兒童急性中耳炎的治療

兒童急性中耳炎的治療第一頁，共七十頁，編輯于2023年，星期日SOURCEINFORMATIONNEnglJMed,2011,364:105-115(hadbeencitedby16articles)FromtheDepartmentofPediatrics,UniversityofPittsburghSchoolofMedicine,USA.Correspondenceauthor:Dr.HobermanE-mail:hoberman@.2第二頁，共七十頁，編輯于2023年，星期日美國科學(xué)信息所（ISI）公布3第三頁，共七十頁，編輯于2023年，星期日IntroductionofTheNewEnglandJournalofMedicine(NEJM)1812年創(chuàng)刊，由美國麻州醫(yī)學(xué)協(xié)會所出版的同行評審性質(zhì)之綜合性醫(yī)學(xué)期刊。全科醫(yī)學(xué)周刊，每年52期出版風(fēng)格：重要的研究成果、臨床發(fā)現(xiàn)以及觀點。注重文章的實用性，多為指導(dǎo)臨床實踐。嚴(yán)格的審稿程序，稿件的處理流程通常需10—12周。來稿的刊用率約為7%。4第四頁，共七十頁，編輯于2023年，星期日BACKGROUNDAcuteotitismedia(AOM)isthemostfrequentlydiagnosedillnessinchildrenintheUS.MostchildrenhaveroutinelybeentreatedwithantimicrobialdrugsintheUS.1.TahtinenPA,etal.Aplacebo-controlledtrialofantimicrobialtreatmentforacuteotitismedia.NEnglJMed2011;364:116-1262.KleinJO.Isacuteotitismediaatreatabledisease?NEnglJMed2011;364:168-1695第五頁，共七十頁，編輯于2023年，星期日Awatchful-waitingstrategyhaslongbeenappliedinseveralcountriestominimizetheuseofantimicrobialdrugs.-NetherlandsandScotland4,5

-USA,2004,6,7-Canada8

4.AppelmanCL,etal.Otitismediaacuta:NHG-standaard(eersteherziening).HuisartsWet1999;42:362-3665.ScottishIntercollegiateGuidelinesNetwork.Diagnosisandmanagementofchildhoodotitismediainprimarycare.Guidelineno.66.Edinburgh:RoyalCollegeofPhysiciansinEdinburgh,2003.8.ForgieS,ZhanelG,RobinsonJ.Managementofacuteotitismedia.PaediatrChildHealth(Oxford)2009;14:457-4646第六頁，共七十頁，編輯于2023年，星期日AOMinchildrenaged6to23monthsis“nonsevere”6(mildotalgiaandT≤39℃duringthepreceding24hours)DiagnosisofAOMisuncertain.7IndicationsofWatchfulWaiting6.KaleidaPH,etal.Amoxicillinormyringotomyorbothforacuteotitismedia:resultsofarandomizedclinicaltrial.Pediatrics1991;87:466-474

7.AmericanAcademyofPediatricsSubcommitteeonManagementofAcuteOtitisMedia.Diagnosisandmanagementofacuteotitismedia.Pediatrics2004;113:1451-14657第七頁，共七十頁，編輯于2023年，星期日Thewatchfulwaitingstrategyhasbeenbasedontheresultsofclinicaltrials3thatshowedrelativelyhighratesofspontaneousimprovementinchildrenwithacuteotitismedia.Fundament3.RosenfeldRM,etal.Clinicalefficacyofantimicrobialdrugsforacuteotitismedia:metaanalysisof5400childrenfromthirty-threerandomizedtrials.JPediatr1994;124:355-3678第八頁，共七十頁，編輯于2023年，星期日Limitationsofearliertrials:-Thelackofstringentdiagnosticcriteria;-Theinclusionoffewveryyoungchildren;-Antimicrobialdrughadlimitedefficacyorwasadministeredinsuboptimaldoses.9

9.ParadiseJL.Short-courseantimicrobialtreatmentforacuteotitismedia:notbestforinfantsandyoungchildren.JAMA1997;278:1640-1642Tochooseamoxicillin–clavulanate(themosteffectivetreatmentforAOM)7,10inthisstudy.10.HobermanA,etal.Largedosageamoxicillin/clavulanate,comparedwithazithromycin,forthetreatmentofbacterialacuteotitismediainchildren.PediatrInfectDisJ2005;24:525-5329第九頁，共七十頁，編輯于2023年，星期日Ratesofspontaneousimprovementsimilartotheratesseeninthosestudiesamongchildrenreceivingplacebohavenotbeenfounduniformly.6

Therefore,forchildrenwithAOM,thecircumstancesinwhichimmediateantimicrobialtreatmentisthepreferredstrategyhaveremainedunclear.10第十頁，共七十頁，編輯于2023年，星期日OBJECTIVESToevaluatetheextenttowhichantimicrobialtreatment(Amoxicillin-clavulanate)andplacebotreatmentaffectthecourseofbothsymptomsandsignsofAOMinchildrenaged6to23months.11第十一頁，共七十頁，編輯于2023年，星期日METHODSEligibilityandEnrollmentRandomizationAssessmentofSymptomsOtoscopicExamination,OverallAssessment,andManagementOutcomesStatisticalAnalysis12第十二頁，共七十頁，編輯于2023年，星期日1.EligibilityandEnrollmentFromNovember2006toMarch2009attheChildren'sHospitalofPittsburghandArmstrongPediatrics,Pennsylvania.ThestudyprotocolwasapprovedbytheinstitutionalreviewboardattheUniversityofPittsburgh;writteninformedconsentwasobtainedfromaparentofeachenrolledchild.Theprotocol

isavailablewiththefulltextofthisarticleatNEJM.org.13第十三頁，共七十頁，編輯于2023年，星期日

InclusionCriteriaEligiblechildren(1)willbeaged6to23months,(2)havereceivedpneumococcalconjugatevaccine,and(3)haveevidenceofAOMdefinedas:Recent(within48hours),onsetofsignsandsymptomsandascoreof≥3ontheAOM-SOSscale.Presenceofmiddle-eareffusionModerateormarkedbulgingofthetympanicmembraneorslightbulgingaccompaniedbyeitherotalgiaormarkederythemaofthemembrane.14第十四頁，共七十頁，編輯于2023年，星期日AOM-SOSTheAcuteOtitisMediaSeverityofSymptoms(AOM-SOS)scale11,12

TheAOM-SOSscaleconsistsofsevenitems:tuggingofears,crying,irritability,difficultysleeping,diminishedactivity,diminishedappetite,andfever.As“none,”“alittle,”or“alot,”withcorrespondingscoresof0,1,and2scoresrangefrom0to14,withhigherscoresindicatinggreaterseverityofsymptoms11.ShaikhN,etal.Developmentandpreliminaryevaluationofaparent-reportedoutcomeinstrumentforclinicaltrialsinacuteotitismedia.PediatrInfectDisJ2009;28:5-812.ShaikhN,etal.Responsivenessandconstructvalidityofasymptomscaleforacuteotitismedia.PediatrInfectDisJ2009;28:9-1215第十五頁，共七十頁，編輯于2023年，星期日AOM-SOS16第十六頁，共七十頁，編輯于2023年，星期日ExclusionCriteriaChildren(1)hadanotheracuteillness(e.g.,pneumonia)orachronicillness(e.g.,cysticfibrosis),(2)wereallergictoamoxicillin,(3)hadreceivedmorethanonedoseofanantimicrobialdrugwithintheprevious96hours,(4)hadhadotalgiaforlongerthan48hours,or(5)hadperforationofthetympanicmembrane.17第十七頁，共七十頁，編輯于2023年，星期日ExclusionCriteria(protocol)(1)certainsignsorsymptoms(e.g.,toxicappearance,otalgia>48hours,spontaneousperforationofthetympanicmembraneanddrainageortemperature≥105?F);

(2)clinicaloranatomicalcharacteristicsthatmightobscureresponsetotreatment(e.g.,tympanostomy,submucouscleftpalate,high-archedpalate,orDown'ssyndrome);(3)underlyingsystemicproblemsthatmightobscureresponsetoinfection(e.g.,seriousunderlyingdisease[e.g.,cysticfibrosis,neoplasm,juvenilediabetes]),concomitantinfection,knownrenalinsufficiency,knownhepaticinsufficiency,historyofimmunedysfunction,chronicgastrointestinalconditions,malignancy;18第十八頁，共七十頁，編輯于2023年，星期日(4)sensorineuralhearingloss;(5)comedications(e.g.,systemiccorticosteroidsatanypointwhileenrolledinthestudy,morethanonedoseofsystemicantimicrobialtherapywithin96hours,anyinvestigationaldrugorvaccine;(6)hypersensitivitytopenicillin,amoxicillinoramoxicillin-clavulanate,orphenylketonuriaorknownhypersensitivitytoaspartame;(7)unabletocompletethestudyprotocolornothavingaccesstoatelephone;and(8)currentenrollmentinanotherstudyorpreviouslyenrolledinthisstudy.

aspartame阿司帕坦;phenylketonuria苯丙酮酸尿19第十九頁，共七十頁，編輯于2023年，星期日2.RandomizationStratificationaccordingtohistoryofrecurrentAOM(definedas≥3episodesin6monthsor≥4episodesin1year)andaccordingtotheirexposureornonexposuretothreeormorechildrenforatleast10hoursperweek.Ateachstudysite,withineachstratum,werandomlyassignedchildreninblocksoffour,ina1:1ratio20第二十頁，共七十頁，編輯于2023年，星期日Amoxicillin–clavulanate(AugmentinES,GlaxoSmithKline),90/6.4mg/kg/dayin2divideddosesfor10days.PlacebowassimilartoAmoxicillin–clavulanateinappearanceandtaste.Theparentswereunawareofthechildren'sgroupassignments.Parentspreparedacetaminophenasneededforthereliefofsymptoms.21第二十一頁，共七十頁，編輯于2023年，星期日3.AssessmentofSymptomsStructuredinterviewbytelephoneeverydayuntilthefirstfollow-upvisitandinpersonateachvisit.Parentsrecordtheirchild'sAOM-SOSscoresandotherpertinentclinicalinformationinadiarytwiceadayfor3daysandonceadaythereafter.22第二十二頁，共七十頁，編輯于2023年，星期日4.OtoscopicExamination,OverallAssessment,andManagementOtoscopyonday1,day4-5,day10-12,day21-25.SlightOtoscopicPhotographsModerate

markedbulgingoftympanicmembrane23第二十三頁，共七十頁，編輯于2023年，星期日OverallAssessmentTocategorizeclinicalsuccessorclinicalfailureateachvisit.Clinicalfailureatorbeforetheday4–5visit:alackofsubstantialimprovementinsymptoms,aworseningofsignsonotoscopicexamination,orboth.Clinicalfailureattheday10–12visit:thefailuretoachievecompleteornearlycompleteresolutionofsymptomsandofotoscopicsigns.13.KaleidaPH.Assessmentofotoscopists'accuracyregardingmiddle-eareffusion:otoscopicvalidation.AmJDisChild1992;146:433-43524第二十四頁，共七十頁，編輯于2023年，星期日ManagementforclinicalfailurecasesAstandardized10-dayregimenoforallyadministeredamoxicillin,atadoseof90mg/kg/day,andcefixime,atadoseof8mg/kg/day.Onceachildhadmetthecriteriaforclinicalfailure,heorsheremainedinthatcategoryfortheanalyses.25第二十五頁，共七十頁，編輯于2023年，星期日Relapseattheday21–25visit:thereappearanceofAOMinachildwhohadpreviouslybeencategorizedashavingmetthecriteriaforclinicalsuccess.26第二十六頁，共七十頁，編輯于2023年，星期日Toobtainnasopharyngealspecimensfromthechildrenforculturing,atstudyentryandattheday10–12andday21–25visits.27第二十七頁，共七十頁，編輯于2023年，星期日5.OutcomesTheprimaryoutcomemeasures

A.Thetimetoresolutionofsymptoms:

-ThetimetothefirstrecordingofanAOM-SOSscoreof0or1-Thetimetothesecondoftwosuccessiverecordingsofthatscore.B.Thesymptomburdenovertime:

-ThemeanAOM-SOSscoreofeachdayoverthefirst7daysoffollow-up-Thegroups'weightedmeanscoresforthatperiod.28第二十八頁，共七十頁，編輯于2023年，星期日Thesecondaryoutcomes:OverallclinicalefficacyTheoccurrenceofadverseeventsNasopharyngealcolonizationratesTheuseofacetaminophenTheuseofhealthcareresources.29第二十九頁，共七十頁，編輯于2023年，星期日6.StatisticalAnalysisSampleestimates:asampleof120childrenineachstudygroup.Alltheanalyseswerebasedontheintention-to-treatprinciple,wereperformedwiththeuseoftwo-sidedtests,andincludedadjustmentforthestudystratificationvariables.30第三十頁，共七十頁，編輯于2023年，星期日Tocomparethetimetotheresolutionofsymptomsbetweenthestudygroupsusinglife-tableplots,andtoconducttestsofequalhazardfunctionsusingaproportional-hazardsmodel.TocomparethemeanAOM-SOSscoresinthetwogroupsatindividualassessmentseachdayoverthefirst7daysoffollow-upusinggeneralizedestimatingequations,andthegroups'weightedmeanscoresforthatperiodusingregressionanalysis.31第三十一頁，共七十頁，編輯于2023年，星期日Foranalysesofclinicalsuccessorfailure,weusedlogisticregression.Todeterminewhethervariableswereprognosticoreffectmodifiers,weusedtheproportional-hazardsmodelorlogistic-regressionmodels.TousedMcNemar'stestforanalysesofnasopharyngealcolonizationrates.32第三十二頁，共七十頁，編輯于2023年，星期日RESULTS1.StudyPopulation2.EfficacyofTreatment

-SymptomaticResponse-ClinicalFailure-PrognosticFactorsandEffectModifiers-RelapseandResidualMiddle-EarEffusion3.NasopharyngealColonizationandOtherOutcomes4.ComplicationsandAdverseEvents33第三十三頁，共七十頁，編輯于2023年，星期日1.StudyPopulation1385Childrenwereassessedforeligibility887Werenoteligible498Wereeligible291Underwentrandomization207Hadparentwhodeclinedparticipation144Wereassignedtoandreceivedamoxicillin–clavulanate147Wereassignedtoandreceivedplacebo34第三十四頁，共七十頁，編輯于2023年，星期日35第三十五頁，共七十頁，編輯于2023年，星期日

SelectedDemographicandClinicalCharacteristics(1)1.Ageatentry6–11mo12–17mo18–23mo2.SexMaleFemale3.RaceWhiteBlackOther4.MaternallevelofeducationLessthanhighschoolHigh-schoolgraduateCollegegraduate5.TypeofhealthinsurancePrivateMedicaid6.ExposuretootherchildrenYesNo36第三十六頁，共七十頁，編輯于2023年，星期日7.AOM-SOSscore(1)Baselinescore3–56–89–1112–14(2)Meanbaselinescore(±SD)8.LateralityofacuteotitismediaBilateralUnilateral9.DegreeoftympanicmembranebulginginworseearSlightModerateMarkedSelectedDemographicandClinicalCharacteristics(2)Therewerenosignificantdifferencesincharacteristicsbetweenthetwostudygroups.37第三十七頁，共七十頁，編輯于2023年，星期日Therewerenosignificantdifferencesincharacteristicsbetweenthetwostudygroups.38第三十八頁，共七十頁，編輯于2023年，星期日Therewerenosignificantdifferencesbetweenenrolledchildrenandchildrenwhoseparentswithheldconsentorbetweenthechildreninthetwostudygroups.Therewerenosignificantcorrelationbetweenchildren'sAOM-SOSscoresatentryandthedegreeofbulgingoftheiraffectedtympanicmembranes.39第三十九頁，共七十頁，編輯于2023年，星期日2.EfficacyofTreatment:2.1SymptomaticResponseTheproportionofchildreninwhomsymptomshadnotresolved40第四十頁，共七十頁，編輯于2023年，星期日

Day2Day4Day7GroupA35%61%80%GroupB28%54%74%P=0.14fortheoverallcomparisonRatesofthefirstrecordingofa

scoreof0or1GroupA:childrenwhoweretreatedwithamoxicillin–clavulanateGroupB:childrenwhoweretreatedwithplacebo41第四十一頁，共七十頁，編輯于2023年，星期日42第四十二頁，共七十頁，編輯于2023年，星期日Day2Day4Day7GroupA20%41%67%GroupB14%36%53%P=0.04fortheoverallcomparisonRatesoftwosuccessiverecordingsofascoreof0or1

In54%oftheinstancesinwhichscoresfellto0or1,asubsequentscorewashigherthan1.43第四十三頁，共七十頁，編輯于2023年，星期日44第四十四頁，共七十頁，編輯于2023年，星期日ThemeanAOM-SOSscoresoverthefirst7dayswerelowerintheamoxicillin–clavulanategroupthanintheplacebogroupateachtimepoint(P=0.02)andatthe10–12dayvisit(1.59±0.21vs.2.46±0.20;P=0.003).GroupAGroupBPValue*Score≤82.21±0.162.58±0.190.14Score＞83.59±0.274.50±0.280.02*InitialAOM-SOSscoreattrialentryThe7-dayweightedmeanscore45第四十五頁，共七十頁，編輯于2023年，星期日The7-dayweightedmean(±SE)scorewaslowerintheamoxicillin–clavulanategroupthanintheplacebogroup(2.79±0.16vs.3.42±0.18;P=0.01).46第四十六頁，共七十頁，編輯于2023年，星期日GroupAGroupBPValue*Day4-54%23%<0.001Day10-1216%51%<0.001*Atorbeforetheday(n)Ratesofclinicalfailureatdifferenttime2.2ClinicalFailure47第四十七頁，共七十頁，編輯于2023年，星期日nofC.F.nofascore≥2%#*Day4-5393385%Day10-12956063%*Atorbeforetheday(n)C.F.denotesclinicalfailure#Nodifferencebetweentheproportions.Proportionsofascore≥2inallclinicalfailureatdifferenttime48第四十八頁，共七十頁，編輯于2023年，星期日Nochildwascategorizedashavingmetthecriteriaforclinicalfailureonthebasisofsymptomsalone.MeanscoresofclinicalfailureandnotclinicalfailureatdifferenttimeMeanscoreofC.F.MeanscoreofnotC.F.Atday4-55.0±3.22.2±2.3Atday10-123.7±3.31.2±1.8C.F.denotesclinicalfailure49第四十九頁，共七十頁，編輯于2023年，星期日2.3PrognosticFactorsandEffectModifiersAtday10to12Children’sexposureornonexposure,(P=0.007)ChildrenwithhigherAOM-SOSscoresatentryandwithlowerscores(P=0.004)ChildrenwithbilateralAOMwithunilateralAOM(P=0.002)Childrenwithmorebulgingofthetympanicmembraneandwithlessbulging(P<0.001)50第五十頁，共七十頁，編輯于2023年，星期日51第五十一頁，共七十頁，編輯于2023年，星期日Atday10–12,theratesofclinicalfailureinsevereandnonsevereconditionsinitiallyGroupAGroupB*Severe12/63(19%)40/66(61%)Nonsevere11/79(14%)33/77(43%)*SeveredenotesmoderateorsevereotalgiaorT＞39℃duringthepreceding24hours52第五十二頁，共七十頁，編輯于2023年，星期日Children18to23monthsofagewhoreceivedamoxicillin–clavulanatehadahigherrateofclinicalfailurethandidchildren12to17monthsofageandchildren6to11monthsofage(38%vs.12%and11%,respectively)53第五十三頁，共七十頁，編輯于2023年，星期日2.4RelapseandResidualMiddle-EarEffusionAttheday21–25visit.GroupAGroupBPValueRelapse19/119(16%)13/70(19%)0.5671/141(50%)87/139(63%)0.05Middle-eareffusion54第五十四頁，共七十頁，編輯于2023年，星期日3.NasopharyngealColonizationandOtherOutcomesFromday1totheday21–25visit,therewerenosignificantchangesineithergroupintheratesofnasopharyngealcolonizationwithnonsusceptibleStreptococcuspneumoniae.

55第五十五頁，共七十頁，編輯于2023年，星期日Therewerenosignificantdifferencesbetweenthestudygroupineitherthemeandailynumberofdosesofacetaminophenadministered(0.37and0.43,respectively;P=0.35)ortheuseofhealthcareresources.56第五十六頁，共七十頁，編輯于2023年，星期日4.ComplicationsandAdverseEventsMastoiditisdevelopedinonechildintheplacebogrouponday5.Diarrheaanddiaper-areadermatitisweremorecommonamongchildrenwhoreceivedamoxicillin–clavulanate.PerforationoftympanicmembraneOralthrushVomitingRash57第五十七頁，共七十頁，編輯于2023年，星期日58第五十八頁，共七十頁，編輯于2023年，星期日DISCUSSIONChildrentreatedwithamoxicillin–clavulanatehadconsistentlymorefavorableshort-termoutcomes,including:Asustainedsymptomaticresponse,Anabsenceofotoscopicevidenceofpersistentmiddle-earinfection,Areducedrateofresidualmiddle-eareffusion.59第五十九頁，共七十頁，編輯于2023年，星期日Therewerenosignificantbetween-groupdifferencesintheuseofanalgesicdrugsorhealthcareresources.60第六十頁，共七十頁，編輯于2023年，星期日Theratesofclinicalfailureweregreatestamongchildrenwhoweremostseverelyaffectedinitially.61第六十一頁，共七十頁，編輯于2023年，星期日Theprincipalsideeffectswerediarrheaanddermatitisinthediaperarea,butthesideeffectswereusuallynotsevereenoughtodiscontinuethetreatmentofthedrugs.62第六十二頁，共七十頁，編輯于2023年，星期日Inkeepingwithrecentrecommendations,15Theauthorschosetheresolutionofsymptomsandthesymptomburdenovertimeastheprimaryoutcomeofinterest.Tocategorizeoveralloutcomesaseitherclinicalsuccessorclinicalfailureaccordingtothecombinationofsymptomaticresponseandmiddle-earfindings.15.Guidanceforindustry—acutebacterialotitismedia:developingdrugsfortreatment.Revision1.Rockville,MD:FoodandDrugAdministration,CenterforDrugEvaluationandResearch,200863第六十三頁，共七十頁，編輯于2023年，星期日Thedifferencesinsymptomscoresbetweenthetwostudygroupsweremodestduringthefirst10days;thedifferenceswereobservedmainlyamongthechildrenwiththemostseveresymptomsinitially.Incontrast,differencesintheoverallclinicalresponseweresubstantial,irrespectiveoftheinitialseverityofAOM.64第六十四頁，共七十頁，編輯于2023年，星期日Overallclinicalresponseconstitutesthemoretellingmeasureofoutcome.Amonginfantsandyoungchildren,AOMmaybeentirelyasymptomatic16,17

SymptomsmaynotdifferentiateAOMfromotherrespiratoryillnesses18