www.jped.com.br
REVIEW
ARTICLE
Reviewing
the
use
of
corticosteroids
in
bronchopulmonary
dysplasia
夽
,
夽夽
Fernanda
Aparecida
de
Oliveira
Peixoto
a,b,∗,
Paulo
Sérgio
Sucasas
Costa
aaDepartmentofPediatrics,FaculdadedeMedicina,UniversidadeFederaldeGoiás(UFG),Goiânia,GO,Brazil bNeonatalIntensiveCareUnit(NICU),HospitaldasClínicas,UniversidadeFederaldeGoiás(UFG),Goiânia,GO,Brazil
Received20July2015;accepted30July2015 Availableonline20December2015
KEYWORDS Bronchopulmonary dysplasia;
Corticosteroids; Treatment
Abstract
Objective: Reviewtherisksandbenefitsofpostnatalcorticosteroiduseforthetreatmentof
bronchopulmonarydysplasia,consideringthatthereisnotamoreeffectivetherapy.
Datasources: TheliteraturereviewwascarriedoutintheBIREMEdatabase,usingtheterms
‘‘bronchopulmonarydysplasia andcorticosteroid’’inthe LILACS,IBECS,MEDLINE, Cochrane Library,andSciELOdatabases,selectingthemostrelevantarticlesonthesubject,withemphasis onrecentliteraturepublishedinthelastfiveyears.
Summaryofthedata: Inpreterminfants,bronchopulmonarydysplasiaisstillacommon
prob-lemandremainswithoutaspecifictherapy,despiteknowledgeoftheseveralriskfactors.The treatmentessentiallyconsists ofsupportivemeasures,but inthepast,corticosteroidswere widelyused, astheyarethe onlymedicationsthathaveanimpact ondisease progression. However,theemergenceofcerebralpalsyassociatedwiththeindiscriminateuseof cortico-steroidshaspreventedtheprescription ofthisdrug inthelast15years.Sincethen,nonew measureshavebeentaken,andtheincidenceofthedisease tendedtoincreaseduringthis period, creatingthe needfor a review ofcorticosteroid useand, possibly,more restricted indications.
Conclusions: Theassociationbetweenrisksandbenefitsofcorticosteroiduseinpreterminfants
needstobeconsideredduetothefactthatsomeinfantsubpopulationsmayshowmorebenefits thanrisks,suchasthoseusingmechanicalventilationwithdifficultweaning.
©2015SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Allrightsreserved.
夽 Pleasecitethisarticleas:deOliveiraPeixotoFA,CostaPS.Reviewingtheuseofcorticosteroidsinbronchopulmonarydysplasia.JPediatr (RioJ).2016;92:122---8.
夽夽
StudycarriedoutattheDepartmentofPediatrics,UniversidadeFederaldeGoiás(UFG),Goiânia,GO,Brazil. ∗Correspondingauthor.
E-mail:fernandapeixoto20@gmail.com(F.A.deOliveiraPeixoto).
http://dx.doi.org/10.1016/j.jped.2015.07.007
PALAVRAS-CHAVE Displasia
broncopulmonar; Corticoide; Tratamento
Revendoousodoscorticosteroidesemdisplasiabroncopulmonar
Resumo
Objetivo: Oobjetivodesseestudoérevisarosriscosebenefíciosdousodocorticoidepós-natal
paraotratamentodadisplasiabroncopulmonar,umavezqueaindanãoháoutraterapiamais eficaz.
Fontesdedados: ArevisãodaliteraturafoirealizadapelobancodedadosdaBIREME,utilizando
ostermosbronchopulmonarydysplasiaandcorticosteroidnossistemasLILACS,IBECS,MEDLINE, BibliotecaCochrane,SciELO,sendoselecionadososartigosdemaiorrelevânciasobreotema, comênfasenaliteraturadosúltimoscincoanos.
Síntesedosdados: Emrecém-nascidosprematuros,abroncodisplasiaaindaéumproblema
fre-quenteesemterapêuticaespecífica,apesardoconhecimentodosváriosfatores derisco. O tratamento, basicamente, éfeito pormedidas desuporte,mas ocorticoide nopassadofoi largamenteutilizadoporsetratardaúnicamedicac¸ãocomimpactonaevoluc¸ãodadoenc¸a. Porém, o aparecimento de paralisiacerebralassociada ao uso indiscriminadodo corticoide inviabilizouaprescric¸ãodadroganosúltimos15anos.Desdeentão,nenhumanovamedidafoi tomadaeaincidênciadadoenc¸atendeuaumaumentonesteperíodo,criandoanecessidade darevisãodousodocorticoideedepossíveisindicac¸õesmaisrestritas.
Conclusões: Arelac¸ãodoriscoebenefíciodoscorticoidesutilizadosemrecém-nascidos
pre-maturosprecisaserponderadadiantedealgumassubpopulac¸õesdebebêsquepodemtermais benefíciosqueriscos,comonaquelesemventilac¸ãomecânicaecomdesmamedifícil. ©2015SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Todososdireitos reservados.
Introduction
Despite perinatal care improvement and greater survival of increasingly young infants, bronchopulmonary dyspla-sia (BPD) is still a common complication and one of the most prevalent and important sequelae of prematurity. Between2008and2013,therecordsoftheRedeBrasileira de Pesquisas Neonatais (Brazilian Network of Neonatal Research) showed that, despite the improved survival of extremely preterm infants, the incidence of BPD ranged from14.7%to14.0%,remainingvirtuallyunaltered.1
Better prenatal conditions, early surfactant replace-ment, oxygen supplementation, mechanical ventilation, better invasive and non-invasive monitoring, total par-enteral nutrition, and extracorporeal membrane oxygen-ationareexamplesofneonatologyadvancesinthelastfour decades,butunfortunatelylittlehaschangedregardingBPD preventionortreatment.2
BPDpredisposestoincreasedhospitallengthofstayand increases neonatalmortality. During childhood,dysplastic infantshaveworseneurodevelopmentandprolonged hospi-talizations,in additiontothe possibilitytohaveimpaired lung function throughout life.3 Furthermore, the disease
representsamajorburdenonthefamilystructureofthese children,inadditiontothenegativeimpactonpublichealth resources.
The wait for new therapeutic measures has not been a promising one, which forces researchers to try to bet-ter understand the risk factors and preventive measures for BPD. Once disease onset has occurred, the treat-ment is mostly restricted to support measures, because the proposed therapies in recent years have not altered disease evolution. Among these therapies, corticosteroid
administrationisthemostcontroversial;itsusestartedto decreaseinthe2000s,whenitwasbelievedthattherisks of using corticosteroids were greater than their benefits. Someauthors,however,attributethisdecreasetotherise inBPDincidence.Thus,giventhelackofnewtherapeutic options,corticosteroidsarecausingcontroversyonceagain, generatingnewinsightsontheirapplication.2,4
Riskfactors
SeveralriskfactorsareinvolvedinthedevelopmentofBPD; however,itisdifficulttodefinewhichoneisthemost impor-tant,astheyinteractindifferentwaysduringthedifferent stagesofpretermnewborndevelopment.Moreover,notall preterm infants develop BPD, as individual responses to lung lesions are modulated by genetics, epigenetics, and by combining different disease protection and resilience factors.4
BPD is essentially the product of tissue inflammatory responsecausedbyitsownrepair.Asthelungisconstantly developing,notonlyinthefetus,butalsointhenewborn, understandingthepotentiallesionsthatcan occurgreatly dependsonthematurationphasethelesion.Fromalveolar septal fibrosis found in classic bronchopulmonary dyspla-sia,observedinlaterpreterminfants, totheinhibition of pulmonary alveolus formation found in ‘‘new dysplasia,’’ observedinpreterminfantsyoungerthan32weeks,there isalargespectrumofthesamedisease.3---5
Malegender, lower gestationalageat birth, aswell as barotrauma and excessiveoxygen supplementation in the deliveryroomareearly riskfactors.7,8Mechanical
ventila-tion, hyperoxia, and neonatal infections are factors that triggeran inflammatoryprocess,whichin thepresenceof animmaturelungrepresentthemainpillarsofthedisease physiopathology. In a review article, Bhandari4 mentions
thatpreterminfantswithlungsatthecanalicular/saccular stageofdevelopmentaremorelikelytodevelop BPDand that the three abovementioned factors (mechanical ven-tilation,sepsis, and hyperoxia) arethe main contributors tothediseasepathogenesis.The authoralsosuggeststhat itismoreimportanttoavoidneonatalsystemicinfections thanmechanical ventilationinlung inflammatoryresponse decrease,thushavingagreaterimpactonthereductionof BPDincidence.
Genetics is an increasinglystudied risk factor andmay interfere in many different ways, interacting with exter-nalaggressionsandthepulmonarymaturationphaseofthe preterm infant. Let it be supposed, for instance, that a specificfetushasasgeneticinheritanceaparticularallele of the gene of the superoxide dismutase (SOD) enzyme, which promotes susceptibilityof the terminal bronchioles tooxygenfreeradicals.However,thissusceptibilityis pro-grammedtooccurfrom24to28weeksofgestation.Ifthis fetusis bornat 32weeksof gestationalage,their predis-position to BPD will be lower, not only due to increased lungmaturity,butalsothelowerinfluenceoftheSODgene at that particular time of fetal development.9 If, onone
hand,the complexity of theseinteractions prevents com-plete understanding the disease physiopathology, on the other,itcreatesthehopeofnewtherapeuticperspectives forthefuture,withseveralresearchlinestobedeveloped. For now, there are still many questions and, despite thebetterunderstandingofBPDpathogenesis,fewanswers have been provided about the effectiveness of new treatments.6,10
Primarypreventionofprematurityisstillthebestmethod topreventBPD,butevenwithadequateprenatalcare,itis notalwayspossibletopreventpretermbirthsandsecondary preventionisthendiscussedasanattempttoprevent,orat leastminimize,thedamagecausedbythedisease.
Prevention
The best time to start preventing BPD is still unclear, as it is not known when disease is triggered in each infant, anditmayevenbetriggered duringthefetalstage.5 The
incomplete knowledge of the disease’s physiopathology, associatedwiththeinteractionsof diverseand uncontrol-lable risk factors, prevent physicians from individualizing theappropriatetherapyforeachpreterminfant.However, basedontheexistingknowledgeofitsphysiopathology,fetal physiology,andtheimpactofearlyterminationofa preg-nancy, some measures have been studied and sometimes appliedinclinicalpractice.2,6,10
Theuseofantenatalcorticosteroidsforpulmonary matu-rationdecreasesneonatalmortality,respiratorydistress syn-dromeof thenewborn (RDS-NB),and peri-intraventricular hemorrhage.Therefore,itisaformalrecommendationfor pregnantwomeninpretermlabor.11Butevenincombination
withpostnatalsurfactant,despitetheabovementioned ben-efits,studyresultsindicatethattherewasnodecreaseinthe incidenceofBPD.6,10
Theassociation of barotrauma or volutraumawithBPD ledtothesearchforbetterwaystoventilatethepreterm infant,with gentlerventilation proposed,withthe use of permissivehypercapniaandguaranteedvolumeasthe ven-tilation mode.Despite theneed for furtherstudies, more physiologicalventilation,withvolumeandlowoxygen con-centrations,without leadingtohypoventilation,shouldbe recommended.8
Thecaffeineusedtotreatapneaofprematurityhasalso showntodecreasetheriskofBPD,althoughtheaction mech-anism is yet to be clarified.10 Köro˘glu et al.12 evaluated
theeffectofcaffeineinpretermrats,using lipopolysaccha-rideasproinflammatoryagent,andobservedthattherewas an improvement in lung function,suggesting aprotective effectthroughananti-inflammatorymechanism.Moreover, theuseofcaffeinehasbeenshowntoincreasetheresponse ofcarbondioxidechemoreceptors,improverespiratory mus-cleperformance,andincrease thecentralnervoussystem excitability.6,10
VitaminAhasseveralcellfunctions,actingasapotent antioxidantagent.Inadditiontotheinabilitytometabolize andeliminatefreeradicals,preterminfantsalsohave vita-minAdeficiency.6Whenthevitaminissupplemented,upto
thenormalizationofserumlevels,itispossibletoobserve thedecreaseinoxygendependenceat36weekscorrected age.However,inthelongterm,therewasnodifferencein thefinaloutcomebetweeninfantswhoreceivedhighdoses ofvitaminAandthosewhodidnot.13Althoughencouraging,
vitaminAsupplementationisalsohamperedbythelimited availabilityofthemedicationoutsidelargecenters.
Oxidativestressofinjuredcellsreleasesfreeradicals.As freeradicalsaredirectlyinvolvedinBPDprogression, pro-phylactic supplementation withantioxidant enzymes may bepromising.Ofalltheantiradicaltreatments,theuseof superoxide dismutase appears to be the most effective.7
Davis14 studied the intra-tracheal use of superoxide
dis-mutaseanddemonstratedtheminimizationoftheharmful effectsof mechanicalventilationandoxygenuse, withno associatedtoxiceffects.McEvoyetal.3mentiontwoother
antioxidants:glutathioneprecursorsandcimetidine,butto date,thestudieshaveshowndisappointingoutcomes.
Inhaled nitric oxide improves oxygenation and ventila-tion in different situations, such as meconium aspiration syndrome,sepsis, andpulmonary hypertension,aswellas showing anti-inflammatory properties. According to these findings, studies have been carried out toinvestigate the potential benefits of nitric oxide in reducing BPD risk or severity. However, evidence does not support the role of nitric oxide in preventing the disease, although it is not yetclearwhetherthereisanyspecificsubgroupofpreterm infantsthatcouldbenefitfromthistreatment.6
whencomparedtospontaneousclosure.Surgical interven-tion also showed no effect in preventing BPD, whereas better results were obtained when there was no inter-vention, neither pharmacological nor surgical therapy.8
Nevertheless, these results are controversial and some-times discordant. In Brazil,Sadeck etal.15 evaluated494
preterm infants with birth weight <1000g and 33 weeks of gestational age, and concluded that both pharmaco-logical andsurgicaltreatmentsdecreasedthe mortalityin very-lowbirthweightpreterminfants.However,a statisti-callysignificantdifferencewasdemonstratedregardingBPD incidence,demonstratingbenefits intheconservative and pharmacologicaltreatmentgroupsinrelation tothe surgi-caltreatmentgroup,reinforcingtheneedtoperformmore randomizedcontrolledtrialstounderstandPDAinpreterm infants.
Neonatalsepsis hasacloseassociationwithBPDandis consideredan independentriskfactor,aswellas mechan-ical ventilation and oxygenation. Lahra et al.16 reported
an increase in BPD in a cohort of 798 preterm infants withgestational age <30weeks when, in thepresence of chorioamnionitis, the infant showed associated neonatal sepsis.Differentlyfromthisresult,preterminfantswhodid notdevelop neonatalsepsis, evenwhen undergoing treat-ment for chorioamnionitis,hada lowerincidence ofBPD. Althoughthedirectroleofinfectioninthedevelopmentof BPD is not completely understood, the evidence suggests that systemicinflammation, associated withvascular per-meabilityalterations,isamajorcauseofcellinjuryandthe consequent alveolarization process interruption.5,7 Some
animalstudies suggestthatpreventingneonatalinfection, localized or systemic (sepsis), is even more important in reducingtheinflammatoryresponseofthelungsthan inva-sivemechanicalventilation.Inotherwords,itisspeculated thattheremightbeanevengreaterimpactinreducingBPD rates throughneonatalinfectioncontrol, eveninpatients undergoinginvasivemechanicalventilation.4
Althoughsometherapiesmaybesuggestedbasedonthe knowledgeof BPDpredictors,ithasnotbeen sufficientto changethediseaseincidenceovertheyears.Giventhis sce-nario,stillan unclear one,corticosteroids areonce again beingdiscussed.
Onceagain,thecorticosteroid
Historically, the treatment of BPD has always been the mainindicationforcorticosteroiduseinneonatology,even thoughotherindications,suchasrefractoryshockand post-extubationlaryngitis,arebecomingfrequent.
Since it was established that inflammation is a determinant for BPD, corticosteroids, for their potent anti-inflammatory action, have been widely studied as a therapeuticorprophylactictool.Thesystemicuseof corti-costeroidsnotonlyreducesinflammationbutalsoincreases surfactant production, accelerates lung cell differentia-tion,reducesvascularpermeability,andincreaseslungfluid resorption.These actions resultin increasedlung compli-ance and tidal volume, improving ventilatory function.6,8
Regardless of the mechanism, corticosteroids have posi-tiveresultsinthetreatment ofpreterminfants withBPD. The knowledge of these effects led to its abusive use,
especiallyinthelate1990s,whentherewasatendencyfor itsincreasinglyearlyuse,eveninlessseverecases.17
The postnatal effectiveness of dexamethasone in the treatment of mechanical ventilation-dependent BPD was firstdemonstrated in 1983 by Mammel etal.18 Over time
andduetothepromisingresults,theuseofpostnatal high-dosecorticosteroids for extendedperiods oftimebecame routine,particularlyin extremely preterm infants, tothe pointof havingaformalindicationfor BPD prevention.In Canada,between January1996 and October 1997,25% of very-lowbirthweightinfantsstartedreceivingsystemic cor-ticosteroidsinthe firstweek oflife. IntheUnitedStates, thisratewas19%between1995and1996.19
If in the short term, the early use of corticosteroids demonstrated decreased dependence onmechanical ven-tilationand oxygen as immediatebenefits, in addition to thereducedincidenceof BPD,itwouldbeexpectedthat, inthelongterm,therewouldalsobeareductionin neuro-logicalsequelaeassociatedwithBPD.However,aftermore thanadecadeofwidespreaduseofpostnatalsystemic cor-ticosteroids,differently fromwhatwas expected,clinical trialsstarted todemonstrate a significant increase in the incidenceofcerebralpalsy.18
Gradually, the adverse effects of treatment with corticosteroids were established: hyperglycemia, sys-temic hypertension, hypertrophic cardiomyopathy, diges-tivebleeding, gastrointestinal perforation, hypothalamic---pituitary---adrenal axis suppression, failure to thrive, deceleratingheadcircumferencegrowthrate, neurodevel-opmentaldelays,andlungstructurealterations.2
In 2010, Halliday et al. analyzed 28 clinical trials that compared the early use of postnatal systemic cor-ticosteroids in 3740 participants. They found that the groupreceivingdexamethasoneshowedearlierextubation, decreased mortality,and reducedincidence of pulmonary disease, when evaluated at both 28 days of life and at 36 weeks corrected age. There was no difference betweentreatmentand controlgroupsregarding neonatal infection, severe peri-intraventricular hemorrhage, peri-intraventricular leukomalacia, necrotizing enterocolitis, and pulmonary hemorrhage. However, there was a pro-hibitiveincrease ofcerebral palsy casesin the treatment group (RR:1.45, 95% CI: 1.06---1.98).20 Nevertheless, it is
noteworthythatthesereportedadverseeffects arebased onstudieswith high-dosedexamethasone administeredin thefirstdaysoflifeandmaintainedforextendedperiods.
After2002,theuseofcorticosteroids wasformally dis-couragedby the AmericanAcademy of Pediatrics andthe CanadianPediatricSociety (CommitteeonFetusand New-born, 2002), although some authors have pondered that a prudent assessment of the available data should have beenconductedbeforetheformaldrugcontraindication.21
Nonetheless,whathappenedwasexactlytheopposite,and therewas a sudden interruption of all studies related to the use of postnatal corticosteroids. The fact is that, at that time, no distinction was made between treatments withearlyandindiscriminateuseofcorticosteroidsandtheir lateruse,withmorespecificindications.17
usebetweensevenand14daysoflifeand;late,fortheuse aftertwoweeksoflife.22,23Theauthorsconfirmedthatearly
administration of corticosteroids, despite the immediate improvementinpatient’sventilation,shouldbeproscribed becauseofitsassociationwiththehighriskofcerebralpalsy. Moderatelyearlyadministrationwasevaluatedinseven randomizedclinical trials with a sample of 669 patients, showing better ventilatory weaning and decreased BPD incidence,similar to that found with early corticosteroid administration. They also reported that adverse effects, suchashypertension,hyperglycemia,gastrointestinal hem-orrhage,hypertrophiccardiomyopathy,neonatalinfection, and mainly, neurodevelopmental alterations, were not observed.22
Themeta-analysisofdexamethasoneuseafterthethird week of life consisted of nine randomized clinical trials, resultinginatotalof562studiedpatients.Thegroupthat usedcorticosteroids hadlowerrates of extubation failure andBPDincidence.Theobservedshort-termadverseevents were:increaseinbloodpressure,urinaryglucoselevels,and slightincrease inretinopathy of prematurityseverity, but noincreaseincasesofblindness.Therewasnodifference betweenthegroupsregardinginfection,enterocolitis,and gastrointestinalbleeding.Inthegroupthatused corticoste-roids,noneurodevelopmentaldelaywasobserved,although therearelimitationsintheusedmethodologyforthe long-termassessmentofthesechildreninsomeoftheseclinical trials.23
Although none of the studies with dexamethasone use aftersevendaysoflifeshowedanincreasedriskofcerebral palsy,theauthorsrecommendcautionintheindicationof corticosteroids,reservingthemforcaseswithgreater diffi-cultyinmechanicalventilationweaning,alsorecommending smallerdosesandtheshortestpossibletimeofuse.20,22,23
Theproblemincreatingaguidelineforclinicalpractice basedoninterpretationsoftheserandomizedclinicaltrials isthattheremaybeoverlappingoftwoconfoundingfactors. Thefirstfactor isthattheeffectsofcorticosteroids, both beneficialandadverse,aswellaswithanyotherdrug,are sensitivetothe dose andtreatment duration.The second factorisrelatedtoprematurity,asthefetusornewbornare atdifferentdevelopmentalstages,whichprobablyresultsin differentsusceptibilitytotheeffectsofcorticosteroids.For instance,giventheknowledgethatpreterminfantsaremore unstable in thefirst daysof life and knowing that severe events,suchasperi-intraventricularhemorrhage,aremore likelytooccur in thefirstweek of life,it is possiblethat theadverse effectsofcorticosteroidsmaybeexacerbated bytheinfant’spostnatalage.Thesetwofactorsmayalsobe potentiatedbyotherriskfactorsforBPD.Inthisscenario, thereturnofcorticosteroidsopensnewdiscussions.17
Astheindiscriminateuseofcorticosteroidsinthe1990s increasedthecases of cerebralpalsy, theirsudden disuse inthe 2000sreflectedinthe increasingincidenceof BPD, especiallyinvery-lowweightpreterminfants.19
BothprematurityandBPD,aswellthecorticosteroiduse, are associated with worsened neurological development, anditislikelythatthenegativeresultsofearlysteroiduse topreventBPDmayvaryaccordingtodiseaseincidencein thecontrolgroup.24,25Thatis,thenegativeimpactofearly
useofcorticosteroidsisinverselyproportionaltoBPD inci-dence.AgroupwithlowincidenceofBPDwouldshowmore
harmthangoodasaresultofearlycorticosteroiduse. How-ever,iftheincidenceofBPDishighinthispopulation,there will bea higher incidence of survivorswithout neurologi-calimpairment.Consideringthishypothesis, in2006Doyle etal.25 re-evaluatedtheeffectof earlyuseof steroids in
preterminfants,basedon20randomizedcontrolledtrials. The authorsalsoassessedtheeffects ofcorticosteroids in the long term (at least up to12 months of chronological age)in 14ofthe20 selectedclinicaltrials.Through anal-ysisbymeta-regression,theauthorscorrelatedtheresults ofclinicaltrialswithsomeofthemostimportantrisk fac-tors forthedevelopmentof BPDandfound analternative explanation for the adverse effects ofearly treatment of corticosteroids inpreterminfants.The explanationis that corticosteroidsdonothaveonlydirectharmfuleffects,but also,bypromptlyimprovingpulmonaryfunction,indirectly improvebraindevelopment.Thus,futurestudiesmustfind thelineofdemarcation,belowwhichtherisksoftreatment withcorticosteroidswouldoverlaptherisksofthedisease.17
In 2014,the authorsextended the meta-analysiswiththe latest six newclinicaltrials andsuggested theuse of risk predictorstoguidethedecisionof usingcorticosteroids in thetreatmentofBPDinmechanical-ventilationdependent preterminfants.25
Duringthe preterm infant’s follow-up, several triggers of the systemic inflammatory response can interact with each other, even with one or more of these factors, potentiating the injuries. Neonatalsepsis associated with chorioamnionitis occurssimultaneously withthe early use ofcorticosteroids,andbothinteractwithbronchopulmonary dysplasia, makingit difficulttorecognizethecontribution ofeachfactorinthedevelopmentofcerebralpalsy. Hent-gesetal.26evaluated94preterminfantswithvery-lowbirth
weightandneonatalsepsisandwereabletoassociatethe infectionwithanincreasedventilatorysupporttime,longer hospital stays,and higherincidence of bronchopulmonary dysplasiaandseizures.
Another consideration is that most of the early stud-ieswerewithpatientsusinghigh-dosedexamethasonewith early treatment onset and prolonged duration. Some of these patients started corticosteroids before72h of life, moreaspreventionthantreatment ofBPD,andcontinued itsuseforupto42daysoflife.17
Titrationoftheidealdosefortheuseofcorticosteroids is also subject to debate. The first clinical trials used a standard dose of0.5mg/kg ofdexamethasone, whichwas reducedslowlyoverseveralweeks.Themostrecentclinical trialusedlowerinitialdosesof0.2,0.15,or0.1mg/kg, in decreasing doses, duringseven to10 days;thetreatment wasterminatediftherewasnotherapeuticresponse.16
Inrecentyears,theroleofothercorticosteroids,rather thandexamethasone, hasbeenquestioned regardingtheir use in BPD prophylaxis or treatment. Because hydrocor-tisone is a natural hormone, its higher degree of safety waspostulatedwhencomparedtodexamethasone. Watter-berg et al.27 evaluatedthe use of hydrocortisonefor the
concluded,therewerenosignificantdifferencesfor mortal-ityandBPD,except inthoseexposedtochorioamnionitis, whichshowedlowermortalityandlowerincidenceofBPD whentreatedwithhydrocortisone.
Finally,thesearchforsteroidswiththesametherapeutic effectandfeweradverseeffectsthandexamethasone con-tinues.Theinhaled route,for instance,seemedpromising due totwo advantages: directdrug action onthe inflam-mation site and rapid action onset, with low doses and lesssystemicabsorption.However,thereisverylittle evi-dence of the efficacyof inhaled corticosteroids tojustify theirroutineuse.28 Aclinicaltrialstartedin2009andstill
inprogress, proposesthestudyof850 infantsbetween 23 and27weekscorrectedage,randomizedwithin12hoflife intotwogroups:inhaledbudesonidevs.placebo.Thisstudy, known as NEUROSIS (Neonatal European Study of Inhaled Steroids), will evaluate survivors without BPD as the pri-maryoutcome, when theyreach36weeks corrected age. Subsequently, the study participants will be followed for theneurologicaloutcomeupto18---22weekscorrectedage. Additionalpharmacodynamicsstudies anda study excerpt toassessgeneticsusceptibilitywillalsobeperformedinthe future.29
In 2008, Yeh et al.30 published a pilot study on the
use of budesonide instilled directly into the trachea and distributed to the lung periphery through the surfactant. Preliminary resultsshowednosignificant differencein the incidenceofBPDormortalitywhenassessedalone.However, aftercombiningthetwooutcomes,deathandBPD,thebest resultswereobservedinthetreatmentgroup.Currently,Yeh etal.arereplicatingthesamestudyatmulticenterlevel.
Conclusion
Giventheabovementionedfacts, itisnowtimetodiscuss preterm subpopulationswith clear indications for theuse ofcorticosteroidsinthetreatmentofBPD.Preterminfants, onmechanicalventilationandshowingdifficultyinweaning, areprobablythestartingpointforfurtherresearch.
IntheneonatalintensivecareunitatHospitaldas Clini-cas,UniversidadeFederaldeGoiás,systemiccorticosteroids areusedinselectedcases.Thecriteriaare:preterminfants onmechanicalventilationformorethantwoweeks, show-ingdifficultyinweaningfrommechanicalventilation,after excluding other causes, such as sepsis, shock, congeni-talmalformations,andcentralnervoussystem depression. The corticosteroid of choice is dexamethasone and treat-mentisinitiatedatadoseof0.20mg/kg/day,dividedinto two daily doses, which are reduced every three days to 0.15mg/kg/dayandfinally,0.10mg/kg/day.Thetreatment is discontinued if the patient does not show any clinical improvementuptothe3rddayofuse.
Thefactisthat,intheabsenceofalternatives,insome mannercorticosteroidswillcontinuetobeusedinthe peri-natalperiod.Itisimportanttounderstandthat,whenusing corticosteroidsforthetreatmentofBPD,physiciansshould notbedeluded bythe immediatebenefitsonly. Andafter selectingthegroupthatfitsinthetreatment, therisksof adverseeffectsofcorticosteroiduseinthelongtermshould not be forgotten,especially thoserelated to neurodevel-opment. While the results of studies and new treatment
proposalsareawaited,prematurityprevention,risk factor identification, and the judicious use of corticosteroids in specificpopulationsaretheonlytoolsavailable.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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