New Definitions and Concepts of Pediatric Pulmonary Hypertension

Transcription

1 Congrés Médico Chirurgical de la FCPC Schoelcher, La Martinique, French West Indies. 21 au 24 Novembre Session: Pulmonary Hypertension New Definitions and Concepts of Pediatric Pulmonary Hypertension Ian Adatia, Pediatric Pulmonary Hypertension Service and Pediatric Cardiac Intensive Care Unit, Stollery Children s Hospital, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. Fellow, Pulmonary Vascular Research Institute.

2 What do we mean by pediatric pulmonary hypertension? How do we define pediatric pulmonary hypertension?...it depends who you ask... Cardiologist Cardiac surgeon Pulmonologist Intensivist

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4 Definitions Pulmonary Hypertension Admission to NIH registry definition mean PA pressure > 25 mmhg BUT Normal PA pressure at rest systolic 20.8±4.4 Mean 14.0 ±3.3 mmhg diastolic 8.8±3.0 Normal Pulmonary Vascular Resistance 0.9± 0.4 Wood Units (74 ±30 dynes.sec.cm -5 ) G. Kovacs, A. Berghold, S. Scheidl and H. Olschewski Eur Respir J 2009; 34:

5 Mean pulmonary artery pressure at rest in normal subjects G. Kovacs, A. Berghold, S. Scheidl and H. Olschewski Eur Respir J 2009; 34:

6 Upper limit of Normal ±2 SD Systolic 30 mmhg Mean mmhg ±3 SD Systolic 34 mmhg Mean 24 mmhg

7 Pulmonary hypertensive vascular disease instead of pulmonary hypertension Exclude patients with pulmonary hypertension but without an increased pulmonary vascular resistance children with large aortopulmonary shunts Include patients with symptomatically increased pulmonary vascular resistance but mean PA pressure < 25 mmhg Children undergoing staged approach to single ventricle lesions Data from the Spanish Pediatric registry suggests that 15% of children receiving PH specific therapy are in this category

8 Definition Pediatric Pulmonary Hypertensive Vascular Disease Biventricular Circulation (older than 2-3 months) Mean PAP 25 mmhg and PVRI 2-3 Wood Units x m 2 After Cavopulmonary Surgery Transpulmonary gradient > 6mmHg and PVRI 2-3 Wood Units x m 2 ( even if mean PAP<25 mmhg) Del Cerro et al Pulm Circ 2011:1:286 & Abman et al Circulation 2015: 132:November

9 Definition of Pulmonary Hypertension in Childhood After 3 months of age in term babies PH is present if mean pulmonary artery pressure exceeds 25 mmhg in the presence of equal blood flow to all segments of both lungs Does not imply presence or absence of pulmonary hypertensive vascular disease Pulmonary vascular resistance is important in determining diagnosis and management of pulmonary hypertensive vascular disease in congenital heart

10 Important aspects of neonatal and childhood pulmonary hypertensive disorders not included Fetal origins of pulmonary vascular disease The potential importance of developmental mechanisms in both childhood and adult onset disease Inconsistent approach to neonatal pulmonary vascular disease Importance of perinatal maladaptation, maldevelopment and pulmonary hypoplasia in pulmonary vascular disease Heterogeneity of pediatric cardiac, pulmonary, genetic, syndromes with pulmonary vascular disease Adult survivors of pediatric pulmonary vascular disease

11 Pathophysiology of Pulmonary Hypertensive Vascular Disease unique to childhood Pulmonary vascular Maldevelopment Maladaptation Growth arrest Dysregulated repair after in utero, neonatal or early childhood injury Is the pathophysiology reflected in the phenotype? Is it recognizable in everyday clinical practice?

12 Is pediatric onset pulmonary hypertensive vascular disease different from adult onset? del Cerro et al Pulmonary Circulation 2011:1:286-9 Illustrative Case Chromosome 3 & 11 translocation Premature with long NICU course Laryngo-tracheo-malacia Scoliosis Portal vein obstruction Hepatic cirrhosis Spinal fusion age 12 yrs PAp 96/45 m 61 mmhg, LA 3 mmhg, CI 3.5 L/min/m 2 Idiopathic Thrombocytopenia Purpura Night time CPAP Oral targeted PH therapy Transferred to adult PH clinic

13 Changes in pulmonary blood flow before and after birth Courtesy of Jeff Fineman and Abraham Rudolph UCSF

14 Perinatal Changes in Pulmonary Vascular Hemodynamics Courtesy Jeffrey Fineman & Abraham Rudolph UCSF

15 Neonates and the transitional circulation Saling E. Archiv Gynäk 1960;194:

16 Prenatal (?preconceptual) influences on post natal pulmonary vascular reactivity The systolic pulmonary artery pressure at high altitude (3450 m) was 30% higher (P<0.001) using assisted reproductive technology (ART) than in control children. Copyright American Heart Association Scherrer U et al. Circulation 2012;125:

17 Prenatal echocardiogram in transposition of the great arteries at 28 weeks gestation restrictive ductus arteriosus Maeno, Y. V. et al. Circulation 1999;99:

18 Transposition of the great arteries Prenatal echocardiogram at 35 weeks Maeno, Y. V. et al. Circulation 1999;99:

19 In utero pulmonary vascular disease Maeno, Y. V. et al. Circulation 1999;99:

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22 Chen et al Ultrasound Obstet Gynecol 2010

23 Group 3.7 Developmental Lung Diseases Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins Eulmelsekian et al 2 Cullinane et al 1992 Eulmesekian et al J Perinat Med:2005:33:347

24 3.7 Developmental Lung Disease Congenital Diaphragmatic Hernia Courtesy C Parshuram Toronto

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26 From Maria Jesus del Cerro, PVRI, Panama 2011

27 Pulmonary vascular changes 16 years after premature birth and bronchopulmonary dysplasia Steve Abman PVRI Lisbon 2010

28 3.7 Developmental Lung Disease Bronchopulmonary Dysplasia Bronchopulmonary Dysplasia pulmonary vascular hypoplasia pulmonary vein stenosis left ventricular diastolic dysfunction with systemic to pulmonary shunts -aortopulmonary collaterals - atrial septal defect -patent ductus arteriosus - ventricular septal defect with significant hypercarbia and /or hypoxia del Cerro et al (PVRI) Pulm Circ 2011:1:286

29 Panama Pediatric Pulmonary Hypertensive Vascular Disease due to: 1. Prenatal or developmental pulmonary hypertensive vascular disease 2. Perinatal pulmonary vascular maladaptation 3. Pediatric cardiovascular disease 4. Bronchopulmonary dysplasia 5. Isolated pediatric pulmonary arterial hypertension 6. Multifactorial pulmonary hypertensive vascular disease in congenital malformation syndromes 7. Pediatric lung diseases 8. Pediatric thromboembolic disease 9. Pediatric hypobaric hypoxic exposure 10. Pediatric pulmonary vascular disease associated with other system disorders del Cerro MJ et al Pulm Circ: 2011:1:286-9

30 Modified Classification of PH: Nice 2013 Simonneau et al J Am Coll Cardiol 2013:62:D Pulmonary Arterial Hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK-1,endoglin,SMAD9, CAV1, KCNK Unknown 1.3 Drugs and toxins induced 1.4 Associated with: Connective tissue disease HIV infection Portal hypertension Congenital heart diseases Schistosomiasis 1. Pulmonary Veno Occlusive Disease and/or Pulmonary Capillary Hemangiomatosis 1. ' Persistent Pulmonary Hypertension of the Newborn 2. Pulmonary Hypertension Due to Left Heart Disease 2.1 Left Ventricular Systolic Dysfunction 2.2 Left Ventricular Diastolic Dysfunction 2.3 Valvular disease 2.4 Congenital / acquired left heart inflow/outflow tract obstruction 3.Pulmonary Hypertension Due to Lung Diseases and/or Hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases Congenital diaphragmatic hernia Bronchopulmonary dysplasia 4.Chronic Thromboembolic Pulmonary Hypertension 5.Pulmonary Hypertension with Unclear Multifactorial Mechanisms 5.1.Hematologic disorders:chronic hemolytic anemias myeloproliferative disorders splenectomy, 5.2 Systemic disorders, Sarcoidosis, pulmonary Langerhans cell histiocytosis, Lymphangioleiomyomatosis, neurofibromatosis, vasculatis 5.3 Metabolic disorders: Glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: Segmental PAH, tumoral obstruction, fibrosing mediastinitis, chronic renal failure

31 Figure 3: WSPH 2013 Consensus Pediatric IPAH/HPAH Treatment Algorithm * Expert Referral General: Consider Diuretics, Oxygen, Anticoagulation, Digoxin Acute Vasoreactivity Testing Oral CCB Positive + > 1 y.o. Lower Risk Negative Higher Risk - Improved - Sustained reactivity Yes Continue CCB No ERA or PDE-5i (oral) Iloprost (inhaled) Treprostinil (inhaled) Reassess consider early combination therapy Ambrisentan (IIaC), Bosentan (IB), CCB (IC), Epoprostenol (IB), Iloprost (IIbC), Sildenafil (IB**USA?), Tadalafil (IIaC), Treprostinil SQ/IV (IIbC/IIaC), Modified from J Am Coll Cardiol. 2009;53: Treprostinil Inh (IIbC), atrial septostomy (IIaC) Epoprostenol or Treprostinil (IV/SQ) Consider Early Combination ERA or PDE-5i (oral) Atrial septostomy Lung transplant *Use of all agents is considered off label in children aside from sildenafil in EU **Dosing recommendations per EU approved dosing for children

32 Acute Vasodilator Testing Usually inhaled nitric oxide Modified Barst Criteria 20% decrease in mean PAp normal or sustained CI Unchanged or decrease in PVR:SVR ratio Sitbon Criteria not adequately studied in children Decrease in mean PAp by 10mmHg to less than 40 mmhg CI sustained

33 Acute Vasodilator Testing Response to calcium channel blockers in children over 1 year of age Assessment of operability in children with congenital heart disease Assessment of long term prognosis

34 Table 5: Pediatric Determinants of Risk LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes No Progression of Symptoms Yes No Syncope Yes Growth Failure to thrive I,II WHO Functional Class III,IV Minimally elevated BNP / NTproBNP Significantly elevated Rising level Echocardiography Severe RV enlargement/dysfunction Pericardial Effusion Systemic CI > 3.0 L/min/m 2 mpap/msap < 0.75 Acute Vasoreactivity Hemodynamics Systemic CI < 2.5 L/min/m 2 mpap/msap > 0.75 RAP > 10mmHg PVRI > 20 WU*m 2

35 Survival Childhood IPAH in Japan Figure 3 Kaplan-Meier curves for survival of all patients. Five- and 10-year survival probabilities were 76% and 72%, respectively. Ayako Chida, Masaki Shintani, Hisato Yagi, Maya Fujiwara, Yasuko Kojima, Hiroki Sato, Shinichiro Imamura,... Outcomes of Childhood Pulmonary Arterial Hypertension in BMPR2 and ALK1 Mutation Carriers The American Journal of Cardiology, Volume 110, Issue 4, 2012,

36 Figure 5 Survival of BMPR2 and ALK1 mutation carriers and mutation noncarriers with PAH (log-rank test, p = ). Ayako Chida, Masaki Shintani, Hisato Yagi, Maya Fujiwara, Yasuko Kojima, Hiroki Sato, Shinichiro Imamura,... Figure 5 Survival of BMPR2 and ALK1 mutation carriers and mutation noncarriers with PAH (log-rank test, p = ).Outcomes of Childhood Pulmonary Arterial Hypertension in BMPR2 and ALK1 Mutation Carriers The American Journal of Cardiology, Volume 110, Issue 4, 2012,

37 Classification of Pediatric Pulmonary Hypertensive Vascular Disease Panama Classification: Emphasized perinatal pulmonary vascular maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension Highlighted the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension Divided pediatric pulmonary hypertensive vascular disease into 10 broad categories

38 Summary Diagnosis of Pulmonary Hypertensive Vascular Disease mean PAP 25mmHg, PVRI 2-3 WU m 2 Diagnosis Pulmonary Arterial Hypertension mean PAP 25mmHg, PAWP/left atrial pressure 15mmHg Classification Nice 2013 concise, understood by physicians who care for adults and pharmaceutical and government agencies

39 Many thanks to current and former Stollery Children s Hospital Pediatric Pulmonary Hypertension Service Research Fellows and Coordinators Prashant Bobhate Moe Elgendi Long (Elven) Guo Shreepal Jain Tarek Khaddoura Shine Kumar Linda Maghoub Karunakar Vadlamudi Jennifer Keis Elina Williams

40 9 th International Conference NEONATAL AND CHILDHOOD PULMONARY VASCULAR DISEASE March 10-12, 2016 Westin Market Street Hotel, San Francisco, California