6/21/2013 Disclosures Long-term Consequences of • No conflict of interest to disclose. Bronchopulmonary Dysplasia and • Off-label use of sildenafil will be discussed Pulmonary Hypertension in this presentation. Sharon McGrath-Morrow, MD, MBA Objectives Impact of prematurity in the US 4,317,119 Live Births in the US in 2007 • Recognition of pulmonary hypertension as a complication in 1.5% infants with Bronchopulmonary Dysplasia (BPD) 11% • Risk factors for pulmonary hypertension in BPD. <32 Weeks • Approach to diagnosis and treatment of pulmonary 32-37 hypertension and BPD Weeks • What we learned from our population of BPD infants with 87% pulmonary hypertension About 60,000 infants born each year in the US are at risk for developing bronchopulmonary dysplasia Heron M et.al ., Pediatrics , 2010. 1
6/21/2013 Bronchopulmonary dysplasia Extremely low birth weight infants- at highest risk for pulmonary hypertension • Diagnosed in premature infants (<32 wk gestation) who required supplemental oxygen for 28 days or greater – Pulmonary hypertension affects at least 1 in 6 extremely • BPD severity (mild, moderate, severe) based on need for low birth weight infants (<1000 grams) supplemental oxygen/PPV at 36 weeks post conception • Prospective analysis of pulmonary hypertension in extremely low birth weight infants. ( Bhat R, Pediatrics, 2012 ) Extremely low birth weight infants 60 % infants with BPD at highest risk for BPD • PH defined by ECHO 50 – Right ventricular hypertrophy, 40 – Flattening of interventricular septum 30 – Presence of tricuspid regurgitation in the absence of pulmonary 20 stenosis, 10 – Elevated right ventricular pressures as estimated by Doppler 0 studies of tricuspid regurgitation jet. 510-750 751-1000 1001-1250 1251-1500 Birth weight (grams) Ehrenkranz et.al. 2005 Chronic lung disease contributes to PH Impact of BPD and PH in the US prevalence in children worldwide • About 12,000 US infants develop BPD each year- • 31 centers, 19 countries, enrolled patients < 18 years of most are ELBW ( American Lung Association Lung Disease Data: 2008). age at time of PH diagnosis- 456 patients in TOPP registry • Estimated 1600 infants born each yr with BPD and • 12% of patients had PH associated with lung disease- PH in the US – BPD most common cause of lung disease associated • Estimated 40 infants/yr born in Maryland with BPD with PH and PH Berger et. al., Lancet, 2012 2
6/21/2013 Mortality is higher in infants with BPD and PH What causes BPD and (PH)? Boston Children’s Hospital • • Seoul University (Khemani E et al ; Pediatrics ; 2007). (Kim D et al ; Neonatology ; 2012). Abnormal airways Abnormal Abnormal 20/25 growth of pulmonary 21/34 alveoli vasculature Chronic respiratory Average gestational age 26 wks symptoms Impaired alveolar growth in BPD Small airway abnormalities in BPD - gas exchange abnormalities -airflow obstruction – Structural and reactive – Postnatal dysanaptic airway growth due to prematurity • Not responsive to anti-inflammatory meds – Airway inflammation • Likely responsive to anti-inflammatory meds Postnatal alveolar growth Growth of airways and blood vessels Kennedy, J. Paediatr Child Health, 1999. Mechanisms and limits of induced postnatal lung growth. Thebaud and Abman, AJRCCM, 2007 Am J Resp Crit Care Med, Vol170, 2004 3
6/21/2013 Impaired vascular growth in BPD Rodent models of impaired vascular and alveolar - pulmonary hypertension growth in neonates with disruption of VEGF/VEGFR2 signaling Control VEGFR VEGFR2 antibody (DC101) inhibitor (S5416) 3 week rat lung 2 week mouse lung Adult rat lung Lung histology Barium arteriograms LeCras, et.al. 2002 McGrath-Morrow et.al., 2005 Abman, S, Adv Exp Med Biol, 2010 Other Risk Factors associated with BPD Role of genetics and epigenetics in BPD and and development of PH PH children Small for gestational age Abnormal lung physiology • • • Genetic susceptibility accounts for approximately 50% of – Ventilation/perfusion (V/Q) • Maternal preeclampsia BPD development (Bhandari et.al., 2006, Lavoie et. al., 2008). mismatch • Postnatal Infections – Genes associated with PH development in BPD have not – Intermittent hypoxia/hypercarbia • Malnutrition been identified. Future studies could include identifying – Poor airway clearance/mucous • Chorioamnionitis plugs modifiers genes thru candidate SNP studies of genes • Oligohydramnios involved in familial PH, such as, BMPR2, ENG and ALK1 • Cardiovascular shunts – Atrial septal defects • The role of epigenetic changes that effect BPD infants – Patent ductus arteriosus with PH needs to be explored – Aorto-pulmonary collateral arteries 4
6/21/2013 Lung CT at 6 months Management and screening for PH in the preterm infant • BPD Infant born at 26 weeks gestation with history of premature rupture of membranes at 22 weeks gestation • Briefly intubated in the NICU, but developed cystic emphysematous lung disease and had ECHO evidence of PH at 6 months of age. PH in this BPD child may be structural due to But a component of PH in this BPD child may be inadequate postnatal lung growth reactive and respond to vasodilator medications * Fewer number of alveoli and micro-vessels due to decreased surface area Preterm Infant Figure concept from Humbert et.al., 2004 Thurlbeck W.M. Thorax 37:564-571, 1982 5
6/21/2013 Treatment of BPD child with PH • Minimize further lung injury and decrease work of Screening of ELBW infants and infants breathing (aggressive supportive care) with BPD for PH • Minimize hypoxic/hypercarbic episodes • Maximize nutrition to promote lung growth • Consider other factors such as cardiac shunts, pulmonary vein stenosis as contributing factors • Consider trial of vasodilator medications if indicated No guidelines exist for screening of Are there biomarkers to track disease ELBW or BPD infants for PH progression • Bhat et.al.- 2/3 of ELBW infants with PH missed with ECHO at 1 month of • BNP and NT-proBNP are adult biomarkers for PH age – Problematic in the BPD infant since BNP is a cardiac • Hopkins NICU guidelines to be tested: – < 26 week gestation or <1000 grams at birth: ECHO at 8 to 10 wks of age protein and is developmentally regulated – > 26 weeks gestation: ECHO if infant has moderate to severe BPD at 36 PCA – ECHOs obtained at the discretion of the Attending Neonatologist if child is felt to be at high risk for pulmonary hypertension due to clinical course/other risk factors Correlation of ECHO with catheterization in pediatric patients • – Mid-Atlantic Group of Interventional Cardiology and Mourani et.al., study • Poor correlation of ECHO with catheterization in predicting severity of PH 6
6/21/2013 Circulating NT-proBNP concentration is developmentally regulated and declines during the first 1-2 months of life • BNP and NT-proBNP may be useful for tracking response to treatment in the preterm infant with PH • Ongoing novel discovery projects, may provide better biomarkers for infants and children with PH Nir A, et al . NT-pro-B-type natriuretic peptide in infants and children: reference values based on combined data from four studies. Pediatr Cardiol 2009 Jan;30(1):3-8. Anesthesia in infants with BPD and PH Use of cardiac catheterization in patients with BPD and PH differs across centers • Risk of perioperative cardiac arrest is 6-fold higher in children with PH. Carmosino, et al. Anesth Analg 2007;104:521-527. • Denver- most patients undergo catheterization before starting • 50% of pediatric anesthetic-related deaths occur in children with PH. chronic vasodilator medication Mourani PM, et al. J Pediatr 2009;154:378-384. van der Griend BF, et al. Anesth Analg 2011;112:1440-1447.- deaths-0.98/10,000 cases • Boston group reported catheterization of 31% of their patients • But, anesthesia can be performed safely . Khemani E, et al. Pediatrics 2007;120:1260-1269. Hill KD, et al. Catheter Cardiovasc Unterv 2010;76:865-873 Magic collaboration - • Hopkins catheterizes about 11% of patients with BPD and PH. Adverse events were rare (n = 7) with no procedural deaths . – Before escalating/weaning vasodilator Rx in refractory PH • Ways to minimize anesthesia risk- – For evaluation/closure of CV shunts – Cardiac anesthesiologist – Preoperative consultation – Prepare for management of a PH crisis, i.e., NO/milrinone/prostanoids/PICU bed availability 7
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