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 2nd 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 I2

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!