Drug Treatment of Pulmonary Hypertension in Children

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease in infants and children that is associated with significant morbidity and mortality. The disease is characterized by progressive pulmonary vascular functional and structural changes resulting in increased pulmonary vascular resistance and eventual right heart failure and death. In many pediatric patients, PAH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. PAH associated with developmental lung diseases such as bronchopulmonary dysplasia or congenital diaphragmatic hernia is increasingly more common in infants and children. Although treatment of the underlying disease and reversal of advanced structural changes have not yet been achieved with current therapy, quality of life and survival have improved significantly. Targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogues and phosphodiesterase type 5 inhibitors, have resulted in hemodynamic and functional improvement in children. The management of pediatric PAH remains challenging as treatment decisions depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. This article reviews the current drug therapies and their use in the management of PAH in children.

1. Introduction

Pulmonary arterial hypertension (PAH) is a rare but life-threatening disease. It is characterized by progressive structural changes to the pulmonary vascular bed with resultant increase in pulmonary vascular resistance and pulmonary arterial pressures that ultimately result in right heart failure and death (1). The pathogenesis of the disease includes a combination of vasoconstriction, inflammation, structural remodeling, in situ thrombosis, and an imbalance of vasoactive mediators (2–4). Proliferative, vasoconstrictive mediators, including thromboxane A2 and endothelin-1 (ET-1), are increased, and antiproliferative, vasodilatory mediators, such as prostacyclin and nitric oxide (NO), are decreased (3,5,6). The current pulmonary vasodilatory and antiproliferative therapies for PAH aim to shift the balance of these mediators.

The distribution of etiologies of pediatric PAH is very different from adults. In children, many cases are idiopathic (IPAH) or associated with congenital heart disease (PAH-CHD) (7–10). In contrast to adults, PAH associated with connective tissue disease remains a rare cause in children (7–10). Large pediatric pulmonary hypertension registries, including the Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry (8), the Nationwide Netherlands Pulmonary Hypertension service registry (11), and the combined adult and pediatric U.S. REVEAL registry (Registry to Evaluate Early and Long-Term PAH Disease Management) (7) have described the etiologies of pediatric PAH.

The current World Health Organization (WHO) classification of adult and pediatric pulmonary hypertension was updated at the 6^th World Symposium on Pulmonary Hypertension held in 2018 in Nice, France (12). The updated 2018 Nice classification includes additional causes of neonatal and infantile PAH including persistent pulmonary hypertension of the newborn (PPHN), PAH with post-capillary obstruction (pulmonary venous obstructive disease and pulmonary capillary hemangiomatosis), congenital post-capillary obstructive lesions (pulmonary vein stenosis and other left heart obstruction), developmental lung diseases, and novel genetic causes of pediatric PAH. However, the WHO classification may not adequately reflect the complexity of pediatric disease and the many developmental, perinatal, genetic, and chromosomal factors that influence pediatric PAH (13–15). Another classification system of pediatric pulmonary hypertensive vascular disease was developed by the Pulmonary Vascular Research Institute Pediatric Taskforce at a 2011 meeting in Panama (13). The Panama classification highlights the multifactorial causes of pediatric pulmonary hypertension including abnormal lung growth and development, congenital heart disease, chromosomal anomalies, sleep disordered breathing, chronic aspiration, and prenatal insults that contribute to postnatal lung disease (Fig. 1). Although it has not yet been widely integrated into clinical practice, this classification system may provide a more comprehensive classification of pediatric PAH, and may ultimately be integrated into pediatric treatment algorithms.

Fig. 1.

Pulmonary Vascular Research Institute Classification of Pediatric Pulmonary Hypertensive Vascular Disease (Panama 2011) (From Del Cerro MJ, et al. Pulm Circ. 2011, with permission).

Historically, pulmonary hypertension was defined in both children and adults as a mean pulmonary artery pressure (mPAP) ≥25 mmHg by cardiac catheterization; patients with normal left heart filling pressure defined as pulmonary capillary wedge pressure ≤15 mmHg are sub-classifed as having PAH (16,17). Pulmonary vascular resistance (PVR) had not been included in the adult definition of PAH, but it is an important consideration in pediatric PAH as infants and children with unrepaired left to right shunt lesions may have increased pulmonary artery pressure in the setting of increased pulmonary blood flow. Therefore, it was previously recommended to include indexed PVR (PVRI) >3 Wood units × m² in the definition of pediatric PAH to assess for the presence of pulmonary vascular disease. However, at the 2018 World Symposium, the definitions were modified in two ways. Data from healthy adults now suggest that 20 mm Hg is the upper limit of normal for mPAP. As elevation of mPAP could result from increased cardiac output or increased wedge pressure, a PVR criteria was added in order to identify pre-capillary PAH. The new proposed definition of pulmonary hypertension in adults and children is mPAP ≥20 mm and PVR ≥3 WU for adults and 3 WU.m² for children (18). Further research is needed to see if children with borderline or high-normal mPAP are at risk of progression of PAH and right ventricular failure.

The current definitions are applicable to children with biventricular circulation but less so for children with single ventricle heart defects undergoing cavopulmonary anastomosis. Elevated pulmonary vascular resistance (PVR) and/or mPAP is poorly tolerated by a circulation dependent on passive pulmonary blood flow, even when mPAP is < 20–25 mmHg (19,20). Therefore, the Panama classification defines pediatric pulmonary hypertensive vascular disease following cavopulmonary anastomosis as a PVRI >3.0 indexed Wood units or a transpulmonary gradient >6 mmHg even when mPAP ≤ 25 mm Hg (13).

Data from the Netherlands in 2011 demonstrate an annual incidence and point prevalence (per million children) of 0.7 and 4.4 for IPAH and 2.2 and 15.6 for PAH-CHD (Fig. 2) (11). Prior to the availability of targeted PAH therapies, median survival of a child with IPAH was 10 months based on data published in the early 1990s (21). In 1995, a single center cohort study demonstrated similar median survival of children and adults with idiopathic PAH (4.12 years versus 3.12 years, respectively) (22). With targeted pulmonary vasodilators, the survival rate has continued to improve in pediatric patients with PAH. Children in the combined adult and pediatric U.S. REVEAL registry demonstrated 1-, 3-, and 5-year estimated survival rates from diagnostic catheterization of 96+/−4%, 84+/−5%, and 74+/−6%, respectively (7). Retrospective reports from the United Kingdom and the Netherlands have also shown improved survival rates in children with PAH (9,11,23). The retrospective study from the UK Pulmonary Hypertension Service for Children (n= 216) demonstrated 1-, 3-, and 5-year survival rates of 85.6%, 79.9% and 71.9% in children with idiopathic PAH and of 92.3%, 83.8% and 56.9% in associated PAH (Fig. 3) (9). Amongst children with associated PAH, those with PAH and repaired CHD have experienced worse outcomes compared to all other subgroups (9), however survival is variable amongst subgroups. Those with PAH-CHD with post-tricuspid shunt or abnormal pulmonary vasculature development have shown better survival than IPAH (11). Despite the variability in reported outcomes, survival has improved in patients with Eisenmenger syndrome using advanced PAH therapies (24).

Fig. 2.

Annual incidence rates for pediatric pulmonary hypertension based on epidemiological data from the Netherlands during a 15-year period. PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; PAH-CHD, PAH associated with congenital heart disease; iPAH, idiopathic PAH. (From Van Loon RL, et al. Circulation. 2011, with permission).

Fig. 3.

Survival curves for idiopathic pulmonary arterial hypertension (IPAH) and associated pulmonary arterial hypertension (APAH). Cases were censored for time in the study and transplantation. (From Haworth SG, et al. Heart. 2009, with permission).

Therapeutic options for pediatric PAH have increased over the past 3 decades. Management strategies include the prevention and inhibition of active pulmonary vasoconstriction, support of right ventricular function, and promotion of regressive remodeling of structural pulmonary vascular changes. Currently approved PAH therapies impact one of three endothelial-based pathways including NO, prostaglandin, or ET-1 (Fig. 4). Although treatments approved for PAH in adults have shown favorable affects in children, pediatric treatment decisions largely depend on results from evidence-based adult studies and the experience of clinicians. The purpose of this review is to summarize the current knowledge regarding PAH drug therapies and their clinical use in the management of pediatric PAH.

Fig. 4.

Schematic diagram of endothelial vascular biology depicting the relevant vasoactive mediators that have led to targeted treatment of pulmonary hypertension, including the nitric oxide-cGMP system, the endothelin system, and the prostacyclin system. (Reproduced with permission from Diller GP, et al. IJCP. 2010).

2. Challenges in the Treatment of Pediatric PAH

Despite recent advances, the management of pediatric PAH remains challenging. Characteristics of the pediatric population including variable drug metabolism, growth, and development make it difficult to extrapolate conclusions from adult data to children. Adult PAH therapies have not been sufficiently studied in children. Questions regarding potential toxicities, optimal dosing regimens, and appropriate therapeutic endpoints for children remain. Nevertheless, children with PAH are currently treated with targeted PAH drugs and do benefit from these new therapies.

2.1. Clinical Presentation

Establishing a diagnosis of PAH in children may be difficult because the clinical presentation is often non-specific. Failure to thrive, tachypnea, and irritability due to low cardiac output are often seen in infants with PAH whereas older children may present with exercise intolerance and occasionally chest pain, similar to adults. The most frequent presenting symptom in IPAH and PAH-CHD is dyspnea on exertion (7,8). Near syncope or syncope is a marker of severe disease and is more frequently seen in IPAH and familial PAH patients (7,8). Cyanosis is seen in patients with significant lung disease or intra-cardiac shunting. Due to the variable presentation and often non-specific symptoms, a high index of suspicion is required to improve the time to diagnosis in children.

Classifications of functional status are designed to indicate how a patient feels and functions with a disease. The Functional Classification of Pulmonary Hypertension in adults is based on the New York Heart Association (NYHA) heart failure classification and was published after the 1998 WHO Evian symposium (25). WHO functional status is a strong predictor of transplant-free survival in children with PAH. Functional status should be assessed at presentation and throughout childhood and followed as a treatment endpoint (26). The WHO classification system may not be easily applicable to all children. A functional class designed specifically for children was proposed in 2011 but has not yet been validated or widely adopted (27).

2.2. Diagnostic Evaluation

A methodical and comprehensive diagnostic PAH evaluation is essential, given the various associated diseases and conditions. Treatment or correction of an underlying abnormality is very important to the successful treatment of PAH, often even before the initiation of vasodilator therapy. A complete evaluation to rule out underlying diseases that may contribute to the development of PAH, including investigations for obstructive sleep apnea, gastroesophageal reflux disease, and aspiration is recommended in all patients prior to initiation of pulmonary vasodilatory therapy. A diagnostic algorithm is shown in Figure 5 (28).

Fig. 5.

A diagnostic algorithm for investigating pulmonary hypertension. CXR, chest x ray; PH, pulmonary hypertension; V/Q, ventilation/perfusion. (From Haworth SG, et al. Arch Dis Child. 2008, with permission).

3. Conventional Therapies

Despite the introduction of advanced pulmonary vasodilatory therapies, conventional therapies continue to play an important role in the management of PAH. Diuretic therapy is often necessary in children with heart failure but should be initiated carefully as children with PAH may be pre-load dependent to maintain adequate cardiac output. Diuretics are essential in the management of patients with pulmonary hypertension related to left ventricular diastolic dysfunction. The use of digitalis has not shown clear benefits, though it may be beneficial in the management of right heart failure (29). Although its role is not well studied in children, chronic anticoagulation may be beneficial in patients with low cardiac output, central venous lines, or hypercoagulable states at risk of thrombosis in situ. Risks and benefits of anticoagulation should be weighed, particularly in younger children that may be at higher risk of hemorrhagic complications. The use of anticoagulation in patients with Eisenmenger physiology is controversial as it has not been shown to impact long-term survival (30). Oxygen supplementation is used to avoid chronic hypoxemia and is considered in patients with severe right heart failure or significant hypoxemia with exercise.

3.1. Calcium Channel Blockers

Calcium channel blockers (CCBs) were initially used the management of PAH in the absence of alternative therapies. By inhibiting calcium flux into the cardiac and smooth muscle cells, CCBs cause relaxation of vascular smooth muscle but may decrease myocardial contractility. CCB therapy for PAH is only indicated in patients who demonstrate an acute response to vasodilator testing in the cardiac catheterization laboratory, however the criteria to determine acute vasoreactivity response has been debated. The most commonly used vasoreactivity criteria have included the Barst criteria [decrease in mPAP of ≥20%, unchanged or increased cardiac index, and decreased or unchanged pulmonary to systemic vascular resistance ratio (PVR/SVR)] (31), Rich criteria (decrease in mPAP and PVR of ≥20%) (32), and Sitbon criteria (decrease in mPAP of ≥10 mmHg to a mPAP value of ≤ CHANGE < 40 mmHg or a decrease in mPAP of ≥10 mmHg in those with baseline mPAP <40 mmHg, without a fall in cardiac output) (33). The reported proportion of children with acute vasoreactivity varies from 7–40% and depends highly on the criteria used (17,34) and the conditions under which the testing is performed (35). The Sitbon criteria has been shown to identify children with IPAH/heritable PAH (HPAH) who may benefit from longterm CCB therapy (33,35) and should be used for acute vasoreactivity testing in children (12). Nifedipine, diltiazem, and amlodipine are the preferred CCBs for PAH therapy, while verapamil is contraindicated due to its negative inotropic effects. Recommended pediatric dosing is shown in the Table. CCBs should be avoided in patients with severe ventricular dysfunction, high right atrial pressure, decreased cardiac output, or those < 1 year of age. The benefits of CCB therapy have been reported in pediatric patients, including improved survival in acute vasoreactive responders (17,34), but careful follow-up is essential as patients may deteriorate over time on CCB therapy alone (36).

Table:

Treatment options for pediatric PAH. Safety and dosing of these medications is not established in children. Bosentan is the only FDA-approved drug for children with PAH. PAH; pulmonary arterial hypertension; FDA, U.S. Food and Drug Administration.

Agent	Dose	Mechanism of action	Side effects	Cautions
Calcium Channel blockers
Nifedipine	Initial dose: 0.6–0.9 mg/kg/day in 3 divided doses Maintenance dose: 2–5 mg/kg/day Maximum adult dose: 120–240 mg/day	Pulmonary/systemic vasodilation	Headache, constipation, dizziness, fatigue, nausea, edema, rash, gum hyperplasia, bradycardia, and systemic hypotension	Uptitrate from a lower dose If possible, use extended release preparations Potential risk of hypotension
Diltiazem	Initial dose: 1.5–2 mg/kg/day in 3 divided doses Maintenance dose: 3–5 mg/kg/day in 3 divided doses Maximum adult dose: 240–720 mg/day
Amlodipine	Initial dose: 2.5–5 mg/day Maintenance dose: 2.5–5 mg/kg/day twice daily Maximum adult dose: 20 mg/day
Agent	Dose	Mechanism of action	Side effects	Cautions
Prostacyclin
Epoprostenol	Initial dose: 1 to 3 ng/kg/min Maintenance dose: 50 to 80 ng/kg/min	Pulmonary/systemic vasodilation Inhibition of vascular remodeling Antiplatelet aggregation	Flushing, headache, nausea, diarrhea, jaw discomfort, foot pain, rash, hypotension, thrombocytopenia	Potential risk of hypotension and bleeding in children receiving concomitant drugs such as anticoagulants, platelet inhibitors, or other vasodilators
Iloprost	Initial dose: 2.5 μg per inhalation 6–9 times per day; Maintenance dose: 5 μg per inhalation Maximum 9 times per day	Pulmonary vasodilation Inhibition of vascular remodeling Antiplatelet aggregation	Cough, headache, flushing, jaw pain, diarrhea, rash, and hypotension	Reactive airway symptoms, hypotension possible at high dose
Treprostinil	Intravenous/subcutaneous Initial dose: 1.25 to 2 ng/kg/min; Maintenance dose: 50 to 80 ng/kg/min Inhaled Initial dose: 3 breaths (18 μg) 4 times per day; Maintenance dose: 9 breaths (54 μg) 4 times per day	Pulmonary vasodilation Inhibition of vascular remodeling Antiplatelet aggregation	Intravenous infusion Similar to epoprostenol but may require higher doses Subcutaneous Pain at the infusion site Inhaled Cough, headache, nausea, dizziness, flushing, throat irritation	Intravenous/subcutaneous Similar to epoprostenol Inhaled Reactive airway symptoms, hypotension possible at high dose
Agent	Dose	Mechanism of action	Side effects	Cautions
Phosphodiesterase type 5 inhibitor
Sildenafil	Oral Initial dose: 0.5 mg/kg/dose Maintenance dose: 1 mg/kg/dose tid Europe: <20 kg 10 mg tid > 20 kg 20 mg tid Intravenous 0.4mg/kg bolus over 3 hours 1.6mg/kg/day: continuous infusion	Pulmonary vasodilation Inhibition of vascular remodeling	Headache, flushing, rhinitis, dizziness, hypotension, peripheral edema, dyspepsia, diarrhea, myalgia, back pain, visual disturbances	Cautious chronic use in children 1–17 years of age Concomitant use of CYP3A4 inhibitors reduce clearance of sildenafil Co-administration of bosentan leads to decreased sildenafil concentrations and increased bosentan concentrations Use in premature neonates not well studied
Tadalafil	Preliminary studies suggest 1mg/kg/day	Pulmonary vasodilation Inhibition of vascular remodeling	Similar to sildenafil No significant influence on vision	Concomitant use of CYP3A4 inhibitors reduce clearance of tadalafil No clinically significant alterations in co-administered bosentan or ambrisentan
Agent	Dose	Mechanism of action	Side effects	Cautions
Endothelin receptor antagonist
Bosentan	2 mg/kg bid 10–20 kg: 31.25 mg bid 20–40 kg: 62.5 mg bid >40 kg: 125 mg bid after uptitration	Pulmonary vasodilation Inhibition of vascular remodeling	Abdominal pain, vomiting, extremity pain, fatigue, flushing, headache, edema, nasal congestion Potential risk of dose-dependent increases in aminotransaminase levels Teratogenicity May decrease effectiveness of birth control	Routine monitoring of liver enzymes required Not recommended in patients with moderate or severe hepatic impairment Teratogenic; requires birth control Anemia Caution in concomitant use of CYP3A4 inducers and inducers Co-administration of sildenafil leads to decreased sildenafil concentrations and increased bosentan concentrations
Agent	Dose	Mechanism of action	Side effects	Cautions
Ambrisentan	2.5 / 5 /10 mg daily	Pulmonary vasodilation Inhibition of vascular remodeling	Peripheral edema, nasal congestion, headache, flushing, and nausea Low incidence of serum aminotransferase elevation Teratosgenicity May decrease effectiveness of birth control	Routine monitoring liver enzymes not required Not recommended in patients with moderate or severe hepatic impairment Teratogenic: requires birth control Anemia Caution in concomitant use of CYP3A4 inducers and inhibitors No drug to drug interactions between ambrisentan and sildenafil or tadalafil

3.2. Inhaled Nitric Oxide

Inhaled NO (iNO) is used commonly in the acute management of PAH presenting with hemodynamic instability and right heart failure. Similar to endogenously produced NO, iNO diffuses rapidly across the alveolar-capillary membrane and induces vasodilation through a cyclic guanosine monophosphate (cGMP) dependent pathway (37,38). The role of iNO in improving oxygenation in term infants with severe PPHN has long been recognized (39–44). After review of two multicenter randomized controlled trials demonstrating improved outcomes in term and near-term neonates with PPHN and hypoxic respiratory failure treated with iNO (45,46), the FDA issued formal approval for its use in those patients. The impact of iNO on survival of preterm infants with respiratory distress syndrome and pulmonary hypertension is less clear; iNO is not formally recommended or approved in these patients. Studies of iNO in congenital diaphragmatic hernia (CDH) have failed to demonstrate benefits, and some have demonstrated worse outcomes (46–49). Some patients with CDH may have left ventricular dysfunction and not tolerate pulmonary vasodilation with iNO. Therefore, guidelines from United States and Canadian professional organizations state that iNO can be used to treat infants with CDH and normal left ventricular function, but should be discontinued if there is no response to treatment after 24 hours (50,51) In the cardiac catheterization lab, iNO has also proven to be an ideal agent for acute vasoreactivity testing (Fig. 6) (52,53) in patients with IPAH, PAH-CHD, as well as those with bronchopulmonary dysplasia (54). Inhaled NO has also been used successfully in the management of postoperative PAH associated with CHD (55–57). Despite its growing indications in acute care management, inhaled NO has not been used in the long-term management of PAH given its risk of toxic metabolites, short half-life, and complicated delivery system (58), but trials are underway to determine feasibility (59).

Fig. 6.

Percentage of pediatric patients with pulmonary hypertension that demonstrated acute vasodilatory response to the evaluated agents. The greatest number of acute responders was seen with the use of iNO and oxygen. iNO, inhaled nitric oxide; O₂, oxygen. (Reproduced with permission from Barst RJ, et al. Pediatr Cardiol. 2010).

4. Targeted Pharmacological Therapies

The prognosis of children with PAH has improved in the past 3 decades owing to new therapeutic agents and off-label application of adult PAH specific therapies to children. Use of targeted pulmonary vasodilators in children is primarily based on clinical experience, although there is increasing evidence from an growing number of pediatric studies. Targeting one of three endothelial-based pathways (Fig. 4), three drug classes, including phosphodiesterase inhibitors, endothelin receptor antagonists, and prostacyclin analogues have been well studied in PAH treatment.

4.1. Phosphodiesterase Type 5 Inhibitors

Phosphodiesterase-5 (PDE-5) inhibitors have been used for over a decade in the treatment of children with pulmonary hypertension. PDE-5 inhibitors have antiproliferative, proapoptotic, and vasodilating effects in the pulmonary vasculature through an increase in cGMP (60,61). PDE-6 inhibition can also occur with therapeutic dosing of sildenafil (62,63). PDE-5 inhibitors are most commonly administered orally and are well tolerated. Most frequent adverse effects include headache, agitation, and flushing (64–66). Dose related ocular effects, including blurred vision, changes in light perception, and transient blue/green visual abnormalities, rarely occur with therapeutic dosing due to PDE-6 inhibition (62,63). Erections occur in about 10% of males. Rare cases of sensorineural hearing loss have been reported in adults on PDE-5 inhibitors but the physiologic mechanism remains unclear (67). Sildenafil is the only PDE-5 inhibitor available for intravenous administration and is used solely in the acute care setting due to the risks of systemic effects. Serial monitoring is not required but routine vision and hearing assessments should be considered with long-term PDE-5 therapy, especially in premature infants.

4.1.1. Sildenafil

Sildenafil was approved by the U.S. Food and Drug Administration (FDA) in 2005 for the treatment of adult PAH as it was found to improve exercise ability and delayed time to clinical worsening at a dose of 20 mg three times daily (65). Pediatric use of sildenafil was initially studied in 14 children with PAH treated as outpatients for 12 months. The mean 6-minute walk distance (6MWD) increased at 6 months and was sustained at 12 months. Mean mPAP and PVRI decreased with treatment (68). In children with IPAH and PAH-CHD, sildenafil improved oxyhemoglobin saturation and exercise capacity without significant side effects (69).

The STARTS-1 trial was an international, 16-week randomized, double blind placebo-controlled study of the effects of oral sildenafil monotherapy in treatment naïve pediatric patients with PAH (64). Children (n=235) with PAH (aged 1–17 yrs., ≥8 kg) received low (10 mg), medium (10–40 mg), or high (20–80 mg) dose sildenafil or placebo orally three times daily (Fig. 7). The primary endpoint was percent change in peak oxygen consumption (pVO₂); exercise testing was performed only in children able to exercise reliably. Secondary endpoints, including mPAP, PVRI, and WHO functional class, were assessed in all enrolled patients, including those unable to reliably exercise. The estimated mean ± standard error percentage change in pVO₂ for the low-, medium- and high-doses combined versus placebo was 7.7% ± 4.0% (95% CI, −0.2% to 15.6%; P=0.056) (Fig. 8). Thus, there was no statistically significant change in the pre-specified primary outcome measure. Peak VO₂ only improved with the medium dose. Secondary outcomes were variable. Functional class only improved with high dose sildenafil. PVRI improved with medium and high dose sildenafil, but mean PAP was lower only with medium dose sildenafil (64).

Fig. 7.

Treatment allocation in the STARTS-1 trial. Patients were randomized to placebo, low, medium, or high dose oral sildenafil. (From Barst RJ, et al. Circulation. 2012, with permission).

Fig. 8.

Percent change in peak oxygen consumption (VO₂) from baseline to week 16 of sildenafil monotherapy in treatment-naïve children, aged 1–17 years, with pulmonary arterial hypertension (STARTS-1). Given the small number of developmentally able children in the 8- to 20-kg group, this group was combined with the 20- to 45-kg group. Greatest improvement in VO₂ was demonstrated with medium and high doses of sildenafil. (From Barst RJ, et al. Circulation. 2012, with permission).

In STARTS-2, the long-term extension study, sildenafil-treated children remained on the STARTS-1 dose; children receiving placebo were randomized to low, medium, or high dose (70). Sildenafil dose could be up-titrated by the treating physician and was also increased for weight gain. After three years of extension phase treatment, there were 37 deaths (26 patients on treatment) and mortality appeared to be dose related. Kaplan-Meier 3-year survival rates from the start of sildenafil therapy were 94%, 93%, and 88%, for low-, medium-, and high-dose. Hazard ratios for mortality were 3.95 (95% CI, 1.46–10.65) for high versus low dose sildenafil and 1.92 (95% CI, 0.65–5.65) for medium versus low dose. However, those who died were more likely to have IPAH or heritable PAH and had worse functional class and hemodynamics at baseline, which raised concerns about the dose-mortality relationship.

Review of the STARTS-2 data by the FDA and the European Medicines Agency (EMA) resulted in disparate recommendations. Sildenafil was approved by the European Medicines Agency in 2011, with a subsequent warning to avoid use of the high dose (71). In August 2012, the FDA released a strong warning against the (chronic) use of sildenafil for pediatric patients (ages 1 through 17) with PAH, stating a higher risk of death in children taking high dose sildenafil and a lack of improvement in exercise ability in those taking low doses of sildenafil (72).

In response to the FDA warning, pediatric pulmonary hypertension experts published a statement highlighting the limitations of the STARTS-1 and −2 mortality data and calling for continued assessment of the efficacy and safety of sildenafil in children. The group cautioned against the abrupt discontinuation of sildenafil. Similar to the EMA’s position, the group recommended avoiding high dose sildenafil (73). In March 2014, the FDA clarified its initial warning and stated that sildenafil could be used in individual children with a favorable risk-benefit profile under close monitoring (74).

Sildenafil is increasingly used in the treatment of PAH related to chronic lung disease. In a study of 25 children with PAH associated with chronic lung disease (including bronchopulmonary dysplasia, CDH, PPHN, and pulmonary hypoplasia), 88% demonstrated improvement in echocardiographic measures of PH after a median sildenafil treatment duration of 40 days. In those with interval estimates of PAP by echocardiogram, there was improvement in 85% of patients. Adverse, medication-related events were rare (Fig. 9) (75). In a recent description of 269 PAH patients, half with bronchopulmonary dysplasia, treated with sildenafil mono- or add-on therapy at a single institution, PH was most likely to improve in those with bronchopulmonary dysplasia such that the medication was discontinued in 45% (76) Sildenafil may also be useful in the setting of iNO therapy withdrawal (77–79), in post-operative pulmonary hypertension (80), and in single ventricle physiology with high PVR (81–84).

Fig. 9.

Changes in systolic pulmonary artery pressures (sPAP) (A) and pulmonary/systemic systolic artery pressure (sPAP/ssBP) (B) as determined by echocardiogram in response to prolonged sildenafil therapy in infants with chronic lung disease. Median duration of treatment between studies was 58 days (range: 25 – 334). Individual data plotted together with mean ± SD. (Reproduced with permission from Mourani PM, et al. J Peds. 2009).

Although no definitive sildenafil dosing guidelines have been established in the United States, conservative sildenafil dosing is recommended based on the STARTS-1 and −2 data and the EMA dosing recommendations (71) (Table). An oral sildenafil dose of 10 mg three times daily is recommended in children weighing between 8 and 20 kg and a dose of 20 mg three times daily in children weighing greater than 20 kg. Higher dosing of oral sildenafil is discouraged based on the STARTS-2 mortality data. For children less than 8 kg, sildenafil doses of 0.5–1 mg/kg three times daily have been beneficial (85). In some centers, sildenafil has been dosed four times daily in the neonatal population. Oral suspensions are available for children that cannot tolerate pill format (86).

As sildenafil is primarily metabolized by hepatic cytochrome P450 (CYP) enzymes, co-administration of sildenafil with potent CYP3A inducers or inhibitors such as ketoconazole or rifampin should be avoided. Bosentan decreases the maximum plasma concentration (Cmax) of sildenafil by 55.4%,whereas sildenafil increases the Cmax of bosentan by 42.0% but the clinical effect of this interaction is unclear (87). Recommendations for dose adjustment are not available, so monitoring may be advisable with co-administration.

Intravenous sildenafil has been studied in children with PPHN and in postoperative CHD. In an open-label, dose-escalation trial in infants with PPHN and an oxygenation index (OI) > 15, there was significant improvement in OI after 4 hours of sildenafil infusion in the higher dose groups (88). In postoperative pulmonary hypertension after CHD surgery, the use of intravenous sildenafil has been associated with shorter time to extubation, shorter intensive care unit stay, and augmentation of pulmonary vasodilatory effects when co-administered with iNO (89–91). Dosing recommendations are based on the PPHN dose-escalation trial (Table) (88). Use of intravenous sildenafil in premature infants is not well studied. Cautious use is recommended in postoperative patients with CHD and those with significant lung disease due to the risk of increased intrapulmonary shunting and systemic delivery (90).

4.1.2. Tadalafil

Tadalafil, a selective PDE-5 inhibitor with a longer duration of action than sildenafil, was FDA approved in 2009 for use in adults with PAH after it was shown to improve exercise capacity and quality of life measures while reducing time to clinical worsening (92). In retrospective study of 33 children with PAH on tadalafil (88% having transitioned from sildenafil to tadalafil), tadalafil was well-tolerated without major side effects, and mPAP and PVRI were improved on tadalafil vs. sildenafil in those patients with repeat cardiac catheterization (Fig. 10) (93).

Fig. 10.

Change in hemodynamic measures after transition from sildenafil to tadalafil for 14 pediatric patients with PAH. Hemodynamic data, including mPAP, PVRi and Rp/Rs, improved in comparison to the last catheterization data on sildenafil therapy during follow-up period (23.5 ± 8.3 months). mPAP, mean pulmonary arterial pressure; PVRi, pulmonary vascular resistance index; Rp/Rs, pulmonary-to-systemic vascular resistance ratio. (From Takatsuki S, et al. Pediatr Cardiol. 2012, with permission).

The once daily dose administration of tadalafil may improve compliance for pediatric patients with PAH (93,94). Recommended tadalafil dose in adults is 40 mg once daily (92). Although pediatric dosing recommendations are not available, a tadalafil dose of 1 mg/kg/day is well tolerated, with a favorable side effect profile, and results in clinical improvement (Table) (93,95). Tadalafil can be compounded into a stable suspension (5mg/mL) to facilitate use in children (96). Use in the neonatal and infant population is contraindicated due to lack of maturation of the glucuronidation pathway. Reported adverse events are similar to those seen with sildenafil but tadalafil has little effect on PDE-6 so visual disturbances are rarely seen (92,93). As with sildenafil, concomitant use of CYP3A inducers or inhibitors is not recommended and co-administration with bosentan will decrease plasma concentration of tadalafil (97).

4.2. Endothelin receptor antagonists (ERA)

Endothelin-1 (ET-1), a potent vasoactive peptide produced primarily in the vascular endothelial and smooth muscle cells, is considered the predominant pathophysiological endothelin isoform in PAH. The over-expression of ET-1 protein has been demonstrated in patients with PAH and correlates with the degree of pulmonary remodeling (98,99). Vasoconstriction by ET-1 is mediated by 2 types of endothelin receptors, type A (ET_A) and type B (ET_B), located on vascular smooth muscle. ET_B receptors on endothelial cells also facilitate clearance of ET-1 and cause release of NO and prostacyclin (100). Bosentan, a dual ET_A and ET_B receptor antagonist, and ambrisentan, a selective ET_A receptor anatagonist, both improve hemodynamics and survival in adult patients and are approved by the FDA for oral PAH therapy in adults. In September 2017, the FDA approved bosentan for use in pediatric patients with idiopathic or congenital PAH, making bosentan the first FDA approved pediatric PAH medication (101). Oral ERA therapy is generally well tolerated, and the most common adverse events include abdominal pain, nausea, flushing, headache, peripheral edema, and nasal congestion (98,102–104). Important clinical side effects of ERA therapy include transaminitis, anemia, seminiferous tubular atrophy, and impaired fertility. Due to the risk of teratogenicity, ERA therapy is contraindicated in pregnancy and appropriate contraception is required in sexually active patients. Caregivers who may be pregnant should wear gloves while handling ERAs. Effectiveness of oral contraception is decreased with ERA therapy so use of two reliable methods of contraception is recommended.

4.2.1. Bosentan

Bosentan, an oral dual ERA, is approved in pediatric and adult patients with PAH (103). The pharmacokinetics of bosentan are similar in children and adults (102). Several pediatric studies demonstrated improved exercise capacity, functional class, and long-term outcomes in children with IPAH and PAH-CHD treated with bosentan (9,23,102,105–117). A retrospective study of 86 children with PAH (IPAH, PAH-CHD, or connective tissue disease) treated with bosentan for median 14 months as monotherapy or in combination with a prostacyclin demonstrated improved hemodynamics and functional class in the majority without significant adverse events. One- and 2-year survival estimates were 98% and 91%, respectively (114). This retrospective cohort was later re-examined over a median observation period of 39 months (range 2–60 months). At 4 years, survival estimate was 82% (112). In a study that included both children and adults with PAH and a systemic-to-pulmonary shunt, bosentan produced short-term improvements in functional class and 6MWD (116). Bosentan therapy also resulted in decreased PVRI (Fig. 11) and improved exercise capacity by 6MWD (Fig. 12) in patients with Eisenmenger syndrome in the 16-week, multicenter, randomized, double-blind, placebo-controlled Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) trial (118). In patients with single ventricle physiology after staged cavopulmonary anastamosis, treatment with bosentan has resulted in improvement in functional class, systolic ventricular function, and hemodynamics (117,119).

Fig. 11.

Change in indexed pulmonary vascular resistance (PVRi) from baseline to week 16 in placebo and bosentan groups (BREATHE-5). PVRi, the secondary endpoint, was significantly improved with bosentan therapy demonstrating a treatment effect of −472 (SE 221.9) dyn.sec.cm(−5). TE, treatment effect. (Reproduced with permission from Galie N, et al. Circulation. 2006).

Fig. 12.

Change in 6 minute walk distance (6MWD) from baseline to week 16 in placebo and bosentan groups (BREATHE-5). Exercise capacity measured by 6MWD was significantly improved with bosentan therapy demonstrating a treatment effect of 53.1 (SE 19.2) m. TE, treatment effect. (Reproduced with permission from Galie N, et al. Circulation. 2006).

The BREATHE-3 and FUTURE-1 trials have investigated the pharmacokinetics of twice daily bosentan dosing in pediatric patients with PAH (102,120). In the FUTURE-1 trial, bosentan concentrations were lower in children compared to adults but were similar following doses of 2 and 4 mg/kg, suggesting the recommended dose to be 2mg/kg twice a day (Fig. 13) (120). Based on the results of the noncomparative, multicenter, pharmacokinetic BREATHE-3 trial, bosentan doses of 31.25 mg, 62.5 mg, or 125 mg twice daily are currently recommended for children 10–20 kg, >20–40 kg, or >40 kg, respectively (Table) (102).

Fig. 13.

Pharmacokinetics in FUTURE −1. Arithmetic mean (±SD) plasma concentration vs. time profiles of bosentan in patients with pediatric pulmonary arterial hypertension after multiple dose administration of bosentan at a dose of 2 and 4mg/kg twice daily. (n = 11). 2mg kg-1 (■); 4mg kg-1 (□)(Reproduced with permission from Beghetti M, et al. Br J Clin Pharmacol. 2009).

Bosentan may cause dose-dependent increases in aminotransaminase levels, but these risks are lower in children than adults (107). In pediatric studies, the incidence of elevated aminotransaminase levels (>3x normal) were 3% in extended FUTURE-2 trial (102) and 16% in the BREATHE-3 trial (98). Although the incidence of serum aminotransferase elevation due to bosentan therapy is low in children, monthly liver function tests are required.

4.2.2. Ambrisentan

Ambrisentan, an oral selective ETA receptor antagonist, results in improved exercise tolerance and functional class in adult patients with PAH while maintaining a good safety and side effect profile (103,104,121,122). The clinical efficacy and safety of ambrisentan therapy has not been extensively studied in children with PAH, but its use in children is increasing due to its favorable once daily dosing, lack of interaction with PDE-5 inhibitors, and decreased risk of elevated aminotransaminase levels. A retrospective study of 38 children with PAH that were either transitioned from bosentan to ambrisentan therapy or started on adjunctive ambrisentan therapy demonstrated improved mPAP and functional class without elevation of aminotransferase levels (123,124). In a single center study, ambrisentan therapy resulted in increased exercise capacity without systemic desaturation or longer term clinical deterioration in patients with Eisenmenger syndrome (124).

The initial ambrisentan dose of 5 mg once daily may be increased to 10 mg once daily as tolerated in adult patients (103,104,121). Pediatric dosing is not available due to insufficient clinical data, but retrospective data demonstrate that pediatric patients can be started on ambrisentan at 2.5 mg (<20 kg) or 5 mg (≥20 kg) and up-titrated to 5 mg or 10 mg, respectively, if tolerated (Table) (123). As the incidence of elevated hepatic aminotransferase levels is similar in treatment and placebo groups in adult studies (103), monthly liver function testing while on ambrisentan is no longer required by the FDA, however most pediatric centers still monitor every 3 to 4 months. Similar to bosentan, teratogenicity is a concern. Ambrisentan is contraindicated in pregnancy and contraception should be discussed with women who may become pregnant. There are no drug interactions between ambrisentan and sildenafil, which facilitates combination therapy (125).

In adults with PAH, initial combination treatment with ambrisentan plus tadalafil results in improved clinical status, decreased N-terminal brain natriuretic peptide levels, and improved 6MWD compared to monotherapy with either ambrisentan or tadalafil (126). The effect of combination therapy in children is unknown but is an area of active research.

4.2.3. Macitentan

Macitentan, a novel dual ERA with tissue targeting properties, may have improved receptor binding capacity and fewer drug-drug interactions than bosentan (127,128). In a multicenter, double-blind, randomized, placebo-controlled, event-driven, phase III trial of patients ≥ 12 years of age with PAH on a stable treatment regimen (SERAPHIN), the addition of macitentan significantly reduced morbidity and mortality (129). Macitentan was approved for treatment of adult PAH (IPAH, HPAH, PAH-CHD, and PAH associated with connective tissue disease) in 2013. Limited data suggest improved 6MWD in teenagers and young adults transitioned from bosentan to macitentan (130).

4.3. Prostacyclins

Prostacyclin, a metabolite of arachidonic acid produced endogenously by the vascular endothelium, is a potent vasodilator and has anti-thrombotic, anti-proliferative, and anti-inflammatory effects (131–133). The biological functions of prostacyclin are mediated by cell-surface G-protein receptors on pulmonary endothelial cells and platelets that result in increased intracellular cyclic adenosine monophosphate (cAMP) and activation of protein kinase A. Protein kinase A increases smooth muscle relaxation and inhibition of platelet aggregation (134). In patients with severe PAH, prostacyclin metabolites and prostacyclin synthase are decreased (133). Epoprostenol was the first prostacyclin therapy approved for PAH in 1995 and was followed by treprostinil (subcutaneous 2002, intravenous 2004, inhaled 2009, oral 2013), iloprost (2004), and room temperature stable epoprostenol (2010). Since its introduction, prostacyclin therapy has formed the mainstay of PAH therapy and has drastically improved functional status and survival for both adult and pediatric patients.

4.3.1. Epoprostenol

Epoprostenol, a prostacyclin analogue delivered by intravenous infusion, was the first drug approved by the FDA for the management of PAH and has been used for over two decades with good results (9,34,36,111,135–140). Epoprostenol is recommended for first-line treatment of adult PAH patients with functional class III-IV symptoms (141,142). Although epoprostenol is not FDA-approved in children, continuous intravenous epoprostenol therapy is effective for improving symptoms, hemodynamics, and survival in children with IPAH or PAH-CHD (34,36,111,138–140,143). Clinical improvements occur with long-term use even in patients without a response during acute vasodilator testing. In 44 patients with IPAH treated with intravenous epoprostenol after it became consistently available in the United States in 1995, survival at 1, 5, and 10 years was 97%, 97%, and 78% (36). In the United Kingdom, patients treated with intravenous epoprostenol demonstrated significant improvement in somatic growth and cumulative survival of 94%, 90%, and 84% at 1, 2 and 3 years, respectively (139). Patients with marked hemodynamic improvement on intravenous epoprostenol have also been successfully transitioned to oral or inhaled targeted PAH therapy without deterioration of clinical and hemodynamic parameters (144).

Epoprostenol has a short elimination half-life of approximately 3 to 5 minutes that necessitates administration by continuous intravenous infusion, placement of a permanent central venous catheter, and delivery by a portable infusion pump. Due to the complicated nature of dose titration, epoprostenol therapy should be initiated in the inpatient setting by a pulmonary hypertension specialist. In a monitored hospital setting, intravenous epoprostenol is initiated at 1–3 ng/kg/min, rapidly increased over the first few days, and then steadily increased by 1–2 ng/kg/min every 1 to 2 weeks as tolerated (Table). Dose titration can be managed on an outpatient basis, aiming to maximize efficacy while keeping side effects tolerable. Children often require higher doses than adults, commonly in the range of 50–80 ng/kg/min, with further up-titration on an individual basis.

Side effects of epoprostenol therapy are dose-dependent and usually occur within hours of dose titration. Common side effects include flushing, headache, nausea, diarrhea, jaw discomfort, foot pain, rash, and thrombocytopenia (136,145,146). Severe adverse events such as bradycardia, systemic hypotension, and profound thrombocytopenia may occur, with either insufficient or excessive dosage of epoprostenol. Patients with PAH due to pulmonary veno-occlusive disease or pulmonary vein disease may develop life threatening pulmonary edema. Systemic desaturation due to ventilation-perfusion mismatching can occur in patients with significant lung disease. Serious complications, including infection and sepsis secondary to the indwelling catheter, catheter dislodgement, or catheter thrombosis can occur and may result in severe “rebound” pulmonary hypertension if therapy is acutely discontinued (147,148).

4.3.2. Treprostinil

Treprostinil, an alternative prostacyclin analogue, was initially approved by the FDA for subcutaneous use and subsequently approved for intravenous, inhaled, and oral use. The advantages of treprostinil therapy compared to epoprostenol include its stability at room temperature, longer half-life, and fewer side effects. The successful transition from epoprostenol to intravenous treprostinil therapy was demonstrated in 13 children with stable PAH who had been treated with epoprostinil for ≥ 1 year (138). There was no significant change in 6MWD with the transtion, but there were fewer prostanoid side effects (with the exception of leg pain) on treprostinil despite higher doses. Survival (Fig. 14) and hemodynamic changes (Fig. 15) on intravenous treprostinil are similar to epoprostenol (149). Subcutaneous treprostinil has the added advantage of administration without a central venous catheter. Children treated with subcutaneous treprostinil therapy after failure of combined oral treatment or due to severe complications of intravenous epoprostenol demonstrated significant improvement in functional class, hemodynamics, and 6MWD (150). Although injection site pain and pruritis due to subcutaneous infusion remain major disadvantages, treatment with oral and topical analgesics and histamine blockers may render subcutaneous treprostinil treatment tolerable in many children (150). Recent reports demonstrate the safety, tolerability, and efficacy of both intravenous and subcutaneous treprostinil in infants and children with chronic lung disease of prematurity, CDH, and failing single ventricle physiology (151–155). Inhaled treprostinil has been used as add-on therapy or for patients who have severe injection site pain due to subcutaneous infusion (156–158). Inhaled treprostinil has also been shown to be effective and well tolerated for acute vasoreactivity testing in children (Fig. 16) (159). Oral treprostinil is used for the treatment of PAH in adults. In a multicenter, open label, 24-week uncontrolled study to evaluate the safety, tolerability, and pharmacokinetics of oral treprostinil in children, oral treprostinil was successfully used as add-on PAH therapy or as a transition from intravenous or subcutaneous treprostinil with preservation of exercise capacity and functional class (160). Drug-related adverse events were common, including headache, diarrhea, nausea, vomiting, and flushing. Oral treprostnil use has been reported in children as young as 4 years of age (161), but the tablet formulation and the need to eat a substantial meal or snack with each of the three daily doses may limit its use in some children. Adverse events may result in drug discontinuation in many patients (161).

Fig. 14.

Kaplan-Meier survival curve for a cohort of pediatric PAH patients receiving prostacyclin therapy, comprised of patients on epoprostenol, treprostinil, and those who transitioned, with 95% confidence intervals (CI) depicted. Transplant-free 5-year survival was 70% (95% CI, 56%–80%). (Reproduced with permission from Siehr SL, et al. J Heart Lung Transplant. 2013).

Fig. 15.

Change in pulmonary-to-systemic vascular resistance ratio (Rp/Rs) over time in pediatric PAH patients receiving intravenous epoprostenol or treprostinil. Initial improvement was seen in Rp/Rs at 1 to 2 years on therapy that was not sustained long-term. (Reproduced with permission from Siehr SL, et al. J Heart Lung Transplant. 2013).

Fig. 16.

Hemodynamic change in the mean pulmonary artery pressure and the pulmonary vascular resistance index during acute pulmonary vasodilator testing with inhaled nitric oxide and inhaled treprostinil in children with PAH. Inhaled nitric oxide (iNO) and inhaled treprostinil significantly decreased the mean pulmonary artery pressure and the pulmonary vascular resistance index. iNO, inhaled nitric oxide; NS. not significant. (From Takatsuki S, et al. Pediatr Cardiol. 2013, with permission).

Intravenous and subcutaneous treprostinil are bioequivalent with a terminal elimination half-life of approximately 4.5 hours. Intravenous and subcutaneous treprostinil are generally initiated at 1.25–2 ng/kg/min, and the dose is gradually increased based upon clinical status, hemodynamic changes, and side effect profile (Table). A stable dose is commonly around 50–80 ng/kg/min with doses of intravenous treprostinil typically higher than intravenous epoprostenol. Due to need for indwelling catheter placement and the risk of systemic vasodilation, intravenous treprostinil requires in-hospital initiation. Most centers will initiate subcutaneous treprostinil in the hospital as well, given the risk of systemic vasodilation as well as the family teaching required for home administration. However, up-titration can be done at home under expert surveillance.

Prostacyclin side effects with either intravenous or subcutaneous treprostinil administration include headache, diarrhea, nausea, rash, flushing, jaw pain, and foot pain (138,150). Continuous infusion of treprostinil through a central venous catheter is associated with an increased risk of catheter related blood stream infections by gram negative organisms (162). The risk of bacteremia is reduced with the use of an alkaline buffer, closed hub systems, and protection of catheter connections while showering (148,163,164). Infusion site pain and reaction are common side effects of subcutaneous therapy, which can negatively impact tolerance. Incidence and severity of site pain appear to improve 5–7 days after subcutaneous catheter placement and by maintaining the infusion volume as low as possible. Additional techniques to control site pain include: initiation of systemic H1 and H2 histamine blockers, placing a “dry” site without medication 24 hours prior to infusion start, application of topical anti-inflammatory agents prior to site initiation, and administration of oral analgesics during the first 5–7 days of a new site. It is not uncommon for sites to last 1–2 months in older children.

Inhaled treprostinil has fewer systemic effects and can be started in the outpatient setting as add-on therapy for stable patients. Inhaled treprostinil is dosed in breaths (1 breath = 6 mcg treprostinil). The starting dose of inhaled treprostinil for an adult is 3 breaths (18 mcg) 4 times per day, given approximately 4 hours apart during waking hours. The dose is generally increased by an additional 3 breaths every 1–2 weeks as tolerated to a target maintenance dose of 9 breaths (54 mcg) per treatment (Table). Smaller children (< 20kg) should be monitored for systemic hypotension and may require slower up-titration of 1 breath every 2–4 weeks with an initial target maintenance dose of 5–6 breaths (30–36 mcg) per treatment. Proper inhalation technique is required for effective drug delivery, so patient education and family support are essential to optimize administration in children. Common side effects include cough, headache, throat irritation, nausea, and flushing. Acute inhalation of inhaled treprostinil is as effective as iNO in lowering mPAP and PVRI (Figure 17) (159). Inhaled therapies may have less risk of worsening ventilation-perfusion mismatch than intravenous therapies. Worsening respiratory symptoms have been reported in patients with reactive airway disease with inhaled treprostinil therapy but have been improved with bronchodilators prior to administration (158).

Fig. 17.

Change in pulmonary-to-systemic vascular resistance ratio (Rp/Rs) in children with congenital heart disease and pulmonary hypertension in response to inhaled nitric oxide (iNO) and aerosolized iloprost. (Reproduced with permission from Rimensberger P, et al. Circulation. 2001).

4.3.3. Iloprost

Similar to inhaled treprostinil, iloprost is an inhaled prostacyclin analogue and has several advantages over intravenous prostacyclin therapy including lower risk of systemic hypotension and may have lower risk of ventilation-perfusion mismatch (143,165–170). Iloprost has been shown to improve hemodynamics and functional class in IPAH and PAH-CHD (Fig. 17) (167,168,171). Due to a short biologic half-life, low risk of toxic metabolites, and ease of delivery in the acute care setting, inhaled iloprost is considered an alternative to iNO for postoperative care and vasoreactivity testing (168,169,171,172). Although the clinically effective dose of inhaled iloprost is not established in children, one study suggested that an initial dose of 2.5 mcg inhaled 5 to 9 times daily could be increased to 5 mcg per inhalation as maintenance therapy (Table) (167). Side effects, such as bronchospasm, as well as poor compliance with frequent administrations (6–9 times daily) have resulted in little integration into the outpatient management of pediatric PAH (167).

4.3.4. Beraprost

Beraprost is an oral prostacylin analogue that is not currently available in the United States or Europe. In a few studies, beraprost has been shown to improve hemodynamics and exercise capacity in patients with IPAH (173–175). A double-blind randomized placebo control trial in 116 patients with PAH suggested benefits in early phases of treatment but these were not sustainable over time (176). Evidence to support the use of beraprost in children is limited.

5. Novel Therapies

Although current PAH-specific therapies have improved outcomes, additional therapies are needed to optimize the care of pediatric patients with PAH. Imatinib, an oral tyrosine kinase inhibitor, is a potent antiproliferative agent that may have a role in the treatment of PAH. In the randomized efficacy study in adult patients with advanced PAH on ≥ 2 therapies (IMPRES), imatinib improved exercise capacity and hemodynamics (177). Study drug discontinuations and serious adverse events, including subdural hematoma formation in patients on anticoagulation, were common, thereby questioning the long-term safety of imatinib in patients with PAH.

Riociguat, an oral agent with dual mechanism of action including synergy with endogenous NO and direct stimulation of soluble guanylyl cyclase, is a promising therapy (178,179). In phase III trials of PAH therapy in patients with chronic thromboembolic pulmonary hypertension (CHEST-1) and in patients with symptomatic PAH (PATENT-1), riociguat demonstrated improved hemodynamics, functional class, and time to clinical worsening (180,181). Riociguat is approved for the treatment of PAH and chronic thromboembolic PH in adults. No pediatric studies have been completed. A recent case report described use of riociguat in a child with severe, suprasystemic PH (182).

Selexipeg is the first FDA-approved oral selective prostacyclin receptor agonist (183) and was anticipated to have fewer gastrointestinal side effects than prostacyclins (184). In a phase II study in adults, selexipeg was well tolerated with a favorable side effect profile and resulted in significant reduction in PVR compared to placebo (185). In the event-driven, phase 3, randomized, double blind, plaebo controlled trial, the risk of the composite endpoint of death or a PAH complication was lower in selexipag, but the treatment effect was driven by disease progression and PAH hospitalizations; there was no significant difference in mortality between the two groups (186). Data regarding use of selexipag in children are limited to case reports (187,188). Gastrointestinal side effects and headache are still commonly reported by patients in clinical practice. Further investigation is needed to determine its efficacy. At this time, it is still considered “experimental therapy” and has been used primarily in compassionate use circumstances (189).

Loss-of-function mutations in bone morphogenic protein receptor 2 (BMPR2) are associated with pulmonary vasculopathy in patients with IPAH and HPAH (190–193). Additionally, low expression of BMPR2 is seen even in PAH patients without mutations (194). Low-dose FK506 (tacrolimus) has been identified as a potent BMPR2 activator (195) and successfully reverses occlusive vasculopathy in rodents (196–198). In a small number of patients with end-stage PAH offered compassionate treatment with FK506, BMPR2 signaling, functional class, and hemodyamic measures improved (199). In a randomized, double-blind, placebo-controlled, 16-week, single center phase IIa trial, low-dose FK506 was well tolerated and increased BMPR2 signaling in a subset of patients (200). A phase IIb efficacy trial is planned.

Statins have also received attention in the treatment of PAH. The results of a randomized, double-blind, placebo-controlled clinical trial of aspirin and simvastatin in patients with PAH did not support the use of these medications in the treatment of PAH as no improvement in 6MWD was demonstrated (201).

Fasudil, a Rho-kinase inhibitor, has been shown to improve hemodynamics but has not been studied in larger clinical trials (202–205).

Regeneration of lung vascular endothelium by treatment with bone-derived endothelial progenitor cells (EPCs) has demonstrated marked improvement in survival in animal PAH models (206). Use of EPCs has not been adequately studied in humans but offers the hope of a curative therapy for PAH (207,208).

6. Treatment Algorithms

Currently, there is no definitive cure for PAH, therefore treatment goals focus on improving survival, hemodynamics, quality of life, and exercise tolerance. Due to limited randomized controlled clinical trials evaluating the safety and efficacy of specific treatments in children, pediatric PAH treatment algorithms are largely extrapolated from evidence-based adult guidelines. Some challenges, including lack of applicability of the WHO functional status classification to children of all ages and developmental statuses, limit the use of adult algorithms in children and highlight the need for pediatric-specific treatment algorithms.

A pediatric PAH risk assessment and treatment algorithm have been published by the American Heart Association and American Thoracic Society based on the consensus of a working group of PAH experts (Fig. 18 and 19) (50). Although acute vasoreactivity may be demonstrated in only a limited number of pediatric PAH patients, it remains an important component of the treatment approach and does have long-term prognostic value (7,17). The Sitbon criteria for positive acute vasoreactivity testing (defined above as a decrease in mPAP by at least 10 mm Hg to a value < 40 mm Hg with sustained cardiac output) has been shown to identify children who may respond to intial CCB therapy (33,35). For those patients with baseline mPAP <40 mm Hg, a positive test is defined as a decrease in mPAP by at least 10 mm Hg with no change in cardiac output. It is recommended that the Sitbon criteria be used to identify acute responders (12). Although CCBs should be considered in responders to acute vasodilator testing, a substantial number of patients will worsen on CCB therapy alone, and most children will ultimately require additional forms of PAH therapy (36).

Fig. 18.

Features that distinguish disease severity in pediatric pulmonary hypertension. RV, right ventricular; WHO, World Health Organization; PVRI, pulmonary vascular resistance index; iWU, indexed Wood units; CI, cardiac index; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; BNP, brain natriuretic peptide; NTproBNP, N-terminal pro-brain natriuretic peptide; 6MWD, 6-minute walk distance; VO2, oxygen consumption; CPET, cardiopulmonary exercise test. (Reproduced with permission from Rosenzweig E, et al. Eur Resp J. 2019)

Fig. 19.

Treatment algorithm for children with pulmonary arterial hypertension. CCB, calcium channel blocker; ERA, endothelin receptor antagonist; PDE-5, phosphodiesterase-5; IV, intravenous; SQ, subcutaneous. (Reproduced with permission from Rosenzweig E, et al. Eur Resp J. 2019)

Continuous prostacyclin therapy should be considered in non-responder patients with symptomatic right heart failure, while oral PAH medications are first line therapy in non-responders without significant exercise intolerance or functional impairment. Future pediatric PAH treatment algorithms should include more relevant pediatric risk factors that impact the choice of intravenous treprostinil over oral PAH therapy in children. Although pediatric studies remain limited, use of combination therapy has demonstrated improved outcomes in adults with PAH and should be considered in children with progressive disease and functional decline. Co-administration of PAH therapies should be done cautiously due to the risk of drug interactions. Atrial septostomy, palliative pulmonary-to-systemic shunts, and lung transplantation are additional therapeutic options for children but should be reserved for patients with WHO functional class IV, who have progressed despite maximal medical therapy.

7. Combination therapy

In patients with progressive PAH, combination therapy to address the multiple pathophysiologic pathways may produce additive or synergistic effects. Combination therapy is well tolerated and can improve exercise capacity, hemodynamic measurements, and time to clinical worsening in adults (209–212). In adult patients on epoprostenol, combination therapy may result in stabilization of hemodynamics and allow reduction of epoprostenol dose with fewer prostacyclin side effects (144). Combination therapy in children is increasing as most patients in the REVEAL registry received combination PAH therapy (7). In the limited number of studies that have included pediatric patients, combination therapy has proven to be safe and effective (144,213). Whether combination therapy should be employed as simultaneous initiation of two or more drugs or by sequential addition of drugs is still not known. More studies are needed to help establish guidelines for combination therapy in children.

8. Conclusion

In the last three decades, the long-term survival of children with PAH has improved with the introduction of targeted pulmonary vasodilator drug therapies. Although current treatment strategies in children have improved their prognosis dramatically, the management of pediatric PAH remains challenging in the current era. Vasodilator therapies in children are largely based on experience or expert opinion, whereas the therapies in adults are evidence based from randomized trials. With growing collaboration, the number of multicenter trials for children with PAH is increasing which may ultimately improve the development of specific treatment strategies and clinical endpoints for children with pulmonary hypertension.

KEY MESSAGES.

• Over the last three decades, survival of children with pulmonary arterial hypertension has improved with targeted pulmonary vasodilatory therapies.

• However, the management of children remains challenging as therapies are largely based on clinical experience or expert opinion, while adult therapies are evidence-based from randomized trials.

• With collaboration and more multicentered trials for children with PAH, we hope to develop specific treatment strategies and relevant clinical endpoints for children with PAH.