The effects of intranasal dexmedetomidine premedication in ...

Intranasal dexmedetomidine premedication is a newly introduced method for reducing stress and anxiety before general anesthesia in children. Skiptomaincontent Advertisement SearchSpringerLink Search Theeffectsofintranasaldexmedetomidinepremedicationinchildren:asystematicreviewandmeta-analysis DownloadPDF DownloadPDF AbstractPurposeIntranasaldexmedetomidinepremedicationisanewlyintroducedmethodforreducingstressandanxietybeforegeneralanesthesiainchildren.Weperformedameta-analysistoidentifytheeffectsofintranasaldexmedetomidinepremedicationinchildren.SourceWeconductedasystematicreviewtofindpublishedrandomized-controlledtrialsusingintranasaldexmedetomidineaspremedication.WesearcheddatabasesinEMBASE™,MEDLINE®,andtheCochraneControlledTrialsRegisterusingtheOvidplatform.ThisstudywasconductedbasedontheCochraneReviewMethods.PrincipalfindingsThisreviewincluded1,168participantsin13studies.Intranasaldexmedetomidinepremedicationprovidedmoresatisfactorysedationatparentseparation(relativerisk[RR],1.45;95%confidenceinterval[CI],1.19to1.76;P=0.0002;I2=80%)thanotherpremedicationregimes.Inaddition,itreducedtheneedforrescueanalgesics(RR,0.58;95%CI,0.40to0.83;P=0.003;I2=0%).Nevertheless,therewerenodifferencesinsedationatmaskinduction(RR,1.25;95%CI,0.98to1.59;P=0.08;I2=71%)orintheincidenceofemergencedelirium(RR,0.52;95%CI,0.24to1.13;P=0.10;I2=67%).Intranasaldexmedetomidinewasassociatedwithasignificantlylowerincidenceofnasalirritation(RR,0.05;95%CI,0.01to0.36;P=0.003;I2=0%)andpostoperativenauseaandvomiting(RR,0.63;95%CI,0.40to0.99;P=0.04;I2=0%)thanotherpremedicationtreatments.Italsoshowedsignificantlylowersystolicbloodpressure(weightedmeandifference[WMD],−6.7mmHg;95%CI,−10.5to−2.9;P=0.0006;I2=96%)andheartrate(WMD,−6.8beats·min−1;95%CI,−11.3to−2.6;P=0.002;I2=98%).ConclusionsIntranasaldexmedetomidineprovidedmoresatisfactorysedationatparentseparationandreducedtheneedforrescueanalgesicsandtheincidenceofnasalirritationandpostoperativenauseaandvomitingwhencomparedwithotherpremedicationtreatments.RésuméObjectifLadexmédétomidineintranasaleestuneprémédicationnouvellementintroduitequipermetderéduirelestressetl’anxiétéavantuneanesthésiegénéralechezl’enfant.Nousavonsréaliséuneméta-analyseafind’identifierleseffetsdelaprémédicationintranasalededexmédétomidinechezl’enfant.SourceNousavonsentreprisunerevuesystématiquedelalittératureafind’extrairelesétudesrandomiséescontrôléespubliéesquiavaientexaminél’administrationintranasalededexmédétomidineenprémédication.Àl’aidedelaplateformeOvid,nousavonseffectuédesrecherchesdanslesbasesdedonnéesEMBASE™,MEDLINE®etdansleRegistredesétudescontrôléesCochrane.CetteétudeaétéréaliséeselonlaméthodologiederévisionCochrane.ConstatationsprincipalesCecompte-renduainclus1168participantstirésde13études.Laprémédicationintranasalededexmédétomidineaprocuréunesédationplussatisfaisantelorsdumomentdeséparationd’aveclesparents(risquerelatif[RR],1,45;intervalledeconfiance[IC]95%,1,19à1,76;P=0,0002;I2=80%)quelesautresrégimesdeprémédication.Enoutre,cerégimeposologiquearéduitlebesoinenanalgésiquesdesauvetage(RR,0,58;IC95%,0,40à0,83;P=0,003;I2=0 %).Toutefois,aucunedifférencen’aétéobservéeauniveaudelasédationaumomentdel’inductionaumasque(RR,1,25;IC95%,0,98à1,59;P=0,08;I2=71%)oudansl’incidencededéliriumauréveil(RR,0,52;IC95%,0,24à1,13;P=0,10;I2=67%).Ladexmédétomidineintranasaleaétéassociéeàuneincidencesignificativementplusbassed’irritationnasale(RR,0,05;IC95%,0,01à0,36;P=0,003;I2=0%)etdenauséesetvomissementspostopératoires(RR,0,63;IC95%,0,40à0,99;P=0,04;I2=0%)quelesautrestraitementsenprémédication.Unebaissesignificativedelatensionartériellesystolique(différencemoyennepondérée[DMP],−6,67mmHg;IC95%,−10,50à−2,85;P=0,0006;I2=96%)ainsiquedelafréquencecardiaque(DMP,−6,81battements·min−1;IC95%,−11,03à−2,59;P=0,002;I2=98%)aégalementétéobservée.ConclusionParrapportauxautrestraitementsenprémédication,ladexmédétomidineintranasaleaprocuréunesédationplussatisfaisantelorsdelaséparationdel’enfantetduparentetréduitlebesoind’analgésiquesdesauvetage,l’incidenced’irritationnasaleainsiquelesnauséesetvomissementspostopératoires. Premedicationinchildrenishelpfulforbothseparatingthechildfromtheirparentandreducingthechild’sstressandanxiety,thusfacilitatingsmoothinductionofanesthesia.Eventhoughintendedproceduresareexplainedtochildreninappropriatedetail,theyareanxiousaboutneedlesticksandareoftentechnicallychallengingtosedate.Furthermore,thedrugsgivenforthispurposeshouldhavelittleeffectonhemodynamicsandrespirationsoastoallowthechildtorecoverquicklyandtofacilitateearlydischargewithoutsideeffects.Severalapproacheshavebeenattemptedtoachievethisgoal.1 Tosedateachild,clinicianscommonlyuseintravenousdrugadministration.Nevertheless,sinceintravenouscannulationispainfulandoftenrequirestheuseofrestraints,itcouldleadtolong-termpsychologicalproblemsinthechild,suchasrefusingcontactwithhealthcareprofessionals.2Therefore,variousroutesforpremedicationhavebeenusedtoalleviatethepainofintravenouscannulation.Intranasalpremedicationdoesnotrequirevenouspunctureandrepresentsapotentialalternativeadministrativerouteforchildren.Thissitehasrichvascularizationandgooddrugpermeability;hence,intranasaladministrationleadstorapidabsorptionintosystemiccirculationandensuingeffectiveandrapidsedation.3,4Dexmedetomidineisapotent,highlyselective,andspecificalpha-2adrenoreceptoragonistwithbothsedativeandanalgesiceffects.5,6Whendexmedetomidineisadministeredthroughthenasalmucosa,itisaneasyandnoninvasiveroutewithahighbioavailabilityof81.8%.7Untilnow,therelativeeffectivenessofintranasaldexmedetomidinecomparedwithotherintranasalororalpremedicantsremainsincompletelystudied.Therefore,weconductedthisstudytoidentifytheefficacyandsafetyofpremedicationwithintranasaldexmedetomidineinchildren.Weperformedameta-analysisofrandomized-controlledtrialscomparingintranasaldexmedetomidinewithotherintranasalororalpremedications.MethodsWeusedasystematicapproachtoidentifypublicationsthatevaluatedtheefficacyandsafetyofintranasaldexmedetomidinepremedicationinchildren.Thissystematicreviewandmeta-analysisisbasedonthePreferredReportingItemsforSystematicReviewsandMeta-Analyses(PRISMA)andtheCochraneReviewMethods.8 DatasourcesandliteraturesourcesWesearchedEMBASE™(from1974),MEDLINE®In-Process&OtherNon-IndexedCitations,OvidMEDLINE(R)Daily,OvidMEDLINE(R)1946topresent,CochraneControlledTrialsRegister,andCochraneDatabaseofSystematicReviews.WeusedtheOVIDplatformtoexamineeachsourcefromitsinaugurationtoNovember3,2016.Inaddition,weperformedaliteraturesearchofWebofScience®,GoogleScholar,andKoreaMeddatabasestoretrievetherelevantstudies.Themainkeywordsweredexmedetomidine,intranasaldrugadministration,andrandomized-controlledtrial.StudyselectionTworeviewers(J.Y.K.andJ.H.J.)independentlyidentifiedallthestudiesusingpredefinedselectioncriteria.Athirdreviewer(K.N.K.)arbitrateddisagreementsthatoccurredintheprimarystudyselection.Studieswereincludedinthismeta-analysisiftheysatisfiedthefollowingcriteria:1)Literaturetype:randomized-controlledtrialsinallpublishedinternationaljournalswithoutlanguagerestriction;2)Subjects:childrenundergoingpremedicationtreatmentbeforesurgery;3)Interventions:studiesevaluatingtheefficacyandsafetyofintranasaldexmedetomidinepremedication;4)Outcomes:theprimaryoutcomesweresedationatseparationfrompatients,sedationatanesthesiamaskinduction,andtheincidenceofemergenceagitation;secondaryoutcomesweretheneedforpostoperativerescueanalgesia,durationofstayinthepostanesthesiacareunit,hemodynamicchanges,andadverseeffects(e.g.,incidenceofnauseaandvomiting,nasalirritation,laryngospasm,andshivering).Theoutcomevariablesaretheincidenceofeventsormeandifferencesbetweengroups.DataextractionTworeviewers(J.Y.K.andJ.H.J.)independentlyabstractedthedatausingapre-specifieddataabstractionform.Thethirdreviewer(K.N.K.)thenverifiedtheabstracteddata.Thefollowingvariableswereabstracted:1)thenumberofpatientsandpatientcharacteristics;2)theprotocolforpremedicationadministrationmethodanddose;3)theincidenceofeventsormeansandstandarddeviationsoftheoutcomedata;4)thetimepointofoutcomedatameasurement;and5)theincidenceofadverseeventsineachmethod.Ifthevariableswerenotreportedinanarticle,weemailedtheauthorstorequestthedata.AssessmentofmethodologicalqualityTworeviewers(K.N.K.andJ.H.J.)independentlyassessedtheriskofbiasusingtheCochraneriskofbiastool,whichconsidersthemethodsofrandomsequencegeneration,allocationconcealment,blindingofparticipantsandtheoutcomeestimator,incompletereportingofoutcomedata,selectivereportingofoutcomes,andothersourcesofbiasrisk.QualityoftheevidenceWeusedtheGRADE(GradesofRecommendation,Assessment,DevelopmentandEvaluation)WorkingGroupsystemtoevaluatethequalityoftheevidence.8Tworeviewers(K.N.K.andJ.H.J.)independentlyassessedthequalityofeachoutcome.ThefivecategoriesusedfortheGRADEqualityassessmentwere:limitationsofdesign,inconsistency,indirectness,imprecision,andpublicationbias.WeusedGRADEprofiler(GRADEpro)softwaretocreatethe“Summaryoffindings”table(Table 3),whichincludesthefollowingoutcomes:1)satisfactorysedationatparentseparation;2)satisfactorysedationatmaskinduction;3)incidenceofemergencyagitation;4)requirementofrescueanalgesics;5)incidenceofnasalirritation;6)systolicbloodpressure(SBP);and7)heartrate.StatisticalanalysisWereportcontinuousdataasmeandifferencesandtheirassociated95%confidenceintervals(CIs)withanalysesusingweightedmeandifferences(WMDs)determinedviathegenericinversevariancemethod.Binaryoutcomesarereportedasariskratio(RR)with95%CI.Heterogeneitybetweenstudieswasassessedusingtheχ2testandtheI2statistic.9WeconsideredanI2statistic>50%andaχ2testwithaPvalue<0.10toindicatestatisticalheterogeneity.Weusedrandomeffectsmodelswhensignificantstatisticalorclinicalheterogeneitywasdetected.Subgroupanalysiswasperformedaccordingtothepremedicationregimestoevaluatetheeffectofeachpremedicationmethod.Toevaluatehowtheriskofbiascouldaffectourestimates,weconductedsensitivityanalysisbyanalyzingonlystudieswithalowriskofbias.Thestudieswithmorethanoneareaofunclearorhighriskofbiaswereexcludedfromanalysis.Weusedfunnelplotstoassesspublicationbiasofthestudiesincludedinthismeta-analysis.AllstatisticalanalyseswereconductedusingtheCochraneCollaborationReviewManagerSoftware(RevManversion5.2).ResultsIdentificationofstudiesInitialdatabasesearchesidentified273publications.Afterremoving144duplicatedarticles,wefurtherexcluded106articlesbyscreeningtheirtitlesandabstracts.Followingreviewofthefullmanuscriptsfortheremaining23publications,weidentified13publicationsreportingpotentiallyrelevantstudies.Theothertenarticleswereeliminatedduetodifferentstudydesigns(fourarticles),onlyareportedabstract(onearticle),andinappropriateoutcomedata(fivearticles).Consequently,weincluded13studies10,11,12,13,14,15,16,17,18,19,20,21,22and1,168participantsinthismeta-analysis(Fig. 1).Fig. 1FlowdiagramoftheliteraturesearchstrategyFullsizeimage StudycharacteristicsandpatientpopulationsTheincludedarticleswereundertakenfrom2008-2016ineightdifferentcountries:USA(one),Turkey(one),SaudiArabia(one),India(three),China(three),Egypt(two),Mexico(one),andOman(one).Fourstudies13,18,19,22comparedtheeffectsofintranasaldexmedetomidinewiththoseoforalmidazolam,andsixstudies10,11,14,16,17,21comparedtheeffectsofintranasaldexmedetomidinewiththoseofintranasalmidazolam.Onestudycomparedintranasaldexmedetomidinewithintranasalclonidine,15andtwostudiescomparedintranasaldexmedetomidinewithintranasalnormalsaline.12,20Onestudyadditionallycomparedintranasaldexmedetomidinewithintranasalketamine,14andonestudyadditionallycomparedintranasaldexmedetomidinewithintranasalnormalsaline.10ThecharacteristicsoftheincludedstudiesaresummarizedinTable 1.Table 1Characteristicsoftheincludedrandomized-controlledtrialsevaluatingintranasaldexmedetomidinepremedicationFullsizetable QualityoftheincludedstudiesAlloftheincludedstudiesusedarandomallocationmethod.Tenstudies10,11,12,13,14,15,16,17,18,22describedtheallocationconcealmentindetail,andsixstudies10,11,13,15,16,22concretelyexplainedtheirblindingmethods.Theriskofallocationconcealmentandblindingwasunclearintheotherstudies.Inmoststudies,therewaslowriskofincompleteoutcomedataandselectivereporting.RiskofbiasgraphsandsummariesarepresentedinFig. 2AandB.Fig. 2(A)risk-of-biasgraphforalltheincludedrandomized-controlledtrials;(B)risk-of-biassummaryFullsizeimage PublicationbiasFunnelplotsoftheoutcomesdidnotshowasymmetricalshape(ElectronicSupplementaryMaterialFigs 1-3);however,theaccuracyofthefunnelplotsisuncertainduetothelow(i.e.,<10)numberofincludedstudies.8 SatisfactorysedationatparentseparationSatisfactorysedationatparentseparationwasreportedinninerandomizedtrials11,13,14,16,17,18,19,21,22with896patients.Satisfactorysedationatparentseparationwasevaluatedbysedationscoresonafour-pointsedationscale14,16,17,18andontheModifiedObserver’sAssessmentofAlertness/SedationScale.11,19,21,22Eachstudydeterminedasleepyorlethargicresponsetoparentseparationasasatisfactorylevelofsedation.Wefoundthatpatientswhowerepremedicatedwithintranasaldexmedetomidineweresignificantlysedatedatparentseparationwhencomparedwithotherpremedicationtreatments(RR,1.45;95%CI,1.19to1.76;P=0.0002;I2=80%)(Fig. 3A).Asubgroupanalysisofthetrialscomparingintranasaldexmedetomidinewithoralmidazolamrevealedthatintranasaldexmedetomidinewasmoreeffectivethanoralmidazolam(RR,1.56;95%CI,1.15to2.11;P=0.005;I2=82%).Therewasnodifferencebetweenintranasaldexmedetomidineandintranasalmidazolam(RR,1.42;95%CI,0.96to2.11;P=0.08;I2=85%).Fig. 3Theeffectsofintranasaldexmedetomidinepremedication(A)impactonsatisfactorysedationatparentseparation;(B)impactonsatisfactorysedationatmaskinductionFullsizeimage SatisfactorysedationatmaskinductionSeventrials11,13,16,17,18,19,21with648patientscomparedsatisfactorysedationatmaskinduction.Similartosatisfactorysedationatparentseparation,sedationstatusatmaskinductionwasevaluatedbysedationscoresonafour-pointsedationscale14,16,17,18andonaModifiedObserver’sAssessmentofAlertness/SedationScale.19,21,22Therewerenodifferencesinsatisfactorysedationatmaskinductionbetweenintranasaldexmedetomidineandpremedicationwithotherdrugs(RR,1.25;95%CI,0.98to1.59;P=0.08;I2=71%)(Fig. 3B).Asubgroupanalysisalsorevealednodifferencesbetweenintranasaldexmedetomidineandintranasalmidazolam(RR,1.14;95%CI,0.77to1.67;P=0.51;I2=78%)orbetweenintranasaldexmedetomidineandoralmidazolam(RR,1.40;95%CI,0.99to1.99;P=0.06;I2=71%).EmergenceagitationTheincidenceofemergenceagitationwasextractedfromsixtrials.10,11,13,15,16,18Emergenceagitationwasevaluatedbyafour-pointsedationscale,16,18modifiedYalescale,13PediatricAnesthesiaEmergenceDeliriumscale,10orAonosfour-pointscale.15Intranasaldexmedetomidinepremedicationshowednoevidenceofreducingemergenceagitationwhencomparedwithotherpremedicationtreatments.(RR,0.52;95%CI,0.24to1.13;P=0.10;I2=67%)(Fig. 4A).Also,subgroupanalysisshowednodifferencewhendexmedetomidinepremedicationwascomparedwithintranasalmidazolam(RR,0.70;95%CI,0.29to1.68;P=0.42;I2=51%),oralmidazolam(RR,0.27;95%CI,0.02to3.94;P=0.34;I2=87%),andintranasalclonidine(RR,0.64;95%CI,0.31to1.31;P=0.22).Fig. 4Theeffectsofintranasaldexmedetomidinepremedication(A)impactontheincidenceofemergenceagitation;(B)impactontheneedforrescueanalgesicsFullsizeimage NeedforrescueanalgesicsIntranasaldexmedetomidinepremedicationreducedtheneedforrescueanalgesicswhencomparedwithotherpremedicationtreatments(RR,0.58;95%CI,0.40to0.83;P=0.003;I2=0%)(Fig. 4B).Subgroupanalysisrevealedthatintranasaldexmedetomidinepremedicationwasmoreeffectiveindecreasingpostoperativepainthanoralmidazolam(RR,0.53;95%CI,0.30to0.96;P=0.04;I2=0%).PostoperativenauseaandvomitingTheincidenceofpostoperativenauseaandvomitingwasextractedfromsixtrials10,11,14,15,16,17including496patients.Patientswhoreceivedintranasaldexmedetomidinepremedicationexperiencedasignificantlylowerincidenceofpostoperativenauseaandvomitingwhencomparedwithotherpremedicationregimes(RR,0.63;95%CI,0.40to0.99;P=0.04;I2=0%)(Fig. 5A).Fig. 5Theeffectsofintranasaldexmedetomidinepremedication(A)impactontheincidenceofpostoperativenauseaandvomiting;(B)impactontheincidenceofnasalirritation;(C)impactonthetimetodischargefromthepostanesthesiacareunit(min)Fullsizeimage NasalirritationTheincidenceofnasalirritationwasextractedfromthreetrials10,16,17including198patients.Patientswhoreceivedintranasaldexmedetomidinepremedicationexperiencedasignificantlylowerincidenceofnasalirritationthanpatientswhoreceivedintranasalmidazolam(RR,0.05;95%CI,0.01to0.36;P=0.003;I2=0%)(Fig. 5B).TimetodischargefromthepostanesthesiacareunitFourtrials10,15,16,22including338patientsreportedthetimetodischargefromthepostanesthesiacareunit.Wefoundnodifferencesbetweenintranasaldexmedetomidineandtheotherpremedication(WMD,1.2min;95%CI,−1.7to4.1;P=0.43;I2=94%)(Fig. 5C).HemodynamicvariablesWeextractedSBPdatafor167patientsfromfivetrials.14,17,19,21,22FourtrialsreportedSBP30minafterpremedication,andonetrial22reportedSBPatthetimeoftransfertotheoperatingroom.IntranasaldexmedetomidinepremedicationsignificantlydecreasedSBP(WMD,−6.7mmHg;95%CI,−10.5to−2.9;P=0.0006;I2=96%)(Fig. 6A).Heartratewasreportedinseventrials13,14,17,18,19,21,22comprisedof675patients.Intranasaldexmedetomidinepremedicationalsosignificantlydecreasedheartrate(WMD,−6.8beats·min−1;95%CI,−11.0to−3.0;P=0.002;I2=98%)(Fig. 6B).Therewasnoincidenceofhypoxia(oxygensaturation<95%),bradycardia,orhypotensioninanygroup,andthesedatawereextractedfromsixtrials,13,14,16,19,21,22sixtrials,11,13,14,16,17,22andfivetrails,11,13,16,17,22respectively.Fig. 6Theeffectsofintranasaldexmedetomidinepremedication(A)impactonsystolicbloodpressure(mmHg);(B)impactonheartrate(beats·min−1)Fullsizeimage SensitivityanalysisWeconductedasensitivityanalysistoevaluatehowtheriskofbiascouldaffectourestimates.Thesensitivityanalysisoftheriskofbiasdidnotaffecttheresults(Table 2).Thesensitivityanalysis,includingonlythosestudieswithlowriskofbiasandsatisfactorysedationatparentseparation,showedthatchildrenreceivingintranasaldexmedetomidineweresignificantlysedatedatparentseparation(RR,1.26;95%CI,1.06to1.75;P=0.002;I2=55%).Therewerenodifferencesinsatisfactorysedationatmaskinductionbetweenintranasaldexmedetomidineandpremedicationwithotherdrugs(RR,1.19;95%CI,0.83to1.70;P=0.34;I2=80%).Intranasaldexmedetomidinepremedicationshowednoevidenceofreducingemergencedelirium(RR,0.47;95%CI,0.19to1.13;P=0.09;I2=73%).Table 2SensitivityanalysisofprimaryandsecondaryoutcomesFullsizetable QualityoftheevidenceTheGRADEapproachwasusedtoassessthequalityofeachoutcomeand“Summaryoffindings”tableswerepresented(Table 3).Asaresult,theoverallqualityofevidenceinthismeta-analysiswaslowormoderate.Althoughthequalityofstudydesignwashigh,mostoutcomeshadproblemsofinconsistencyandimprecision.Table 3GRADEsummaryoffindingstableFullsizetable DiscussionThismeta-analysisrevealedthatintranasaldexmedetomidinepremedicationforpediatricpatientsresultedinmoresatisfactorysedationatparentseparationandreducedtheneedforrescueanalgesicscomparedwithotherpremedicationregimes.Nevertheless,itshowednodifferencesfromotherintranasalororalpremedicantsinsatisfactorysedationatmaskinductionorintheincidenceofemergenceagitation.Intranasaldexmedetomidinepremedicationwasalsoassociatedwithasignificantlyreducedincidenceofpostoperativenauseaandvomitingandnasalirritationcomparedwithotherpremedicationregimes.Asforitssafety,althoughchildrenexperiencedlowerSBPandheartrateusingintranasaldexmedetomidinepremedication,nooneneededtreatmentforhypotensionandbradycardia.Althoughcliniciansfrequentlyusepremedication,theidealagentandrouteofadministrationforpremedicationinchildrenremainsuncertain.Themostcommonrouteforpremedicationinchildrenisoraladministration,butithaslowbioavailability.23Rectaladministrationoftencausespain,couldleadtoexpulsioninyoungchildren,andmightnotbeappropriateforolderchildren.Anintramuscularapproachisnotrecommendedforchildrenbecauseitisinvasive.24Themosteffectiverouteforpremedicationinchildrencouldbetransmucosal,includingintranasal,sublingual,andbuccaladministration,duetothehighvascularizationofmucosaanditsabilitytobypassfirst-passmetabolism.25Especiallyforyoungchildren,compliancewithnasalsedationismoreeasilyattainedthanoralsedation.26 Thus,intranasalmidazolamcanbeaneffectivepremedicationinchildren.Itresultsinrapidsedationandiscommonlyadministered30minbeforeinductionorsurgery.24Nevertheless,thesensationofburningandnasalirritationisadisadvantageofthismethod,andsneezingorcoughingcausedbythenasalirritationcouldreducetheeffectsofnasalpremedication.27Incontrasttothenasalirritationoftencausedbyintranasalmidazolam,inourmeta-analysis,noneofthechildrengivenintranasaldexmedetomidinepremedicationexhibitedsignsofnasalirritation.Moreover,consideringthepoorbioavailabilityoforallyadministereddexmedetomidine,intranasaladministrationisamoresuitablenoninvasiverouteforpremedication.7 Althoughintranasaldexmedetomidinewasfoundtobemoreeffectivethanintranasalandoralmidazolaminachievingsatisfactorysedationforseparatingchildrenandparents,itdidnotprovidesatisfactorysedationatmaskinduction.Asdescribedabove,sedationwithdexmedetomidinehasamechanismsimilartonaturalsleep,withhyperpolarizationofnorepinephrinereceptorsinthelocuscoeruleus.28Thus,dexmedetomidineleadstosedationwithoutexcessivedrowsiness,andtheresultingsedationissubjecttoeasyandrapidarousal,likenaturalsleep.6Therefore,itisnotunexpectedthatpatientsrespondedtoexternalstimulisuchasmaskventilation.Dexmedetomidine,apotentialalpha-2agonist,decreasesbloodpressureandheartrateinadose-dependentmanner.29Furthermore,rapidinjectionofdexmedetomidinecanhavebiphasiceffectsonbloodpressure,withtemporaryincreasesfromadirectα2-adrenoceptor-inducedvasoconstrictiveresponseintheperipheralvasculaturefollowedbyalowerarterialpressurefromadecreasedsympatheticoutflow.5,30Thisbiphasiceffectonbloodpressurecanbeattenuatedbyinjectingdexmedetomidineslowly.28Inourmeta-analysis,childrenwhoreceivedintranasaldexmedetomidineaspremedicationshowedlowerSBPandheartratebeforeinduction.Nevertheless,nopatientsintheincludedtrialsneededtreatmentforbradycardiaorhypotension.Moreover,smallchanges(adecreaseinheartrateof6.8beats·min−1andadecreaseinSBPof6.7mmHg)indicateonlyminorclinicalsignificanceasregardsthesedecreases.Becausethehemodynamicchangesafterusingdexmedetomidinerequirednopharmacologicinterventionsanddidnotresultinanyadverseevents,dexmedetomidineisconsideredanappropriatesedativeforchildren.31Therefore,aslongasitisusedcarefullyandavoidedforpatientsatriskofhemodynamicinstability,intranasaldexmedetomidineissafetogiveaspremedicationtomostchildren.Theincidenceofpostoperativenauseaandvomitingandtheneedforrescueanalgesicsdecreasedsignificantlywithintranasaldexmedetomidinepremedicationcomparedwithothertreatments.Itsantiemeticpropertiescomefromthealpha-2adrenoreceptoragonisteffect,whichdecreasesnoradrenergicactivitybybindingtothealpha-2presynapticinhibitoryreceptorsinthelocuscoeruleusinthebrain.32Inaddition,theanalgesicpropertyofdexmedetomidinethatreducedpostoperativeopioidrequirementsalsohelpedreduceopioid-inducednauseaandvomiting.33,34Thesefactssupporttheuseofintranasaldexmedetomidineaspremedicationtoreducepostoperativenauseaandvomiting.LimitationsThismeta-analysishassomelimitations.First,wedidnotprospectivelyregisterthisreviewonPRISMAasitwasnotarequirementforpublicationatthetimeweundertookthereview.Second,wefoundsignificantheterogeneityamongstudies.Clinicalheterogeneity,suchaspremedicationdose,typeofintervention,typeofsurgery,anddifferentagerangeswereidentified.Becauseofthisclinicalheterogeneity,weusedrandomeffectsmodelsforourmeta-analysis.Furthermore,varioussedationscalesandmeasurementsprecludedfurthersynthesisofthedata.Third,wetriedtosynthesizethedataonadverseeffects;however,weleftoutsomeadverseoutcomes,e.g.,laryngospasmandshivering,duetolackofdata.Lastly,weincludedonlyasmallnumberofpatientsinthisstudy.Theinterventioneffectsofsmallclinicaltrialswithincompleteallocationsequencegeneration,allocationconcealment,anddoubleblindingareatriskofbeingoverestimated.35Althoughallstudiesinthismeta-analysisusedarandomallocationmethodandobjectivelymeasuredoutcomedata(e.g.,hemodynamicvalues,postoperativerescueanalgesia,andtimeinthepostanesthesiacareunit)cautionisneededwheninterpretingourresults.Therefore,well-controlledrandomizedstudiesarestillneededtoevaluatethesafetyofintranasaldexmedetomidinepremedication.Inconclusion,thismeta-analysishasprovidedevidencethatintranasaldexmedetomidineprovidesmoresatisfactorysedationatparentseparationthanotherintranasalororalpremedicants.Additionaladvantagestointranasaldexmedetomidinepremedicationincludeareductionintheincidenceofpostoperativenauseaandvomiting,nasalirritation,andtheneedforrescueanalgesics.Althoughlowersystolicandmeanbloodpressureandheartrateswerefound,thosedecreasesareconsideredtobeofminorclinicalsignificance. 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Editorialresponsibility ThissubmissionwashandledbyDr.HilaryP.Grocott,Editor-in-Chief,CanadianJournalofAnesthesia. Authorcontributions JongHunJunandKyuNamKimwereinvolvedinthestudydesignandwritingthearticle.JongHunJun,KyuNamKim,JiYoonKim,andShinMeSongwereinvolvedintheanalysisandinterpretationofdata.KyuNamKimandJiYoonKimwereinvolvedinstudyselection,dataextraction,andassessmentofmethodologicalquality. Financialdisclosure Theauthorshavenofinancialrelationshipsrelevanttothisarticle. Fundingsource Therewasnoexternalfunding. AuthorinformationAffiliationsDepartmentofAnesthesiologyandPainMedicine,HanyangUniversityHospital,222,Wangsimni-ro,Seongdong-gu,Seoul,133-792,RepublicofKoreaJongHunJunMD,PhD, KyuNamKimMD,PhD, JiYoonKimMD & ShinMeSongMDAuthorsJongHunJunMD,PhDViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKyuNamKimMD,PhDViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJiYoonKimMDViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarShinMeSongMDViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto KyuNamKimMD,PhD.ElectronicsupplementarymaterialBelowisthelinktotheelectronicsupplementarymaterial. Fig 1Funnelplotfor(A)satisfactorysedationatparentseparation;(B)satisfactorysedationatmaskinduction;(C)theincidenceofemergenceagitation(PDF51kb)Fig 2Funnelplotfor(A)theneedforrescueanalgesics;(B)theincidenceofpostoperativenauseaandvomiting;(C)theincidenceofnasalirritation(PDF53kb)Fig. 3Funnelplotfor(A)thetimetodischargefromthepostanesthesiacareunit;(B)systolicbloodpressure;(C)heartrate(PDF49kb)RightsandpermissionsReprintsandPermissionsAboutthisarticleCitethisarticleJun,J.H.,Kim,K.N.,Kim,J.Y.etal.Theeffectsofintranasaldexmedetomidinepremedicationinchildren:asystematicreviewandmeta-analysis. CanJAnesth/JCanAnesth64,947–961(2017).https://doi.org/10.1007/s12630-017-0917-xDownloadcitationReceived:09February2017Revised:19April2017Accepted:15June2017Published:21June2017IssueDate:September2017DOI:https://doi.org/10.1007/s12630-017-0917-xSharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative DownloadPDF Advertisement