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Pulmonary hypertension in children: Management and prognosis

Pulmonary hypertension in children: Management and prognosis
Literature review current through: May 2024.
This topic last updated: Jun 15, 2023.

INTRODUCTION — Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery pressure, which can result in right ventricular 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 (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 'Criteria and timing for 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 "Management of gastroesophageal reflux disease in children and adolescents" 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; patients with progressive idiopathic/heritable PH; and those with hypercoagulable states, indwelling central venous catheters, or prior thrombosis. When the decision is made to use chronic anticoagulant therapy, warfarin is the agent most commonly used. Aspirin is sometimes used as an alternative, albeit with unclear benefit [2]. 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

Overview — Targeted therapy, sometimes referred to as "pulmonary vasodilator therapy," is directed at the PH itself. Agents that are used for targeted PH therapy include (table 2):

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

Phosphodiesterase type 5 inhibitors (PDE5 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, observational studies involving children, and clinical experience [3]. Randomized clinical trial data in children are limited to a single trial assessing sildenafil in pediatric patients with PH [4,5] and trials of inhaled nitric oxide (iNO) for neonatal hypoxic respiratory failure (which found that iNO was not effective in reducing bronchopulmonary dysplasia [BPD] or improving survival) [6-8]. Most medical therapy for pediatric PH is "off label." (See "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Inhaled nitric oxide'.)

Treatment of pediatric pulmonary arterial hypertension (PAH) is based on the severity of disease as shown in the algorithm (algorithm 1) [1]. While there is a fair amount of latitude in this algorithm and not every patient will be optimally served using this approach, it represents consensus of many experts regarding optimal pediatric PH therapy. This algorithmic approach applies specifically to patients with PAH (ie, group 1 PH) (table 1). In children, the most common etiologies within this category are familial, idiopathic, and PAH associated with congenital cardiac shunting defects. This approach is generally consistent with the recommendations of the American Heart Association, the American Thoracic Society, the European Paediatric Pulmonary Vascular Disease Network, and the Sixth World Symposium on Pulmonary Hypertension [1,2,9]. Links to these and other guidelines are provided separately. (See 'Society guideline links' below.)

Management of persistent pulmonary hypertension of the newborn (PPHN), which is also included in the category of group 1 PH, differs considerably from that of PAH in older infants and children, and separate treatment guidelines are available [10]. Treatment guidelines are also available for neonates and young infants with PH secondary to lung disease (eg, bronchopulmonary dysplasia, congenital diaphragmatic hernia) [10,11] and children with sickle cell disease [12]. These are conditions are discussed separately:

(See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'General Principles' and "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Management approach'.)

(See "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome", section on 'Postnatal management'.)

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

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

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

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 [13-15]. 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 [1,16]:

History and physical examination

Electrocardiogram

Brain natriuretic peptide level

Chest radiograph

Echocardiogram

Cardiac catheterization with acute vasoreactivity testing (AVT)

Other testing may be warranted in depending on the specific clinical circumstances and additional baseline blood tests may be required depending on 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 (eg, syncope, symptoms of right heart failure), functional class (table 3), and the findings on echocardiography and cardiac catheterization (table 4).

Choice of agent — The choice of initial agent for treatment of PH is based in large part on the results of AVT and the severity of disease, though other factors such as comorbidities, clinician and patient preference, availability, and cost also influence decision-making.

The following sections outline the clinical approach to selecting an initial agent for targeted PH therapy. The available targeted PH agents are summarized in the table (table 2) and are described in greater detail below. (See 'Specific agents for targeted PH therapy' below.)

Reactive acute vasoreactivity testing — Patients who have vasoreactivity documented on cardiac catheterization can often be effectively treated with CCBs. However, CCBs should not be used in patients with depressed RV function. 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]. (See 'Calcium channel blockers' below.)

Only a minority of patients respond favorably to these agents. Patients with reactive AVT ("responders") usually show a long-term fall in pulmonary artery pressure (PAP) with CCBs, whereas patients with nonreactive AVT ("nonresponders") do not and may suffer deterioration in their condition if treated with CCBs. Responders account for 10 to 40 percent of pediatric patients with PH, depending on the AVT criteria used [17-19]. Repeat AVT is warranted in follow-up monitoring because some patients who are initially reactive on AVT may subsequently become nonreactive [17]. (See 'Follow-up' below.)

Nonreactive acute vasoreactivity testing — For patients with nonreactive AVT, CCBs are not used, because they have not been shown to be beneficial in these patients and may be harmful [1]. Alternative agents include PDE5 inhibitors (eg, sildenafil, tadalafil), ERAs (eg, bosentan, ambrisentan, macitentan), and prostacyclin analogues (eg, epoprostenol, treprostinil, iloprost). The choice of initial agent is based upon the severity assessment (algorithm 1).

Lower risk — For patients who are deemed to be at lower risk based on symptoms, functional class (table 3), echocardiography findings, and catheterization data (table 4), initial treatment options include:

Oral PDE5 inhibitors (see 'Phosphodiesterase type 5 inhibitors' below)

Oral ERAs (see 'Endothelin receptor antagonists' below)

Inhaled prostanoids (see 'Prostacyclin analogues' below)

PDE5 inhibitors are most commonly used for initial therapy; however, the choice is based largely on patient and provider preference. Combination therapy (eg, PDE5 inhibitor plus oral ERA) may be used if PAP remains elevated despite monotherapy. (See 'Combination therapy' below.)

High risk — Patients who are deemed to be at high risk based on symptoms, functional class (table 3), echocardiography findings, and catheterization data (table 4) are typically treated with IV or subcutaneous (SC) prostanoids. Combination therapy is also commonly used in high-risk patients. (See 'Prostacyclin analogues' below and 'Combination therapy' below.)

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 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 [17,20].

CCBs are used in patients who have vasoreactivity documented on cardiac catheterization. However, CCBs should not be used in patients with depressed RV function. 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].

Side effects of CCBs include hypotension and bradycardia.

The efficacy of CCBs in treating PH patients with reactive AVT is supported by observational data in pediatric and adult patients demonstrating improved survival for vasoreactive patients treated with CCBs [17,19,20]. (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 (PDE5) inhibitors that are approved by the US Food and Drug Administration (FDA) for targeted PH therapy include sildenafil (approved for use in children and adults) and tadalafil (approved for use in adults) (table 2) [21]. There is greater experience with sildenafil in children and it is the only targeted PH therapy that has been evaluated in a randomized controlled trial in pediatric patients [5].

Sildenafil can be given orally or intravenously (IV). Tadalafil is an oral agent. These drugs cause pulmonary vasodilation and may inhibit pathologic pulmonary vascular remodeling by reducing the breakdown of cyclic guanosine monophosphate (cGMP). These agents have been shown to decrease PAP and improve exercise capacity in adults with group 1 PH [22]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Nitric oxide-cyclic guanosine monophosphate enhancers'.)

In the STARTS-1 trial, 235 pediatric patients (ages 1 to 17 years) with group 1 PH were randomized to one of three doses of sildenafil or placebo [5]. The primary endpoint was exercise capacity (measured by percent change from baseline in peak oxygen consumption [VO2peak]) at the end of 16 weeks. Patients who received medium and high doses of sildenafil had greater improvement in VO2peak, functional class, and pulmonary vascular hemodynamics compared with placebo. Patients who received low-dose sildenafil had similar outcomes as those in the placebo group. In STARTS-2 (which 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), increased mortality was observed with higher doses over three years [4]. However, subsequent analysis of the survival data from STARTS-2 suggested that survival with all doses of sildenafil was better than that reported in children treated without PH targeted medications [4,23].

The efficacy and safety of sildenafil for treatment of pediatric PH is also supported by observational studies [13,15,24,25]. Use of sildenafil in patients with PH secondary to bronchopulmonary dysplasia is discussed separately. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Targeted pulmonary hypertension pharmacotherapy'.)

Tadalafil is a longer-acting PDE5 inhibitor and can be given once a day. There is less experience with tadalafil, especially in pediatrics, although limited published information suggests that it may be as effective as sildenafil [26].

Riociguat is not a PDE5 inhibitor but also increases intracellular cGMP (by sensitizing the enzyme that produces cGMP to activation by nitric oxide [NO] and by stimulating it directly). It has been approved for use in adults for groups 1 and 4 PH [27,28]. The available published data in children are limited to case reports [29].

Endothelin receptor antagonists — 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 and macitentan are nonselective and antagonize both endothelin receptors A and B; ambrisentan selectively antagonizes endothelin receptor A.

All three medications have been shown to improve functional status and clinical outcomes in adults with group 1 PH and are approved by the FDA for use in adults with group 1 PH [30]. Bosentan is FDA approved for use in pediatric patients >3 years old [31]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Endothelin receptor antagonists'.)

There are no randomized studies of these agents in children, but retrospective case series suggest that bosentan improves functional and hemodynamic status of pediatric patients with PH, although its effects may not persist over the long term [32-35]. Published information regarding ambrisentan is limited, but one retrospective cohort study indicated that the drug improved pulmonary hemodynamics and clinical outcomes in children with group 1 PH [36]. There are no available data on use of macitentan in pediatric patients.

Major side effects with ERAs include reversible hepatotoxicity (the risk is less for ambrisentan and macitentan compared with bosentan), anemia, headache, and peripheral edema. 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.

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 a variety of cellular processes including inhibiting inflammation, smooth muscle cell proliferation, and platelet aggregation [37]. As PH therapy, prostanoids may be administered through IV, subcutaneous (SC), inhaled, and oral routes with challenges posed by the short half-lives of the molecules.

Inhaled and oral prostacyclin analogues – Inhaled prostacyclin analogues include iloprost and treprostinil (table 2).

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. Hence, its use is mostly limited to patients with low-risk disease. (See 'Lower risk' above.)

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 [38-43]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Iloprost'.)

An oral form of treprostinil (Orenitram) was approved by the FDA in 2014 for treatment of PAH in adults, primarily on the basis of a small but statistically significant increase in six-minute walk distance [44]. There are limited data on the use of this agent in children. [45,46]. 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 a novel selective nonprostanoid prostacyclin receptor agonist that is FDA approved for oral and IV use in adult patients with PH. Data in pediatric patients are limited. In the largest series, which included data on 15 consecutive children with PAH treated with add-on oral selexipag, the drug was well-tolerated and 75 percent of patients had improvement in mean PAP and/or some echocardiographic measures of RV systolic function [47]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Oral prostacyclin receptor agonists'.)

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 [48,49]. 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 through inhalation, as previously discussed). It has a four-hour half-life and room temperature stability. In clinical trials of adults with group 1 PH, 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 [50-52]. Transition from IV epoprostenol to treprostinil has been shown to be safe and effective in adult and pediatric patients [53].

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 [54].

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. (See 'Lower risk' above.)

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 together or as "add-ons" (ie, one followed by another).  

Clinical trials evaluating combined versus single-agent therapy in adult patients have yielded conflicting results. Some trials have indicated that the combination of PDE5 inhibition and ERAs, or prostacyclin derivatives and ERAs, are superior to either drug alone, while others have not. These data 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'.)

Similar data from controlled trials in pediatric patients are lacking, though a clinical trial is underway [55]. 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) [56]. Combination therapy was independently associated with improved survival in this study. 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.

ACUTE PH CRISIS — Acute PH crisis is a potentially fatal complication of PH [57]. 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 [1,58]. 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 [57,59,60]:

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 inhaled nitric oxide

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.

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 [61,62]. 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.

Potts procedure – The Potts procedure 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 (figure 1). A similar communication between the PA and aorta can be effected by the use of a stent placed into a (small) patent ductus arteriosus (PDA), or a covered stent inserted between the aorta and left PA in the catheterization laboratory [63-66]. A conduit connecting the PA with the descending aorta has also been described [67]. The use of this procedure 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 [63,65,66]. 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 [68]. 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 [69-71]. 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 [72-74]. (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. PH is the most frequent condition leading to lung transplantation in children ages one to five years and the second most frequent indication for lung transplant pediatric patients overall [75]. Outcomes are similar in pediatric and adult patients with median survival after transplant 2.7 years [75]. As has been shown in adults, decreased RV function normalizes in children after lung transplant [76]. 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 transplant evaluation'.)

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 [1,77]:

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")

COVID-19 vaccination (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, 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: 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) are 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 as yet undefined. (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 (ie, familial, idiopathic, or due to congenital shunting defects) is approximately 60 to 75 percent [18,25,78].

"High-risk" and "low-risk" factors that are associated with poor or favorable prognosis, respectively, are summarized in the table (table 4) [1,9,18,25,78,79]. In a registry study of 58 children with idiopathic or hereditary PAH who were followed for a median of 3.1 years, patients with a higher number of low-risk variables had longer transplant-free survival [80]. For patients with ≥7 low-risk variables at the time of diagnosis, five-year survival was 100 percent, whereas for patients with ≤3 low-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 5th to 6th 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 10th to 12th 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 – Targeted therapy consists of medications directed at the PH itself. The classes of drugs used for targeted PH 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 is based on acute vasoreactivity testing performed via cardiac catheterization and the severity of disease as determined by the degree of symptoms (eg, syncope, symptoms of right heart failure), functional class (table 3), and the findings on echocardiography and cardiac catheterization (algorithm 1) (see 'Choice of agent' above):

For most patients with vasoreactivity documented on cardiac catheterization, we suggest an initial trial of CCB therapy (eg, nifedipine, amlodipine, or diltiazem, but not verapamil) (Grade 2C). (See 'Reactive acute vasoreactivity testing' above and 'Calcium channel blockers' above.)

For most nonreactive low-risk patients, we suggest initial treatment with an oral PDE5 inhibitor (eg, sildenafil, tadalafil) rather than other agents (Grade 2C). This is based largely on the greater experience using PDE5 inhibitors in children with PH. Oral ERAs (eg, bosentan, ambrisentan, macitentan) and inhaled prostanoids (eg, iloprost, treprostinil) are reasonable alternatives. (See 'Lower risk' above and 'Phosphodiesterase type 5 inhibitors' above.)

For most high-risk patients, we suggest a regimen that includes a parenteral prostacyclin analogue (eg, epoprostenol, treprostinil) rather than oral therapy alone (Grade 2C). Combination therapy is commonly used in this setting. (See 'High risk' above and 'Prostacyclin analogues' above and 'Combination therapy' 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, Potts or Potts-like procedures, 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 include 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, counselling regarding exercise, reproductive health counselling 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.

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Topic 109342 Version 18.0

References

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