofInterestStatementTheauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest.AcknowledgmentsWethankLetPub(www.letpub.com)foritslinguisticassistanceduringthepreparationofthismanuscript.ReferencesAono,J.,Ueda,W.,Mamiya,K.,Takimoto,E.,Manabe,M.(1997).Greaterincidenceofdeliriumduringrecoveryfromsevofluraneanesthesiainpreschoolboys.Anesthesiology87,1298–1300.doi:10.1097/00000542-199712000-00006PubMedAbstract|CrossRefFullText|GoogleScholarAouad,M.T.,Kanazi,G.E.,Siddik-Sayyid,S.M.,Gerges,F.J.,Rizk,L.B.,Baraka,A.S.(2005).Preoperativecaudalblockpreventsemergenceagitationinchildrenfollowingsevofluraneanesthesia.ActaAnaesthesiol.Scand.49,300–304.doi:10.1111/j.1399-6576.2005.00642.xPubMedAbstract|CrossRefFullText|GoogleScholarBoku,A.,Hanamoto,H.,Oyamaguchi,A.,Inoue,M.,Morimoto,Y.,Niwa,H.(2016).Effectivenessofdexmedetomidineforemergenceagitationininfantsundergoingpalatoplasty:arandomizedcontrolledtrial.Braz.J.Anesthesiol.66(1),37–43.doi:10.1016/j.bjan.2015.11.001PubMedAbstract|CrossRefFullText|GoogleScholarBuck,M.L.(2010).Dexmedetomidineuseinpediatricintensivecareandproceduralsedation.J.Pediatr.Pharmacol.Ther.15(1),17–29.PubMedAbstract|GoogleScholarChoi,G.J.,Baek,C.W.,Kang,H.,Park,Y.H.,Yang,S.Y.,Shin,H.Y.,etal.(2015).Emergenceagitationafterorthognathicsurgery:arandomisedcontrolledcomparisonbetweensevofluraneanddesflurane.ActaAnaesthesiol.Scand.59(2),224–231.doi:10.1111/aas.12435PubMedAbstract|CrossRefFullText|GoogleSchola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