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1、ClinicalepidemiologyofALI/ARDSIncidenceofrespiratoryfailure,mechanicalventilation,andALI/ARDSinICUStandarddiagnosisandcaremanagementClinicaltrial,controlandinterventionFollowupoutcomesAssesscost-effectivenessMedicalresources,network第1页/共54页上海市医院急性呼吸窘迫综合征临床发病情况调查上海市医院急性呼吸窘迫综合征临床发病情况调查A12-MonthSurveyo
2、fARDSinAdultICUsShanghaiARDSStudyGroupIntensiveCareMed2004;30(12):2197-2203 第2页/共54页Morbidity15PICUs,5320admissions/2001-2002(12mon)108ARDS(2%ofadmission)(Europe6-7%)15yearsold24hofadmission,2.5(n)33Intensive Care Med 2004;30(12):2197-2203第3页/共54页MortalityDeath:74(68.5%)in-hospital76(70.4%)at3months
3、afteronsetDeathrate(病死率)ICUtotaldeath548/5320(10.3%)ARDS/ICUtotaldeath 74/548(13.5%)ARDS:non-ARDS6.4:1(RR)IntensiveCareMed2004;30(12):2197-2203第4页/共54页PredisposingfactorsofARDSDeathPulmonaryorigin41(39%)32-Pneumonia37(34.3%)29Non-pulmonary67(61%)42-Sepsis33(30.6%)MODS44/74(60%)Respiratoryfailure17/7
4、4(23%)Septicshock9/74(12%)IntensiveCareMed2004;30(12):2197-2203第5页/共54页PediatricARDSA12-monthsurveyofincidence,managementandoutcomeofARDSin25pediatricICUinChinaChinesePediatricARDSStudyGroupATS2005SanDiegoIntlConference第6页/共54页第7页/共54页北京儿童医院首都儿研所儿童医院北京大学第一医院哈尔滨儿童医院中国医科大学第二医院河北医科大学第二医院天津儿童医院山西省儿童医院郑州
5、儿童医院重庆医科大学儿童医院广州儿童医院湖南省儿童医院长春市儿童医院深圳儿童医院成都市儿童医院泉州儿童医院江西省儿童医院浙江大学儿童医院温州育英儿童医院南京儿童医院苏州儿童医院上海儿童医学中心上海新华医院上海儿童医院复旦大学儿科医院小儿小儿ARDSARDS协作组协作组第8页/共54页PICU alladmissionsCriticalALI/ARDSSurvivaldeathPIM+GuidePIM+Guide1994 AECC1994 AECCTreatment基基本本流流程程第9页/共54页25 Pediatric ICU25 Pediatric ICU 2004.01-12 2004.0
6、1-12PICU total 11453Critical 6839RF呼吸衰竭1862MV 1883ALIALI303303ARDSARDS 97 97第10页/共54页ResultsIncidence/PICUadmissionARDS患病率 1.42%ALI患病率4.4%DeathrateARDS病死率62.9%(61)TotalPICU6.8%RRARDS:non-ARDS8.3:1Cost:ARDS/non-ARDS4.5:1第11页/共54页PredisposingfactorsofpediatricARDSPneumonia40Sepsis14Immunocompromised15
7、Intoxication8Post-operation4Trauma4Asphyxia3Others11第12页/共54页MeasurementtoreducemortalityEarlydiagnosisandmanagementVentilation:lowtidalvolumeSpecifictherapy:alveolaratelectasis:PEEP,surfactantintrapulmonaryshunting:inhaledNOfluidbalance:restrictedinfusionalveolarleakage:selectedcoloidrenal:CRRTexac
8、erbated:ECMO第13页/共54页临床意义ARDSARDS是是ICUICU最具代表性的、高死亡风险的危重症最具代表性的、高死亡风险的危重症 (综合征综合征)之一之一患病率占患病率占ICUICU收治收治1.5-2.0%,1.5-2.0%,病死率病死率60%60%临床流行病研究对于形成正确的诊断和治疗有助临床流行病研究对于形成正确的诊断和治疗有助于开展临床干预治疗于开展临床干预治疗(对照和基础治疗对照和基础治疗)中国人口高度集中的城市医院成为研究中国人口高度集中的城市医院成为研究ARDSARDS发生发生发展和转归的重要场所发展和转归的重要场所人群流行病资料依靠正确的临床诊断人群流行病资料依
9、靠正确的临床诊断加强区域、国际合作研究加强区域、国际合作研究第14页/共54页SurfactanttreatmentforARDS60sAdultRDSandneonatalRDS80Surfactantreplacementtherapy30RCT90SurfactantandARDS/NOandARDS2000-:RCTSurfactant/NO第15页/共54页EarlycasestudyofsurfactantreplacementforARDS(SpraggR,Chest1994;105:195-204)6ARDS,2days,3survivedCurosurf80mg/ml,4g/
10、50ml,50mg/kg(WalmrathAJRCCM1996;154:57-62)10ARDS,5survivedAlveofact300mg/kg,multipledosePaO2/FiO2200mmHg,Qs/Qt20%第16页/共54页MulticenterrandomizedcontrolledtrialAnzuetoANEJM1996,Exosurfaerosol(noSP)GregoryTJAJRCCM1997SurvantaLuchettiMPCCM2002Curosurf(Pediatric)WalmrathDERJ2002AlveolfactSpraggRAJRCCM200
11、3Venticute(SP-C)SpraggRNEJM2004VenticuteWillsonDFJAMA2005Calfactant第17页/共54页EffectofRecombinantSurfactantProteinCBasedSurfactantontheARDSSpraggRGetalNEJM2004;351:884-892448adultpatientswithARDSstandardtherapyalone(control)standardtherapy+surfactant(test)exogenoussurfactantdidnotimprovesurvival.exoge
12、noussurfactantimprovegasexchangeduring24-hourtreatmentperiod.第18页/共54页第19页/共54页EffectofCalfactantinPediatricALIWillsonDFetalJAMA.2005;293:470-6153children(age1weekto21years)withrespiratoryfailurefromALIAirplacebo(control)IntratrachealCalfactant100mg/kg(test)Calfactantgroup:oxygenationindex(20to13.9)
13、omortality(15/77)Placebogroup:oxygenationindex(20.5to15.1)oooomortality(27/75)Calfactantimprovedoxygenationanddecreasedmortality第20页/共54页SurfactantTreatmentofNeonatesWithRespiratoryFailureandGBSInfectionHertingEetal.Pediatrics2000;106:957-964118neonateswithGBSinfectionandrespiratoryfailuretreatedwit
14、hCurosurf(test);236noninfectedprematureneonatesRDS(control).Surfactantimprovesgasexchange;ResponsetosurfactantinGBSgroupisslowerthanincontrolgroup.第21页/共54页A-B,FiO2,PaO2/FiO2,aftersurfactanttreatment.*P.01*P.001versusbeforesurfactant.第22页/共54页Treatment of Severe Meconium Aspiration Syndrome with Por
15、cine Surfactant:A Multicenter,Randomized,Controlled TrialChinese Collaborative Study Group for Neonatal Respiratory DiseasesActaPaediatrica2005第23页/共54页QuestionsWhy surfactant does not work well in ALI/ARDS as neonatal RDS?Adverse effects of excessive fluid loadingVentilationMetabolism of surfactant
16、 in injured lungs第24页/共54页AlveolarandtissuepoolsizesinhumanlungsAlveolar(extracellular)surfactant(1-80yrs)Phospholipids3-5mg/kgDisaturatedphosphatidylcholine1-2mg/kgSP-A80-120ug/kg(RebelloCMetalAJRCCM1996;154:625-8)NeonatallungsatbirthPhospholipids20-30mg/kgDSPC10-15mg/kg第25页/共54页MetabolismofPCandpa
17、thobiology0.3mcgDPPCcovers1cm2surface3mgDPPC:1m2/kg,ortotalPL5-7mg/kgAdultpatient50-80kg,alveolarsurfacearea?Adultrat,rabbit,dog,pig50%VD:25-30%VT50%VTV/Q:0.81.0Qs/Qt:30%第28页/共54页SurfactantdysfunctionanddeficiencyinALI/ARDSAlveolaristhesiteofALI，injuryoftypeIIalveolarepithelialcellsConsistentevidenc
18、eofalteredsurfactantcompositionandfunctioninthelungs,amountofthemajorcomponentsisinverselycorrelatedtotheseverityofALI/ARDSHallmanM,JCI1982;70:673-683GregoryTJ,JCI1991;88:1976-1981SchmidtR,AJRCCM2001;163:95-100第29页/共54页SurfactantreplacementforALI/ARDSRationalesToincreasepoolsizeofsurfactantinalveoli
19、Tofacilitatere-distributionoflungfluidTocounter-balanceserumproteinleakageandinhibitionToalleviateworkingeffortofbreathandimprovecomplianceandresistenceToimproveventilation-perfussion第30页/共54页AminalmodelsforsurfactantreplacementLunglavagetodepletesurfactantOleicacidi.v.toinducealveolarcapillaryimpai
20、rmentEndotoxin,G-bacteriaNNNMethylurethaneMeconium,acid第31页/共54页AnimalmodelsforsurfactantreplacementAdvantageAcuteandsubacuteonsetoflunginjuryMeasurementoflungmechanics,hemodynamics,morphologyandchemistryDisatvantageTooshortinclinicalcourseLackingofrecoveryandlongtermoutcome第32页/共54页Multicenterrando
21、mizedcontrolledtrialQuestionsandproblems:PatientselectionandunderlyingdiseasesTypeofsurfactantTiming,dosinganddeliveryCost-benefitassessmentLimitationCombinedtherapyandsynergy第33页/共54页MulticenterrandomizedcontrolledtrialSolutions:SelecteandwelldefinepatientenrolmentStandardcare(controltidalvolume,ai
22、rwaypressure,fluidintake,etc.)SurfactantenrichedwithSP-B/CEarlierandmorearebetterBronchoscopicdelivery,bolusCombinedwithHFO,iNO,PP,CRRT,ECMO第34页/共54页InhaledNOandALI/ARDSSaynotoARDS,butsayNOtoALIRCTiNOvs.ARDS:failuretoimprovesurvivalReasonsComplexityofunderlyingdiseasesandoutcomeSingleintervention,me
23、chanisticreductionTiminganddosingandsafetyNewhopeaftersuccessinneonatesandinfants第35页/共54页DoseResponseCharacteristicsofNOinPatientswithSevereARDSGerlachHetalAmJRespirCritCareMed2003;167:1008-1015prospective,randomizedstudyin40ARDSpatientsconventionaltherapy:0ppmiNO(control);continuoustreatmentwith10
24、ppmiNO(test).measuredoseresponse(DR)curvesofPaO2/FiO2versustheiNOdoseatregularintervals0dayand2dayapeakresponseat10ppm(both)4daysapeakresponseat1ppm(iNOgroup)0apeakresponseat10ppm(controlgroup)第36页/共54页long-terminhaledNOwithconstantdosesof10ppmleadstoenhancedsensitivityafterseve-raldays,whichmaybeco
25、meoverdosesleadingtodeteriorationofoxygenationafterseveraldays.第37页/共54页iNOtoPreventIschemiaReperfusionInjuryafterLungTransplantationMaureenOetalAmJRespirCritCareMed2003;167:1483-1489Concealed,randomized,placebo-controlledtrialPaO2/FiO2150:(iNOversuscontrolgroup)14.6%versus9.5%p=0.48Timestounassiste
26、dbreathing:25vs.27hoursp=0.76ICUdischarge:3.0daysforbothgroupsNosignificanteffectofiNOonoutcomesinlungtransplantpatients.第38页/共54页Low-DoseiNOinAdultPatientswithALI JAMA2004;291:1603-1609Multicenter,randomized,placebo-controlledstudyintheICUof46hospitalsinUSANon-septic,nonpulmonaryMOSDPlacebo:nitroge
27、ngas(control);iNO:5ppm(test)iNOimprovesoxygenation,buthasnoimpactondurationofventilatorysupportormortality.第39页/共54页Effectsof10ppmiNOongasexchangein108childrenwithacutehypoxemicrespiratoryfailureDobynsELetalJPediatr1999;134:384-387Oxygenationindex:FiO2xMAPx100/PaO2OI:40ECMOControlNOp4h-2.7-10.2.0141
28、2h-2.8-9.2.007iNOcausesimprovementinoxygenationinHRF第40页/共54页iNOinPrematureInfantswithRDSSchreiberMDetalNEJM2003;349:2099-2105Randomized,double-blind,placebo-controlledstudyinvolving207prematureinfants iNO10ppmonday1,5ppmforsixdays(test)inhaledoxygenplaceboforsevendays(control)Mortalityormorbilityof
29、CLD:048.6%VS.63.7%P=0.03(iNOvs.Control)iNOinprematureinfantswithRDSdecreasestheincidenceofCLDanddeath第41页/共54页McCurnin DC et al:Inhaled NO&baboon CLDAm J Physiol Lung 2005;288:L450-459第42页/共54页iNOinVLBWinfantswithhypoplasticlungduetooligohydramniosUgaNetal PediatricsInternational2004;46:10-14Aretros
30、pectivecomparativestudyVLBW,pulmonaryhypoplasia,iNO(test);VLBW,pulmonaryhypoplasia(control).iNOimprovedoxygenationandsurvivalrate.第43页/共54页第44页/共54页SurfactantandinhaledNOZhuYRetalPulmonPharmacolTherap2005;18:303-3134weekpiglet,8-10kgIntraperitonealE.coliSepticALIin6hTreatmentfor24h1.Control2.Inhaled
31、NO10ppm3.Porcinesurfactant100mg/kg4.BothNOandsurfactant5.NormalcontrolwithoutE.coli第45页/共54页ControlNOSurfactant第46页/共54页SurfactantandNONormalZhu YR et al Pulmon Pharmacol Therap 2005;18:303-313第47页/共54页*NF-kappa BKGF mRNAIL-8 mRNAIL-10 mRNA第48页/共54页Figure 1-ANSNOSNOCZhu YR et al Pulmon Pharmacol The
32、rap 2005;18:303-313第49页/共54页Figure 1-BNSNOSNOC第50页/共54页Figure 1-CCNOSSNON第51页/共54页结论1.CombinedsurfactantandinhaledNOshouldplayakeyroleinlungprotectionforALI/ARDS2.Theeffectsareassociatedwithanti-inflammatoryinjurythroughNF-kappaBpathway3.Clinicalinvestigationmayhelptoevaluatecost/benefitofthesetherapiesinALI/ARDSfrompediatrictoadultpatients4.Betterlatethannever:inclinicaltrial第52页/共54页AcknowledgementShanghaiARDSStudygroupPediatricARDSStudygroupResearchstaffsandPhDstudents教育部，上海市科委，上海市教委、上海教育发教育部，上海市科委，上海市教委、上海教育发展基金会，上海市卫生局，美国展基金会，上海市卫生局，美国CMBCMB基金等资助基金等资助第53页/共54页感谢您的观看！第54页/共54页