OVERVIEW: What every practitioner needs to know

Are you sure your patient has pulmonary hypertension? What are the typical findings for this disease?

Pulmonary hypertension (PH) is an important cause of morbidity and mortality in neonates and children. Since the introduction of new targeted therapies, survival has markedly improved. Nevertheless, there is still no cure for most forms of PH.

Therefore, the aim of treatment is to prolong survival and improve quality of life, reduce symptoms, increase exercise capacity, and improve hemodynamics. Identification and treatment of the known causes of PH are crucial because the best treatment includes treatment of any underlying disorders.

Selection of appropriate therapies for pulmonary hypertension is complex; therapies must be carefully chosen according to the etiology and determination of pulmonary vasoreactivity at cardiac catheterization.

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The symptoms of pulmonary hypertension in children are frequently misleading, and the diagnosis may be unrecognized for some time. A high degree of suspicion should be the rule. Pulmonary hypertension should be suspected in any child with undue shortness of breath, tiredness, chest pain, or syncopal episodes. In patients with asthma who do not respond appropriately to medical therapy, pulmonary hypertension should be considered.

Physical Examination:

The physical signs of pulmonary arterial hypertension (PAH) include:

right ventricular lift

accentuated second heart sound

hepatomegaly with peripheral edema in the case of heart failure

diastolic murmur of pulmonary insufficiency, holosystolic murmur of tricuspid regurgitation, or gallop rhythm may be audible

The resting systemic arterial oxygen saturation should be normal in the absence of an intracardiac shunt or in the absence of significant pulmonary parenchymal disease or a pulmonary arteriovenous malformation.

What other disease/condition shares some of these symptoms?


Congestive heart failure

Seizure disorder

What caused this disease to develop at this time?

Idiopathic Pulmonary Arterial Hypertension (IPAH):

IPAH (formerly known as Primary Pulmonary Hypertension-PPH) is a rare disease which occurs most frequently in young adult females, but can occur at any age. IPAH is characterized by progressive and sustained elevations of pulmonary artery pressure without a defined etiology. IPAH is a diagnosis of exclusion.

Familial – Heritable Pulmonary Artery Hypertension:

Between 6% and 12% of cases of IPAH are familial with an autosomal dominant pattern of inheritance. The most common genetic abnormality is a mutation in the BMPRII receptor. Recent studies suggest that over 80% of patients with familial IPAH have BMPRII mutations.

Congenital Heart Disease:

A variety of congenital cardiac lesions can cause PH. The age at which these lesions produce irreversible pulmonary vascular disease varies. In general, patients with a ventricular septal defect or patent ductus arteriosus do not develop irreversible pulmonary vascular changes before 2 years of age. Similarly, infants with an atrial or ventricular septal defect with concomitant chronic lung disease are at an increased risk for early development of pulmonary vascular disease.

Patients with cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, and univentricular heart with high pulmonary blood flow, also may develop PH. Palliative shunting operations for certain cardiac anomalies designed to increase pulmonary blood flow also may lead to the subsequent PH. Hypoxia with increased shunting is believed to be a potent stimulus for rapid development of pulmonary vascular disease.

Eisenmenger Syndrome:

Eisenmenger syndrome describes PH with a reversed central shunt. In general, the term “Eisenmenger syndrome” is used for shunts distal to the tricuspid valve, but some studies have included patients with a large atrial septal defect. The syndrome is characterized by elevated pulmonary vascular resistance and bidirectional or right-to-left shunting through a systemic-to-pulmonary connection, such as a ventricular septal defect, patent ductus arteriosus, univentricular heart, or aortopulmonary window. The shunt is initially left-to-right, but as the condition continues and pulmonary vascular resistance increases, the shunt changes to a right-to-left configuration, leading to cyanosis and erythrocytosis.

Respiratory Disease:

Parenchymal lung disease is an important cause of PH. Complications include hypoxic pulmonary vasoconstriction causing increased pulmonary artery pressures and can lead to right ventricular hypertrophy and failure. Right ventricular function is usually preserved until disease is advanced. In most cases, correction of hypoxia can lead to reversal of PH. Patients with chronic lung disease related to bronchopulmonary dysplasia or congenital diaphragmatic hernia are increasingly prevalent.

Thromboembolic Disease:

Chronic thromboembolic disease as a cause of PH in children is uncommon. However, the condition can occur rarely, and an accurate diagnosis is essential for treatment. Predisposing factors include collagen vascular diseases, thrombophilia as in antiphospholipid antibody syndrome, bacterial endocarditis, and ventriculo-atrial shunt for the treatment of hydrocephalus. Likewise, the use of estrogen-containing oral contraceptive agents may cause hypercoagulability, leading to pulmonary thromboembolic phenomena.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnostic work-up of the child with suspected pulmonary hypertension is comprehensive and challenging, consisting of noninvasive and invasive testing that may include chest radiography, electrocardiography, echocardiography, cardiac catheterization, laboratory studies, ventilation-perfusion scintigraphy, pulmonary function testing, nocturnal oximetry, and evaluation for reflux/aspiration.

Chest x-ray may show enlargement of the central pulmonary artery and/or right ventricle, which suggests the presence of PAH. Prominence of the main pulmonary arteries is apparent in most, but not all, patients with IPAH.

Chest radiography findings may also be useful in uncovering secondary causes of pulmonary hypertension, as follows:

Pulmonary venous congestion may suggest pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis.

Hyperinflation or kyphosis are signs of restrictive lung disease.

Asymmetry of the enlarged central pulmonary arteries may warrant investigation of chronic thromboembolic disease or portopulmonary hypertension.

Asymmetric lung volumes may suggest either pulmonary arterial or pulmonary venous abnormalities.

A unilateral small lung may be seen in unilateral “absence” of a pulmonary artery, scimitar syndrome, or unilateral congenital absence of pulmonary veins.

Electrocardiography is often the first test to suggest PAH by showing right ventricular hypertrophy (RVH) and right atrial enlargement. Evidence of right ventricular hypertrophy on ECG is present in most but not all children with PH. ECG findings include a qR complex in lead V1 or V3R regardless of voltage. An upright T-wave in V1 is indicative of right ventricular hypertrophy from 7 days to 7 years.

Echocardiography is the most useful noninvasive screening tool to evaluate patients with a clinical suspicion of PAH. Echocardiography can identify most if not all, congenital heart diseases. The echocardiogram documents right ventricular size and function, left ventricular systolic and diastolic function, morphology and function of valves, and the presence of pericardial effusion or a patent foramen ovale.

Transthoracic Doppler echocardiography can provide an estimate of the systolic pulmonary arterial pressure in the absence of pulmonary outflow obstruction. Doppler echocardiography may underestimate or overestimate systolic pulmonary arterial pressure. If a complete “tricuspid regurgitation envelope” is not well seen by echocardiography, the estimated RV systolic pressure is not accurate.

Color flow Doppler imaging usually can detect intracardiac shunting, although contrast echocardiography may be more suited to visualize right-to-left shunting in patients with a small atrial communication.

Laboratory Assessment:

A comprehensive serologic evaluation is required to assess for other systemic conditions that might lead to PAH and warrant additional treatment. Elevations in antinuclear antibodies are seen in up to 10% of patients with IPAH and do not necessarily imply an associated connective tissue disease. In addition, increased anticardiolipin antibodies and positive lupus anticoagulant can occur in IPAH. Testing for the presence of human immunodeficiency virus (HIV) and sickle cell should be routinely performed in at-risk patients. For patients with a family history of PH or early/sudden death, clinicians may offer genetic testing for a BMPR2, ALK-1, Endoglin, Caveolin-1, KCNK3 or SMAD 9.

Would imaging studies be helpful? If so, which ones?

Cardiac Catheterization: PAH must be confirmed by catheterization, and acute pulmonary vasoreactivity testing should be performed to determine appropriate therapy.

Recommendations regarding this procedure include:

  • – An anesthesiologist experienced in the management of PH should be present during the cardiac catheterization, because sedation may pose a significant risk to the patient with PAH.
  • – The catheterization procedure should be performed by a skilled specialist experienced in performing cardiac catheterizations on children with PAH.
  • – During catheterization, baseline measures should be obtained for right atrial pressure, pulmonary arterial pressure, systemic arterial pressure, mixed venous and systemic arterial saturation, cardiac index, pulmonary capillary wedge pressure, pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), and PVR/SVR ratio.
  • – Evaluation of shunts during the procedure is critical.
  • – Particular care is needed at the time of catheterization to exclude additional intracardiac as well as extracardiac defects and to measure left ventricular filling pressure accurately to rule out postcapillary pulmonary hypertension.
  • – Acute vasodilator testing is essential at the baseline diagnostic catheterization to assist in determining the optimal therapeutic regimen.

Ventilation-perfusion lung scanning is mandatory in patients in whom IPAH/PPH is suspected to exclude chronic thromboembolic disease as a cause of the elevated pulmonary artery pressure, which may be amenable to surgical treatment. Although thromboembolic disease is rare in children, it is one of the few diseases that can be cured with appropriate therapy.

Computed tomography (CT) scans are important in patients with suspected IPAH/PPH and to rule out interstitial lung disease.

Pulmonary Function Testing: Evaluation for obstructive or restrictive lung disease should be performed as part of the evaluation of children with pulmonary hypertension.

Pulmonary function findings relating to PH include:

  • – Abnormalities of pulmonary function may be present in PAH patients, particularly in the more advanced stages of the disease.
  • – A mild obstructive lung defect is seen in 20% to 50% of patients with IPAH/PPH.
  • – The presence of moderate or severe restrictive or obstructive physiologic defects should suggest another diagnosis.
  • – Mild reduction in the diffusion capacity is seen in most patients with IPAH/PPH.

Nocturnal oximetry / sleep study should be performed as a screening test for obstructive sleep apnea (OSA) or sleep-disordered breathing if there is a suspicion of OSA (e.g., in a child with enlarged tonsils or adenoids and history of snoring).Sleep-disordered breathing may cause mild pulmonary hypertension, which may resolve with nighttime continuous positive airway pressure (CPAP) therapy.

Confirming the diagnosis

A Pediatric Pulmonary Arterial Hypertension Diagnostic Work-up Algorithm is shown in Figure 1.

A Treatment Algorithm for PAH is given in Figure 2.

If you are able to confirm that the patient has pulmonary hypertension, what treatment should be initiated?

Treatment of any underlying conditions before use of pulmonary vasodilators is an important principle of treatment.

Based on known mechanisms of action, three classes of drugs have been extensively studied for the treatment of PAH: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (bosentan, ambrisentan, macitentan), phosphodiesterase inhibitors (sildenafil, tadalafil), and soluble guanylate cyclase stimulators (riociguat).

Without therapy, and sometimes despite appropriate surgical correction of congenital cardiac lesions, PAH progresses at a variable rate. As vasoconstriction is an important component in the development of medial hypertrophy, vasodilators are frequently used to decrease pulmonary artery pressure, improve cardiac output, and potentially reverse some of the pulmonary vascular changes noted in the lung.

Before commencing vasodilator therapy for chronic PAH, vasodilator responsiveness should be assessed in the cardiac catheterization unit. A positive response is defined by assessing the change of cardiac and pulmonary catheter data to vasodilators. The younger the child at the time of testing, the greater the likelihood of acute pulmonary vasodilation in response to vasoreactivity testing. Inhaled nitric oxide with oxygen is most commonly used.

What are the adverse effects associated with each treatment option?

Endothelin receptor antagonists (ERAs) may cause liver function abnormalities and must be stopped if AST/ALT are over 3 times normal; ERAs are teratogenic; ERAs may interact with other medications, such as antifungals.

Phosphodiesterase type-5 inhibitors (PDE-5i) may cause vasodilation and thus headache or mild systemic hypotension. They should not be used with nitrate-containing medications; PDE-5i may cause irritability and rare erections in male children. There is an association between use of high-dose sildenafil and late death in children on sildenafil monotherapy.

Prostacyclins are potent vasodilators and may cause hypotension. Common expected side effects include headache, nausea, dizziness, jaw pain, and bone pain.

What are the possible outcomes of pulmonary hypertension?

Pediatric IPAH/PPH carries a dismal prognosis without treatment. In the NIH cohort, children without treatment carried a median survival of only 10 months in individuals less than 16 years old.

The best strategy for prevention of PH associated with congenital heart disease is early repair.

Treatment of underlying disorders associated with chronic lung disease in children should precede use of pulmonary vasodilators.

What causes this disease and how frequent is it?

See Table I and Table II and Figure 3

What complications might you expect from the disease or treatment of the disease?

Morbidity and mortality from PH are high. In most disease states, the presence of PH portends worse survival.

What is the evidence?

Beghetti, M, Hoeper, MM, Kiely, DG. “Safety experience with bosentan in 146 children 2-11 years old with pulmonary arterial hypertension: results from the European Postmarketing Surveillance program”. Pediatr Res. vol. 64. 2008. pp. 200-4.

Berger, RM, Beghetti, M, Humpl, T, Raskob, GE, Ivy, DD, Jing, ZC, Bonnet, D, Schulze-Neick, I, Barst, RJ. “Clinical features of paediatric pulmonary hypertension: a registry study”. Lancet. vol. 379. 2012. pp. 537-46. (Data from the largest pediatric PH registry)

van Loon, RL, Roofthooft, MT, Hillege, HL, Ten Harkel, AD, van Osch-Gevers, M, Delhaas, T, Kapusta, L, Strengers, JL, Rammeloo, L, Clur, SA, Mulder, BJ, Berger, RM. “Pediatric Pulmonary Hypertension in the Netherlands: Epidemiology and Characterization During the Period 1991 to 2005”. Circulation. 2011. (Epidemiology of pediatric PH)

Rosenzweig, EB, Feinstein, JA, Humpl, T, Ivy, DD. “Pulmonary arterial hypertension in children: Diagnostic work up and challenges”. Prog Pediatr Cardiol. vol. 27. 2009. pp. 4-11.

Barst, RJ, Ertel, SI, Beghetti, M, Ivy, DD. “Pulmonary arterial hypertension: a comparison between children and adults”. Eur Respir J. vol. 37. 2011. pp. 665-77. (This paper is an important review of clinical studies and issues regarding similarities and differences between some forms of PAH in pediatric and adult patients.)

McLaughlin, VV, Archer, SL, Badesch, DB. “ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association”. Circulation. vol. 119. 2009. pp. 2250-94.

Ivy, DD, Abman, SH, Barst, RJ, Berger, RM, Bonnet, D, Fleming, TR, Haworth, SG, Raj, JU, Rosenzweig, EB, Schulze, Neick, Steinhorn, RH, Beghetti, M. “Pediatric pulmonary hypertension”. J Am Coll Cardiol. vol. 62. 2013. pp. D117-26. (Important guidelines for diagnosis and treatment of pulmonary hypertension.)

Haworth, SG, Hislop, AA. “Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006”. Heart. vol. 95. 2009. pp. 312-7.

Mourani, PM, Abman, SH. “Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond”. Curr Opin Pediatr. vol. 25. 2013. pp. 329-37.

Mourani, PM, Abman, SH, Abman, SH. “Pulmonary vascular disease in bronchopulmonary dysplasia: physiology, diagnosis and treatment”. 2010. pp. 347-63. (This is a review of the important role of dysmorphic vascular growth in the pathogenesis and pathophysiology of BPD, as well as clinical issues regarding pulmonary hypertension in premature infants with chronic lung disease.)

Tissot, C, Ivy, DD, Beghetti, M. “Medical therapy for pediatric pulmonary arterial hypertension”. J Pediatr. vol. 157. 2010. pp. 528-32.

Vorhies, EE, Ivy, DD. “Drug treatment of pulmonary hypertension in children”. Paediatric drugs. vol. 16. 2014. pp. 43-65. (Review on pharmacologic approach to pediatric pulmonary hypertension.)

Ongoing controversies regarding etiology, diagnosis, treatment

The current medications used to treat childhood PH are not FDA approved. Use of these medications is based on experience and not evidence, as it is in adults.