3/13/2009. Bronchopulmonary Dysplasia (BPD) Congenital Diaphragmatic Hernia. Congenital Heart Disease. Connective Tissue Disease.

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1 Pulmonary vascular alterations in chronic lung disease: The clinical problem Fetal circulation-gas exchange occurs in the placenta David N. Cornfield, M.D. Anne T. and Robert M. Bass Professor of Pulmonary Medicine Director-Center of Excellence in Pulmonary Biology and the Divisions of Pulmonary, Allergy, and Critical Care Medicine Professor of Pediatrics Stanford University Medical School Service Chief-Pulmonary, Allergy, and Critical Care Medicine Lucile Salter Packard Children s Hospital Stages of Lung Development Saccular Alveolar Burri PH, Biol Neonate,

2 Cell and Matrix Interactions During Alveologenesis Lung growth continues until 10 years of age Fibroblasts Elastin Collagen Fibronectin Extracellular Matrix Proliferation Migration Differentiation PDGF-A MMPs Remodeling Angiogenesis VEGF-A VEGFR-2 Alveolar Epithelium Capillary Endothelium Adapted from Bourbon et al. Pediatr Res, 2005 Cooney and W M Thurlbeck, 1982 Pulmonary parenchymal and vascular disease Bronchopulmonary dysplasia Congenital Diaphragmatic Hernia Congenital Heart Disease Connective Tissue Disease Cystic Fibrosis Chronic aspiration Bronchopulmonary Dysplasia (BPD) Originally described by Northway et al. in 1967, originally described in preterm infants exposed to aggressive mechanical ventilation and high amounts of inspired oxygen. The most common chronic lung disease of infancy affecting 10-15,00015,000 newborns each year. Old BPD characterized by: Diffuse damage of the airways Vascular smooth muscle cell hypertrophy Inflammation Parenchymal Fibrosis 2

3 Preterm infant with chronic lung disease Chest Radiograph Postmortem Lung Etiology of Old BPD Surfactant deficient lungs Mechanical ventilation Oxygen toxicity and free-radical related injury Lower respiratory tract infection Inflammation Compromised nutrition Hypoxia Diagnosis: need to breathe O 2 -rich gas at age 28 days, or at 36 weeks post-conception Lung damage depends on timing and mechanism Bronchopulmonary Dysplasia (BPD) Therapeutic strategies such as antenatal steroids and surfactant replacement, and lung protective strategies have reduced the old form of BPD. New BPD results from arrested lung development larger and fewer alveoli (alveolar simplification) decreased septation impaired vascular development, Baraldi and Filippone, NEJM, 357, minimal inflammation and fibrosis. 3

4 New BPD Risk increases with decreasing weight (post-surfactant) surfactant) >85% of infants weigh grams Occurs in 30% of infants < 1000 gms 2/3 infants that develop BPD have only minimal exposure to O 2 and MV Disruption of distal alveolar growth 3-month old chronically oxygenand ventilatordependent infant born at 24 weeks gestation Enlarged, simplified alveoli from 8 month old, former 28 wk gestation infant VEGFR-2 Regulates Angiogenic Pathways VEGF-A VEGFR-2 PI3K PLCγ Akt Src PKC Raf1 Bad Csp9 PI3K FAK ERK MEK Survival Migration Proliferation 4

5 Recombinant VEGF Improves Alveolarization After Hyperoxia VEGFR Blockade Causes Emphysema and Pruning of the Pulmonary Vasculature Control SU-5416 Normoxia Hyperoxia Normoxia + rhvegf Hyperoxia + rhvegf Kunig et al. AJP-Lung, 2005 Kasahara et al. JCI, 2000 ino increases lung vascular and alveolar growth in VEGF inhibited rats Balasubramaniam et al, AJP, 2005 Clinical Presentation 1: 15 year old female presents with hypercarbia, hypoxemia and respiratory distress Past Medical History: Born at 36 week gestation, 3.3 kg Left congenital diaphragmatic hernia, 6 days of ECMO, Surgical repair at 8 days of age Tracheostomy at 3 mo Mechanical ventilation x 20 mo Decannulation at 10 years of age 5

6 History of present illness Chest radiograph: scoliosis, pulmonary edema, & retrocardiac consolidation Increased O 2 requirement 12 months PTA intermittent O LPM 6 months PTA continuous O 2 4 LPM Syncopal episode 6 months PTA Decreased exercise tolerance Diuretics initiated 6 months PTA Sildenafil started 3 months PTA On admission - pneumonia,respiratory failure, mechanical ventilation Chest CT: lobular septal thickening, opacification of RUL, RML, cystic changes 6 minute walk 3 months PTA: Marked desaturation with exercise, DOE Heart Rate (b/min) Blood Pressure (mmhg) Baseline Exercise 2 minutes post exercise 133 bpm 174 bpm 159 bpm 108/68 99/49 101/66 Oxygen (L/min) 3 lpm 3 lpm 3 lpm Pulse Oximetry Dyspnea (0-10) by Borg scale 6 per pt s mother 8 per pt s mother 7 per pt s mother Distance walked 420ft 6

7 Echocardiogram shows dilated RV, mild TR, RVP 70 mmhg + RA Cardiac cath revealed small L lung, vascular pruning and pulmonary hypertension Baseline data: intubated, 50% FiO2, ino 10 ppm, BP 87/43 Pressure data RAP 8 mm Hg RVP 52/9 mm Hg Hemodynamic data CI 2.3 L/min/m2 PVRI 12.2 woods units Hospital course 7-week hospital course Mechanically ventilated, high FiO 2 Antibiotics, bronchodilator therapy, pulmonary toilet Pulmonary vasodilator therapy: sildenafil, ino therapy, epoprostenol infusion Outcome Unremitting respiratory failure Sepsis, hemodynamic instability At parent s request, withdrawal of support Clinical Presentation 2: 17 year old female presents with hypoxemia, respiratory distress, and hemodynamic instability Medical History: Juvenile Rheumatoid Arthritis Diagnosed 3 Years PTA Well controlled with pulse corticosteroid Pneumonia as proximate insult Macrophage Activation Syndrome Diagnosed 7

8 Incipient respiratory failure with pulmonary hypertension Hospital Course: 14 months in duration Systemic levels of pulmonary hypertension Multi-organ insufficiency Invasive, non-invasive mechanical ventilation Aggressive immune modulation Corticosteroids, cyclosporine, kineret Combination pulmonary vasodilator therapy ino, endothelin receptor antagonist, PDE V inhibition Progressive and gradual improvement Improvement in PAP correlates with DLCO 50 % Predicted Diffusion Capacity of Carbon Monoxide (corrected For VA, HgB) PAP Systolic (mmhg) 100 8

9 Clinical Presentation 3: 16 year old female presents with hypoxemia, respiratory distress, and hypercarbia (PaCO 2 ~90) Medical History: Low lung volumes, atelectasis Marfan s Syndrome Kyphoscoliosis Pectus excavatum Malnutrition v. anorexia Pulmonary hypertension Prosthetic Mitral Valve Tracheotomy, chronic ventilation, g-tube Medical Course Tracheostomy Gastrostrostomy Tube Sildenafil Daytime supplemental oxygen Nighttime ventilation Progressive normalization of carbon dioxide Improvement in oxygenation Progressive decline in PAP from systemic to 0.3 systemic levels Increased component of calories from lipid Home and ambulatory 9

10 Generalizable lessons? Severe BPD is correlated with pulmonary hypertension Pulmonary hypertension has prognostic implications Treatment must address the underlying etiology Oxygenation and ventilation are important The pulmonary circulation often forgives parenchymal insults, especially in children Address underlying cause and consider combination vascular therapies. Khemani, et al. Pediatrics 120, 2007 Infants with BPD and PA hypertension have high mortality rates Prolonged Sildenafil Treatment improves PAP in infants with CLD and PH Khemani, et al. Pediatrics 120, 2007 Mourani et al, J. Peds,

11 Use complementary outcome metrics to regularly assess response to therapy In children, BNP may distinguish between cardiac and pulmonary disease PFT, including DLCO Biomarkers (BNP, endothelin levels) ECHO 6 minute walk Growth, feeding Parental reporting Imaging Cohen, S. et al. Pediatrics 2005;115: Decrease in BNP correlates with clinical improvement Limited fidelity between severity of PH diagnosed by ECHO and cardiac cath Cohen, S. et al. Pediatrics 2005;115: Mourani, P. M. et al. Pediatrics 2008;121:

12 Healed chronic lung disease? Are there long-term sequelae of resolved lung disease and pulmonary hypertension? Survivors of BPD have decreased lung function Flow limitation in infants with BPD predicts obstruction at school age BW=903 grams EGA=28.3 wks O2 x d MV for 30.7 d Filippone, et al. Lancet, 2003 Baraldi and Filippone, NEJM, 357,

13 Long term effects of BPD on lung function Baraldi and Filippone, NEJM, 357, 2007 Early lung development and chronic obstructive lung disease? Lung function in early adulthood predicts COPD Neonatal lung function predicts lung function at age 22 yrs Fetal and neonatal endothelial compromises lung growth/function Epigenetic factors may modulate neonatal endothelial development Maternal cigarette smoking Nutritional? Genetic? Might now be the time to focus upon a potential childhood antecedent of COPD, an adult disease that is #3 cause of death worldwide? Treatment for children with congenital heart and vascular disease: Inhaled iloprost decreases PVR Limsuwan, et al.,