Chronicotitismediascopingdocument(abbreviatedversion)30thJanuary2017

Chronic Otitis Media

Ascopingexerciseforareasofpriorityforsystematicreview

Projectlead:ChrisBrennan-Jones(TelethonKidsInstitute,UniversityofWesternAustralia&PrincessMargaretHospital)Projectclinicians:MahmoodBhutta(TheUniversityofWesternAustraliaandRoyalPerthHospital)MartinBurton(CochraneENT,Oxford)AnneSchilder(CochraneENT,evidENT)ShyanVijayasekaran(PrincessMargaretHospitalandTheUniversityofWesternAustralia)Systematicreviewers/methodologists:Lee-YeeChong(AteimedConsultingLtd)KarenHead(KarenHeadFreelanceLtd)InformationScientist:SamanthaFaulkner(CochraneENT)PatientRepresentative:CourtneyMcMahen Editor:JennyBellorini(CochraneENT)Funders&collaborators

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Summary of the scoping process for proposed reviews BackgroundTheaimofthisscopingexerciseistoidentifypriorityareasfornewandupdatedevidencesummariesinpatientswithchronicotitismedia(COM).COMinthisdocumentisdefinedaschronicinflammationofthemiddleearandmastoidcavitywithpersistentorrecurrenteardischargethroughatympanicmembrane(eardrum)perforation.

COMisestimatedtohaveanincidencerateof31millionepisodesperyear,or4.8newepisodesper1,000people(allages).Childrenareparticularlyaffected,with22%ofallcasesaffectingchildren<5yearsofage.TheprevalenceofCOMvarieswidelybetweencountries,butitdisproportionatelyaffectspeopleinlow-incomeandmiddle-incomecountries,resourcelimitedareas,certainindigenousgroupsandpeoplewithspecificconditionssuchascleftpalateandDownSyndrome.ManypeoplewhoareaffectedbyCOMdonothavegoodaccesstomodernprimaryhealthcare,letalonespecialisedear,noseandthroat(ENT)care.Therefore,itiscrucialthattheevidenceispresentedinawaythatcouldsupportthedevelopmentandupdatingofguidelinesaffectingthesesettings.

TerminologyOtitismedia(OM)orinflammationofthemiddleearisabroadtermthatincludesacuteOM(AOM),OMwitheffusion(OME;‘glueear’)andchronicsuppurativeOM(CSOM).Theseconditionsarecloselyrelatedandcanoverlap.Oneofthechallengesofresearchinthisareaisthevariationinterminologyusedacrossstudiesandregions,andbetweenclinicians.Thefocusofthisworkistoexaminetheinterventionsusedinthemanagementofpatientswithchroniceardischargeduetochronicotitismedia(COM),whichistypicallyreferredtoaschronicsuppurativeotitismedia(CSOM)oractivechronicmucosalotitismedia.However,chronicdischargefromtheearcanalsobeasymptomofinflammationoftheexternalear(chronicotitisexterna)andthedifferentiationbetweeneardischargeduetoCOMandeardischargeduetochronicotitisexternamaynotalwaysbeclear.Therefore,forthepurposesofthisdocumentwewillrefertopatientsashavingchroniceardischarge(CED)ifthecauseofthedischargeisunknownandthedurationisatleasttwoweeks,andwewillusethetermchronicotitismedia(COM)todescribechronicorpersistenteardischargeforatleasttwoweekswithaperforatedtympanicmembrane,whichreflectsthemoretraditionaldefinitionassociatedwithCSOM.Cholesteatomaisanabnormalaccumulationofsquamousepitheliumthatisusuallyfoundinthemiddleearcavityandmastoidprocessofthetemporalbone.Mostcliniciansconsider‘cholesteatoma’tobeavariantofCSOM.Itisunclearwhethertheresponsetonon-surgicaltreatmentsinpatientswithcholesteatomatonon-surgicaltreatmentswillbeidenticaltotheresponseinpatientswhohaveCOMwithoutcholesteatoma.Managementofpatientswithacuteotitismedia(AOM)andotitismediawitheffusion(OME)willnotbeconsideredinthisproject.MethodsandfindingsofourscopingexerciseThisdocumentprovidesanoverviewofthemethodsweplantousetoconductthereviewofCOMevidence.Thisdocumentisnowcirculatedtocliniciansaroundtheworldaspartofourconsultationprocess(inwhichyouareparticipating).Patientrepresentativeswillalsoprovideinputintotheproposedscope.

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Thisdocumenthasbeendevelopedbygatheringpreliminaryinputfromcliniciansanditisinfluencedbyliteraturesearchesandreviewsofcurrentclinicalguidelinesandkeypapers,especiallytheCochranedatabaseandmajorsystematicreviews.Wealsoconductedsearchestoidentifythenumberofnewtrialabstracts,inordertoestimatetheamountofnewevidenceavailable.Thenumberofpotentialrandomisedcontrolledtrialsinthisareaissmall,asreflectedbytherelativelysmallnumbersofabstractsfound.

ExistingguidelinesidentifiedOursearchesidentifiedonemajorinternationalguideline:thecurrentWorldHealthOrganization(WHO)guideline,publishedin2004(CSOM–burdenofillnessandmanagementoptions).PartoftheevidencebasethatwasusedtosupportthisguidelinewaspublishedastwoCochranesystematicreviewsontheuseofantibiotics1.Wefoundonlytwonational-levelguidelines(fromIndonesiaandAustralia).Wenoticedmajorvariationsinpractice,especiallyaroundtheuseoftopicalantibiotics,topicalantisepticsandauraltoileting.

TopicsofpriorityforevidencereviewThelistofproposedreviewsispresentedinthefollowingsections(Section2:Reviewquestions).Thereisalsoanaccompanyingdocumentdetailingthescopingprocessanditsfindings.

Webelievethatreviewsonthreegroupsofinterventionswillpotentiallyhavethehighestimpact.Thistakesintoconsiderationtheuncertaintyandvariationincurrentclinicalpractice,thecurrentevidencebase,thepotentialeconomicimpactandtheareasintheworldwhereCOMismostprevalent.Thethreegroupsofinterventionsofpriorityare:

1. Topicalantiseptics2. Antibiotics(systemicandtopical)3. Auraltoileting

Therationaleforfocusingontheabovetopicsincludestheconsiderationthattheseareinterventionsthataremostusedandthereislargevariationinpracticeinthisarea.Thediseasedisproportionatelyaffectspeoplefromresource-limitedcountries,thereforetopicalantiseptics(whichareoftencheaperthantopicalantibiotics)andalternativeformsof‘auraltoileting’(ratherthanmicro-suctionmethods,whicharesometimesonlyavailableinmorespecialisedcaresettings)areoftenusedduetocostandotherlimitations.Thepotentialeconomicimpactandtheissueofaccesstocaremeanthattheseinterventionsareimportant.

Weconsideredtheroleoftopicalsteroidstobeimportantbecausesteroidsareoftenaddedtotopicalantibiotics.However,weareunclearwhetherthisinterventioncouldberegardedasmoreimportantthattheotherthreeinterventiongroups.AreviewoftheevidenceforsurgicalinterventionsisoflowerprioritybecauseonlyasmallproportionofpatientsarereferredtoanENTspecialistsettingandrequiresurgery.Intheliteraturewefoundmentionsofotherclassesofdrugsbeingused,suchasantifungals,antihistaminesanddecongestants,buttheseinterventionsareuncommonandthereisnostrongbiologicalbasisfortheiruse.Thereis,therefore,unlikelytobehigh-levelevidencefromRCTsinthesethreeclasses.

OutcomesusedtoassesstheeffectsofinterventionsWewilluseacommonsetofoutcomemeasuresthatareimportanttopatientstoassesseffectivenessacrossallthereviews.Qualityoflifeisthemostimportantoutcomeandwillbea

1CD005608:Systemicantibioticsversustopicaltreatmentsforchronicallydischargingearswithunderlyingeardrumperforations;CD004618:Topicalantibioticswithoutsteroidsforchronicallydischargingearswithunderlyingeardrumperforations

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primaryoutcomeinthereviews.However,wehavefoundneitherwell-validatedpatient-reportedsymptomscoresnordisease-specificqualityoflifeinstrumentsbeingusedinclinicaltrialsofnon-surgicalinterventions.Therefore,wealsosuggestmeasuringresolutionofdischarge(dryear)asaprimaryoutcome.Forthesecondaryoutcomes,wesuggestmeasuringrecurrenceofeardischarge,hearinglossandcomplicationsfromCSOM(includingintracranialcomplications,extracranialcomplicationsanddeath).Wewillalsoassessthepotentialharmsofallinterventionsreviewedbasedonthecharacteristicsoftheinterventionsconsidered.

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1 PROPOSED SCOPE OF REVIEWS Thefollowingsectionssetoutthescopeandprioritiesoftheproposedreviewsbasedonthefindingsofthescopingexercisethusfar.Figure1presentsaflowchartofthepatientjourneywiththeboxesinbluerepresentingtheareasproposedforevidencereviewinthecurrentscope.

1.1 SETTING Wewillincludeevidencefromallhealthcaresettings.Therewillbenolimitsonthelanguageoryearofpublicationorthecountrywheretheresearchwasconducted.

1.2 POPULATION

1.2.1 Populat ions that wi l l be included: Wewillincludestudiesthatincludedpatients(adultsandchildren)whohad:

• chroniceardischargeofunknowncause;or• chronicotitismedia.

Patientswithchroniceardischarge(CED)willbedefinedaspatientswithatleasttwoweeksofeardischarge,wherethecauseofthedischargewasunknown.

Patientswithchronicotitismedia(COM)willbedefinedaspatientswith:

• chronicorpersistenteardischargeforatleasttwoweeks;and• aperforatedtympanicmembrane.

Wewillnotexcludeanypopulationsbasedonage,riskfactors(cleftpalate,Downsyndrome),ethnicity(e.g.AustralianAboriginalorTorresStraitIslanders)orthepresenceofgrommets.AlthoughtheincidenceandriskofdevelopingCOMarehigherinthesesubgroupsofpatients,wehavenotfoundevidencethatthesepatientsresponddifferentlytotreatment(i.e.thereisdifferentrelativeeffectiveness)comparedtopatientswhodonothavethesecharacteristics.Whereavailable,wewillrecordthesefactorsinthepatientcharacteristicssectionduringdataextractionfromthetrials.Ifanyoftheincludedstudiesmostlyrecruitthesepatients,wewillanalysetheminasubgroupanalysis(see‘Analysis,subgroupsandpoolingofevidence’).

1.2.2 Populat ions that wi l l not be included: WewillexcludestudiesthatspecificallyrecruitedpopulationswithoutCOMandstudieswithparticipantswhereanalternativediagnosistoCOM(e.g.otitisexterna)formedthemajority(morethan50%)ofparticipants.

StudieswithinclusioncriteriaofpatientswithCEDorCOMmayincludepeoplewithunderlyingcholesteatoma.Giventhatcholesteatomadoesnotrespond,orwillrespondonlytemporarilytonon-surgicaltreatment,wewillexcludethosestudieswheremorethan50%oftheparticipantswerediagnosedwithcholesteatoma.

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Figure1:Areasinchronicotitismediacoveredinproposedscope

Note:boxesinblueareincludedintheproposedscope;boxesinorangeareoutsidetheproposedscope.

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1.3 INTERVENTIONS Takingintoconsiderationtheuncertaintiesincurrentpractice,theamountofpotentialevidenceavailableandtheageandrelevanceofrecentreviews,wehaveprioritisedthereviewsofinterventionsthatarelikelytomakethemostimpact.

1.3.1 Types of intervention to be included in reviews 1. Topicalantibiotics2. Systemicantibiotics3. Topicalantiseptics4. Auraltoileting

Wewillincludeallmethodsofauraltoileting.Thetopicalantisepticsusedwillincludeagentssuchaspovidone-iodine(i.e.Betadine),aceticacid,boricacidandhydrogenperoxide.

1.3.2 Types of interventions to be excluded from the reviews 1. Topicalsteroids,whetherasanadd-ontherapy(e.g.toantibiotics)oralone2. Antifungals3. Decongestants4. Antihistamines5. Surgery(mastoidectomy,and/ormyringoplastyortympanoplasty)

1.4 MAIN OUTCOMES Weplantousetwoeffectivenessoutcomesacrossallthereviews(coreoutcomes)toallowforcomparabilityacrossreviews:

1. Completeresolutionofeardischarge,measuredatbetween1weekandtoupto2weeks,2to4weeksandafter4weeks(measuredasproportionofpeople)

2. Health-relatedqualityoflife(e.g.COMOT-12,COMOT-15,CES)

Wewillchoosetheotheroutcomesbasedontheinterventionandcomparisonsassessed.Dependingonthesefactors,theseoutcomesmayinclude:

1. Recurrence(durationoftimeeardischargefree/timetorecurrence)2. Hearingloss(e.g.forchildrenahearinglossof≥30dBaveragedacrossfrequencies0.5,1,2

and4kHz)3. ComplicationsfromCOM–extracranial4. ComplicationsfromCOM–intracranial5. Death6. Adverseeffectsfromtreatment(thiswillbedependentonthetypeoftreatmentreviewed)

Adverseevents:differentadverseeventswillbemeasureddependingontheinterventionassessedbutmayinclude:

• Pain• Ototoxicity• Fungalinfection

Wedidconsiderotheroutcomesbutthoughtthatthesemightbeoflowerpriority.Weconsidereddiseaseseveritymeasuredusingsymptomscores,butdecidedthatthiswaslessimportant,ontheassumptionthatpatientswishtoachieveadryearratherthanjustsymptomimprovement.Moreover,wearenotawareofanyvalidatedscores.Wealsoconsideredsmell(ofthedischarge)asanimportant,potentiallybothersomesymptom.However,thisoutcomedidnotappeartobe

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capturedinclinicaltrialsandshouldinanycaseresolvewithadryear,whichisalreadymeasuredasaprimaryoutcome.

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2 REVIEW QUESTIONS

Table1liststhereviewstobeconducted,withdetailsofthetypesofpatient(population),interventionandcomparisontobeincluded.Wewillprioritisereviews1to6inthisprojectandwewilldeliverthesewithinthetimelinestipulatedandwithinthegrantprovided.

Table1:Listofpopulations,interventionsandcomparisonsforthesuiteofreviewsandwithinwhichreviewsthesearelikelytobepresented.Key: COM Chronicotitismedia CEDChroniceardischarge(Tentative)Reviewshortname2

Pair Population3

Intervention4

Comparison

Comments5 Mainclinicalquestions

1. Antibiotics–topical

1. CED Antibiotics–topical

Placeboornointervention

Thiswillincludestudieswhereanotherinterventionisusedasanadjuvanttreatmentinbotharms(e.g.topicalantiseptics,topicalcorticosteroids).

1. Aretopicalantibioticseffective?

2. Aretopicalantibioticseffectivewhenaddedtootherinterventions(e.g.auraltoileting)?

2. CED Antibiotics-topical

Antibiotics-topical(otherclasses)

ThecurrentCochranereviewincludesninestudies.

3. Whichtopicalantibioticismoreeffective(whentheyarecomparedtoeachother)?

4. Whichtopicalantibioticismoreeffectivewhenaddedtootherinterventions?

2. Antibiotics–systemic

3. CED Antibiotics-systemic

Placeboornotreatment

Thiswillincludestudieswhereanotherinterventionis

5. Aresystemicantibioticseffective?

6. Aresystemicantibioticseffectivewhenaddedonto

2Thisreflectsthetentativeorganisationofdifferentcomparisonpairsinthereviews.Theorganisationofinformationintodifferentreviewsmayneedtobechanged,dependingonthenumberofstudieseventuallyincludedandtheclinicalrelevanceoftheavailablecomparisons.3Characteristicsofpopulationstobeexploredassubgroupsare:whethermostofthepatientshaveadefiniteCOMdiagnosisandagegroup.4Wewillexploretheeffectsofthetypeofactiveintervention(withinaclass),methodofdelivery,doseanddurationofintervention,andcomparisonsusingsubgroupanalysiswhereappropriate.Ifauraltoiletinghasbeenused,wewillalsoreportthis.5Whencombinationsoftreatmentsarecompared,thereviewinwhichtheevidenceislocatedwillbebasedonthecomparisonused.Forexample,wewillanalyseauraltoileting+topicalantibioticsversusauraltoiletingastopicalantibioticsversusnointervention(withauraltoiletingasanadjuncttreatment)inReview1:Antibiotics-topical)

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(Tentative)Reviewshortname2

Pair Population3

Intervention4

Comparison

Comments5 Mainclinicalquestions

usedasanadjuvanttreatmentinbotharms(e.g.topicalantiseptics).

otherinterventions(e.g.topicalantibiotics)?

4. CED Antibiotics-systemic

Systemicantibiotics(otherclasses)

7. Whichtypeofsystemicantibioticismoreeffective(whentheyarecomparedtoeachother)?

8. Whichsystemicantibioticismoreeffectivewhenaddedtootherinterventions?

3. Antibiotics-topicalversussystemic

5. CED Antibiotics-topical

Antibioticssystemic

ThisisthemaincomparisoncoveredbythecurrentCochranereviewofsystemicversustopicaltreatment,whichincludesninestudies.

9. Whataretherelativeeffectsoftopicalantibioticscomparedwithsystemicantibiotics(forthesameantibiotic)?

10. Whataretherelativeeffectsoftopicalantibioticscomparedwithsystematicantibiotics(fordifferentantibiotics)?

4. Topicalantibioticversustopicalantiseptic

6. CED Antibiotics-topical

Antiseptics

Thismayinvolvemanycomparisonpairsofdifferentclassesofantibioticcomparisons.

11. Whataretherelativeeffectsoftopicalantibioticscomparedwithantiseptics?

12. Whataretherelativeeffectsoftopicalantibioticscomparedwithantisepticswhenaddedontodifferentinterventions?

5. Auraltoileting

7. CED Auraltoileting

Noauraltoileting

13. Areauraltoiletingmethodseffective(comparedtonotreatment)?

14. Areauraltoiletingmethodseffectivewhenaddedtootherinterventions(e.g.auraltoileting,systemicantibiotics)?

8. CED Auraltoileting

Auraltoileting(anothe

Thisincludescomparingthevariousdifferentauraltoileting

15. Whataretherelativeeffectsofdifferentauraltoiletingmethods?

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(Tentative)Reviewshortname2

Pair Population3

Intervention4

Comparison

Comments5 Mainclinicalquestions

rmethod)

methodsandwhetherantisepticswereusedduringorimmediatelyaftertheauraltoiletingsession.

16. Whataretherelativeeffectsofdifferentauraltoiletingmethodswhenaddedontootherinterventions(e.g.topicalantibiotics)?

6. Antiseptics

9. CED Antiseptics

Placeboornointervention

Thiswillincludestudieswhereanotherinterventionisusedasatreatmentinbotharms(e.g.auraltoileting).

Inthiscaseauraltoiletingversusauraltoiletingwithantisepticsrelatestothedailyuseofantisepticsaftertheauraltoileting

17. Aretopicalantisepticseffective(comparedwithnotreatment)?

18. Aretopicalantisepticseffectivewhenaddedtootherinterventions(e.g.auraltoileting,systemicantibiotics)?

10. CED Antiseptic Otherantiseptics

19. Whataretherelativeeffectsofdifferentantiseptics?

20. Whataretherelativeeffectsofdifferentantisepticswhenaddedontootherinterventions(e.g.topicalantibiotics)?

7. Topicalcorticosteroids

11. CED Topicalcorticosteroids

Placeboornointervention

Thiswillincludestudiesthatlookattheimpactofaddingatopicalcorticosteroid(e.g.topicalcorticosteroidsplustopicalantibioticsversusanidenticaltopicalantibiotic).

21. Aretopicalsteroidseffective?

22. Aretopicalsteroidseffectivewhenaddedtootherinterventions(e.g.topicalantibiotics)?

12. CED Topicalcorticosteroids

Othertopicalsteroids

Thiswilllookatstudiesinvestigating

23. Whataretherelativeeffectsofdifferenttopicalsteroidpreparations?

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(Tentative)Reviewshortname2

Pair Population3

Intervention4

Comparison

Comments5 Mainclinicalquestions

differenttypesofcorticosteroids(e.g.AntibioticAplustopicalsteroidBversusantibioticAplustopicalsteroidC)

24. Whataretherelativeeffectsofdifferenttopicalsteroidswhenaddedtootherinterventions?

13. CED Topicalcorticosteroids+otherinterventions

Placeboornointervention

25. Isacombinationoftopicalsteroidsplustopicalantibioticeffective?

26. Isacombinationoftopicalsteroidsplusantibioticseffectivewhenaddedtootherinterventions?

14. CED Topicalcorticosteroids+otherinterventions

Otherinterventions

E.g.Topicalcorticosteroidsplustopicalantibioticsversusanothertopicalantibiotic

27. Whataretherelativeeffectsofacombinationoftopicalantibioticsplustopicalsteroidswhencomparedtootherinterventions?

28. Whataretherelativeeffectsofacombinationoftopicalantibioticsplustopicalsteroidswhencomparedotherinterventionswhenbothgroupsalsoreceiveanotherintervention?

8. Antifungals

15. CED Antifungals

Placebo

16. CED Antifungalsplusotherinterventions

Otherinterventions4

9. Decongestants

17. CED Decongestants

Placebo

18. Decongestants

Otherinterventions4

10. Antihistami 19. CED Antihista Placebo

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(Tentative)Reviewshortname2

Pair Population3

Intervention4

Comparison

Comments5 Mainclinicalquestions

nes

mines

20. Antihistamines

Otherinterventions4

11. Surgery

21. CSOM–specificdiagnoses

Surgery Nosurgery

22. Specificdiagnoses

Surgery Astep-upinconservativetherapy

23. CSOM-diagnoses

Surgery Anothersurgicalmethod

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3 REVIEW METHODS

WewillusestandardCochranesystematicreviewmethodology.Inaddition,wewillalsoensurethattheformulationofreviewquestionsandinterpretationofeffectsareinlinewiththerecommendationsofGRADEandwiththeNICEguidelinesmanual.Fullprotocolswillbepublishedbeforethereviewsareconducted.Onlythemethodsthatarespecifictothesereviewsarehighlightedhere.

3.1 SEARCHES Systematicsearchesforrandomisedcontrolledtrials(RCTs)andcontrolledclinicaltrialswillbeconductedusingthestandardCochranemethods.

3.2 TYPES OF RESEARCH DESIGNS CONSIDERED FOR REVIEW Wewillincluderandomisedcontrolledtrials,includingcluster-randomisedtrialsandquasi-randomisedtrials.

Wewillnotincludecross-overtrialsforpharmacologicalinterventions,sinceCSOMisnotexpectedtobeastablechronicconditioniftreatmentiseffective.

Wewillnotexcludestudiesthatrandomisedpatientsbyear(within-patientcontrolled).Thesestudieswillonlybeincludedifdataarepresentedinawaythatallowsanalysisaspairwisedataandiftheinterventionsstudieddonothavespecificpropertiesthatmakethemunsuitableforrandomisationbyear(e.g.systemictreatments).

Wewillonlyincludestudieswherepatientswerefollowedupforatleast1week.

3.3 DATA EXTRACTION, RISK OF BIAS ASSESSMENT WewillusethecurrentstandardsforCochraneReviewprocess.

Allthereviewswillshareacommonsetofoutcomemeasuresofeffectivenesstoensurecomparabilitybetweenreviews.Thetypeofadverseeffectsforeachreviewwillbedependentontheinterventionsevaluated.

3.4 ANALYSIS, SUBGROUPS AND POOLING OF EVIDENCE

3.4.1 Subgroup analys is Subgroupsareusedtoinvestigatefactorsthatcanaffecttherelativeeffectivenessofinterventions.

3.4.1.1 We wil l consider the fol lowing POPULATION subgroups in the meta-analysis : 1. DiagnosisofCOM:itislikelythatsomestudieswillincludepatientswithchronicear

dischargebutwhohavenothadadiagnosisofCOM.Therefore,wewillsubgroupstudieswheremostpatients(80%ormore)metthecriteriaforCOMdiagnosisinordertodeterminewhethertheeffectoftheinterventionisdifferentcomparedtopatientswheretheprecisediagnosisisunknownandinclusionintothestudyisbasedpurelyonchroniceardischargesymptoms.

2. Patientage(veryyoungpatientsversusyoungpatientsversusadults16yearsandabove).3. Durationofeardischarge(morethansixweeks’versuslessthansixweeks)

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4. Othersubgroups–cleftpalate,DownSyndromeandspecificethicgroupsknowntohavepotentialanatomicaldifferences,suchasIndigenousAustralians.

3.4.1.2 We wil l consider the fol lowing INTERVENTION subgroups in the meta-analysis :

WewillusethefollowingconsiderationsfortheanalysisofeachINTERVENTIONgroup:

Antibioticclass:Wewillanalyseeachantibioticclassassubgroups.Forsystemicantibiotics,wewillconsiderthebioavailabilitypriortopooling.Wewillincludemoredetailedanalysisplansinthereviewprotocolandtheywillbesetoutaprioribeforethereviewscommence.

Auraltoileting:Wewillconsiderthevariousmethodsofauraltoiletingassubgroupsandpoolthemifthereisnoevidenceofadifferenceineffects.Thetypeofsolutionusedduringauraltoiletingwillalsobeconsideredwhensubgroupingtheinterventions.

Antisepticagent:Wewilltreateachtypeofantisepticasaseparatesubgroupunlessthereisinformationthattheysharethesamemechanismofactionandareusedinthesameway(e.g.thesameeffectiveconcentrationlevelsandwhethertheyareusedasstand-alonedropsoraspartofanauraltoiletingprocedure).

3.4.2 Time points of outcomes measurement Toavoidmultiplicityofanalysisorreviewerbias,wewillpredeterminethetimepointsforanalysisforeachoutcome,andwewillonlyusethelongestavailabledatafromthestudywithinthespecifiedperiodintheanalysis.Wewillspecifythetimepointsfordataanalysisintheprotocolforeachinterventionreviewandtakeintoconsiderationboththemechanismsofactionoftheintervention-comparisonpairinvolvedandthenaturalhistoryofCOM.

3.5 RATING OF QUALITY OF EVIDENCE WewillratethequalityofevidenceusingtheGRADEcriteriaforsystematicreviews.