Download pdf - Chronic Otitis Media · 2019-05-02 · Chronic otitis media scoping document (abbreviated version) 30th January 2017 Chronic Otitis Media A scoping exercise for areas of priority

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

CONFIDENTIAL-Chronicotitismediascopingdocument 2

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.


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


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


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.


Figure1:Areasinchronicotitismediacoveredinproposedscope

Note:boxesinblueareincludedintheproposedscope;boxesinorangeareoutsidetheproposedscope.


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


capturedinclinicaltrialsandshouldinanycaseresolvewithadryear,whichisalreadymeasuredasaprimaryoutcome.


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)


(Tentative)Reviewshortname2

Pair Population3

Intervention4

Comparison


usedasanadjuvanttreatmentinbotharms(e.g.topicalantiseptics).

otherinterventions(e.g.topicalantibiotics)?

4. CED Antibiotics-systemic

Systemicantibiotics(otherclasses)

7. Whichtypeofsystemicantibioticismoreeffective(whentheyarecomparedtoeachother)?

8. Whichsystemicantibioticismoreeffectivewhenaddedtootherinterventions?

3. Antibiotics-topicalversussystemic


Antibioticssystemic

ThisisthemaincomparisoncoveredbythecurrentCochranereviewofsystemicversustopicaltreatment,whichincludesninestudies.

9. Whataretherelativeeffectsoftopicalantibioticscomparedwithsystemicantibiotics(forthesameantibiotic)?

10. Whataretherelativeeffectsoftopicalantibioticscomparedwithsystematicantibiotics(fordifferentantibiotics)?

4. Topicalantibioticversustopicalantiseptic


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?



Pair Population3

Intervention4

Comparison


rmethod)

methodsandwhetherantisepticswereusedduringorimmediatelyaftertheauraltoiletingsession.

16. Whataretherelativeeffectsofdifferentauraltoiletingmethodswhenaddedontootherinterventions(e.g.topicalantibiotics)?

6. Antiseptics

9. CED Antiseptics


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


Thiswillincludestudiesthatlookattheimpactofaddingatopicalcorticosteroid(e.g.topicalcorticosteroidsplustopicalantibioticsversusanidenticaltopicalantibiotic).

21. Aretopicalsteroidseffective?

22. Aretopicalsteroidseffectivewhenaddedtootherinterventions(e.g.topicalantibiotics)?

12. CED Topicalcorticosteroids

Othertopicalsteroids

Thiswilllookatstudiesinvestigating

23. Whataretherelativeeffectsofdifferenttopicalsteroidpreparations?



Pair Population3

Intervention4

Comparison


differenttypesofcorticosteroids(e.g.AntibioticAplustopicalsteroidBversusantibioticAplustopicalsteroidC)

24. Whataretherelativeeffectsofdifferenttopicalsteroidswhenaddedtootherinterventions?

13. CED Topicalcorticosteroids+otherinterventions


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



Pair Population3

Intervention4

Comparison


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)

15

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.