Chronic Lung Disease in Infancy Bronchopulmonary Dysplasia

Richard B. Moss MDCenter for Excellence in Pulmonary Biology

Department of PediatricsStanford University Medical CenterLucile Packard Children’s Hospital

27th Annual Advances in Respiratory CareAmerican Lung Association of Nevada

Las VegasSeptember 13, 2012

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

Nosology of Chronic Lung Disease of Infancy

BPD - bronchopulmonary dysplasiaRDS - respiratory distress syndromeCLDP - chronic lung disease of prematurityCLDI - chronic lung disease of infancy

Allen J et al. Am J Resp Crit Care Med 2003;168:356-96

Conditions Unrelated but Similar to CLDI

Allen J et al. Am J Resp Crit Care Med2003;168:356-96

Fetal Lung Development

Changing Definitions of BPD1967-2001

•Northway 1967 - CLD & CXR+ in setting of IPPV

and high 02 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, 02 >28 days, CXR+

• 02 dependent & CXR+ on postnatal day 28-30

• 02 dependent & CXR+ at 36 weeks PMA or PCA

• 02 dependent & CXR+ at 40 weeks EGA

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

“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

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

Pathology of Classic BPD

• Early • Late

Elements of Classic BPD Pathology

Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

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

Inflammation in Pathogenesis of BPD

• Cytokines -- IL-1b, IL-1RA, IL-6, IL-8, TNF-a• Eicosanoids -- LTB4, 5-/12-HETES, TxB2, PGE2, PGF1, PAF, LTE4

• 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, a1-antitrypsin, glycolipids• Adhesins -- E-selectin, ICAM-1• Low cortisol, surfactant protein-A, retinol

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

Interplay of Alveolar and Vascular Development

Thébaud B & Abman SH. Am J Respir Crit Care Med 2007;175:978-85

Vascular Growth Factors Control Alveolarization

Thébaud B & Abman SH. Am J Respir Crit Care Med 2007;175:978-85

Stenmark KR & Abman SH. Annu Rev Physiol 2005;67:623-61

Effect of VEGF Inhibition and Reversal by iNO

Pathology of New BPD

Coalson JJ. Semin Neonatol 2003;8:73-81

Elements of New BPD Pathology

Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

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)• Fi02 ≥ .40 (day 2)• Nosocomial Infection

Lung Development and Risk Factors for BPD

Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

Integrated View of BPD Causation

Stenmark KR & Abman SH. Annu Rev Physiol 2005;67:623-61

Ventilatory Strategies to Prevent BPD

• Limit tidal volume (5-6 ml/kg)• Maintain oxygenation with PEEP, Fi02

• Avoid atelectasis – maintain mean airway pressure: surfactant, PEEP, vent

• HFOV ? Models – yes, Trials - no• Permissive hypercapnea ?

Animal Model Effect of Ventilatory Strategy and Vitamin A Status

Bland RD. Biol Neonate 2005;88:181-91

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

Incidence of BPD

Outcome at 36 Weeks Postmenstrual Age

Vent > 48 Hr No Vent/Vent < 48 Hr

Birth weight (gm) Survivors % BPD Survivors % BPD500-750 123 57 0 -

751-1000 220 46 49 18

1001-1250 172 33 169 6

1251-1550 106 23 262 2

Young TE et al. Pediatrics 1999;104:e17

North Carolina 1994

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

Patterns of oxygen requirement and subsequent BPD

Laughon M et al. Pediatrics 2009;123;1124-31

Pulmonary deteriorationFiO2 <0.23 then >0.25

Early and persistent pulmonary deteriorationFiO2 > 0.23

FiO2 < 0.23

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:– <23 or >30 weeks gestational age

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 FiO2 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

Treatments to Prevent BPD

Wright CJ & Kirpalani H. Pediatrics 2011;128:111-26

Signs and Symptoms

• Tachypnea• Recurrent wheezing• Crackles• Cough• Asthma-like symptoms• Symptoms subside over time

CXR: Birth

CXR: Postnatal day 9

CXR: Postnatal day 13

CXR: Postnatal day 40

CXR: Postnatal day 74

Pulmonary function

• Obstructive disease– Worse in the first year then improves after 3rd 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

Therapy of BPD

• Oxygen– V02 > 25% higher vs controls– Eliminate sleep & feeding hypoxemia for growth– Goal Pa02 > 50 mm Hg, Sa02 > 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

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?

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

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 O2

– Less later steroid treatment– ? Decreased hospital time– ? Increased survival– ? Decreased risk of BPD

Adrenal Insufficiency and BPD Risk

Watterburg KL et al. Pediatrics 2000;105:320-4

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

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

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

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

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

Pulmonary Hypertension in BPD Decreases Survival

Kim DH et al. Neonatology 2012;101:40-6

Non-PH

+PH

Infants with Severe Pulmonary Hypertension have Lower Survival

Khemani E et al. Pediatrics 2007;120:1260-9

n=18

n=24

Childhood Respiratory Outcome of BPD

Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

Outcome of BPD in Later Life

Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-55

Conclusion

• Contemporary (“new”) BPD is mainly arrest of alveolar development in severe prematurity

• Definition is O2 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