Rev. Bras. Anestesiol. vol.64 número6

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

Effects

of

ketamine

and

midazolam

on

emergence

agitation

after

sevoflurane

anaesthesia

in

children

receiving

caudal

block:

a

randomized

trial

夽

Ayse

Ozcan

,

Ayse

Gunay

Kaya

,

Namik

Ozcan

,

Gul

Meltem

Karaaslan

,

Esen

Er

_,

_Bulent

_Baltaci

_,

_Hulya

_Basar

a_{DepartmentofAnesthesiologyandReanimation,AnkaraTrainingandResearchHospital,Ankara,Turkey} b_{AnesthesiologyandReanimationClinic,VanTrainingandResearchHospital,Van,Turkey}

Received22November2013;accepted2January2014

Availableonline7February2014

KEYWORDS

Caudalblock; Children;

Emergenceagitation; Sevoflurane

anaesthesia; Ketamine; Midazolam

Abstract

Backgroundandobjectives: Emergence agitation is a common postanaesthetic problem in children after sevoflurane anaesthesia. We aimedto compare the effectsof ketamine and midazolamadministeredintravenously,beforetheendofsurgery,forpreventionofemergence agitationinchildrenwhoreceivedcaudalblockforpainreliefundersevofluraneanaesthesia. Methods:62AmericanSocietyofAnesthesiologistspatientclassificationstatusIchildren,aged 2---7years,scheduledforinguinalherniarepair,circumcisionororchidopexywereenrolledto thestudy.Anaesthesiawasinducedwithsevoflurane8%inamixtureof50%oxygenandnitrous oxide.Afterachievingadequatedepthofanaesthesia,alaryngealmaskwasplacedandthen caudalblockwasperformedwith0.75mLkg−1_{,0.25%bupivacaine.Attheendofthesurgery,} ketamine0.25mgkg−1_{,midazolam0.03mgkg}−1_{andsalineweregiventoketamine,midazolam} andcontrolgroups, respectively.Agitationwas assessed usingPaediatric Anaesthesia Emer-genceDeliriumscaleandpostoperativepainwasevaluatedwithmodifiedChildren’sHospital ofEasternOntarioPainScale.

Resultsandconclusions:ModifiedChildren’sHospitalofEasternOntarioPainScalescoreswere foundhigherincontrolgroupthaninketamineandmidazolamgroups.PaediatricAnaesthesia EmergenceDeliriumscoresweresimilarbetweengroups.ModifiedChildren’sHospitalofEastern OntarioPainScaleandPaediatricAnaesthesiaEmergenceDeliriumscoresshowedasignificant decreasebytimeinallgroupsduringfollow-upinpostanaesthesiacareunit.Thepresentstudy resulted insatisfactory Paediatric Anaesthesia EmergenceDelirium scores which arebelow 10 inall groups. Asa conclusion, neither ketamine nor midazolam added to caudal block

夽 _{ThepresentstudywaspresentedintheCongressofTurkishSocietyofAnesthesiology,2011,inoralpresentationcontest.}

∗_{Correspondingauthor.}

E-mail:ayseongun@gmail.com(A.Ozcan).

0104-0014/$–seefrontmatter©2014SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.Allrightsreserved.

undersevofluraneanaesthesiadidshowfurthereffectonemergenceagitation.Inaddition,pain reliefstillseemstobethemajorfactorinpreventingemergenceagitationaftersevoflurane anaesthesia.

©2014SociedadeBrasileiradeAnestesiologia.PublishedbyElsevier EditoraLtda.Allrights reserved.

PALAVRAS-CHAVE

Bloqueiocaudal; Crianc¸as; Incidênciade agitac¸ão; Anestesiacom sevoflurano; Cetamina; Midazolam

Efeitosdecetaminaemidazolamsobreaincidênciadeagitac¸ãopós-anestesiacom sevofluranoemcrianc¸assubmetidasaobloqueiocaudal:estudorandomizado

Resumo

Justificativaeobjetivos: Aincidênciadeagitac¸ãoéumproblemapós-anestésicocomumem crianc¸asapósaanestesiacomsevoflurano.Nossoobjetivofoicompararosefeitosdecetamina emidazolamadministradosporviaintravenosa,antesdotérminodacirurgia,paraprevenir aincidênciade agitac¸ãoem crianc¸assubmetidas ao bloqueiocaudal para alíviodadorsob anestesiacomsevoflurano.

Métodos: Foraminscritosno estudo62 pacientes pediátricos,entre 2-7anos, estado físico classificadode acordocomaSociedadeAmericana deAnestesiologistas(ASA: I), programa-dospara correc¸ãode hérniainguinal,circuncisãoouorquidopexia.A anestesiafoi induzida com sevoflurano a8% em uma mistura de oxigênio (50%) e óxido nitroso (50%). Depois de atingir a profundidade adequada da anestesia, uma máscara laríngea foi colocada e, em seguida,obloqueiocaudalfoifeitocombupivacaínaa0,25%(0,75mLkg−1_).Nofimda cirur-gia,cetamina(0,25mgkg−1_{),midazolam(0,03mgkg}−1_{)esoluc¸ãosalinaforamadministrados} aosgrupos cetamina, midazolame controle, respectivamente.A incidência deagitac¸ão foi avaliadacomaescalaPaediatricAnaesthesiaEmergenceDelirium(PAED)eadornoperíodo pós-operatórioavaliadacomaescalamodificadaChildren’sHospitalofEasternOntarioPain Scale(mCHEOPS).

Resultadoseconclusões: OsescoresdedordaescalamodificadamCHEOPSforammaioresno grupocontroledoquenosgruposcetaminaemidazolam.OsescoresPAEDforamsemelhantes entreos grupos.Osescores dessas duasescalasmostraram umadiminuic¸ão significativado tempoemtodososgruposduranteoacompanhamentoemsaladerecuperac¸ãopós-anestesia. OpresenteestudoresultouemescoressatisfatóriosdaescalaPAED,queficaramabaixode10em todososgrupos.Comoconclusão,tantocetaminaquantomidazolam,adicionadosaobloqueio caudal sob anestesiacom sevoflurano,não mostraram efeitos adicionais sobre aincidência deagitac¸ão.Alémdisso,oalíviodadoraindapareceseroprincipalfator naprevenc¸ãoda incidênciadeagitac¸ãoapósanestesiacomsevoflurano.

©2014SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos direitosreservados.

Introduction

Emergenceagitation(EA)isacommonpostanaesthetic prob-leminchildren aftersevofluraneanaesthesia.1---4 _However,

the aetiology of EA has not yet been identified clearly. The predisposing factors are preschool age, preoperative anxiety, lack of premedication, type of surgery, awaken-ing in a strange environment.4,5 _{The incidence of EA had}

beenreportedbetween10%and80%indifferentstudies.5,6,7

Although EA is also seen in pain-free procedures, pain is thoughttobethemajorcontributingfactorforEA.In addi-tiontopaintreatment,benzodiazepines,opioids,ketamine, alpha-2agonistsandpropofolhavealsobeenusedtoprevent EA.8

Inthepresentstudy,weaimedtocomparetheeffectsof ketamineandmidazolamforpreventionofEAafter sevoflu-raneanaesthesia,inchildrenwhoreceivedcaudalblockfor painrelief.

Methods

ThestudywasapprovedbytheInstitutionalEthics Commit-teeof AnkaraResearchandTrainingHospital(Chairperson AssocProfY.Aral)withprotocolnumber00165on13March 2008. Writteninformedconsentswere obtainedfrom par-ents of the children. Sixty-two ASA I children, aged 2---7 years who were scheduled for inguinal hernia repair, circumcision or orchidopexy were enrolled in the study. Exclusioncriteriawerementalretardation,physical devel-opmentaldelay,preoperativeagitationandcontraindication forcaudalblock.

depthofanaesthesia,alaryngealmaskwasplacedandthen childrenwerepositionedinthelateraldecubituspositionfor caudalanaesthesia.0.75mLkg−1_{,0.25% plain bupivacaine} was injected using a 20-22 G caudal needle. Thereafter, anaesthesia was maintained with sevoflurane 3% in 50% oxygen---nitrous oxidemixture. No other hypnotic, muscle relaxantoranalgesicdrugwasadministeredduringsurgery. Skin incision wasmade 15min after caudal block. Caudal blockwasacceptedadequateifheartrateandblood pres-suredidnotincreasemorethan20%ofbaselinevalueafter skinincision.Thechildrenwithfailedblockwereexcluded fromthestudyandfentanyl2␮gkg−1_{wasadministered.}

Patients were randomized into 3 groups as control (GroupC,n=20),midazolam(GroupM,n=21)andketamine (GroupK,n=21)groups.Ketamine0.25mgkg−1_,midazolam 0.03mgkg−1_{andsalineatequalvolumeswereadministered} intravenouslytochildrenapproximately10min beforethe endofsurgery,inketamine,midazolamandcontrolgroups, respectively in a blinded fashion.9,10 _{Then, sevoflurane}

concentration was reduced, laryngeal mask was removed andinhaled anaesthetics werediscontinued.The children were allowed tobreathe 100% oxygen for 5min andthen transferredtothepostanaesthesiacareunit(PACU).Before the transfer to PACU, the caudal blocks were confirmed as functioning by lack of response to toe pinch. Heart rate,NIBP,andSpO2weremonitoredandthechildrenwere assessed in the PACU by an anaesthetist blinded to the study groups. Agitation was assessed using PAED (Paedi-atric Anaesthesia Emergence Delirium) scale at 0, 5, 10 and30thminandmCHEOPS(modifiedChildren’sHospitalof EasternOntarioPainScale)wasusedtoevaluate postopera-tive painat 5, 10and 30thmin in therecovery room.11,12

Allagitatedchildren withPAED scoremorethan10at the 10thmin received1mgkg−1 _{propofol,and ifthe agitation} was notcontrolled in following 10min, propofol adminis-tration was repeated. Children with mCHEOPS score ≥6 receivedmorphine0.05mgkg−1_{ivforrescueanalgesic.} Chil-drenwereobserved60mininthePACUandthendischarged totheward.The sideeffectslikenausea,vomiting, bron-chospasm,laryngospasm,desaturation,hallucination were alsorecorded.

Statistical analysis was performed by using Medcalc softwareprogramme(MedcalcSoftwarebvba,Mariakerke, Belgium),version11.3.3.0.Todeterminethesamplesize,a pilotstudywith10patientsreceivingonlycaudalanalgesia, likeincontrolgroup,wasperformed.WeobservedEAin6of 10patients.A40%reductioninEAwasconsideredtobe clin-icallysignificant, wecalculated20patientswererequired

foreachgroupwithtypeIerror(˛=0.05)andtypeIIerror (ˇ=0.2).Kolmogorov---Smirnovtestwasusedtoanalyzethe normaldistributionofmeasuredvariables.Intergroup com-parisonsweremadewithANOVAorKruskal---Wallisvariance test and Friedman test was used for with-in group com-parisons.Dataarepresentedasthemean±SDandmedian (minimum---maximum). Chi-square test was used for com-parisonofcategorical data.p Valueofless than0.05 was consideredstatisticallysignificant.

Results

Sixty-twochildrenwereenrolledinthestudy.Twochildren wereexcludedfromthestudybecauseofinadequatecaudal block.

Thecharacteristicsofthepatients(age,gender,weight), durationof anaesthesiaand surgery and types of surgery weresimilarbetweengroupsandshowninTable1.

Systolic blood pressure values were found similar betweengroups at all measurement times.Systolic blood pressurewasmeasuredlowerwithinketaminegroupatthe 15thand30thminfollowingcaudalblockthanatinduction (p=0.026).

Heart rates were found similar between groups at all measurementtimes.Heartratesdecreasedsignificantly dur-inganaesthesiawithineachgroup.

Pain was evaluated using mCHEOPS scoring system at postoperative5,10and30mininPACU.Themedianvalues werefoundbelow6atallmeasurementtimesinallgroups. Scoreswerehigher incontrolgroup thanin ketamineand midazolamgroupsatallmeasurementtimes(Fig.1).When thegroupswereassessedindividually,therewere5,2and3 childrenat5thminwithmCHEOPS≥6incontrol,ketamine andmidazolamgroups,respectively.At10thmin,therewere 1 and 2 patients with mCHEOPS score ≥6 in midazolam andcontrolgroups,respectively.Onepatientofthecontrol groupalsohadahigherPAEDscoreatthesamemeasurement timeand received propofol. The other twochildren, one ineachgroup,withmCHEOPSscore≥6receivedmorphine 0.05mgkg−1_{ivasrescueanalgesic.ThemCHEOPSscoresof} thepatientsinallgroupsdecreasedgraduallyduring follow-upinPACU.

PAEDscoresweresimilarbetweengroupsatall measure-menttimes (Fig.2).The median valuesofPAED scores of the groups were found below 10 except at the arrival of the control group toPACU. There were 11, 6 and 9 chil-dren with PAED score above 10 in control, ketamine and

Table1 Thecharacteristicsofthepatients,durationofanaesthesiaandsurgery.Valuesareexpressedasmean±SD,median (min-max).

Control Midazolam Ketamine pValue

Age(years) 5(2---7) 5(2---7) 4(1---7) 0.87

Gender(M/F) 13/7 14/6 14/6 0.862_=0.29

Bodyweight(kg) 17.3±3.9 18.6±6.1 18.1±5.5 0.74

Durationofsurgery(min) 26.8±11 33.4±13.3 28.3±10 0.15 Durationofanaesthesia(min) 53.6±11.6 57.8±14.1 53±12.9 0.41 Typesofsurgery(IHR/O/C) 11/4/5 10/4/6 11/5/4 0.962_=0.62

10

8

6

4

2

0

5 min 10 min 30 min

Group Ketamine Control Midazolam

Time

mCHEOPS

Figure1 mCHEOPSscoresofthegroups.*p<0.05vsketamine andmidazolamgroups.(Valuesareexpressedasmedian (min-max)).

20

18

16

14

12

P

AED 10

8

6

4

2

0

0 min 5 min 10 min 30 min

Group Ketamine Control Midazolam

Time

Figure2 PAEDscoresofthegroups.(Valuesareexpressedas median(min-max)).

midazolam groups, respectively at the arrival. Since EA couldshowspontaneousresolution, we observedthe chil-dren for 10min to administer the rescue drug propofol. In fact, 8, 6 and 8 children with EA showed spontaneous resolution in 10min in control, ketamine and midazolam groups,respectively.Threepatientsincontroland1patient in midazolam groups with PAED score above 10 received 1mgkg−1_{propofol,intravenously.AlsoPAEDscoresshowed}

a significant decrease in all groups during follow up in PACU.

No side effects like nausea, vomiting, bronchospasm, laryngospasm,desaturation,hallucinationwererecordedin anypatientofthegroups.

AllpatientscouldbedischargedfromPACUafter60min follow-up.

Discussion

Inthepresent study,theeffects ofketamineand midazo-lamonEAwereassessedinagroupofpatientswhoareat highriskforEAregardingtotheirageandtheusedinhaled

anaesthetic. The results showed that ketamine or mida-zolam added to caudal block decreased mCHEOPS scores butdidnotaffectPAEDscoresinchildrenaftersevoflurane anaesthesia.

Pain,rapidemergenceinanunknownenvironment, sep-aration fromparents,and preoperativeanxiety aremajor factorscontributingtoEA.8

DifferentdefinitionsandscalesexistforevaluationofEA, butPAEDscaleispreferredinmostofthestudies.Ascoreof 10/20onthePAEDscalewasreportedasthebestthreshold pointfordeterminingthepresenceofEA.13_{However,Bajwa}

etal.reportedthataPAEDscoregreaterthan12hadgreater sensitivity thana score of≥10.14 _{In ourstudy, we useda}

scoreof≥10onPAEDscalefortheassessmentofEA. Painisthoughttobethemajorfactor thatcontributes to EA. In previous studies several analgesics including acetaminophen, ketorolac, fentanylwere administeredto preventEAaftersevofluraneanaesthesia.Inmostofthese studies, addition of analgesics reduced the incidence of EA.1,15,16 _{Caudal block is another preferred technique for}

painreliefinchildren.Aouadetal.hadshownthatthe inci-dence of EA and pain scores in patients receiving caudal block were significantly lower compared to those receiv-ingintravenousfentanylundersevofluraneanaesthesiafor inguinal hernia repair.6 _{However,Aono etal. reported EA}

in 40%ofchildren withcaudalblockfollowing sevoflurane anaesthesiaforminorurologicsurgery.17_{WeusedmCHEOPS}

scoring system to evaluate andtoexclude pain asa con-tributingfactorofEA.

Althoughpainisthoughttobeimportantinaetiology,EA isalsoseeninpainfreeprocedures.2,3_{Thismayduetorapid}

emergenceinanunknownenvironmentwithaltered cogni-tivefunctionwhichisanotherriskfactorforEA.Itisdifficult forthechildrentocooperatetoastrangeenvironmentupon rapid emergencefollowing anaesthesia.Therefore,agents thatprovidesedationatthetimeofemergencemaybe help-fulinpreventionofEA.17---19_{Thispointwasoneofthereasons}

toestablishthisstudy.

Lowdoses of midazolam andketamine aresafely used for sedation. Chen et al. found that 0.05mgkg−1 mida-zolam in combination with 0.5␮gkg−1 _{of fentanyl at the} endofsurgerywaseffectiveinreducingtheincidenceand severityofEA.19_{Ozcengizetal.found0.5mgkg}−1_oral mida-zolam,givenforpremedication,veryeffectiveinreducing EA.20_{Kararmazetal.hadshownthatoralketaminereduced}

the incidence of EA after desflurane anaesthesiawithout delayingrecovery.21 _{Abu-Shahwanshowedthat}

administra-tionof0.25mgkg−1_{iv ketamineattheendofanaesthesia} reducedsignificantlytheincidenceandseverityofEAin chil-drenundergoingdentalrepair.22_{Dalensetal.administered}

0.25mgkg−1_{ketamine,0.1mgkg}−1_{nalbuphineandsalinein} threegroupsofpatients,andtheyfoundsignificantlylower EAinketamineandnalbuphinegroupscomparedtocontrol without a delay in awakeningand discharge.9 _{In contrary}

toliterature,ketamineandmidazolamdidnotaffectEAin childreninwhompainwasrelievedbycaudalblockinthe presentstudy.

parentalpresencealonegroups.23_{Inourstudy,parentswere}

presentatthearrivaltoPACU.

Inchildrenitisdifficulttoassesspainandalsoitcanbe confusingtodifferentiatepainandEA.Inthepresentstudy, althoughthePAEDscoresweresimilar,mCHEOPSscoreswere statistically different among groups. Since all the caudal blockswerefunctioningandallpatientswereconsideredto befreeofpain,sedationcausedbyketamineandmidazolam might havereduced themCHEOPS scoresin thesegroups. ThismayduetotheparametersofmCHEOPSwhicharenot specificforpainandmayberelatedwithsedation.12,24

Inthisstudy,weacceptedparentstoPACUandprovided effective pain reliefwith caudalblock in all groups. This resultedin satisfactoryPAEDscores whicharebelow10in allgroups. As aconclusion, neitherketaminenor midazo-lamaddedtocaudalblockundersevofluraneanaesthesiadid showfurthereffectonEA.Inaddition,painreliefstillseems tobethe majorfactor in preventingEAafter sevoflurane anaesthesia.

Conflicts

of

interest

Theauthorsdeclaresnoconflictsofinterest.

References

1.Johannesson GP,Floren M, Lindahl SG. Sevoflurane for ENT-surgery in children. A comparison with halothane. Acta AnaesthesiolScand.1995;39:546---50.

2.UezonoS, GotoT, Terui K,et al. Emergence agitationafter sevofluraneversuspropofolinpediatricpatients.AnesthAnalg. 2000;91:563---6.

3.CraveroJ,SurgenorS,WhalenK.Emergenceagitationin pae-diatricpatientsaftersevofluraneanaesthesiaandnosurgery: a comparison with halothane. Paediatr Anaesth. 2000;10: 419---24.

4.LapinSL, AudenSM,Goldsmith LJ,et al. Effects of sevoflu-raneanaesthesiaonrecovery inchildren:a comparisonwith halothane.PaediatrAnaesth.1999;9:299---304.

5.Voepel-LewisT,MalviyaS,TaitAR.Aprospectivecohortstudyof emergenceagitationinthepediatricpostanesthesiacareunit. AnesthAnalg.2003;96:1625---30.

6.Aouad MT, Kanazi GE, Siddik-Sayyid SM, et al. Preopera-tive caudal block prevents emergence agitation in children following sevoflurane anesthesia. Acta Anaesthesiol Scand. 2005;49:300---4.

7.WelbornLG,HannallahRS, Norden JM,etal. Comparison of emergenceandrecoverycharacteristicsofsevoflurane, desflu-rane,andhalothaneinpediatricambulatorypatients.Anesth Analg.1996;83:917---20.

8.DahmaniS,StanyI,BrasherC,etal.Pharmacologicalprevention ofsevoflurane-anddesflurane-relatedemergenceagitationin children:ameta-analysis ofpublishedstudies.Br JAnaesth. 2010;104:216---23.

9.Dalens BJ, Pinard AM, Letourneau DR, et al. Prevention of emergence agitation after sevoflurane anesthesia for pedi-atriccerebralmagnetic resonanceimagingbysmalldosesof ketamineornalbuphineadministeredjustbeforediscontinuing anesthesia.AnesthAnalg.2006;102:1056---61.

10.KarlHW, CoteCJ,Mc CubbinMM,etal.Intravenous midazo-lamforsedationofchildrenundergoingprocedures:ananalysis of age- and procedure-related factors. Pediatr Emerg Care. 1999;15:167---72.

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

12.SplinterWM,BassJ,KomocarL.Regionalanaesthesiafor her-niarepairinchildren:localversus caudalanaesthesia.CanJ Anaesth.1995;42:197---200.

13.BongCL,NgAS.EvaluationofemergencedeliriuminAsian chil-drenusingthePediatricAnesthesiaEmergenceDeliriumScale. PaediatrAnaesth.2009;19:593---600.

14.BajwaSA,CostiD,CynaAM.Acomparisonofemergence delir-iumscalesfollowing generalanesthesia inchildren. Paediatr Anaesth.2010;20:704---11.

15.Davis PJ, Greenberg JA, Gendelman M, et al. Recovery characteristics of sevoflurane and halothane in preschool-aged children undergoing bilateral myringotomy and pres-sure equalization tube insertion. Anesth Analg. 1999;88: 34---8.

16.Galinkin JL, Fazi LM, Cuy RM,et al. Use of intranasal fen-tanylinchildrenundergoingmyringotomyandtubeplacement duringhalothane andsevoflurane anesthesia.Anesthesiology. 2000;93:1378---83.

17.AonoJ,UedaW,MamiyaK,etal.Greaterincidenceofdelirium duringrecoveryfromsevofluraneanesthesiainpreschoolboys. Anesthesiology.1997;87:1298---300.

18.BreschanC,PlatzerM,JostR,etal.Midazolamdoesnotreduce emergencedeliriumaftersevofluraneanesthesia inchildren. PediatrAnesth.2007;17:347---52.

19.ChenJ,LiW,HuX,etal.Emergenceagitationaftercataract surgeryinchildren:acomparisonofmidazolam,propofoland ketamine.PediatrAnesth.2010;20:873---9.

20.OzcengizD,GunesY,OzmeteO.Oralmelatonin, dexmedetomi-dine,andmidazolamforpreventionofpostoperativeagitation inchildren.JAnesth.2011;25:184---8.

21.KararmazA,Kaya S,TurhanogluS, etal.Oralketamine pre-medicationcanpreventemergenceagitationinchildrenafter desfluraneanesthesia.PaediatrAnaesth.2004;14:477---82.

22.Abu-ShahwanI,ChowdaryK.Ketamineiseffectiveindecreasing theincidence ofemergenceagitation inchildrenundergoing dental repair under sevoflurane general anesthesia. Pediatr Anesth.2007;17:846---50.

23.Arai YC, Ito H, KandatsuN, et al. Parentalpresence during inductionenhancestheeffectoforalmidazolamonemergence behaviorofchildrenundergoinggeneralanesthesia.Acta Anaes-thesiolScand.2007;51:858---61.