1、1.ARDS临床流行病调查临床流行病调查2.肺表面活性物质肺表面活性物质/吸入吸入NO治疗治疗ALI/ARDS 孙波孙波 复旦大学儿科医院复旦大学儿科医院Clinical Epidemiology of ARDS in ChinaSurfactant and iNO in Treatment of ARDSBo Sun,MD,PhDChildrens Hospital of Fudan University2005-03-19 BeijingClinical epidemiology of ALI/ARDS Incidence of respiratory failure,mechanical
2、 ventilation,and ALI/ARDS in ICU Standard diagnosis and care management Clinical trial,control and intervention Follow up outcomes Assess cost-effectiveness Medical resources,network上海市医院急性呼吸窘迫综合征上海市医院急性呼吸窘迫综合征临床发病情况调查临床发病情况调查A 12-Month Survey of ARDS in Adult ICUsShanghai ARDS Study GroupIntensive
3、Care Med 2004;30(12):2197-2203 Morbidity 15 PICUs,5320 admissions/2001-2002(12 mon)108 ARDS(2%of admission)(Europe 6-7%)15 years old 24 h of admission,2.5(n)33Intensive Care Med 2004;30(12):2197-2203MortalityDeath:74(68.5%)in-hospital 76(70.4%)at 3 months after onsetDeath rate(病死率病死率)ICU total death
4、548/5320(10.3%)ARDS/ICU total death 74/548(13.5%)ARDS:non-ARDS6.4:1(RR)Intensive Care Med 2004;30(12):2197-2203 Predisposing factors of ARDSDeath Pulmonary origin41(39%)32-Pneumonia37(34.3%)29 Non-pulmonary67(61%)42-Sepsis33(30.6%)MODS44/74(60%)Respiratory failure17/74(23%)Septic shock 9/74(12%)Inte
5、nsive Care Med 2004;30(12):2197-2203 Pediatric ARDSA 12-month survey of incidence,management and outcome of ARDS in 25 pediatric ICU in ChinaChinese Pediatric ARDS Study GroupATS 2005 San Diego Intl Conference北京儿童医院北京儿童医院首都儿研所儿童医院首都儿研所儿童医院北京大学第一医院北京大学第一医院哈尔滨儿童医院哈尔滨儿童医院中国医科大学第二医院中国医科大学第二医院河北医科大学第二医院河
6、北医科大学第二医院天津儿童医院天津儿童医院山西省儿童医院山西省儿童医院郑州儿童医院郑州儿童医院重庆医科大学儿童医院重庆医科大学儿童医院广州儿童医院广州儿童医院湖南省儿童医院湖南省儿童医院长春市儿童医院长春市儿童医院深圳儿童医院深圳儿童医院成都市儿童医院成都市儿童医院泉州儿童医院泉州儿童医院江西省儿童医院江西省儿童医院浙江大学儿童医院浙江大学儿童医院温州育英儿童医院温州育英儿童医院南京儿童医院南京儿童医院苏州儿童医院苏州儿童医院上海儿童医学中心上海儿童医学中心上海新华医院上海新华医院上海儿童医院上海儿童医院复旦大学儿科医院复旦大学儿科医院小儿小儿ARDSARDS协作组协作组PICU alladm
7、issionsCriticalALI/ARDSSurvivaldeathPIM+GuidePIM+Guide1994 1994 AECCAECCTreatment基本流程基本流程25 Pediatric ICU25 Pediatric ICU 2004.01-12 2004.01-12PICU total 11453Critical 6839RF呼吸衰竭呼吸衰竭1862MV 1883ALIALI303303ARDSARDS 97 97ResultsIncidence/PICU admission ARDS 患病率患病率 1.42%ALI 患病率患病率4.4%Death rateARDS病死率病
8、死率62.9%(61)Total PICU 6.8%RRARDS:non-ARDS 8.3:1Cost:ARDS/non-ARDS 4.5:1Predisposing factors of pediatric ARDS Pneumonia40 Sepsis14 Immunocompromised15 Intoxication 8 Post-operation 4 Trauma 4 Asphyxia 3 Others11Measurement to reduce mortality Early diagnosis and management Ventilation:low tidal volu
9、me Specific therapy:alveolar atelectasis:PEEP,surfactantintrapulmonary shunting:inhaled NOfluid balance:restricted infusionalveolar leakage:selected coloidrenal:CRRTexacerbated:ECMO 临床意义临床意义 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%
10、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Surfactant treatment for ARDS 60s Adult RDS and neonatal RDS 80 Surfactant replacement therapy 30 RCT
11、90 Surfactant and ARDS/NO and ARDS 2000-:RCT Surfactant/NOEarly case study of surfactant replacement for ARDS(Spragg R,Chest 1994;105:195-204)6 ARDS,2 days,3 survived Curosurf 80 mg/ml,4 g/50 ml,50 mg/kg(Walmrath AJRCCM 1996;154:57-62)10 ARDS,5 survived Alveofact 300 mg/kg,multiple dose PaO2/FiO2 20
12、0 mmHg,Qs/Qt 20%Multicenter randomized controlled trialAnzueto A NEJM 1996,Exosurf aerosol(no SP)Gregory TJ AJRCCM 1997 SurvantaLuchetti M PCCM 2002 Curosurf(Pediatric)Walmrath D ERJ 2002 AlveolfactSpragg R AJRCCM 2003 Venticute(SP-C)Spragg R NEJM 2004 VenticuteWillson DF JAMA 2005 CalfactantEffect
13、of Recombinant Surfactant Protein CBased Surfactant on the ARDSSpragg RG et al NEJM 2004;351:884-892Effect of Calfactant in Pediatric ALIWillson DF et al JAMA.2005;293:470-6 153 children(age 1 week to 21 years)with respiratory failure from ALI Air placebo(control)Intratracheal Calfactant 100 mg/kg(t
14、est)Calfactant group:oxygenation index(20 to 13.9)o mortality (15/77)Placebo group:oxygenation index(20.5 to 15.1)o o o o mortality (27/75)Calfactant improved oxygenation and decreased mortalitySurfactant Treatment of Neonates With Respiratory Failure and GBS Infection Herting E et al.Pediatrics 200
15、0;106:957-964 118 neonates with GBS infection and respiratory failure treated with Curosurf(test);236 noninfected premature neonates RDS(control).Surfactant improves gas exchange;Response to surfactant in GBS group is slower than in control group.A-B,FiO2,PaO2/FiO2,after surfactant treatment.*P.01*P
16、.001versus before surfactant.Treatment of Severe Meconium Aspiration Syndrome with Porcine Surfactant:A Multicenter,Randomized,Controlled Trial Chinese Collaborative Study Group for Neonatal Respiratory DiseasesActa Paediatrica 2005Questions Why surfactant does not work well in ALI/ARDS as neonatal
17、RDS?Adverse effects of excessive fluid loading Ventilation Metabolism of surfactant in injured lungsAlveolar and tissue pool sizes in human lungs Alveolar(extracellular)surfactant(1-80 yrs)Phospholipids3-5 mg/kgDisaturated phosphatidylcholine1-2 mg/kgSP-A 80-120 ug/kg(Rebello CM et al AJRCCM 1996;15
18、4:625-8)Neonatal lungs at birthPhospholipids 20-30 mg/kgDSPC 10-15 mg/kgMetabolism of PC and pathobiology 0.3 mcg DPPC covers 1 cm2 surface 3 mg DPPC:1 m2 /kg,or total PL 5-7 mg/kg Adult patient 50-80 kg,alveolar surface area?Adult rat,rabbit,dog,pig 50%VD:25-30%VT50%VT V/Q:0.81.0 Qs/Qt:30%Surfactan
19、t dysfunction and deficiency in ALI/ARDS Alveolar is the site of ALI，injury of type II alveolar epithelial cells Consistent evidence of altered surfactant composition and function in the lungs,amount of the major components is inversely correlated to the severity of ALI/ARDSHallman M,JCI 1982;70:673
20、-683Gregory TJ,JCI 1991;88:1976-1981Schmidt R,AJRCCM 2001;163:95-100Surfactant replacement for ALI/ARDSRationales To increase pool size of surfactant in alveoli To facilitate re-distribution of lung fluid To counter-balance serum protein leakage and inhibition To alleviate working effort of breath a
21、nd improve compliance and resistence To improve ventilation-perfussionAminal models for surfactant replacement Lung lavage to deplete surfactant Oleic acid i.v.to induce alveolar capillary impairment Endotoxin,G-bacteria NNN Methylurethane Meconium,acid Animal models for surfactant replacementAdvant
22、age Acute and subacute onset of lung injury Measurement of lung mechanics,hemodynamics,morphology and chemistryDisatvantage Too short in clinical course Lacking of recovery and long term outcomeMulticenter randomized controlled trialQuestions and problems:Patient selection and underlying diseases Ty
23、pe of surfactant Timing,dosing and delivery Cost-benefit assessment Limitation Combined therapy and synergyMulticenter randomized controlled trialSolutions:Selecte and well define patient enrolment Standard care(control tidal volume,airway pressure,fluid intake,etc.)Surfactant enriched with SP-B/C E
24、arlier and more are better Bronchoscopic delivery,bolus Combined with HFO,iNO,PP,CRRT,ECMOInhaled NO and ALI/ARDS Say no to ARDS,but say NO to ALI RCT iNO vs.ARDS:failure to improve survivalReasonsComplexity of underlying diseases and outcomeSingle intervention,mechanistic reductionTiming and dosing
25、 and safetyNew hope after success in neonates and infantsDoseResponse Characteristics of NO in Patients with Severe ARDSGerlach H et al Am J Respir Crit Care Med 2003;167:1008-1015 prospective,randomized study in 40 ARDS patients conventional therapy:0 ppm iNO(control);continuous treatment with 10 p
26、pm iNO(test).measure doseresponse(DR)curves of PaO2/FiO2 versus the iNO dose at regular intervals 0 day and 2day a peak response at 10 ppm(both)4 daysa peak response at 1 ppm (iNO group)0 a peak response at 10 ppm (control group)long-term inhaled NO with constant doses of 10 ppm leads to enhanced se
27、nsitivity after seve-ral days,which may become overdoses leading to deterioration of oxygenation after several days.iNO to Prevent IschemiaReperfusion Injury after Lung Transplantation Maureen O et al Am J Respir Crit Care Med 2003;167:1483-1489 Concealed,randomized,placebo-controlled trial PaO2/FiO
28、2150:(iNO versus control group)14.6%versus 9.5%p=0.48 Times to unassisted breathing:25 vs.27 hours p=0.76 ICU discharge:3.0 days for both groups No significant effect of iNO on outcomes in lung transplant patients.Low-Dose iNO in Adult Patients with ALI JAMA 2004;291:1603-1609 Multicenter,randomized
29、,placebo-controlled study in the ICU of 46 hospitals in USA Non-septic,nonpulmonary MOSD Placebo:nitrogen gas(control);iNO:5 ppm(test)iNO improves oxygenation,but has no impact on duration of ventilatory support or mortality.Effects of 10 ppm iNO on gas exchange in 108 children with acute hypoxemic
30、respiratory failureDobyns EL et al J Pediatr 1999;134:384-387Oxygenation index:FiO2 x MAP x 100/PaO2OI:40 ECMOControlNOp4 h-2.7-10.2.01412 h-2.8-9.2.007 iNO causes improvement in oxygenation in HRFiNO in Premature Infants with RDS Schreiber MD et al NEJM 2003;349:2099-2105 Randomized,double-blind,pl
31、acebo-controlled study involving 207 premature infants iNO 10 ppm on day 1,5 ppm for six days (test)inhaled oxygen placebo for seven days(control)Mortality or morbility of CLD:0 48.6%VS.63.7%P=0.03(iNO vs.Control)iNO in premature infants with RDS decreases the incidence of CLD and deathMcCurnin DC e
32、t al:Inhaled NO&baboon CLDAm J Physiol Lung 2005;288:L450-459iNO in VLBW infants with hypoplastic lung due to oligohydramniosUga N et al Pediatrics International 2004;46:10-14 A retrospective comparative study VLBW,pulmonary hypoplasia,iNO(test);VLBW,pulmonary hypoplasia(control).iNO improved oxygen
33、ation and survival rate.INO treated group Control group P value Survived more than 7days 8 5 0.05 28 days 8 5 0.05 Oxygenation index 6.73.7*12.29.79.7 0.05 Air leak 2 1 NS IVH 1-2 1 2 NS 3-4 0 0 NS Bronchopulmonary 6 3 NS IVH,intraventricular hemorrhage;NS,not significant.*P0.001,before and after th
34、e iNO treatment in the iNO-treated group.Surfactant and inhaled NOZhu YR et al Pulmon Pharmacol Therap 2005;18:303-313 4 week piglet,8-10 kg Intraperitoneal E.coli Septic ALI in 6 h Treatment for 24 h1.Control2.Inhaled NO 10 ppm3.Porcine surfactant 100 mg/kg4.Both NO and surfactant5.Normal control w
35、ithout E.coliControlNOSurfactantSurfactant and NONormalZhu YR et al Pulmon Pharmacol Therap 2005;18:303-313*00.40.81.2CNOSurfSNONKGF/-actin ratioNF-kappa BKGF mRNAIL-8 mRNAIL-10 mRNAFigure 1-ANSNOSNOCZhu YR et al Pulmon Pharmacol Therap 2005;18:303-313Figure 1-BNSNOSNOCFigure 1-CCNOSSNON结论结论1.Combin
36、ed surfactant and inhaled NO should play a key role in lung protection for ALI/ARDS2.The effects are associated with anti-inflammatory injury through NF-kappa B pathway3.Clinical investigation may help to evaluate cost/benefit of these therapies in ALI/ARDS from pediatric to adult patients4.Better late than never:in clinical trialAcknowledgementShanghai ARDS Study groupPediatric ARDS Study groupResearch staffs and PhD students教育部，上海市科委，上海市教委、上海教育发展教育部，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，美国基金会，上海市卫生局，美国CMBCMB基金等资助基金等资助
