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Chronic Lung Disease in Infancy Bronchopulmonary Dysplasia Richard B. Moss MD Center for Excellence in Pulmonary Biology Department of Pediatrics Stanford.

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Presentation on theme: "Chronic Lung Disease in Infancy Bronchopulmonary Dysplasia Richard B. Moss MD Center for Excellence in Pulmonary Biology Department of Pediatrics Stanford."— Presentation transcript:

1 Chronic Lung Disease in Infancy Bronchopulmonary Dysplasia Richard B. Moss MD Center for Excellence in Pulmonary Biology Department of Pediatrics Stanford University Medical Center Lucile Packard Children’s Hospital 27th Annual Advances in Respiratory Care American Lung Association of Nevada Las Vegas September 13, 2012

2 Chronic lung disease Any pulmonary disease resulting from a neonatal respiratory disorder – Premature: Bronchopulmonary dysplasia, prematurity, respiratory distress syndrome – Term: Pneumonia, sepsis, aspiration, persistent pulm hypertension of the newborn, pulmonary hypoplasia, diaphragmatic hernia, congenital heart disease

3 Nosology of Chronic Lung Disease of Infancy BPD - bronchopulmonary dysplasia RDS - respiratory distress syndrome CLDP - chronic lung disease of prematurity CLDI - chronic lung disease of infancy Allen J et al. Am J Resp Crit Care Med 2003;168:356-96

4 Conditions Unrelated but Similar to CLDI Allen J et al. Am J Resp Crit Care Med 2003;168:356-96

5 Fetal Lung Development

6 Changing Definitions of BPD 1967-2001 Northway 1967 - CLD & CXR+ in setting of IPPV and high 0 2 for > 6 days Ross Report 1986 - CLD (tachypnea, retractions, abnormal ABG in RA), IPPV ≥ 1 day, CXR+ BMCHRD 1989 - IPPV for ≥ 3 days in 1st 2 wks, CLD > 28 days, 0 2 > 28 days, CXR+ 0 2 dependent & CXR+ on postnatal day 28-30 0 2 dependent & CXR+ at 36 weeks PMA or PCA 0 2 dependent & CXR+ at 40 weeks EGA

7 BPD: Current Definition and Grading Oxygen dependence for 28 days Graded at 36 postmenstrual weeks if < 32 weeks GA – Or 56 days of life if >32 weeks Severity – Mild: No supplemental oxygen – Moderate: FiO2 <30% – Severe: FiO2 >30% or positive pressure National Institute of Child Health and Human Development, 2001

8 “Classic” and “New” BPD ‘Classic’ BPD - “injury & inflammation” – Distorted lung architecture, atelectasis, mucus plugging, overdistension – Decreased alveolarization – Interstitial & peribronchial fibrosis – Epithelial hyperplasia & squamous metaplasia – Smooth muscle hypertrophy, reactive airways ‘New’ BPD - “arrest of lung development” – Mild interstitial & peribronchial fibrosis – Arrested alveolar septation – Chronic reactive airways

9 Classic BPD: Pre-Surfactant Era Directly related to severity of respiratory distress syndrome Due to lung immaturity, lung injury from mechanical ventilation and oxygen, inadequate repair of initial lung injury Larger infants: mean 2200 gm More mature: mean GA 34 weeks Mortality rate 67% 90% mortality in extremely premature infants, 24-26 weeks

10 Pathology of Classic BPD Early Late

11 Elements of Classic BPD Pathology Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

12 Pathogenesis of Classic BPD Mechanical injury – Volutrauma - overdistended airways and air spaces Oxygen toxicity – Cellular damage by reactive oxygen metabolities (free radicals, hydrogen peroxide) – Premature infants have inadequate antioxidant defenses Infection Inflammation

13 Inflammation in Pathogenesis of BPD Cytokines -- IL-1 , IL-1RA, IL-6, IL-8, TNF-  Eicosanoids -- LTB 4, 5-/12-HETES, TxB 2, PGE 2, PGF 1, PAF, LTE 4 Oxidants -- 3-Nitrotyrosine Soluble mediators -- elastase, fibronectin, lactoferrin, lysozyme, endothelin-1, tryptase, eosinophil cationic protein Cells -- neutrophils, macrophages, neuroendocrine cells Chemotactic activity -- interleukin-8, C5a anaphylatoxin Injury (plasma leak) -- albumin,  1-antitrypsin, glycolipids Adhesins -- E-selectin, ICAM-1 Low cortisol, surfactant protein-A, retinol

14 New BPD: Post-Surfactant Era Arrest of alveolar development – Born during canalicular and saccular stage – Fewer, larger alveoli develop- alveolar surface reduced – Dysmorphic arteries Additional injury from ante/postnatal exposures – Ventilator induced injury, oxidative stress, infections, nutrition, pulmonary fluid overload

15 Interplay of Alveolar and Vascular Development Thébaud B & Abman SH. Am J Respir Crit Care Med 2007;175:978-85

16 Vascular Growth Factors Control Alveolarization Thébaud B & Abman SH. Am J Respir Crit Care Med 2007;175:978-85

17 Stenmark KR & Abman SH. Annu Rev Physiol 2005;67:623-61 Effect of VEGF Inhibition and Reversal by iNO

18 Pathology of New BPD Coalson JJ. Semin Neonatol 2003;8:73-81

19 Elements of New BPD Pathology Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

20 Risk Factors for BPD Lower Birth Weight/Gestational Age Male Chorioamnionitis, esp Ureaplasma urealyticum Patent ductus/Early Fluid Overload Adrenal Insufficiency Assisted Ventilation (day 2) Fi0 2 ≥.40 (day 2) Nosocomial Infection

21 Lung Development and Risk Factors for BPD Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

22 Integrated View of BPD Causation Stenmark KR & Abman SH. Annu Rev Physiol 2005;67:623-61

23 Ventilatory Strategies to Prevent BPD Limit tidal volume (5-6 ml/kg) Maintain oxygenation with PEEP, Fi0 2 Avoid atelectasis – maintain mean airway pressure: surfactant, PEEP, vent HFOV ? Models – yes, Trials - no Permissive hypercapnea ?

24 Animal Model Effect of Ventilatory Strategy and Vitamin A Status Bland RD. Biol Neonate 2005;88:181-91

25 BPD Rates Boston (Beth Israel, Brigham & Women’s) vs NY (Babies’ & Children’s) Van Marter LJ et al. Pediatrics 2000;105:1194-1201 Why? Early CPAP vs IPPV

26 Incidence of BPD Outcome at 36 Weeks Postmenstrual Age Vent > 48 Hr No Vent/Vent < 48 Hr Birth weight (gm) Survivors % BPDSurvivors % BPD 500-750123 57 0 - 751-1000220 46 49 18 1001-1250172 33169 6 1251-1550106 23262 2 Young TE et al. Pediatrics 1999;104:e17 North Carolina 1994

27 Variable Courses: “Atypical BPD” “Classic” CLDI = BPD after RDS No initial RDS = “delayed CLDI” CLDI after RDS “resolved” Charafeddine L et al. Pediatrics 1999; 103:759-65 Atypical CLDI 30% of total CLDI BW <1250 gm

28 Patterns of oxygen requirement and subsequent BPD Laughon M et al. Pediatrics 2009;123;1124-31 Pulmonary deterioration FiO2 0.25 Early and persistent pulmonary deterioration FiO2 > 0.23 FiO2 < 0.23


30 Methods Secondary analysis of data from NIH neonatal research network Benchmarking Trial Study period: 2000-2004 17 academic centers Inclusion: – Infants surviving >12 hours – Birthweight 401-1250 gm Excluded: – 30 weeks gestational age

31 Predictive Conclusions of NIH Study The model provides an estimate of risk for BPD that could help with counseling of families The strongest early variables were gestational age and birth weight, consistent with arrest of alveolar development Respiratory support and FiO 2 were the most significant risk factors at 21 and 28 days, supporting role of barotrauma and oxygen toxicity Severity was inversely proportional to gestational age and birth weight and related to PDA, sepsis, surgical NEC Center effect was small

32 Treatments to Prevent BPD Wright CJ & Kirpalani H. Pediatrics 2011;128:111-26

33 Signs and Symptoms Tachypnea Recurrent wheezing Crackles Cough Asthma-like symptoms Symptoms subside over time

34 CXR: Birth

35 CXR: Postnatal day 9

36 CXR: Postnatal day 13

37 CXR: Postnatal day 40

38 CXR: Postnatal day 74

39 Pulmonary function Obstructive disease – Worse in the first year then improves after 3 rd year of life – Only partially reversed by beta agonists – Due to remodeling process: airway wall thickening, parenchymal fibrosis Airway hyperresponsiveness: reason unclear Reduced exercise performance Reduced gas transfer

40 Therapy of BPD Oxygen – V0 2 > 25% higher vs controls – Eliminate sleep & feeding hypoxemia for growth – Goal Pa0 2 > 50 mm Hg, Sa0 2 > 85% Nutrition – >15% higher energy expenditure vs controls – Goal adequate growth, weight gain 15-30 gm/day Diuretics – Improved mechanics (Cdyn, Raw) and oxygenation – Loop agent (furosemide) ± thiazide – Restrict fluids to 140-150 ml/kg/day, follow electrolytes

41 Therapy of BPD 2 Avoid environmental hazards (irritant, allergen, infectious) Immunization – Influenza, palivizumab (40% reduction in re- admissions) Bronchodilators – Inhaled albuterol, ipratropium bromide – Early > late subgroup reversibility Anti-inflammatories – Steroids?

42 Palivizumab Humanized monoclonal antibody against the RSV F glycoprotein Infants and children younger than 2 years of age with BPD who have required medical therapy for their pulmonary disease within 6 months of the anticipated RSV season

43 Steroids for Early Intervention? Rationale - Anti-inflammatory, treat adrenal insufficiency Issues - drug, timing, dose, route, duration, baseline severity Early Benefits – Improved lung function – Less assisted ventilation & supplemental O 2 – Less later steroid treatment – ? Decreased hospital time – ? Increased survival – ? Decreased risk of BPD

44 Adrenal Insufficiency and BPD Risk Watterburg KL et al. Pediatrics 2000;105:320-4

45 Steroids for Early Intervention? Late Benefits - ? Less CLD, better survival Early Risks – Transient hypertension, hyperglycemia, hypertrophic cardiomyopathy – Growth suppression – ? GI bleeds, ? Intracranial bleeds – No increase in sepsis, ROP Late Risks – Increased CP, abnormal head U/S or neurological exam – Neurodevelopmental impairment

46 Corticosteroids AAP Committee on Fetus & Newborn: High-dose dex (0.5 mg/kg/d) not recommended; low-dose dex (<0.2 mg/kg/d) no recommendation; high-dose hydrocortisone (3-6 mg/kg/d) no recommendation; low-dose hydrocortisone(1 mg/kg/d) may benefit subgroup (prenatal inflammation) Watterburg KL et al.Pediatrics 2010;126:800-8 Improve lung mechanics Can have serious short-term side effects Can cause neurodevelopmental impairment Can be given in short courses for wheezing Inhaled corticosteroids not shown to reduce symptoms or improve outcomes

47 Complications of BPD Poor growth Rehospitalization (LRTI, FTT) – >50% (on home O2) – Admits >65% higher vs controls LRTI severity - RSV, rhinovirus, other Acquired tracheobronchomalacia, inspiratory flow limitation Glottic and sublglottic damage – vocal cord paralysis, subglottic stenosis Sleep hypoxemia, SIDS Anemia

48 Complications of BPD 2 GER, aspiration and Nissan fundoplication failure Hypertension Lobar emphysema (esp RLL) and atelectasis (esp RUL) Extrapyramidal movement disorder Ciliary dyskinesia Iatrogenic - diuretics (electrolytes, renal), steroids Pulmonary hypertension, cor pulmonale

49 Pulmonary hypertension in BPD Abnormal development: – Abnormal number and size of intra-acinar pulmonary arteries – Significantly reduced total cross-sectional area of pulmonary vascular bed. – Increased PVR and heightened vasoreactivity Acute lung injury: – Smooth muscle cell proliferation, incorporation of fibroblast in vessel wall – Narrowing of vessel diameter and decreased compliance

50 Pulmonary Hypertension in BPD Decreases Survival Kim DH et al. Neonatology 2012;101:40-6 Non-PH +PH

51 Infants with Severe Pulmonary Hypertension have Lower Survival Khemani E et al. Pediatrics 2007;120:1260-9 n=18 n=24

52 Childhood Respiratory Outcome of BPD Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

53 Outcome of BPD in Later Life Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

54 Conclusion Contemporary (“new”) BPD is mainly arrest of alveolar development in severe prematurity Definition is O 2 requirement for 28 postnatal days before 36 postmenstrual weeks Severity is based on oxygen need Treatment is supportive care Implications are long-term, possibly lifelong

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