Rev. Bras. Anestesiol. vol.64 número1

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

Do

metoclopramide

and

ondansetrone

alter

mivacurium-induced

neuromuscular

blockade?

---

a

randomised

trial

Mehmet

Tercan

_,

_Esra

_Mercanoglu

_Efe

,

Gurkan

Turker

,

Fatma

Nur

Kaya

,

Belgin

Yavascaoglu

_,

_Yesim

_Ozarda

_,

_Elif

_Basagan

_Mogol

a_{AnesthesiologyandReanimationDepartment,MedicalFaculty,UludagUniversity,Bursa,Turkey} b_{BiochemistryDepartment,MedicalFaculty,UludagUniversity,Bursa,Turkey}

Received27January2013;accepted1April2013

KEYWORDS

Mivacurium; Metoclopramide; Ondansetrone; Neuromusculary; Blockade; Anesthesia

Abstract

Background: We aimed to investigate the effects ofmetoclopramide andondansetrone on mivacuriumneuromuscularblockade.

Methods:Seventyfive,ASAI-IIpatients,aged18-65andscheduledforelectivesurgeryrequiring trachealintubationwereincludedinthestudy.Thepatientsreceivedmetoclopramide10mg, ondansetrone 4mgornormalsaline5mL;groupM,groupO, groupNS(n=25),respectively. Before anesthesia study drugs wereadministered inavolume of5mL.The levelofplasma cholinesterasewereobtainedbeforeand5minutesaftertheadministrationofstudydrugsand 5minutesafter theadministrationofmivacurium.Onsettime,T25,T75,T25-75, T90levels were compared with eachotheranddifferences between eachpatients were investigated. AfterrecordingT90,thestudywasterminatedandsurgerywasstarted.

Results:OnsettimewassignificantlyshorteringroupM,thantheothertwogroups.Onsettime ingroupOwassignificantlyshorterthaningroupNS.InGroupMT25,T75,T90andrecovery indicesweresignificantlygreaterthaninGroupNS(p<0.001).InGroupOT25,T75weregreater thanGroupNS(p<0.01andp<0.05,respectively).InGroupMT75,T90andemergenceindices weresignificantlyhigherthanGroupO(p<0.001,p<0.01,p<0.001,respectively).InGroups MandO,plasmacholinesteraselevelsdecreasedsignificantly(p<0.001)afteradministration ofstudydrugsandmivacurium.PlasmacholinesterasealsowasreducedinGroupNS5minutes aftertheadministrationofmivacurium(p<0.001).

Conclusion: Ondansetroneisbelievedtobemorereliableagentthanmetoclopramidewhen usedwithmivacurium.

© 2013SociedadeBrasileirade Anestesiologia.Publishedby ElsevierEditoraLtda.Allrights reserved.

∗_{Correspondingauthor.}

E-mail:[email protected],[email protected](E.M.Efe).

Introduction

Mivacuriumchlorideisashortactingnon-depolarizing neu-romuscular blocking agent rapidly hydrolised by plasma cholinesterase (pCHE). Drugs which inhibit pCHE prolong mivacuriumneuromuscularblock.1,2_{Delayedrecoveryfrom}

neuromuscularblockmaycompromiserespiratoryeffortand airwayintegrityduring emergencefromanesthesia. Meto-clopramide,whichhastensgastricemptyinganddecreases gastroesophagealreflux, is commonly usedfor prevention ofnauseaandvomitingintheearlypostoperativeperiod.3---6

MetoclopramideinhibitsPche,7_{andgivingitbefore}

mivac-urium can prolong recovery time by 30%, probably via increasedbioavailabilitycausedbydecreasedplasma clear-ance of mivacurium.8,9 _{Ondansetrone, a serotonin type-3}

receptor antagonist, is also used to prevent nausea and vomiting.10 _{Theserotonintype-3receptorisfound inboth}

peripheralandcentralnervoussystems.Ondansetronemay alsoaffect neuromuscular blockade by possible inhibiting of Ach releasing to neuromuscular junction.11---14 _{In this}

placebo controlled, prospective, randomised and double blindstudy,we aimed toinvestigatethe effects of meto-clopramideandondansetroneonmivacuriumneuromuscular blockade.

Materials

and

methods

After Hospital Ethics Committee approval and receipt of written informed consent, seventy five ASA I-II status patients, aged 18-65 and scheduled for elective surgery requiring tracheal intubation were included in the study. Patientswithneuromuscular,liverand kidneydiseases, or under medication known to affect neuromuscular trans-mission, withhistory of difficult intubation, malnutrition, alcohol abuse, fluid electrolyte disturbances, or BMI>35 were rejected. The patients were randomly assigned accordingtocomputer-generatedrandomnumbersequence into one of three groups to receive metoclopramide, ondansetroneor normal saline; group M(n=25), group O (n=25)andgroupNS(n=25),respectively.

Inthe operatingroommonitoringof DII derivatedECG,

pulseoximetryandnon-invasivearterialpressurewas per-formed by Datex-Ohmeda CardiocapTM_{/5 (GE, Finland). A}

peripheric intravenous line was inserted with 20 gauge catheterand0.9NaClinfusionwasstarted.

Metoclopramide 10mg, ondansetrone 4mg or normal saline were administered in a volume of 5mL, 5minutes before anesthesia induction. The study drugs were pre-paredbyanotherphysiciansoalldrugswereadministered blindly.Bloodsampleswereobtainedtomeasurethelevel ofplasmacholinesteraseactivity,beforeand5minutesafter theadministrationof study drugs and 5minutes afterthe administrationofmivacurium.Duringtwohours,these sam-ples were sent to be centrifuged in gel contained tubes at 5,000rpm for five minutes.One ml of obtained serum wereinsertedtotheeppendorf.Thosesampleswerelabeled as 1, 2, 3 in order. They were kept in ----20◦_{C in}

bio-chemistry laboratory. Plasma cholinesterase levels were measuredcolorimetricallywithVitros250ChemistrySystem (Ortho-ClinicalDiagnostics, a Johnson Johnson Company).

Plasmacholinesterasereferencelevelwasconsideredas 4-12U.mL---1_.

Anesthesia was induced with 2␮g.kg---1 _{fentanyl and}

2.5mg.kg---1_{propofolandpatientwasventilatedmanuallyby}

maskwith%100oxygenuntiltheintubation.Duringthistime usingTOF-Watch®_{SX(Organon,Ireland)andulnarnerveof}

thenon-cannulatedarmwasstimulatedwithsupramaximal (50mA) trainoffourstimulationto1Hzmode toobtain a %100controllevel(EMAX).

After obtaining a neuromuscular block control level, 0.2mg.kg---1 _{mivacurium wasadministeredand thepatient}

wasintubated.AnesthesiawasmaintainedbyMAC1 sevoflu-raneinanequalpartsO2/N2Omixtureduringoperationand

patientwasventilatedtomaintain normocapnia.Forearm skintemperaturewaskeptgreaterthan32◦_C.

The time from mivacurium injection up to performing 100%neuromuscularyblockadewasrecordedasonsettime. Forassessmentofneuromusculartransmission,TOFimpulse with50mAcurrent wasusedat5minutesintervalsinfirst 10minutesandonceeveryminuteafter10minutes.T25,T75,

T25-75,T90wererecordedduringthestudy.Onsettime,T25,

T75,T25-75,T90 levelswerecomparedwitheach other and

differencesbetweeneachpatientswereinvestigated.After recording T90, the study was terminated and surgery was

started.

At1st_,3rd_,5th_,10th_,20th _and30th _minutesafter

intuba-tion,meanarterialpressure(MAP),heartrate(HR),ETCO2,

SPO2 were recorded. 0.5␮g.kg---1 IVfentanyl and10mgIV

efedrinwereplannedtobeadministeredatthetimeof20% increaseordecreaseofMAPrespectively.

Thedata werestatisticallyanalyzed usingSPSSversion 13.0 (SPSS Inc., Chicago, IL). The Kruskal-Wallis test was used to assess differences among the three groups with respect to non-parametric variables. If this revealed sig-nificant differences,theMann-Whitney Utestwasusedto analyzedifferences between thegroups in pairs. Nominal non-parametric data were analyzed using the Chi-square test and Fisher’s exact test. Data were presented as mean±SD,median (range),and numberof patients (per-centage) percategory.P values<0.05 wereconsidered to indicatestatisticalsignificance.

Results

The three study groups did not differ significantly in gender, ASA, age, weight, height and BMI (p>0.05) (Table1).

Therewerenodifferencesinhemodynamicparameters between groups. Onset time was significantly shorter in group M than the other two groups. Onset timein group OwassignificantlyshorterthaningroupNS.Therewasno significantdifferenceinEMAXvalues(p>0.05)(Table2).

InGroup MT25,T75, T90 andrecoveryindices were

sig-nificantlygreaterthan inGroupNS(p<0.001).InGroup O T25,T75 weregreaterthanGroupNS(p<0.01andp<0.05,

respectively). In Group M T75, T90 andemergence indices

weresignificantlyhigherthanGroupO(p<0.001,p<0.01, p<0.001respectively)(Table3).

Table1 Demographicdata(number,mean±standarddeviationornumber).

GroupM GroupO GroupNS

n=25 n=25 n=25

Gender(M/F) 4/21 5/20 4/21

ASA(I/II) 18/7 20/5 22/3

Age(year) 44.24±10.38 33.52±10.57 41.32±12.24 Weight(kg) 66.16±9.46 68.08±9.61 65.48±8.52 Height(cm) 163.84±5.41 166.36±7.33 162.92±5.61

BMI 24.60±2.96 24.50±2.00 24.60±2.36

ASA, AmericanSocietyof Anesthesiologists;BMI, Bodymassindex; F,female;M,male;M, metoclopramide;NS,normal saline; O, ondansetrone.

Table2 MAXandonsettime(mean±standarddeviation).

EMAX Onsettime(sec)

GroupM 99.6±0.48 138.8±5.82a

GroupO 99.4±0.50 162.0±9.89b

GroupSF 99.3±0.47 168.8±7.67

levels decreased significantly (p<0.001) after administra-tionof study drugs and mivacurium. In Group NS,plasma cholinesteraselevelwasfoundtoreduce5minutesafterthe administrationofmivacurium(p<0.001).

Discussion

Metoclopramideand ondansetronearecommonly givento preventnauseaandvomitingbuttheirpossibleinteractions withmivacuriumarenotfullyunderstood.Metoclopramide

prolongsthe actionof succinylcholine,suggesting possible depression of pCHE activity,15---17 _{and indeed, it has been}

shown to prolong the effect of mivacurium.8 _{The 5-HT} 3

antagonistondansetronemaycauseincreasedsensitivityto thecompetitive neuromuscular blockade induced by non-depolarising muscle relaxants by reducing the release of Ach.14

Wefoundthatmetoclopramide reducedtheonsettime ofmivacuriumsignificantlycomparedtoondansetroneand saline;ondansetronereducedonsettimesignificantlybutto alesserextent.Metoclopramidealsoreduced neuromuscu-lartransmissionmorethanondansetrone,buttherewasno differencebetweenthetwodrugsintheireffectsonpCHE aftergivingmivacurium.

Motamed et al.16 _{studied the effect of 10 and 20mg}

metoclopramide on mivacurium-induced neuromuscular blockade.Tenor20mgmetoclopramidebeforeanintubating doseofmivacuriumhastenedtheonsetofmaximum block-adeby30% andprolonged recoveryby at least50%. Time

Table3 T25,T75,T90andrecoveryindices(minute)(mean±standarddeviation).

T₂₅ T₇₅ T_{90 Recoveryindex}

GroupM 20.92±1.70a _27.92

±1.75a,b _33.40

±1.77a,c _7.00

±0.70a,b

GroupO 19.80±2.12d _25.04±2.38e _{30.44±2.88 5.48±0.87}

GroupNS 17.56±2.45 23.12±2.83 29.72±3.03 5.24±0.87

M,metoclopramide;NS,normalsaline;O,ondansetrone. a _{p<0.001;comparingwithGroupNS.}

b _{p<0.001;comparingwithGroupO.} c _{p<0.01;comparingwithGroupO.} d _{p<0.01;comparingwithGroupNS.} e _{p<0.05;comparingwithGroupNS.}

Table4 Plasmacholinesteraselevels(med±standardeviation).

PC1 PC2 PC3

GroupM 6.502±0.922 5.674±0.817a _5.033±0.790a

GroupO 6.124±1.418 5.634±1.387a _4.884

±1.203a

GroupNS 5.895±1.204 5.894±1.204 4.998±1.190a

M, metoclopramide; NS, normal saline; O, ondansetrone; PC1, plasma cholinesterase level in first blood sample; PC2, plasma cholinesteraselevel5minafteradministrationofstudydrug;PC3,plasmacholinesteraselevel5minafteradministrationofmivacurium.

to25%recovery wassignificantlygreater inboth metoclo-pramidegroupscomparedtosaline.Aslightbutsignificant reductionincholinesteraseactivitywasdetected2minutes afterthe administrationof 20mgmetoclopramide. Inour studyonly10mgmetoclopramide decreasedpCHEactivity significantly.

El Ayass and Hendrickx found a reduction of mivac-uriuminfusionrateandadelay inneuromuscularrecovery aftermetoclopramide10or20mgintheirrandomised dou-bleblindplacebo-controlled studyof 45 patients.18 _There

wasno significant change in the onsettime compared to saline,probablyduetoaninadequatenumberofpatients. Plasma cholinesterase level decreased in both metoclo-pramide groups. The recovery indices were greater with metoclopramidecomparedtosaline.Whiletherewere sig-nificant increases in the time to recovery at 25%, 50%, 75% and 90% with 20mg, there was only 75% and 90% increase in the time of recovery with 10mg, compared to saline. We had similar results with this study; 10mg metoclopramide prolonged the recovery timeand indices by25%,75%and90% anddecreasedpCHElevel significan-tly.

Skinner etal.8_{investigatedthe influenceof 15mg.kg}---1

metoclopramide on pCHE and the duration of action of mivacurium in a randomised double-blind study of 30 patients.Onsettimeandrecoveryindexwerenotaffected, buttherewasa reductionofpCHEactivityat thetimeof maximumblockade withbothmetoclopramide andsaline. Anincreased timetorecovery of T1 to25%, 75% and90%

wasseeninthemetoclopramidegroup.

Lienetal.14_{foundthat8and16mgondansetrondidnot}

affecttheneuromuscularblockadeinducedbyatracuriumin theirstudyof30patients;ondansetronmaythusbe prefer-ableasan antiemeticagentwhenusedwithothermuscle relaxantagentsotherthanmivacurium.Wefoundthat4mg ondansetronedidnotaffectmivacurium-induced neuromus-cularblockade.

Mivacurium is hydrolyzed by pCHE, an enzyme whose activity is known to be affected by age, gender, ethnic groups and by some physiologic and pathologic situa-tions. Lepage et al.19 _{studied factors affecting biological}

variations in total pCHEin 3,372 apparently healthy sub-jects more than four years old. They concluded that genetic factors, hormonal status, age and some medica-tions and, especially in males, BMI, affected pCHE. In our study we excluded patients who were more than 65 years old and with BMI>35. In our study it was impor-tanttoshowthatpCHEactivity wasindeed inthenormal range, because low pCHE activity causes prolongation ofmivacurium induced neuromuscularblockade.20,21 _After

giving metoclopramide and ondansetrone, enzyme levels decreasedindifferentratios.Aftermivacurium,enzyme lev-elsdecreased significantly in allgroups but stayed within thenormal range, withno significant differencebetween groups.

Considering that 10mg metoclopramide prolonged mivacurium-inducedneuromuscularblock,we believethat neuromuscularfunctionshouldbemonitoredduringsurgery in order to avoid the complications of excessive dosage. Because ondansetrone did not prolong T90 or recovery

indices, and affected other parameters of neuromuscular blockadelessthanmetoclopramide,webelievethatitisa

morereliable agentthanmetoclopramidewhen usedwith mivacurium.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

References

1.Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuro-muscularpharmacologyofmivacuriumchloride(BWB1090U): a short-acting nondepolarizing ester neuromuscular blocking drug.Anesthesiology.1988;68:723---32.

2.CookDR,StillerRL,WeaklyJN,etal.Invitrometabolismof mivacuriumchloride(BWB1090U) andsuccinylcholine.Anesth Analg.1989;68:452---6.

3.HenziI,WalderB,TramerMR.Metaclopramideintheprevention ofpostoperativenauseaandvomiting:aquantitativesystematic reviewofrandomisedplacebo-controlledstudies.BrJAnaesth. 1999;83:761---7.

4.PerelMS,MooreC,HershT,etal.Metoclopramidetherapyin patientswithdelayedgastricemptying:arandomiseddouble blindstudy.DigDisSci.1979;24:662---6.

5.Wright RA, Clemente R, Wathen R. Diabetic gastroparesis: anabnormality ofgastricemptying ofsolids. AmJMedSci. 1985;289:240---3.

6.Brock-Utne JG, Dow TGB, Welman S, et al. The effect of metoclopramideonloweroesophagealtoneinlatepregnancy. AnaesthIntCare.1978;6:26---9.

7.KaoYJ,TellezJ,TurnerDR.Dose-dependenteffectof metoclo-pramideoncholinesterasesandsuxamethoniummetabolism.Br JAnaesth.1990;65:220---4.

8.SkinnerHJ,GirlingKJ,WhitehurstA,NathansonMH.Influence ofmetoclopramideonplasmacholinesteraseand durationof actionofmivacurium.BrJAnaesth.1999;82:542---5.

9.NijsN, DuvaldestinP,SlavovV,etal. Istherecovery profile ofmivacuriumindependentoftherateofdecayofitsplasma concentrationinpatients withnormal plasmacholinesterase activity?ActaAnaesthesiolScand.1998;42:1175---9.

10.Cubeddu LX, Hoffman IS, Fuenmayor NT, et al. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cis-platininducednauseaandvomiting.NEnglJMed.1990;322: 810---6.

11.RichardsonBP,EngelG,DonarschP,etal.Identificationof sero-toninM-receptorsubtypesandtheirspecificblockadebyanew classofdrugs.Nature.1985;316:126---31.

12.Fozard JR. Neuronal 5-HT receptors in the periphery. Neu-ropharmacology.1984;23:1473---86.

13.KilpatrickGJ,JonesBJ,TyersMB.Identificationanddistribution of5-HT3receptorsintheratbrainusingradioligandbinding. Nature.1987;330:746---8.

14.LienCA,GadallaF,KudlakTT,etal.Theeffectofondansetron onatracurium-inducedneuromuscularblockade.JClinAnesth. 1993;5:399---403.

15.KambamJR,ParrisWCV,FranksJJ,etal.Theinhibitoryeffect of metoclopramideon plasma cholinesterase activity. Can J Anaesth.1988;5:476---8.

16.MotamedC,KirovK,CombesX,etal.Effectofmetoclopramide onmivacurium-inducedneuromuscularblock.ActaAnaesthesiol Scand.2002;46:214---6.

17.Turner DR, Kao YJ, Bivona C. Neuromuscular block by succinylcholine following treatment with histamine type 2 antagonists or metoclopramide. Br J Anaesth. 1989;63: 348---50.

randomizeddoubleblindplacebo-controlledstudy.EurJ Anaes-thesiol.2005;22:197---201.

19.Lepage L, Schiele F, Guequen R, et al. Total cholinesterase in plasma: biological variations and references. Clin Chem. 1985;31:546---50.

20.MaddineniVR,MirakhurRK.Prolongedneuromuscularblock fol-lowingmivacurium.Anesthesiology.1993;78:1181---4.