Rev. Bras. Anestesiol. vol.67 número2

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

REVIEW

ARTICLE

Effect

of

dexmedetomidine

in

children

undergoing

general

anesthesia

with

sevoflurane:

a

meta-analysis

Marco

Aurélio

Soares

Amorim

,

Catia

Sousa

Govêia

,

Edno

Magalhães

,

Luís

Cláudio

Araújo

Ladeira

_,

_Larissa

_Govêia

_Moreira

_,

_Denismar

_Borges

_de

_Miranda

a_{CentrodeEnsinoeTreinamentoJoséQuinan,Goiânia,GO,Brazil}

b_{UniversidadedeBrasília(UnB),CentrodeEnsinoeTreinamento,Brasília,DF,Brazil} c_{SociedadeBrasileiradeAnestesiologia,RiodeJaneiro,RJ,Brazil}

d_{UniversidadedeBrasília(UnB),FaculdadedeCiênciasMédicas,Brasília,DF,Brazil} e_{UniversidadedeBrasília(UnB),Brasília,DF,Brazil}

f_{UniversidadeFederaldeSãoPaulo(Unifesp),SãoPaulo,SP,Brazil} g_{HospitalUniversitáriodeBrasília,Brasília,DF,Brazil}

h_{SecretariadeSaúdedoDistritoFederal,Brasília,DF,Brazil}

i_{PontifíciaUniversidadeCatólicadeGoiás(PUC-GO),Goiânia,GO,Brazil}

j_{UniversidadeFederaldeGoiás(UFG),InstitutodeMedicinaTropicaleSaúdePública,Goiânia,GO,Brazil}

Received18December2015;accepted15February2016 Availableonline25November2016

KEYWORDS

Generalanesthesia; Inhalational anesthetics; Dexmedetomidine; Psychomotor agitation; Meta-analysis

Abstract

Backgroundandobjectives: Sevofluraneisoftenusedinpediatricanesthesiaandisassociated

withhighincidenceofpsychomotoragitation.Insuchcases,dexmedetomidine(DEX)hasbeen used,but itsbenefit andimplicationsremainuncertain.We assessedthe effectsofDEXon agitationinchildrenundergoinggeneralanesthesiawithsevoflurane.

Method: Meta-analysis ofrandomizedclinicalanddouble-blindstudies,withchildren

under-going electiveproceduresundergeneralanesthesiawithsevoflurane,usingDEXorplacebo. WesoughtarticlesinEnglishinPubMeddatabaseusingthefollowingterms:Dexmedetomidine, sevoflurane(MethylEthers/sevoflurante),andagitation(PsychomotorAgitation).Duplicate arti-cleswithchildrenwhoreceivedpremedicationandusedactivecontrolwereexcluded.Itwas adoptedrandomeffectsmodelwithDerSimonian---Lairdtestingandoddsratio(OR)calculation for dichotomousvariables,andstandardizedmeandifferencefor continuous variables,with theirrespective95%confidenceinterval(CI).

Results:Of 146studiesidentified,10wereselected totaling558patients(282inDEXgroup

and276controls).TheuseofDEXwasconsideredaprotectivefactorforpsychomotoragitation (OR=0.17;95%CI0.13---0.23;p<0.0001)andnauseaandvomitinginPACU(OR=0.49;95%CI 0.35---0.68;p<0.0001).Wake-uptimeandPACUdischargetimewerehigherinthe dexmedeto-midinegroup.Therewasnodifferencebetweengroupsfor extubationtimeanddurationof anesthesia.

∗_{Correspondingauthor.}

E-mail:[email protected](M.A.Amorim).

http://dx.doi.org/10.1016/j.bjane.2016.02.007

Conclusion:Dexmedetomidinereducespsychomotoragitationduringwake-uptimeofchildren undergoinggeneralanesthesiawithsevoflurane.

©2016SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALAVRAS-CHAVE

Anestesiageral; Anestésicos inalatórios; Dexmedetomidina; Agitac¸ão

psicomotora; Metanálise

Efeitodadexmedetomidinaemcrianc¸assubmetidasàanestesiageral comsevoflurano:umametanálise

Resumo

Justificativaeobjetivos: Sevofluranoéfrequentementeusadoemanestesiapediátricaeestá

associadoàaltaincidênciadeagitac¸ãopsicomotoraaodespertar.Nessescasosa dexmedeto-midina(dex)temsidousada,porémpermanecemincertosseusbenefíciosesuasimplicac¸ões. Foramavaliados osefeitos dadex sobre aagitac¸ão nodespertar decrianc¸as submetidasà anestesiageralcomsevoflurano.

Método: Metanálisedeensaiosclínicosrandomizadoseduplamenteencobertos,comcrianc¸as

submetidas aprocedimentos eletivos sob anestesiageral comsevoflurano,que usaram dex

ou placebo. Buscaram-se artigos em língua inglesa nabase de dados Pubmed com termos

como Dexmedetomidine, sevoflurane (MethylEthers/sevoflurane) eagitation(Psychomotor

Agitation).Artigosduplicados,comcrianc¸asquereceberammedicac¸ãopré-anestésicaeque

usaramcontroleativoforamexcluídos.Adotou-semodelodeefeitosaleatórioscomtestesde DerSimonian-Lairdecálculodeoddsratio(OR)paravariáveisdicotômicasediferenc¸ademédia padronizadaparavariáveiscontínuas,comseusrespectivosintervalosdeconfianc¸ade95%(IC).

Resultados: Dos146estudosidentificados,10foramselecionados,com558pacientes(282no

grupodexe276controles).Ousodadexfoiconsideradofatordeprotec¸ãoparaagitac¸ão psi-comotora(OR=0,17;95%IC0,13-0,23;p<0,0001)eparanáuseasevômitosnaSRPA(OR=0,49; 95%IC0,35-0,68;p<0,0001).TempoparadespertareparaaltadaSRPAforammaioresnogrupo dexmedetomidina.Nãohouvediferenc¸aentreosgruposparatempodeextubac¸ãoedurac¸ão daanestesia.

Conclusão:A dexmedetomidinareduzaagitac¸ãopsicomotoranodespertardecrianc¸as

sub-metidasàanestesiageralcomsevoflurano.

©2016SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Este ´eum artigoOpen Accesssobumalicenc¸aCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Sevoflurane is widely used in pediatric anesthesia for its pharmacological profile, which allows rapid inhalational inductionand awakeningfromanesthesia, low hepatotox-icityandhemodynamicstability.1_{However,theoccurrence}

ofagitationisacommonphenomenoninchildrenundergoing generalanesthesiawithsevoflurane.1

Emergence agitation in children wasfirst described in the early 1960s and is characterized by a dissociated state of consciousness in which the child becomes incon-solable,irritable,uncooperative,andsometimesaggressive. Althoughtemporary,itisanextremelydistressingeventfor children,parents,andhealthprofessionals.2

Prevalence of agitation varies from 25% to 80% in the literature, depending on the definition and criteria used by the authors.1,3 _{It is influenced by the technique}

and anesthetic agents.4 _{Different drugs such as opioids,}

ketamine, benzodiazepines, and ␣₂-agonists,2 have been

used in the prevention and treatment of agitation, but withvaryingsuccess,whichcontributestothedevelopment

of studies to improve perioperative care delivered to children.

Dexmedetomidine (Dex), dextrorotatoryenantiomer of medetomidine,isahighlyselective␣₂-adrenergic,withan ␣₂:␣₁receptorratioof1,600:1,andimportantsedativeand

analgesiceffects.5_{Itssedativeeffectoccursthrough}

inter-actionwithpostsynaptic␣₂-receptorsinthelocuscoeruleus,

reducesnoradrenalinrelease,andfacilitatestheaction of inhibitory neurons, particularly gamma-aminobutyric acid system.Theanalgesiceffectispromotedbytheactionof␣₂

-receptorsondorsalhornandsupraspinalcordanddecreased releaseofsubstanceP.6

Methods

This is a meta-analysis of clinical trials evaluating the use of dexmedetomidine to prevent emergence agi-tation in children undergoing general anesthesia with sevoflurane. PRISMA guidelines7 _{were followed to}

per-form a systematic review and meta-analysis of random-ized controlled trials. Articles in English (2000---2014) were selected in the Pubmed database with key-words such as Dexmedetomidine, sevoflurane (Methyl Ethers/sevoflurante)andagitation(PsychomotorAgitation), or its synonyms separated by AND/OR interlocutors with the following search strategy: (dexmedetomidine[MeSH Terms]) OR adrenergic alpha agonists[MeSH Terms]) OR dexmedetomidine[Title/Abstract]) OR dexmedetomi-dine) OR adrenergic alpha agonists) AND anesthet-ics, intravenous[MeSH Terms]) OR anesthetics, intra-venous[Title/Abstract])AND(hypnoticsandsedatives[MeSH Terms])) OR (hypnotics and sedatives[Title/Abstract])) AND sevoflurane) OR sevoflurane[Title/Abstract]) OR sevoflurane[Supplementary Concept]))ANDchildren[MeSH Terms]))ANDagitation,psychomotor[MeSHTerms].In addi-tiontothesearch,wereviewedmanuallythereferencesof studiesmeeting theinclusioncriteria, inordertoidentify originalstudiesthatwerenotpreviouslyfound.

Randomized, double-blind, controlled studies, with children (under 10 years old) undergoing elective proce-dures under general anesthesia with sevoflurane, using dexmedetomidineorplacebowereincluded.Duplicate arti-cles or with children using premedication, involving only sedationandusingactivecontrolwereexcluded.

Two independent researchers (MA and CG) conducted a preliminary assessment of the titles/abstracts and data extraction. Selectedstudies were read in full considering the inclusion and exclusion criteria. In case of disagree-ment, a third researcher (LC) made the final evaluation. Dataregarding patient’s age, anesthesia(Dex dose), type ofprocedure,andoutcomeswererecordedona standard-ized form developed by the authors. For this study, the followingoutcomeswereconsidered:emergence agitation (definedby each paper according tothe scale used: Pae-diatricAnaesthesiaEmergenceDelirium---PAED,8_Watcha,9

andfive-pointscale)10_{;PONV(presentorabsent);andtimes}

forextubation,emergence,PACUdischarge,anddurationof anesthesia(timeintervaldescribedbyarticlesinminutes). Sensitivity analysis was planned to explore sources of heterogeneity between studies, when present. Statistical heterogeneitywascalculatedusingthechi-squaremethod (2) and Higgins’ test (I2).11 Presence of heterogeneity

was considered at p<0.05 and I2_{≥50%. Odds ratio (OR)} with 95% confidence interval (CI) was used to quantify thestatistical differencebetweengroups fordichotomous variablesandstandardizedmeandifference(SMD)for con-tinuous variables (time in minutes). After assessing the qualityandstatisticalheterogeneityofstudies,weadopted the random effects model using the DerSimonian---Laird12

method and statistical analysis using the BioEstat® 5.0 software.13_{Theassessmentofpotentialforpublicationbias}

was made by visual analysis of funnel plots and Begg’s14

and Egger’s15 _{tests, with statistical significance level set}

at5%.

Results

Initially,146studieswereidentified(116studiesinPubmed and30 manuallysearched),of which10 wereselected to composethismeta-analysis,asshowninFig.1.

The 10studies included 558patients, 282in the inter-vention group, and 276 in the control group (Table 1). ThreestudieswereconductedinTurkey,17---19 _threestudies

inChina,21---23 _{andothersstudiesinChile,}1_{UnitedStates,}16

Japan,20_{andSouthKorea.}24

Emergenceagitationwasassessedin10studies,andthe useofdexmedetomidine wasconsideredaprotection fac-tor(OR=0.17;95% CI0.13---0.23; p<0.0001), as shown in

Fig.2.Surgerysubgroupanalysisshowednoeffectchange (urogenital1,24 _{with OR=0.14; 95% 0.04---0.44; p=0.0008;}

ophthalmic21,23_{withOR=0.06;95%CI0.01---0.45;p=0.0067,}

ENT,17,19_{withOR=0.20;95%CI0.14---0.30;p<0.0001).}

The use of dexmedetomidine reduces the incidence of PONV (Fig. 3), with OR=0.49 (95% CI 0.35---0.68 and

p<0.0001).

Emergencetimewasassessedinsevenstudies,17---19,21---23

(SMD=1.78; 95% CI 1.12---2.44; p=0.0001) and PACU dis-chargeinfourstudies1,16,18,23_{(SMD=8.54;95%CI6.62---10.44;}

p<0.0001),higherindexmedetomidinegroup.

Therewasnodifferencebetweengroupsregarding extu-bation time (SMD=0.70; 95% CI 0.33---1.06; p=0.0002), assessedin eight studies,1,16---19,21---23 _{and duration of}

anes-thesia(SMD=3.19;95%CI−0.79---7.14;p=0.11),assessedin

sevenstudies.1,16,18---20,23,24

Based on the funnel plot analysis (Fig. 4), thereis an asymmetry with no small sample studies to the right of thesummaryeffect,whichsupportsapotentialfor publica-tionbiasconfirmedbyBegg’s(p=0.02)andEgger’s(p=0.03) tests.

Discussion

Thismeta-analysisconsistsof10randomizedcontrolled tri-alspublishedbetween 2004 and2014,which assessedthe effectofdexmedetomidineonemergenceagitationin chil-drenundergoinggeneralanesthesiawithsevoflurane.

Search result (n=146)

Excluded duplicates (n=20)

Title and abstract reading (n=126)

Excluded: not relevant (n=104), adults (n=6) and

active control (n=1)

Eligible for full-text reading (n=15)

Studies included in the meta-analysis (n=10)

Excluded for using premedication (n=5)

Table1 Descriptionofselectedstudies.

Study Yearofpublication Studydetails n Age Proceduretype

Ibacache1 _{2004 Dex0.3mcgkg}−1 _{30 1---10 Inguinalherniarepair,orchidopexy}

andcircumcision Salinesolution 30

Shukry16 _{2005 Dex0.2mcgkg}−1 _{23 1---10 Electivesurgeries}

Salinesolution 23

Guler17 _{2005 Dex0.5mcgkg}−1 _{30 3---7 Adenotonsillectomy}

Salinesolution 30

Isik18 _{2006 Dex1mcgkg}−1 _{21 1---10 Magneticresonanceimaging}

Salinesolution 21

Erdil19 _{2009 Dex0.5mcgkg}−1 _{30 2---7 Adenoidectomywithorwithout}

myringotomy Salinesolution 30

Sato20 _{2010 Dex0.3mcgkg}−1 _{39 1---9 Outpatientsurgery}

Salinesolution 42

Lili21 _{2012 Dex0.5mcgkg}−1 _{30 3---7 Vitrectomy}

Salinesolution 30

He22 _{2013 Dex1mcgkg}−1 _{32 3---7 Smallsuperficialsurgeries}

Salinesolution 26

Chen23 _{2013 Dex1mcgkg}−1 _{27 2---7 Strabismus}

Salinesolution 24

Kim24 _{2014 Dex1mcgkg}−1 _{20 1---5 Hernioplastyororchidopexy}

Salinesolution 20

Weight (%) Control

(n/N)

9.39 11/30

11.21

12.27

4.82

12.32

19.39

9.54

0.22 (0.06-0.82)

0.24 (0.07-0.82)

0.17 (0.05-0.53)

0.08 (0.01-0.51)

0.24 (0.08-0.78)

0.16 (0.04-0.62)

7.40

8.87

4.75

100 14/23

17/30

10/21

14/30

27/42

13/30

11/26

11/24

11/20

0.01 0.1 0.2 0.5 1.0 2.0 5.0 10.0 139/276

Dex (n/N)

3/30

6/23

5/30

1/21

5/30

7/39

3/30

2/32

3/27

1/20

38/282

Favors dexmedetomidine

Favors control

Overall effect test: Z=11.92 (p<0.0001) Study

Ibacache 2004

Shukry 2005

Guler 2005

Isik 2006

Erdil 2009

Sato 2010

Lili 2012

He 2013

Chen 2013

Kim 2014

Total

Heterogeneity test;

χ2 _{= 3.19; df=9 (p=0.96); I}2 _{= 0%}

0.11 (0.02-0.49)

0.17 (0.04-0.66)

0.06 (0.01-0.41)

0.17 (0.13-0.23) 0.23 (0.09-0.57) OR (95% CI)

Figure 2 Meta-analysis of dexmedetomidine effect on emergence agitation in children undergoing general anesthesia with sevoflurane.

There was variation in dexmedetomidine dosage (0.2---1.0mcgkg−1_{),aswellasinadministrationtechnique.} One used continuous infusion of dexmedetomidine16 _and

the others used it for a short period, ranging from 5 to 10min. Regarding the time of administration, only one studyadministeredthedrugat theendoftheprocedure17

and all others after induction of anesthesia, with similar resultsregardingemergenceagitation,whichconfirmsthat thereisnoidealtimefordexmedetomidineadministration. The causes of emergence agitation following general anesthesiaaremultifactorial;itmayinvolvepain,anxiety, anddisorientationonrapid awakening.25 _{Inanattempt to}

minimizethisevent,numerousdrugshavebeenused,such as opioids, ketamine, benzodiazepines, and ␣₂-agonists,

but with uncertain results.2 _{This meta-analysis presents}

dexmedetomidine as a protective factor for emergence agitation in children undergoing general anesthesia with sevoflurane, similar result already described by other authors.2 _{Although the actual mechanism for this effect}

remains unknown, it is believed that the analgesic and sedative effects of dexmedetomidine contribute to this phenomenon, aspostoperative analgesic consumptionwas lower.2

Sevoflurane has been associated with high incidence of emergence agitation in children undergoing general anesthesia,1,17 _{evenwithout surgery.}18 _{Thisfact isnot yet}

0.01 0.1 0.2 0.5 1.0 2.0 5.010.0

Favors dexmedetomidine

Favors control

Overall effect test: Z=4.21 (p<0.0001) Guler 2005

Isik 2006

Erdil 2009 1/30 1/30

Sato 2010 3/42 3/39

Chen 2013 4/27 11/24

Total 20/150 33/144 1/21 2/21 11/30 16/30

7.72 1.00 (0.10-10.18)

17.31 0.92 (0.20-4.35)

25.37 0.22 (0.06-0.81)

100 0.49 (0.35-0.68) 9.26

40.34 0.52 (0.19-1.43)

0.57 (0.07-4.74)

Heterogeneity test;

χ2_{=2.46; df=4 (p=0.65); I}2_=0%

Weight (%) Control

(n/N) Dex (n/N)

Study OR (95% CI)

Figure3 Meta-analysisofdexmedetomidineeffectonnauseaandvomitingincidenceinchildrenundergoinggeneralanesthesia withsevoflurane.

Standard error

Log odds ratio

1.120

–4.00 –2.00 0.00

0.280

Figure4 Funnelplotofdexmedetomidine effecton emer-genceagitationinchildrenundergoinggeneralanesthesiawith sevoflurane.

system.26_{Thedecreaseinemergenceagitationprovidedby}

dexmedetomidine mayalsobejustifiedby thelower con-sumptionofsevoflurane.27

PONV are common complications in children undergo-ing general anesthesia with sevoflurane.18 _{Studies have}

shown conflicting results on the effect of dexmedetomi-dine for this complication.20,23 _{In the present study, the}

use of dexmedetomidine appeared as a protective fac-tor for the incidenceof nausea andvomiting. The use of dexmedetomidine hasbeen associated withreducedneed for postoperativeopioidanalgesics,whichimplies alower incidenceofnauseaandvomitinginducedbyopioid.28

More-over, dexmedetomidine hasbeen usedsuccessfully in the treatmentofcyclicalvomitingsyndromeinchildren,by yet-unknownmechanisms.29

Inthisstudy,thetimesofemergenceandPACUdischarge were considered statistically higher in dexmedetomidine group,justifiedbyitssedativeeffect,5_{butwithoutclinical}

repercussions.17---19,22

Regardingthetimeofextubationanddurationof anes-thesia, thismeta-analysisfound nostatisticallysignificant differencebetweendexmedetomidine andcontrolgroups. Thisresultdisagreeswithsomeindividualstudies,by find-ingalongerextubationtimeanddurationofanesthesiain dexmedetomidinegroup.17,18

It is noteworthy that the studies used different scales to assess agitation. One study23 _{used the PAED scale}8_,

four studies1,16,21,24 _{used the Watcha scale,}9 _{and five}

studies17---20,22_{usedthefive-pointscale.}10 _{Althoughonlythe}

PAEDscalehasbeenvalidated,8_{theothersarewidelyused}

inclinicalresearches.

Themeta-analysisqualitydependsontheselectionof rel-evantstudies, heterogeneity,anddetectionbias.2_Despite

thedifferentstrategiesusedinthisstudytominimize possi-blebiases,itmaynotbediscarded.Asearchwasconducted inanimportantdatabaseandselectedworksweresubmitted to two independent evaluators. Double-blind randomized clinical trials were included. The use of random effects model is justified by the observation of clinical hetero-geneityidentifiedin studies:different dosesandtimes of dexmedetomidine administration, procedures, and emer-gence assessment scales. Another limitation of this study refersto the use of only one database for search, which confirmstheoccurrenceofpublicationbias,asidentifiedin thismeta-analysis.

Duetoitsgoodhemodynamicstability,dexmedetomidine hasbeen usedasanadjuvantanestheticandmaybeused aspre-anesthetic medication, during anesthesia, or even postoperatively,andprovidessedationandanalgesia5

with-outrespiratorydepression.17,18,20,30_{Itsuseentailsbenefits,}

suchaslowerconsumptionofinhalationalanesthetics,21_less

needfor postoperativeanalgesic andopioid drugs,2,28 _and

loweroxygenconsumption.31

In conclusion, this meta-analysis highlights the use of dexmedetomidineinreducingemergenceagitationin chil-drenundergoinggeneralanesthesiawithsevoflurane.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

References

1.Ibacache ME, Mu˜noz HR, Brandes V, et al. Single-dose dexmedetomidinereducesagitationaftersevoflurane anesthe-siainchildren.AnesthAnalg.2004;98:60---3.

2.Pickard A, Davies P, Birnie K, et al. Systematic review and meta-analysis of the intraoperative ␣₂-adrenergic ago-nists on postoperative behaviour in children. Br J Anaesth. 2014;112:982---90.

4.DahmaniS,StanyI,BrasherC,etal.Pharmacologicalprevention ofsevofluranoanddesfluranerelatedemergenceagitationin children:a meta-analysisofpublished studies.Br JAnaesth. 2010;104:216---23.

5.VillelaNR,NascimentoJuniorP.Usodedexmedetomidinaem anestesiologia.RevBrasAnestesiol.2003;53:97---113.

6.Gertler R, BrownHC, Mitchell DH,et al. Dexmedetomidine: anovelsedativeanalgesicagent. Proc(BaylUnivMedCent). 2001;14:13---21.

7.MoherD,LiberatiA,TetziaffJ,etal.Preferredreportingitems for systematicreviewsandmeta-analyses:thePRISMA state-ment.AnnInternMed.2009;151:264---9.

8.SikichN,LermanJ.Developmentandpsychometricevaluation ofthepediatricanesthesiaemergencedeliriumscale. Anesthe-siology.2004;100:1138---45.

9.Watcha MF, Ramirez-Ruiz M, White PF, et al. Periopera-tiveeffectsof oralketorolacand acetaminopheninchildren undergoing bilateral myringotomy. Can J Anaesth. 1992;39: 649---54.

10.ColeJW,MurrayDJ,McAlisterJD,etal.Emergencebehaviour inchildren:definingtheincidenceofexcitementandagitation followinganaesthesia.PaediatrAnaesth.2002;12:442---7. 11.HigginsJP,ThompsonSG.Quantifyingheterogeneityina

meta-analysis.StatMed.2002;15:1539---58.

12.DerSimonianR,LairdN.Meta-analysisinclinicaltrials.Control ClinTrials.1986;7:177---88.

13.Ayres M,AyresJunior M,Ayres DL,etal.BioEstat: aplicac¸ão estatísticanasáreasdasciênciasbiomédicas.4rded.Belém; 2007.

14.BeggCB,MazumdarM.Operatingcharacteristicsofarank corre-lationtestforpublicationbias.Biometrics.1994;50:1088---101. 15.Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629---34.

16.ShukryM,ClydeMC,KalarickalPL,etal.Doesdexmedetomidine preventemergencedeliriuminchildrenaftersevoflurane-based generalanesthesia?PaediatrAnaesth.2005;15:1098---104. 17.Guler G, Akin A, Tosun Z, et al. Single-dose

dexmedeto-midine reduces agitation and provides smooth extubation afterpediatricadenotonsillectomy.PaediatrAnaesth.2005;15: 762---6.

18.IsikB,ArslanM,DoganA, etal.Dexmedetomidinedecreases emergence agitation in pediatric patients after sevoflurane anesthesiawithoutsurgery.PaediatrAnaesth.2006;16:748---53.

19.Erdil F, Demirbilek S, Begec Z, et al. The effects of dexmedetomidine and fentanyl on emergence characteris-ticsafteradenoidectomyinchildren.AnaesthIntensiveCare. 2009;37:571---6.

20.SatoM,ShirakamiG,Tazuke-NishimuraM,etal.Effectof single-dosedexmedetomidine onemergenceagitationandrecovery profilesaftersevoflurane anesthesia in pediatric ambulatory surgery.JAnesth.2010;24:675---82.

21.Lili X, Jianjun S, Haiyan Z. The application of dexmedeto-midineinchildrenundergoingvitreoretinalsurgery.JAnesth. 2012;26:556---61.

22.He L, Wang X, Zheng S, et al. Effects ofdexmedetomidine infusiononlaryngeal maskairway removalandpostoperative recoveryinchildrenanaesthetised withsevoflurane.Anaesth IntensiveCare.2013;41:328---33.

23.Chen JY, Jia JE, Liu TJ, et al. Comparison of the effects of dexmedetomidine, ketamine, and placebo on emergence agitationafterstrabismussurgeryinchildren. CanJAnesth. 2013;60:385---92.

24.KimNY,KimSY,YoonHJ,etal.Effectoddexmedetomidineon sevofluranerequirementsandemergenceagitationinchildren undergoingambulatorysurgery.YonseiMedJ.2014;55:209---15. 25.VlajkovicGP,SindjelicRP.Emergencedeliriuminchildren:many

questions,fewanswers.AnesthAnalg.2007;104:84---91. 26.Woodforth IJ, Hicks RG, Crawford MR, et al.

Electroen-cephalographic evidence of seizure activity under deep sevofluraneanesthesiainanonepilepticpatient. Anesthesiol-ogy.1997;87:1579---82.

27.NaHS,SongIA,HwangJW,etal.Emergenceagitationinchildren undergoing adenotonsillectomy: a comparison ofsevoflurane vs.sevoflurane-remifentaniladministration.ActaAnaesthesiol Scand.2013;57:100---5.

28.LinTF,YehYC,LinFS,etal.Effectofcombining dexmedetomi-dineandmorphineforintravenouspatient-controlledanalgesia. BrJAnaesth.2009;102:117---22.

29.TobiasJD.Dexmedetomidineinthetreatmentofcyclicvomiting syndrome.PaediatrAnaesth.2005;15:709---10.

30.Mason KP, Lerman J. Dexmedetomidine in children: cur-rent knowledge and future applications. Anesth Analg. 2011;113:1129---42.