2 MLR Paper.Jnt

ORIGINALCONTRIBUTION

RoutineMorphineInfusioninPretermNewbornsWhoReceivedVentilatorySupport

ARandomizedControlledTrial

SinnoH.P.Simons,MSc

MoniquevanDijk,PhDRichardA.vanLingen,MD,PhDDaniellaRoofthooft,MD

HugoJDuivenvoorden,PhDNiesjeJongeneel,RN

CarinBunkers,RN

EnnaSmink,RN

K.J.S.Anand,MBBS,DPhil

JohnN.vandenAnker,MD,PhD DickTibboel,MD,PhD

ORPHINEHASBEENONEOF

themostfrequentlyuseddrugstorelievepaininmanyagegroups.Nev-

ertheless,debatecontinuesaboutwhethermorphineandanalgesictherapyshouldserveasstandardofcareforpretermnewbornswhohavere-ceivedventilatorysupport,1despitetherecognitionthatallpretermneonatesfeelpain.

Lackofagoldstandardtoassessneo-natalpain,fearofadverseeffects,anduncertaintyaboutthelong-termef-fects of opioidsintheneurodevelop-mentaloutcomeofnewbornscontrib-utetothisclinicalconundrum.

ContextNewbornsadmittedtoneonatalintensivecareunits(NICUs) undergoava-rietyofpainfulproceduresandstressfulevents.Becausetheeffectofcontinuousmor-phineinfusioninpreterm neonateshasnotbeeninvestigatedsystematically,thereisconfusionregardingwhethermorphineshouldbeusedroutinelyinthissetting.

ObjectiveToevaluatetheeffectsofcontinuousintravenousmorphineinfusiononpainresponses,incidenceofintraventricularhemorrhage(IVH),andpoorneurologicoutcome(severeIVH,periventricularleukomalacia,ordeath).

Design, Setting, and Patients A randomized, double-blind, placebo-controlledtrial conducted between December2000and October2002 in2levelIIINICUs intheNetherlandsof150newbornswhohadreceivedventilatorysupport(inclusioncrite-ria:postnatalage youngerthan3daysandventilationforlessthan8hours;exclusioncriteria:severeasphyxia,severeIVH,majorcongenitalmalformations,andadminis-trationofneuromuscularblockers).

InterventionsIntravenousmorphine(100µg/kgand10µg/kgperhour)orpla-ceboinfusionwasgivenfor7days(orlessbecauseofclinicalnecessityinseveralcases).

MainOutcomeMeasuresTheanalgesiceffectofmorphine,asassessedusingvali-datedscales;theeffect of morphineontheincidenceof IVH; andpoor neurologicoutcome.

ResultsTheanalgesiceffectdidnotdifferbetweenthemorphineandplacebogroups,judgingfromthefollowingmedian(interquartilerange)painscores:PrematureInfantPainProfile,10.1(8.2-11.6)vs10.0(8.2-12.0)(P=.94);NeonatalInfantPainScale,

4.8(3.7-6.0)vs4.8(3.2-6.0)(P=.58);andvisualanalogscale,2.8(2.0-3.9)vs2.6(1.8-4.3)(P=.14),respectively.RoutinemorphineinfusiondecreasedtheincidenceofIVH(23%vs40%,P=.04)butdidnotinfluencepoorneurologicoutcome(10%vs16%,P=.66).In addition, analyseswereadjustedforthe useof additional open-labelmorphine(27%ofmorphinegroupvs40%ofplacebogroup,P=.10).

ConclusionsLackofa measurableanalgesiceffectandabsenceofabeneficialeffectonpoorneurologicoutcomedonotsupporttheroutineuseofmorphineinfusionsasastandardofcareinpretermnewbornswhohavereceivedventilatorysupport.Fol-low-upisneededtoevaluatethelong-termeffectsofmorphineinfusionsontheneu-robehavioraloutcomesofprematurity.

JAMA.2003;290:2419-2427

Althoughnumerousneonatalpainin-strumentsareavailable,theyhavebeenbasedandvalidatedonmodelsofacutepain.2Itisdifficult,therefore,tomea-suretheanalgesiceffectofmorphineinneonates.Suggestedadverseeffectsofmorphinearehypotension,3-6 sei-

AuthorAffiliations:Departments ofPediatric Sur-gery(DrsvanDijkandTibboelandMrSimons)andPediatrics(DrvandenAnker),andDivisionofNeo-natology(DrRoofthooft,MrSimons,and MsJongeneel),ErasmusMC-Sophia,andDepartmentofMedicalPsychology,Erasmus-MC(DrDuivenvoorden),Rotterdam,theNetherlands;DepartmentofPediat-rics,DivisionofNeonatology,IsalaClinics,Zwolle,theNetherlands(DrvanLingenandMssBunkersandSmink);DepartmentofPediatrics,Universityof

ArkansasforMedicalSciencesandArkansasChil-dren'sHospital,LittleRock(DrAnand);andDivisionofPediatricClinicalPharmacology,DepartmentsofPe-diatricsandPharmacology, GeorgeWashingtonUni-versity,Washington,DC(DrvandenAnker).

CorrespondingAuthorandReprints:DickTibboel,MD,PhD,DepartmentofPediatricSurgery/Pediatrics,ErasmusMC-Sophia,DrMolewaterplein60,3015GJRotterdam,theNetherlands(e-mail:j.illsley

@erasmusmc.nl).

zures,7bradycardia,decreasedgastro-intestinalmotility,8intestinalobstruc-tion,urinaryretention,andrespiratorydepression.9,10Althoughafewlong-termeffectsofneonatalmorphineex-posurehavebeensuggestedfromani-malstudies,11-13theeffectsseemtobeminimalat5to6yearsinacohortofformerpreterminfants.14Ontheotherhand,morphineadministrationmaydecreasemorbidity,suchasintraven-tricularhemorrhage(IVH)andperi-ventricularleukomalacia(PVL).15Wehypothesizedthatcontinuousmor-phineinfusionsmayimproveout-comesanddiminishpainresponsesofnonsurgicalneonateswhohavere-ceivedventilatorysupportinstressfulconditions.Furthermore,repeatedpainexposuremaycause hypersensitivityandlowerpainthresholdinpretermneonates,16-20andmorphineadminis-trationmightprotectpretermneo-natesfromtheharmfuleffectsofpainontheirshort-andlong-termout-comes.21,22

Consensusstatementsontheanal-gesictreatmentofneonatalpain23,24havesuggestedtheuseofcontinuousopi-oidinfusionsforpretermneonateswhohavereceivedventilatorysupport.Stud-ies25-28investigatingintravenousopi-oidsinneonateswhohavereceivedven-tilatorysupportdonotprovideconclusiveevidence.Therefore,double-blindrandomizedcontrolledtrialshavebeensuggestedasameanstoresolvetheuncertaintyoverwhetherandwhentoadministeranalgesicstocriticallyillneonates.1,29

Basedontheprotocolofamulti-centertrial(NEOPAINstudy[Neuro-logicOutcomesandPre-emptiveAn-algesiaInNeonates]),weperformedarandomized,double-blind,placebo-controlledtrialtoevaluatetheeffectofcontinuousintravenousmorphinein-fusiononpainresponses,theinci-denceofIVH,andpoorneurologicout-comes(severeIVH,PVL,ordeath)inpretermneonateswhohadreceivedventilatorysupport.Wetestedthehy-pothesisthatcontinuousmorphineadministrationinneonateswhohadreceivedventilatorysupportwouldre-

duceboththedegreeofpainexperi-encedandtheincidence ofpoor neu-rologicoutcomeandIVH(allgrades).

METHODS

Patients

Allneonatesadmittedtotheneonatalintensivecareunit(NICU)whore-quiredmechanicalventilationwereeli-gibleforinclusion.Otherinclusioncri-teriawerepostnatalageyoungerthan3days,artificialventilationforlessthan8hours,andindwelling(peripheralorumbilical) arterialcatheter. Excludedwereneonateswithsevereasphyxia(Apgarscoreafter5minutesof4orcordbloodpH7.0),30severeIVH(gradeIIIorIVHplusapparentperi-ventricularhemorrhagicinfarction),majorcongenitalmalformationsandfa-cialmalformations(eg,cleftlipandpalate),neurologicdisorders,orreceiv-ingcontinuous orintermittentneuro-muscularblockers.

Patientswererecruitedfrom2levelIIINICUsintheNetherlands:Eras-musMC-Sophia,Rotterdam(center1),auniversityhospital,andtheIsalaClin-icsinZwolle,anonuniversityhospital(center2).Seventy-fourpercentofneo-natesadmittedtotheNICUswereborninthestudyhospital.Thelocalethicscommitteesoftheparticipatingcen-tersapproved thestudyprotocol.

Theparentsofeligiblepatientswereaskedtogivewritteninformedcon-sentwithin8hoursafterendotrachealintubation.Ifpossible,parentswerein-formedaboutthestudybeforethebirthoftheirchild.Ifconsentwasrefused,informationaboutmorphineuseofthepatientinvolvedwascollectedretro-spectivelyandcomparedwithinfor-mationontheparticipants.Datafromnonenrolledpatientswerenotincor-poratedintootheroutcomeanalysesorpooledwiththatfromanyotherpa-tients.Enrolledpatientswereran-domlyallocatedtoreceivea loadingdose (100µg/kg) followedbya con-tinuousinfusion(10µg/kgperhour)ofeithermorphinehydrochlorideorplacebo(sodiumchloride),bothdis-solvedin5%glucose.Topreventpos-sibleoverdosing,thestudymedica-

tionloadingdosewasnotgivenifapreintubationmorphineloadingdosehadbeengivenlessthan3hoursbe-fore thestart ofthestudy. Theuseofmaskedstudymedicationwascontin-uedfor7daysorless,asrequiredbythepatient'sclinicalcondition.After7days,studymedicationwasweanedandstoppedorreplacedbyopen-labelmor-phineinfusion.

Ifpatientsfromeithergroupwerejudgedtobeinpainordistressduringmaskedstudymedicationuse,theyweregivenadditionalmorphinebasedondecisionsoftheattendingphysi-cian(independentofthestudy).Al-lowedadditionaldoseswere50µg/kgfollowedby5to10µg/kgperhourofcontinuousopen-labelmorphine.

Outcomes

Primaryoutcomesweredefinedastheanalgesiceffectsofmorphine,assessedbyvalidatedpainmeasurementinstru-mentsatbaseline,beforestudymedica-tion,30minutesaftertheloadingdose,andtwicedailyatastandardizedtimepointbefore,during,andafterendotra-chealsuctioning.Ateachtimepoint,wevideotapedtheinfantsfor2minuteswith2cameras:oneobtainingawhole-bodyimageandtheotherfocusedonthepa-tient'sface. Simultaneously, thecare-giving nurse applied the visual analogscale(VAS)forpainatbedside.TheVASscorerangesfrom0to10onahorizon-tal,continuouslinewith"nopain"ontheleftand"extremepain"ontheright;observersindicatedthelevelofpainbymarkingtheline.Allnurseshadbeentrainedtoassessneonatalpain.Thevid-eotapeswereanalyzedafterwardusingtheNeonatalInfantPainScale(NIPS)31andtheVASduringallmomentsandthePrematureInfantPainProfile(PIPP)32duringsuctioning.Videotapeswereas-sessedby2researchers(N.j.andS.H.P.S)withacceptableinterraterreliability(in-traclasscorrelationcoefficientof0.70and0.73fortheNIPSandPIPP,respec-tively,and0.67fortheVASscore).

Secondaryoutcomemeasureswerepoorneurologicoutcomedefinedasse-vereIVH,PVL,ordeathwithin28daysandtheincidenceofallgradesofIVH.

ROUTINEMORPHINEINFUSIONINPRETERMNEWBORNS

Otherclinicaloutcomemeasureswerealsocomparedbetweenthemorphineandplacebogroups,includingdura-tionofartificialventilation,lengthofNICUstay,incidenceofcomorbidity,andnumberofpainfulprocedures.Re-gardingdurationofartificialventila-tion,wedistinguishedbetweenthefirstventilationperiod(includingfurtherpe-riodsofventilationiftheinfantwasex-tubatedinbetweenfor24hours)andthesecondventilationperiod(allfur-therperiodsofartificialventilation,af-terextubationfor24hours).Duringthefirst14daysofapatient'sNICUad-mission, we recordedallpainful pro-cedures.

Apoweranalysisshowedthat75pa-tientspergroupwereneededtoachieveamediumeffectsize(Cohend=0.55),withanerrorof.05(2-tailed)andapowerof90%.Neonateshadanequalprobabilityofbeingassignedtoeithercondition.Therandomizationcodewasdevelopedusingacomputerrandom-numbergeneratortoselectrandomper-mutedblocks.Theseblocksof10werestratifiedinto5groupsofgestationalageranges( 27,27-30,31-33,34-36,and

37weeks)toobtainabalancednum-berofinfantswithineachstratum.

Using the computer-generatedran-

domizationlist,independentpharma-cistsplacedampulesofeither1mLofmorphinehydrochlorideor1mLofpla-cebointoboxes.Theseboxeswerenumberedwiththestudynumbersandstoredwithincreasingnumbersforthedifferentgestationalagegroupsinalockedclosetaccessibleonlytothere-searchers.Atapatient'senrollment,thenextboxinlineforthespecificgroupwastakenoutbyoneoftheresearch-ers.Allresearchandclinicalstaff,aswellastheparentsoftheinfants,wereblindedtotreatment.

StatisticalAnalyses

DatawereanalyzedusingSPSSstatisti-calsoftwareversion10.1(SPSSInc,Chi-cago,Ill).Nonparametrictestswereusedandresultsareshown asmediansandinterquartileranges(IQRs)whenvari-ablesdeviatedfromthenormaldistri-bution.Backgroundcharacteristicsbe-

tweenthe2treatmentgroupswerecomparedusingnonparametricMann-WhitneyUtestsorFisherexacttests(incaseoflowincidences).Characteris-ticsofthenonparticipatingpatientswerecomparedwithdatafromstudyinfantsusingKruskal-Wallistests.

PainScores.MultipleregressionanalyseswereperformedwithVAS-bedsideandNIPS(scored30minutesafterstudymedicationloadingdose)asoutcomevariables predictedbytreat-mentgroup,havingreceivedamor-phinedosebeforeintubation,gesta-tionalage,ClinicalRiskIndexforBabies(CRIB)score,center,sex,andpostna-talagein hourscorrected bythe painscoredbeforetheboluswasgiven.Painscoreswerelog10transformedtoap-proximate anormaldistribution.

Acrossallassessments,meanPIPP,NIPS,andVASscores,scoredduringendotrachealsuctioning,werecalcu-latedforeachpatientandusedasout-comevariablesinmultipleregressionanalyses. Summarystatistics (meanscoresforeachpatient)wereusedtoin-creasereliabilityandtotake repeatedmeasuresintoaccountduringanaly-ses.Predictors were treatmentgroup,meanamountofadditionalmorphine,center,sex,anddurationinstudy.Theimportanceofthepredictorsisshownbyunstandardizedcoefficients.

ClinicalOutcome.Logisticregres-sionanalyseswereusedwithpoorneu-rologicoutcome(deathwithin28days,IVHgradeIIIorIVHplusapparentperi-ventricularhemorrhagicinfarction,and/or PVL) and IVH (allgrades)asoutcomevariables;treatmentcondi-tionandadditionalmorphineuseaspredictorvariables;andcenter,gesta-tionalage,sex,CRIBscore,deviationfrommeanbirthweightforgesta-tionalage,33prenatalcorticosteroiduse,preeclampsiaand/orHELLP(hemoly-sis,elevatedliverenzymes,lowplate-lets)syndrome,andtheuseofindo-methacinascovariates.

Collinearityforthelogisticregres-sionanalyseswascheckedbyperform-ing amultipleregression analysis in-steadofthelogisticregressionanalysestocalculate the variance inflation fac-

tors,whichwereallwellbelow2.0.Thesamewas true forthemultiple regres-sionanalyses.Theriskofoverfittingwascontrolledbyusingaratioof1:10atleastforthenumberofexplanatoryvari-ablesandsamplesize.Toassessover-fittingmoreprecisely,thepatientsinthese2groupsweresplitintodeciles.Tocross-validate,thetrainingsamplewascomposedof9ofthe10deciles;thevali-dationsamplecontainedtheremain-ingdecile.Thepredictedvaluesfortheremainingdecilewereobtainedbytheparameters ofthe logisticregressionanalysisperformedon9oftheotherdeciles.Thisprocedurewasrepeated10timesbecauseeachdecilefunctionedasavalidationsample.Theoverallmeanobtainedfromthe10meanvaluesandthepooledSDderivedfromthe10SDsofthevalidationsamplesforeachcon-ditionseparatelywerecomparedwiththeoverallmeanandSDofthepre-dictedvaluesofthetotalsample.Ahighlevelofagreementbetweentheoverallsolutionandthecross-validationsamplesindicateshighstability.Step-wiseprocedureswereused.

Comorbidity(eg,chroniclungdis-ease,necrotizingenterocolitis,dura-tionofartificialventilation)wascom-paredusingtheMann-WhitneyUtestand Fisherexacttest. Missing valueswereexcludedlistwiseduringallanaly-sesinthesensethatallcasesthathadanyvaluesmissingonanyofthevari-ablesusedintheanalyseswereex-cluded.Inallanalyses,theintention-to-treatprinciplewasusedandinvolvedallincludedinfantswhowereran-domlyassignedtothemorphineandplacebogroups.

RESULTS

Atotalof210infantswereeligiblebe-tweenDecember2000andOctober2002;theparentsof60newbornsre-fusedinformedconsentand150wererandomized(FIGURE).Thepercentageofnonenrolledpatientswas36%incen-ter1(n=51)and13%incenter2(n=9).Seventy-threepatients wereallocatedtoreceivecontinuousmorphineinfusion(44 in center 1and29incenter2),and77patientswereassignedtoreceivepla-

cebo(48incenter1and29incenter2).Mediandurationofstudymedicationin-fusionwas48hours(IQR,19-96hours).Useofthemedicationwasstoppedforthefollowingreasons:extubation(n=106),7daysinstudy(n=24),hy-potension(n=6),continuoususeofneu-

Figure.ParticipantFlowThroughtheStudy

210PatientsEligible
60ParentsofPatientsRefusedParticipation
51atCenter1
9atCenter2

150 Randomized

92atCenter1

58atCenter2

romuscularblockers(n=5),death(n=4),surgery(n=2),theneedfortoomuchadditionalmorphine(n=2),andoverdosing(n=1).

Patientcharacteristicsforbothtreat-mentgroupsareshowninTABLE1.Allpatientcharacteristicswerecompa-rablebetweenthegroups.Demo-graphic characteristicsofthenonpar-ticipantsalsoshowednosignificantdifference comparedwith the partici-patinginfants.Painfulprocedureswerecountedforamediandurationof6days(IQR,3-10days).Thenumberofdailypainfulprocedureswassimilarin themorphinegroup(median,13;IQR,10-16)andplacebogroup(median,13;IQR,9-16)(Mann-WhitneyUtest,2479;P=.66).

PainScores

Atbaseline,medianNIPSscoresinthemorphineandplacebogroupswere0.0(IQR,0.0-0.0)and0.0(IQR,0.0-0.8)

andmedianVASscoreswere0.6(IQR,0.3-2.2)and0.7(IQR,0.3-1.5),respec-

tively.Thirtyminutesafterstudymedi-cationadministration,medianNIPSscoresinthemorphineandplacebo

(IQR,0.0-1.0),andmedianVASscoreswere0.6(IQR,0.3-1.6)and0.6(IQR,

0.2-1.4),respectively.

Duringsuctioning,medianPIPPscoresinthemorphineandplacebogroupswere10.1(IQR,8.2-11.6)and

10.0(IQR,8.2-12.0)(P=.94),median

NIPSscoreswere4.8(IQR,3.7-6.0)and4.8(IQR,3.2-6.0)(P=.58),andme-

dianVASscoreswere2.8(IQR,2.0-3.9)and2.6(IQR,1.8-4.3)(P=.14),re-

spectively(TABLE2).Therewerenosignificantdifferencesbetweengroupsforpainscores.Ofthe2530VASscores,only293valuesindicatedmoderatepain34byexceeding4(69%werescoredduringsuctioning),with146and147valuesnoted inthe morphine andpla-cebogroups,respectively.Table2showspainscoresatthedifferenttimepointsfor themorphine- andplacebo-treatedinfants.ThemeanSDsofpainscoresforthosepatientswhounderwentmul-tipleprocedureswere2.5forthePIPP,

2.2fortheNIPS,and2.2forVASscores.Multipleregression analysesre-vealedthatVASandNIPSscoresaftertheloadingdoseof study medicationdidnotsignificantlydifferbetweenthe2

groupswere0.0(IQR,0.0-0.0)and0.0

Table1.BaselineDemographicandClinicalCharacteristics

groups(unstandardizedregressionco-

P=.46;and

Sex,No.(%)

MorphineGroup(n=73)

PlaceboGroup(n=77)

P=.47)andwerenotinfluencedbywith-

Male42(57.5)44(57.1)

Female31(42.5)33(42.9)

BirthcharacteristicsBirthplace,No.(%)

Inthe studyhospital57(78)54(70)

Atanonstudyhospitalorathome16(22)23(30)

Gestationalage,median(IQR),wk29.1(27.4-31.6)29.2(27.3-31.4)

Birthweight, median(IQR),g1130(850-1680)1230(915-1560)

Postnatalage,median(IQR),h9(5-13)8(5-12)Apgarscore,median(IQR)

1min6(4-8)6(4-8)

5min8(7-9)8(7-9)

P=.65;and

P=.67).Thesepainscoresweresignifi-cantlypredicted,however,bythepainscoresbeforebolusadministration(B=0.65;95%CI,0.53to0.78;P .001;

andB=0.54;95%CI,0.34to0.73;

P .001).VASscoreswerehigheringirls

P=.03)andhigherincenter2comparedwithcenter1

CRIBscore,median(IQR)*2(1-6)3(1-7)

CoP=.02).Pain scores tendedto behigher

whennomorphinewasgivenbeforein-

0.002;P

Abbreviations:CRIB,ClinicalRiskIndexforBabies;IQR,interquartilerange.

*TheCRIB measuresseverity of illnessbasedonbirth weight, gestation,congenital malformations, base excess, andminimumandmaximumoxygenrequirementsduringthefirst12postnatalhours.Thescalerangesfrom0to23.

P=.02).

ThePIPP,NIPS,andVASscoresdur-ingsuctioningwerenotpredictedin

multipleregression analysesbytreat-

ROUTINEMORPHINEINFUSIONINPRETERMNEWBORNS

mentgrouporbytheamountofaddi-tionalmorphineused(TABLE3).MeanNIPSandVASscoresdecreasedwithin-creasinglengthofstudy,andVASscoreswerelowerincenter1comparedwithcenter2.Spearmancorrelationcoef-ficientsbetweenthedifferentpainscoreswere0.44(NIPSvsPIPP,P.001),0.31(NIPSvsVAS,P.001),and0.22(PIPPvsVAS,P=.02).

ClinicalOutcome

TABLE4liststheclinicaloutcomesandincidencesofmorbidityandmortalityforthe2groups.Overall,11infantsdiedwithin28days,and48werediag-nosedashavingIVH,10ofwhichhadtheseveretype(gradeIIIorIVHplusapparentperiventricularhemorrhagicinfarction).FourinfantshadPVL.Lo-gisticregressionanalysisshowedthattheincidenceofpoorneurologicout-comewasnotrelatedtotreatmentgrouportoadditionalmorphineuse(TABLES).Itwas,however,associatedwithlowergestationalages(P=.005)

andhigherCRIBscores(P=.004)andwasmoreapparentinboyscomparedwithgirls(P=.003).

TheincidenceofIVH(allgrades),alsoevaluatedwithlogisticregressionanalysis,wassignificantlyhigherintheplacebogroupcomparedwiththemor-phinegroup(adjustedoddsratio,2.36;95%CI,1.05-5.28;P=.04).Further-

more,theincidenceofIVHwasasso-ciatedwithlowergestationalages(P=.006)andwashigherinthosebornsmallforgestationalage(P=.05)andininfantsbornoutsidethestudyhos-pital(P=.04).Mediandurationofthefirstperiodofartificialventilation,me-diantotaldurationofventilation,andmedianlengthofNICUstaydidnotsig-nificantlydifferbetweengroups(P=.72,P=.81,andP=.92,respectively).

MorphineUse

Open-labelmorphinewasadminis-teredto 20infants(27%) inthemor-phinegroupand31(40%)intheplacebogroup( 2=2.76,P=.10)

(TABLE6), with comparablemediandosagesof3.0µg/kgperhour(IQR,1.3-

6.8µg/kgperhour)and4.3µg/kgperhour(IQR,1.6-7.7µg/kgperhour)inthemorphineandtheplacebogroups,respectively (Mann-WhitneyUtest,282.5; P=.60). Of the60eligible butnonenrolledpatients,55%receivedmorphine,withamediandoseof3.6

µg/kgperhour(IQR,1.7-6.7µg/kgperhour).Theseinfantsreceivedaddi-tionalmorphinemorefrequentlythanthestudyinfants(Kruskal-Wallistest:2=10.4,P=.005).Amongthe2cen-ters,nonenrolledpatientsreceivedmor-phinemorefrequentlyincenter2(Mann-WhitneyUtest,94.0;P=.03).

COMMENT

Wehypothesizedthatcontinuousmor-phineinfusioninpretermneonateswouldreducepainexperienceandinci-dencesofpoorneurologicoutcomeandIVH.However,painmeasurementsvali-datedforthis agegroupdidnot revealanyanalgesiceffectsofmorphine.Al-

Table2.PainScoresfortheMorphine-andPlacebo-TreatedInfants*

Median(IQR)

NIPS / PIPPt / VAS
Morphine / Placebo / Morphine / Placebo / Morphine / Placebo
Group / Group / Group / Group / Group / Group
Baseline / 0.0(0.0-0.0) / 0.0(0.0-0.8) / 0.6(0.3-2.2) / 0.7(0.3-1.5)
30minafterstartofinfusion / 0.0(0.0-0.0) / 0.0(0.0-1.0) / 0.6(0.3-1.6) / 0.6(0.2-1.4)
Beforesuctioning / 0.5(0.0-1.0) / 1.0(0.0-1.0) / 0.8(0.5-1.3) / 0.9(0.6-1.6)
Duringsuctioning / 4.8(3.7-6.0) / 4.8(3.2-6.0) / 10.1(8.2-11.6) / 10.0(8.2-12.0) / 2.8(2.0-3.9) / 2.6(1.8-4.3)
30minaftersuctioning / 0.0(0.0-1.0) / 0.0(0.0-1.0) / 0.9(0.6-1.4) / 0.9(0.6-1.4)

Abbreviations:IQR,interquartilerange;NIPS,NeonatalInfantPainScale(scalerange,0-7);PIPP,PrematureInfantPainProfile(scalerange,0-21);VAS,visualanalogscale(scalerange,0-10).

*Painscoreswerenotsignificantlydifferentbetweenthe2groups.Painscoreswereaveragedinthecaseofrepeatedmeasures.Forallscales,thehigherthenumber,themoreseverethepain.

tThePIPPwasassessedonlyduringsuctioning.

Table3. Resultsof MultipleRegression AnalysesofPainScoresMeasuredDuringSuctioning*

PIPPNIPSVAS

OutcomeVariable

B(95%CI)P ValueB(95%CI)P ValueB (95% CI)PValue

Amountofextramorphine,

per1µg/kg/h

.001

Correlationcoefficient(adjustedR2)0.14(0.026)0.22(0.012)0.46(0.19)

Abbreviations:CI,confidenceinterval;NIPS,NeonatalInfantPainScale;PIPP,PrematureInfantPainProfile;VAS,visualanalogscale.

*Pvaluesshowthesignificanceofthepredictivevalueofeachindependentvariableonthedifferentoutcomevariables.Bvaluesareunstandardizedregressioncoefficients.

ROUTINEMORPHINEINFUSIONINPRETERMNEWBORNS

thoughroutinemorphineinfusionsdidnotaffectpoorneurologicoutcomesoranyotherclinicaloutcomemeasure,pre-emptivemorphineanalgesiasignifi-cantlydecreasedtheincidenceofIVH.Thesefindingssuggestthatroutinemor-phineinfusioninpretermnewbornswhohave receivedventilatorysupportnei-

therimprovespainreliefnorprotectsagainst poorneurologicoutcome.TheimpactofdecreasedIVH in the mor-phine-treatedneonates,however,shouldbeevaluatedwiththeirlong-termneu-robehavioraloutcomes.

Overall,wefoundthatpainscoresdidnotsignificantlydifferbetweenthe

2randomizedgroups.Althoughthere-sultsofpain scoresshouldbeviewedwithsomecaution,thePIPPandNIPShavebothbeenvalidatedfortheassess-mentofproceduralpaininpretermneo-nates.31,32,35,36Thesensitivityandspeci-ficityofthesemethodsformeasuringacuteorchronicpaininpretermin-fantsremainunknown.TheVAShas

Table4.ClinicalOutcomes

notbeenspecificallyvalidatedforthis

Poorneurologicoutcome

MorphineGroup(n=73)

PlaceboGroup

(n= 77)PValue*

groupofpatientsbutappearstore-

flecttheintensityofpain.34Inthisstudy,theVASwasappliedbyexperienced

28-Daymortality, No.(%)4(5)7(9)NA

Periventricular leukomalacia,No.(%)2(3)2(3)NAIntraventricularhemorrhage,No.(%)

Severet

OverallComorbidities,No.(%)

NICU nurses who were specificallytrainedforassessingneonatalpain.Measuringtheeffectofmorphineonthepainexperiencedbypretermneonatesremainsdifficultbecauseofthelackof

Abbreviations: IQR,interquartilerange; NA,notapplicable;NICU,neonatalintensive careunit.

*Outcomes reportedasNAwere analyzedusinglogistic regressionanalyses (see Table5).PvalueswerecalculatedusingtheMann-WhitneyU test,asymptoticsignificance(2-sided),exceptfornecrotizingenterocolitis,whichwascalculatedwiththeFisherexacttest,exactsignificance(2-sided).

tGradeIIIintraventricularhemorrhageorintraventricularhemorrhageplusapparentperiventricularhemorrhagicinfarction.

Table5.ResultsofLogisticRegressionAnalysesWithPoorNeurologicOutcomeandIVH(AllGrades)asOutcomeVariables

utesaftertheloadingdose.Takingthelimitedtimespanfrombirth tostudyenrollment(median,8hours;IQR,5-12hours)intoconsideration,thelowpainscoresmaybeexplainedbyreleaseofendorphins,resultingfrombirth37-39andpostnatalstress.40Sinceseverepainwas

OutcomeVariable

PoorNeurologicOutcome*IVH(AllGrades)

OR(95%CI)PValueOR(95%CI)PValue

mostlyabsent,itneednotberelieved

bymorphine.

Painscoreswereobtainedduringan

Treatmentgroup1.35(0.40-4.57).632.36(1.05-5.28).04

invasive,presumablynoxiousproce-

Amountofextramorphine,

1.04(0.84-1.29).731.13(0.97-1.31).11

dure.Endotrachealsuctioningwasthe

per1µg/kg/h

onlyrepetitively,frequently,androu-tinelyperformedinvasiveproceduredur-ingourstudy.Heellanceswerenotper-

Deviationofmeanbirthweight,

1.34(0.83-2.18).231.44(1.00-2.05).05

formedroutinelybecauseallpatientshad

per1SDt

CRIBscore,per1-pointdifference1.42(1.12-1.80).0041.05(0.91-1.22).49Birthplace(inoroutof studyhospital)1.49(0.20-11.0) .70 3.87(1.07-14.0) .04 Prenatalcorticosteroids 1.42(0.31-6.42) .65 1.96(0.75-5.14) .17

arterialcatheters.Furthermore,previ-

ousstudieshaveshownthattrachealsuctioningisrelatedto increasedpainscores15,41,42andstressresponses43and

Preeclampsiaand/orHELLPsyndrome

1.20(0.21-6.82).840.79(0.27-2.33).67

isconsideredpainful.44-47Inourstudy,

trachealsuctioningwasassociatedwith

IndomethacinforPDA2.51(0.59-10.6).211.08(0.40-2.90).87

NagelkerkeR20.400.30

amedianPIPPscoreof10,NIPSscoreof4.8,andVASscoreof2.7,indicating

Hosmer-Lemeshow 2

7.6.4712.5.13

mildtomoderatepain.Thesephysi-

Abbreviations:CI,confidenceinterval;CRIB,ClinicalRiskIndexforBabies;HELLP,hemolysis,elevatedliverenzymes,

lowplatelets;IVH,intraventricularhemorrhage;OR,oddsratio;PDA,patentductusarteriosus.

*PoorneurologicoutcomewasdefinedassevereIVH(gradeIIIorIVHplusapparentperiventricularhemorrhagicin-farction),periventricularleukomalacia,ordeathatday28.

tForeach infant,thedeviation ofbirthweightfrom themeanforgestationalagewas calculatedasameasure ofsmallforgestationalage.

ologicandbehavioralresponsesarein-dicatorsofneonatal pain,but they arealsoinfluencedbyfactorssuchasges-tationalage,severityofillness,andtime

ROUTINEMORPHINEINFUSIONINPRETERMNEWBORNS

fromthepreviouspainfulprocedure.48Previousstudiesusingthesemeasureshavereportedlargeinterindividualvari-ability.49

Thelowcorrelationbetweenthedif-ferentpainscoresalsounderlinesthe

Table6.UseofMorphineinAllGroups

MorphineGroup / PlaceboGroup / Nonparticipants / P
(n=73) / (n=77) / (n=60) / Value*
Open-labelmorphine, / 0.0(0.0-0.6) / 0(0-3.1) / 0.8(0-4.6) / .005

median (IQR), µg/kgperhour

difficultyofpainassessmentinthis

Totalmorphineamount,

median (IQR), µg/kgper

10.0(10.0-10.6)0(0-3.1)0.8(0-4.6).001

groupofpatients, aswas recentlyre-

hour

viewedbyourgroup.2,34However,mul- / Patientsreceivingadditional / 20(27) / 31(40) / 33(55)
tivariateanalyses,adjustingfortheseco- / morphine,No.(%)
variates,didnotshowanystatistically / Amountofadditional
open-labelmorphine, / 3.0(1.3-6.8) / 4.3(1.6-7.7) / 3.6(1.7-6.7) / .80

orclinicallysignificantdecreaseinpain

scoresresultingfromcontinuousmor-phineadministration.Theexplained

median (IQR), µg/kgper

hour

Abbreviation:IQR,interquartilerange.

*PvaluesdeterminedbyKruskal-Wallistestscomparingtheuseofmorphinebetweengroups.

varianceoftheseanalyseswaslow,

probablytheresultoflowvariability of

painscores.Thefewpreviousstudies

onthissubjectpresentconflictingfind-ings.Thedecreaseinpainthatre-sultedfromhighermorphinedosescomparedwiththeonesusedinourstudyduringendotrachealsuctioningandheellances15,50wasnotconfirmedinanotherstudyusingmorphinedosesofthesamemagnitude.51Thesamplessizesinourstudywereconsiderablylargerandtheamountsofmorphineusedinourstudyconformedtointer-nationallyrecommendeddoses.52

Despitethelowpainscores,anum-berofinfantsweregivenadditionalmor-phine(27%inthemorphinegroupand40%intheplacebogroup).Becausethisstudyaimedtoevaluatetheeffectofrou-tinecontinuous morphineinfusioninnewbornswhoreceivedventilatorysup-portonprimaryandsecondaryout-comemeasures,placebo-treatedinfantsreceivedopen-labelmorphineifdeemedtobeinpain.Byreflectingvariationsamongpatientsthatoccurinrealclini-calpractice,thisstudyis a pragmatictrialthataimedtoinformchoicesbetweentreatments(routinemor-phineadministrationornoroutinemor-phineinfusion).Inpragmatictrials,thetreatment responseisthetotaldiffer-encebetween 2treatments, includingbothtreatmentandassociatedplaceboeffects,sincethiswill bestreflect thelikelyclinicalresponseinpractice.Becausetheintention-to-treatprin-ciplewasusedinourstudy,patientsinbothgroupsreceivingopen-labelmor-phinewerenotdroppedoutbut

includedintheanalyses.Indailyprac-

tice,anewborninpainwhoreceivesventilatorysupportneedstoreceiveanalgesictreatment,independentofanyroutinemorphineadministration.Ifaninfantwasinpain,morphinewasgiven.Inthisway,ourstudywasarealisticreflectionof2differentstrategiesofdailyNICUpractice.

Clinicalbiaswasminimizedviaran-domizationofpatientsandblindingofphysicians,parents,andinvestigators.Theattendingphysiciansandnursesobviouslyconsidered theseinfantstobeuncomfortableandinneedofextrapainrelief,althoughthiswasnotre-flectedintheirpainscores.Theuseofextramorphinewasnotsignificantlydifferentbetweentherandomizedgroups,asreportedpreviously.15Thenonparticipatinginfantsreceivedopen-labelmorphinesomewhatmorefre-quentlythanthoseinthestudygroup,suggestingthatparticipationinthistrialwasnotacausativefactorforaddi-tionalmorphineprescription.Further-more,additionalmorphinecouldbeusedonlyaccordingtotheprotocol.Therefore,physicianswereallowedtoadministeradditionaldosesof50µg/kgfollowedby5to10µg/kgperhourcon-tinuousopen-labelmorphine.Thenon-participants,however,oftenreceivedstandardmorphinebolusesof100µg/kg.Additionalmorphineuseinnon-participantsdifferedbetweenthe2cen-tersperhapsduetodifferentprescribingpoliciesortodifferentpatientcharac-teristics.

Ourresultsareindicativeofnon-

standardizedpainmanagementunderwhichlackofdecisionrulesresultsinprescribinganalgesicsonthebasisofpersonalclinicalexperience.Thisisnotonlythecaseinourcentersbutalsorep-resentativeofclinicalpracticeinmostNICUsworldwide.53Implementationofpainscores(ie,usingcutoffpointsforprescribingadditionalanalgesicsthatareintegratedinclinicalalgorithmsorflowcharts)mayberequiredforratio-nalizingtheuseofopioidanalgesicsintheNICU.Thedevelopmentofnewtechniques,suchasfunctionalmag-neticresonanceimagingandpositronemissiontomographicscans,mightbeusefulinthenearfuturetofurtherob-jectifytheanalgesiceffectsofopioidsinnewborns,buttheyarenotappli-cableindailyNICUcare.

Morphineusemightdecreasethefluctuationsincerebralbloodvolumeandintracranialpressurecausedbyneo-natalreactionstopainandpainfulpro-cedures.Morphinemaythusprotectagainstthedevelopmentofvenoushemorrhageinthegerminalmatrixorbrainparenchymaoragainsttheex-tension ofasmall previousIVH.54,55HighpainscoreswerenotrelatedtotheincidenceofIVHorpoorneurologicoutcome.Oberlanderetal56alsofoundthatparenchymalbraininjurydidnotcauseadifferenceinpainresponseinprematureneonates.Significantlyfewerneonatesinthemorphine-treatedgroupwerefoundtohaveIVHcomparedwiththeplacebogroup.Thiseffectofmor-

ROUTINEMORPHINEINFUSIONINPRETERMNEWBORNS

phinecanbepartlyexplainedbyade-creasedincidenceoflow-gradeIVH.Theimpactofroutinemorphinead-ministration,byreductionoflow-gradeIVH,onlong-termoutcomeishardtopredict.BothPVLandIVHwerediagnosedandstagedfromcranialul-trasoundsbystaffneonatologists,us-ingstandardcriteria.57,58Itisdifficulttodeterminetheneurobehavioralout-comeininfantswithIVHbecauseotherconfoundingcriteria,suchascomor-bidity,areinvolved.Mortalityandma-jorneurologicsequelaearegenerallyre-latedtothedegree ofhemorrhage59-63and,toagreaterextent,tothedegreeofassociatedparenchymalinjury.58In-fantswithIVHgradeIandII,withoutvenousinfarction,seemtohavelittleincreasedriskofadverseoutcomecom-paredwiththosewithoutIVH.58,60,64-66Whenwestudiedtheimpactofmor-phineinfusiononpoorneurologicout-comes(eg,death,PVL,IVHgradeIII,orIVHandapparentperiventricularhemorrhagicinfarction),therewerenodifferencesbetweenthe2groups.

Theneurologicconditionofourpa-tients,however,needstobereevalu-atedatolderages.AstudybyQuinnetal67alsoshowed comparableclinicaloutcomesbetweenplacebo-andmor-phine-treatedneonates.ApilotstudybyAnandetal,15 withaslightlydiffer-entstudydesign,showeddecreasedpoorneurologicoutcomesonaccountofmorphinecomparedwithmid-azolamhydrochlorideandplacebo.Relativelysmallgroups,numberingap-proximately20,inthosestudies,aswellas differencesinmorphine doseregi-men,mightexplainthedifferingre-sults.Furtherresultsofthatstudyshouldconclusivelyshowwhetherrou-tineuseofmorphinereducestheinci-dencesofIVHandpoorneurologicoutcome.

Overall, ourresultsshowalackofmeasurableanalgesiceffectandab-senceofabeneficialeffectonpoorneu-rologicoutcomefromroutinecontinu-ousmorphineinfusioninpretermneonates.Futureresearchisneededtoestablishcutoffpointsandanalgo-rithmfortheadministrationofanalge-

sicagentsinthisspecificagegroupofchildren,whichshouldbeincludedinconsensusstatements.23,24Further-more,betterunderstandingofindi-vidualdifferencesinresponsestomor-phineandpainisnecessarytoimproveneonatalpainmanagement.

Ourfindingssuggestthatmorphineinfusioninpretermnewbornswhore-ceiveventilatorysupportshouldnotbeusedasastandardofcare.Thelong-termconsequencesofreducedIVHincidenceinthemorphine-treatedneo-natesshouldbeevaluatedatpredeter-minedtimepointsatolderages,usingvalidatedassessmentinstrumentsforneurodevelopmentaloutcome.

AuthorContributions:Studyconceptanddesign:Simons,vanDijk,vanLingen,Roofthooft,Anand,vandenAnker,Tibboel.

Acquisition ofdata:Simons,vanDijk,vanLingen,Jongeneel,Bunkers,Smink,Tibboel.

Analysisandinterpretationofdata: Simons,vanDijk,vanLingen,Roofthooft,Duivenvoorden, Anand,vandenAnker,Tibboel.

Drafting ofthemanuscript:Simons,vanDijk,vanLingen,Jongeneel,Bunkers,Smink,vandenAnker.Criticalrevisionofthe manuscriptforimportantintellectualcontent:vanLingen,Roofthooft,Duivenvoorden,Anand,vandenAnker,Tibboel.

Statisticalexpertise:Simons,vanDijk, Duivenvoorden,

Obtainedfunding:vanLingen,Tibboel.Administrative,technical,ormaterialsupport:Simons,vanDijk,Roofthooft,Jongeneel,Bunkers,Smink,vandenAnker.

Studysupervision:vanLingen,Roofthooft,Anand,vandenAnker,Tibboel.

Funding/Support:ThisstudywassupportedbygrantMW-NWO940-31-048fromtheNetherlandsOrganizationforScientificResearch(DrsvanLingen,vandenAnker,andTibboel).

Acknowledgment:WethankJ. Hagoort forhis helpinpreparingthemanuscript.Furthermore,wethankthestaffandnursesoftheNICUsfortheircontribu-tiontothisstudyandtheparentsandinfantswhopar-ticipatedinthisstudy.

REFERENCES

1.KennedyKA,TysonJE.Narcoticanalgesiaforven-tilatednewborns:areplacebo-controlledtrialsethi-calandnecessary?JPediatr.1999;134:127-129.

2.vanDijkM,PetersJW,BouwmeesterJ,TibboelD.Arepostoperativepaininstrumentsusefulforspe-cificgroupsofvulnerableinfants?ClinPerinatol. 2002;29:469-491.

3.RutterN,EvansN.Cardiovasculareffectsofanin-travenousbolusofmorphineintheventilatedpre-terminfant.ArchDisChildFetalNeonatalEd. 2000;83:F101-F103.

4.WoodCM,RushforthJA,HartleyR,DeanH,WildJ,LeveneMI.Randomiseddoubleblindtrialofmor-phineversusdiamorphineforsedationofpretermneo-nates.ArchDisChildFetalNeonatalEd.1998;79:F34-F39.

5.SabatinoG,QuartulliL,DiFabioS,RamenghiLA.Hemodynamiceffectsofintravenousmorphineinfu-sioninventilatedpretermbabies.EarlyHumDev.1997;47:263-270.

6.HartleyR,GreenM,QuinnM,LeveneMI.Phar-macokineticsofmorphineinfusioninprematureneo-nates.ArchDisChild.1993;69(1specNo.):55-58.

7.KorenG,ButtW,PapeK,ChinyangaH.Morphine-inducedseizuresinnewborninfants.VetHumToxi-col.1985;27:519-520.

8.Saarenmaa E, Neuvonen PJ,Rosenberg P, Fell-manV.Morphineclearanceandeffectsinnewborninfantsinrelationtogestationalage.ClinPharmacolTher.2000;68:160-166.

9.WayWL,CostleyEC,WayEL.Respiratorysensi-tivityofthenewborninfanttomeperidineandmor-phine.ClinPharmacolTher.1965;6:454-461.

10.LynnAM,NespecaMK,OpheimKE,SlatteryJT.Respiratoryeffectsofintravenousmorphineinfu-sionsinneonates,infants,andchildrenaftercardiacsurgery.AnesthAnalg.1993;77:695-701.

11.HandelmannGE,Dow-EdwardsD.Modulationofbraindevelopmentbymorphine:effectsoncen-tralmotorsystemsandbehavior.Peptides.1985;6(suppl2):29-34.

12.TempelA.Visualizationofmuopiatereceptordownregulationfollowingmorphinetreatmentinneo-natalratbrain.BrainResDevBrainRes.1991;64(1-2):19-26.

13.BhuttaAT,RovnaghiC,SimpsonPM,GossettJM,ScalzoFM,AnandKJS.Interactionsofinflammatorypain andmorphineininfantrats:long-termbehav-ioraleffects.PhysiolBehav.2001;73(1-2):51-58.

14.MacGregorR,EvansD,SugdenD,GaussenT,Lev-eneM.Outcomeat5-6yearsof prematurelyborn chil-drenwhoreceivedmorphineasneonates.ArchDisChildFetalNeonatalEd.1998;79:F40-F43.

15.AnandKJS,BartonBA,McIntoshN,etal.Anal-gesiaandsedationinpretermneonateswhorequireventilatorysupport:resultsfromtheNOPAINtrial(NeonatalOutcomeandProlongedAnalgesiainNeonates).ArchPediatrAdolescMed.1999;153:331-338.

16.FitzgeraldM,MillardC,MacIntoshN.Hyperal-gesiainprematureinfants[letter].Lancet.1988;1:292.

17.FitzgeraldM,MillardC,McIntoshN.Cutaneoushypersensitivityfollowingperipheraltissuedamageinnewborninfantsanditsreversalwithtopicalanaes-thesia.Pain.1989;39:31-36.

18.Andrews K, FitzgeraldM.The cutaneouswith-drawalreflexinhumanneonates:sensitization,re-ceptivefields,andtheeffectsofcontralateralstimu-lation.Pain.1994;56:95-101.

19.AnandKJS,CoskunV,ThrivikramanKV,Nem-eroffCB,PlotskyPM.Long-termbehavioraleffectsofrepetitivepain inneonatalrat pups. PhysiolBe-hav.1999;66:627-637.

20.GrunauRE,OberlanderTF,WhitfieldMF,Fitzger-aldC,LeeSK.Demographicandtherapeuticdeter-minantsof pain reactivity in verylow birthweight neo-natesat 32 weeks'postconceptionalage.Pediatrics.2001;107:105-112.

21.PorterFL,GrunauRE,AnandKJS.Long-termef-fectsofpainininfants.JDevBehavPediatr.1999;20:253-261.

22.PetersJW,KootHM,deBoerJB,etal.Majorsur-gerywithinthefirst3monthsoflifeandsubsequentbiobehavioralpainresponsestoimmunizationatlaterage:acasecomparisonstudy.Pediatrics.2003;111:129-135.

23.AnandKJS.Consensusstatementforthepreven-tionandmanagementofpaininthenewborn.ArchPediatrAdolescMed.2001;155:173-180.

24.AmericanAcademyofPediatrics,CommitteeonFetusandNewborn,CommitteeonDrugs,SectiononAnesthesiology,SectiononSurgery,CanadianPae-diatricSociety,FetusandNewbornCommittee.Pre-ventionandmanagementofpainandstressintheneo-nate.Pediatrics.2000;105:454-461.

25.FranckLS,MiaskowskiC.Theuseofintrave-nousopioidstoprovideanalgesiaincriticallyill,pre-

ROUTINEMORPHINEINFUSIONINPRETERMNEWBORNS

matureneonates:aresearchcritique.JPainSymp-tomManage. 1998;15:41-69.

26.KartT,ChristrupLL,RasmussenM.Recom-mendeduseofmorphineinneonates,infantsandchil-drenbasedonaliteraturereview,part1:pharmaco-kinetics.PaediatrAnaesth.1997;7:5-11.

27.KartT,ChristrupLL,RasmussenM.Recom-mendeduseofmorphineinneonates,infantsandchil-drenbasedonaliteraturereview,part2:clinicaluse.PaediatrAnaesth.1997;7:93-101.

28.BerdeCB,SethnaNF.Analgesicsforthetreat-mentofpaininchildren.NEnglJMed.2002;347:1094-1103.

29.AmbalavananN,CarloWA.Analgesiaforventi-lated neonates:where dowestand?JPediatr.1999;135:403-405.

30.CommitteeonFetusandNewborn,AmericanAcademyofPediatrics,andCommitteeonObstetricPractice,AmericanCollegeofObstetriciansandGy-necologists.UseandabuseoftheApgarscore.Pedi-atrics.1996;98:141-142.

31.LawrenceJ,AlcockD,McGrathP,KayJ,MacMurraySB,DulbergC.Thedevelopmentofatooltoassessneonatalpain.NeonatalNetw. 1993;12:59-66.

32.StevensB,JohnstonC,PetryshenP,TaddioA.Pre-matureInfantPainProfile:developmentandinitialvali-dation.ClinJPain.1996;12:13-22.

33.UsherR,McLeanF.Intrauterinegrowthoflive-bornCaucasianinfantsatsealevel:standardsob-tainedfrommeasurementsin7dimensionsofinfantsbornbetween25and44weeksofgestation.JPedi-atr.1969;74:901-910.

34.vanDijkM,KootHM,SaadHH,TibboelD,Pass-chierJ.Observationalvisualanalogscaleinpediatricpainassessment:usefultoolorgoodriddance?ClinJPain. 2002;18:310-316.

35.BlauerT,GerstmannD.Asimultaneouscompari-sonofthreeneonatalpainscalesduringcommonNICUprocedures.ClinJPain.1998;14:39-47.

36.BallantyneM,StevensB,McAllisterM,DionneK,JackA.Validationoftheprematureinfantpainpro-fileintheclinicalsetting.ClinJPain.1999;15:297-303.

37.RaisanenI,Paatero H,SalminenK,Laatikainen

T.Beta-endorphininmaternalandumbilicalcordplasmaatelectivecesareansectionandinspontane-ouslabor.ObstetGynecol.1986;67:384-387.

38.PohjavuoriM,RovamoL,LaatikainenT,Karini-emiV,PetterssonJ.Stressofdeliveryandplasmaen-dorphinsandcatecholaminesinthenewborninfant.BiolResPregnancyPerinatol.1986;7:1-5.

39.BacigalupoG,LangnerK,SchmidtS,SalingE.Plasmaimmunoreactivebeta-endorphin,ACTHandcor-tisolconcentrations inmothersandtheir neonates im-mediatelyafterdelivery:theirrelationship to thedura-tionoflabor.JPerinatMed.1987;15:45-52.

40.PokelaML,KoivistoM.Physiologicalchanges,plasmabeta-endorphinandcortisolresponsestotra-chealintubationinneonates.ActaPaediatr.1994;83:151-156.

41.SaarenmaaE,HuttunenP,LeppaluotoJ,Fell-manV.Alfentanilasproceduralpainreliefinnew-borninfants.ArchDisChildFetalNeonatalEd.1996;75:F103-F107.

42.GrunauRE,HolstiL,WhitfieldMF,LingE.Aretwitches,startles,andbodymovementspainindica-torsin extremelylowbirthweightinfants?ClinJPain.2000;16:37-45.

43.GreisenG,FrederiksenPS,HertelJ,ChristensenNJ.Catecholamineresponsetochestphysiotherapyandendotrachealsuctioningin preterm infants.ActaPaediatrScand.1985;74:525-529.

44.SkovL,RydingJ,PrydsO,GreisenG.Changesincerebraloxygenationandcerebralbloodvolumedur-ingendotrachealsuctioninginventilatedneonates.ActaPaediatr. 1992;81:389-393.

45.PokelaML.Painreliefcanreducehypoxemiaindistressedneonatesduringroutinetreatmentproce-dures.Pediatrics.1994;93:379-383.

46.McCullochKM,JiSA,RajuTN.Skinbloodflowchangesduringroutinenurseryprocedures.EarlyHumDev. 1995;41:147-156.

47.EvansJC,VogelpohlDG,BourguignonCM,Mor-cottCS.PainbehaviorsinLBWinfantsaccompanysome"nonpainful"caregivingprocedures.NeonatalNetw. 1997;16:33-40.

48.JohnstonCC,StevensBJ,FranckLS,JackA,Strem-lerR,PlattR.Factorsexplaining lackofresponsetoheelstickinpretermnewborns.JObstetGynecolNeo-natalNurs.1999;28:587-594.

49.JohnstonCC,StevensBJ,YangF,HortonL.Dif-ferentialresponse topainbyveryprematureneo-nates.Pain.1995;61:471-479.

50.ScottCS,RiggsKW,LingEW,etal.Morphinepharmacokineticsandpainassessmentinprematurenewborns.JPediatr.1999;135:423-429.

51.QuinnMW,WildJ,DeanHG,etal.Randomiseddouble-blindcontrolledtrialofeffectofmorphineoncatecholamineconcentrationsinventilatedpre-termbabies.Lancet.1993;342:324-327.

52.Anand KJS. Systemic analgesictherapy. In:An-andKJS,StevensBJ, McGrathPJ,eds.PaininNeo-nates. Vol10.2ndrevisedandenlargeded. Amster-dam,theNetherlands:Elsevier;2000:180.

53.KahnDJ,RichardsonDK,GrayJE,etal.Varia-tionamongneonatalintensivecareunitsinnarcoticadministration.ArchPediatrAdolesc Med.1998;152:844-851.

54.PerlmanJM,McMenaminJB,VolpeJJ.Fluctuat-ingcerebralblood-flowvelocity inrespiratory-distresssyndrome: relationtothedevelopmentofin-traventricularhemorrhage.NEngl JMed.1983;309:204-209.

55.Ghazi-BirryHS,BrownWR,MoodyDM,ChallaVR,BlockSM,ReboussinDM.Humangerminalma-trix:venousoriginofhemorrhageandvascularchar-acteristics.AJNRAmJNeuroradiol.1997;18:219-229.

56.OberlanderTF,GrunauRE,FitzgeraldC,Whit-fieldMF.Doesparenchymalbraininjuryaffectbiobe-havioralpainresponsesinverylowbirthweightin-fantsat32weeks'postconceptionalage?Pediatrics.2002;110:570-576.

57.deVriesLS,EkenP,DubowitzLM.Thespec-trumofleukomalaciausingcranialultrasound.Be-havBrainRes.1992;49:1-6.

58.VolpeJJ.Intracranialhemorrhage:germinalmatrix-intraventricularhemorrhageoftheprematureinfant.In:NeurologyoftheNewborn.4thed.Philadelphia,Pa:WBSaunders;2000:428-491.

59.ThorburnRJ,LipscombAP,StewartAL,Rey-noldsEO,HopePL,PapeKE.Predictionofdeathandmajorhandicapinverypreterminfantsbybrainul-trasound.Lancet.1981;1:1119-1121.

60.ShankaranS,SlovisTL,BedardMP,PolandRL.Sonographicclassificationofintracranialhemor-rhage:aprognosticindicatorofmortality,morbidity,andshort-termneurologicoutcome.JPediatr. 1982;100:469-475.

61.SmithWL,McGuinnessG,CavanaughD,Court-neyS.Ultrasoundscreeningofprematureinfants:lon-gitudinalfollow-upofintracranialhemorrhage.Ra-diology.1983;147:445-448.

62.VohrB,GarciaCollC,FlanaganP,OhW.Effectsofintraventricularhemorrhageandsocioeconomicsta-tusonperceptual,cognitive,andneurologicstatusoflowbirthweightinfantsat5yearsofage.JPediatr.1992;121:280-285.

63.FeingoldE,Sheir-NeissG,MelnychukJ,BachrachS,PaulD.HRQLandseverityofbrainultrasoundfindingsinacohortofadolescentswhowerebornpreterm.JAdolescHealth.2002;31:234-239.

64.PapileLA,Munsick-BrunoG,SchaeferA.Rela-tionshipofcerebralintraventricularhemorrhageandearlychildhoodneurologichandicaps.JPediatr.1983;103:273-277.

65.StewartAL,ThorburnRJ,HopePL,GoldsmithM,LipscombAP, ReynoldsEO.Ultrasoundappearanceofthebraininverypreterminfantsandneurodevel-opmentaloutcomeat18months ofage.ArchDisChild.1983;58:598-604.

66.DubowitzLM,DubowitzV,PalmerPG,MillerG,FawerCL,LeveneMI.Correlationofneurologicas-sessmentinthepretermnewborninfantwithout-comeat1year.JPediatr.1984;105:452-456.

67.QuinnMW,deBoerRC,AnsariN,BaumerJH.Stressresponseandmodeofventilationinpretermin-fants.ArchDisChildFetalNeonatalEd.1998;78:F195-F198.