Pulmonary hypertension in infants and children can be neonatal, cardiac-related, acquired, or idiopathic. The gold standard test to confirm pulmonary hypertension is cardiac catheterization. Current pharmacologic treatments target three pathways - the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. Combination drug therapy and non-pharmacologic options like atrial septostomy may also be used, but pulmonary hypertension remains a challenging condition to treat in children.

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.
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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
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4. Causes of Pulmonary Hypertension
• Neonatal
• Cardiac
• Acquired
• Idiopathic
• (New Classification Scheme Lists
10 Groups)
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5. Neonatal
• Persistent pulmonary hypertension of
the newborn (persistent fetal
circulation)
• Bronchopulmonary dysplasia
• Infection
• Structural disease
– Congenital diaphragmatic hernia
– Pulmonary hypoplasia
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6. Persistent Fetal Circulation
http://msrcol.org/nu/pphn.gif
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7. Conditions Predisposing to
Neonatal Pulmonary Hypertension
• Respiratory Distress Syndrome
• Asphyxia
• Congenital diaphragmatic hernia
• Hypoglycemia/hypothermia
• Meconium aspiration syndrome
• Pulmonary hypoplasia
• Sepsis/pneumonia
• Pneumothorax
• Polycythemia
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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?
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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
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10. Pulmonary Hypoplasia/CDH
Pulmonary arterioles
Hypoplastic lung
Normal lung
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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)
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12. Pulmonary Hypertension
Beyond the Newborn
Intensive Care Unit
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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
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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
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15. Acquired
• Chronic hypoxia, cystic fibrosis, high altitude
• Scoliosis with severe restrictive disease
• Airway obstruction
• Vasculitic connective tissue disease,
interstitial lung disease, sickle cell
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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
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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
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18. Bone Morphogenetic Protein Receptor 2
http://img.medscape.com/fullsize/migrated/527/555/pharm527555.fig1.gif
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19. Other Diagnoses
• Collagen vascular disease
• Sickle cell disease
• Down’s syndrome
• Eisenmenger syndrome
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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
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21. Clinical
• Physical Exam
– Right ventricular heave
– Increased 2nd heart sound
– Diastolic heart murmur
– Tachycardia
– Tachypnea
– Diaphoresis
– Peripheral edema/acrocyanosis
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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
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23. Right-Sided Heart Failure
http://healthguide.howstuffworks.com/cor-pulmonale-picture.htm
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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
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25. Pulmonary Hypertension
http://ph-central.com/2011/03/the-secondary-pulmonary-hypertension-causes-prognosis-treatment.html
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26. Histopathology
http://www.pah-info.com/what_is_PAH
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27. Histopathology
http://www.pvrireview.org/article.asp?issn=0974-
6013%3Byear=2009%3Bvolume=1%3Bissue=1%3Bspage=34%3Bepage=38%3Baulast=Aiello
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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)
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29. Pulmonary Hypertension
http://www.riversideonline.com/source/images/image_popup/r7_pulmonaryhypertens.jpg
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30. Clinical
• Blood work
– Gene testing (BMPR2)
– Thyroid function
– Thrombophilia screen
– Antiphospholipid antibody
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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
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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.
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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
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34. Pharmacologic Treatment
• Calcium Channel Blockers
– Nifidipine
– Small percentage are acute responders
– 50% acute responders lose beneficial effect
within one year
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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)
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36. Pharmacologic Treatment
• Phosphodiesterase-5 Inhibitors
– Vasodilitation and antiproliferation
– Work through nitric oxide/cyclic
guanosine monophosphate pathway
– Sildenafil
– Tadalafil
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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
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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
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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
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40. Clinical Endpoints
• 6-minute walk test
• Time to clinical worsening
• Quality of life
• Echocardiogram
• Heart catherization
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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
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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
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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
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44. Q&A
Thank you for attending!
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