Pulmonary hypertension in children: Management and prognosis

INTRODUCTION — 

Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery pressure, which can result in right ventricular (RV) failure. In children, PH is most commonly associated with underlying cardiac or lung disease (eg, bronchopulmonary dysplasia [BPD]). PH may also be idiopathic or familial. Other causes of PH are rare in childhood (table 1). PH is associated with considerable risk of morbidity and mortality. Management of children with PH requires a multidisciplinary team with experience and expertise in this area.

The management and prognosis of PH in children are reviewed here. Classification, evaluation, and diagnosis of PH in children are reviewed separately. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

Other related issues are reviewed separately:

●Persistent PH of the newborn (see "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis" and "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome")

●PH associated with BPD (see "Pulmonary hypertension associated with bronchopulmonary dysplasia")

●Eisenmenger syndrome and PH in adults with congenital heart disease (CHD) (see "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis" and "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis")

●Pulmonary arterial hypertension in adults (see "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)")

TERMINOLOGY — 

The following terms are used in this topic:

●Pulmonary hypertension (PH) – PH refers to elevated pulmonary artery pressure (PAP; mean PAP >20 mmHg). PH can be due to a primary elevation of pressure in the pulmonary arterial system alone, increased blood flow through the pulmonary circulation (eg, systemic-to-pulmonary shunting lesions), or elevations of pressure in the pulmonary veins. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

●Pulmonary artery hypertension (PAH) – PAH refers to elevation of the pressure in the pulmonary arterial system (PAP >20 mmHg) and elevated pulmonary vascular resistance (PVR >3 Wood units) with normal pulmonary venous and left atrial pressures (pulmonary artery wedge pressure [PAWP] <15 mmHg). PH occurring as a consequence of underlying heart or lung disease is not classified as PAH. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Etiologic classification'.)

●Pulmonary venous hypertension (PVH) – PVH refers to elevations of pressure in the pulmonary venous and pulmonary capillary systems (PAWP ≥15 mmHg).

●Pulmonary hypertensive vascular disease (PHVD) – PHVD (previously called pulmonary vascular obstructive disease) refers to pathologic remodeling of pulmonary small vessels that results in narrowing the vascular lumen. PHVD is characterized by elevated PVR and/or elevated transpulmonary gradient; PAP is typically elevated but may be <20 mmHg in some cases (eg, single ventricle with cavopulmonary palliation).

Although there are important distinctions between the terms PH and PAH (as noted above), for simplicity, the term PH will be generally used in this topic review, except when the distinction is important.

MULTIDISCIPLINARY APPROACH — 

Infants and children with PH should be managed in centers with the experience, special expertise, and multidisciplinary teams necessary to provide care for these patients. The information provided below is a general overview of the management of pediatric PH. It is beyond the scope of this topic review to provide detailed therapeutic recommendations regarding all types of pediatric PH. The management of PH must always be individualized according to each patient's disease course.

TREATMENT OF UNDERLYING DISORDERS — 

For patients with PH that is either caused by or exacerbated by treatable underlying disorders, treating or ameliorating the underlying disorder is a critical part of management:

●For infants with systemic-to-pulmonary cardiac shunting lesions (eg, atrial or ventricular septal defects), closure of the defect alone may result in resolution of PH, though in some cases it may persist. However, if the PH is long standing and severe, closure of the defect may not be advised. (See "Isolated ventricular septal defects (VSDs) in infants and children: Management", section on 'Closure interventions' and "Isolated atrial septal defects (ASDs) in children: Management and outcome", section on 'Indications for ASD closure'.)

●For patients with PH due to left heart obstructive lesions (eg, mitral stenosis), the PH may improve or resolve following correction of the obstruction. (See "Rheumatic mitral stenosis: Overview of management", section on 'Indications for intervention'.)

●For patients with underlying hypoxic lung disease, an important component of therapy consists of providing supplemental oxygen, ventilatory support (if needed), and treating the underlying cause of hypoxia. (See "Bronchopulmonary dysplasia (BPD): Management and outcome", section on 'Respiratory support'.)

●For patients with PH that is caused by or exacerbated by obstructive sleep apnea, nighttime supplemental oxygen, adenotonsillectomy, ventilatory support at night, or other therapies may be warranted. (See "Management of obstructive sleep apnea in children".)

●For patients with PH that is exacerbated by gastroesophageal reflux and/or chronic aspiration, acid suppressing medication and efforts to reduce aspiration can be helpful. (See "Gastroesophageal reflux disease in children and adolescents: Management" and "Aspiration due to swallowing dysfunction in children".)

●For patients with PH that is exacerbated by an acute respiratory infection, treatment of the infection is critical. (See "Pneumonia in children: Inpatient treatment".)

●For patients with PH due to underlying systemic disease (eg, collagen vascular disease), treatment with immunosuppressive therapy may be warranted. (See "Systemic lupus erythematosus (SLE) in children: Treatment, complications, and prognosis" and "Treatment of pulmonary sarcoidosis: Initial approach".)

●For patients with PH due to thromboembolic disease (a rare cause of PH in children), anticoagulation is an important component of therapy. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

SUPPORTIVE MEDICAL THERAPY — 

Supportive medical therapy for PH consists of:

●Oxygen therapy – Oxygen therapy can be helpful in patients with arterial desaturation due to lung disease, sleep-disordered breathing, or in infants with delayed resolution of high (in utero) pulmonary vascular resistance. (See "Bronchopulmonary dysplasia (BPD): Management and outcome", section on 'Supplemental oxygen' and "Management of obstructive sleep apnea in children", section on 'Adjunct therapies'.)

●Diuretics – Diuretics can be helpful in patients with right heart failure and peripheral edema. Careful attention to fluid balance is necessary when using diuretics in this patient population since some patients with right ventricular (RV) hypertension may be preload dependent, and excessive intravascular volume removal may compromise cardiac output. (See "Heart failure in children: Management", section on 'Diuretics'.)

●Digoxin – The role of digoxin in treating RV failure is unclear. It is sometimes used in patients with overt right heart failure [1]. (See "Heart failure in children: Management", section on 'Digoxin'.)

●Anticoagulation – Anticoagulation is indicated in patients with PH secondary to thromboembolic disease; however, this is a rare cause of PH in children. (See "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy", section on 'Anticoagulant therapy (indefinite)'.)

The role of anticoagulation in other types of PH is less clear as there are few data to guide these decisions [1,2]. Anticoagulation may be considered on a case-by-case basis in patients with low cardiac output, hypercoagulable condition, indwelling central venous catheters, or prior thrombosis. When the decision is made to use chronic anticoagulant therapy, warfarin is the most commonly used agent, though direct oral anticoagulants (DOACs) are increasingly used for this purpose. Aspirin is sometimes used as an alternative, albeit with unclear benefit. Given the uncertain benefits, the use of anticoagulant therapy in children with PH must be weighed against the risks of bleeding (which are increased in young children given their greater predisposition to trauma) and the difficulty monitoring such therapy and maintaining therapeutic levels in young children. Certain diseases (eg, hereditary hemorrhagic telangiectasia) may preclude the use of anticoagulation. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Choice of agent'.)

The available evidence on the use of anticoagulation in patients with PH largely comes from studies involving adult patients, which were inconclusive. These data are discussed in greater detail separately. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

TARGETED PULMONARY HYPERTENSION THERAPY — 

Targeted therapy for PH consists of pulmonary vasodilator agents, which can be administered in combination or as monotherapy. Agents that are used for targeted pulmonary artery hypertension (PAH) therapy include (table 2):

●Calcium channel blockers (CCBs; eg, nifedipine, amlodipine, diltiazem – but not verapamil) (see 'Calcium channel blockers' below)

●Phosphodiesterase type 5 inhibitors (PDE-5 inhibitors; eg, sildenafil, tadalafil) (see 'Phosphodiesterase type 5 inhibitors' below)

●Endothelin receptor antagonists (ERAs; eg, bosentan, ambrisentan, macitentan) (see 'Endothelin receptor antagonists' below)

●Prostacyclin analogues (eg, epoprostenol, treprostinil, iloprost) (see 'Prostacyclin analogues' below)

Targeted therapy in pediatric patients is informed by clinical trials in adult patients, limited clinical trial and observational data in pediatric patients, and clinical experience [2,3]. Sildenafil and bosentan are the only agents approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of PH in pediatric patients. In addition, tadalafil (in children ≥2 years) and ambrisentan (in children ≥8 years) are approved by the EMA. Most other pulmonary vasodilator therapy for pediatric PH is "off label."

The management approach described in the following sections is generally consistent with the recommendations of the American Heart Association, the American Thoracic Society, the Pediatric Pulmonary Hypertension Network (PPHNet), the European Paediatric Pulmonary Vascular Disease Network, and the 7^th World Symposium on Pulmonary Hypertension [1,2,4-6]. Links to these and other guidelines are provided separately. (See 'Society guideline links' below.)

Management of persistent pulmonary hypertension of the newborn (PPHN) differs considerably from that of PH in older infants and children, and separate treatment guidelines are available [7]. Treatment guidelines are also available for neonates and young infants with PH secondary to developmental lung disease (eg, bronchopulmonary dysplasia [BPD], congenital diaphragmatic hernia) [7,8] and children with sickle cell disease [9]. These conditions are discussed separately:

●(See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome".)

●(See "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome".)

●(See "Pulmonary hypertension associated with bronchopulmonary dysplasia".)

●(See "Pulmonary hypertension associated with sickle cell disease", section on 'Management'.)

Patient selection — Factors that impact decisions regarding initiation of targeted PH therapy in children include the type of PH (table 1), severity, degree of symptoms, and right ventricular (RV) function.

The role of targeted PH therapy according to the type of PH is as follows (table 1):

●Group 1 PAH – Targeted PH therapy is generally indicated for patients who have symptoms and/or functional limitations related to PAH (ie, World Health Organization [WHO] functional class II, III, or IV (table 3)). In addition, targeted therapy may be used in some patients with severe PAH even if they lack apparent symptoms, particularly young children in whom it may be difficult to elicit symptoms.

●Group 2 PH – Targeted PH therapy is not used to treat patients with group 2 PH (PH due to left heart disease (table 1)) given the risk of harm and lack of convincing evidence of benefit. Data supporting the use of targeted therapy in pediatric group 2 patients are lacking. The approach in pediatric patients is consistent with the guidance for management of adult patients in this category. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults".)

●Group 3 PH – Although targeted PH therapy is not routinely recommended for adults with group 3 PH (PH owing to lung disease (table 1)), the use of targeted therapy may be useful in select pediatric patients with certain lung diseases (eg, BPD, congenital diaphragmatic hernia) based on observational data [10-12]. Management of these conditions is discussed in greater detail separately. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Management' and "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome", section on 'Management of pulmonary hypertension'.)

●Groups 4 and 5 PH – Groups 4 and 5 PH are rare in children, and targeted PH therapy is used on a case-by-case basis.

Baseline assessment — Prior to initiating targeted PH therapy, all patients should undergo a baseline assessment, including [1,13]:

●History and physical examination

●Electrocardiogram

●Brain natriuretic peptide level

●Chest radiograph

●Echocardiogram

●Cardiac catheterization with acute vasoreactivity testing (AVT)

Other baseline testing may be warranted depending on the specific clinical circumstances and the specific agent used (table 2). The details of the evaluation are described separately. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Evaluation'.)

Disease severity is determined by the degree of symptoms, functional class (table 3), and the findings on echocardiography and cardiac catheterization, as summarized in the table (table 4).

Choice of agent — The choice of initial agent for treatment of PAH is based on the severity of disease, results of AVT, and other factors such as comorbidities, clinician and patient preference, availability, and cost.

The following sections outline our suggested approach to selecting an initial agent or combination of agents for targeted therapy, as summarized in the algorithm (algorithm 1). The available targeted PH agents are summarized in the table (table 2); additional details on each agent are provided below. (See 'Specific agents for targeted PH therapy' below.)

There is a fair amount of latitude in the treatment algorithm, and not every patient will be optimally served using this approach. Nevertheless, it represents consensus of many experts regarding optimal pediatric PAH therapy [2]. This algorithmic approach applies specifically to patients with the following etiologic classes of PH (table 1) (see "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Etiologic classification'):

●Idiopathic (IPAH)

●Heritable (HPAH)

●Drug or toxin-induced (DT-PAH)

●PAH associated with congenital heart disease (CHD)

●PH associated with developmental lung disorders (eg, BPD, congenital diaphragmatic hernia)

For other types of pediatric PH, established treatment guidelines are lacking.

Patients with IPAH or HPAH — For patients in these categories, the choice of initial therapy is based upon whether the patient has a reactive or nonreactive AVT. Details of AVT (including criteria for reactivity) are provided separately. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Cardiac catheterization'.)

●Reactive AVT – For patients with IPAH/HPAH who demonstrate reactivity on AVT, we suggest initial treatment with a long-acting calcium channel blocker (CCB; eg, nifedipine, amlodipine, or diltiazem; but not verapamil) (table 2). An important exception is the patient presenting with evidence of depressed RV function, for whom CCB therapy is contraindicated. (See 'Calcium channel blockers' below.)

●Nonreactive AVT and nonresponders – For patients with nonreactive AVT and those with reactive AVT who have inadequate response to CCB therapy, the choice of therapy depends on the severity assessment (table 4 and algorithm 1):

•Lower-risk – For most patients in the lower-risk category, we suggest combination therapy with an oral ERA (eg, bosentan) plus PDE-5 inhibitor (eg, sildenafil, tadalafil). This can be done either by starting both agents simultaneously or in sequence (starting one agent and then rapidly adding on the second agent). If the patient does not respond adequately to dual therapy, a third agent can be added (eg, a prostacyclin analogue administered by oral, inhaled, subcutaneous [SC], or intravenous [IV] route). (See 'Endothelin receptor antagonists' below and 'Phosphodiesterase type 5 inhibitors' below and 'Combination therapy' below.)

•High-risk – Patients in the high-risk category are often treated with a combination of parenteral prostanoid therapy (eg, IV or SC treprostinil or epoprostenol) plus oral therapy with an ERA and/or PDE-5 inhibitor. (See 'Prostacyclin analogues' below and 'Endothelin receptor antagonists' below and 'Phosphodiesterase type 5 inhibitors' below and 'Combination therapy' below.)

Patients with CHD-associated PAH — This represents a heterogeneous population, and the approach to therapy depends upon the type of defect and whether it is repaired or unrepaired. The following subgroupings of group 1 CHD-associated PAH have been proposed to account for the variability in this population [2,14]:

●Subgroup A: Eisenmenger syndrome (ie, defects initially causing left-to-right shunting with subsequent development of PAH resulting in shunt reversal and cyanosis)

●Subgroup B1: Left-to-right shunt that is correctable

●Subgroup B2: Left-to-right shunt that is not correctable

●Subgroup C: Small coincidental CHD defect or an isolated atrial septal defect (ASD) in childhood

●Subgroup D: Corrected CHD (without clinically significant residual defects)

●Subgroup E: Without prolonged initial shunt (eg, neonatal arterial switch for D-transposition of the great arteries)

Based on this classification schema, we suggest the following approach (algorithm 1) [2]:

●Subgroups A and B2 (Eisenmenger syndrome and noncorrectable left-to-right shunts) – For patients in these categories, we suggest initial monotherapy with either a PDE-5 inhibitor (eg, sildenafil, tadalafil) or an ERA (eg, bosentan). If the patient's response to monotherapy is inadequate, we suggest adding a second agent from the other class (eg, add an ERA if the patient was initially treated with a PDE-5 inhibitor). (See 'Phosphodiesterase type 5 inhibitors' below and 'Endothelin receptor antagonists' below and 'Combination therapy' below.)

●Subgroup B1 (correctible left-to-right shunts) – For patients with PAH in the setting of a correctible left-to-right shunting defect, the first step of management is to perform an individualized evaluation of the patient's candidacy for operative or transcatheter repair of the defect. These decisions should be made using a multidisciplinary approach. (See 'Multidisciplinary approach' above.)

●Subgroups C, D, and E (small coincidental defects, isolated ASD, corrected CHD, and defects without prolonged initial shunt) – For patients in these categories, the approach is generally the same as for patients with IPAH/HPAH who have nonreactive AVT, as described above (see 'Patients with IPAH or HPAH' above). The CHD defect is unlikely to be the sole explanation for PAH for patients in these categories. This is because small coincidental defects, isolated ASDs, corrected CHD, and lesions without prolonged initial shunt generally do not cause elevated pulmonary vascular resistance in childhood. For example, PAH secondary to an unrepaired isolated ASD is a complication that would not be seen until the fourth or fifth decade of life. Thus, patients in these categories who present with PAH in childhood are likely to have an additional cause of PAH (eg, a genetic variant), and management is similar to management of IPAH/HPAH.

Patients with developmental lung disease — Management of PH in patients with developmental lung disease (eg, BPD, congenital diaphragmatic hernia) is discussed separately. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia" and "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome", section on 'Management of pulmonary hypertension'.)

Other types of pulmonary hypertension — Other types of PH (groups 2, 4, and 5 (table 1)) are uncommon in children, and the use of targeted PH therapy is individualized in these patients. (See 'Patient selection' above.)

SPECIFIC AGENTS FOR TARGETED PH THERAPY — 

The following sections review the pharmacology and efficacy of the available agents for targeted PH therapy in children (table 2). The clinical approach to selecting an agent (or combination of agents) for initial therapy is described above. (See 'Choice of agent' above.)

Calcium channel blockers — Calcium channel blockers (CCBs) relax vascular smooth muscle and possibly reduce pathologic growth of pulmonary vessels. These were the first drugs found to have demonstrated efficacy in treating PH [15,16].

●Clinical use – CCBs are used in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) who have vasoreactivity documented on cardiac catheterization. However, CCBs should not be used in patients with depressed right ventricular (RV) function. (See 'Choice of agent' above.)

●Preferred agents – Long-acting forms of CCBs are preferred, including nifedipine, amlodipine, and diltiazem (table 2). Verapamil should not be used, because it has minimal pulmonary vasodilatory effects and is a negative inotropic agent [1].

●Adverse effects – Adverse effects of CCBs include hypotension and bradycardia. Gingival hyperplasia and dental dysplasia can occur with long-term high-dose CCB therapy [17].

●Efficacy – The efficacy of CCBs in treating patients IPAH/HPAH with reactive acute vasoreactivity testing (AVT) is supported by observational studies [15,17,18]. In one study that reported on 31 children with IPAH/HPAH who were treated with long-term diltiazem (median maximal tolerated dose 13 mg/kg per day), all patients had stable or improved World Health Organization (WHO) functional status at median follow-up of six years [17].

Additional indirect evidence supporting CCB therapy comes from adult studies, which are described separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Calcium channel blockers (trial)'.)

Phosphodiesterase type 5 inhibitors — Phosphodiesterase type 5 (PDE-5) inhibitors include sildenafil and tadalafil (table 2). These drugs reduce breakdown of cyclic guanosine monophosphate (cGMP), resulting in pulmonary vasodilation and potentially a reduction in pathologic pulmonary vascular remodeling. Sildenafil is approved by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in children ≥1 year [19,20]. Tadalafil is approved by the EMA for use in children ≥2 years [21].

●Clinical use – PDE-5 inhibitors are the most commonly used agents for targeted PH therapy in children. They may be used as monotherapy or in combination with other agents. (See 'Choice of agent' above and 'Combination therapy' below.)

●Dosing and administration – Sildenafil can be given orally or intravenously (IV). The oral form is given three times per day. Tadalafil is a longer acting oral agent that is given once daily. Dosing guidance is provided in the table (table 2).

●Adverse effects – Potential adverse effects of PDE-5 inhibitors include headache, flushing, dizziness, hypotension, priapism, and diarrhea.

●Efficacy – The efficacy of PDE-5 inhibitors in pediatric patients with PH is supported by a large clinical trial investigating sildenafil [22], a smaller trial investigating tadalafil as add-on therapy in patients receiving an endothelin receptor antagonist (ERA) [23], and numerous observational studies [10,12,24-30]. In the STARTS-1 trial, 235 pediatric patients (ages 1 to 17 years) with group 1 PAH were randomized to one of three doses of sildenafil or placebo [22]. At 16 weeks, patients who received medium- or high-dose sildenafil had greater improvement in exercise capacity (measured by percent change from baseline in peak oxygen consumption [VO₂ peak]), functional class, and pulmonary vascular hemodynamics compared with those in the placebo group. Patients who received low-dose sildenafil had similar outcomes as those in the placebo group. STARTS-2 was an extension of STARTS-1 in which patients who received sildenafil in the initial trial continued the same dose, and those who initially received placebo were randomized to low-, medium-, or high-dose sildenafil [31]. Kaplan-Meier estimated three-year survival rates from start of sildenafil were 94, 93, and 88 percent for patients randomized to low-, medium-, and high-dose sildenafil, respectively. A separate analysis suggested that these survival rates were better than those reported in children managed without PH targeted medications [32].

In a smaller trial (n = 35 patients) investigating the efficacy and safety of tadalafil as add-on therapy in patients receiving an ERA, tadalafil-treated patients had greater improvements in 6-minute walk distance (6MWD) at 24 weeks compared with those in the placebo group (mean difference 24 meters) [23].

Additional support comes from studies involving pediatric patients with bronchopulmonary dysplasia (BPD)-associated PH and clinical trials in adult patients with PAH. These data are described separately. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Targeted pulmonary hypertension pharmacotherapy' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Nitric oxide-cyclic guanosine monophosphate enhancers'.)

Endothelin receptor antagonists — ERAs include bosentan, ambrisentan, and macitentan (table 2). ERAs bind to receptors on endothelial cells and block the actions of endothelin-1, which is a potent endogenous vasoconstrictor and mitogen. Bosentan is approved by both the FDA (in children ≥3 years old) and EMA (in children ≥1 year old) [33,34]. Ambrisentan is approved by the EMA for use in children ≥8 years [35]. Macitentan is not approved for use in children by either agency.

●Clinical use – ERAs are commonly used for targeted PH therapy in children. They may be used as monotherapy or in combination with other agents. (See 'Choice of agent' above and 'Combination therapy' below.)

●Dosing and administration – Bosentan is administered orally twice daily; ambrisentan is given once daily. Dosing guidance is provided in the table (table 2).

●Adverse effects – Major side effects with ERAs include reversible hepatotoxicity (the risk is less for ambrisentan and macitentan compared with bosentan), peripheral edema, anemia, and headache, and peripheral edema (table 2). These agents are teratogenic, and pregnancy must be excluded prior to commencing treatment and appropriate contraception utilized. Baseline and monthly monitoring of aspartate aminotransferase, alanine transferase, bilirubin, and hematocrit are required for bosentan. Less frequent monitoring is appropriate for ambrisentan and macitentan.

●Efficacy – The efficacy and safety of ERAs in pediatric patients is supported by retrospective case series, which reported on the experience using bosentan and ambrisentan [36-43]. Clinical trials are limited to a few pharmacokinetic studies that compared different dosing regimens of these agents without a placebo arm [39,44-46]. In most studies, use of either bosentan or ambrisentan was associated with improvements in functional and/or hemodynamic status [36-39].

In a single-center retrospective study of 101 children with IPAH or congenital heart disease (CHD)-associated PAH who were treated with bosentan for a median of 31 months, the 6MWD improved from an average pretreatment baseline of 258 meters to 312 meters by six months, and this improvement was maintained at follow-up of up to three years [42]. Before initiating treatment, approximately 70 percent of patients were classified as WHO functional class III or IV; by 12 months, this had declined to approximately 45 percent.

In a clinical trial involving 41 pediatric patients with PAH who were treated with either low- or high-dose ambrisentan for 24 weeks, an improvement in the 6MWD was seen in both groups; the overall mean difference from pretreatment baseline was 41 meters [46].

All three ERA agents have been shown to improve functional status and clinical outcomes in adults with group 1 PAH. These data are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Endothelin receptor antagonists'.)

Prostacyclin analogues — Prostacyclins are endogenous signaling molecules produced in the vascular endothelium. They are potent dilators of pulmonary and systemic blood vessels and also mediate various cellular processes including inhibiting inflammation, smooth muscle cell proliferation, and platelet aggregation [47]. As PH therapy, prostacyclin analogues may be administered through intravenous (IV), subcutaneous (SC), inhaled, and oral routes with challenges posed by the short half-lives of the molecules.

●Inhaled prostacyclin analogues – Inhaled prostacyclin analogues include iloprost and treprostinil (table 2). The IV agent epoprostenol can be administered via nebulizer in the intensive care unit setting (eg, for managing an acute PH crisis); this is an off-label use of the drug, and there are few data on this in children. (See 'Acute PH crisis' below.)

Inhaled agents have the theoretical advantage of targeting the lung vasculature, and they do not require central venous catheter as the IV prostacyclin analogues do. However, the efficiency of inhaled delivery is dependent on inhalational technique, and it is generally thought to be less effective than IV administration.

Based on clinical trial data in adults with PH and observational data in children, inhaled prostacyclin analogues seem to be generally well tolerated and may be effective in improving functional status [48-52]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Iloprost'.)

●Oral agents – An oral form of treprostinil was approved by the FDA in 2014 for treatment of PAH in adults. There are limited data on the use of this agent in children [53,54]. Based on the available data, it does not appear to achieve an adequate response in patients requiring high doses of parenteral prostacyclin. Oral treprostinil needs to be taken with food (to prevent gastrointestinal upset) at fairly uniform intervals (every six to eight hours).

Selexipag is another oral agent that is in a similar pharmacologic class (it is a selective nonprostanoid prostacyclin receptor agonist). It is discussed below. (See 'Other agents' below.)

●IV/SC prostacyclin analogues – Prostacyclin analogues that are given via IV or SC administration include epoprostenol and treprostinil (table 2). In pediatric patients, epoprostenol is primarily used acutely in critically ill or unstable patients due the short half-life of the drug and ease of titration. By contrast, treprostinil is used more commonly for long-term management of more stable patients.

Epoprostenol is delivered intravenously through a dedicated central venous line. It has a three- to five-minute half-life and is unstable at room temperature, although a more stable formulation (Veletri) is available [55,56]. Studies in adults with PH demonstrated functional and hemodynamic benefits and improved survival. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Epoprostenol'.)

Treprostinil can be given via IV or SC administration (and also orally or through inhalation, as previously discussed). It has a four-hour half-life and room temperature stability. In clinical trials of adults with group 1 PAH, treprostinil improved hemodynamic parameters, symptoms, exercise capacity, and possibly survival. It has not been evaluated in adult patients with other types of PH. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Treprostinil'.)

Limited data on the use of chronic parenteral prostanoid therapy (ie, IV epoprostenol, IV or SC treprostinil) in pediatric patients suggest that these agents improve hemodynamics and may improve survival [57-59]. Transition from IV epoprostenol to treprostinil has been shown to be safe and effective in adult and pediatric patients [60].

Side effects of prostacyclin analogues include hypotension, jaw pain, diarrhea, nausea, flushing, headache, and arthralgias. In addition, adverse effects related to central venous catheters (eg, thrombosis, occlusion, infection) and the delivery system (eg, pump malfunction, interruption of the infusion) may occur [61].

The cumbersome nature of continuous IV or SC infusion of prostacyclin analogues, as well as interest in targeted delivery, led to the development of inhaled forms of iloprost and treprostinil, which are typically used in patients with less severe PH or in whom parenteral delivery is difficult or impossible.

Other agents

●Selexipag is a selective nonprostanoid prostacyclin receptor agonist that is FDA approved for oral and IV use in adult patients with PH. Data on pediatric patients are limited [62-67]. A 2024 systematic review identified 14 case reports and case series reporting on 58 pediatric patients who received selexipag either as add-on therapy or when transitioning from parenteral prostanoid therapy [63]. In these reports, the drug was well-tolerated and WHO functional status improved or remained stable in 72 percent of treated patients. In addition, 6MWD improved in 75 percent of patients, and hemodynamics improved in 60 to >90 percent. Additional data on this agent are described separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Oral prostacyclin receptor agonists'.)

●Riociguat is an oral soluble guanylate cyclase stimulant that increases intracellular cGMP. It has been approved for use in adults for groups 1 and 4 PH [68,69]. There are limited published data on use of riociguat in children [70,71]. The largest study was a 24-week multicenter single‐arm study involving 24 children ages 6 to 17 years with PAH who were receiving stable targeted PH therapy with an ERA and/or prostacyclin analogue [71]. Riociguat was generally well tolerated, though two patients (8 percent) experienced serious drug-related adverse events including hypotension and right ventricular failure. From baseline to week 24, 6MWD improved on average by 23 meters. The study did not detect any changes in WHO functional status. Two patients experienced clinical worsening requiring hospitalization for right heart failure. Additional data on this agent are described separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Nitric oxide-cyclic guanosine monophosphate enhancers'.)

Combination therapy — The notion that using two or more medications with different mechanisms of action (combination therapy) may be more effective than a single drug has gained wide acceptance in PH therapeutic practice. Combination therapy may be administered as two agents initiated simultaneously or as "add-ons" (ie, one followed by another).  

While many experts favor using multiple agents in patients with an unsatisfactory response to a single drug, it is unclear which patients need or will benefit from combination therapy, how many medications to use, or what medications are best used in combination.

In a retrospective report of the experience of three large pediatric PH treatment centers, a substantial majority of patients were treated with a single agent for the first few years, but by five years after diagnosis, roughly as many patients were on combination as monotherapy (excepting patients on CCB monotherapy) [72]. Combination therapy was independently associated with improved survival in this study.

An ongoing clinical trial is investigating the safety and efficacy of first-line combination therapy (sildenafil plus bosentan) compared with sildenafil monotherapy in children with PH [41,73].

Clinical trials evaluating combination therapy in adult patients with PAH are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Combination oral therapy' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Combination therapy containing a parenteral agent'.)

ACUTE PH CRISIS — 

Acute PH crisis is a potentially fatal complication of PH [74]. It is manifested by a rapid rise in pulmonary vascular resistance leading to acute right heart failure, and inadequate cardiac output. Acute PH crisis can be triggered by multiple causes including surgery/anesthesia, acute lung disease (eg, pneumonia), fever, hypovolemia, or interruption of prostanoid infusion. PH crises complicate approximately 5 percent of elective cardiac catheterization procedures in children with PH [1,75]. Patients with suprasystemic pulmonary artery pressure and right ventricular dysfunction are at increased risk for this complication.

The specific details of management of acute PH crisis are beyond the scope of this topic review. Immediate consultation with a cardiologist and/or intensivist (preferably with pediatric PH experience) should be obtained whenever possible. General principles of management and prevention of PH crises include [74,76,77]:

●Provide pediatric advanced life support for cardiac arrest associated with PH (see "Pediatric advanced life support (PALS)")

●Administer supplemental oxygen

●Avoid hypercarbia

●Correct metabolic acidosis

●Avoid hypovolemia/provide careful fluid resuscitation

●Administer an inhaled pulmonary vasodilator such as inhaled nitric oxide or a prostacyclin analogue (eg, nebulized or intravenous epoprostenol or iloprost)

●Provide analgesia/sedation if warranted

●Support cardiac output with inotropes

●Mechanical support (eg, extracorporeal membrane oxygenation) may be used in some cases (see 'Mechanical support' below)

SEVERE AND REFRACTORY PH — 

Patients with severe PH that is refractory to medical therapy have a high risk of mortality. Treatment modalities that have been used with variable success in these patients include right-to-left shunt procedures, mechanical support, and lung transplantation [5].

Right-to-left shunt procedures — Creation of an atrial septal opening or pulmonary artery (PA) to aortic communication to permit right-to-left shunting is not a routine intervention in the management of pediatric PH. However, in patients with severe and refractory symptomatic PH, these procedures may be considered.

Patients with severe PH face significant morbidity and mortality due to progressive right heart failure. Markedly elevated pulmonary vascular resistance (PVR) leads to a reduction in left ventricular (LV) preload and, consequently, systemic pressure that can precipitate syncope and death. The purpose of right-to-left shunting is to avoid these undesirable outcomes by diverting blood flow to bypass the pulmonary vascular bed and enter the systemic circulation (ie, a "pop-off" communication), thereby providing adequate systemic blood flow and maintaining tissue perfusion, albeit with less oxygenated blood.

Procedures that have been used to generate right-to-left "pop-off" shunts in patients with pulmonary arterial hypertension (PAH) include balloon atrial septostomy and placement of a Potts shunt.

●Atrial septostomy – An atrial "pop-off" communication produced in the cardiac catheterization laboratory may reduce syncope and symptoms of right heart failure by providing a means for blood to bypass the lungs, fill the LV, and hence improve cardiac output. There are multiple reports of catheter-based atrial septostomy reducing syncope and improving functional class of patients with severe PH [78,79]. This procedure, which is attended with risk of significant complications, including death, is reserved for select patients and should only be performed in centers with personnel experienced in PH and this intervention.

●Reverse Potts shunt – The Potts shunt is a side-to-side anastomosis of the descending aorta to the left PA, originally developed as palliation for certain forms of cyanotic congenital heart disease (CHD) (figure 1). A similar communication between the PA and aorta can be made with transcatheter procedures in the cardiac catheterization laboratory (eg, by placing a stent into a small patent ductus arteriosus [PDA], or inserting a covered stent between the aorta and left PA) [80-84]. A surgical conduit connecting the PA with the descending aorta has also been described [85]. The use of these procedures in PH is based on the observation that patients who have PVR exceeding systemic vascular resistance with a large ventricular septal defect or PDA tend to have better outcomes than those with similarly elevated PVR but no "pop off." The aortic-to-PA communication reduces maximum right ventricular (RV) pressure and increases systemic blood flow by virtue of the RV pumping some blood across the shunt to the systemic circulation. Available data are limited, but they suggest that this procedure may durably improve functional class in patients with severe PH [80,82,83]. However, Potts palliation is less likely to benefit patients with significant RV dysfunction or severe disease decompensation, and it may be best to avoid this procedure in such patients [86]. This intervention is not standard practice and should be only performed in centers with considerable expertise in the required fields.

Mechanical support — The extracorporeal membrane oxygenator (ECMO) can be used to resuscitate patients with PH suffering cardiac arrest and/or as support while awaiting lung transplantation. Pumpless paracorporeal lung assist devices (eg, Novalung or Quadrox oxygenator) have also been used as a bridge to lung transplant in patients with PH and severe RV failure [87-89]. A cannula carries blood from the PA to the oxygenator, then back to the left atrium, so that a fraction of the RV output bypasses the high-resistance lungs. The utility of either form of mechanical support is constrained by the typically long delay between need for new lungs and their availability. In addition, mechanical support is often accompanied by complications within the first few days or weeks after its initiation. ECMO is most likely to be useful when used to support a patient with a reversible deterioration in condition rather than as a bridge to transplantation, but both ECMO and paracorporeal pumpless devices have been used to bridge patients to lung transplant [90-92]. (See "Short-term mechanical circulatory assist devices", section on 'Extracorporeal membrane oxygenation'.)

Lung transplantation — Lung transplantation is an important treatment option for pediatric patients with progressive severe PH and deteriorating clinical status despite optimized medical therapy. Lung transplantation carries substantial risks and burdens, and may provide only relatively short-lived relief of symptoms, but waiting too long to list a patient can result in patient demise before donor lungs are available; timing of listing therefore requires considerable care. Severe refractory PH is the second most common condition leading to lung transplantation in children (second only to cystic fibrosis) [93]. For pediatric patients who undergo lung transplantation for PH, estimated five-year survival is approximately 60 percent [93]. Independent risk factors for mortality include requiring mechanical ventilation at the time of undergoing transplant and having a primary diagnosis other than idiopathic pulmonary arterial hypertension (IPAH) [93]. As has been shown in adults, decreased RV function normalizes in children after lung transplant [94]. Ongoing challenges in this field include appropriate selection of candidates and timing of transplant for patients with PH, reducing wait list mortality, treatment of acute and chronic rejection, and repeat-transplantation. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Lung transplantation' and "Cystic fibrosis: Management of advanced lung disease", section on 'Lung transplantation'.)

FOLLOW-UP — 

Most patients should be seen every three to six months, with more frequent visits for patients with severe disease and after therapeutic changes [1]. Such frequent reassessment is necessary because of the complex nature of the disease and its treatments.

Follow-up visits should include a thorough history to assess symptoms of right heart failure, exercise tolerance, and medication side effects; physical examination for signs of right heart failure; and an echocardiogram. Repeat cardiac catheterization is generally recommended within 3 to 12 months after starting therapy or with clinical deterioration [1]. Additional follow-up testing (eg, brain natriuretic peptide, six-minute walk test) should also be performed at regular intervals to assess for disease progression.

LONG-TERM HEALTH MAINTENANCE — 

Longitudinal care for children with PH should be closely coordinated with the child's multidisciplinary PH team. Primary care clinicians should be familiar with the associated complications of PH and the disease course. Important aspects of long-term health care maintenance in children with PH include [1,95]:

●Immunizations – Children with PH should receive all routine childhood vaccinations and prophylaxis, including (see "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'):

•Respiratory syncytial virus (RSV) for all eligible infants (see "Respiratory syncytial virus infection: Prevention in infants and children")

•Pneumococcal vaccination according to the high-risk protocol (see "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents')

•Yearly influenza vaccination (see "Seasonal influenza in children: Prevention with vaccines")

•Coronavirus disease 2019 (COVID-19) (see "COVID-19: Vaccines", section on 'Children')

●Monitoring of growth parameters – It is important to monitor growth and development in children with PH, as it is in all children. Failure to thrive may be the main clinical sign of right heart failure in young infants and children. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Clinical features' and "Normal growth patterns in infants and prepubertal children".)

●Treatment of respiratory illnesses – Respiratory illnesses can be associated with considerable morbidity and mortality in children with PH. It is important to promptly recognize acute respiratory illnesses and to provide appropriate treatment if warranted. (See "Community-acquired pneumonia in children: Outpatient treatment" and "Pneumonia in children: Inpatient treatment".)

●Antibiotic prophylaxis – Antibiotic prophylaxis for the prevention of infective endocarditis should be provided prior to relevant procedures in patients with unrepaired cyanotic congenital heart disease (CHD), prosthetic heart valves, or other high-risk conditions or implanted devices. The approach is summarized in the figure (algorithm 2) and discussed in detail separately. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

●Exercise and sports participation – Children with PH may engage in light to moderate aerobic activity but should be allowed to self-limit their activity if needed. They should be instructed to remain well hydrated during exercise, and strenuous or isometric exertion should be avoided. Children who wish to participate in competitive athletic activities should undergo cardiopulmonary exercise testing. Patients with severe PH (ie, World Health Organization functional class III or IV (table 3)) or recent history of syncope should not participate in competitive sports. (See "Physical activity and exercise in patients with congenital heart disease".)

●Reproductive health counseling for adolescent females – Pregnancy in patients with PH is associated with considerable risks, including maternal and fetal mortality. Female adolescents with PH should be provided with counseling about pregnancy risks and options for contraception. Estrogen-containing contraceptives should be avoided due to the associated risk of venous thromboembolism. (See "Contraception: Overview of issues specific to adolescents" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Pregnancy'.)

●Planning of noncardiac surgery – Children with PH are at increased risk for severe adverse events (eg, acute pulmonary hypertensive crisis) when undergoing surgery and other procedures under anesthesia. Careful perioperative planning (including consultation with cardiac anesthesia, coordination with the PH team, and appropriate postprocedural monitoring) is vital for pediatric patients with PH undergoing surgery or other procedures requiring anesthesia/sedation. (See 'Acute PH crisis' above.)

●Airplane travel – Supplemental oxygen is warranted in patients during airplane travel, but the precise indications for supplemental oxygen are poorly defined. (See "Approach to patients with heart disease who wish to travel by air or to high altitude".)

PROGNOSIS — 

The estimated five-year survival for pediatric patients with pulmonary arterial hypertension (PAH) (ie, familial, idiopathic, or due to congenital shunting defects) is approximately 60 to 75 percent [25,96,97]. Among children with PH who require admission to a pediatric cardiac critical care unit, mortality is approximately 10 percent overall and up to 30 percent for those requiring invasive mechanical ventilation and vasoactive infusions [98].

"High-risk" and "lower-risk" factors that are associated with poor or favorable prognosis, respectively, are summarized in the table (table 4) [1,2,4,25,96,97,99-102]. Prognostic factors that most consistently correlated with outcome in multiple different cohorts include WHO functional class (table 3), tricuspid annular plane systolic excursion (TAPSE) and brain natriuretic protein (BNP) or N-terminal pro-BNP [2]. In addition to the predicative value these parameters have at the time of diagnosis, changes in these parameters over time also strongly correlate with outcome.

In a registry study of 58 children with idiopathic or hereditary PAH who were followed for a median of 3.1 years, the number of parameters in the "lower-risk" category correlated with longer transplant-free survival [100]. For patients with ≥7 lower-risk variables at the time of diagnosis, five-year survival was 100 percent, whereas for patients with ≤3 lower-risk variables at the time of diagnosis, five-year survival was 35 percent.

Functional status tends to decline with age, highlighting the need for frequent follow-up with these patients to reassess disease severity and adjust treatment if warranted. (See 'Follow-up' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in children".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Pulmonary hypertension (The Basics)")

SUMMARY AND RECOMMENDATIONS

●General measures – Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery pressure, which can result in right ventricular failure. PH is associated with considerable risk of morbidity and mortality. (See 'Terminology' above and 'Prognosis' above.)

Key aspects of management include:

•Multidisciplinary care – Infants and children with PH should be managed in centers with the experience, special expertise, and multidisciplinary teams necessary to provide care for these patients. The management of PH must always be individualized according to each patient's disease course. (See 'Multidisciplinary approach' above.)

•Addressing the underlying condition – For patients with PH that is either caused by or exacerbated by treatable underlying disorders, treating or ameliorating the underlying disorder is a critical part of management. (See 'Treatment of underlying disorders' above.)

•Supportive medical therapy – Supportive medical therapy for PH includes oxygen therapy for patients with hypoxemia and careful use of diuretics. Digoxin is sometimes used for patients with overt right heart failure, though its benefit is unclear, and practice varies. Anticoagulation is used selectively. (See 'Supportive medical therapy' above.)

●Targeted PH therapy – The classes of drugs used for targeted pulmonary vasodilator therapy include calcium channel blockers (CCBs), phosphodiesterase type 5 (PDE5) inhibitors, endothelin receptor antagonists (ERAs), and prostacyclin analogues (table 2). (See 'Targeted pulmonary hypertension therapy' above.)

The choice of initial agent(s) is based upon the etiology of PH, disease severity (table 4), results of acute vasoreactivity testing (AVT), and other factors such as comorbidities, clinician and patient preference, availability, and cost. Our suggested approach is as follows (algorithm 1) (see 'Choice of agent' above):

•Idiopathic or hereditary pulmonary arterial hypertension (IPAH/HPAH)

-Reactive AVT – For patients with IPAH or HPAH who have reactive AVT and lack evidence of right ventricular (RV) dysfunction, we suggest initial therapy with a CCB rather than other agents (Grade 2C). (See 'Patients with IPAH or HPAH' above and 'Calcium channel blockers' above.)

-Nonreactive AVT, lower risk – For lower-risk patients with nonreactive AVT or inadequate response to CCB therapy, we suggest combination therapy with an oral ERA plus PDE-5 inhibitor (Grade 2C). This can be done either by starting both agents simultaneously or in sequence. (See 'Patients with IPAH or HPAH' above and 'Phosphodiesterase type 5 inhibitors' above and 'Endothelin receptor antagonists' above and 'Combination therapy' above.)

-High-risk – For high-risk patients with IPAH or HPAH, we suggest a combination of parenteral prostanoid therapy plus an oral ERA and/or PDE-5 inhibitor (Grade 2C). (See 'Patients with IPAH or HPAH' above and 'Prostacyclin analogues' above and 'Combination therapy' above.).

•Congenital heart disease (CHD)-associated PAH – This represents a heterogeneous population, and the choice of therapy is based on the subgroup, as outlined in the algorithm (algorithm 1):

-Subgroups A and B2 (Eisenmenger syndrome and noncorrectable left-to-right shunts) – For patients in these categories, we suggest initial monotherapy with either a PDE-5 inhibitor or an ERA (Grade 2C). If the patient's response to monotherapy is inadequate, we suggest adding a second agent from the other drug class (Grade 2C). (See 'Patients with CHD-associated PAH' above and 'Phosphodiesterase type 5 inhibitors' above and 'Endothelin receptor antagonists' above and 'Combination therapy' above.)

-Subgroup B1 (correctible left-to-right shunts) – For patients with correctible left-to-right shunting defects, the first step of management is to perform an individualized evaluation of the patient's candidacy for operative or transcatheter repair of the defect. These decisions should be made using a multidisciplinary approach. (See 'Multidisciplinary approach' above.)

-Subgroups C, D, and E (small coincidental defects, isolated atrial septal defect, corrected CHD, and defects without prolonged initial shunt) – For patients in these categories, the approach is generally the same as for patients with IPAH/HPAH who have nonreactive AVT, as outlined in the bullets above. The CHD defect is unlikely to be the cause of PAH in these patients, and it is more likely that they have an additional cause of PAH (eg, a genetic variant). Thus, management follows the same approach as for IPAH/HPAH. (See 'Patients with CHD-associated PAH' above and 'Patients with IPAH or HPAH' above.)

•PH associated with developmental lung disease – Management of PH in patients with developmental lung disease (eg, bronchopulmonary dysplasia [BPD], congenital diaphragmatic hernia) is discussed separately. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia" and "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome", section on 'Management of pulmonary hypertension'.)

•Other types of PH – Other types of PH (groups 2, 4, and 5 (table 1)) are uncommon in children, and the use of targeted PH therapy is individualized in these patients. (See 'Patient selection' above.)

●Options for severe refractory PH – Patients with severe PH that is refractory to medical therapy have a high risk of mortality. Treatment modalities that have been used with variable success in these patients include atrial septostomy, reverse Potts shunt, and lung transplantation. Mechanical support may sometimes be used as a bridge to recovery from an acute insult or to lung transplantation. (See 'Severe and refractory PH' above.)

●Long-term management

•Follow-up – Follow-up for children with clinically significant PH typically occurs every three to six months and includes an interval history, physical examination, echocardiogram, and additional testing if needed. More frequent visits are warranted for patients with severe disease and after therapeutic changes. (See 'Follow-up' above.)

•Long-term health maintenance – Important aspects of long-term health maintenance in children with PH include routine immunizations, monitoring of growth parameters, prompt recognition and treatment of respiratory illnesses, antibiotic prophylaxis for prevention of infective endocarditis if warranted, counseling regarding exercise, reproductive health counseling for adolescent females, planning of noncardiac surgery, and advice regarding air travel. (See 'Long-term health maintenance' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Thomas Kulik, MD, who contributed to an earlier version of this topic review.