Management of Idiopathic PAH in Children: Reexamining the Evolving Treatment Algorithm

The treatment of pediatric idiopathic pulmonary arterial hypertension (IPAH) is challenging due to the serious nature of the disease, its rapid progression, and limited treatment options available for children. Similar to adults, IPAH in children is characterized by progressive elevation of the pulmonary arterial pressure leading to right ventricular failure and clinical deterioration if left untreated. In children, disease progression appears to be more rapid. In the 1980s, prior to the current treatment era, the median untreated survival for children under 16 years of age, was reported to be as short as 10 months as opposed to 2.8 years for adults.1 Fortunately, recent advances in the treatment of pulmonary arterial hypertension have resulted in significant improvements in the prognosis for children with IPAH. However, clinical data on pediatric pulmonary arterial hypertension is quite limited and treatment strategies are often extrapolated from adult studies. Furthermore, the selection of the optimal therapy is complex, as there are no consistently successful treatments, and some agents may involve complicated delivery systems, specific dosing regimens, side effects and potential complications. This article will review current strategies for the management of pediatric IPAH patients.Medical management of children with pulmonary arterial hypertension includes conventional therapies to treat sequelae of right ventricular failure and associated thrombosis, and targeted treatment for the pulmonary vasculopathy.Conventional medications that target right ventricular failure and thromboembolic events are frequently used in pulmonary arterial hypertension patients.2 Digoxin is often used when right ventricular function is diminished, although there are no clear data documenting its beneficial effect in children. Warfarin may be used to prevent right heart thrombi and thromboemboli when right ventricular function is depressed and to prevent thrombosis in situ, commonly seen in the histopathology of pulmonary arterial hypertension. Again, the use of coumadin in children is based on studies in adults with pulmonary arterial hypertension.34 Whether thrombosis in situ is a significant exacerbating factor in children in IPAH is unknown. When prescribing coumadin in children special attention should be paid to the level of activity, eg, toddlers with severe right ventricular failure require close monitoring of the prothrombin international normalized ratio (INR). Diuretics are also used to control peripheral edema and/or ascites in children with right heart failure. Oxygen therapy is indicated in cases of chronic hypoxemia to maintain systemic arterial oxygen saturation above 90%. IPAH children should be treated with supplemental oxygen when they experience systemic arterial desaturation during sleep or during an upper respiratory tract infection. Children with severe right ventricular failure and resting hypoxemia due to heart failure may also benefit from chronic supplemental oxygen.As in adult pulmonary arterial hypertension patients, right heart cardiac catheterization with acute vasodilator testing is essential prior to selecting targeted therapy. Acute vasodilator testing is performed during cardiac catheterization and includes assessment of the acute response to a short-acting vasodilator, such as inhaled nitric oxide, intravenous epoprostenol, intravenous adenosine, or inhaled iloprost. In the past, patients were considered responsive to acute vasodilator testing if the mPAP fell 20% or more without a fall in the cardiac output.5 While a more stringent definition was recently introduced in adults (fall in mPAP >10 mmHg to <40 mmHg) to predict long-term response to oral calcium channel blockade,6 either definition appeared to predict long-term response to calcium channel blockade in children in a study by Yung et al.7 Unlike adults, in whom only 7% demonstrate a robust long-term response to treatment with oral calcium channel blockade, children are more likely to have a favorable response to acute vasodilator testing and thus to long-term treatment with high-dose oral calcium channel blockers. Studies have reported up to 40% of children are responsive to acute vasodilator testing, and that the likelihood of response decreases with age (Figure 1).5 Close monitoring of children responsive to acute vasodilator testing is still critical since the benefits observed with calcium channel blocker treatment in IPAH children who are responders (97% 5-year survival) are not always preserved over the long term (81% 10-year survival).7 Furthermore, “treatment success” at 10 years in children who are acute responders is approximately 50% (Figure 2).7 Thus, serial monitoring of these children is critical to determine whether additional treatment is warranted. Because of significant side effects (systemic hypotension, right ventricular failure), treatment with high-dose calcium channel blockers is not recommended for patients who are not acute responders and for those who have significant right heart failure.Prostacyclin is well known as a vasodilator of the pulmonary circulation and an inhibitor of platelet aggregation. The rationale for the use of epoprostenol or other prostacyclin analogues in the treatment of IPAH is based on the imbalance between thromboxane and prostacyclin89 and the decreased expression of prostacyclin synthase10 observed in adult and pediatric IPAH patients. Intravenous epoprostenol use in children with pulmonary arterial hypertension was first described in the 1980s. In the mid 1990s, epoprostenol became the gold standard for treatment of IPAH patients who were not responsive to acute vasodilator testing, and therefore would not benefit from oral calcium channel blockers. In these patients, although there may not have been an immediate, dramatic reduction of pulmonary pressures in response to epoprostenol, long-term treatment has yielded substantial improvements in clinical status. This supports the idea that epoprostenol may have remodeling properties on the pulmonary vascular bed in addition to its role as a pulmonary vasodilator (Figure 3).5Epoprostenol has been shown to improve hemodynamics, quality of life, and exercise capacity in patients with IPAH.11–14 Although few pediatric studies are available, sustained clinical and hemodynamic benefits have been reported for IPAH children receiving intravenous epoprostenol for over 10 years (Figure 4).57The clinical indication for long-term continuous intravenous epoprostenol therapy is similar in children and in adults, although younger patients tend to need higher doses than adults (50 to 80 ng/kg/min after 1 year of treatment in children versus 20 to 40 ng/kg/min in adults). The starting dose is the same as for adults (2 ng/kg/min) and is uptitrated by increments of 1 to 2 ng/kg/min based on side effects and pulmonary hypertension symptoms, with the most rapid increases implemented during the first several months of treatment. Epoprostenol has a number of side effects, including jaw pain, headache, nausea, diarrhea, and foot and leg pain,5 that are often not medically significant but that may impact a child’s overall quality of life. These side effects tend to be dose-dependent and often respond to dose reduction. Because epoprostenol is chemically unstable at room temperature and has a short half-life (1 to 2 minutes), chronic intravenous epoprostenol treatment requires a continuous intravenous delivery system on ice packs. This is particularly problematic in active pediatric patients because of increased risk of line-related complications, including infections and/or dislodgement.15 In addition, because of the short half-life of epoprostenol therapy, interruptions due to pump malfunction or line dislodgement can lead to rebound pulmonary hypertension crises that can be life threatening. The complexity of administration and side effects of epoprostenol has led to a search for alternative routes of drug delivery and to the development of prostacyclin analogues with alternate delivery systems.Treprostinil sodium is a chemically stable prostacyclin analogue with a longer half-life than epoprostenol (approximately 4? hours), which can be infused intravenously or subcutaneously. When administered acutely to IPAH patients, intravenous treprostinil has similar effects on hemodynamics as intravenous epoprostenol and induces comparable short-term decreases in pulmonary vascular resistance as subcutaneous treprostinil.16 In a 12-week, double-blind, placebo-controlled multicenter trial involving 470 patients (including children over 8 years old) with World Health Organization (WHO) class II-IV pulmonary arterial hypertension (idiopathic or associated with connective tissue disease or congenital systemic-to-pulmonary shunts) subcutaneous treprostinil improved exercise capacity, indices of dyspnea, signs and symptoms of pulmonary arterial hypertension, and hemodynamics.17 The risk of intravenous line infection is eliminated with subcutaneous treprostinil although pain at the site of infusion is commonly reported,17 which may be especially troublesome for children. Topical cold and hot packs, topical and oral analgesics, and antiinflammatory drugs are variably effective in controlling these adverse effects. Common side effects also include headache, diarrhea, nausea, rash, and jaw pain. In contrast, intravenous treprostinil is a viable treatment option with a more favorable risk:benefit profile; eg, because of its longer half-life there is a decreased risk of a cessation phenomenon with rebound pulmonary hypertension. In addition, from a practical standpoint, eliminating the need for carrying ice packs along with the pump may ease the physical burden associated with a continuous intravenous infusion, particularly for children. Many patients, including some children, have now been safely transitioned from intravenous epoprostenol to intravenous treprostinil because of its favorable safety profile.18 Treprostinil (either via subcutaneous infusion or intravenously) is currently approved in the United States for class II-IV pulmonary arterial hypertension patients.Iloprost is a chemically stable prostacyclin analogue (half-life, 20 to 25 minutes) that can be used for inhaled or intravenous administration. It has both vasodilator and platelet aggregation inhibition properties similar to epoprostenol.1920 The hemodynamic efficacy and side effects of intravenous iloprost are also similar to those seen with intravenous epoprostenol.2122 Inhaled iloprost therapy is an appealing approach for the management of pulmonary arterial hypertension, given the selectivity for the pulmonary vascular bed with less systemic side effects. The first randomized, placebo-controlled study of inhaled iloprost in pulmonary arterial hypertension was performed in 203 adult patients with class III-IV pulmonary hypertension (idiopathic or associated with connective tissue disease or with inoperable chronic thromboembolic pulmonary hypertension).23 Beneficial effects of inhaled iloprost after 12 weeks of treatment included improvement of exercise capacity, hemodynamics, New York Heart Association (NYHA) functional class and quality of life. Sustained beneficial effects have been reported after one year of treatment in adult IPAH patients.24 In a study including 15 children with pulmonary arterial hypertension related to congenital heart defects, acute inhaled iloprost was found as effective as inhaled nitric oxide in selectively lowering pulmonary vascular resistance.25 Common side effects reported with inhaled iloprost are headache, flushing, nausea, and dizziness. Syncope has also been reported in patients who do not have an inhalation on arising in the morning. The obvious benefit for this inhaled prostanoid therapy is that it avoids the need for a central venous catheter and its inherent risks. However, the need for six to nine treatments a day because of its short half-life may be burdensome for children.26 In addition, the inhalation system, which requires coordination of breaths with the nebulizer device, may be challenging for children to use. Based on available data, inhaled iloprost appears as a safe, effective, and well-tolerated treatment for severe pulmonary arterial hypertension and has been approved in the United States for treatment of the disease. Although most of the studies have been performed in adult patients, this drug shows promise for patients of all ages in the future. Pediatric studies are warranted to confirm the benefits in the pediatric population.Beraprost sodium is a chemically stable and orally active prostacyclin analogue. Several small, open-label, uncontrolled studies have reported beneficial hemodynamic effects with beraprost in IPAH patients2728 and improved survival.29 However, longer term studies have failed to demonstrate sustained benefit. Therefore, beraprost is not currently approved for use in the United States, although it is still often used in Japan.Endothelin, one of the most potent endogenous vasoconstrictors identified to date, has been implicated in the pathogenesis of pulmonary arterial hypertension, providing the rationale for endothelin antagonists for treatment of the disease.30 Endothelin is present at elevated concentrations in the plasma and lung tissue of adult and pediatric patients with pulmonary arterial hypertension and appears to correlate with prognosis in IPAH patients.31–33 There are at least two different receptor subtypes. ETA receptors are located on smooth muscle cells while ETB receptors are found predominantly on endothelial cells.34 Both ETA and ETB receptors play a fundamental role in pulmonary vasoconstriction, inflammation, proliferation of smooth muscle cells, fibrosis and bronchoconstriction.The first endothelin receptor antagonist to gain FDA approval in the United States for patients over 12 years of age is bosentan, an oral nonselective endothelin receptor antagonist that binds to both ETA and ETB receptor subtypes. Patients over 12 years old treated with bosentan had improvement in exercise capacity, functional class, and symptoms and demonstrated a decreased rate of clinical worsening.35Bosentan is an approved therapy for pulmonary arterial hypertension patients in NYHA functional class III or IV in the United States and in Europe; however, data on bosentan therapy for pulmonary arterial hypertension in children remain limited. In a prospective open-label, non-controlled study involving 19 pediatric patients with pulmonary arterial hypertension, the safety and efficacy of bosentan appeared comparable to results previously reported in adult patients.36 Subsequently, a retrospective analysis of 86 pediatric patients with IPAH or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease (NYHA class II-III) confirmed the safety and beneficial long-term effects of bosentan (alone or in combination with intravenous epoprostenol) on functional capacity, hemodynamics, and survival in children.37 In 7 of 8 children with IPAH treated with intravenous epoprostenol for over one year, concomitant use of bosentan permitted a reduction in the epoprostenol dose, thereby decreasing epoprostenol side effects without apparent clinical or hemodynamic worsening.38 In 3 of these children, the addition of bosentan resulted in the discontinuation of intravenous epoprostenol with unchanged hemodynamics for up to one year. Additional studies are required to confirm the safety of weaning or discontinuation of intravenous epoprostenol with the addition of bosentan therapy.Sitaxsentan and ambrisentan, selective oral ETA endothelin receptor antagonists, have been evaluated in randomized clinical trials and also appear promising for the treatment of pulmonary arterial hypertension. However, to date, these trials have not included sufficient numbers of pediatric patients for a meaningful analysis.Adverse effects associated with endothelin receptor antagonists include acute hepatotoxicity (dose-related), teratogenicity, and possible male infertility. Common side effects reported with endothelin receptor antagonists are headache, flushing, and dose-related decreases in hemoglobin.The clinical experience with endothelin receptor antagonists is promising for patients whose condition does not respond to calcium channel blockers. Furthermore, the possibility of combined therapy with other therapeutic agents, such as intravenous epoprostenol, intravenous or subcutaneous or inhaled prostacyclin analogues, or oral sildenafil, which have different mechanisms of action, may lead to treatment regimens with an overall enhanced efficacy and reduced dosage for each agent, ie, decreasing side effects.Nitric oxide is an endogenous vasodilator that relaxes vascular smooth muscle through stimulation of soluble guanylate cyclase and increased production of intracellular cyclic guanosine monophosphate (cGMP) in smooth muscle cells.39 In patients with pulmonary arterial hypertension, nitric oxide production is often altered and nitric oxideinduced vasodilation is decreased.40 However, the complexity of the drug delivery system for inhaled nitric oxide will likely limit its clinical development for the long-term treatment of pulmonary arterial hypertension.In chronic pulmonary arterial hypertension, phosphodiesterase type 5 gene expression and activity are also increased,4142 resulting in decreased cGMP levels. Phosphodiesterase type 5 inhibitors prevent the inactivation of cGMP and may potentiate pulmonary vasodilation with inhaled nitric oxide. Sildenafil is an oral phosphodiesterase type 5 inhibitor that has recently been approved for the treatment of pulmonary arterial hypertension. Acute vasoreactivity studies in pulmonary arterial hypertension patients suggest that sildenafil may have greater acute hemodynamic effects than inhaled nitric oxide and may further reduce pulmonary vascular resistance43 in patients already demonstrating a benefit from chronic intravenous epoprostenol.44 Sildenafil may also prevent rebound pulmonary arterial hypertension on withdrawal of inhaled nitric oxide.45In a randomized, placebo-controlled, double-blind crossover study,46 22 patients (aged over 12 years) with IPAH (NYHA functional class II-III) received sildenafil (25 to 100 mg three times daily, depending on weight) or placebo for 16 weeks. Patients treated with sildenafil had significantly improved exercise time on treadmill testing and dyspnea.In the SUPER-1 trial, 278 NYHA class II-IV patients (aged over 18 years) with pulmonary arterial hypertension (idiopathic or associated with connective tissue disease or congenital systemic-to-pulmonary shunts) received placebo, 20, 40, or 80 mg sildenafil three times daily for 12 weeks.47 At week 12, exercise capacity, hemodynamics, and functional class were improved in the sildenafil-treated patients; sildenafil was well tolerated. Randomized clinical trials evaluating sildenafil in children with pulmonary arterial hypertension are in progress.Children with recurrent syncope and signs of right heart failure who are refractory to medical treatment may benefit from atrial septostomy.4849 An atrial septostomy is performed during a cardiac catheterization to create an atrial septal defect which can serve as a “pop-off” valve for the hypertensive right heart (ie, permitting right to left shunting). This intervention can reduce right atrial pressure and increase cardiac output and systemic oxygen transport, improving exercise capacity and survival in IPAH patients.4950 Atrial septostomy may serve as a palliative bridge to heart-lung or lung transplantation. However, the procedure carries a significant risk and should be performed only in experienced centers as well as in selected patients.Transplantation is the final treatment option for IPAH patients. The shortage of donor organs and the poor long-term prognosis, particularly in children, are limitations to its more widespread use. Both heart-lung and lung (single lung, bilateral lung) transplantations have been performed in pediatric patients with pulmonary vascular disease.51 In general, most forms of pulmonary arterial hypertension, except for complex congenital heart disease, do not require heart-lung transplantation but there is currently no consensus regarding the optimal procedure.5253 Recent data from the Registry of the International Society for Heart and Lung Transplantation report overall 1-, 5-, and 10-year survival rates for lung/heart-lung transplantation in IPAH patients of 65/67%, and Therefore, lung and heart-lung transplantation is for children in whom medical treatment has approach for is to children who have a life of less than 50% without or who have forms of pulmonary arterial hypertension, eg, pulmonary and pulmonary disease that are not to medical patients with IPAH have a pulmonary they may maintain physical that are to Patients are to if they children tend to but is age children are to in class with specific including to the to and should be for those at risk of in all pulmonary hypertension Children with pulmonary arterial hypertension, particularly those with a of are physical activity they are on a and medical of the effects of respiratory tract infections in children with and are recommended in addition to up to with recommended include by effective in of with or can be considered in patients with no of thromboembolic pulmonary arterial hypertension treatment based on the from clinical trials was at the World on This is limited to adult patients in NYHA functional class III or with IPAH or pulmonary arterial hypertension associated with because these patients the included in the clinical In the of studies the clinical response of children to pulmonary hypertension therapy, similar clinical strategies have been for the management of pulmonary hypertension in children. However, without data, these should be used with clinical approach for the treatment of pulmonary arterial hypertension in children is in The approach a of pulmonary arterial hypertension in a is to treat the child’s right heart failure with and with and supplemental oxygen if Patients who are responders to acute vasoreactivity testing are also treated with high-dose calcium channel and responders who remain in NYHA functional class III should be considered for treatment with either an endothelin receptor antagonist a phosphodiesterase type 5 inhibitor or a prostacyclin analogue subcutaneous inhaled NYHA functional class IV patients and class III patients who do not improve with an endothelin receptor a phosphodiesterase 5 or with subcutaneous or inhaled prostacyclin analogues should be considered for treatment with an intravenous prostacyclin the of drugs with targeted mechanisms of action, combination therapy may an option for patients whose condition to improve or with a agent, although clinical data are currently limited. atrial septostomy and transplantation can be considered for refractory pulmonary arterial hypertension. The treatment to as additional treatments In the with agents under may further increase treatment options for children with this challenging disease.