Late onset sepsis in newborn babies: epidemiology and effect of a bundle to prevent central line associated bloodstream infections in the neonatal intensive care unit

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Original

article

Late

onset

sepsis

in

newborn

babies:

epidemiology

and

effect

of

a

bundle

to

prevent

central

line

associated

bloodstream

infections

in

the

neonatal

intensive

care

unit

Daiane

Silva

Resende

_,

_Anna

_Laura

_Gil

_Peppe

_,

_Heloisio

_dos

_Reis

_,

Vânia

Olivetti

Steffen

Abdallah

_,

_Rosineide

_Marques

_Ribas

_,

_Paulo

_Pinto

_Gontijo

_Filho

b_{FacultyofMedicine,UberlândiaUniversityHospital,UberlândiaFederalUniversity,Uberlândia,MG,Brazil} c_{NeonatologyDepartment,UberlândiaUniversityHospital,UberlândiaFederalUniversity,Uberlândia,MG,Brazil}

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Articlehistory:

Received11July2014 Accepted17September2014 Availableonline15December2014

Keywords:

Lateonsetsepsis Bundle

Neonates

a

b

s

t

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Aim:Weassessedlateonsetsepsis(LOS)ratesofneonatesinaneonatalintensivecareunit (NICU)beforeandafterimplementinganevidence-basedbundletopreventtheseinfections inacountrywithpoorresources.

Methods:WeevaluatetrendsofLOSbetweenOctober2010andAugust2012inalargetertiary hospitalinBrazil.WedesignedaprotocolbasedofCDCguidelinesforinsertionof mainte-nanceofcentralvenouscathetertargetedtoreductionofbloodstreaminfections.During thisperiodtwomajoreventsoccurred:agreatincreaseofLOSratesinJanuarymonthsand relocationoftheunittoaprovisoryplace.Additionallyweevaluatedtheriskfactorsand etiologyoftheseinfections.

Results:Atotalof112(20.3%)casesdefinedasLOSwerefound.Theoverallincidencerate ofLOSinthestudywas16.1/1000patient/daysand23.0/1000CVC-days.Ourmonthlyrates dataofLOS/1000patient-dayrevealfluctuationsoverthestudiedperiod,withincidence rates ofthese infectionsin staff vacation period (January 2011 and2012) significantly higher(59.6/1000 patients-days)thancomparedwith theothermonthsrates (16.6/1000 patients-days)(IRR=3.59;p<0.001).Asopposite,theincidenceratesofLOSduringrelocation periodwaslower(10.3/1000patients-days)whencomparedwithbaselineperiod26.7/1000 patients-days(IRR=2.59;p=0.007).Aftertheinterventionperiod,theseratesdecreasedin thepostinterventionperiod,whencomparedwithpreintervention14.7/1000patients-days and23.4/1000patients-days,respectively(IRR=1.59;p=0.04).

Conclusion:Throughsimpleinfectioncontrolmeasures,LOScanbesuccessfullycontrolled especiallyinNICUsoflimitedresourcescountriessuchasours.

©2014ElsevierEditoraLtda.Allrightsreserved.

∗ _{Correspondingauthorat:UberlândiaFederalUniversity,ParáAvenue,1720Umuarama,Uberlândia,MG,Brazil.} E-mailaddress:daianeresendebio@hotmail.com(D.S.Resende).

http://dx.doi.org/10.1016/j.bjid.2014.09.006

Introduction

Late-onsetneonatalsepsis(LOS)remainsanimportantcause ofdeath,morbidityandlong-termcomplicationsamong pre-matureinfants,whichareassociatedwithprolongedhospital stayandincreasedhealth-carecosts.1_{Itisofgreatinterestto}

knowtheincidenceandthestrategiesthatareeffectivefor preventingLOSinneonatalintensivecareunits(NICUs).2–4

Themostcommon infectionsseeninneonatesare cen-tralline-associatedbloodstream infections(CA-BSIs),which substantiallycontributetotheburdenandcostofneonatal care.5_{OneproposedapproachtoachievelowCA-BSIratesis}

implementationofcathetercarebundles.6

BesidestheclassicriskfactorsforLOS,neonates requir-ing intensive carein developing countries are athigh risk duetostructuralfactorssuchasovercrowding,shortagesof nursingandmedicalstaff,lackorimproperuseofbasic sup-pliesandequipment,excessiveuseofantibiotics,insufficient knowledgeanddifficultiesintheimplementationofinfection controlpractices.7–9

The aim of this study was to evaluate the changes in LOSincidenceratesinareferenceNICUataBrazilian hos-pitalconsideringdifferenttimeperiods:staffvacationperiod, relocationoftheunittoatemporarysite,and theeffectof implementationofanevidencebasedcarebundle.

Materials

and

methods

Patientsandsetting

ThetertiaryNICUofHospitaldasClinicasofUberlandiacity, Minas Gerais receives both inborn patients from high-risk pregnanciesandpatientsreferredfromawidesurrounding region.ThepermanentNICUhas15beds,ratedlevelIII(10 beds)andlevelII(5beds)andadmitsanaverageof500infants eachyear.Wedesignedaprospectiveinterventionalcohort studyintheNICUincludingallinfantsadmittedfromOctober 2010toAugust2012.

Datacollection

Bloodcultures positiveforany microorganism and/or with clinicalsymptomsofsepsiswereactivelyandprospectively identifiedaccording tothe NationalHealthcare Safety Net-work (NHSN) surveillance.10 _{Patients were followed from}

theiradmissiontotheunittheirdischargeordeath.Standard definitionsforhealthcareassociatedinfectionswereused.10

Laboratoryinformationwasrequiredtoidentifyallpositive bloodcultureresults.Medicalrecordswerereviewedto deter-minewhetherpositivebloodcultureresultsmetthecriteria forLOSoutlinedbytheNationalHealthcareSafetyNetwork oftheCentersforDiseaseControl(CDC),10_{withassistanceof}

aneonatologistfromtheunit.Forallstudypatientsthe fol-lowingcharacteristicswereabstractedfromclinicalrecords: placeofbirth;gestationalage; birthweight; lengthoftotal hospital stay; antibiotics use; invasive procedures such as centralvenous catheter(CVC), mechanicalventilation, and parenteral nutrition; and the following clinical scores: the

ScoreofNeonatalAcutePhysiologyversionII(SNAPII)and APGARatfiveminutesoflife.Data frompatientswithLOS werecomparedwiththosewithnoinfectiontocomputerisk factorsassociatedwithLOS.

Intervention

TheinterventionwasimplementedinFebruary2012.Practices primarilyaddressedinterventionsrelatingtotheevaluation andpreventionofcentralline-associatedbloodstream infec-tions. Literature was assessed for methodological quality and applicability,and basedprimarilyoncategories IAand IB byCDC guidelines,and the staff for CVC insertion and maintenancedrafteda newprotocol.These included com-plying withdiagnostic criteriaand standardtechniquesfor monitoring nosocomialinfections;improvinghand-hygiene compliance;preventingintravascularcatheter-related infec-tionsbyadoptingstringentinsertionpracticesandcatheter maintenanceroutines,including maintainingclosed vascu-larsystemsandreliable,antisepticmethodsforlineinsertion andmaintenance(dressingchanges,administrationof med-ication,dailychlorhexidineapplicationtotheumbilicalcord stump,dailycatheterhubscrubwith70%isopropylalcohol), dressingchangesonlywhensoiled,insteadofroutineweekly changes, using full-barrier precautions during insertion of centralvenous catheters,cleaningthe skinwith chlorhexi-dine0.2%,avoidingthefemoralsiteifpossible,andremoving unnecessarycathetersbesidesbetterknowledgeabout pre-ventionofCA-BSIinneonates.Theinterventionfocusedon groupsessionsandfeedbackonpathogenesisanddataof CA-BSI per 1000CVC daysin the unit before intervention. All staffwasinvitedtoattendthemeetingsinordertoreviewthe infectionratesanddeviceuseandcare.Acatheterchecklist wascreatedtoensureadherencetoCA-BSIprevention prac-ticesatthetimeofCVCinsertion.CVCinsertionwasobserved byanursetoensurethataseptictechniquewasmaintained. Otherwise, visual displays with A3-size color posters that emphasizedcarewithCVCweredistributedatstrategicpoints oftheunit.

Comparisonrates

We accessed the incidence of LOS in the NICU in differ-ent periods during the study: (1) January 2011 and 2012, staff vacation period; (2) April–October 2011, relocation of theunittoatemporary nurseryforrepairingtheair condi-tionersystem;and(3)February2012,theinterventionperiod designedtoreducebloodstreaminfection(intervention bun-dle). Ratesduringstaffvacation werecomparedtoratesof othermonthsduringthestudy(October2010–December2010; February2011–March2011;November2011–December2011), excludingrelocationandpost-interventionperiods.Ratesof LOS duringthe relocationperiod(from April 2011to Octo-ber2011)werecomparedratesobservedintheperiodbefore unit relocation (from October 2010to March 2011, exclud-ingJanuary2011).Toevaluatetheimpactoftheintervention bundle, the incidencerates ofLOS duringpre-intervention period(October2010–December2011,excludingJanuary2011 and relocation period) were compared to rates during the post-interventionperiod(February2012–August2012).Agraph

basedonaPoissonprobabilisticdistributionwasconstructed forthemonitoringofLOSperthousandpatient-days, accord-ingtoArantesetal.(2003).11

Bacterialidentification

Cultures were processed using the BACT/Alert®

(bioMérieux–Durham, USA). Microbial identification and antimicrobial susceptibility testing were performed on the VITEKIIautomatedsystem(bioMérieux).

Statisticalanalysis

Theincidencerate,expressedasthenumberofLOSepisodes per1000patient-daysforeachmonth,wascalculated includ-ingalladmittedneonatestotheunit.Totalpatient-daysfor aparticularmonthwasthesumofthetotalnumberofdays allinfantswhostayedintheNICUinthatparticularmonth. TotalCVCdayswasthesumofthetotalnumberofdayswith aCVCofallinfantswhostayedintheNICUinthatparticular month.TheincidenceofLOSwascalculatedforeachmonth usingpatient-daysandCVC-daysinaparticularmonthasthe denominatorandnumberofinfectionsdiagnosedduringthat monthasthe numerator.A 95%CI foreachincidencerate wasestimatedusingaPoissondistribution.Theincidencerate ratio(IRR)foreacheventrelativetotheIRRofthefollow-up andits95%CIwascalculated.Univariateanalysisofrisk fac-torsforBSIwasperformedbyapplyingtheChi-squaretest. Statisticalsignificancelevelwassetatp≤0.05.Thevariables withp≤0.05inunivariateanalyseswereincludedinthe mul-tivariatelogisticregressionmodeltoidentifyindependentrisk factorsforBSI.SoftwareBioEstat(Version5.0,Brazil)wasused formultiplelogisticregression,andGraphPadPrism(Version 5.0,SanDiego,USA)wasusedforotheranalyses.

Ethicalapproval:Ourstudywasevaluatedandapprovedby theresearch Ethics Committeeofthe FederalUniversity of Uberlandiaunderthenumber464/2010.

Table1–EpidemiologicalindicatorsforLOSinaNICU fromOctober2010toAugust2012.

Epidemiologicalindicators N(%) Sepsis 178(32.3) LOS 139(25.2) Clinicalcriteria 32(23.2) Microbiologicalcriteria 107(76.9) LOS/1000patient-days 16.1 LOS/1000CVC-days 23.0

LOS,late-onsetsepsis;CVC,centralvenouscatheter;NICU,neonatal intensivecareunit.

Results

Outof551neonatesadmittedintheNICUduringthestudy period,112neonatesdevelopedsepsis(20.3%)withatotalof 178episodes(32.3%);139(25.2%)wasdefinedasLOSandonly 38(6.8%)asearlyonsetsepsis(EOS).ForLOS,76.9%(107/139)of episodeshadlatepositivebloodculture(Table1).Theoverall incidencerateofLOSinthestudywas16.1/1000patient-days and 23.0/1000CVC-days. Themean lengthofstaywas 18.8 days and CVC utilization density rate was 0.7. Univariate and multivariate analysesof potential riskfactors forLOS are displayedinTable2. Overall,gestationalage<37weeks (p=0.01)birthweight<1500g(p=0.001),useofCVC(p<0.001), parenteral nutrition (p<0.001), and mechanical ventilation (p<0.001)wereriskfactorsforLOSinunivariateanalysis.The following risk factors remained independently associated withLOS:useofCVC(p<0.001),parenteralnutrition(p=0.05), and mechanical ventilation (p<0.001) (Table 2). Our data haveshownthat66.3%(71/107)ofLOSwerecausedby Gram-positive cocci, 25.1% (27/107) byGram-negativebacilli, and 8.4%(9/107)byCandidasp.Staphylococcusepidermidiswasthe mostfrequentagent(37.9%),followedbyStaphylococcusaureus

(12.9%). AmongGram-negative bacilli, Klebsiella pneumoniae

Table2–Riskfactorsforlate-onsetsepsis(LOS)intheneonatalintensivecareunitfromOctober2010toAugust2012.

Total542 Neonates Univariateanalysis Multivariateanalysis

WithLOS 112(20.3%)

WithoutLOS 439(79.6%)

p-value OR(95%CI) p-value OR(95%CI)

Characteristics

Gestationalage<37weeks 366 86(76.7) 280(65.1) 0.01 1.77(1.07–2.95) 0.04 1.83(1.03–3.26) Birthweight<1500g 173 60(53.5) 113(26.2) <0.001 3.24(2.06–5.09) 0.01 2.70(1.16–3.74) Apgarat5min<5 14 2(1.7) 12(2.7) 0.74 0.69(0.10–2.50) – – SNAPPEIIscore 0–10 192 28(25.0) 164(38.1) 0.01 0.54(0.33–0.88) – – 11–20 119 20(17.8) 99(23.0) 0.29 0.73(0.41–1.27) – – 21–30 65 22(19.6) 43(10.0) 0.008 2.20(1.21–4.00) – – 31–40 41 11(9.8) 30(6.9) 0.41 1.45(0.66–3.14) – – >40 72 21(18.7) 51(11.8) 0.07 1.71(0.95–3.09) – – CVC 359 106(94.6) 253(58.8) <0.001 12.36(5.10–31.93) <0.001 5.10(2.32–11.26) Parenteralnutrition 223 77(68.7) 146(33.9) <0.001 4.28(2.68–6.86) – – Mechanicalventilation 242 76(67.8) 166(38.6) <0.001 3.36(2.11–5.35) <0.001 2.72(1.65–2.42) Lengthofstay>7days 308 90(80.3) 218(50.6) <0.001 3.38(2.35–6.80) <0.001 3.13(1.85–5.31) CVC,centralvenouscatheter;LOS,late-onsetsepsis;OR,oddsratio.

Table3–Pathogensisolatedfrombloodculturesincases oflate-onsetsepsis(LOS)fromOctober2010toAugust 2012. Microorganisms LOSn=107(%) Staphylococcusepidermidis 41(38.3) OtherCNS 7(16.5) Staphylococcusaureus 14(13.0) Enterococcusfaecalis 6(5.5) OtherGPC 3(2.8) Escherichiacoli 8(7.4) Enterobactercloacae 1(0.9) Klebsiellapneumoniae 9(8.4) Citrobacterkoseri 2(1.8) Serratiamarcescens 2(1.8) Stenotrophomonasmaltophilia 1(0.9) Acinetobacterbaumannii 2(1.8) Pseudomonasaeruginosa 1(0.9) OtherGNB 1(0.9) Candidaspp. 9(8.3)

LOS,late-onsetsepsis;CNS,coagulasenegativeStaphylococcus;GPC, Gram-positivecocci;GNB,Gram-negativebacilli.

wasthemostfrequent(8.3%). Thepathogens isolatedfrom LOSareshowninTable3.

OurmonthlyratesofLOS/1000patient-daysreveal fluctu-ationsoverthestudyperiod(Fig.1),withincidenceratesof theseinfectionsduringstaffvacationperiods(January 2011 and2012)significantlyhigher(59.6/1000patient-days)when comparedwithratesduringothermonths(16.6/1000 patient-days) [IRR=3.59; p<0.001]. In contrast, the incidence rates of LOS during the relocation period were lower (10.3/1000 patient-days) when compared with rates of the baseline period(26.7/1000patient-days)[IRR=2.59;p=0.007].Table 4

showsthatpost-interventionrates(14.7/1000patients-days) decreased in relation to pre-intervention rates (23.4/1000 patient-days)[IRR=1.59;p=0.04].Nonetheless,therewasno significantdifferenceingestationalage,SNAPPE-IIscore,low birth weight, and APGAR<5 at five minutes, in all these periods.

Discussion

Thepresentstudydemonstratesthatthroughinfection con-trolmeasures,LOScanbesuccessfullycontrolledtemporally, even ina NICU withhigh endemic levels ofS. epidermidis.

AlthoughtheoverallincidenceofLOSinourNICUwashigher than ratesreportedindevelopedcountries12_theyare

simi-lartoratesreportedindevelopingcountriesincludingother settingsinBrazil.13,14

Ourapproachplacedgreatemphasisand valueonlocal context,consideringthatthetechnicalinterventiononCVC insertionreducesinfectionrates,itsintroductionand applica-tionreflectthedifferentconditionsamongstaffofeachNICU. Themainaimofthisstudywastoevaluatethe effective-ness ofacare bundledesigned toreduce LOSinthe unit. Overthe surveillanceperiod,we identifiedtwoevents that significantlyincreasedandreduced,respectively,theratesof LOS: staffvacations (monthsofJanuary) and theunit relo-cationtoatemporarynursery.Accordingtoliterature,there is an association between nurse staffing and outcome of healthcare-associatedinfectionsininfants.Ensuringthatstaff receives infection control training is important to guaran-tee thatthe NICUisadequatelystaffed.15,16 _{In themonths}

of January there was less trained nurse staff in the unit, duetotheirvacationperiod,withasubsequentincreaseof bloodstreaminfectionsrates.Wehypothesizethatinadequate nurse staffingand increasedworkloadinanintensivecare unit, canresultinlowhand-hygienecompliance,breaksin aseptic technique, or compromises in practice that might increase the risk of infection. Other studies from western countries havedemonstratedadirectlinkbetweenstaffing levelsand infectionratesinNICUs,mainlydueshortageof trainedhealthcareworkers.16,17

Itshouldalsobepointedoutthedecreaseofinfectionrates observedinthisstudy whentheunitwastransferredtoan improvisedarea,probablybecauseofmoreisolationfacilities, morespacepercot,andenforcementofhandwashing com-plianceduringinthattemporaryplace.Theseaspectshave alsobeen showninother studieswithimpactoninfection rates.18,19 70 60 50 40 30 20 10 0 LOS/1000 pcatient-days

LOS/1000 patients-days LOS/1000 CVC-days Mean LOS/1000 patient-days UAL UCL

Intervention Relocation period

Oct/10 Nov-10 Dec-10 Jan-11 Feb-11 Mar-11 Apr/11 May/11 Jun-11 Jul-11Aug/11 Sep/11 Oct/11Nov-11 Dec-11 Jan-12 Feb-12 Mar-12 Apr/12 May/12 Jun-12 Jul-12Aug/12

Fig.1–Monthlyratesoflateonset-sepsisper1000patient-daysandper1000CVC-daysfromOctober2010toAugust2012. LOS,late-onsetsepsis;UAL,upperalertlimit;UCL,uppercontrollimit.

Table4–ComparisonofincidenceratesofLOSduringthemonthsofJanuary,timeofunitrelocation,andquality improvementbundle.

Majorevent Incidencerate/1000patient-days IRR P(95%CI)

MonthsofJanuary JanuaryMonths OtherMonths IR(monthsofJanuary)/IR(othermonths) <0.001(1.85–6.60)

59.6 16.6 3.59

Unitrelocation Baseline Relocation IR(baseline)/IR(relocation) 0.007(1.20–3.66)

26.7 10.3 2.59

Intervention Pre-intervention Post-intervention IR(baseline)/IR(followup) 0.04(1.01–2.69)

23.4 14.7 1.59

IR,incidencerate;IRR,incidencerateratio.

Despitesomeunexpectedeventsduringthestudyperiod, wecould demonstrate an importantreductionin LOSrate amongtheneonatesafterasustainedeffortinFebruary2012 thatweremaintainedatlowerratesoverfivemonths, prob-ablyduetheimplementationofthebundle.Ourresultsare consistentwithpreviousreportsshowingreductionsin over-allNImultifacetedinterventions,andespeciallythoserelated tocentrallines.20,21 _{Wehaveshownthatspecificeducation}

and a protocol adopting the recommended procedures for CVCinsertionandcarebesidesfeedbacktohealthcare work-ers(HCWs)canresultinsignificantreductionofCA-BSIrates. In our NICU, earlier approach by our team, using simple and inexpensive intervention to increase compliance with evidence-basedinfectioncontrolpractices, decreaseCA-BSI rates.4 _{Afterimplementationofthesemeasures,theoverall}

CA-BSIratedeclinedfrom32% to19.6%,andfrom 37.3%to 15.2%inlowbirthweightneonates.

Allthesestrategiesdescribedsofarwerebasedonour find-ingsfromthesurveillancestudythatdetectedhighincidence ofLOSintheunitassociatedtoS.epidermidis,amajorcausative agentoftheseinfectionsinourNICU.Fromourdataitwas possibletodesignacase–controlstudytodetectthemainrisk factorsassociates toLOSincriticalneonates. Thus,inthis reportthemultivariateanalysisidentifiedlowbirthweight, lengthofstayintheunit>7days,useofCVC,mechanical ven-tilation,andparenteralnutritionasindependentriskfactors forBSI,similartothosefoundinotherstudies.22,23_The

cen-tralvenouscathetersandlowbirthweightplacedinfantsat ahigherriskofdevelopingLOS,ashasbeenshowninother studies.22

The organisms causing neonatal infections often differ fromoneplacetoanotherandmaychangeovertimewithin thesamesetting.InthisstudymostofLOSwas microbiolog-icallyconfirmed,andS.epidermidiswasidentifiedasamajor causeofLOSintheunit.Gram-positivebacteria,particularly coagulasenegativeStaphylococci,arethemostcommoncause ofLOSinmanyindustrializedaswellasinsomedeveloping countries.24 _{Gram-negative bacillaryand Candidainfections}

havebecomeanothermajorcauseofneonatalsepsis,asseen inourstudywhenaroundone-fourthoftheepisodeswere causedbyBGN,mainlyK.pneumoniae,withahighcasefatality andlong-termcomplications.14,25

Ourstudyhasseverallimitations.First,wehadtwomain events,summeroutbreaksandunitrelocationthatinterfered intheanalysisofthebaselineperiodofintervention.Second, we were not able to ensure the adoption of the checklist to achieve stable compliance inorder toevaluate the real

adherenceandascertainthefullimpactofthebundle.Third, our study was performed at asingle unit, although repre-sentativeofBrazilianteachinghospitals,buttheresultsmay notbeapplicabletootherunits.Finally,boththeintervention and post-intervention periodshas lasted onlyone and six months,respectively,and effortsofshortdurationmaynot beassuccessfulasyearsofsustainedstrategiesreduceLOS.

Inconclusion,theincidenceofLOSinourNICUishigh,in bothoverallaswellasinlowbirthweightneonates, reflect-ing the situationinresource-poorcountries andshow that application ofevidence-based practicescan leadto signifi-cantreductioninLOSrate.Additionally,theanalysisoftrends overaperiodof22monthsshowedanincreaseofLOSrates during staffvacation monthsand areductionofLOSrates during the relocation of the unit. Finally, these infections are preventable,andtheireliminationpresentsan opportu-nity to improve patient outcomes and reducecosts in the unit. Lessons learnedabout the importanceand feasibility ofanindividualizedlocalapproachonspecifictechniquesto decrease CA-BSI asevidenced inour proposed bundlethat describessimpleandinexpensivepracticesthatleadtothe reductionoftheseinfectionsintheNICU.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgment

The authors would like to thankthe financial support by BrazilianFundingAgencyFAPEMIG(Fundac¸ãodeAmparoà PesquisadoEstadodeMinasGerais).

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