肺表面活性物质吸入NO治疗ALIARDS

1、ARDS临床流行病调查2. 肺表面活性物质/吸入NO治疗ALI/ARDS 孙波 复旦大学儿科医院,Clinical Epidemiology of ARDS in China Surfactant and iNO in Treatment of ARDS Bo Sun, MD, PhD Childrens Hospital of Fudan University 2005-03-19 Beijing,Clinical epidemiology of ALI/ARDS,Incidence of respiratory failure, mechanical ventilation, and AL

2、I/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临床发病情况调查,A 12-Month Survey of ARDS in Adult ICUs Shanghai ARDS Study Group Intensive Care Med 2004; 30 (12): 2197-2203,M

3、orbidity,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)33 Intensive Care Med 2004; 30 (12): 2197-2203,Mortality,Death: 74 (68.5%) in-hospital 76 (70.4%) at 3 months after onset Death rate (病死率) ICU total death548/5320 (

4、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 ARDS,Death Pulmonary origin41 (39%)32 - Pneumonia37 (34.3%)29 Non-pulmonary67 (61%)42 - Sepsis33 (30.6%) MODS44/74 (60%) Respiratory failure17/74 (23%) Septic sh

5、ock 9/74 (12%) Intensive Care Med 2004; 30 (12): 2197-2203,Pediatric ARDS,A 12-month survey of incidence, management and outcome of ARDS in 25 pediatric ICU in China Chinese Pediatric ARDS Study Group ATS 2005 San Diego Intl Conference,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

6、西省儿童医院 郑州儿童医院 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ARDS协作组,PICU all admissions,Critical,ALI/ARDS,Survival death,PIM+Guide,1994 AECC,Treatment,基本流程,25 Pediatric ICU 2004.01-12,PICU total 11453,Critical 6839,R

7、F呼吸衰竭1862,MV 1883,ALI303,ARDS 97,Results,Incidence/PICU admission ARDS 患病率 1.42 % ALI 患病率4.4 % Death rate ARDS病死率62.9 % (61) Total PICU 6.8 % RRARDS : non-ARDS 8.3 : 1 Cost: ARDS/ non-ARDS 4.5 : 1,Predisposing factors of pediatric ARDS,Pneumonia40 Sepsis14 Immunocompromised15 Intoxication 8 Post-ope

8、ration 4 Trauma 4 Asphyxia 3 Others11,Measurement to reduce mortality,Early diagnosis and management Ventilation: low tidal volume Specific therapy: alveolar atelectasis: PEEP, surfactant intrapulmonary shunting: inhaled NO fluid balance: restricted infusion alveolar leakage: selected coloid renal:

9、CRRT exacerbated: ECMO,临床意义,ARDS是ICU最具代表性的、高死亡风险的危重症 (综合征)之一 患病率占ICU收治1.5-2.0%, 病死率60% 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(对照和基础治疗) 中国人口高度集中的城市医院成为研究ARDS发生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 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 90 Surfa

10、ctant and ARDS /NO and ARDS 2000-: RCT Surfactant /NO,Early 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 P

11、aO2/FiO2 200 mmHg, Qs/Qt 20%,Multicenter randomized controlled trial,Anzueto A NEJM 1996, Exosurf aerosol (no SP) Gregory TJ AJRCCM 1997 Survanta Luchetti M PCCM 2002 Curosurf (Pediatric) Walmrath D ERJ 2002 Alveolfact Spragg R AJRCCM 2003 Venticute (SP-C) Spragg R NEJM 2004 Venticute Willson DF JAM

12、A 2005 Calfactant,Effect of Recombinant Surfactant Protein CBased Surfactant on the ARDSSpragg RG et al NEJM 2004; 351:884-892,448 adult patients with ARDS standard therapy alone (control) standard therapy + surfactant (test) exogenous surfactant did not improve survival. exogenous surfactant improv

13、e gas exchange during 24-hour treatment period.,Effect 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 (test) Calfactant group : oxygenation index (20

14、 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 mortality,Surfactant Treatment of Neonates With Respiratory Failure and GBS Infection Herting E et al. Pediatrics 2000; 106: 957-964,118 neonates with

15、 GBS infection and respiratory failure treated with Curosurf(test); 236noninfected 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.001 versus before su

16、rfactant.,Treatment of Severe Meconium Aspiration Syndrome with Porcine Surfactant: A Multicenter, Randomized, Controlled Trial Chinese Collaborative Study Group for Neonatal Respiratory Diseases Acta Paediatrica 2005,Questions,Why surfactant does not work well in ALI/ARDS as neonatal RDS ? Adverse

17、effects of excessive fluid loading Ventilation Metabolism of surfactant in injured lungs,Alveolar and tissue pool sizes in human lungs,Alveolar (extracellular) surfactant (1-80 yrs) Phospholipids3-5 mg/kg Disaturated phosphatidylcholine1-2 mg/kg SP-A 80-120 ug/kg (Rebello CM et al AJRCCM 1996; 154:

18、625-8) Neonatal lungs at birth Phospholipids 20-30 mg/kg DSPC 10-15 mg/kg,Metabolism 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 5-7 mg/kg total PL De novo synthesis o

19、f PC 10%, recycling 90% In ALI/ARDS, hypoxia impairs PC synthesis, protein leakage inhibits surfactant properties, pathogen damages alveolar epithelial cells,Surface tension and PL,SurfacePhospho- Tension mN/mRespiration lipids _ maximum 30-35inspirationSat-PC + uSat-PC minimum 0-5expirationuSat-PC

20、_ At least 3 mg/kg uSat-PC to cover whole alveolar surface, equal to 6-7 mg/kg total PL,Altered tidal volume and ventilation-perfussion mismatching,NormalALI/ARDS VT: 5-7 (6) ml/kgunder- or over-vent TC: FRC: 25-30 ml/kgreduced 50% VD: 25-30% VT50% VT V/Q: 0.81.0 Qs/Qt: 30%,Surfactant dysfunction an

21、d 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/ARDS Hallman M, JCI 1982; 70: 673-683 Gregor

22、y TJ, JCI 1991; 88: 1976-1981 Schmidt R, AJRCCM 2001; 163: 95-100,Surfactant replacement for ALI/ARDS,Rationales 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 an

23、d improve compliance and resistence To improve ventilation-perfussion,Aminal 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 replacement,A

24、dvantage Acute and subacute onset of lung injury Measurement of lung mechanics, hemodynamics, morphology and chemistry Disatvantage Too short in clinical course Lacking of recovery and long term outcome,Multicenter randomized controlled trial,Questions and problems: Patient selection and underlying

25、diseases Type of surfactant Timing, dosing and delivery Cost-benefit assessment Limitation Combined therapy and synergy,Multicenter randomized controlled trial,Solutions: Selecte and well define patient enrolment Standard care (control tidal volume, airway pressure, fluid intake, etc.) Surfactant en

26、riched with SP-B/C Earlier and more are better Bronchoscopic delivery, bolus Combined with HFO, iNO, PP, CRRT, ECMO,Inhaled NO and ALI/ARDS,Say no to ARDS, but say NO to ALI RCT iNO vs. ARDS: failure to improve survival Reasons Complexity of underlying diseases and outcome Single intervention, mecha

27、nistic reduction Timing and dosing and safety New hope after success in neonates and infants,DoseResponse 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 (

28、control); continuous treatment with 10 ppm 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 wi

29、th constant doses of 10 ppm leads to enhanced sensitivity 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,Co

30、ncealed, randomized, placebo-controlled trial PaO2/FiO2150: (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 Adu

31、lt Patients with ALI JAMA 2004; 291: 1603-1609,Multicenter, randomized, 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 mort

32、ality.,Effects of 10 ppm iNO on gas exchange in 108 children with acute hypoxemic respiratory failureDobyns EL et al J Pediatr 1999; 134: 384-387,Oxygenation index: FiO2 x MAP x 100/ PaO2 OI: 40 ECMO ControlNOp 4 h -2.7 -10.2 .014 12 h -2.8 -9.2 .007 iNO causes improvement in oxygenation in HRF,iNO

33、in Premature Infants with RDS Schreiber MD et al NEJM 2003; 349: 2099-2105,Randomized, double-blind, placebo-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

34、% P=0.03 (iNO vs. Control) iNO in premature infants with RDS decreases the incidence of CLD and death,McCurnin DC et al: Inhaled NO 288: L450-459,iNO 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 (