REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
OfficialPublicationoftheBrazilianSocietyofAnesthesiologywww.sba.com.br
SCIENTIFIC
ARTICLE
Sugammadex
versus
neostigmine
in
pediatric
patients:
a
prospective
randomized
study
Turhan
Kara,
Ozgur
Ozbagriacik,
Hacer
Sebnem
Turk,
Canan
Tulay
Isil
∗,
Ozan
Gokuc,
Oya
Unsal,
Emrah
Seyhan,
Sibel
Oba
DepartmentofAnesthesiologyandReanimation,SisliEtfalTrainingandResearchHospital,Istanbul,Turkey
Received9December2013;accepted11March2014 Availableonline3April2014
KEYWORDS
Sugammadex; Neostigmine; Pediatric
Abstract
Backgroundandobjectives: Acetylcholinesteraseinhibitorsmay causepostoperativeresidual curarizationwhentheyareusedforreversalofneuromuscularblockade.Sugammadexreverses neuromuscularblockadebychemicalencapsulationandisnotassociatedwiththesideeffects thatmay occur with theuse ofanticholinesterase agents.Because ofincreasedoutpatient surgicalprocedurespostoperativeresidualcurarizationandrapidpostoperativerecoveryhave agreaterimportanceinthepediatricpatientpopulation.Theaimofthisstudywastocompare theefficacyofsugammadexandneostigmineonreversingneuromuscularblockadeinpediatric patientsundergoingoutpatientsurgicalprocedures.
Methods:80patients,aged2---12years,scheduledforoutpatientsurgerywereenrolledinthis randomizedprospectivestudy.Neuromuscularblockadewasachievedwith0.6mgkg−1
rocuro-niumandmonitorizedwithtrain-of-four.GroupRN(n=40)received0.03mgkg−1neostigmine,
GroupRS(n=40)received2mgkg−1sugammadexforreversalofrocuronium.Extubationtime
(timefromthereversalofneuromuscularblockadetoextubation),train-of-fourratioduring thistime,timetoreachtrain-of-four>0.9,andprobablecomplicationswererecorded.
Results:There was nosignificant differencebetween the patients’ characteristics. Extuba-tiontimeandtimetoreachtrain-of-four>0.9weresignificantlyhigherinGroupRN(p=0.001,
p=0.002).Train-of-fouratthetimeofneostigmine/sugammadexinjectioninGroupRNwere sig-nificantlyhigherthanintheRSgroup(p=0.020).Extubationtrain-of-fourratiowassignificantly lowerinGroupRN(p=0.002).
Conclusion:Sugammadexprovidessaferextubationwithashorterrecoverytimethan neostig-mineinpediatricpatientsundergoingoutpatientsurgicalprocedures.
©2014SociedadeBrasileiradeAnestesiologia.PublishedbyElsevier EditoraLtda.Allrights reserved.
∗Correspondingauthor.
E-mail:[email protected](C.T.Isil).
http://dx.doi.org/10.1016/j.bjane.2014.03.001
PALAVRAS-CHAVE
Sugammadex; Neostigmina; Pediatria
Sugammadexversusneostigminaempacientespediátricos:Estudoprospectivoe randomizado
Resumo
Justificativaeobjetivos: Osinibidoresdaacetilcolinesterasepodemcausarcurarizac¸ão resid-ual no pós-operatório quando usados para reverter o bloqueio neuromuscular. Sugamadex reverteobloqueioneuromuscularporencapsulac¸ãoquímicaenãoestáassociadoaosefeitos colaterais que podem ocorrer como usode agentes anticolinesterase. Devido ao aumento dosprocedimentoscirúrgicosambulatoriais.Acurarizac¸ãoresidualearápidarecuperac¸ãono pós-operatóriosãomuitoimportantesparaapopulac¸ãodepacientespediátricos.Oobjetivo deste estudofoi comparar aeficáciade sugamadexeneostigmina nareversãodobloqueio neuromuscularempacientespediátricossubmetidosaprocedimentoscirúrgicosambulatoriais.
Métodos: 80pacientes,comidadesentre2-12anos,programadosparacirurgiasambulatoriais foramincluídosnesteestudoprospectivoerandomizado.Obloqueioneuromuscularfoiobtido com0,6mgkg−1derocurônioemonitorizadocomainterpretac¸ãodasequênciadequatro
estí-mulos.OGrupoRN(n=40)recebeu0,03mgkg−1deneostigminaeoGrupoRS(n=40)recebeu
2mgkg−1desugamadexparaareversãoderocurônio.Otempodeextubac¸ão(tempodesde
areversãodobloqueioneuromuscularatéaextubac¸ão),arazãodasequênciadequatro estí-mulosduranteessetempo,otempoparaatingirumasequênciadequatroestímulos>0,9eas complicac¸õesprováveisforamregistrados.
Resultados: Nãohouvediferenc¸asignificativaentreascaracterísticasdospacientes.Ostempos deextubac¸ãoeparaatingirumasequênciadequatroestímulos>0,9foramsignificativamente maioresnoGrupoRN (p=0,001,p=0,002).A sequênciadequatroestímulosnomomentoda injec¸ãodeneostigmina/sugamadexfoisignificativamentemaiornoGrupoRNquenoGrupoRS (p=0,020).A razãoentreextubac¸ãoe sequênciadequatro estímulosfoisignificativamente menornoGrupoRN(p=0,002).
Conclusão:Sugamadexproporcionaextubac¸ãomaisseguracomumtempoderecuperac¸ãomais curtoqueodeneostigminaem pacientespediátricossubmetidosaprocedimentoscirúrgicos ambulatoriais.
©2014SociedadeBrasileira deAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos direitosreservados.
Background
Postoperativeresidualcurarization(PORC)inpostoperative patientsisasuccessionofthepresenceofblockednicotinic receptors.1,2Eveninobservationallyasymptomaticpatients,
60---70%ofthesereceptorscanbestillblocked.1PORC can
cause delayed recovery, hypoxia, metabolic derangement andrarelydeath.2
Cholinesteraseinhibitorsaretraditionallyusedfor rever-salofneuromuscularblockade(NMB).Among theseagents neostigmineisthemostpotentandselectiveone.3Itshould
bekept in mindthat cholinesteraseinhibitor agents have multi-systemic side effects. Since these agents are not selectivetonicotinicreceptorsandalsostimulatethe mus-carinic system, there can bequite a few serious adverse effects as follows: Bradycardia, QT lengthening, bron-choconstriction,hypersalivationandincreasedmotility.3To
avoid these effects, concomitant anticholinergic agents, such as atropine or glikopirolat, are administered to the patient before the cholinesterase inhibitors.3 Today,
sugammadexisanalternativetothedecurarization proce-dure,whichwastraditionallyexecutedwithcholinesterase inhibitors. PORC and the muscarinic side effects are not anticipatedwhenusingsugammadex,whichhasbeen devel-opedsoastobeselectiveforrocuroniumandvecuronium.4---6
Therudimentaryneuromuscularjunction,thevariability offibrinfibers,thedifferencesindrugdistributionandbody volumeinchildrenchangetheirneuromuscularconduction. Thesefactorscancauseprolongedrecovery andincreased riskofPORC.7,8
Sugammadexisproved tobeasafeandsuperioragent inNMBreversalcomparedtoneostigmineinadults.4---6
How-ever, thereis only onestudy in the literatureconcerning sugammadexadministrationinpediatricpatients.9Theaim
ofthisstudywastocomparetheefficacyofsugammadexand neostigmineonreversingNMBinpediatricpatients undergo-ingoutpatientsurgicalprocedures.
Methods
Table1 Age,meantimeofsurgeryandanesthesia.
Variable GroupRN(n=40) GroupRS(n=40) pvalue Age 5.07±3.24 6.48±2.81 0.065 Surgeryduration(min) 60.37±43.71(43) 63.52±39.78(49.5) 0.341 Anesthesiaduration(min) 85.50±47.49(70) 71.77±40.80(59.5) 0.108
Table2 Evaluationoftimevariations.
GroupRN(n=40) GroupRS(n=40) pvalue LastNMBadministration-reversingtime(min) 44.45±22.17 40.05±23.29 0.390 LastNMBadministration-extubationtime(min) 47.70±22.05 41.55±23.37 0.230 Meanextubationtime(min) 3.25±1.79(3) 1.15±1.44(1) 0.001a
ap<0.05(mean±SD).
Any patients with known drug hypersensitivity, kidney failure,liverfailure,diseasesaffecting theneuromuscular junction, or a history of malign hyperthermia, and those mentallyretarded,werenotincludedinthestudy.
All patients were applied 0.5mgkg−1 oral midazolam 30---45min beforesurgery. Electrocardiogram (EKG),mean arterial pressure (MAP), oxygen saturation (SPO2), heart rate and EtCO2 (End-Tidal CO2) (Draeger Primus, Draeger Medical,Drammen,Norway)wereallmonitoredinthe oper-atingroom.Thetrain-of-four(TOF)equipmentworkingwith thenerve-muscleacceleromyometryprinciple(TOFWatch, OrganonTechnica,Eppelheim,Germany)wasplacedonthe ulnarnervetraceandtransducerthumbsofallthepatients, andtheperipheralheatsensorwasplacedintothepalmar sideofthehand.
Vascularaccesswasprovidedon theother arm, where neuromuscularmonitoring wasnotapplied.General anes-thesia was induced in both groups with 5---7mgkg−1 thiopental,1gkg−1fentanyland0.6mgkg−1 rocuronium. 90safterthefirstdoseofrocuroniumthepatientswere oro-tracheallyintubated.ThefirstTOFratiowas100%calibrated andmeasured.Maintenanceofanesthesiawasprovidedwith 2%sevofluraneand50%O2---50%N2O.Duringtheoperation TOFwasnotmeasured.
Theeffectoftheneuromuscularblockerwasevaluated clinicallyaccordingtotheincreaseofrespirationfrequency, disruption to respiration curve, and the onset of muscu-lar movements. When necessary 0.2mgkg−1 rocuronium wasadministered, andthetimeof thelastNMBdose was recorded.
Attheendofsurgery, sevofluraneinhalationwas inter-ruptedandswitchedto100%O2.TOFmonitorizationbegan. Thechildrenwererandomlyassignedtooneoftwogroups byacomputer-generatedtableofrandomnumbers.When T2 reappeared, Group RN (n=40) received 0.01mgkg−1 atropineand0.03mgkg−1neostigmineandGroupRS(n=40) received2mgkg−1sugammadexforthereversaloftheNMB. Injectiontimeofneostigmineorsugammadexafterthe last NMB and the TOF ratio at injection were recorded. Patients were clinically assessed for NMB recovery (50% of normal tidal volume, eye opening and movement) andextubated. DurationfromNMBreversal toextubation was evaluated as the extubation time. The TOF ratio at
extubationandthetimetoreachTOF>0.90wererecorded. Operationandanesthesiaduration(timeintervalbetween induction andinterruptionofsevofluraneinhalation) were alsorecorded.Adverseeffectssuchasbradycardia, tachy-cardia, QT lengthening, hypotension, nausea, vomiting, bronchoconstriction,hypersalivation,diplopia,rash,fever, ordysgeusiawerenoted.
Statisticalanalysis
Inthisstudy,statisticalanalyseswereperformedwithNCSS (Number CruncherStatistical System) 2007 andPASS 2008 StatisticalSoftware(Utah,USA)program.Forevaluationof obtained data, along with descriptive statistical methods (mean, standard deviation), an independentsamples test wasusedforthecomparisonofquantitativedata,andthe Mann---WhitneyUtestwasusedforacomparisonof abnor-mal distribution parameters between two groups. Results were considered statistically significant when thep value wasunder0.05.
Results
Eighty patients aged 2---12 years, who underwent lower abdominal or urogenital surgery, completed this study and were included in one of the two groups. Mean age was5.73±3.11years.Therewasnosignificantdifference betweenthegroupsinage,timeofsurgeryortimeof anes-thesia(Table1).
Timeforapplyingneostigmineorsugammadexafterthe last NMBand timefrom the lastNMB toextubation were similarinbothgroups(Table2).
ExtubationtimeinGroupRNwasstatisticallyhigherthan thatinGroupRS(p=0.001)(Fig.1).
TOF rate at the time of neostigmine or sugammadex injectioninGroup RNwassignificantlyhigherthan thatin GroupRS(p=0.020)(Table3).
TOF rate of Group RN at extubation was significantly lowercomparedtoGroupRS(p=0.002)(Table3;Fig.2).
ThetimewhenTOFrateexceeded0.90wassignificantly higherintheRNGroup(p=0.002)(Table3;Fig.3).
Table3 TOFratioevaluation.
GroupRN(n=40) GroupRS(n=40) pvalue TOFratiobeforereversing 47.25±38.52(43.5) 28.62±27.58(23.5) 0.020a
TOFratioatextubation 76.95±31.0 96.35±21.34 0.002a
TimetoreachTOFratio>0.90(min) 1.97±2.14(1) 0.46±0.70(0) 0.002a
a p<0.05(mean±SD).
Group RN
Mean min.
Group RS 3
2,5
1,5
0,5
Figure1 Meanextubationtimedifferencebetweengroups.
Group RN Group RS
Mean
100
Figure2 ExtubationTOFratioofthegroups.
2
1,5
1
0,5
0
Mean min
Group RN Group RS
Figure3 MeantimetoreachTOFratio>0.90(min).
Discussion
NMBagents are stillindispensable for surgical procedures requiring general anesthesia. Unfortunately applications of NMB agents entail complications, which can lead to increasedmortality,suchasPORC,airwayobstruction, aspi-rationandhypoxia.Therefore,completeandrapidreversal ofNMBmustbeensuredattheendofsurgery.1,2,10
NMBhaveadifferentefficacyinadultsandchildren.NMB disperseintheextracellulararea.Becausetheextracellular areaisrelativelylargerinchildrenthaninadults,the neu-romuscularblockerscreatelowerplasmaconcentrationsin children.HigherdosesofNMBmaybenecessarytoreachthe sameNMBlevelinchildren,asinadults.7,8The
neuromuscu-larjunctionininfantsisnotsufficientlymature.Therefore, theionchannelsremainopenforalongertimeandthe mus-clescaneasilybedepolarized.Moreover,thereceptorshave aloweraffinityforthenon-depolarizingagents.7,8Because
achild’sdiaphragmhasmoretypeIfibrinsthananadult’s, thediaphragmismorevulnerabletoNMBthanthe periph-eralmuscles.Allthesefactorsleadtoanincreasedriskof
post-operativeapnea inpediatric patients.11 At thispoint
anNMBreversingagentwithareducedPORCriskisofgreat importance.8,9
Vuksanajetal.12investigatedthepharmacokinetic
prop-erties of rocuronium in children. They stated that higher doses of rocuronium may be necessary in children for rapid onset of effect and rapid recovery. It has been ascertained that NMB reverses in a shorter time with rocuronium.12,13Therefore,wepreferredtouserocuronium
inourstudy.
PORCis oneof thefearedcomplicationsafter anesthe-sia.Acceleromyographyistheonlyrecommendedobjective methodfordetectionofresidualblock.1,14,15UnlesstheTOF
ratiois≥0.9,normalvitalmusclefunctionsandspontaneous respiration are not safe.2,14,15 TOF monitoring was
impor-tantin thisstudy toprovide an objectiveassessment and thereforeacceptedcut-offvaluewasTOFratio>0.9.
Sugammadexhascreated a newapproachto therapid reversalofNMB.Incomparativestudies,ithasbeenshown that sugammadex is more effective than cholinesterase inhibitorsinthereversalofNMBwhenrocuroniumor vecuro-niumwas administered.16,17 Jones et al.18 found that the
timetoreach0.90TOFratiowas18timesshorterwith sug-ammadexthanwithneostigmineinroutinereversalofdeep NMB.Plaudmentionedthatinhisstudysugammadexwas10 timesfasterinefficiency.19
Sorgenfrei et al. compared different doses of sugam-madex(0.5,1,2,3,4mgkg−1)withaplaceboadministration in male patients, aged 18---64 years. They analyzed the mediantimenecessarytoreachTOF0.90ratioafter admin-istrationofsugammadexandfoundthatwitheverydoseof sugammadexthetimetoreach 0.90TOF ratioshortened. When they compared the different sugammadex doses, theyobserved that the timeto reach0.90 TOF ratio was significantlyshorterwithsugammadexdoses ≥2mgkg−1.20
Other studies showed that ≥2mgkg−1 sugammadexdoses areefficient.21,22Debaeneetal.23reportedthataTOF
mea-surementforthedepthofNMBisimportantindecidingthe appropriatesugammadexdose.Therefore,weadministered 2mgkg−1sugammadex,andmeasuredthedepthofNMBwith TOFmonitoring.
Khuenl-Brady et al.24 compared neostigmine with
sug-ammadexin arandomizedmulticentrestudywhere itwas appliedtoreversethemediumNMBobtainedwith rocuro-niumorvecuroniuminadults.Intherocuroniumgroup,the durationfromsugammadex or neostigmine administration toreach0.90TOFratiowasfoundtobe1.4minwith sugam-madexand17.6minwithneostigmine.InastudyofBlobner etal.,25 11%of patientsintheneostigminegroupreached
0.90TOFratio,whichwas0.46mininthesugammadexgroup and1.96minintheneostigminegroup.
DellaRoccaetal.26 reportedthatthe pharmacokinetic
effects of sugammadex were the same in children and adults.Plaud etal.comparedtheefficiencyandsafetyof sugammadexin infants (28 days---23 months old), in chil-dren(2---11yearsold),inadolescents(12---17yearsofage), and in adults (18---65 years of age). Doses of 0.5, 1, 2, 4mgkg−1 sugammadex and a placebo were compared in patientsafterNMBachievedwithrocuronium.Thedifferent agegroupswereevaluatedforpossiblesideeffects,timeto reachTOF0.90ratio,electrocardiographicvariations, sug-ammadexandrocuroniumplasmalevels.When ≥2mgkg−1 sugammadexwasapplied,thetimetoreachTOF0.90was significantlyshorterthanin theplacebogroup. Ininfants, children, adolescents and adults NMB reversal time with sugammadex,andsugammadex-rocuroniumconcentrations weresimilar. Reappearance of block, insufficient reversal of NMB and QT lengthening were not observed in any of thegroups.This wasthe onlypriorstudywhich evaluated the efficiency of sugammadex in children.9 In our study,
sugammadex2mgkg−1 wasadministeredto2---12-year-old pediatricpatients.InthestudyperformedbyPlaudetal., thetimetoreach0.90TOFratiowasfoundtobe1.2minin bothpediatricandadultpatientswhoweregiven2mgkg−1 sugammadex. However, the number of patients included in that study is insufficient. Therefore, it is necessary to conducta comprehensive study involving large infantand pediatricpatientgroups.
In our study the extubation times were significantly higherin the neostigminegroup compared to the sugam-madexgroup. TOF ratios of the neostigminegroup in the processof NMBreversal wereconfirmedtobehigherthan thoseof the sugammadexgroup.Despite that difference, theTOFratiosin theneostigminegroupweresignificantly lowerattheextubationthaninthesugammadexgroup.The extubationTOFmeanwas76.95±31.0fortheneostigmine groupand96.35±21.34 for thesugammadexgroup. Time toreachTOFratesover0.90wasfoundtobeprolongedas fourtimesintheneostigminegroupcomparedtothe sugam-madexgroup.Resultsinourstudyweresimilartoprevious studies.18,19
No significant effects on heart rate were recorded with sugammadex; however, neostigmine caused signifi-cantincreasesin themeanheartrate inthesecond, fifth andtenthminutesafteradministration.18 In ourstudy,we
didnotconductahemodynamiccomparison.However,the potentialsideeffectsofbradycardia,tachycardia, hypoten-sion and hypertension were observed in neither of the groups.
Conclusion
Lowerabdominal and urogenital surgery make up a large proportionofthe pediatricsurgery outpatientoperations. ThisbringsNMBreversalandPORCavoidancetogreat impor-tance,especiallywhendealingwithyoungerchildren.Our studyindicatedthattheadministrationofsugammadexfor the reversal of rocuronium induced NMBis making faster andalsosaferNMBreversalpossible,whencomparedwith atraditionaldrug,asneostigmineis.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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