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Pulmonary Hypertension in Infants and Children

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Dr. Maynard’s update on pulmonary hypertension in infants and children (presented on 6/22/11).

Dr. Maynard’s update on pulmonary hypertension in infants and children (presented on 6/22/11).

Published in: Health & Medicine

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  • 1. Pulmonary Hypertension in Infants and Children Roy Maynard, M.D. June 22, 2011
  • 2. Objectives• Understand the difference between neonatal and pediatric pulmonary hypertension.• Describe the best test to confirm pulmonary hypertension.• Identify the 3 metabolic pathways for current pharmacologic approach to treating pulmonary hypertension. 2 of 44
  • 3. Definition• Increase in pulmonary artery (PA) pressure in the pulmonary vascular bed• PA pressure >25 mmHg at rest or >30 mmHg with exercise• Systolic PA pressure > half systolic systemic pressure 3 of 44
  • 4. Causes of Pulmonary Hypertension • Neonatal • Cardiac • Acquired • Idiopathic • (New Classification Scheme Lists 10 Groups) 4 of 44
  • 5. Neonatal• Persistent pulmonary hypertension of the newborn (persistent fetal circulation)• Bronchopulmonary dysplasia• Infection• Structural disease – Congenital diaphragmatic hernia – Pulmonary hypoplasia 5 of 44
  • 6. Persistent Fetal Circulation http://msrcol.org/nu/pphn.gif 6 of 44
  • 7. Conditions Predisposing toNeonatal Pulmonary Hypertension • Respiratory Distress Syndrome • Asphyxia • Congenital diaphragmatic hernia • Hypoglycemia/hypothermia • Meconium aspiration syndrome • Pulmonary hypoplasia • Sepsis/pneumonia • Pneumothorax • Polycythemia 7 of 44
  • 8. Treatment of Neonatal Pulmonary Hypertension• Persistent Pulmonary Hypertension of the Newborn – Oxygen – Decrease stress – IV dextrose/antibiotics – Intubation/mechanical ventilation – High frequency ventilation – Surfactant therapy – Neuromuscular paralysis – Pressors – Nitric oxide – Sildenafil – Steroids? 8 of 44
  • 9. Bronchopulmonary Dysplasia• Elevated pulmonary pressures very common in patients with moderately severe to severe disease• Aim to keep oxygen sats >95• Exacerbated by infection• Pulmonary hypertensive crisis uncommon• May benefit by tracheostomy and long-term mechanical ventilation• Generally improves with time and normal lung remodeling and growth• Death from progressive pulmonary hypertension is uncommon 9 of 44
  • 10. Pulmonary Hypoplasia/CDH Pulmonary arterioles Hypoplastic lung Normal lung 10 of 44
  • 11. Pathophysiology of Pulmonary Hypertension • Small vascular bed • Reversible vasoconstricted vascular bed • Structural alterations to the vascular bed – Primarily arterioles – Small to medium-sized pulmonary arteries – May affect all three components of the artery: intima (endothelial cells), media (smooth muscle cells), adventitia (collagen, fibroblasts) 11 of 44
  • 12. Pulmonary Hypertension Beyond the Newborn Intensive Care Unit 12 of 44
  • 13. Epidemiology• Idiopathic in 35% of pediatric patients• Associated with congenital heart disease in 52% of pediatric patients• Slightly more common in girls• Median age of diagnosis age 3• Disease tends to progress more rapidly in children relative to adults 13 of 44
  • 14. Cardiac Structural Heart Disease• Left-to-right shunt VSD, AV canal, PDA, AP window• Transposition of the great arteries• Obstructive lesions TAPVC, MS, HLHS, Cardiomyopathy• Eisenmenger syndrome: elevated pulmonary vascular resistance and pulmonary hypertension induced reversal of a previous left-to-right shunt 14 of 44
  • 15. Acquired• Chronic hypoxia, cystic fibrosis, high altitude• Scoliosis with severe restrictive disease• Airway obstruction• Vasculitic connective tissue disease, interstitial lung disease, sickle cell 15 of 44
  • 16. Idiopathic• Sporadic 20% genetic in origin• 6–10% of idiopathic cases are familial with autosomal dominant pattern• Females > males (1.7:1)• Bone morphogenetic protein gene (BMP II) responsible in 50% of familial and 10% of sporadic 16 of 44
  • 17. Bone Morphogenetic Protein Receptor 2 • BMPR2 • A transforming growth factor • A decrease in BMPR2 expression (downregulation) leads to abnormal proliferative responses in pulmonary vascular cells 17 of 44
  • 18. Bone Morphogenetic Protein Receptor 2 http://img.medscape.com/fullsize/migrated/527/555/pharm527555.fig1.gif 18 of 44
  • 19. Other Diagnoses• Collagen vascular disease• Sickle cell disease• Down’s syndrome• Eisenmenger syndrome 19 of 44
  • 20. Clinical• History (SILENT DISEASE) – Heart disease – Shortness of breath – Syncope – Poor endurance/fatigue – Cyanotic spells – Symptoms not present till pressures > 60 – Poor appetite/failure to thrive – Irritability 20 of 44
  • 21. Clinical• Physical Exam – Right ventricular heave – Increased 2nd heart sound – Diastolic heart murmur – Tachycardia – Tachypnea – Diaphoresis – Peripheral edema/acrocyanosis 21 of 44
  • 22. Clinical• Laboratory – Pulse oximetry usually normal – Exercise testing – ECG - RVH – Echocardiogram: dilated right heart chamber, right ventricular hypertrophy, tricuspid regurgitation, paradoxical motion of cardiac septum 22 of 44
  • 23. Right-Sided Heart Failure http://healthguide.howstuffworks.com/cor-pulmonale-picture.htm 23 of 44
  • 24. Clinical• Laboratory – CXR - enlarged central pulmonary arteries, pruning of peripheral pulmonary arteries – CT scan of chest – R/O interstitial lung disease, hemangiomatosis, thromboembolic defects – Pulmonary function testing – Lung biopsy – veno-occlusive disease 24 of 44
  • 25. Pulmonary Hypertensionhttp://ph-central.com/2011/03/the-secondary-pulmonary-hypertension-causes-prognosis-treatment.html 25 of 44
  • 26. Histopathology http://www.pah-info.com/what_is_PAH 26 of 44
  • 27. Histopathology http://www.pvrireview.org/article.asp?issn=0974-6013%3Byear=2009%3Bvolume=1%3Bissue=1%3Bspage=34%3Bepage=38%3Baulast=Aiello 27 of 44
  • 28. Pathophysiology of Pulmonary Hypertension • Small vascular bed • Reversible vasoconstricted vascular bed • Structural alterations to the vascular bed – Primarily arterioles – Small to medium-sized pulmonary arteries – May affect all three components of the artery; intima (endothelial cells), media (smooth muscle cells), adventitia (collagen, fibroblasts) 28 of 44
  • 29. Pulmonary Hypertension http://www.riversideonline.com/source/images/image_popup/r7_pulmonaryhypertens.jpg 29 of 44
  • 30. Clinical• Blood work – Gene testing (BMPR2) – Thyroid function – Thrombophilia screen – Antiphospholipid antibody 30 of 44
  • 31. Clinical• Gold Standard Cardiac Catherization – Direct measure of PA pressure – Calculate pulmonary vascular resistance – Cardiac output – Pulmonary vasoreactivity – prognosticate • Oxygen • Sildenafil • Nitric oxide • Prostacyclin 31 of 44
  • 32. WHO Functional Classification of Pulmonary Hypertension• Class I: Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain or near syncope• Class II: Comfortable at rest, ordinary physical activity causes undue dyspnea, fatigue, chest pain or near syncope• Class III: Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes undue dyspnea, fatigue, chest pain or near syncope• Class IV: Unable to perform any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present at rest. Discomfort is increased with any physical activity. 32 of 44
  • 33. Treatment of Pediatric Pulmonary Hypertension Obliterated arteriole Prostacyclin Pathway Endothelin Pathway Nitric Oxide Pathway Endothelial cells proendothelin Arachadonic acid -> prostaglandin I2 Endothelin-1 Arginine -> Citrulline prostacyclin sildenafil Nitric oxide cAMP Block endothelial receptors With bosentan ; results in vasodilitation cGMP And antiproliferation Vasodilitation Vasodilitation Phosphodiester Antiproliferation Antiproliferation ase type - 5 Smooth muscle cells 33 of 44
  • 34. Pharmacologic Treatment• Calcium Channel Blockers – Nifidipine – Small percentage are acute responders – 50% acute responders lose beneficial effect within one year 34 of 44
  • 35. Pharmacologic Treatment• Endothelin 1-Receptor Antagonists – Two receptors A and B • Receptor A vasoconstriction • Receptor B vasodilitation and anti-mitogenic – Potent vasoconstrictors and mitogens • Bosentan (A&B) • Sitaxetan (A) • Ambrisentan (A) 35 of 44
  • 36. Pharmacologic Treatment • Phosphodiesterase-5 Inhibitors – Vasodilitation and antiproliferation – Work through nitric oxide/cyclic guanosine monophosphate pathway – Sildenafil – Tadalafil 36 of 44
  • 37. Pharmacologic Treatment• Prostanoids – Epoprostenol IV (most experience) – Treprostinil IV or SQ (painful SQ) – Iloprost nebulized – Beraprost oral (less efficacious)• Side Effects – Flushing, jaw pain, headaches, rashes, thrombocytopenia 37 of 44
  • 38. Pharmacologic Treatment• Combination Therapy• Rho-kinase inhibitors (promote vasodilitation)• Vasoactive Intestinal Polypeptide (VIP)• Anticoagulation (reduced cardiac output, polycythemia)• Glucocorticoids for co-existing diseases like collagen vascular disease 38 of 44
  • 39. Non-Pharmacologic Therapies • Atrial septostomy – Create pop-off between right and left atrium – Improves syncopal episodes – Improves right heart failure – Improves survival • Lung or lung/heart transplant – 77% survival one year – 62% survival two years – 55% survival five years – 10% survival ten years 39 of 44
  • 40. Clinical Endpoints• 6-minute walk test• Time to clinical worsening• Quality of life• Echocardiogram• Heart catherization 40 of 44
  • 41. Prognosis• Survival better with secondary pulmonary hypertension than with idiopathic pulmonary hypertension• UK Pulmonary Hypertension Service for Children – 85.6% one-year survival – 79.9% three-year survival – 71.9% five-year survival 41 of 44
  • 42. Conclusion• Improved understanding of genetic aspects of familial pulmonary hypertension may lead to new therapies• Much better delineation of pathobiology causing pulmonary hypertension now• New pharmacological approaches to treating pulmonary hypertension have prolonged and improved quality of life• None of these interventions have cured pulmonary hypertension 42 of 44
  • 43. Conclusion• Limited pharmacologic data for pulmonary hypertension treatment in children• Most treatment schemes extrapolated from adults to children though pulmonary hypertension may be more prevalent in children• Difficult to measure clinical endpoints in children• Placebo-controlled studies are difficult to conduct and may be deemed ethically unacceptable 43 of 44
  • 44. Q&AThank you for attending! 44 of 44

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