NEONATAL AND CHILDHOOD PULMONARY HYPERTENSIVE VASCULAR IN NEONATES AND CHILDREN: suggestions for a novel uniquely pediatric classification

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1 NEONATAL AND CHILDHOOD PULMONARY HYPERTENSIVE VASCULAR IN NEONATES AND CHILDREN: suggestions for a novel uniquely pediatric classification 63 pts COHORT: 71% ONE associated condition 24% TWO associated conditions 43% of this pediatric cohort HAD SYNDROMAL ABNORMALITIES Multifactorial ETIOLOGY in 34% of cases 2% SPANISH REGISTRY FOR PEDIATRIC PH The most frequent association was Congenital heart disease and lung disease DANA POINT CLASSIFICATION AND MULTIPLE CONGENITAL ABNORMALITIES PAH LEFT HEART HYPOXIA/LUNG 29% 3% SHUNT (VSD) MITRAL STENOSIS DIASTOLIC DYSFUNCTION Tracheoesophageal fistula Espphageal Atresia Gastroesopageal reflux CHRONIC LUNG Preliminary data 104 cases of pediatric pulmonary hypertension 66% 1 etiologia 2 etiologias 3 etiologias 4 etiologias BRONCHOPULMONARY DYSPLASIA And Dana Point Classification PAH LEFT HEART HYPOXIA/LUNG HETEROGENEOUS / MULTIFACTORIAL Hypoplasia of vascular bed SHUNT lesions PDA, ASD, aortoplmonary collaterals Pulmonary vein stenois Diastolic dysfunction VASCULAR BED HYPOPLASIA! CHRONIC LUNG Underdeveloped alveoli Hypoxia, hypercarbia Lung infections, Neonates and Children Lungs are GROWING IS A COMMON FEATURE IN BRONCHOPULMONARY DYSPLASIA, CONGENITAL HEART, CHROMOSOMAL ABNORMALITIES, CONGENITAL DIAPHRAGMATIC HERNIA,. GENETIC FACTORS

2 1. Prenatal Pulmonary Vascular Disease 2. PPHN: Pulmonary Vascular Maladaptation in newborns 3. Pediatric Heart Disease 1. PRENATAL PULMONARY VASCULAR 4. Bronchopulmonary Dysplasia 5. Isolated Pediatric PAH 6. Multifactorial PH Associated with multiple congenital malformations/syndromes 7. Pediatric Lung disease 8. Pediatric Thrombo-embolic Disease 1.1. Maternal or Placental Abnormalities 1.2. Fetal Pulmonary Maldevelopment 1.3. Fetal Cardiac Maldevelopment Causing Intrauterus Anomalies Of Lung Vessels 9. Hypobaaric hypoxic exposure 10. PH associated with System s Disorders 1. PRENATAL PULMONARY VASCULAR 1.1. ASSOCIATED WITH MATERNAL OR PLACENTAL ABNORMALITIES Pre-eclampsia Chorioamnionitis Maternal drug ingestion (aspirin/indomethacin/ serotonin reuptake inhibitors?..) 1.2. ASSOCIATED WITH FETAL PULMONARY VASCULAR MALDEVELOPMENT Associated With Fetal Pulmonary Hypoplasia a. Idiopathic pulmonary hypoplasia b. Familial pulmonary hypoplasia c. Congenital diaphragmatic hernia oligohydramnios d. Hepatopulmonary fusion omphalocele/gastroschisis e. Scimitar syndrome cystic adenomatosis f. Associated with fetal pulmonary compression. fetal tumours or masses g. Associated with skeletal malformations Associated With Fetal Lung Growth Arrest/Maldeveloment a. Acinar dysplasia b. Congenital alveolar dysplasia c. Alveolar capillary dysplasia with/out misalignment of pulmonary veins d. Lymphangiectasia e. Pulmonary artery abnormalities f. Pulmonary venous abnormalities 1.3. FETAL CARDIAC MALDEVELOPMENT Premature closure of foramen ovale or ductus arteriosus Idiopathic Drug induced Congenital heart defects associated/causing PVD in the fetus TGA/IVS Hypoplastic left heart syndrome with intact atrial septum Obstructed total anomalous pulmonary venous connection Common pulmonary vein atresia PRENATAL Pulmonary Vascular Disease 1.1. MATERNAL OR PLACENTAL ABNORMALITIES Pre-eclampsia Chorioamnionitis Maternal drug ingestion aspirin, indometacine Serotonin reuptake inhibitors? PRENATAL pulmonary vascular disease FETAL LUNG GROWTH ARREST/MALDEVELOMENT: c. Alveolar capillary dysplasia with misalignment of pulmonary veins FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA PRENATAL pulmonary vascular disease 1.2. FETAL PULMONARY MALDEVELOPMENT FETAL PULMONARY HYPOPLASIA c. CONGENITAL DIAPHRAGMATIC HERNIA CDH Control Number of arterioles thickness media layer intraacinar arterioles ANATOMIC FACTORS Am J Hum Genet June 12; 84(6): Paweł Stankiewicz Association with gastrointestinal malformations, and heart maformations (HLHS) ENDOTHELIAL DYSFUNCTION Increased expression ENDOTELIN receptors ET-A y ET-B

3 PRENATAL pulmonary vascular disease 1.3. FETAL CARDIAC MALDEVELOPMENT Causing Intrauterus Anomalies Of Lung Vessels Premature closure of foramen ovale or ductus arteriosus In utero pulmonary vascular disease Prenatal echocardiogram at 28 weeks restrictive ductus In D TGA D-tga with intact ventricular septum and restrictive ASD Maeno, Y. V. et al. Circulation 1999;99: PULMONARY VASCULAR MALADAPTATION TO EXTRAUTERINE LIFE Lung Collapse Low Pa O2 Hypercarbia ENDOTHELIN and LEUCOTRIENES levels endogenous synthesis of NÍTRIC Oxide and PROSTACYCLINS PHYSIOLOGIC PULMONARY VASOCONSTRICTIÓN In the FETUS (PPHN) fetal pattern persistency Ventilated lung ET-1 levels bradikinin levels + COX-1 1 y NOS endogenous synthesis of PG I 2 y NO PPHN Pa O2Pa PCO2 2.PPHN :1-2 /1000 newborns NORMALLY DEVELOPED LUNGS, TERM NEWBORNS Idiopathic PPHN Associated with or triggered by -pneumonia -sepsis -meconium aspiration -congenital heart defects -trisomy21 - congenital diaphragmatic hernia MORTALITY 10-20% Neurologic SEQUELS 20% Pulmonary vascular MALADAPTATION TO EXTRAUTERINE LIFE RV Dilatatión and failure Left ventricle failure Right-Left Shunt Hypoxia acidosis ECMO 4.Bronchopulmonary dysplasia Alveolar Growth Disrruption Angiogenesis Disruption 3.1. SYSTEMIC TO PULMONARY SHUNTS 3. PEDIATRIC HEART - PAH associated with S P shunt high PVRI, no cyanosis - Eisenmenger syndrome: Simple /Complex lesion - Small defect with elevated PVRI (idiopatic-like PAH) 3.2. POST OPERATIVE PAH WITHOUT ELEVATED PWP, after - closure of shunt with persistent or recurrent elevation in PVRI - arterial or atrial switch operation for TGA/IVS - surgery of left heart obstruction - repair of tetralogy of Fallot - repair of pulmonary atresia with VSD and MAPCA s - surgical aortopulmonary shunt PVD following palliation for SINGLE VENTRICLE PHYSIOLOGY 3.4. PH DUE TO congenital or acquired LEFT HEART WITH ELEVATED PWP Pulmonary vein obstruction, EFE, Cor triatriatum,

4 5. ISOLATED PEDIATRIC PULMONARY ARTERIAL HT 18/122 pts receiving Pulmonary vasodilators Univentricular Heart Physiology HTP UNIVENTRICULAR PHYSIOLOGY AFTER STAGED PALLIATION FONTAN 14% Idiopathic Inherited BMPR Alk 1, endoglin Unidentified genetic cause Drugs and Toxins Toxic oil Cocaine Amphetamine Methylphenidate Diazoxide Cyclosporin PVOD, lymphangiomatosis, capillary hemangiomatosis. POSTNATAL PVD 6. Multifactorial PH Associated With Multiple Congenital Malformations/Syndroms - Multiple Congenital Malformations Eg:VACTERL, CHARGE, Poland, Adams-Oliver Syndrome, Scimitar complex - Chromosomal Abnormalities Eg: Down S. Di George S. Noonan S. 7. Pediatric Lung Disease (PH due to hypoxia / hypercarbia) Cystic Fibrosis, Interstitial lung diseases, OSAS, chest wall and spinal deformities, restrictive lung diseases, chronic obstructive lung disease 2.6. Multifactorial PH Associated With Multiple Congenital Malformations/Syndroms 8. PEDIATRIC THROMBO-EMBOLIC Chronic thromboemboli from central venous catheters Ventriculo atrial shunt for hydrocephalus Anticardiolipin syndrome Due to malignancy: osteosarcoma, Wilms tumour -- Increased incidence of PPHN PH In -- Hypoxemia/Hypercarbia Down Syndrome -- SHUNT Congenital heart disease -- Failure of UNIVENTRICULAR physiology palliation (Glenn or Fontan)

5 HIPOXEMIA in Down S. PULMONARY HYPOPLASIA MANDIBULAR HYPOPLASIA MACROGLOSIA Smaller airway Tonsillar / adenoid HYPERTROFY TRACHEOMALACIA TRACHEAL MALFORMATION HYPOTONIA NASOGASTRIC tubes OBESITY GASTROESOPHAGEAL REFLUX INMUNODEFICIENCY (more frequent Respiratory infecctons) OSAS Inmune dysfunction in Down s syndrome: primary immunodeficiency or early senescence of the inmune system? Clin Immunol Immunopathol Pulmonary Hypertension associated with other system disorders 10.1 Pediatric portal hypertension: -Congenital extrahepatic portocaval/portosystemic shunt / congenital or acquired portal vein obstruction - Liver cirrhosis Pediatric Hematological Disease: Hemolytic anemias Post splenectomy 10.3 Pediatric Oncological Disease: PVOD after BM transplantation / chemotherapy 10.4.Pediatric Metabolic/Endocrine Disease: Gaucher disease Glycogen storage disease Non ketotic hyperglycinemia Mitochondrial depletion syndrome Mucopolysaccharidosis Hypothyroidism 10.5 Pediatric Autoimmune Disease: POEMS, Scleroderma,SLE, Evans S Pediatric Infectious Disease: Schistosomiasis, HIV infection 10.7.Pediatric Chronic Renal Failure with dialysis