Pulmonary Hypertension�in Infants and Children

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

1. Pulmonary Hypertension
in Infants and Children
Roy Maynard, M.D.
June 22, 2011

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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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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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Causes of Pulmonary Hypertension
•Neonatal
•Cardiac
•Acquired
•Idiopathic
•(New Classification Scheme Lists
10 Groups)

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Neonatal
•Persistent pulmonary hypertension of
the newborn (persistent fetal
circulation)
•Bronchopulmonary dysplasia
•Infection
•Structural disease
–Congenital diaphragmatic hernia
–Pulmonary hypoplasia

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Persistent Fetal Circulation
http://msrcol.org/nu/pphn.gif

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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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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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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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Pulmonary Hypoplasia/CDH
Normal lung
Hypoplastic lung
Pulmonary arterioles

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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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Pulmonary Hypertension
Beyond the Newborn
Intensive Care Unit

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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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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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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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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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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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Bone Morphogenetic Protein Receptor 2
http://img.medscape.com/fullsize/migrated/527/555/pharm527555.fig1.gif

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Other Diagnoses
•Collagen vascular disease
•Sickle cell disease
•Down’s syndrome
•Eisenmenger syndrome

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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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Clinical
•Physical Exam
–Right ventricular heave
–Increased 2
nd
heart sound
–Diastolic heart murmur
–Tachycardia
–Tachypnea
–Diaphoresis
–Peripheral edema/acrocyanosis

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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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Right-Sided Heart Failure
http://healthguide.howstuffworks.com/cor-pulmonale-picture.htm

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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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Pulmonary Hypertension
http://ph-central.com/2011/03/the-secondary-pulmonary-hypertension-causes-prognosis-treatment.html

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Histopathology
http://www.pah-info.com/what_is_PAH

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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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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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Pulmonary Hypertension
http://www.riversideonline.com/source/images/image_popup/r7_pulmonaryhypertens.jpg

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Clinical
•Blood work
–Gene testing (BMPR2)
–Thyroid function
–Thrombophilia screen
–Antiphospholipid antibody

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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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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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Treatment of Pediatric Pulmonary Hypertension
Prostacyclin Pathway
Nitric Oxide Pathway
Endothelin Pathway
Obliterated arteriole
proendothelin
Arginine -> Citrulline
Arachadonic acid -> prostaglandin I
2
Endothelin-1
Nitric oxide
Phosphodiester
ase type - 5
cGMP
Vasodilitation
Antiproliferation
sildenafil
Endothelial cells
Smooth muscle cells
prostacyclin
cAMP
Vasodilitation
Antiproliferation
Block endothelial receptors
With bosentan ; results in vasodilitation
And antiproliferation

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Pharmacologic Treatment
•Calcium Channel Blockers
–Nifidipine
–Small percentage are acute responders
–50% acute responders lose beneficial effect
within one year

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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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Pharmacologic Treatment
•Phosphodiesterase-5 Inhibitors
–Vasodilitation and antiproliferation
–Work through nitric oxide/cyclic
guanosine monophosphate pathway
–Sildenafil
–Tadalafil

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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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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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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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Clinical Endpoints
•6-minute walk test
•Time to clinical worsening
•Quality of life
•Echocardiogram
•Heart catherization

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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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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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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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Q&A
Thank you for attending!