What is the recommended management approach for pulmonary arterial hypertension (PAH) in children?

Management of Pulmonary Arterial Hypertension in Children

Children with pulmonary arterial hypertension must be evaluated and treated at specialized pediatric centers with multidisciplinary expertise, with treatment stratified by risk level: lower-risk patients should receive oral monotherapy with either a PDE5 inhibitor or endothelin receptor antagonist, while higher-risk patients require immediate initiation of intravenous or subcutaneous prostacyclin therapy. 1, 2

Risk Stratification and Initial Treatment Selection

The cornerstone of pediatric PAH management is accurate risk stratification to guide initial therapy:

• Lower-risk PAH patients (WHO functional class I-II, stable hemodynamics) should start with oral monotherapy using either a phosphodiesterase type 5 (PDE5) inhibitor or an endothelin receptor antagonist (ERA), with bosentan recommended as a first-line ERA option 1, 2

• Higher-risk PAH patients (WHO functional class III-IV, deteriorating hemodynamics, elevated NT-proBNP, declining functional capacity) require immediate initiation of intravenous or subcutaneous prostacyclin therapy (epoprostenol, treprostinil) or prostacyclin analogs (iloprost) without delay 1, 2

• Cardiac catheterization should be performed before initiating PAH-specific drug therapy to confirm diagnosis, measure pulmonary vascular resistance index (PVRI), and assess acute vasoreactivity 1

Calcium Channel Blocker Testing

Calcium channel blockers should ONLY be administered to children >1 year of age who demonstrate acute vasoreactivity during cardiac catheterization 1, 2:

• CCBs are absolutely contraindicated in children who have not undergone acute vasoreactivity testing (AVT) or who are non-responsive to AVT 1
• CCBs are also contraindicated in patients with right-sided heart dysfunction due to potential negative inotropic effects 1
• This represents a critical pitfall: empiric CCB use without vasoreactivity testing can cause hemodynamic collapse

Goal-Directed Therapy Escalation

A progressive treatment escalation strategy should be adopted where PAH-specific drugs are added sequentially to achieve therapeutic targets 2:

• Escalate therapy for persistent WHO functional class III-IV symptoms despite initial therapy 2
• Add medications for worsening hemodynamics on serial echocardiograms, elevated NT-proBNP levels, or declining six-minute walk distance in children >8 years 2
• Combination therapy with bosentan, sildenafil, and inhaled iloprost may improve survival in severe PAH 2

Critical Warning About Sildenafil in Children

The FDA has issued a black box warning regarding increased mortality with chronic sildenafil use in pediatric PAH patients, particularly at higher doses 3:

• A long-term pediatric trial demonstrated a hazard ratio of 3.5 for high-dose versus low-dose sildenafil (p=0.015) 3
• Deaths were first observed after approximately 1 year of treatment 3
• Chronic use of sildenafil is not recommended in children, though it may be considered cautiously as adjunctive therapy in specific circumstances 3
• This represents a major divergence from adult practice and must be carefully weighed when selecting initial therapy

Supportive Care Measures

Essential supportive therapies include:

• Supplemental oxygen for children with oxygen saturations <92%, particularly those with associated respiratory disease 1, 2
• Diuretics (loop diuretics, thiazides, or spironolactone) used cautiously for signs of right heart failure 2
• Anticoagulation with warfarin may be considered in idiopathic/heritable PAH, low cardiac output states, long-term indwelling catheters, or hypercoagulable states 2

Special Population: Congenital Heart Disease-Associated PAH

For children with significant structural heart disease (ASD, VSD, PDA) who have not undergone early repair:

• Cardiac catheterization should be performed to measure PVRI and determine operability 1
• Repair should be considered if PVRI is <6 Wood units·m² or PVR/SVR <0.3 at baseline 1
• If PVRI ≥6 WU·m² or PVR/SVR ≥0.3 with minimal AVT responsiveness, repair is not indicated 1
• In borderline cases, implement PAH-targeted therapy followed by repeat catheterization with AVT after 4-6 months and consider repair if PVRI decreases to <6 WU 1

Special Population: Bronchopulmonary Dysplasia with PH

For infants with established BPD and symptomatic PH:

• Inhaled nitric oxide (10-20 ppm initially, wean to 2-10 ppm maintenance) is recommended 2
• PAH-targeted therapy is useful after optimizing respiratory and cardiac disease 2

Special Population: Sickle Cell Disease-Associated PH

Management differs significantly from idiopathic PAH:

• Optimization of SCD-related therapies (blood transfusions, hydroxyurea, iron chelation, supplemental oxygen) is the primary intervention 1
• PAH-targeted therapy should NOT be used empirically in SCD-associated PH due to potential adverse effects 1
• PAH-targeted therapy may only be considered after cardiac catheterization confirms marked elevation of PVR without elevated pulmonary capillary wedge pressure 1
• If PAH-targeted therapy is warranted, a prostacyclin agonist or ERA is preferred over PDE5 inhibitors 1

Outpatient Monitoring and Follow-Up

Outpatient follow-up visits at 3-6 month intervals are recommended, with more frequent visits for patients with advanced disease or after therapy changes 1:

• Serial echocardiograms to assess right ventricular function and estimate pulmonary artery pressures 2
• NT-proBNP or BNP levels as biomarkers of disease severity 2
• Six-minute walk distance in children >8 years 2
• Rigorous monitoring of growth parameters 1

Preventive Care Measures

Essential health maintenance measures include:

• Respiratory syncytial virus prophylaxis (if eligible) 1
• Influenza and pneumococcal vaccinations 1
• Prompt recognition and treatment of infectious respiratory illnesses 1
• Antibiotic prophylaxis for prevention of subacute bacterial endocarditis in cyanotic patients and those with indwelling central lines 1

Activity and Lifestyle Restrictions

Pediatric patients with severe PH (WHO functional class III-IV) or recent history of syncope should not participate in competitive sports 1:

• A thorough evaluation including cardiopulmonary exercise testing must be performed before engaging in athletic activities 1
• During exercise, children should engage in light to moderate aerobic activity, avoid strenuous and isometric exertion, remain well hydrated, and be allowed to self-limit 1
• Supplemental oxygen use is reasonable during airplane travel 1

Perioperative Management

Elective surgery should be performed at hospitals with expertise in PH, with consultation from the pediatric PH service and experienced cardiac anesthesiologists 1:

• Careful preoperative planning and plans for appropriate post-procedural monitoring are mandatory 1
• This applies to all surgical and dental procedures, even routine ones 1

Pregnancy Counseling

Female adolescents with PH must be provided age-appropriate counseling about pregnancy risks and contraception options due to significant maternal and fetal mortality 1

Transplant Evaluation

Referral to lung transplantation centers is recommended for patients in WHO functional class III-IV on optimized medical therapy or with rapidly progressive disease 1, 2

Psychosocial Support

Children, siblings, and caregivers should be assessed for psychosocial stress and readily provided support and referral as needed, given the profound impact of childhood PAH on the entire family 1