Diagnosis and Classification

PAH is defined hemodynamically as a mean pulmonary artery pressure (PAP) ≥25 mm Hg at rest, with a pulmonary capillary wedge pressure within reference range (≤15 mm Hg). Some definitions have also included the pulmonary vascular resistance, requiring the pulmonary vascular resistance index to be ≥3 Woods units x m².⁴ A revision of the classification including most of the forms of PH was proposed in Dana Point in 2008.⁵ The clinical presentation of children with PH has been reviewed; this outlines the difficulties of classifying pediatric PH according to this classification.⁶ The exact incidence and prevalence of PH in children is not known. In the French registry, the estimated prevalence for PAH in children was 3.7 cases/million. Patients had idiopathic PAH (60%), familial PAH (10%), PAH associated with congenital heart disease (24%), PAH associated with connective tissue disease (4%) or portal hypertension (2%),⁷ with similar results in other registries.^8–10 Those patients with a small congenital heart defect and severe idiopathic PAH remain difficult to classify.¹¹ PH associated with chronic lung disease¹² or with sickle cell disease¹³ is probably underreported in the pediatric population.

Clinical Presentation and Diagnostic Evaluation

Symptoms of PAH in children are frequently misleading, and the diagnosis may be unrecognized for some time. A high degree of suspicion should be the rule, and PAH should be suspected in any child with undue shortness of breath, tiredness, or syncopal episodes.¹⁰ Although associated PAH is rare in children, except for PH related to congenital heart disease, all potential etiologies should be evaluated.¹⁰ PAH must be confirmed with catheterization, and pulmonary vasoreactivity testing should be performed, usually with inhaled nitric oxide (NO).¹⁴ It is uncertain whether the same definition of vasoreactivity should be applied for adults and children (decrease ≥10 mm Hg in the mean PAP with a mean PAP ≤ 40 mm Hg and an unchanged or increased cardiac output).

Therapeutic Approach

There are no evidence-based treatment recommendations for children with PAH, primarily because of the lack of results from randomized clinical trials in pediatric patients or including pediatric patients.^3,15 The aim of medical treatment is to dilate and reverse the abnormal remodeling of the pulmonary vascular bed and to restore endothelial function, by acting on the prostacyclin, endothelin, and NO pathways. In practice, a therapeutic algorithm similar to PAH in adults appears to guide treatment of children with PAH (Figure).^3,15,16 However, there are some difficulties in applying adult criteria and dosage regimens to children. Acute responders with PAH associated with congenital shunt lesions are considered candidates for surgical repair.¹¹ In responders to acute vasodilator testing in repaired congenital heart disease or idiopathic PAH, calcium channel blockers may be considered. In the ‘‘non-responder’’ with right heart failure, the first line of treatment consists of continuous intravenous prostacyclin, whereas in the absence of right heart failure, other targeted therapies (endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or prostacyclin analogues) may be tried first. Non-responders have a very limited survival rate when not treated with targeted therapies.^2,17 Treatment for patients with congenital left-to-right shunts and irreversible PAH (Eisenmengers syndrome) is based on the same selective regimen as in idiopathic PAH, even when data are limited.¹⁸

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Figure

Treatment algorithm in children with severe pulmonary arterial hypertension.

Calcium channel blockers are used infrequently as first-line therapy in children. Chronic calcium channel blockade is efficacious in patients who demonstrate an acute response to vasodilator testing. Approximately 7% to 40% of children with chronic PAH are ‘‘responders’’ and can be effectively treated with oral calcium channel blockers.^2,9 In children with idiopathic PAH, Barst et al showed that 5-year survival rates improved significantly in acute vasoreactive responders treated with calcium channel blockers compared with non-responders.² Careful follow-up is essential because patients treated with calcium channel blockers may deteriorate with time.¹⁹

Prostacyclin is a metabolite of arachidonic acid endogenously produced by the vascular endothelium. It is a potent pulmonary and systemic vasodilator with anti-platelet activity. Children with severe PAH show diminished prostacyclin synthase expression in the lung vasculature.

Epoprostenol is a synthetic prostacyclin used via intravenous infusion, and has been shown to improve hemodynamics, quality of life, exercise capacity, and survival rate in adults and children with idiopathic PAH and APAH.^2,19 Epoprostenol is known to lower PAP, increase cardiac output and increase oxygen transport. Barst et al have shown improved survival rate in children treated with long-term intravenous epoprostenol, with a 4-year survival rate for treated children of 94%, compared with 38% in untreated patients,² and Yung et al have reported a 10-year treatment success rate (freedom from death, transplantation, or atrioseptostomy) of 37%.¹⁹ The development of tolerance or tachyphylaxis is possible, and most children need periodic dose escalation. Diarrhea, jaw pain, bone pain, systemic vasodilation, and thromboembolic events related to catheter delivery are known adverse effects. Epoprostenol has a short half-life (1–2 minutes), rendering a continuous intravenous infusion with a permanent central venous catheter necessary. Complications such as line sepsis, local infection, and catheter dislodgement are not unusual.²⁰

Iloprost is an inhaled prostacyclin analogue with a longer half-life of 20 to 30 minutes. A recent review summarizes its use in pediatric PAH.²¹ In children treated with iloprost, World Health Organization (WHO) functional class has been shown to be improved in 35%, remained unchanged in 50%, and decreased in 15%.²² Lower-airway reactivity is a problem in some children, as is poor compliance with the need for frequent aerosol administrations (6–8 times daily). In the critical care setting of congenital heart defects, inhaled iloprost has been shown to be as efficacious as NO in lowering mean pulmonary vascular resistance and improve systemic oxygen saturation.²³

Treprostinil is a prostacyclin analogue usually administered with continuous subcutaneous infusion and also is approved by the US Food and Drug Administration (FDA) for intravenous and inhaled delivery. Subcutaneous treprostinil has been shown to improve exercise tolerance, clinical signs, symptoms, and hemodynamics in adult patients with PAH,²⁴ but discomfort at the infusion site is common and represents the most limiting factor in children. The use of intravenous treprostinil in children can be considered for patients who have been on a stable dose of intravenous epoprostenol with clinical improvement.²⁵ Treprostinil has been studied in an inhaled form in adults²⁶ and was recently approved by the FDA but there are no data in children.

Endothelin-1 (ET-1) is a potent vasoactive peptide produced primarily in the vascular endothelial cell, but also may be produced by smooth muscle cells. Two receptor sub-types, ET_A and ET_B, mediate the activity of ET-1. ET_A and ET_B receptors on vascular smooth muscle mediate vasoconstriction, whereas ET_B receptors on endothelial cells cause release of NO and prostacyclin and act as clearance receptors for circulating ET-1.²⁷

Bosentan is an oral dual endothelin receptor antagonist²⁸ acting on both ET_A and ET_B receptors. A recent review summarizes its use in pediatric PAH.²⁹ In recent uncontrolled studies in children with PAH, bosentan has been shown to lower mean PAP and PVR³⁰ and improve WHO functional status and survival estimates at 1 and 2 years (98% and 91%, respectively).³¹ However, in a study including both children and adults with PAH and systemic-to-pulmonary shunt, bosentan therapy has been shown to produce only short-term improvement in WHO functional class and 6-minute walk distance.³² There was a progressive decline in the beneficial effect of bosentan after 1 year, with a more pronounced decline in the children, who tended to have more severe disease at baseline.³² Common adverse effects include dose-related hepatotoxicity, teratogenicity, and possibly male infertility;⁸ liver function tests should be performed monthly. The safety of bosentan therapy in children with PAH has been recently reported by Beghetti et al.⁸ Elevated transaminase levels were reported in 2.7% of children, compared with 7.8% of patients aged ≥12 years, and the overall discontinuation rate from bosentan was 14% in children, compared with 28% in patients aged ≥12 years, mainly related to death, hospitalization, or adverse events. Bosentan has been studied in Eisenmenger syndrome in a placebo-controlled trial in adult patients, the Breathe-5 study. Bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation.³³ A specific pediatric formulation has been recently approved in Europe.³⁴

Sitaxsentan and ambrisentan are oral selective ET_A receptor antagonists with a long half life.²⁷ They block the vasoconstrictor effect of ET_A receptors while maintaining the vasodilator effect and clearance function of ET_B receptors. Sitaxsentan and ambrisentan have shown beneficial effects on exercise capacity and New York Heart Association functional class in adult patients,^35,36 but little data are available for children.³⁷

Phosphodiesterase type 5 inhibitors prevent the breakdown of cyclic guanosine monphosphate, resulting in pulmonary vasodilation. Phosphodiesterase type 5 inhibitors are acute pulmonary vasodilators as efficient as inhaled NO and potentiate pulmonary vasodilation with NO. They may be particularly beneficial in conjunction with NO, when withdrawal of NO may lead to rebound PAH.^38,39

Sildenafil can be used orally, and recently the intravenous formulation has been approved by the FDA. Sildenafil has been approved for the treatment of WHO functional class II to IV PAH adult patients;⁴⁰ the data in children remain limited. In a pilot study of 14 children with PAH, oral sildenafil decreased PAP and PVR significantly and improved the mean 6-MWD, but a plateau was reached between 6 and 12 months.⁴¹ In a small study of children with idiopathic PAH and PH associated with congenital heart disease, sildenafil has been shown to improve oxyhemoglobin saturation and exercise capacity without significant adverse effects.⁴² In children with PAH associated with chronic lung disease, sildenafil has been shown to improve hemodynamics in 88% of patients, was well tolerated, and did not worsen oxyhemoglobin saturation.⁴³ Moreover, phosphodiesterase type 5 appears to be highly expressed in the hypertrophied human right ventricle, and acute inhibition with oral sildenafil has been shown to improve right ventricular contractility.⁴⁴ Adverse effects include headache, flushing, exacerbation of nosebleeds, and rare systemic hypotension or erections. A randomized placebo-controlled trial of oral sildenafil has been completed in pediatric patients, with the initial results presented in abstract form.⁴⁵

Intravenous sildenafil has been shown to potentiate the increase in cyclic guanosine monophosphate in response to NO in children with increased PVR related to congenital heart disease or to postoperative state. However, sildenafil infusion was associated with increased intrapulmonary shunting and augmentation of hypoxemia related to V/Q mismatch in the postoperative patient with congenital heart disease.^46,47 However, a recent study of intravenous sildenafil has shown improvement in oxygenation index in persistent pulmonary hypertension of the newborn in patients treated with or without inhaled NO.⁴⁸

Tadalafil is also a selective phosphodiesterase type 5 inhibitor with a longer duration of action (half life, 17 hours). Tadalafil was recently approved by the FDA in 2009 for adults with PAH, but no data are available in children.

As for patients with right heart failure, combination therapy is an attractive option to address simultaneously the multiple pathophysiological pathways present in PAH. It is understandable that acting on the three different pathways of PAH may be more efficacious than acting on a single one, by additive or synergistic effects.^49,50 Whether combination therapy should be used as a first step by simultaneous initiation of two or more drugs or by addition of a second treatment to an earlier therapy once insufficient is still not known; more studies are needed to help establishing guidelines. Even when empiric combinations of drugs is not uncommon in pediatric patients with PAH, there is a clear lack of studies in this area.

Creation of a Right-to-Left Shunt and Transplantation

Children not responding to conventional medical therapy may be candidates for atrioseptostomy or transplantation. Atrioseptostomy may benefit patients with severe PAH with recurrent syncope and intractable right heart failure unresponsive to medical therapy. Right-to-left shunting through an interatrial defect allows maintenance of cardiac output at the expense of increased hypoxemia and alleviates signs of right heart failure by decompression of the right heart.⁵¹ Transplantation should be reserved for children with PAH, which has progressed despite optimal medical therapy, and children should be listed for transplantation when their probability of 2-year survival without transplantation is ≤50%.⁵²

Conclusion

Advances in the understanding of pulmonary vasculature has led to new therapeutic options and improved survival rates in children with PAH. Timely diagnosis is crucial because earlier treatment leads to improved outcome. In children with PAH, an extensive work-up is necessary to determine the etiology, because the most successful strategy involves treatment of the underlying disorder. Initial evaluation includes acute vasodilator testing at cardiac catheterization, which determines initial therapy. Several novel therapeutic agents are under investigation, and evolving clinical research should better define the role of new medical treatments for children with PAH.

Acknowledgments

Glossary

Footnotes

References