A prospective, randomized, blinded-endpoint, controlled study – continuous epidural infusion versus programmed intermittent epidural bolus in labor analgesia

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

A

prospective,

randomized,

blinded-endpoint,

controlled

study

---

continuous

epidural

infusion

versus

programmed

intermittent

epidural

bolus

in

labor

analgesia

Joana

Nunes

,

Sara

Nunes,

Mariano

Veiga,

Mara

Cortez,

Isabel

Seifert

DepartamentodeAnestesiologia,HospitalCentraldoFunchal,Funchal,Portugal

Received15June2014;accepted11December2014 Availableonline19November2015

KEYWORDS Analgesia; Epidural; Epiduralanalgesic techniques; Infusion; Obstetricanalgesia; Programmed intermittentbolus Abstract

Background: Thereisevidencethatadministrationofaprogrammedintermittentepiduralbolus (PIEB)comparedtocontinuousepiduralinfusion(CEI)leadstogreateranalgesiaefficacyand maternalsatisfactionwithdecreasedanestheticinterventions.

Methods:Inthisstudy,166womenwithviablepregnancieswereincluded.Afteranepidural loadingdoseof10mLwithRopivacaine0.16%plusSufentanil10␮g,parturientwererandomly assignedtooneofthreeregimens:A---Ropivacaine0.15%plusSufentanil0.2_␮g/mLsolution as continuousepidural infusion(5mL/h, beginningimmediatelyafter theinitial bolus);B ---Ropivacaine0.1%plusSufentanil0.2_␮g/mLasprogrammedintermittentepiduralbolusandC --- SamesolutionasgroupAasprogrammedintermittentepiduralbolus.PIEBregimenswere programmedas10mL/hstarting60minaftertheinitialbolus.Rescuebolusesof5mLofthe samesolutionwereadministered,withtheinfusionpump.Weevaluatedmaternalsatisfaction usingaverbalnumericscalefrom0to10.Wealsoevaluatedadverse,maternalandneonatal outcomes.

Results:Weanalyzed130pregnants(A=60;B=33;C=37).Themedianverbalnumericscale formaternalsatisfactionwas8.8ingroupA;8.6ingroupBand8.6ingroupC(p=0.83).We found ahighercaesareandeliveryrateingroupA(56.7%;p=0.02).Nodifferencesinmotor block,instrumentaldeliveryrateandneonataloutcomeswereobserved.

Conclusions: Maintenanceofepiduralanalgesiawithprogrammedintermittentepiduralbolus isassociatedwithareducedincidenceofcaesareandeliverywithequallyhighmaternal satis-factionandnoadverseoutcomes.

©2015SociedadeBrasileiradeAnestesiologia.Publishedby ElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗_{Correspondingauthor.}

E-mail:[email protected](J.Nunes). http://dx.doi.org/10.1016/j.bjane.2014.12.006

0104-0014/©2015SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALAVRAS-CHAVE Analgesia; Epidural; Técnicasdeanalgesia epidural; Infusão; Analgesiaobstétrica; Bolusintermitente programado

Estudoprospectivo,randômico,controladoedeavaliac¸ãocegadodesfecho---infusão periduralcontínuaversusbolusepiduralintermitenteprogramadoemanalgesia departo

Resumo

Justificativa:Háevidênciasdequeaadministrac¸ãodeumbolusepiduralintermitente progra-mado(BEIP)comparadaàinfusãoepiduralcontínua(IEC)resultaemmaioreficáciadaanalgesia edasatisfac¸ãomaterna,comreduc¸ãodasintervenc¸õesanestésicas.

Métodos: Nesteestudo,166mulherescomgravidezesviáveisforamincluídas.Apósumadose epiduralde10mLdeRopivacaínaa0,16%eadic¸ãode10␮gdeSufentanil,asparturientesforam aleatoriamentedesignadasparaumdostrêsregimes:A-ropivacaínaa0,15%maissoluc¸ãode sufentanil(0,2_␮g/mL)comoinfusãoperiduralcontínua(5mL/h,comec¸andoimediatamente apósobolusinicial);B-ropivacaínaa0,1%maissufentanil(0,2␮g/mL)comobolusepidural intermitenteprogramado;C-soluc¸ãoidênticaàdoGrupoAcombolusepiduralintermitente programado.OsregimesBEIPforamprogramadoscomo10mLporhora,iniciando60minutos apósobolus inicial.Bolus deresgatede 5mLdamesmasoluc¸ãoforamadministradoscom bombadeinfusão.Asatisfac¸ãomaternafoiavaliadautilizandoumaescalanuméricaverbalde 0a10.Tambémavaliamososresultadosadversosmaternaiseneonatais.

Resultados: Foramavaliadas 30gestantes(A=60,B=33;C=37)foramavaliados.A mediana naescalanuméricaverbalparaasatisfac¸ãomaternafoide8,8nogrupoA;8,6nogrupoBe 8,6nogrupoC(p=0,83).EncontramosumataxamaiselevadaparapartocesárionogrupoA (56,7%;p=0,02).Nãoobservamosdiferenc¸asnobloqueiomotor,taxadepartoinstrumentale resultadosneonatais.

Conclusões:A manutenc¸ão da analgesia peridural combolus epidural intermitente progra-madoestáassociadaaumareduc¸ãodaincidênciadepartocesarianocomsatisfac¸ãomaterna igualmenteelevadaesemresultadosadversos.

©2015SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Este ´eum artigoOpen Accesssobumalicenc¸aCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Childbirth is one of the most painful experiences for woman.1 _{The degree of painexperienced and the quality}

ofpainreliefaffectpatient’ssatisfactionwiththebirthing process,animportantoutcomeofthequalityofcare, con-tributingtolong-termemotionalandpsychologicaleffects.2

Neuraxialanalgesictechniquesoutdidparenteral, inhala-tory andnon-pharmacologicmeasures in laboranalgesia.3

Maintenance technique for epidural labor analgesia has changedfromintermittentmanualbolus---withanincreased riskforcontamination,drugerrorandwidervariationinpain relief4_{---tocontinuousepiduralinfusion(CEI)withorwithout}

patientcontrolledepiduralanalgesia(PCEA).Thelater pro-videsasmootheranalgesicexperiencebutlocalanesthetic consumptionisusuallyhigherandmotorblockmaybemore prominent,5_{withalikelyincreaseinrates ofdystociaand}

instrumentaldeliveries.6

There is evidence that administration of an epidural bolus leads to greater analgesia efficacy7---9 _{and maternal}

satisfactionwithreducedlocalanestheticconsumptionand anestheticinterventions.4,5,10---12_{Howevernostudy,todate,}

hasincluded all women withviable pregnanciesand pro-grammedintermittentepiduralbolus(PIEB)regimentsdiffer significantlyamongstudies.

We hypothesized that, even at lower local anesthetic concentrations,PIEBisassociatedwithsimilarorhigher out-comescomparingtoCEI.Theprimaryoutcomeofthisstudy

is to compare maternal satisfaction, with PIEB at differ-entlocalanestheticconcentrations,tostandardCEIinlabor analgesia.

Methods

We conducted a prospective, randomized, blinded-endpoint, controlledstudy between April and June 2013, approvedbytheClinicalResearchandEthicsCommitteeof Funchal’sCentralHospital.

Women with viable pregnancies who requested labor analgesia,withacervicaldilation>3cmand<5cmandwith abaselinepainscore(assessedatthepeakofthe contrac-tion) from5 to10 in verbal numericscale (VNS)of pain, wereincluded.Writteninformedconsentwasobtainedfrom allsubjectsortheparentsorlegalguardians,forminor sub-jects.Womenwhohadreceivedparenteralopioids,whodid not speakthe languageor were unabletoperform motor blockevaluationtests,wereexcludedfromthestudy.

Immediatelybeforeinitiationofanalgesia,acrystalloid infusion of 500mL (Ringer lactate) was started. Maternal heart rate,non-invasivearterialblood pressure,andfetal heartratetracingwereassessed.Epiduralanalgesiawas ini-tiatedinsittingpositionattheL3---4orL4---5interspaceusing thelossofresistancetosalinetechniquewithan18-gauge Tuohyepiduralneedle.3---4cmoftheclosed-end, multiori-ficeepiduralcatheterwasinsertedintotheepiduralspace

Assessed for eligibility (n=203) pregnant women who received epidural labor analgesia

Enrolment Allocation Follow-up Analysis Randomized (n=166) Even age Excluded (n=13)*

Allocated to group A (CEI 0,15%) (n=78) Allocated to group B (PIEB 0,1%) (n=41)

Received allocated intervention (n=75) Received allocated intervention (n=40) Did not received allocated intervention

(n=3)

Did not received allocated intervention (n=1)

Allocated to group C (PIEB 0,15%) (n=47)

Received allocated intervention (n=47) Did not received allocated intervention (n=0) Discontinued intervention (n=0) Excluded (n=5)* Discontinued intervention (n=0) Excluded (n=7)* Discontinued intervention (n=0) Analysed (n=60)

Excluded from analysis (n=2) because maternal satisfaction was missing.

Analysed (n=33)

Excluded from analysis (n=2) because maternal satisfaction was missing.

Analysed (n=37)

Excluded from analysis (n=2) because maternal satisfaction was missing. Odd age

Last number of clinical file between 0-4

Odd age

Last number of clinical file between 5-9 Not meeting inclusion criteria (n=38)

Declined to participate (n=0)

Figure1 CONSORT2010Flowdiagram.CEI,continuousepiduralinfusion;PIEB,programmedintermittentepiduralbolus;*maternal

satisfactionscoremissing.

andsecured.Withnotestdose,allparturientsreceivedan initialepiduralfractionedloadingdoseof10mLwith0.16% Ropivacaineplus Sufentanil 10␮g.If VNSscore was>3 or ifwomenrequestedanadditionalepiduralbolus,lessthan 30minaftertheepiduralloadingdose,wereexcludedfrom thestudyandsubsequentstatisticalanalysis,ponderingthat theyhadafailedblock.

Parturientwererandomizedtoreceiveoneofthethree followingregimensforthemaintenanceofanalgesia accord-ingtoFig.1.

Forthepurposeofthisworkweusedthesameinfusion pump programmedtodeliverCEIorPIEB accordingtothe protocolofthestudy.Allpump’sinfusiontubingwere con-nectedtothepatient’sepiduralcatheteraftertheloading dose.

The pumpforCEI,groupA,wasprogrammedtodeliver theRopivacaine0.15%plusSufentanil0.2␮g/mLsolutionat arateof5mL/h,withPCEAbolusesof5mLwithalockout intervalof20min,andaperhourmaximumvolumeof15mL. Patientswereinstructed,beforeor immediatelyafter the epiduralcatheterplacement,onhowtousethePCEApump andtopushthebuttonwhenevertheyfeltpainful.

The PIEB pump in group Bwasprogrammed to deliver 10mL of0.1%Ropivacaine plusSufentanil0.2␮g/mL solu-tioneveryhourbeginning60minaftertheadministrationof theinitialepiduralloadingdose.ThePIEBpumpingroupC, wasprogrammedtodeliver10mLofRopivacaine0.15%plus Sufentanil0.2␮g/mLsolutioneveryhour beginning60min aftertheadministrationoftheinitialepiduralloadingdose.

Patientsin the PIEB groups were instructed, to push the nursingbuttonwhenevertheyfeltpainfulandthe anesthe-siologistwascalled toadministeranadditionalbolus with theinfusionpump.

The epiduralanalgesia wascontinuedthroughthe sec-ondstageoflaboruntildeliveryofthefetus.Theadditional bolusinallgroupswasdefinedas5mLofthesolution.

Data noted for each subject included demographic characteristics,co-morbidities, pregnancyandlabordata, adverseeffects,maternalsatisfaction,motorblock evalua-tion,modeofdeliveryandApgarscore.

VNS score for pain and motor function was evaluated everyhourbeginning30minaftertheepiduralloadingdose. The degree of motor block was evaluated in both lower extremitiesusingthe Bromagescore.13 _{The endpoint was}

anydegreeofmotorblockinoneorbothlowerextremities atanytime,duringlabor.

Maternal satisfaction was assessed after labor using a verbalnumericscalefrom0(notsatisfiedatall)to10 (com-pletely satisfied). A blinded nurse assessed this endpoint afterthedelivery.

Usingdatafrompreviousstudies14,15 _{wecalculatedthat}

asamplesizeof113patientswouldgivethestudyapower of >0.9 to detect a statistically significant difference in maternal satisfaction. Data were expressed asmedian or mean±SDornumberwhereappropriate.Allanalyseswere performedusingthestatisticalsoftwareIBMSPSSStatistics 19.Associationbetweencategoricalvariableswasevaluated using2 _{test and Fisher exact test. Continuous outcomes}

Table1 Subjectandlaborcharacteristicspresentedasmean(SD)ornumber(n).

A---CEI B---PIEB0.1% C---PIEB0.15% p-Value

(n=60) (n=33) (n=37)

Age(y) 29.2(6.1) 29.4(6.3) 28.1(6.7) 0.65

Weight(kg) 76.6(11.8) 79.9(15.1) 78.2(12.6) 0.76 Height(cm) 161.8(4.9) 161.7(6.4) 161.9(6.4) 0.70 Gestationalage(wk) 39.3(1.5) 39.5(1.2) 39.5(1.3) 0.69 Durationoflaboranalgesia(h) 6.7(4.6) 6.8(4.5) 6.4(4.0) 0.98

Inducedlabor(n) 22 12 14 0.99

Co-morbidities(n) 1 3 4 0.13

Multiparous(n) 19 11 13 0.94

Twinpregnancy(n) 1 0 3 0.10

CEI,continuousepiduralinfusion;PIEB,programmedintermittentepiduralbolus.

were compared between groups with the Kruskal---Wallis test.Ap-value<0.05wasconsideredstatisticallysignificant.

Results

Onehundredsixty-fivesubjectsrecruitedwererandomized togroupA(CEI0.15%),groupB(PIEB0.1%)orgroupC(PIEB 0.15%).Afterallocationandfollow-upasshownintheflow diagram(Fig.1),130subjectswheresubmittedtodata anal-ysis(A=60;B=33;C=37).Subjectandlaborcharacteristics arereportedinTable1.

ThemedianVNSformaternalsatisfactionwas8.8(95%CI 8.3---9.3)forgroupA(CEI);8.6(95%CI7.9---9.3)forgroupB (PIEB0.1%)and8.6(95%CI7.7---9.4)forgroupC(PIEB0.15%) (p>0.05).

Motorblockoccurredatleastonceduringlaborin6.7% ofcasesintheCEIgroupand2.7%ofcasesinthePIEB0.15% group(p>0.05).NoparturientinPIEB0.1%groupreported motorblock.Theoddsratioforoccurrenceofmotorblock inCEIandPIEB0.15%was2.47(95%CI0.28---21.3).

When we analyze labor outcomes(reported in Fig.2), comparingthethreemaintenancetechniques,we founda

60% 50% 40% 30% 20% 10% 0%

Eutocic* Caesarean* Instrumental

CEI PIEB 0.1% PIEB 0.15% 56.5% (n=13) 50.6% (n=39) 26% (n=20) 23.4% (n=18) 34.8% (n=8) 36.6% (n=11) 26.7% (n=8) 36.6% (n=11) 8.7% (n=2)

Figure2 Laboroutcomepresentedaspercentageand

num-ber(n).CEI,continuous epiduralinfusion; PIEB,programmed intermittentepiduralbolus;*statisticallysignificantdifference (p<0.05).

significantdifferenceinceasareandelivery(p=0.02)rates, butnodifferenceininstrumentaldeliveryrates(p=0.74).

NeonataloutcomesevaluatedbytheApgarscoreat1st and 5thminutes where similarbetween groups (p>0.05). MeanApgarscoresarepresentedinTable2.

There was no significant difference in sensory spread (describedasnumbnessbytheparturient)betweengroups (p=0.59).Cardiovascularchangesandincidenceofnausea andvomiting hada verylowincidence withnosignificant differencesbetweengroups.

Discussion

Maternalsatisfactionisoneofthesecondaryoutcomes indi-catedin theresultsof manystudies,4,14---17 _{which compare}

differentnewtechniquesoflaboranalgesiamaintenance. Analgesiaandsatisfactionwithanalgesiaarenot equiv-alent concepts. Continuousand stableanalgesia,sense of control,painlessuterinecontractionfeeling,abilitytowalk, absenceof numbnessandmotor blockand abilitytopush arealsoimportanttodeterminematernalsatisfactionwith laboranalgesia.14

Otherauthorsfoundagreatersatisfactionratingin sub-jectswhoreceivedPIEB.4_{TheycomparedPIEBandCEI,both}

withPCEA,inwomenundergoinginductionoflabor,hence withhigherpainscoresandinwhichtheanalgesiaefficacyof PIEBmayhaveoverstatedthisdifference.4_Alsomost

stud-iestodatearehighlycontrolledandtheirresultsmaynot bereadilyapplicable inthe contextofday-to-dayclinical practice.

Wefoundnostatisticaldifferenceinneonataloradverse outcomesasnumbnessandmotorblock.Nevertheless,there wasalowerincidenceofmotorblockadeinPIEB0.1%group. Thisislikelyexplainedbytheuseofalessconcentratedlocal anestheticsolutionasshowninpreviousstudies.4,18_Because

motorblockadeisconsideredundesirableduringlabor anal-gesia,thepotentialdose-sparingeffectofanintermittent bolustechniquemaybemoreclinicallyrelevantwhenlower concentrationoflocalanestheticsolutionsareused.4

Themostsignificantfindingwasasignificantlower inci-dence of caesareandelivery withPIEB and specially PIEB 0.1%. Althoughour studywas notvalidated for labor out-comeswecannotoveremphasizethedifferenceincaesarean delivery rates between groups, especially if we consider

Table2 MeanApgarscoresat1stand5thminutespresentedasmean(SD).

A---CEI B---PIEB0.1% C---PIEB0.15% p-Value

(n=60) (n=33) (n=37)

Apgar1 8.98(0.68) 8.82(1.0) 8.89(0.9) 0.72

Apgar5 9.80(0.61) 9.88(0.3) 9.92(0.3) 0.71

CEI,continuousepiduralinfusion;PIEB,programmedintermittentepiduralbolus.

thatwedoubledthevolumeinPIEBgroups. Thisfindingis probablyrelatedtothereducedincidenceof motorblock from the combinedbenefits of Ropivacaine, the use of a lowerlocalanestheticconcentration18_{andmainlythePIEB}

technique.

The incidence of instrumental delivery in PIEB groups washigherthanweexpectedandhigherthanotherstudies results,12_{howeversimilartoourusualstatistics.One}

possi-ble explanationis theinfluence of obstetric performance and other obstetric factors in labor outcome. Further-moretheprogrammedintermittentbolus mayoverlapthe expulsionperiodandhencemake theparturientunableto accomplishaneffective expulsiveeffort.Inthe futurewe intendtoclarify theseand other factorsthat canhelp us improve labor analgesia protocols. Although instrumental delivery was higherthan we expected, therewasno sta-tistically significant difference between groups, as other studieshaveshown.4,10_{Weemphasizethatthereductionof}

caesarean delivery,which has higher risksto mother and newborn, is a crucial clinical finding, however larger tri-als aimedatevaluatinglaboroutcomesareneededin the future.

We conducted this study due tothe growing evidence of the efficacyof epidural bolus injection.Several mech-anisms have been suggested toexplainthe benefitsof an epiduralboluscomparedwithacontinuousinfusionof solu-tion.Invitroandlaboratorystudieshavedemonstratedthat an epidural bolus results in a further uniform spread of the solutions in the epidural spaceas opposedto contin-uous administration.7,8 _{Indeed, analgesiaand motorblock}

are produced by the movement of local anesthetic from the extraneural to the intraneural space by a diffusion gradient.9_{Nerveblockadeisachievedwhentheintraneural}

concentrationishigherthantheextraneuralconcentration. If we use low concentrations of local anesthetic in inter-mittent boluses, the total amount of solution inside the nerveisinsufficienttoresultinmotorblockade.Ifweusea continuousinfusion,theextraneuralconcentrationoflocal anesthetic is persistently higher allowing the intraneural concentrationtoreachthethresholdformotorfiberblock.9

Despite these scientific proves, there is still lacking consistency in studies comparing CEI and PIEB. We can hypothesizethat the variationfromour results andother studies results may conceivablybe associatedto the fact thatweanalyzed asamplethatrepresentstheday-to-day women encountered in our clinical practice, as opposed to other conducted controlled studies. Additionally, the localanestheticconcentrations,totalanestheticdose,bolus volumesandtimeintervalsweused,differfromother inves-tigations.

Arecentsystematicreview,12_{revealedthatmorestudies}

shouldbecarriedouttodeterminetheidealPIEBregimen

(pump settings and local anesthetic concentration/opioid dose),thatshowsaconsistentimprovementinlabor analge-siawithafavorableeffectonobstetricoutcomes.However itisclearthatintermittentepiduralbolustechniqueallows theuseoflessconcentratedlocalanestheticsolutionswith clinicallyrelevanteffects.

To findtheoptimumsettings for thebolus volumeand timeintervalinthemaintenanceofepidurallaboranalgesia, astudiedconductedwithnulliparouswomen,manipulating bolustimeintervalandbolus volume.19 _Extendingthe

pro-grammed intermittentbolus intervaland volume from15 to60min resulted in lower local anesthetic consumption withsimilaranalgesia.Therewerealsolessadditionalbolus requestsforbreakthrough pain,anincreaseinthetimeto thesedoses and, consequently, earlier feelingof comfort andhighersatisfaction.

Thereareseverallimitationstothegeneralizationofour study conclusions. Firstthe difference in localanesthetic dose perhour between CEI andPIEB groups is an obvious methodologicallimitationthatwecouldnotcontroldueto hospitalpolicies.InsubjectsrandomizedtoCEIgroup,PCEA wasusedasarescuemodality,whichmayhaveattenuated thedifferenceinsatisfactionbetweengroups.PCEAwithout a background infusion is also an intermittent bolus tech-niquebutwhetherthePIEBissuperiortoPCEAremains to bedetermined.

Weusedone-dimensionalscaletoevaluatematernal sat-isfaction because it was simpler but these scales do not reflectthemultipledimensionsofmaternalsatisfaction.

Anotherobvious limitationwasthe lack of controland potentialimpactofmultipleconfoundingfactorsknownto influencethematernalsatisfactionandoutcomes,including theperformance fromanesthesiaandobstetricproviders, labor management, social level and schooling. Another such confounding factor is the density of neuraxial anal-gesia during the second stage of labor. Relaxation of the abdominalwallmusculaturesecondarytoepiduralanalgesia couldresultindecreasedeffectivenessofmaternal expul-sive efforts and ability to coordinate these with uterine contractions.20 _{Additionally, higher amounts and}

concen-trations of neuraxial local anesthetic might relax pelvic floormusculature andinterfere withfetalrotationduring descent.Alsoobstetriciansmightbemorelikelytoperform instrumentalvaginaldeliveriesinparturientswitheffective second-stageanalgesiathaninparturientswithout analge-sia.

In conclusion, we found that maintenance of epidural analgesiawithprogrammedintermittentbolus was associ-atedwithalowercaesareandeliveryrate,withequallyhigh maternalsatisfactionandnoadverseoutcomes.

Although PIEB is emerging in epidural labor analgesia, therearestill many options toexplore when it comes to

choosingthelocalanesthetics, volume,concentrationand timeintervalidealforPIEBregiments.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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