M. de C. Romanelli Bouzada , Gabriela C.F. M. de Oliveira , Wanessa T. Clemente ,Roberta Viviane Rosado , Paulo A.M. Camargos , Lêni M. Anchieta ,Maria in a neonatal population --- systematicreview factors for Risk central venous catheter-relatedinfection

JPediatr(RioJ).2018;94(1):3---14

www.jped.com.br

REVIEW ARTICLE

Risk factors for central venous catheter-related infections in a neonatal population --- systematic review ^夽,夽夽

Viviane Rosado

, Paulo A.M. Camargos

, Lêni M. Anchieta

,

Maria C.F. Bouzada

, Gabriela M. de Oliveira

, Wanessa T. Clemente

, Roberta M. de C. Romanelli

aUniversidadeFederaldeMinasGerais(UFMG),ProgramadePós-graduac¸ãoemSaúdedaCrianc¸aedoAdolescente,Belo Horizonte,MG,Brazil

bUniversidadeFederaldeMinasGerais(UFMG),HospitaldasClínicas,ComissãodeControleeInfecc¸ãoHospitalar,Belo Horizonte,MG,Brazil

cUniversidadeFederaldeMinasGerais(UFMG),FaculdadedeMedicina,DepartamentodePediatria,BeloHorizonte,MG,Brazil

dUniversidadeFederaldeMinasGerais(UFMG),HospitaldasClínicas,UnidadedeCuidadosNeonataisProgressivos,Belo Horizonte,MG,Brazil

eUniversidadeFederaldeMinasGerais(UFMG),FaculdadedeMedicina,BeloHorizonte,MG,Brazil

fUniversidadeFederaldeMinasGerais(UFMG),FaculdadedeMedicina,DepartamentodeAvaliac¸ãoComplementar,Belo Horizonte,MG,Brazil

gUniversidadeFederaldeMinasGerais(UFMG),HospitaldasClínicas,EquipedeDoenc¸asInfecciosasdoTransplantedeÓrgãos, BeloHorizonte,MG,Brazil

Received31August2016;accepted21January2017 Availableonline30August2017

KEYWORDS Catheter-related infections;

Centralvenous catheterization;

Riskfactors

Abstract

Objective: Thiswasasystematicreviewoftheincidencedensityandriskfactorsforcentral venouscatheter-relatedinfectionsinaneonatalpopulation.

Datasource:The MEDLINE, Embase, Cochrane, BDENF, SciELO, and LILACS databases were usedwithoutdateorlanguagerestriction.Studiesthatanalyzedriskfactorsforbloodstream infectionsinnewbornswereidentified.

夽 Pleasecitethisarticleas:RosadoV,CamargosPA,AnchietaLM,BouzadaMC,OliveiraGM,ClementeWT,etal.Riskfactorsforcentral venouscatheter-relatedinfectionsinaneonatalpopulation---systematicreview.JPediatr(RioJ).2018;94:3---14.

夽夽StudycarriedoutatUniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil.

∗Correspondingauthor.

E-mail:vivrosado@gmail.com(V.Rosado).

https://doi.org/10.1016/j.jped.2017.03.012

0021-7557/©2017SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

4 RosadoVetal.

Datasynthesis: Atotal of134articles werefound thatmettheeligibilitycriteria.Ofthese articles, 14 were selected that addressed risk factors for central venous catheter-related infectioninneonates.Catheter-related bloodstreaminfectionsremainanimportantcompli- cation,asshownbytheincidenceratesreportedinthestudiesincludedinthisreview. The observed riskfactors indicatethat lowbirthweight, prematurity, andlongercatheterper- manence arerelated toahigherincidenceofbloodstreaminfections.Ithasbeenobserved that low rates of catheter-related infections, i.e., close to zero, are already a reality in health institutionsindeveloped countries,sincethey useinfectionsurveillanceandcontrol programs.

Conclusion: Catheter-relatedbloodstreaminfectionsstillshowhighincidencedensityratesin developingcountries.Theauthorsemphasizetheneedforfurtherlongitudinalstudiesandthe needforbetterstrategiestopreventriskfactors,aimingatthereductionofcatheter-related infections.

©2017SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/

4.0/).

PALAVRAS-CHAVE Infecc¸ões

relacionadasa cateteres;

Cateterismovenoso central;

Fatoresderisco

Fatoresderiscoparainfecc¸ãoassociadaacateteresvenososcentraisempopulac¸ão neonatal--- revisãosistemática

Resumo

Objetivo: Trata-sedeumarevisãosistemáticasobreadensidadedeincidênciaedefatoresde riscoparainfecc¸ãoassociadaacatetervenosocentralempopulac¸ãoneonatal.

Fontesdosdados: Utilizou-seosbancosdedadosMedline,Embase,Cochrane,Bdenf,Scielo, Lilacs,semrestric¸ãodedataoudeidioma.Identificaram-seosestudosqueanalisaramfatores deriscoparainfecc¸ãodacorrentesanguíneaemrecém-nascidos.

Síntesedosdados: Foram encontrados 134 artigos conforme os critérios de elegibilidade.

Destesartigos,foramselecionados14queabordaramfatoresderiscoparainfecc¸ãoassociada acatetervenosocentralemneonatos.Ainfecc¸ãodacorrentesanguíneaassociadaacateter continuaamostrar-secomoumaimportantecomplicac¸ão,conformedemonstramastaxasde incidênciarelatadasnosestudosincluídosnestarevisão.Osfatoresderiscoobservadosapon- tamquebaixopesoaonascer,prematuridadeemaiortempodepermanênciadocateterestão relacionadosàmaiorincidênciadeinfecc¸ãodacorrentesanguínea.Observou-sequetaxasde infecc¸ão associadaacateter em valoresbaixos, próximos azero, já sãoumarealidade em instituic¸õesdesaúdedepaísesdesenvolvidos,umavezqueutilizamprogramasdevigilânciae controledeinfecc¸ão.

Conclusão: Ainfecc¸ãodacorrentesanguíneaassociadaacateteraindaapresentaaltastaxasde densidadedeincidênciaempaísesemdesenvolvimento.Destaca-seanecessidadederealizac¸ão demaisestudoslongitudinaiseanecessidadedemelhoresestratégiasdeprevenc¸ãodosfatores deriscoparaareduc¸ãodeinfecc¸ãoassociadaacateter.

©2017SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Este ´eumartigo OpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.

0/).

Introduction

Care procedures for the neonate in intensive care units requiretheuseofadvancedtechnology;thecentralvenous catheter(CVC)isoneofthemostcommonamongtheinva- siveproceduresusedinthesepatients.^1---3Dependingonthe material and caliber, it can be inserted at the bedside, suchasthe peripherally inserted central catheter(PICC), and remain for a prolonged period to allow the adminis- trationofsolutionsandmedications,sample collectionfor examinations,bloodproducttransfusion,andmonitoringof hemodynamics.^3,4 Among the complications related to its use, infections show the highest frequency and the most potentialformorbidityandmortality.⁵

Newborns,especially preterm,are at increasedrisk of infectionand areconsidered immunocompromised due to

their immunesystem immaturity.⁶ Theirimmune response is characterized by a decrease in neutrophil---endothelial adhesion, lowlevelsof complementfactors, andimmatu- rityregardingthedifferentsubpopulationsoflymphocytes andmononuclearphagocyticsystemcells.^6,7

The use of invasive devices implies the impairment of the natural physical barrier consisting of the skin, which allows bloodstream invasion by opportunistic microorgan- isms.Whenbacteremiaprogressesintoseveresepsis,itcan lead tohemodynamic changes,and evendeath.⁸ The risk factorsforearlysepsis,definedasthosethatoccurwithin thefirst48h oflife,arerelatedtothe underlyingdisease andtothequalityofthecareprovided.Regardinglatesep- sis,whichoccursafterthefirst48hoflife,itisrelatedto theindirectcontactwiththecontaminatedhospitalenviron- ment,withlowbirthweight,theuseofinvasivedevicessuch

Centralcatheter-relatedinfectionsinneonates 5 asCVC and mechanical ventilation (MV), delayed start of

enteralnutrition,prolongeduseofparenteralnutrition,and complicationsofprematurity,suchaspatentductusarterio- susandnecrotizingenterocolitis,whichmayrequiresurgical intervention.^9,10

According to theNational HealthSurveillance Network (NHSN),¹¹ the rates of central venous catheter-associated bloodstream infections (CVC BSI) were between 0.6/1000 CVC-day and 2.5/1000 CVC-day. Other studies reported a widevariationininfectionrates,rangingfrom2to49/1000 CVC-day.Newbornsweighing<1000ghaveahighermortality risk,withattributablemortalityof4---20%.¹²

InBrazil,CVC-relatedsepsisrepresentsaserioushealth problemfortheneonatalpopulation.TheBrazilianNational HealthSurveillanceAgency(AgênciaNacionaldeVigilância Sanitária[ANVISA])Bulletinreportstheincidencedensityof primarybloodstreaminfectioninpatientssubmittedtocen- tralvenouscatheteruseinBrazilianneonatalintensivecare unitsasranging from7.6to8.9/1000CVC-day.¹³ The rate ofneonatal mortalityduetosepsisis ashighas68%,¹⁴ so surveillancemeasuresarerequiredtodirectactionsaimed at reducing the rates of healthcare-associated infections (HAIs),sincetheycanprovidedatathatallowcomparisons andevaluationoftheimpactofthecontrolmeasure,inaddi- tiontoallowingcomparisonswithotherhealthcareservices withthesamecharacteristics.^8,9

A study of adverse events associated with the use of central venous catheters in a neonatal unit in the state ofRioGrandedoSul,Brazil,observedahigherprevalence of mechanical obstruction in centralperipherally-inserted central catheters (PICC) and a higher prevalence of catheter-associatedinfection(CAI)inthesurgically-inserted catheters, with clinical sepsis being the most frequent (16%).¹⁵Moreover,studiesindicatethatthemicro-organisms mostoftenassociatedwithsepsisaregram-positive,mainly coagulase-negativeStaphylococcus.^14,16---19Despitetheneed touseCVCforthetreatmentofnewbornsadmittedatthe neonatalintensive care unit (NICU),its timely removalis usuallyassociatedwithalowerincidenceofinfection.^20,21 Therehavebeenfew studiesinBrazilonpatients’clinical evolutionaftercatheterremoval.²²

Itisknownthatindevelopedcountries,evidence-based strategiesare usedbythe teamsresponsible for neonatal catheter-related infection prevention programs.²³ In con- trast,indevelopingcountriessuchasBrazil,inadditionto theneedtoestablishsuchstrategies,systematicepidemi- ologicalsurveillanceisperformedinfewhealthservices.¹⁸ There are structural shortcomings,such as overcrowding, lack of or shortage of multiprofessional staff, lack of or misuseofsuppliesandequipment,andexcessiveantibiotic use.²⁴ Forthesereasons,moreevidence-basedstudiesare neededtoevaluatetherisksrelatedtoCVCuse.²⁵

The aim of this article is to carry out a systematic reviewoftheriskfactorsforCVC-associatedinfectioninthe neonatalpopulation,consideringnationalandinternational references.

Methods

The search for thearticles wascarriedout in thefollow- ingdatabases:MEDLINE,Embase,Cochrane,BDENF,SciELO,

andLILACS,inadditiontosearchingforthereferencesmen- tioned in the studies that were identified, as well as by searchingthegrayliterature,according tothedescriptors andeligibility criteria. Formalsearch was not considered onlyif therewas noaccessto any ofthe databases. The searchperiodstartedinJanuary2010andendedinDecem- ber2016,withnodateorlanguagerestrictions.

Thefollowingdescriptorswereused:‘‘crossinfection,’’

‘‘catheter-related infections,’’ ‘‘catheterization, central venous,’’‘‘riskfactors,’’‘‘newborn,’’‘‘infant,’’according tothefollowingstrategy:

PubMed: ((((‘‘Cross Infection’’[Title/Abstract] OR

‘‘Infeccion Hospitalaria’’[Title/Abstract] OR ‘‘Infeccao Hospitalar’’[Title/Abstract] OR ‘‘Cross Infection’’[Title/

Abstract] OR ‘‘Infeccion Hospitalaria’’[Title/Abstract]

OR ‘‘Infeccao Hospitalar’’[Title/Abstract] OR ‘‘Catheter- Related Infections’’[Title/Abstract] OR ‘‘Infecciones RelacionadasconCateteres’’[Title/Abstract]OR‘‘Infeccoes Relacionadas a Cateter’’[Title/Abstract])) OR ((‘‘Cross Infection’’[Mesh:noexp])OR‘‘Catheter-RelatedInfections’’

[Mesh:noexp])))AND(((‘‘Catheterization,CentralVenous’’

[Title/Abstract] OR ‘‘Cateterismo Venoso Central’’

[Title/Abstract] OR ‘‘Cateterismo Venoso Central’’[Title/

Abstract] OR ‘‘Central Venous Catheters’’[Title/Abstract]

OR ‘‘Cateteres Venosos Centrales’’[Title/Abstract] OR

‘‘Cateteres Venosos Centrais’’[Title/Abstract])) OR ((‘‘Catheterization, Central Venous’’[Mesh:noexp]) OR

‘‘CentralVenousCatheters’’[Mesh:noexp]))

BVS: (w:(tw:(((‘‘Cross Infection’’OR ‘‘InfecciónHospi- talaria’’ OR ‘‘Infecc¸ão Hospitalar’’ OR ‘‘Cross Infection’’

OR ‘‘Infección Hospitalaria’’ OR ‘‘Infecc¸ão Hospitalar’’

OR ‘‘Catheter-Related Infections’’ OR ‘‘Infecciones Rela- cionadas con Catéteres’’ OR ‘‘Infecc¸ões Relacionadas a Cateter’’) AND (‘‘Catheterization, Central Venous’’ OR

‘‘Cateterismo Venoso Central’’ OR ‘‘Cateterismo Venoso Central’’ OR ‘‘Central Venous Catheters’’ OR ‘‘Catéteres Venosos Centrales’’ OR ‘‘Cateteres Venosos Centrais’’)) AND (‘‘Risk Factors’’ OR ‘‘Factores de Riesgo’’ OR

‘‘Fatores de Risco’’)) AND (instance:‘‘regional’’) AND (limit:(‘‘newborn’’OR ‘‘infant’’) AND la:(‘‘en’’ OR ‘‘es’’

OR ‘‘pt’’) AND year cluster:(‘‘2013’’ OR ‘‘2011’’ OR

‘‘2012’’ OR ‘‘2014’’ OR ‘‘2010’’ OR ‘‘2015’’))) AND (ins- tance:‘‘regional’’)

Thearticlesincludedinthereviewwereassessedbytwo independentexaminersandmetthefollowingcriteria:(A) tohave beenpublishedbyDecember2016 inanynational orinternational journal andother specializedmedicallit- erature;(B)beingavailableinanylanguage;(C)addressing risk factors associated with bloodstream infections, com- paringgroupsofnewbornswithandwithoutcentralvenous catheter;(D)beinganoriginalstudywithacase---controlor cohortdesign.

To select the publications, the title and the abstract were initially evaluated, to confirm whether they con- templated the research question and if they met the previously established inclusion criteria. Subsequently, the evaluation of Methods, Results, and Discussion was performed.

The research question was defined as: ‘‘In neonates admittedtotheNICU,whataretheriskfactorsidentifiedfor theoccurrenceoftheoutcome laboratory-confirmedCVC- associatedbloodstreaminfection?

6 RosadoVetal.

Table1 QualitativeevaluationofstudiesaccordingtotheGRADEsystem.

ID Author Methodological

limitations

Inconsistency Indirect evidence

Inaccuracy Publicationbias Consequence

E1 Hruszkewyczetal. Moderate Elevated Low Elevated Low +1

E2 SenguptaAetal. Moderate Low Low Low Low −2

E3 Jen-FuHsuetal. Moderate Moderate Low Moderate Low −1

E4 OhkiYetal. Moderate Low Low Low Low −2

E5 MilstoneAMetal. Moderate Low Low Low Low −2

E6 GreenbergRGetal. Moderate Moderate Low Moderate Low −1

E7 YumaniDFetal. Moderate Low Low Low Low −2

E8 DuarteEDetal. Moderate Low Low Low Moderate −1

E9 BarbosaMHetal. Moderate Elevated Low Elevated Moderate +1

E10 ShalabiMetal. Moderate Moderate Low Moderate Low −1

E11 Bellemin,Ketal. Moderate Low Low Low Low −2

E12 CostaPetal. Moderate Low Low Low Moderate −1

E13 GeffersCetal. Moderate Low Low Low Low −2

E14 Padulaetal. Moderate Moderate Low Moderate Low −1

GRADE,GradingofRecommendation,Assessment,Development,andEvaluation.

The PICOS^26,27 strategy wasused,which comprisedthe following:

- Population:newbornsadmittedtotheNICU - Intervention(orexposure):riskfactors

- Comparison(definedasastandardintervention,themost oftenusedintervention,ornointervention):noriskfac- tors

- Outcome:CVC-associatedbloodstreaminfection - Studytype:cohortandcase---controlstudies.

As exclusion criteria, studies not assessing neonates, thosethatdidnothaveaCVC-BSIoutcome,andthosethat didnotaddressriskfactorsforCVC-BSIwereexcluded.

Fordataextraction,thesearchandanalysis-in-fullofthe pre-selectedarticleswerecarriedoutbytwoindependent researchers. Data analysis was performed by qualitative evaluationofthestudies.Themethodusedforstudyeval- uationwas‘‘StrengtheningtheReportingofObservational Studies in Epidemiology’’ (STROBE) and the strength of evidence of the findings was evaluated according to the

‘‘Gradingof Recommendation, Assessment, Development, andEvaluation’’(GRADE)system,²⁸asshowninTable1.

Results

Atotalnumberof250articleswereidentifiedinthePubMed database,ofwhich77mettheinclusioncriteria.Thesearch in the Virtual Health Library database totaled 70 refer- ences;however,67ofthosethatmettheinclusioncriteria werethesamefound inthePubMeddatabase.Forty-three articleswere found in the Embasedatabase, of which 25 wereselected.Another14articleswerefoundinreferences citedin articleslocatedintheabovementioned databases or throughanInternet search,using thesame descriptors andthesameeligibilitycriteria.

Atotalof134articlesmettheeligibilitycriteria.Among those,thosethataddressedriskfactorsforthepre-defined outcome were selected, i.e., CVC-associated infection in

14 other sources (3.71%) 70 BVS

(18.56%)

43 Embase(11.4

0%) 250 PubMed

(66.31%)

377 articles

67 duplicates removed 134 articles identified

According to the inclusion criteria, according to the title,and the abstract, we

selected:

47 PubMed;

Three BVS;

25 Embase;

Nine other sources

70 articles excluded because:

did not assess neonates did not deal with CVC-BSI did not address risk factors for CVC- BSI

- - -

14 articles reviewed according to the selection criteria

Figure1 Flowchartofthebibliographicsearchofstudieson riskfactorsforinfectioninpatientswithCVC.

newborns;therefore,14articleswereincluded inthissys- tematicreview,asshowninFig.1flowchart.

Ofthese,11representedstudiescarriedoutinEurope, NorthAmerica, and Asia, whereasthreewere fromSouth America; no articles were found that were carried out in other Latin American countries. Table 2 shows the

Centralcatheter-relatedinfectionsinneonates 7 identification of the studies, their design, included popu-

lation,analyzedoutcomes,andresults.

The firststudy(S1) wascarriedoutina universityhos- pital,aiming toevaluatethe incidenceandcomplications associated with CVCs inserted in NICU infants. In their results, only 13 (4.9%) of 263 newborns had infection, five of which were central-venous catheter-associated bloodstreaminfections(CVC-BSI).TheriskfactorsforCVC- BSI were gestational age (p=0.04) and low birth weight (p=0.02).Theinfectionratewascalculatedwithadenomi- natorof100patients-day,differentfromthatrecommended by theNational Healthcare Safety Network (NHSN) of the Centersfor DiseaseControl (CDC),which is1000CVC-day.

As 29% of the inserted CVCs were associatedwith sepsis, thestudydemonstratesthatcatheteruserequiresextreme caution and preparation by the care team to reduce the infectionrisk.²⁹

TheincreaseinthedailyriskofCVC-BSIafter35daysof PICCinsertioninanNICUwasrecordedintheretrospective cohortstudyS2.Itusedastatisticalmodelthatallowedthe evaluationofpotentialchangesintheriskfactorforCVC-BSI overtime.Theinfectionrate(2/1000 CVC-day)wasbased onNHSNcriteria,andthesampleof683newbornsisoneof thelargestfoundtoevaluatethedurationofPICC inNICU neonates.³⁰

Another retrospective cohort (S3) with 275 newborns showed that CVC-BSI wasthe most common complication associated with catheter (incidence: 8.3/1000 CVC-day).

Femoral access for catheter insertion (increased risk of CVC-BSI compared to non-femoral catheters: 1.76, 95%

CI, 1.01---3.07, p=0.045) and a longer duration of PICC (p<0.001)werefoundtoberiskfactors.³¹

TheS4multicenterstudy,carriedoutinJapan,foundthat timeofPICC usewasarisk factor forcatheter-associated BSI(OR1.35,95%CI:1.14---1.60,p=0.005).Thestudyshows an incidence of catheter-associated BSIof 1.6/1000 CVC- day, with most PICCs remaining for a maximum of two weeks.Infection rates werecompared whenthe catheter wasinserted usingthe maximal barrier precaution(MBP), standardprecautions,ornospecificprecaution,butnosta- tistically significant differences were found.³² However, a retrospective USA multicenter study (S5), witha six-year evaluationperiodandasampleof3967neonates,whichfol- lowed thediagnostic criteriarecommended by theNHSN, observedthat thepermanence ofPICC formore thantwo weeksresultedinahigherriskforinfectionthanthosewith lessthantwoweeksofpermanence(p<0.0005).³³

Another multicenter retrospective study (S6), with 13,327 infants from 141 NICUs, reported an incidence of CVC-BSI of 0.93 per 1000 CVC-day. The mean gestational agewas29weeks(interquartilerange:26---33).Thelonger duration of PICC was not associated with an increased risk of CVC-BSI. For long-term catheters, the incidence of infection was significantly higher at weeks seven and nine when compared to the first week after catheter insertion.³⁴

The S7 study, carried out in a university hospital in theNetherlands, useda sampleof196 neonatestodeter- minethe incidence and potential risk factors for CVC-BSI in newborns. There were 18.1 infections/1000 CVC-day (95% CI: 13.7---23.8) according to the diagnostic criteria used by the CDC before 2008. Umbilical catheters had a

higherinfectionrate thannon-umbilical centralcatheters (rate ratio of 2.4, 95% CI: 1.2---4.9) and if left for more thanfivedays,anincrease ininfectionratewasobserved (p<0.05).³⁵

In Brazil, the S8 study recruited a sample of 233 neonatesandobserved,aftermultivariateadjustment,the followingfactorsassociatedwithCVCremovalduetosus- pected infection: weight less than 2500g at the time of catheterinsertion,catheterrepair,andpermanence.³⁶ The S11study,aretrospective cohortwith18neonates, found low birth weight, prematurity, and parenteral nutrition as factors that may have influenced the occurrence of infection.³⁷

Study S10 shows a comparisonof the CVC-BSI rates in preterminfantsbornwithlessthan30weeksgestationwho had a PICC inserted vs. umbilical venous catheter imme- diatelyafter birth as primary venous access.Infants who receivedaPICConthefirstdayafterbirthwerecombined withtwoadditionalgroups ofinfants (thosewhoreceived anumbilical catheterondayone,and thosewhohadthis catheterandswitchedtoaPICCafterfourdaysormore).No significantdifferencewasverifiedintheinfantswithCVC- BSI/1000CVC-dayamongtheassessedgroups,despitelower ratesoflatesepsisinthegroupofinfantswhoreceivedonly anumbilicalcatheter.³⁸

StudyS11evaluatedtheincidencedensity andrisk fac- torsforCVC-BSI.Theincidencedensitywas16/1000CVC-day (95%CI:14.0---18.2):6.5(95%CI:4.3---9.3)forumbilicalCVC and20.2%(95%CI:17.5---23.1)forother CVCs.Themedian time to CVC-BSI was eight days. After multivariate anal- ysis, birth weight≤750g (HR 6.3, 95% CI: 1.0---38.1) and intravenouslipidemulsion(HR2.3,95% CI:1.3---3.9)were significantlyassociatedwithCVC-BSIforumbilicalCVC.Sim- ilarresultswereobservedforotherCVCs.³⁹

IntheS12study,themultivariateanalysisdisclosedthat corrected gestational age (RR 1.12, 95% CI: 1.061---1.186, p<0.002), transient metabolic disorder (RR 3.02, 95% CI 1.72---5.05,p<0.000), apnea (RR2.38, 95% CI:1.10---4.56, p<0.016), and two-way and polyurethane catheters (RR 3.70, 95% CI: 2.0---6.9, p<0.0000) were risk factors asso- ciated with CVC-BSI. The study considered only PICC catheters for data analysis in neonates from a Brazilian institution.⁴⁰

The S13 study, a multicenter prospective cohort with 2126 neonates from 22 NICUs in Germany, described the associationbetweentheuseofCVCandperipheralcatheters andtheriskoflaboratory-confirmedBSIfornewbornswith birth weight below 1500g. The incidence density for BSI was3.3/1000patient-days.Themultivariateanalysisiden- tifiedthefollowingsignificantindependentriskfactorsfor BSI:lowerbirth weight(hazardratio[HR], 1.1---2.2),vagi- naldelivery(HR,1.5),useofcentralvenouscatheter(HR, 6.2)oruse ofperipheralvenous catheter(HR,6.0)within twodaysbeforedevelopingBSI, andindividualcharacter- istics(HR, 0.0---4.6).Afteradjustingforother riskfactors, theuseofperipheralvenouscatheterandCVCuseweresig- nificantlyassociatedwiththeoccurrenceofBSIinverylow birthweightnewborns.⁴¹

AlsointheUSA,aretrospectivecohortstudy(S14)with 196neonatesfoundthattheuseofenteralcontrastwithin 48hofinfectiononsetwasthemostsignificantrisk factor forlaboratoryconfirmedBSI(oddsratio[OR],9.58;95%CI,

8RosadoVetal.

Table2 RiskfactorsforCVC-relatedinfectionintheneonatalpopulationinoriginalstudies.

ID Author/country Design

characteristics

Study population/timeof

follow-up

Objective Results

S1 Hruszkewyczetal./USA Case---control 263neonates 1989 Toassesstheincidenceand spectrumofcomplications associatedwithcentralvenous catheter(CVC)placementin severelyillneonates.

Fiveinfants(29%)developedsix episodesofbloodstreaminfection.

InfantswithCVC-relatedinfection hadlowergestationalage(24 weeksvs.32weeks,p=0.04)and lowerbirthweight(580gvs.1285g, p=0.02).Theoverallbloodstream infectionratewasoneepisodeper 100daysofcatheteruse.

S2 SenguptaA,LehmannC, Diener-WestM,PerlTM, MilstoneAM/USA

Retrospective cohort

683neonates 2006---2008 Todetermineriskfactorsfor CVC-BSIduringPICCusein high-risknewborns.

Thedurationofcatheteruseisa riskfactorforCVC-BSI(IRR:1.33 [95%CI:1.12---1.57]).Therewasa significantdailyincreaseintherisk ofCVC-BSIafter35days.

S3 Jen-FuHsu,Ming-Horng Tsai,Hsuan-RongHuang, ReyinLien,Shih-Ming Chu,Chung-BinHuang Risk/Taiwan

Retrospective cohort

275neonates 2005---2006 Toverifytheriskofinfection andothercomplications associatedwithPICCinvery low-birthweightneonates.

SignificantriskfactorsforCVC-BSI:

femoralcatheters(increasedriskof CVC-BSIcomparedtonon-femoral catheters:(OR1.76,95%CI:

1.01---3.07,p=0.045)andlonger timeofPICCuse:(RR4.66,95%CI:

1.93---11.28;p<0.001)).

S4 OhkiY,MaruyamaK, HarigayaA,KohnoM, ArakawaH/Japan

Multicenter prospectivecohort

946neonates/19 NICUs

2005---2007 Toinvestigatetheincidence andriskfactorsfor

PICC-relatedcomplications usingamulticentersurvey.

Multiplelogisticregressionanalysis showedthatlongercatheteruse (OR,1.35,95%CI:1.14---1.60, p=0.0005)independently contributedtooverall complications.

S5 MilstoneAM,ReichNG, AdvaniS,etal./USA

Multicenter retrospective cohort

3967

neonates/nine NICUs

2005---2009 Todeterminetheassociationof riskofCVC-associated

bloodstreaminfectionsduring thetimeofpermanenceof peripherally-insertedcentral catheters(PICCs)inhigh-risk newborns.

PICCswithatimeofuseof8---13 days,from14to22days,andthose

≥23dayseachhadanincreasedrisk ofinfectioncomparedtoPICCsthat remained≤7days(p<0.05).There wasanincreasedriskofCVC-BSIin neonateswithPICCs(adjusted incidencerateratioof2.04, 1.12---3.71).

Centralcatheter-relatedinfectionsinneonates9 Table2 (Continued)

ID Author/country Design

characteristics

Study population/timeof

follow-up

Objective Results

S6 GreenbergRG etal./USA³⁴

Multicenter retrospective cohort

13,327 neonates/141 NICUs

2011---2013 Totestthehypothesisthata longerCVCtimeofuseis associatedwithahigher incidenceofCVC-BSI.

Meangestationalagewas29weeks (interquartilerange:26---33).The incidenceofCVC-BSIwas0.93per 1000CVC-day.Thelongertimeof deviceusewasnotassociatedwith anincreasedriskofBSIforPICC.

Forlong-termcatheters,the incidenceofinfectionwas significantlyhigheratweekseven (HR4.0;95%CI:1.1---15,p<0.004) andweeknine(HR4.7;1.1---20 p<0.003)comparedtoweekone.

S7 YumaniDF,vanden DungenFA,van WeissenbruchMM/The Netherlands³⁵

Retrospective cohort

196neonates 2007 Todeterminetheincidence andpotentialriskfactorsfor catheter-associated

bloodstreaminfectionsin newborns.

18.1infections/1000CVC-day(95%

CI:13.7---23.8)accordingtothe adjustedcriteriausedbytheCDC before2008.Umbilicalcatheters hadahigherinfectionratethan non-umbilicalcentralcatheters (rateratio=2.4;95%CI:1.2---4,

<0.0009),andifitremainedfor morethanfivedays,theinfection rateincreased(p<0.05).

S8 DuarteED,PimentaAM, SilvaBCNe,Paula CMd./Brazil³⁶

Prospectivecohort 233newborns 2010 Toanalyzethefactorsrelated toinfectionassociatedwith theuseof

peripherally-insertedcentral cathetersinneonatesadmitted atanintensivecareunit.

Factorsassociatedwithremoval duetoinfectionsuspicionafter multivariateadjustmentwere:

weight<2500gattheinsertion(RR 1.99;95%CI:1.06---3.73,p=0.031), repair(RR2.3;95%CI:1.08---4.89, p=0.030);andtimeofcatheteruse (RR1.04;95%CI:1.02---1.06, p<0.0000).

S9 BarbosaMH etal./Brazil³⁷

Retrospective cohort

18neonates 2005 Toanalyzetheriskfactors associatedwiththeoccurrence ofcentralvenous

catheter-associated bloodstreaminfectionsin newbornsadmittedata neonatalintensivecareunit (NICU).

Lowbirthweight,prematurity,and theuseofTPNmayhaveinfluenced theoccurrenceofinfection.

10RosadoVetal.

Table2 (Continued)

ID Author/country Design characteristics

Study population/timeof

follow-up

Objective Results

S10 ShalabiM etal./Canada

Prospectivecohort 7919/29NICU 2010---2013 TocompareCVC-BSIratesin preterminfantsbornat<30 weeksgestationwhoreceived aPICCvs.umbilicalvenous catheterimmediatelyafter birthasprimaryvenousaccess.

Therewasnosignificantdifference ininfantswithCVC-BSI/1000 CVC-daybetweentheevaluated groups,althoughlowerratesoflate sepsisinthegroupofinfantswho receivedonlyoneumbilical catheterwereobserved.Therewas anincreaseinepisodesoflate sepsis/1000CVC-dayinthePICC groupcomparedtoneonateswho hadanumbilicalcatheterandPICC (RR1.73;95%CI:1.15---2.60, p<0.001).

S11 BelleminK etal./France

Retrospective cohort

1111/threeNICUs 2007---2011 Toevaluateincidenceandrisk factorsforCVC-BSI.

Theincidencedensitywas16/1000 CVC-day(95%CI:14.0---18.2):6.5 (95%CI:4.3---9.3)forumbilicalCVC and20.2(95%CI:5---23.1)forother CVCs.ThemediantimetoCVC-BSI waseightdays.Inthemultivariate analysis,birthweight≤750g(HR 6.3,95%CI:1.0---38.1)and intravenouslipidemulsion(HR2.3, 95%CI:1.3---3.9)weresignificantly associatedwithCVC-BSIfor umbilicalCVC.Similarresultswere observedforotherCVCs.

Centralcatheter-relatedinfectionsinneonates11

Table2 (Continued)

ID Author/country Design

characteristics

Study population/timeof

follow-up

Objective Results

S12 CostaPetal./Brazil Prospectivecohort 383 2010---2012 Identifytheriskfactorsfor PICC-associatedbloodstream infectioninneonates.

Inthebivariateanalysis,lower meanweightandcorrected gestationalage,andlonger catheterusewereassociatedwith theoccurrenceofCVC-BSI.Inthe multivariateanalysis,corrected gestationalage(RR1.12;95%CI:

1.061---1.186,p<0.002),transient metabolicdisorder(RR3.02;95%

CI:1.72---5.05,p<0.000),apnea(RR 2.38;95%CI:1.10---4.56,p<0.016), andtwo-wayandpolyurethane catheters(RR3.70;95%CI:2.0---6.9, p<0.0000)wereassociatedwith CVC-BSI.

S13 GeffersC,GastmeierA, SchwabF,GronebergK, RudenH,Gastmeier P/Germany⁴¹

Multicenter prospectivecohort

2126neonates/22 NICUs

2010 Todescribetheassociation betweenCVCand

peripherally-insertedcentral catheteruseandtheriskof laboratory-confirmedBSIfor newbornswithbirthweight

<1500g.

TheincidencedensityforBSIwas 3.3/1000patient-days.Theuseofa centralvenouscatheter(HR6.2;

95%CI:3.83---9.97,p<0.001)was oneoftheindependentsignificant factorsforBSI.

S14 Padulaetal./USA⁴² Prospectivecohort 409neonates 2006---2009 Todeterminetheclinicalsigns andriskfactorsassociatedwith laboratory-confirmedBSIin patientsassessedforlate sepsisinatertiaryNICU.

Useofenteralcontrastwithinthe previous48hwasthemost significantriskfactorfor

laboratory-confirmedBSI[OR:9.58 (95%CI:2.03---45.19)],followedby thepresenceofacentralvenous catheter.

ID,identification;NICU,neonatalintensivecareunit;TPN,totalparenteralnutrition;PICC,peripherally-insertedcentralcatheter;CVC-BSI,centralvenouscatheter-associatedbloodstream infection;BSI,bloodstreaminfection;CDC,CentersforDiseaseControlandPrevention.

12 RosadoVetal.

2.03---45.19),followedbythepresenceofacentralvenous catheter.⁴²

Therefore,CVC-BSIcontinuestobeanimportantcompli- cation,as shownby the incidenceof thisinfection inthe analyzedstudies,varyingfrom0.93to18.1infections/1000 CVC-day.The observedriskfactorsindicate thatlowbirth weight,prematurity, and longer timeof catheter use are relatedtoahigherincidenceofCVC-BSI.

Discussion

The S1, S2, and S3 studies demonstrate that the central venous catheter is an important device for the neonate treatmentintheNICU.Theyalsodonotdisagreeregarding theimportanceofthepreventionandidentificationofrisk factors associatedwith central catheters,^29---31 withinfec- tionamongthemaincomplicationsassociatedwiththeuse ofinvasivedevicesintheNICU,whichmaybeindependently associatedwithanincreasedriskofdeath.^22,43

The relatively small sample size obtained from stud- ies carried out in a single NICU may make it difficult to extrapolatetheresultstootherinstitutions.29,31,35---37 Addi- tionally,the CVC-BSIdefinitioncriteriadid notfollow the NHSNparameters.25,30,35,36

Differences were observed between the analyses per- formed,fromabsoluteandrelativefrequencyevaluationsto theuseofstatisticalmodelsthatalloweddetectingpossible differencesbetweenthe factorsstudiedand theaccuracy ofdataestimation.Multicenterstudieswereabletomore accuratelyassessriskestimatesbecauseofthelargepopula- tionsample;however,asitiswellknown,theretrospective natureofsomestudiesmaybeadisadvantage.

Gestationalageandlowbirthweightwerefactorsassoci- atedwithCVC-BSIinaUScase---controlstudy(S1);however, onlysixCVC-BSIepisodeswereevaluatedinfiveneonates.²⁹ Time of catheter use was the main risk factor for catheter-associatedinfectionidentifiedinfiveofthestudies analyzed in this review (S2, S3, S5, S6, S7). In US, Euro- pean, and Asian institutions,retrospective cohort studies emphasizethetimeofPICCuseinneonatesasariskfactor forCVC-BSI.30,31,33,35 InJapan(S4),itwasverifiedthatthe longertimeofcatheteruse(OR,1.35;95%CI:1.14---1.60for eachweek,p=0.0005)independentlycontributedtooverall complications.³²

A recent study (S6) found a mean of 11 days for PICC use,lower than the25-day mean for long-term catheters (p=0.001). The large study sample and the multicenter natureareadvantageous; however,it wasa retrospective study. It is difficult to compare this study with institu- tionsfromdevelopingcountries,whichhaveverydifferent characteristics fromthosein theUnited States,where 66 (47%) of the 141 NICUs reported an incidence of CVC- BSIequal tozero.⁴⁴ In Brazil, aprospective observational study carried out between 2011 and 2014 compared two periods with different empirical schemes for the treat- ment of late neonatal sepsis and found a BSI density of 17.29/1000CVC-day.⁴⁵ Even in thecase of a study(S6) in whichallparticipatinginstitutionshadalreadyimplemented the quality improvement initiative in PICC care, some factors remained unchanged (unit architecture and care environment) or were not evaluated (antibiotic therapy),

suggesting that it is necessary to evaluate the mainte- nancepackagecomponentsandthatotherfactorshavethe greatest impact on infection prevention. This study (S6) indicatesthatcliniciansshouldfocustheireffortsonredu- cingCVC-BSIininfusion line maintenancecareand timely removal of the central line when the CVC is no longer needed.³⁴

The useof enteralcontrastwithin48hprior tosepsis, presence of CVC (S14), presence of two catheters (S10), weight≤750g,and intravenous lipid emulsion (S11) were statistically significant risk factors for CVC-BSI. However, duetothepeculiaritiesofthestudiedpopulation,theresults may not be extrapolated to other institutions. However, these resultsconfirm that apnea andhypotension maybe useful clinical signs toguide thesepsis investigation and, additionally,theuseofcontrastdeservesfurtherinvestiga- tionasariskfactorforCVC-BSI.⁴²

In Brazil, prematurity and birth weight up to 1500g werefactorsassociatedwiththesuspicionofCVC-associated infection in twostudies (S8, S9), but oneusedonly clini- calsignstodeterminetheinfectiondiagnosis³⁶ and,inthe other, the data wereonly analyzed according to absolute andrelativefrequencies,inadditiontohavingasampleof only18newborns,whichcouldleadtointerpretationbias.³⁷ There is lack of information about practices during patientcare, such asuseof parenteral nutrition, surgical procedures,typeofimplantedcatheter,andotherriskfac- tors withpotential for confusion. The literatureindicates that skin fragility, the need for an infusion line for long periods, insertion made withlimited use of sterile barri- ers, location of the infusion line placement, substitution byguidewire,contaminationofthecatheterhub,catheter useformorethansevendays,andinexperiencedandpoorly qualifiedoperatorsareamongthesignificantriskfactorsfor catheter-associated bloodstream infection in studies with neonatalpopulations.^19,30,41

Studies have shown that neutropenia, prematurity, reducednumbersofnurseswhencomparedtothenumber ofpatients,useof totalparenteralnutrition,failuresdur- ingcathetercare (e.g.,excessivecathetermanipulation), anddeficienciesinconnectiondisinfectionmeasuresduring manipulationshavealsobeenreportedinstudieswiththis typeofpopulation.^33,46,47

It has been observed that low rates of catheter- associatedinfection,closetozero,arealreadyarealityin healthinstitutionsindevelopedcountries,sincesurveillance andinfectioncontrolprogramsareused.Whenthereiscon- stantmonitoring ofthehealth team’s adherence,through regular auditsof the insertionprocedure, duringcatheter maintenanceandregardinghandhygiene,ratescanbekept lowatalltimes.⁴⁸

The strength of the scientific evidence of the findings accordingtotheGRADE²⁸systemindicatesthattheabsence of randomizationin clinical trialsshows a strong possibil- ity of bias, with a lower level of evidence being initially attributed. Observational studies, such as those found in thestudy,areconsideredtobehighly-biased.However,the GRADEsystemalsoevaluatesthemeasureofeffect,suchas RelativeRisk(RR)orOddsRatio(OR),asafactortoincrease thequalityofevidence,sinceitispossibletoobtainahigher effectsizeinobservationalstudies,eveninthepresenceof confoundingfactors.

Centralcatheter-relatedinfectionsinneonates 13 In thepresentreview,therisk factorwiththegreatest

effectmagnitudewastheuseofcontrastintheCVC,witha nine-fold greater risk (S14) and birth weight≤750g,with a six-fold greater risk of infection (S11), whereas longer time of catheter use (S3 and S6), type of CVC (such as polyurethaneandtwo-waycatheters) (S12),andumbilical CVCformorethanfivedays(S7)showedatwotothree-fold higherriskofCVC-BSI.Additionally,CVCrepair(S8)anduse ofalipidsolution(S11) haveshownatwo-foldincreasein theriskforCVC-BSI.

The twostudies (S1and S9)witha higherlevelof evi- dence in favor, but that may be considered weak (grade

‘‘+1’’) according to GRADE assessed gestational age and birth weight and use of parenteral nutrition as risk fac- tors. However,theydidnotshow themeasures of effects foradequateanalysisandqualityassessmentofthestudies.

Itshouldbepointedoutthateveninobservationalstud- ies,withrandomization,selectionbiascanbeavoided,with better methodological quality and less risk of confusion, whichisproposedfornewstudies.²⁸

Oneofthelimitingfactorsofthisreviewisthatfewwell- designedstudies werefound onCVC-BSIin LatinAmerica.

Nationaldataarestillscarceontheevaluationofriskfac- torsrelated tothe clinicalcharacteristics of theneonatal population and those related to the conditions of inser- tionandcareinthemaintenanceofCVCandinfusionlines, timeofuse, andreasonfor insertionandremovalofcen- tral catheters. Furthermore, due to the ethical aspects involved, it is not feasible to carry out a clinical trial for CVC insertion and evaluation of its outcomes, which wouldallowtheuseofobservationalstudiesforasystem- aticreview.Other studiesshouldstilladdress thetraining of thecare teamtoprevent thecomplications associated withthepresence ofaCVC,especiallybloodstreaminfec- tions.

However,theauthors considerthat randomizedstudies ofhighmethodologicalqualityarenecessary toassess the risksrelatedtotheuseofCVCinneonates.Evidence-based interventionsandadequatestatisticalevaluationsofthese complicationsmaycontribute tothereductionofthisrisk andaidtheplanningof theindicationandtimeofperma- nenceofCVCs.

Conclusion

Despite the recommendations for reduction of CVC- associated bloodstream infections, they still show high incidence density rates in Brazil. Low birth weight,small gestationalage,andtimeofuseofthedeviceareassociated withahigherriskfortheseinfections.

Consideringtheepidemiologicalandclinicalimportance ofCVC-BSI,knowledgeoftheriskfactorscancontributeto theconfiguringofclinicalprotocolsandestablishingeffec- tivepreventivemeasuresinthecareofpatientswithCVC.

Thissystematicreviewdemonstratesthatfewstudieson theriskfactorsfortheseinfectionshaveprovidedinforma- tionontheseinfectionsinBraziland,therefore,theneedfor morelongitudinalstudies andbetterprevention strategies toreduceinfectionisemphasized.

Conflicts of interest

Theauthorsdeclarenoconflictsofinterest.

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