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Pharmacologicalclosureofthepatentductusarteriosus

ImagesPaediatrCardiol.2003JanMar5(1):115.

PMCID:PMC3232537

Pharmacologicalclosureofthepatentductusarteriosus
SKMehta,AYounoszai,JPietz,andBPAchanti
Contactinformation:Dr.SudhirKenMehta,ChairmanofPediatrics,DepartmentofPediatricsandPediatricCardiology,FairviewHospital,18101
LorainAvenue,Cleveland,Ohio441115656USATel:2164767236Fax:2164767021Email:ken.mehta@fairviewhospital.org
Copyright:ImagesinPaediatricCardiology
ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNoncommercialShareAlike3.0Unported,whichpermits
unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Abstract

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PharmacologicalclosurebyindomethaciniscustomaryifsymptomsofPDAarenotcontrolledadequatelywith
fluidrestrictionanddiuretics.Itsuse,however,requiresacomprehensiveclinicalassessmentofallthevital
perinatalfactorsandavigilantmonitoringofthesickinfant.Prophylacticuseofindomethacinisdiscouraged.The
decisiontousepharmacologicalversussurgicaltreatmentorbothshouldbeindividualizedbasedonevidence
basedresearchandclinician'sownexperience.Surgicalligationremainstheprimarymodeoftherapyincasesof
pharmacologicaltreatmentfailureorrecurrence.
MeSH:DuctusArteriosus,PatentInfant,Premature,Echocardiography,transthoracic,Prostaglandins,
Prostaglandinantagonists,Indomethacin
Introductionandbackground

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Theductusarteriosusinthefetusisanimportantconduitthatallowsdeoxygenatedbloodtobypassthecollapsed
lungsandentertheplacentathroughthedescendingaortaandumbilicalarteries.Theplacentaactsasanoxygenator
andreturnsoxygenrichbloodthroughtheumbilicalveinandductusvenosustothefetalheart.Duringthefirsttwo
trimesters,bloodflowtothelungsisminimalanditincreasessubstantiallyduringthelasttrimester.Afterbirth,the
ductusarteriosusnormallycloseswithinthefirstseveraldaysoflife.Apersistentlypatentductusarteriosus(PDA)
cancausesignificantproblems,especiallyinprematureinfants.
Physiologicclosureoftheductusarteriosus

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Theouterlayeroftheductusisprimarilycomposedofcircumferentiallyorientedmusclefibers.1Duringthelast
trimesterofpregnancy,thereisrapidgrowthinmedialmusculartissuewithsubsequentmigrationintothe
subintimalspace,probablyduetoincreasedexpressionoftransforminggrowthfactor1.1Thisgrowthaccompanies
asimultaneousincreaseinthesensitivityoftheductusarteriosustooxygentensionforclosure.1Oxygenreaches
themuscularmediaeitherthroughthelumenorthroughintramuralvasavasorumcomingfromtheoutermuscular
layer.Partofthemuscularmediaadjoiningthelumenisrelativelyavascular,devoidofvasavasorumandtherefore
poorlyoxygenated.Duringclosureoftheductus,thethicknessoftheavascularzoneplaysacriticalroleincausing
hypoxiaandanatomicalremodelingoftheductus.Thecontractionofcircumferentialfibersresultsinnarrowingof
theductallumenwhereascontractionoflongitudinalfibersleadstoshorteningoftheductus.
Theplacentaproducesprostaglandins,whichmaintainprenatalpatencyoftheductusand,inearlygestation,inhibit
theabilityoftheductustocontractinresponsetooxygen.Theductusarteriosusitselfalsoproducesprostaglandins
andnitricoxidelikevasodilators.1Duringthepostnatalperiod,finalclosureoftheductusarteriosusresultsfrom
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increasedproductionoflocalvasoconstrictors(likeendothelin)inresponsetohigherarterialoxygen,1removalof
placentalprostaglandinandadecreaseinthenumberofprostaglandinE2receptorsintheductalwall.
Persistentpatencyoftheductusarteriosus

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Duringthefirst60hoursoflife,spontaneousclosureoftheductusoccursin55%offulltermnewborninfants.By
26monthsofage,closureoccursinmorethan95%ofhealthyinfants.1Persistentpatencyoftheductusarteriosus
followingbirthisinverselyrelatedtogestationalage.Thismaybeduetothesmalleramountofmusculartissuein
themediawithlowerintrinsictone,andlowerresponsivenesstooxygenbuthighersensitivitytothevasodilating
effectsofprostaglandinE2andnitricoxide.1Inclinicalpractice,mostextremelylowbirthweightinfantswhoare
lessthan28weeksgestationhaveapatentductusarteriosus(PDA)duringthepostnatalperiod.(Foranexcellent
reviewandimagesonpatentductusarteriosusinprematureinfants,pleaseseeKaratzaetal.).1Prematurity,
however,doesnotguaranteeprolongedpatencyoftheductusarteriosus.Forexample,Relleretal.foundthatthe
PDAclosedspontaneouslyin32of36infantswithagestationalageof3037weeksandrespiratorydistress
syndromebythefourthdayoflife.1Concurrentinfectionsmayincreasethereleaseofprostaglandins(6
ketoprostaglandinF1)andtumornecrosisfactors,andincreasetheriskoflateductalopeningandclosurefailures.1
ThedirectionofbloodflowacrossthePDAdependsonthebalanceofpulmonaryandsystemicvascularresistance.
Inutero,thefetallungsarecollapsedandthepulmonaryvascularresistanceishigh.Conversely,theconnectionof
thelowresistanceplacentatothesystemicvascularbedviatheumbilicalcordallowsforlowsystemicvascular
resistanceresultinginbloodflowfromthepulmonaryarterytotheaorta(i.e.arighttoleftshunt)prenatally(for
furtherdetails,pleaserefertofetalimages1andfigure1).Despitetheincreaseinsmoothmuscleinthewallofthe
pulmonaryarteriolesduringthelasttrimester,pulmonaryvascularresistancefallsprimarilyduetoincreaseinthe
totalcrosssectionalareaofthevascularbedsecondarytothegrowthinthenumberofrespiratoryunits.Thisdrop
inthepulmonaryvascularresistanceleadstoincreaseinthepulmonarybloodflowduringthelasttrimester.
Figure1
Fetalechocardiogramoftheductusarteriosus(CourtesyofDrs.J.Moodley
andY.Shah)

Asthenewbornbeginstobreathe,thelungsexpandandthepulmonaryvascularresistancedrops.Theumbilical
cordissimultaneouslyclampedseparatingtheplacentafromthesystemicbedandthesystemicvascularresistance
quicklyrisesabovethatofthepulmonarybed.Asaresult,afterbirth,bloodflowsfromtheaortaintothe
pulmonaryartery(i.e.alefttorightshunt).Mostofthislefttorightshuntcomesfromthedistalaortaparticularly
duringdiastole.AlargePDAthatoffersnoresistanceofitsown(nonrestrictive)mayresultinaconsiderable
increaseinpulmonarybloodfloweventuallyleadingtohighoutputheartfailuredespiteimprovedventricular
performanceduetodecreasedafterload.1
PathologyofthePDAinprematureinfants

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Incontrasttoolderchildren,fetalandneonatalmyocardiumhasahighernoncontractiletocontractilemassratio,
andislesscompliant.1,2Therefore,withtheincreaseinpreloadresultingfromductallefttorightshunting,higher
leftventricularenddiastolicandleftatrialpressuresensueearly.Inaddition,risinghydrostaticpressurein
pulmonarycapillariesfromhigherpulmonarybloodflowexceedsoncoticpressuresleadingtopatchyatelectasis
withpossiblesegmentalandlobarcollapse,furtherincreasingthepulmonaryvascularresistance.Prematureinfants
commonlyhavelowoncoticpressureandincreasedcapillarypermeabilitythatfurtherworsenstheinterstitialleak.
Infantswithlowerbirthweight(<1200grams)arelessabletotolerateaPDAthanfullterminfants.Suchinfants
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haveunderdevelopedalveoliinadditiontosurfactantdeficiency(Figure2).Theyalsohavealesswelldeveloped
pulmonarylymphaticsystemandarethereforelesscapableofeliminatingtheexcessfluidpresentedtothe
prematurelungbyalargePDA.ArelativelylargerPDAcomparedtoaorticdiameterandarelativelylower
pulmonaryvascularresistanceduetolessmuscleinthepulmonaryvascularbedpermitsrelativelylargerpulmonary
bloodflow.Thisalsostealssignificantbloodflowfromvesselsdistaltotheductsuchasthegut.
Figure2
DevelopmentalfactorsaffectingthehemodynamicsofthePDA

RespiratoryfailureisacommonconsequenceofalargePDAintheprematureinfant.Tachypneacanaidin
drainingtheexcessfluidfromtheinterstitialspacethroughthelymphaticsystem.However,wheninputexceeds
outputinterstitialedemaensues.ThisedemamayresultindecreasedCO2diffusionfromcapillariestoalveoliand
CO2retention.Consequentlyairpassagesarenarrowedandrespiratoryfailureandapneadevelopsmorequicklyin
prematureinfantsastheirfragilerespiratorymusclestireout.Aspoorlungcomplianceiscommoninmostofthese
infants,thisprocessservestoaggravateanyexistingrespiratorydistresssyndrome.
Surfactanthasbecomestandardtherapyforneonatalrespiratorydistresssyndromeassociatedwithprematurity.The
introductionofsurfactantoverthelast10yearshascontributedtoadecreaseinmortalityandmorbidityinvery
lowbirthweightinfants.1Surfactant,however,reducespulmonaryvascularresistanceandincreaseslefttoright
shuntingacrosstheductus.Surfactantdoesnotdelayclosureoftheductusarteriosus.1,2,3
PerfusionofthesystemicvascularbedinthesettingofaPDAhasbeenexamined.EvenwithalargePDA,
prematureinfantsmaintainnormalcerebralbloodflow,althoughflowisdecreasedinpostductalorganssecondary
tolowerperfusionpressure.1Autoregulatorymechanismsinthebraincompensateforcerebralbloodflowchanges
associatedwithductalshuntingthatareprobablyrelatedtodiastolicrunoffandnottoincreaseincerebrovascular
resistance.1,2
Clinicaldiagnosis

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TheclassicaldescriptionofthesignsandsymptomsofthePDAweredescribedinthe1950sbyDr.HelenTaussig.
Shedescribedaprematureinfantwithacontinuouswashingmachinelikemurmurheardbestintheleftupper
sternalborder.Shealsodescribedboundingpulsesduetotherapidrunoff,enlargedheartonchestxrayand
evidenceofpulmonarycongestionandheartfailureinthemoreseverecases.Thesefindingsmustbeproperly
placedincontextofthegestationalageoftheinfantinquestion.Aprematureinfantbeingtreatedin1950probably
wasover1500gramsinbirthweight.Infantsbeingtreatedinthaterawererarelyassmallasneonatesthatare
routinelycaredforintoday'sneonatalintensivecareunits.
Therefore,whentryingtodiagnoseaPDAinthemodernNICUonemustconsiderthephysiologicdifferencesof
theextremelylowbirthweightinfant.Thisisalsocomplicatedbythepresenceofneonatallungdiseasesuchas
RDS.Manyextremelylowbirthweightinfantshaveasilentpatentductusarteriosus.Theymaynothaveamurmur
atall.WhileboundingpulsesareconsideredthehallmarkofthePDA,theymaynotbedetectedintheverytiny
neonateifthatinfantdoesnothaveenoughmyocardialreservetocompensatefortherapidrunoff.Alternatively,
boundingpulsesmaynotbefoundifpulmonaryvascularresistanceisequalornearequaltosystemicvascular
resistance.OftentheeffectofthePDAontheprematureinfantdoesnotbecomeclearuntilsurfactantdeficiency
hasresolved.Whenventilatordependencepersistsbeyondthethirddayoflifeinthesetiniestpatients,surfactant
deficiencybecomesalesslikelycauseofcardiopulmonarysymptoms.Commonly,afterartificialsurfactant,oxygen
requirementswillinitiallydecreaseonlytoincreaseinafewdays.Carbondioxideretentionbecomesmoreofa
problemaswell.Enlargedheartonchestradiographandclinicalsignsofnarrowairwayswillmanifest.Itisnot
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unusualfortheclassicmurmurofthePDAaswellasboundingpulsestoappearatthistimeduetoadropin
pulmonaryvascularresistanceallowingalefttorightshuntthroughthePDA.Ingeneral,PDAevaluationby
clinicalexaminationaloneintheventilatordependentpreterminfantsisoflimitedvalue.1
ThemostreliablenoninvasivediagnostictoolisechocardiographywithDopplerultrasound.Inmostinfants,a
modifiedparasternalshortaxisviewoffersthebestwindowforPDAvisualization(Figure3).Thisviewoffersthe
bestopportunitytodirectlymeasurethePDA.Thesecondaryeffectsoftheincreasedflowcanestimatethevolume
loadfromthelefttorightductalshunt.Alargeshuntleadstodilationoftheleftatriumandleftventricle,aswellas
holodiastolicreversalofbloodflowdistaltotheductusinthedescendingaortaduetorunoffintothepulmonary
bed.Enlargementoftheleftatriumreflectingtheapproximatemagnitudeoftheshunt,canbefurthersupportedby
leftatrialtoaorticrootratioof>1.3.Thepresenceofapatentfossaovalis,presentinmostnewborninfants,can
confoundthesemeasurements.1Inaddition,continuouswaveDopplercanestimatepulmonaryarterypressuresby
measuringDopplervelocitiesofPDAflowandtricuspidregurgitation.1
Figure3
EchocardiographyofthePDA.Theductuscanbewellvisualizedfromthe
leftparasternalarea(A)withlowvelocityflowbackintothepulmonary
arteryfromtheaorta(B).AftertherapywithindomethacinthePDA
significantlydecreasesinsize(C)with...
InthesettingofprenatalductalconstrictiontheTeiindex,anechocardiographicalyderivedmeasureofcardiac
function,appearstobeuseful,betweenthegestationalagesof2039weeks,toevaluatedepressedrightventricular
function.1
Thediagnosisofductusarteriosusaneurysmshouldbeconsideredwhenthereisalocalizedsaccularortubular
dilatationoftheductusarteriosus.Itconceivablyresultsfromabnormalelastinformationorabnormalintimal
cushionformation.Thereportedincidenceofductusarteriosusaneurysm,seenafterthethirdtrimester,varies
between1.58.8%andmayrepresentanormalvariant.1,2ItmaybeobservedinpatientswithMarfan,Ehlers
DanlosandLarsensyndromeandhasthepotentialforspontaneousrupture,thromboembolism,erosion,and
infection.Iflarge,itcancompresstheadjoiningtissuesandstructures.Itspresenceshouldpromptclinicianstolook
fortheassociatedsyndromesparticularlyconnectivetissuediseases.
Pharmacological

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Conservativemedicalmanagementsuchasdiureticsandfluidrestrictionsufficeinmanypatientswithearly
symptoms.Aftertheseconddayoflife,limitingfluidintaketomeetbasicrequirementsofexcretion,insensibleloss,
andgrowthmaylowertheriskfordevelopmentofsymptomsrelatedtoaPDAinprematureinfants.1Theabilityof
aprematureinfanttotolerateaPDAmaybeinverselyproportionaltogestationalage.Closureisindicatedinthe
symptomaticinfantwithasignificantvolumeoverloaddocumentedbyechocardiography.
IntheprematureinfantanimportantaspectofPDAmanagementisfluidintake.Earlyfluidrestrictiontoallowfor
littlemorethaninsensibleandsensiblelosseswillsignificantlyreducetherisksofPDA,necrotizingenterocolitis,
anddeathattheexpenseofpostnatalweightloss.1Ifthesignsandsymptomspersist,oneisleftwithbalancingthe
variousneedsofthepatientagainsttheproblemsoftreatingthesymptomsofthePDA.
SimplefluidrestrictionalongwithdiureticuseisoftenrecommendedtocontrolthesymptomsofaPDA.
Furosemideiscommonlyused.Althoughfurosemideisaprostaglandinagonist,itdoesnotinterferewithPDA
closure.Furosemidemerelyhelpsthelungsclearfluidandtherebyimprovesthepatient'sabilitytotoleratethe
PDA.Shorttermuseoffurosemideandfluidrestrictionrequiresaclosevigilancetopreventdehydration.Long
termuseofthisdrugcanhaveseriousandsubtlesideeffects.Itcausescalciumlossbythekidneyandmayleadto
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rickets.Itcanalsocausehypokalemia,whichleadstoametabolicalkalosisandcarbondioxideretentionthatcanbe
misinterpretedasworseningofcardiopulmonarydiseaseleadingtoanapparentincreaseinventilatorsupport.
Hypokalemiacanbecontrolledwithpotassiumsupplementationbutitisdifficulttoovercometheproblemof
calciumlosscausedbyfurosemide.Forthisreason,manycliniciansprefermilderthiazidediureticsforlongterm
use.
Oneofthecorechallengeswithfluidrestrictionisnutritional.Inagrowinginfant,longtermfluidrestrictionlimits
theamountofcaloriesandmineralsthatcanbegiven.Providingadequatecaloriesandmineralswithfluid
restrictionrequireshighlyconcentratedformulasorparenteralalimentation,whichmayincreasetheriskforfeeding
intoleranceandsepsis.Formanyclinicians,itisapoortradetocontrolthesymptomsofPDAattheexpenseof
goodnutrition.AuthorsrecommendtheuseofLasixandfluidrestrictiononlyforafewdaysatmost.Beyondthat,
thiazidesmaybepreferredandfluidsberestrictedonlytothelevelatwhichadequatecaloriescanbeprovidedfor
goodgrowthinachronicallyillprematureinfant,itisusuallynolessthan120ml/Kg/day.
Indomethacinisapotentstimulatorofductalclosure.Itblockstheenzymecyclooxygenaseinhibitingprostaglandin
synthesistherebyfacilitatingductalclosure(Figure4).Indomethacinalsoincreasesthethicknessoftheavascular
zonebycausingconstrictionofcircumferentialandlongitudinalmuscle,decreasingbloodflowinthevasa
vasorum,andcausingvesselwallhypoxiawithreleaseofvascularendothelialcellgrowthfactor(VEGF).VEGF
inducesformationofneointimalmoundsandstimulatesingrowthofthevasavasorumduringpermanentductal
closure.
Figure4
Biosynthesisofarachidonicacid

Indomethacinisthemostcommonlyusedagentformedicalclosureofaductus.Moststudieshaveshownthatthe
useofindomethacininclosingthePDAhasreducedtheneedforsubsequentsurgicalclosure.Theappropriatetime
toadministerindomethacinisdebatable.Thethreeprimarystrategiesareasfollows:
1. Useofindomethacinwithin24hoursoflifeasaprophylactictreatment
2. Beforeoratearlyonsetofclinicalsymptoms
3. Afterthedevelopmentofclinicalsymptoms
Givenasprophylactictreatmentwithin24hoursofbirth,indomethacinreducestheincidenceofasymptomatic
PDA,theneedforsurgicalclosure,andtheincidenceofgrade3and4intraventricularhemorrhage(pooledrelative
risk=0.66[95%CI0.53to0.82]).ClosureofthePDAbyitself,however,doesnotimprovetheoutcomeinterms
ofmortality,necrotizingenterocolitis(NEC),bronchopulmonarydysplasia,orretinopathyofprematurity.
Additionally,thereareseriousconcernsamongmanycliniciansregardingsideeffectsofindomethacinincluding
transientoliguriaandalteredrenalfunctiondecreaseincerebral,mesenteric,andrenalbloodflowalteredplatelet
functionandnecrotizingenterocolitisorgastrointestinalperforation.Consequently,useofindomethacinin
contraindicatedininfantswithableedingdiathesis,necrotizingenterocolitis,orrenalfailure.
Indomethaciniscommonlyusedininstitutionscaringforprematureinfantshowever,theadministrationofthis
medicationisquitevariable.Thismakesitdifficulttocomparethesideeffects,ortheirlackof,reportedinvarious
studies.Confoundingvariablesincludepostnatalage,gestationalage,dose,delivery,andtherateofdelivery,
prenataluseofmedications,surfactantuse,andinfections.Alackofdocumentationregardingtheexactmodeof
deliveryaddstotheconfusion.Forexample,theeffectivenessandsafetyofIVinfusionover36hoursversusthe
conventionalmodeofinfusionmaybedifferentandneedsfurtherevaluation.Inaddition,theriskfornecrotizing
enterocolitisandahigherrateofductusreopeningremainsaconcerninextremelyprematureinfants(<27weeksof
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gestationalage).
Notwithstandingseveralcontraindications,shouldclinicianselecttouseindomethacin,basedonourown
experienceandreviewoftheliterature,werecommendthefollowingstrategytominimizethesideeffectsof
indomethacin.Toavoidcompromiseincerebralandgastrointestinalbloodflow,infantsshouldreceive0.10.2
mg/kgIVofindomethacinslowlyoveraminimumof30minutesfollowedimmediatelyby1mg/kgoffurosemide.
Atotalof3dosescanbegivendependingontheclinicalresponse&indomethacinlevels.Theusefulnessandthe
factorsthatmaypromptprolongedindomethacintherapyarestillunderinvestigation.Althoughsuccessfulclosure
ofthePDAbyindomethacincanbeachievedevenafter10daysofpostnatalage,closemonitoringof
indomethacinlevelsandclinicalresponseisrequiredforoptimalmanagementofallinfantstominimizeitsside
effects.
Furosemidegivenimmediatelyafterindomethacinmaypreventtherenalsideeffectsofindomethacintherapy
withoutinterferingwithefficacyofindomethacinfortheclosureofPDA.Inaddition,itmayhelpimprove
pulmonarycompliance.Concomitantdopaminetherapyinanattempttoincreasetherenalbloodflow,however,is
ofnobenefitanditdoesnotreducethemagnitudeoftheindomethacininducedoliguria.
Obstetricaluseofindomethacintotreatprematurelaborcanaffectthepostnatalresponseoftheductustomedical
therapy.Inuteroexposuretoindomethacinresultsinproductionofendothelialnitricoxidesynthase,increased
nitricoxideproduction,lossofsmoothmusclecells,andlossofcontractilecapacity.Insuchcases,prostaglandins
playaminimalroleintheclosureoftheductusarteriosusandprematureinfantsbecomeunresponsiveto
indomethacintherapy.ThesechildrenhaveanincreasedincidenceofsurgicalclosureofthePDA.Itremainstobe
seenwhethercyclooxygenase1selectiveinhibitorswouldprovideeffectivedelayofprematurelaborwithout
adverseeffectstofetus.
Ibuprofen,anothernonselectivecyclooxygenaseinhibitor,givenonthethirddayofpostnatallifeappearstobeas
effectiveasindomethacinforPDAclosurebutlesslikelytoinduceoliguria.Itmaybetooearlytojudgeitsfull
safetyprofileasevidencedbyarecentreportof3veryprematureinfantswhodevelopedpulmonaryhypertension
afteribuprofenprophylaxis.
HydrocortisonedecreasesresponsivenessoftheductusarteriosussmoothmuscletoPGE2.Prenataladministration
ofbetamethasonedecreasedtheincidenceofclinicallysignificantPDAfrom34%to18%by24hours.Many
clinicians,whocouldnotuseindomethacin,eitherduetocontraindicationsfordruguseorpersonalpreference,
foundpostnataluseoflowdosecorticosteroidsusefulinthemanagementofhemodynamicallysignificantPDA.
Recentconcernsaboutneurodevelopmentaldelayinverylowbirthweightinfantsassociatedwiththeuseof
dexamethasonestronglyargueagainststeroiduseintheseinfants.
NonPharmacologicalTherapies

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Insmallinfantsthatarenotacandidatefor,orwhohavefailed,medicaltherapy,surgicalligation
remainsaneffectivealternative.Inarandomized,controlledtrialofprophylacticsurgicalligationofPDA,the
incidenceofNECdecreasedfrom30%to8%,however,ithadnosignificanteffectonotheroutcomemeasureslike
death,bronchopulmonarydysplasia,retinopathyofprematurity,andintraventricularhemorrhage.Theclassical
approachviaaleftlateralsternotomywithligationcanbeperformedinanoperatingroomoratthebedsidewith
lowmortality.Theuseofanteriorextrapleuralapproachreportedin5patientsisarelativelynewtechniqueand
morestudiesareneededpriortoitsrecommendationforgeneraluse.Alternatively,tominimizetraumatothechest
wall,avideoassistedthoracoscopicapproachhasbeenusedsuccessfullyinsomeinstitutions.
Surgicalligation

Transcatheterclosure Althoughcoilocclusionhasbeenperformedininfants,alargeshortPDA,whichisthe

typicalanatomyinsymptomaticnewbornsandprematureinfants,isdifficulttoclose.Inaddition,thereisa
significantriskofobstructingthedescendingaortaorleftpulmonaryartery,whicharesmallcalibervesselsin
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neonates.Inchildrenwithasmallerductusandlesssignificantlefttorightshuntingclosurecanbedeferreduntil
theyareolder.Outoftheneonatalperiod,cardiaccatheterizationwithcoilocclusionofthePDAhasbecomethe
primarymodeofclosure(Figure5).NewerocclusiondevicessimilartoonesusedforASDclosurearebeing
developedforclosureofthelargePDAinolderchildrenandadults.
Figure5
ClosureofaPDAbycoilcatheterization.(A)Injectionintotheaortareveals
alargePDAatbaseline.(B)Followingplacementofacoiltheangiographic
dyenolongercrossesintothepulmonaryarteryconfirmingductalclosure
Pharmacologicalmanagementversussurgicalclosure

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Pharmacologicalmanagement(usuallyindomethacin)and/ormechanicalclosure(usuallysurgicalligation)are
consideredifsymptomsofPDAarenotcontrolledadequatelywithfluidrestrictionand/ordiuretics.Choosing
betweentheseapproachesisstilldifficultandcontroversial.WhilestudieshaveshownthatclosureofthePDAis
beneficial,itisbynomeansclearastothebestmethodofclosure,timingorpatientselection.Indomethacindoes
closethePDAinmanycasesbutnotall.Ingeneral,indomethacinismosteffectiveatclosingthePDAininfants
whoneedittheleasti.e.3236weeksgestationlargerinfantswhoarebetterabletotoleratethehemodynamic
effectsofaPDA.Theearliertheinfant'sgestation,thelesslikelyitisthatthePDAisgoingtorespondto
indomethacin.Indomethacinfailurerateinneonatesweighinglessthan800gcanbehigh(43%).Also,neonates
whoarebeyond10dayspostnatalagemaybelessresponsivetoindomethacin.
Sideeffectsofindomethacinarepotentiallyserious.Asmentionedabove,theseincludealteredrenalfunction
decreasedcerebral,mesenteric,andrenalbloodflowalteredplateletfunctionnecrotizingenterocolitis(NEC)and
bowelperforation.Consequently,useofindomethaciniscontraindicatedinpatientswithbleedingdiathesis,
necrotizingenterocolitisoroliguria.Whengiventoapatientwithhighpulmonaryvascularresistance,itcancause
severehypoxia.Necrotizingenterocolitisisaparticularprobleminthepatientswhotendtohavethemostdifficulty
withthePDAi.e.theverytinyinfant.Withincreasingprematurity,theriskforthedevelopmentofNECaswellas
itsseverityincreases.
Consequently,manycliniciansareoptingforclosureofthePDAbymechanicalmeansinsmallprematureinfants
(<800grams).RisksofPDAclosureinthehandsofanexperiencedsurgeontendtobesmallandlimitedtothe
usualproximateconsequencesofsurgerylikesurgicalmishaps,infectionandchylothorax.Inviewofourexcellent
surgicaloutcome,werarelyuseindomethacinintheextremeprematureinfants.Wealsohaveazeroincidenceof
surgicalNECoverthelastseveralyearstreatingover70prematureinfantsweighing<1500grams.Withthe
availabilityofadequatefacilitiesandtrainedstaff,manyneonatalintensivecareunitsprefertoperformthePDA
ligationintheunit,thusavoidingtheneedtomovethealreadycriticallyillpatient.
Summary

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Althougheffective,wedonotrecommendprophylacticindomethacintreatmentorprophylacticsurgicalligationas
itwillleadtounnecessaryindomethacinandsurgicalexposuretoalargenumberofpreterminfantswhomaynever
developPDArelatedsymptomsrequiringpharmacologicaland/orsurgicalclosure.Thedecisiontouse
pharmacologicalversussurgicaltreatmentorbothshouldbebasedongivingcarefulconsiderationtotheabove
factors,individualinfant,evidencebasedresearch,experienceofsurgicalandnursingteam,andclinician'sown
experience.Thedataonthesuccessoftherapyanditsimpactontheoverallmortalityvarydependingonvarious
prenatal,natal,andpostnatalfactorsincludingtheexperienceofthesurgicalandmedicalstaff,timeandmodeof
medicaltreatment,andthetypeofmedicaltherapy.Untilfurtherinformationisavailable,incasesof
pharmacologicaltreatmentfailureorrecurrence,theoptimalmanagementremainssurgicalclosure.Morestudiesare
neededregardingthesafetyandeffectivenessofibuprofeninextremelyprematureinfants.
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