REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
PublicaçãoOficialdaSociedadeBrasileiradeAnestesiologiawww.sba.com.br
SCIENTIFIC
ARTICLE
The
effect
of
palonosetron
on
rocuronium-induced
withdrawal
movement
Ki-Bum
Park
a,
Younghoon
Jeon
b,
Junggu
Yi
c,
Ji-hyun
Kim
c,
Seung-Yeon
Chung
c,
Kyung-Hwa
Kwak
c,∗aKeimyoungUniversity,SchoolofMedicine,DepartmentofAnesthesiologyandPainMedicine,Daegu,RepublicofKorea bKyungpookNationalUniversity,SchoolofDentistry,DepartmentofAnesthesiology,Daegu,RepublicofKorea
cKyungpookNationalUniversity,SchoolofMedicine,DepartmentofAnesthesiologyandPainMedicine,Daegu,RepublicofKorea
Received6February2015;accepted14April2016 Availableonline24May2016
KEYWORDS
Palonosetron; Rocuronium; Injection; Pain; Withdrawal movement
Abstract
Background: Rocuroniumcausespainandwithdrawalmovementduringinductionof anesthe-sia.Inthisstudy,palonosetronwasinvestigatedtohaveanalgesiceffectonthereductionof rocuronium-inducedwithdrawalmovement.
Methods:120patientswererandomlyassignedtooneofthreegroupstoreceiveeithersaline, lidocaine 20mg, or palonosetron 0.075mg with a tourniquet applied two minutes before thiopentalsodium(5mg.kg−1)wasgivenintravenously.Afterlossofconsciousness,rocuronium
(0.6mg.kg−1)wasinjectedandthewithdrawalmovementwasestimatedby4-pointscaleina
double-blindmanner.
Results:The overallincidenceofrocuroniumwithdrawalmovementwas 50%with lidocaine (p=0.038),38%withpalonosetron(p=0.006)comparedwith75%forsaline.Theincidenceof nopaintomildpainwassignificantlylowerinthelidocaineandpalonosetrongroups(85%and 92%respectively)thaninthesalinegroup(58%).However,therewasnosignificantdifference inwithdrawalmovementbetweenthelidocaineandpalonosetrongroups.Therewasnosevere movementwithpalonosetron.
Conclusion: Pretreatmentofpalonosetronwithvenousocclusionmay attenuate rocuronium-inducedwithdrawalmovementaseffectiveastheuseoflidocaine.Itsuggestedthatperipheral actionofpalonosetronwaseffectivetoreducerocuronium-inducedwithdrawalmovement. ©2016PublishedbyElsevierEditoraLtda.onbehalfofSociedadeBrasileiradeAnestesiologia. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
∗Correspondingauthor.
E-mail:kwakkh@knu.ac.kr(K.-H.Kwak).
http://dx.doi.org/10.1016/j.bjane.2016.04.002
0104-0014/©2016PublishedbyElsevierEditoraLtda.onbehalfofSociedadeBrasileiradeAnestesiologia.Thisisanopenaccessarticle
PALAVRAS-CHAVE
Palonosetron; Rocurônio; Injec¸ão; Dor;
Reflexoderetirada
Oefeitodepalonosetronsobreomovimentoderetrac¸ãoinduzidoporrocurônio
Resumo
Justificativa:Rocurônioprovocadorereflexoderetiradaduranteainduc¸ãodaanestesia.Neste estudo,avaliamossepalonosetrontemefeitoanalgésicoparareduziressemovimentoinduzido porrocurónio.
Métodos: Centoevintepacientesforamrandomicamentedesignadosparaumdetrêsgrupos pararecebersoluc¸ãosalina,lidocaína(20mg)oupalonosetron(0.075mg),comaplicac¸ãode torniquetedoisminutosantesdaadministrac¸ãointravenosadetiopentalsódico(5mg.kg−1).
Apósaperdadeconsciência,rocurônio(0.6mg.kg−1)foiinjetadoeoreflexoderetiradafoi
avaliadocomousodeumaescaladequatropontos,demododuplo-cego.
Resultados: Aincidênciaglobaldoreflexoderetiradainduzidoporrocurôniofoide50%para lidocaína(p=0,038),38%parapalonosetron(p=0,006),emcomparac¸ãocom75%parasoluc¸ão salina.Aincidênciadedorausenteoulevefoisignificativamentemenornosgruposlidocaína epalonosetron(85%e92%,respectivamente)quenogruposoluc¸ãosalina(58%).Porém, não houvediferenc¸asignificativanoreflexoderetiradaentreosgruposlidocaínaepalonosetron. Nãohouvemovimentogravecompalonosetron.
Conclusão:Opré-tratamentocompalonosetroncomoclusãovenosapodeatenuaroreflexode retiradainduzidoporrocurôniodemodotãoeficazcomoousodelidocaína.Sugeriu-seque aac¸ão periféricadepalonosetronfoieficaz para reduziroreflexode retiradainduzidopor rocurônio.
©2016PublicadoporElsevierEditoraLtda.emnomedeSociedadeBrasileiradeAnestesiologia. Este ´e um artigo Open Access sobuma licenc¸a CC BY-NC-ND(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Introduction
Rocuronium is a commonly used muscle relaxant with a rapidonsetandintermediatedurationofaction.However, rocuroniuminjectioncauses withdrawalmovementswhich frequentlyoccur with50%---80% of incidence.1,2 The exact
mechanism of rocuroniuminduced pain is notestablished butinrarecase,itcancauseseverecomplicationslike aspi-rationpneumonia.3
Exogenous serotonin 5-Hydroxytryptamine (5-HT) induced neutrophil migration and provoked inflamma-tion and nociception.4 Furthermore prostaglandins and
dopaminecontributeto5-HTevokedpain.5 Pretreatments
of5-HT3antagonistsinsubcutaneousorintrathecal adminis-trationsignificantlyreduced1%formalininducedsecondary mechanicalallodyniaandhyperalgesia inmice.Itsuggests that peripheral and spinal 5-HT3 receptor play a role during pain development.6 Meanwhile, ondansetron, a
5-hydroxytryptamine-3(5-HT3)receptorantagonist,haslocal anesthetic effect 15 times more potent than lidocaine.7
It shows that 5-HT3 antagonists have analgesic effects through central or peripheral action. Pretreatments with ondansetrone,lidocaine,orfentanylpriortotheinjection of rocuronium have been used to decrease rocuronium-induced injection pain but showed limited effects on eliminatingthe pain.2 Palonosetron asa5-HT3 antagonist
recently used for antiemetic, has been reported to be a morepotentagentin PONV8 andtohave ahigheraffinity
of5-HT3receptoramong5-HT3antagonists.9Palonosetron
0.075mg are more effective than 8mg ondansetron to preventionofPONV.10
Therefore, palonosetron may have analgesic effect by action onperipheral 5-HT3 receptoror by local analgesic
property.Forattenuationofrocuroniumwithdrawal move-ment,we investigatedtheefficacyofprioradministration of lidocaine and palonosetron with appliedtourniquet on rocuroniumwithdrawalmovementinlaparoscopicsurgery.
Methods
Onehundredtwentypatientsagedbetween20and70years, belongingtotheAmericanSocietyofAnesthesiologists phys-ical status I or II, who were scheduled for laparoscopic surgery undergeneral anesthesiawere recruitedinto this prospective, randomized, double-blind, controlled study. Patientswereexcluded iftheytookanyanalgesicsbefore operationorhadpastmedicalhistoryofcardiacarrhythmia orcoronaryarterialdisease,orhadahypersensitivity reac-tiontolocalanestheticsorpalonosetron.Writteninformed consent wasobtained aftera detaileddescription of this study,whichwasapprovedbytheInstitutionalReviewBoard ofourmedicalinstitution.
Patientswererandomizedintothreegroupsaccordingto study drugs; saline group(n=40) withnormal salineonly, lidocainegroup(n=40)withlidocaine20mg,palonosetron group (n=40)withpalonosetron 0.075mg. Each total vol-umeof injectionwasmadeupto3mL withnormalsaline preparedbyanindependentanesthesiologistandthe inves-tigatorswereblindedtodrugidentity.
Table1 Demographicdata.
Groups Saline Lidocaine Palonosetron
Age 46.08±13.30 45.72±14.08 46.33±10.96
Sex 14/26 9/31 12/28
Weight 63.92±11.91 61.8±10.48 61.45±11.09 ASAI/II 26/13 22/18 21/19
Allvaluesareexpressedasmeans±SD.
arm to occlude venous drainage, a prepared drug was administered by an investigator who was unaware of the content of the drug. Two minutes after the injection of the drug, the tourniquet was released and 2.5% thiopen-talsodium5mg.kg−1 wasadministeredover10---15s.After
20s,theanesthesiologistcheckedunconsciousnessbyverbal responseandloss ofthe eyelashreflex.Afterloss of con-sciousness,1%rocuronium(0.6mg.kg−1)wasinjectedfor5s
andwithdrawalmovementsweregradedbytheinvestigator accordingtothefollowingscale:1---nopain(noresponse); 2---mildpain(movementatwristonly);3---moderatepain (movementinvolvingthearmonlywithelboworshoulder); 4---severepain(generalizedresponseormovementinmore thanoneextremity).
Weestimatedthesamplesizefromapreviouspilotstudy. Withdrawal movement incidence was to occur in 80% of patientsfollowingadministrationofrocuronium,11,12
there-forethesamplesizerequiredfordetectinga30%reduction was37patientsineachofthe3groups,atapowerof0.8, an˛=0.05.Duetotheconsiderationofdropoutcases,
sam-plesize wasincreasedto 40patients per group.Analyses were performed using SPSS 18.0for Windows(SPSS, Inc., Chicago, IL). Demographic data wereanalyzed using one-way analysis of variance (ANOVA). Values were expressed asmean±SD(standard deviation).The incidenceof with-drawalmovementswereanalyzedbythe2-testandFisher’s
exacttest.Ap-valueof<0.05withBonferronicorrectionwas consideredtobestatisticallysignificant.
Results
All120patientscompletedthisstudy.Therewereno signif-icantdifferencesinthedemographicdataamongthethree groups(Table1).
The grade and incidence of movement withdrawal in each group is shown in Table 2. The overall incidence of rocuronium-induced withdrawal movement was 50% (p=0.038)withlidocaine,38%(p=0.006)withpalonosetron, comparedwith75%ofsaline.Therewasasignificantlylower
incidence of withdrawal movements in patients receiv-ingthe lidocaineand palonosetron comparedwithsaline. Whereastheincidenceofnoormildpainwassignificantly higherinlidocaine(85%,p=0.007)andpalonosetrongroup (92%, p=0.001) than in saline group (58%), severe with-drawal movement was significantly higher in the saline thanthelidocaine(p=0.0017)andpalonosetron(p=0.0003) groups.Nopatientsreceivingpalonosetronhadseverepain. However,therewerenosignificantdifferencesinthe inci-dence of withdrawal movement between lidocaine and palonosetron.
There were no complications such as wheal, inflam-mation, hematoma, or pain on injection site within 24h postoperatively.
Discussion
Thisstudydemonstratedthatpalonosetron,a5-HT3 antag-onist, which is usually used for the prevention of PONV, reduced rocuronium-induced withdrawal movement from 72%inthesalinegroupto42%inthepalonosetrongroup.The nopaintomildpainassociatedwithrocuroniumwithdrawal movementwassignificantlyhigherinthepalonosetronand lidocainegroupscomparedwiththesalinegroup.Nopatient inthepalonosetrongroupshowedsevererocuronium with-drawalmovement.
The exact mechanism of rocuronium-induced pain has notbeen established.ThelowpH orosmolarityof rocuro-niummaybeassociatedwiththecauseofpain,13,14butsome
reportsthatosmolarityandpHwerenotthemajorcauseof rocuronium-inducedinjectionpainexist.15,16 Other
mecha-nismmay be involved in the activation of nociceptors by kinincascade,whichissimilartothemechanismof propo-folevokedpain.17 Thecharacteristic rocuroniuminjection
painwhich patients described was a burning sensation of shortduration18whichcausedthemovementduring
rocuro-niuminjection.16Inaninvivostudy,intradermalstimulation
withhighconcentrationsofrocuroniumrevealedsignificant increasesinhistamineandtryptasereleaseandledto burst-ingdischargefor20---40sofC-fiber.19Therefore,rocuronium
stimulatesC-fiberdirectly.
Variousmethodshavebeenproposedfortheprevention ofrocuroniuminducedpain.Ketamine,lidocaineopioidsand acetaminophen12,20---22wereusedforpretreatmenttoreduce
pain.Pretreatmentwith30---50mgoflidocainewitha tourni-quet applied was more effective than pretreatment with other drugs such as ondansetron, fentanyl, remifentanil, acetaminophen.2,11,22
Table2 Incidenceandintensityscoreofwithdrawalmovements.
Group Withdrawalmovementscore Overallincidence
1---nopain 2---mildpain 3---moderatepain 4---severepain
Saline 11(28%) 12(30%) 6(15%) 11(27%) 29(75%) Lidocaine 20(50%)a 14(35%) 5(13%) 1(2%)a 20(50%)
Palonosetron 23(58%)a 14(35%) 3(7%) 0(0%)a 17(38%)
Valuesarepresentedasnumbersofpatients(percentages).
Ondansetronisa5-hydroxytryptamine-3antagonistused as an anti-emetic. It acts as a local anesthetic drug by blockingsodiumchannels inneurons of ratbrain. Accord-ing to this report, ondansetron is 15 times more potent than lidocaine as a local anesthetic.7 Ondansetron acts
asan opioid u receptor agonist.23 5-HT caused painafter
injection on the hindpaw of rats. Furthermore 5-HT pro-duced an increase in neutrophil activity, local release of prostaglandins anddopamine. Released dopamine con-tributes to 5-HT mediated nociception.5 Zeltz et al.24
indicatedthat5-HT3receptorisexpressednotonlyby pri-maryafferentfiberbutalsobythinlymyelinatedfiberand C-fibers.Inaddition,serotonincontributestopain develop-mentby activationof smalldiameterperipheralafferents andreleaseof proimflamatorypeptidessuchassubstance P. In humans, 5-HT injected into the masseter muscle elicitspainandallodynia/hyperalgesia.25Therefore,5-HT3
antagonistsincludingondansetron,palonosetron,mayhave analgesicpropertiesbyactingasperipheral5-HTreceptor antagonists,sodiumchannelblockers,oropioidagonists.
In general, 4mg of ondansetron is administrated with venous occlusion to reduce the injection pain of rocuro-niumorpropofol.2,26Itsuggestedthattheperipheralaction
ofondansetronreducedrocuroniumwithdrawalmovement. Cho et al.27 reported that palonosetron with systemic
administrationreducedrocuroniumwithdrawalmovement. But intravenous injection of palonosetron without venous occlusion could not reveal the exact action site whether peripherally or centrally. In our study, palonosetron was administratedwithatourniquetappliedandnotonlyshowed asignificantanalgesiceffectwhencomparedwithsalinebut alsoshowedaneffectsimilartothatof20mglidocaineon rocuroniumwithdrawalmovement. Therefore, weshowed thatpalonosetronreduceswithdrawalmovementof rocuro-niumwithvenousocclusionviaperipheralaction.
Palonosetronhas a longhalf-life comparedtoother 5-HT328 andis usuallyinjectedpriortoanestheticinduction
forpreventionofearlyandlatePONV.29Therefore,
pretreat-mentwithpalonosetronpriortoinductionhasmeaningfor preventionof PONVand for reducing rocuronium induced withdrawalmovement.
Thelimitationof ourresearchwaswecouldnotreveal theexactanalgesicmechanismofpalonosetron by periph-eral5-HT3receptor,sodiumchannelor u opioidreceptor. Further research will be needed to determine the kinds of receptors involved in reducing rocuronium withdrawal movement.
Inconclusion,wedemonstratedthatpalonosetronisan effective analgesic for thereduction of rocuronium with-drawalmovementsimilartoasmalldose oflidocainewith tourniquetapplied.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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